Reasons for rarity of anal melanocytic naevi

Abstract

In the last 16 years only seven definite cases of anal melanocytic naevi have been reported in the literature. We describe three new cases, none of which were suspected clinically and were incidentally diagnosed on histological examination of haemorrhoidectomy specimens. The infrequency of these special site flexural melanocytic lesions may be related to changes in the involutionary mechanisms of the anal melanocyte proliferation. However, other factors related to the low detection rates by clinicians and pathologists need also to be considered.

http://ift.tt/2loSJg5

Pemphigus, a pathomechanism of acantholysis

Abstract

Autoantibodies to the desmosomal proteins desmoglein 1 and 3 cause pemphigus foliaceus and pemphigus vulgaris, which are characterised by keratinocyte dissociation (acantholysis) and intraepidermal blister formation. The passive transfer of pathogenic anti-desmoglein antibodies induces blisters in mice in vivo and the loss of keratinocyte adhesion in vitro. The pathogenetic mechanisms of acantholysis due to anti-desmoglein autoantibodies are not fully understood. However, recent studies have revealed that signalling-dependent and signalling-independent pathways are operative in the loss of cell adhesion. In this review, we focus on the pathomechanism of acantholysis due to autoantibodies to desmogleins and recent therapeutic approaches.

http://ift.tt/2lUtv6m

Diagnosis and Management of Mitochondrial Neuro-Ophthalmologic Disorders: Translating Scientific Advances Into the Clinic

No abstract available

http://ift.tt/2loZ5fn

Invasive Aspergillosis Mimicking Sphenoid Wing Meningioma

No abstract available

http://ift.tt/2loVSwt

Swelling of the Optic Nerve Head: A Backstage View of a Staging Scheme

No abstract available

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Are Anemia and Hypotension Causally Related to Perioperative Ischemic Optic Neuropathy?

No abstract available

http://ift.tt/2loTrd6

IgG4 Disease: Is It or Isn't It?

No abstract available

http://ift.tt/2lUAoor

Invited Commentary: Ganglion Cell Complex Measurement in Compressive Optic Neuropathy

No abstract available

http://ift.tt/2loNInN

Ganglion Cell Complex Loss in Chiasmal Compression by Brain Tumors

Background: Patterns of ganglion cell complex (GCC) loss detected by optical coherence tomography provide an objective measure of optic nerve injury. These patterns aid in early diagnosis and localization of chiasmal lesions. Methods: Twenty-three patients with chiasmal compression seen between 2010 and 2015 were imaged with the Cirrus high-definition optical coherence tomography macular cube 512 × 128, retinal nerve fiber layer (RNFL) scan protocols and automated (30-2 Humphrey) visual fields (VFs). Age-matched controls were included for comparison. Generalized estimating equations were performed comparing RNFL and GCC thicknesses between patients and their controls. Effect size (d) was calculated to assess the magnitude of difference between patients and controls. The average GCC and RNFL thicknesses also were correlated with VF mean deviation (MD). Pre operative average GCC thickness was correlated to post operative VF MD. Results: Patterns of GCC thinning corresponded to VF defects. The average GCC thickness was 67 ± 9 μm in patients and 86 ± 5 μm in controls (P

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Neuro-Ophthalmology in Portugal

No abstract available

http://ift.tt/2loNKvV

A Giant Tumefactive Virchow-Robin Space: A Rare Cause of a Homonymous Quadrantanopia

Abstract: A 53-year-old woman was found to have a left inferior homonymous quadrantanopia. Brain MRI disclosed a giant Virchow–Robin space compressing the right optic tract. After fenestration of this cystic lesion, most of the visual field loss resolved. Giant Virchow–Robin spaces may cause homonymous field defects which, with appropriate management, may improve.

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Invited Commentary: Form Versus Function: A State of Disunion?

No abstract available

http://ift.tt/2lUugfS

Literature Commentary.

In this issue of Journal of Neuro-Ophthalmology, M. Tariq Bhatti, MD and Mark L. Moster, MD, will discuss the following 6 articles: 1. Lee YC, Wang JH, Huang TL, Tsai RK. Increased risk of stroke in patients with nonarteritic anterior ischemic optic neuropathy: a nationwide retrospective cohort study. Am J Ophthalmol. 2016;170:183-189. 2. Ray JG, Vermeulen MJ, Bharatha A, Montanera WJ, Park AL. Association between MRI exposure during pregnancy and fetal and childhood outcomes. JAMA. 2016;316:952-961. 3. Kilduff CL, Casswell EJ, Salam T, Hersh D, Ortiz-Perez S, Ezra D. Use of alleviating maneuvers for periocular facial dystonias. JAMA Ophthalmol. 2016;134:1247-1252. 4. Eklund A, Johannesson G, Johansson E, Holmlund P, Qvarlander S, Ambarki K, Wahlin A, Koskinen LO, Malm J. The pressure difference between eye and brain changes with posture. Ann Neurol. 2016;80:269-276. 5. Cortes-Vicente E, Gallardo E, Martinez MA, Diaz-Manera J, Querol L, Rojas-Garcia R, Illa I. Clinical characteristics of patients with double-seronegative myasthenia gravis and antibodies to cortactin. JAMA Neurology. 2016;73:1099-1104. 6. Kim SH, Zee DS, du Lac S, Kim HJ, Kim JS. Nucleus prepositus hypoglossi lesions produce a unique ocular motor syndrome. Neurology. 2016;87:2026-2033. (C) 2017 by North American Neuro-Ophthalmology Society

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Spectrum of Magnetic Resonance Imaging Features in Unilateral Optic Tract Dysfunction

Background: Optic tract dysfunction may be the predominant or only clinical manifestation of an intracranial disorder including mass legion, ischemic infarct, inflammatory disease, and trauma. Documentation of the neuroimaging features of these lesions is limited to reports mostly published before the availability of MRI. This study was undertaken to document the spectrum of MRI features in patients presenting with optic tract dysfunction. Methods: A retrospective study from 2004 to 2015 at a single tertiary care neuro-ophthalmology service of 24 patients who had unilateral optic tract dysfunction defined by a homonymous hemianopia and a relative afferent pupil defect that could not be attributed to optic neuropathy or retinopathy. Two institutional neuroradiologists, who were privy to the presence of optic tract dysfunction but not to its side or cause, independently documented the MRI abnormalities on a standard data collection form and then convened for a consensus review of the imaging abnormalities with the 2 clinician authors. Results: The clinical diagnoses were 6 ischemic strokes, 5 malignant brain tumors, 5 postoperative neurosurgical cases, 4 intracranial hemorrhages, 2 traumatic brain injuries, 1 midbrain/optic tract primary demyelination, and 1 temporal lobe herpes simplex encephalitis. In their independent review, both neuroradiologists identified MRI abnormalities in 20 (83%) cases that were extrinsic to the optic tract in the neighboring temporal lobe, midbrain, thalamus, basal ganglia, or suprasellar space. In 5 of those cases, the extrinsic abnormality included features suggesting compression of the optic tract, but these compressive features were not appreciated by either neuroradiologist until the consensus conference. In 15 cases, MRI abnormalities intrinsic to the optic tract itself were eventually identified, including T2 or fluid-attenuated inversion recovery image (FLAIR) hyperintensity (9 cases) or hypointensity (1 case), thinning (6 cases), thickening (2 cases), and contrast enhancement (1 case). However, none of these intrinsic MRI abnormalities was identified during the independent review, being detected only in the consensus conference. Conclusions: Neuroradiologists aware of unilateral optic tract dysfunction but not of its side detected extrinsic (neighborhood) MRI abnormalities in most cases but did not appreciate that these extrinsic features sometimes included compression of the optic tract. MRI abnormalities intrinsic to the optic tract were entirely overlooked during independent review, being recognized only in a consensus conference with clinician authors. Neuroradiologists are more likely to detect MRI abnormalities pertinent to optic tract dysfunction once they have more complete clinical information and with higher resolution imaging, especially T1 postcontrast axial and coronal sequences and T2 or FLAIR coronal scans.

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Dyschromatopsia in Multiple Sclerosis Patients: A Marker of Subclinical Involvement?: Comment

No abstract available

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Detection of Thyroid Abnormalities in Aquaporin-4 Antibody–Seropositive Optic Neuritis Patients

Objective: This study retrospectively analyzed the frequency of anti-thyroid antibodies (ATAs) and thyroid disease in patients with optic neuritis (ON). Methods: Tests of serum thyroglobulin (TG) and thyroid peroxidase (TPO) antibodies and thyroid function were performed in 97 ON patients. Blood also was drawn to test for AQP4-Ab using cell-based and enzyme-linked immunosorbent assays. Comparisons of the frequencies of ATAs, thyroid diseases and thyroid function were performed based on AQP4-Ab status. Results: Seropositive AQP4-Ab was found in 47/97 (48.5%) patients. ATA was considered positive in 34/97 (35.1%) patients. The prevalence of ATA was two times higher (P = 0.019) in the AQP4-Ab+ group compared to the AQP4-Ab- group. AQP4-Ab+ ON patients exhibited lower FT3 (P = 0.006) and FT4 (P = 0.025) levels and a higher prevalence of definite Hashimoto thyroiditis (HT) (P = 0.005). Among AQP4-Ab+ patients, those with HT had a worse visual outcome than non-HT patients. Conclusion: A high prevalence of ATAs and HT was found in AQP4-Ab+ ON patients, and AQP4-Ab+ patients with HT exhibited worse visual outcomes than non-HT patients.

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New Treatments in Neuro-Ophthalmology: The Role for Evidence

No abstract available

http://ift.tt/2loLPYb

Ciliary Body/Iris Appositioning Producing Mechanical Pupillary Defects in Carotid-Cavernous Sinus Fistula: An Overlooked Pathophysiologic Mechanism

Background: Variable pupillary responses have been described with carotid-cavernous sinus fistulas. These often are associated with a decrease in visual acuity and attributed to retinal ischemia. We propose a novel pathophysiologic mechanism for changes in pupillary reactivity involving anatomic changes secondary to choroidal effusion. Methods: To demonstrate proof-of-concept, we investigated 2 consecutive patients with carotid-cavernous sinus fistulas and pupillary disturbances using repeated refractions and anterior segment ultrasound biomicroscopy. Results: Ultrasound biomicroscopy demonstrated choroidal thickening and ciliary body effusion with forward rotation of the lens–iris diaphragm altering refraction and mechanically limiting iris movements. Conclusions: Where there are acute elevations in orbital venous pressure causing ciliary body effusion, changes in visual acuity and pupillary abnormalities can be produced by mechanical effects.

http://ift.tt/2lUsVWn

Diagnosing Light Chain Amyloidosis on Temporal Artery Biopsies for Suspected Giant Cell Arteritis

Abstract: Although still rarely diagnosed, amyloid light chain (AL) amyloidosis is the most common form of systemic amyloidosis. It is characterized by misfolded monoclonal immunoglobulin light chain fragments that accumulate extracellularly as amyloid fibrils, with consequent organ dysfunction. We report 2 such cases where initial symptoms and signs were identical to and mistaken for those of giant cell arteritis, associated with polymyalgia rheumatica. Neither patient responded to high-dose corticosteroids; instead, their temporal artery biopsies revealed amyloid deposits and other investigations confirmed a diagnosis of systemic AL amyloidosis. Review of the literature reveals similar cases of diagnostic confusion spanning 75 years. We have summarized the findings and learning points from cases reported in the past 30 years and highlight the need for increased awareness and investigation of this underrecognized syndrome.

http://ift.tt/2lUk86Y

Ipsilateral Ophthalmic and Cerebral Infarctions After Cosmetic Polylactic Acid Injection Into the Forehead

Abstract: A 55-year-old woman developed no light perception vision in her right eye 5 days after an injection of polylactic acid cosmetic filler into her right forehead. Diffuse corneal edema and anterior chamber inflammation prohibited any view to the posterior segment to identify the cause of her profound vision loss. MRI of the orbits with diffusion-weighted imaging showed hyperintensity of the right optic nerve with signal reduction on apparent diffusion coefficient mapping, consistent with ischemia. Our patient also was found to have acute infarctions in the distribution of the right anterior cerebral artery on MRI of the brain despite having no permanent focal neurologic deficits aside from vision loss.

http://ift.tt/2lUsUBN

In vitro cytotoxicity evaluation of nano-carbon particles with different sp2/sp3 ratios

Publication date: Available online 16 February 2017
Source:Materials Science and Engineering: C
Author(s): S.S. Li, B.J. Wu, Q.Y. Deng, Y.B. Guo, Y.X. Leng, N. Huang
Graphitization occurs during the long-term service of a diamond-like carbon (DLC) modified artificial joint. Then, DLC wear debris, which are carbon particles with different sp²/sp³ ratios and sizes ranging from the nano- to micro-meter scale produced. In this paper, to promote the application of DLC coating for artificial joint modification, the cytotoxicity of DLC debris (nano-carbon particles, NCs) with different sp²/sp³ ratios was studied. The microstructure and physical characteristics of NCs with different sp²/sp³ ratios were investigated by Raman spectroscopy, X-ray photoelectron spectroscopy (XPS), Transmission Electron Microscope (TEM) and Dynamic Light Scattering (DLS). Meanwhile, osteoblasts and macrophages were applied to characterize the cytotoxicity of the NCs. In vitro cytotoxicity assay results indicated that cells incubated with NCs of different sp²/sp³ ratios had greater osteogenic capacity, and these particles caused a weaker immune response in comparison with CoCrMo particles. Taken together, the results indicated that NCs with different sp²/sp³ ratios presented a good cytocompatibility than CoCrMo particles. But no significant differences were observed among NCs with different sp²/sp³ ratios. The better cytocompatibility of NCs is mainly attributable to their surface charge.



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Screening for Lung Cancer

Publication date: Available online 16 February 2017
Source:Seminars in Oncology
Author(s): Heather F. Sateia, Youngjee Choi, Rosalyn W. Stewart, Kimberly S. Peairs
This review will comprise a general overview of the epidemiology of lung cancer, as well as lung cancer risk factors, screening modalities, current guideline recommendations for screening, and our approach to lung cancer screening.



http://ift.tt/2loPRj9

A granulomatous conundrum: Concurrent necrobiosis lipoidica, cutaneous sarcoidosis and erythema nodosum in a nondiabetic patient

Abstract

Necrobiosis lipoidica (NL) and cutaneous sarcoidosis are granulomatous disorders with a largely unknown aetiopathogenesis. Evidence of co-existing NL and sarcoidosis in the same patient may suggest a degree of overlap between these entities through shared granulomatous inflammatory pathways. Occasionally, one condition can mimic the other, making their distinction difficult. We report a novel case of a non-diabetic woman who presented with concurrent NL, cutaneous sarcoidosis and erythema nodosum. We discuss some of the complexities distinguishing these entities and propose that they may represent different stages of the same granulomatous process linked through yet unknown pathomechanisms.

http://ift.tt/2kELH2j

Is canscore a good indicator of fetal malnutrition in preterm newborn

Publication date: Available online 16 February 2017
Source:Alexandria Journal of Medicine
Author(s): B.N. Ezenwa, V.C. Ezeaka
BackgroundFetal malnutrition is a risk factor for increased neonatal morbidities and mortalities worldwide. BMI and CANScore had been used for determining fetal malnutrition in term newborns.ObjectiveTo assess the nutritional status of preterm newborns at birth using BMI, PI and CANscore and determine the better indicator for FM.MethodsThe study was carried out on consecutive, live-born babies between 28 completed weeks through 36weeks gestation. Birth weights and lengths were recorded as per protocol. BMI was calculated and BMI <10th centile using Brock's chart is considered as FM and a PI <2.2 was considered as malnutrition. Using Metcoff's CANscore, score <25 is FM. Data was analyzed using the SPSS version 22.0.ResultsOne hundred and forty preterm newborns were assessed and 108 (77%) were of LBW. BMI, CANscore and PI identified 40.0%, 34.3% and 30.0% of the preterm newborns as FM. Using BMI as standard for detecting FM, CANscore and PI identified 33.9% and 51.8% of the babies as FM. PI had a better sensitivity for detecting FM in preterm infants compared to CANScore and this was statistically significant, p<0.00.ConclusionFM is common in preterm babies. BMI and PI are simple and easy tools to use in assessing FM in preterm babies. They are also better identifiers of FM in preterm newborns compared to CANScore.



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The Dyslexia-susceptibility Protein KIAA0319 Inhibits Axon Growth Through Smad2 Signaling

<span class="paragraphSection"><div class="boxTitle">Abstract</div>KIAA0319 is a transmembrane protein associated with dyslexia with a presumed role in neuronal migration. Here we show that KIAA0319 expression is not restricted to the brain but also occurs in sensory and spinal cord neurons, increasing from early postnatal stages to adulthood and being downregulated by injury. This suggested that KIAA0319 participates in functions unrelated to neuronal migration. Supporting this hypothesis, overexpression of KIAA0319 repressed axon growth in hippocampal and dorsal root ganglia neurons; the intracellular domain of KIAA0319 was sufficient to elicit this effect. A similar inhibitory effect was observed in vivo as axon regeneration was impaired after transduction of sensory neurons with <span style="font-style:italic;">KIAA0319</span>. Conversely, the deletion of <span style="font-style:italic;">Kiaa0319</span> in neurons increased neurite outgrowth in vitro and improved axon regeneration in vivo. At the mechanistic level, KIAA0319 engaged the JAK2-SH2B1 pathway to activate Smad2, which played a central role in KIAA0319-mediated repression of axon growth. In summary, we establish KIAA0319 as a novel player in axon growth and regeneration with the ability to repress the intrinsic growth potential of axons. This study describes a novel regulatory mechanism operating during peripheral nervous system and central nervous system axon growth, and offers novel targets for the development of effective therapies to promote axon regeneration.</span>

http://ift.tt/2ldFfRB

Piperazines as nootropic agents: New derivatives of the potent cognition-enhancer DM235 carrying hydrophilic substituents

Publication date: Available online 16 February 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Maria Vittoria Martino, Luca Guandalini, Lorenzo Di Cesare Mannelli, Marta Menicatti, Gianluca Bartolucci, Silvia Dei, Dina Manetti, Elisabetta Teodori, Carla Ghelardini, Maria Novella Romanelli
The piperazine ring of the potent nootropic drug DM235has been decorated with H-bond donor and acceptor groups (CH2OH, CH2OMe, CH2OCOMe, COOEt); the aim was to insert new functional groups, suitable for further chemical manipulation. The influence of these modifications on nootropic activity was assessed by means of the mouse passive avoidance test; some of the newly synthesized molecules (alcohol 7b, acetate 8b and ester 10d) showed interesting in vivo potency. This makes it possible to use these functional groups for adding other residues, in order to increase molecular diversity, or for anchoring a biotin group, to obtain compounds useful to capture the biological target. Moreover, the new compounds will improve our knowledge of structure activity relationships of this family of drugs.

Graphical abstract

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Biological Evaluation of Pyridone Alkaloids on the Endocannabinoid System

Publication date: Available online 17 February 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Andrea Chicca, Regina Berg, Henning J. Jessen, Nicolas Marck, Fabian Schmid, Patrick Burch, Jürg Gertsch, Karl Gademann
Naturally occurring pyridone alkaloids as well as synthetic derivatives were previously shown to induce neurite outgrowth. However, the molecular basis for this biological effect remains poorly understood. In this work, we have prepared new pyridones, and tested the effect of thirteen 4-hydroxy-2-pyridone derivatives on the components of the endocannabinoid system. Investigation of binding affinities towards CB1 and CB2 receptors led to the identification of a compound binding selectively to CB1 (12). Compound 12 and a closely related derivative (11) also inhibited anandamide (AEA) hydrolysis by fatty acid amide hydrolase. Interestingly, none of the compounds tested showed any effect on 2-AG hydrolysis by monoacylglycerol lipase at 10 µM. Assessment of AEA uptake did, however, lead to the identification of four inhibitors with IC50 values in the submicromolar range and high selectivity over the other components of the endocannabinoid system.

Graphical abstract

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Novel Pyrrolopyrimidines as Mps1/TTK Kinase Inhibitors for Breast Cancer

Publication date: Available online 16 February 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Yasuro Sugimoto, Dwitiya B. Sawant, Harold A. Fisk, Liguang Mao, Chenglong Li, Somsundaram Chettiar, Pui-Kai Li, Michael V. Darby, Robert W. Brueggemeier
New targeted therapy approaches for certain subtypes of breast cancer, such as triple-negative breast cancers and other aggressive phenotypes, are desired. High levels of the mitotic checkpoint kinase Mps1/TTK have correlated with high histologic grade in breast cancer, suggesting a potential new therapeutic target for aggressive breast cancers (BC). Novel small molecules targeting Mps1 were designed by computer assisted docking analyses, and several candidate compounds were synthesized. These compounds were evaluated in anti-proliferative assays of a panel of 15 breast cancer cell lines and further examined for their ability to inhibit a variety of Mps1-dependent biological functions. The results indicate that the lead compounds have strong anti-proliferative potential through Mps1/TTK inhibition in both basal and luminal BC cell lines, exhibiting IC50 values ranging from 0.05 to 1.0 μM. In addition, the lead compounds 1 and 13 inhibit Mps1 kinase enzymatic activity with IC50 values from 0.356 μM to 0.809 μM, and inhibited Mps1-associated cellular functions such as centrosome duplication and the spindle checkpoint in triple negative breast cancer cells. The most promising analog, compound 13, significantly decreased tumor growth in nude mice containing Cal-51 triple negative breast cancer cell xenografts. Using drug discovery technologies, computational modeling, medicinal chemistry, cell culture and in vivo assays, novel small molecule Mps1/TTK inhibitors have been identified as potential targeted therapies for breast cancers.

Graphical abstract

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Synthesis of antisense oligonucleotides containing acyclic alkynyl nucleoside analogs and their biophysical and biological properties

Publication date: Available online 17 February 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Aya Ogata, Yusuke Maeda, Yoshihito Ueno
The synthesis of oligonucleotide (ON) analogs, which can be used as antisense molecules, has recently gained much attention. Here, we report the synthesis and properties of an ON analog containing acyclic thymidine and cytidine analogs with a 4-pentyl-1,2-diol instead of the d-ribofuranose moiety. The incorporation of these analogs into the ON improved its nuclease resistance to 3′-exonucleases. Furthermore, it was found that the incorporation of the acyclic thymidine analog into a DNA/RNA duplex accelerates the RNA cleavage of a DNA/RNA duplex by Escherichia coli RNase H.

Graphical abstract

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Comparison of the anion inhibition profiles of the β- and γ-carbonic anhydrases from the pathogenic bacterium Burkholderia pseudomallei

Publication date: Available online 16 February 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Sonia Del Prete, Daniela Vullo, Pietro di Fonzo, Vincenzo Carginale, Claudiu T. Supuran, Clemente Capasso
We report the cloning, purification and characterization of BpsβCA, a β-class carbonic anhydrase (CA, EC 4.2.1.1) from the pathogenic bacterium Burkholderia pseudomallei, the etiological agent of melioidosis, and compare its activity and inhibition with those of the γ-CA from the same organism, BpsγCA, recently investigated by our groups. BpsβCA showed a significant catalytic activity for the physiologic, CO2 hydration reaction, with the following kinetic parameters, kcat of 1.6x10⁵ s^-1 and kcat/Km of 3.4 x10⁷ M^-1x s^-1. The inhibition of BpsβCA with a group of anions and small molecules was also investigated. The best inhibitors were sulfamide, sulfamic acid and phenylarsonic acid, which showed KIs in the range of 83 – 92 µM, whereas phenylboronic acid, fluoride, cyanide, azide, bisulfite, tetraborate, perrhenate, perruthenate, peroxydisulfate, perchlorate, tetrafluoroborate, fluorosulfonate and hexafluorophosphate showed KIs> 100 mM. Other inhibitors of this new enzyme were bicarbonate, trithiocarbonate, some complex inorganic anions and N,N-diethyldithiocarbamate, which had inhibition constants of 0.32 – 8.6 mM. As little is known of the life cycle and virulence of this bacterium, this type of study may bring information of interest for the development of novel strategies to fight bacterial infection and drug resistance to commonly used antibiotics

Graphical abstract

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Identification of A New Class of Potent Cdc7 Inhibitors Designed by Putative Pharmacophore Model: Synthesis and Biological Evaluation of 2,3-Dihydrothieno[3,2-d]pyrimidin-4(1H)-ones

Publication date: Available online 16 February 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Osamu Kurasawa, Yuya Oguro, Tohru Miyazaki, Misaki Homma, Kouji Mori, Kenichi Iwai, Hideto Hara, Robert Skene, Isaac Hoffman, Akihiro Ohashi, Sei Yoshida, Tomoyasu Ishikawa, Nobuo Cho
Cell division cycle 7 (Cdc7) is a serine/threonine kinase that plays important roles in the regulation of DNA replication process. A genetic study indicates that Cdc7 inhibition can induce selective tumor-cell death in a p53-dependent manner, suggesting that Cdc7 is an attractive target for the treatment of cancers. In order to identify a new class of potent Cdc7 inhibitors, we generated a putative pharmacophore model based on in silico docking analysis of a known inhibitor with Cdc7 homology model. The pharmacophore model provided a minimum structural motif of Cdc7 inhibitor, by which preliminary medicinal chemistry efforts identified a dihydrothieno[3,2-d]-pyrimidin-4(1H)-one scaffold having a heteroaromatic hinge-binding moiety. The structure-activity relationship (SAR) studies resulted in the discovery of new, potent, and selective Cdc7 inhibitors 14a,c,e. Furthermore, the high selectivity of 14c,e for Cdc7 over Rho-associated protein kinase 1 (ROCK1) is discussed by utilizing a docking study with Cdc7 and ROCK2 crystal structures.

Graphical abstract

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Synthesis and evaluation of a [18F]BODIPY-labeled Caspase-inhibitor

Publication date: Available online 16 February 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Christian Paul Ortmeyer, Günter Haufe, Katrin Schwegmann, Sven Hermann, Michael Schäfers, Frederik Börgel, Bernhard Wünsch, Stefan Wagner, Verena Hugenberg
BODIPYs (boron dipyrromethenes) are fluorescent dyes which show high stability and quantum yields. They feature the possibility of selective ¹⁸F-fluorination at the boron-core. Attached to a bioactive molecule and labeled with [¹⁸F]fluorine, the resulting compounds are promising tracers for multimodal imaging in vivo and can be used for PET and fluorescence imaging. A BODIPY containing a phenyl and a hydroxy substituent on boron was synthesized and characterized. Fluorinated and hydroxy substituted dyes were coupled to an isatin-based caspase inhibitor via cycloaddition and the resulting compounds were evaluated in vitro in caspase inhibition assays. The metabolic stability and the formed metabolites were investigated by incubation with mouse liver microsomes and LC-MS analysis. Subsequently the fluorophores were labeled with [¹⁸F]fluorine and an in vivo biodistribution study using dynamic PET was performed.

Graphical abstract

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Synthesis and Activity of Nucleoside-Based Antiprotozoan Compounds

Publication date: Available online 16 February 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Huu-Anh Tran, Zhaoyan Zheng, Xianghui Wen, Srinivasan Manivannan, Arnaud Pastor, Marcel Kaiser, Reto Brun, Floyd F. Snyder, Thomas G. Back
Parasitic protozoa employ a salvage pathway to synthesize purines and generate essential active nucleotides, whereas mammals are capable of their de novo biosynthesis. This difference provides opportunity for the design of potential new antiprotozoan compounds. A series of 47 adenosine analogues was prepared with modifications at the 2-, 6- and 5'-positions, based on the hypothesis that such compounds would serve as substrates for protozoan nucleoside salvage enzymes, while remaining refractory in mammalian cells. The nucleosides were designed to produce toxic metabolites upon cleavage to the corresponding purine base by the parasite. Three 7-deazaguanosine derivatives were prepared with similar objectives. All of these compounds were tested in vitro against T. brucei (African sleeping sickness), T. cruzi (Chagas' disease), L. donovani (leishmaniasis) and P. falciparum (malaria). In order to determine the therapeutic selectivity indices (SI) of the antiprotozoan nucleosides, their cytotoxicities toward a rat myoblast cell line were also determined. One adenosine derivative proved highly effective against P. falciparum (IC50 = 110 nM and SI = 1010, while a modified guanosine displayed potent activities against L. donovani (IC50 = 60 nM, SI = 2720) and T. brucei (IC50 = 130 nM, SI = 1250), as well as moderate activity against T. cruzi (IC50 = 3.4 µM, SI = 48). These results provide proof of concept for the nucleoside-based antiprotozoan strategy, as well as potential lead compounds for further optimization and validation.

Graphical abstract

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Bronchial allergen challenge – An old, but still useful tool in research and diagnostics

Publication date: Available online 16 February 2017
Source:Alergologia Polska - Polish Journal of Allergology
Author(s): Zenon Siergiejko, Grzegorz Siergiejko, Mark Klukowski, Ewa Maria Swiebocka
A bronchial allergen challenge may serve both as a diagnostic as well as investigative procedure. Its usage in the diagnosis of asthma is infrequent due to its time-consuming nature as well as (in our opinion) an unfounded fear for a patient's safety. It is quite useful in the diagnostics of workplace related illnesses. Due to its ability to produce a controlled, long-lasting allergic-inflammatory reaction in the bronchi, this procedure is commonly used in research settings as well as in the assessment of new substances which may potentially have a place in the treatment of asthma, for ex. through the blocking of late asthmatic reactions. Changes stimulated by a bronchial allergen challenge may be evaluated by many methods using different materials, i.e. samples obtained from direct biopsies, bronchoalveolar lavages, exhaled breath condensates, or measured fractional exhaled nitric oxide. This procedure is a seemingly ideal research and diagnostic tool, however, a common protocol for its execution has not yet been accepted. Recent legal regulations have resulted in difficulties obtaining various allergens for challenge tests. Hopefully this is a temporary and minor setback for this very useful and constantly developing procedure.



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Demographics, epidemiology and the impact of vaccination campaigns in a measles-free world – Can elimination be maintained?

Publication date: Available online 16 February 2017
Source:Vaccine
Author(s): J.M. Prada, C.J.E. Metcalf, S. Takahashi, J. Lessler, A.J. Tatem, M. Ferrari
IntroductionAll six WHO regions currently have goals for measles elimination by 2020. Measles vaccination is delivered via routine immunization programmes, which in most sub-Saharan African countries reach children around 9months of age, and supplementary immunization activities (SIAs), which target a wider age range at multi-annual intervals. In the absence of endemic measles circulation, the proportion of individuals susceptible to measles will gradually increase through accumulation of new unvaccinated individuals in each birth cohort, increasing the risk of an epidemic. The impact of SIAs and the financial investment they require, depend on coverage and target age range.Materials and methodsWe evaluated the impact of target population age range for periodic SIAs, evaluating outcomes for two different levels of coverage, using a demographic and epidemiological model adapted to reflect populations in 4 sub-Saharan African countries.ResultsWe found that a single SIA can maintain elimination over short time-scales, even with low routine coverage. However, maintaining elimination for more than a few years is difficult, even with large (high coverage/wide age range) recurrent SIAs, due to the build-up of susceptible individuals. Across the demographic and vaccination contexts investigated, expanding SIAs to target individuals over 10years did not significantly reduce outbreak risk.ConclusionsElimination was not maintained in the contexts we evaluated without a second opportunity for vaccination. In the absence of an expanded routine program, SIAs provide a powerful option for providing this second dose. We show that a single high coverage SIA can deliver most key benefits in terms of maintaining elimination, with follow-up campaigns potentially requiring smaller investments. This makes post-campaign evaluation of coverage increasingly relevant to correctly assess future outbreak risk.



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Sensitization to bovine serum albumin as a possible cause of allergic reactions to vaccines

Publication date: Available online 16 February 2017
Source:Vaccine
Author(s): Rajiva de Silva, W.M.D.K. Dasanayake, G.D. Wickramasinhe, Chandima Karunatilake, Nayani Weerasinghe, Peshala Gunasekera, Gathsaurie Neelika Malavige
BackgroundImmediate type hypersensitivity to vaccines containing bovine/porcine excipients, such as the measles, mumps and rubella (MMR) vaccine is probably due to sensitization to bovine/porcine gelatin. Most patients with such reactions in Sri Lanka have cow's milk (CM) or beef allergy.ObjectivesWe investigated whether those who had beef and CM allergy had a higher incidence of hypersensitivity reactions to vaccines and the possible trigger of such reactions.Material and methodsTwenty patients with immediate type hypersensitivity reactions to vaccines containing bovine/porcine excipients, controls with allergy to beef/pork (n=11) or CM (n=11), and 8 non atopic controls were recruited. Total serum IgE, specific IgE to beef, CM, casein, beta lactoglobulin, gelatin and bovine serum albumin (BSA) by Phadia ImmunoCap and IgE to porcine gelatin by Western blot were evaluated.Results11/20, 5/20, 2/20, 2/20, 1/20 and 1/20 patients reported allergic reactions to measles containing, JE, rabies primary chick embryo, pentavalent, diphtheria and tetanus, and adult diphtheria and tetanus vaccines, respectively. Only one patient with allergy to vaccines had gelatin specific IgE, whereas IgE to BSA was seen in 73.3%, 90%, 66.6% and 0 of vaccine, beef or CM allergic and non-atopic controls, respectively. The mean IgE to BSA was higher in patients with allergy to vaccines, although not significant. Specific IgE to BSA was present in 54.7% of children with allergy to CM, of whom 11.8% had high levels (>17.5kUA/L). In contrast, 66.6% of these children did not have specific IgE to β-lactoglobulin, which is one of the major components of whey protein.Conclusion and clinical relevanceGelatin does not appear to play a major role in Sri Lankan children with allergy to vaccines. In contrast, due to the higher levels of BSA specific IgE, sensitization to BSA is possibly playing a role.



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Rationale and support for a One Health program for canine vaccination as the most cost-effective means of controlling zoonotic rabies in endemic settings

Publication date: Available online 16 February 2017
Source:Vaccine
Author(s): Robert P. Lavan, Alasdair I. MacG. King, David J. Sutton, Kaan Tunceli
Although dog vaccination has been demonstrated to reduce and eliminate rabies in humans, during meetings there are often calls for further pilot studies. The assembled data proves that a widespread approach is now required. While zoonotic rabies has a minimal presence in developed nations, it is endemic throughout most of Asia and Africa, where it is considered to be a neglected tropical disease. In these areas, rabies causes an estimated annual mortality of at least 55,000 human deaths. Worldwide rabid dogs are the source of the vast majority of human rabies exposures. The World Health Organization (WHO), the Food and Agriculture Organization (FAO) of the United Nations and the World Organization for Animal Health (OIE) advocate a collaborative One Health approach involving human public health and veterinary agencies, with mass canine vaccination programs in endemic areas being the mainstay of strategies to eliminate dog-mediated human rabies. While post-exposure prophylaxis (PEP) is effective in preventing deaths in people exposed to rabies, it is comparatively expensive and has little impact on the canine reservoir that is the primary source of zoonotic rabies. Indiscriminate culling of the dog population is expensive and there is little evidence that it is effective in controlling rabies in non-island locations. Mass canine vaccination programs using a One Health framework that achieves a minimum 70% vaccination coverage during annual campaigns have proven to be cost-effective in controlling zoonotic rabies in endemic, resource-poor regions. Case studies, such as in Tanzania and Bhutan, illustrate how an approach based on mass canine rabies vaccination has effectively reduced both canine and human rabies to minimal levels. The multiple benefits of mass canine rabies vaccination in these cases included eliminating rabies in the domestic dog reservoirs, eliminating human rabies cases, and decreasing the rabies economic burden by reducing expenditures on PEP.



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Midface Osteotomies for Feminization of the Facial Skeleton

Summary: Facial feminization surgery is a term to describe the surgical alteration of a masculine facial appearance to a more feminine appearance, which is most commonly performed for male-to-female transsexual individuals. To alter the midfacial relations, segmentalized osteotomies were performed in selected patients expanding on the established techniques for facial feminization surgery. All patients underwent a preoperative 3D computerized tomography scan and 3D photography before and after the surgery. The inclusion of the midface in surgery was determined based on the relative projection and angle of the zygomatic body compared with the supraorbital region (the supraorbital region was reduced in all patients). Patients were prospectively followed up by 3D surface photography and 3D computerized tomography scans. Rotation and advancement of the zygomatic region was found to be an effective way to further feminize the midfacial appearance in selected male-to-female transsexual patients. No major surgical complications occurred. Although somewhat technically challenging, we suggest that midface surgery should be considered for feminizing purposes in order for the patient to achieve a long-term favorable result compared with other alternative methods.

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Evaluation of augmented pulse pressure variation using the Valsalva manoeuvre as a predictor of fluid responsiveness under open-chest conditions: A prospective observational study.

BACKGROUND: Pulse pressure variation (PPV) is a well known dynamic preload indicator of fluid responsiveness. However, its usefulness in open-chest conditions remains controversial. OBJECTIVE: We evaluated whether augmented PPV during a Valsalva manoeuvre can predict fluid responsiveness after sternotomy. DESIGN: A prospective, observational study. SETTING: Single-centre trial, study period from October 2014 to June 2015. PATIENTS: Forty-nine adult patients who underwent off-pump coronary arterial bypass grafting. INTERVENTION: After midline sternotomy, haemodynamic parameters were measured before and after volume expansion (6 ml kg-1 of crystalloids). PPV was calculated both automatically (PPVauto) and manually (PPVmanual). For PPV augmentation, we performed Valsalva manoeuvres with manual holding of the rebreathing bag and constant airway pressure of 30 cmH2O for 10 s before fluid loading and calculated PPV during the Valsalva manoeuvre (PPVVM). MAIN OUTCOME MEASURES: The predictive ability of PPVVM for fluid responsiveness using receiver-operating characteristic curve analysis. Responders were identified when an increase in cardiac index of at least 12% occurred after fluid loading. RESULTS: Twenty-one patients were responders and 28 were nonresponders. PPVVM successfully predicted fluid responsiveness with an area under the curve (AUC) of 0.88 [95% confidence interval (95% CI) 0.75 to 0.95; sensitivity 91%, specificity 79%, P

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A case of in vivo iontophoresis-assisted corneal collagen cross-linking for keratoconus: An immunohistochemical study

Publication date: Available online 16 February 2017
Source:Acta Histochemica
Author(s): Mirko Manetti, Eleonora Favuzza, Eleonora Sgambati, Rita Mencucci, Mirca Marini
The standard corneal collagen cross-linking (CXL), that includes the removal of corneal epithelium to permit adequate penetration of riboflavin in the stroma, is an established procedure to halting keratoconus progression. However, as epithelial removal may cause postoperative pain and an increased risk of corneal infection, new therapeutic approaches have been proposed. Iontophoresis is a recently developed non-invasive technique which provides the use of electrical current during CXL to enhance transepithelial penetration of riboflavin into the corneal stroma. Here, we describe for the first time the morphological changes of the corneal stromal compartment in a patient with keratoconus who underwent in vivo iontophoresis-assisted CXL (ionto-CXL) before full-thickness corneal transplantation. Immunohistochemistry for type I collagen and CD34 was performed to investigate the stromal distribution of collagen fibers and keratocytes, respectively. The histology of ionto-CXL-treated keratoconic cornea, collected 6 months after the intervention, was compared with that of healthy corneas and either untreated or standard CXL-treated keratoconic corneas. An attempt to restore a normal stromal architecture was observed in the ionto-CXL-treated cornea compared with untreated keratoconic corneas. In particular, the ionto-CXL-treated cornea showed a parallel distribution of type I collagen fibers, although fiber interweaving appeared less organized than in healthy corneas and standard CXL-treated keratoconic corneas. Moreover, the distribution of CD34-positive keratocytes was improved in keratoconic corneas following ionto-CXL treatment, though a scattered CD34 immunoreactivity was still noticeable in the subepithelial stroma. This study provides histological evidence that ionto-CXL may represent a non-invasive alternative in the management of progressive keratoconus in adults.



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The risk of level IB nodal involvement in oropharynx cancer: guidance for submandibular gland sparing irradiation

Publication date: Available online 16 February 2017
Source:Practical Radiation Oncology
Author(s): Nicholas C.J. Lee, Jacqueline R. Kelly, Henry S. Park, Wendell G. Yarbrough, Barbara A. Burtness, Zain A. Husain
PurposeXerostomia remains a common side effect of head and neck irradiation. Conflicting data exists regarding the likelihood of level IB involvement for patients with oropharyngeal squamous cell cancer (OPSCC), and limited data has examined this risk in patients with HPV-positive (HPV+) disease. This study examined surgically-treated OPSCC in order to determine the risk of pathologic level IB nodal involvement and to identify a cohort of patients in whom ipsilateral level IB radiotherapy may be safely omitted.Methods and Materials102 submandibular nodal dissections were identified (92 ipsilateral and 10 contralateral) in 92 patients from 2010–2016 in patients undergoing primary surgical treatment and dissection of ipsilateral level IB lymph nodes. Radiographically positive cases were excluded. Retrospective chart review was used for data collection, and the rate of pathologic level IB involvement was determined.ResultsThe ipsilateral level IB nodal station had negative imaging and pathologically positive nodes at rates of 4.3% in OPSCC and 5.3% in HPV+ OPSCC. Positive node burden in the ipsilateral neck at stations other than IB appeared to correlate with the risk of pathologic positive IB (pIB+) nodes: 50% of pathologically IB-negative patients had 2 or more positive nodes versus 75% of pIB+ patients had 4 or more positive nodes.ConclusionsOur data indicates a low risk of pathologic level IB involvement in early-stageOPSCC. High positive node burden in stations near level IB may be associated with a higher chance of pathologic level IB involvement.



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Conditional Approval Pathways: The “Special” Case of Global Regenerative Medicine Regulation

Rejuvenation Research Feb 2017, Vol. 20, No. 1: 1-3.


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Validated Living Worldwide Supercentenarians

Rejuvenation Research Feb 2017, Vol. 20, No. 1: 64-66.


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Commentary on Some Recent Theses Relevant to Combating Aging: February 2017

Rejuvenation Research Feb 2017, Vol. 20, No. 1: 67-74.


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Are aromatase inhibitors in boys with predicted short stature and/or rapidly advancing bone age effective and safe?

Journal Name: Journal of Pediatric Endocrinology and Metabolism
Issue: Ahead of print


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Adrenarche unmasks compound heterozygous 3β-hydroxysteroid dehydrogenase deficiency: c.244G>A (p.Ala82Thr) and the novel 931C>T (p.Gln311*) variant in a non-salt wasting, severely undervirilised 46XY

Journal Name: Journal of Pediatric Endocrinology and Metabolism
Issue: Ahead of print


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Status and perception of oral health in 6–17-year-old psychiatric inpatients—randomized controlled trial

Abstract

Aim

The following are the aims of the study: assessment of oral health status, oral health-related quality of life (OHRQoL) and the effect of oral health care training over OHRQoL in children and adolescents hospitalized with mental disorders.

Methodology

This randomized case controlled prospective interventional study involved 81 child and adolescent psychiatric inpatients (CAP) aged between 6 and 17 years (mean age 10.6 ± 2.4 years), compared to 81 mentally healthy patients attending routine dental examinations (DC group) matched according to age and sex of the CAP group. Oral examinations were performed by two calibrated dentists. OHRQoL was assessed with the German version of the Child Perceptions Questionnaire. CAP inpatients were randomly divided in two equal subgroups, an intervention (IG) and a non-intervention group (non-IG). The IG received oral health care training at admission to the hospital.

Results

CAP inpatients, especially those with stress-related disorders, revealed significantly higher caries prevalence and experience than DC patients. Although OHRQoL did not differ from the German reference values, CAP inpatients compensated higher impairment due to oral symptoms and functional limitations with lower impairment due to emotional and social well-being. OHRQoL increased in all CAP patients during hospitalization, regardless of receiving oral health care training.

Conclusion

Poorer oral health of CAP inpatients was not accompanied by higher impairment of OHRQoL. Oral problems seem to be overshined by better self-perceived emotional and social well-being. OHRQoL was not improved by individualized oral health care training.

Clinical relevance

Children and adolescents with mental disorders are at risk for oral diseases and need referral to dental services.

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Transesophageal Echocardiography in Swine: Establishment of a Baseline

Publication date: Available online 16 February 2017
Source:Ultrasound in Medicine & Biology
Author(s): Katharina Huenges, Saskia Pokorny, Rouven Berndt, Jochen Cremer, Georg Lutter
The porcine model is a commonly used animal model in cardiovascular research. Along with new innovative operative techniques, choice of the optimal imaging technique is crucial. Transesophageal echocardiography (TEE) is a reliable imaging tool is highly important in a large number of experimental evaluations. But so far, TEE data for swine are limited, and few standard values have been established for the porcine model. The experience and baseline results for TEE in 45 swine are presented in this study. A full TEE examination was conducted in 45 German landrace or German large white swine, with an average body weight of 49 ± 3 kg, before experimental off-pump mitral valved stent implantation. Additionally hemodynamic measurements were evaluated. The valve implantation procedure was guided solely by real-time 3-D TEE. Baseline values of standard echocardiographic parameters are provided and, where appropriate, compared with human reference values. TEE proved to be an adequate imaging technique in this experimental porcine animal model. The baseline TEE and hemodynamic parameters established for the widely used porcine model can serve as a reference in future studies.



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Anatomical Regurgitant Orifice Detection and Quantification from 3-D Echocardiographic Images

Publication date: Available online 16 February 2017
Source:Ultrasound in Medicine & Biology
Author(s): Miguel Sotaquirá, Mauro Pepi, Gloria Tamborini, Enrico G. Caiani
The vena contracta and effective regurgitant orifice area (EROA) are currently used for the clinical assessment of mitral regurgitation (MR) from 2-D color Doppler imaging. In addition to being highly user dependent and having low repeatability, these methods do not represent accurately the anatomic regurgitant orifice (ARO), which affects the adequate assessment of MR patients. We propose a novel method for semi-automatic detection and quantitative assessment of the 3-D ARO shape from 3-D transesophageal echocardiographic images. The algorithm was tested on a set of 25 patients with MR, and compared with EROA for validation. Results indicate the robustness of the proposed approach, with low variability in relation to different settings of user-defined segmentation parameters. Although EROA and ARO exhibited a good correlation (r = 0.8), relatively large biases were measured, indicating that EROA probably underestimates the real shape and size of the regurgitant orifice. Along with the higher reproducibility of the proposed approach, this highlights the limitations of current clinical approaches and underlines the importance of accurate assessment of the ARO shape for diagnosis and treatment in MR patients.



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Icariin promotes mouse hair follicle growth by increasing insulin-like growth factor 1 expression in dermal papillary cells

Summary

Background

Icariin is a major flavonoid isolated from Epimedium spp. leaves (Epimedium Herba), and has multiple pharmacological functions, including anti-angiogenesis, anti-oxidant, anti-inflammatory and immunoprotective effects.

Aim

To investigate whether icariin can stimulate growth of hair follicles in mice and the underlying mechanism.

Methods

In vitro, the effect of icariin on hair growth was assessed by using a vibrissae hair follicle (VHF) organ-culture model. The proliferation of hair matrix keratinocytes and the expression of insulin-like growth factor (IGF)-1 in follicles were examined by double immunostaining for 5-bromo-2′-deoxyuridine and IGF-1, in the presence or absence of icariin. Dermal papilla cells (DPCs) were cultured and IGF-1 level was measured by reverse transcription-PCR and ELISA after icariin treatment. In vivo, the effect of icariin on hair growth was examined by gavage feeding of icariin to mice whose backs had been depilated, and the conversion of telogen to anagen hair was observed.

Results

Treatment with icariin promoted hair shaft elongation, prolonged the hair cycle growth phase (anagen) in cultured VHFs, and accelerated transition of hair cycle from telogen to anagen phase in the dorsal skin of mice. There was significant proliferation of matrix keratinocytes and an increased level of IGF-1 in cultured VHFs. Moreover, icariin treatment upregulated IGF-1 mRNA expression in DPCs and increased IGF-1 protein content in the conditioned medium of DPCs.

Conclusions

These results suggest that icariin can promote mouse hair follicle growth via stimulation of IGF-1 expression in DPCs.

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Severe bullous pemphigoid associated with pembrolizumab therapy for metastatic melanoma with complete regression

Summary

Bullous pemphigoid (BP) is considered to be a humorally mediated autoimmune disease, but autoreactive T-cells and T-regulatory cells (Tregs) have also been implicated in this disease. Tregs and the programmed death-1 (PD-1) : programmed death ligand (PD-L) pathway are both critical in terminating immune response, and elimination of either can result in breakdown of tolerance and development of autoimmunity. We report a patient with metastatic malignant melanoma (MM), who underwent pembrolizumab (anti-PD-1) therapy following unsuccessful treatment with ipilimumab [anti-cytotoxic T-lymphocyte-associated protein (CTLA)-4]. The patient developed BP with increasing serum titres of anti-BP180 IgG autoantibodies and increasing disease severity during pembrolizumab therapy. High doses of corticosteroids and methotrexate were needed to control the BP. Following the termination of pembrolizumab therapy, imaging showed complete regression of all metastatic sites. This result may indicate a crucial role for T-cell suppressive activity in controlling and preventing BP.

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Alitretinoin treatment in mycosis fungoides with CD30-positive large cell transformation

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Detection of SERPINB7 mutation can distinguish Nagashima-type palmoplantar keratoderma from other keratodermas with palmoplantar lesions

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SARS-CoV-Encoded Small RNAs Contribute to Infection-Associated Lung Pathology

Publication date: Available online 16 February 2017
Source:Cell Host & Microbe
Author(s): Lucía Morales, Juan Carlos Oliveros, Raúl Fernandez-Delgado, Benjamin Robert tenOever, Luis Enjuanes, Isabel Sola
Severe acute respiratory syndrome coronavirus (SARS-CoV) causes lethal disease in humans, which is characterized by exacerbated inflammatory response and extensive lung pathology. To address the relevance of small non-coding RNAs in SARS-CoV pathology, we deep sequenced RNAs from the lungs of infected mice and discovered three 18–22 nt small viral RNAs (svRNAs). The three svRNAs were derived from the nsp3 (svRNA-nsp3.1 and -nsp3.2) and N (svRNA-N) genomic regions of SARS-CoV. Biogenesis of CoV svRNAs was RNase III, cell type, and host species independent, but it was dependent on the extent of viral replication. Antagomir-mediated inhibition of svRNA-N significantly reduced in vivo lung pathology and pro-inflammatory cytokine expression. Taken together, these data indicate that svRNAs contribute to SARS-CoV pathogenesis and highlight the potential of svRNA-N antagomirs as antivirals.

Graphical abstract

Teaser

SARS-CoV causes exacerbated inflammatory responses, extensive lung pathology, and lethal disease in humans. Morales et al. identify SARS-CoV-encoded small viral RNAs (svRNAs) expressed during lung infection. Virus N gene-derived svRNA (svRNA-N) contributes to enhanced lung inflammatory pathology. Antisense svRNA-N inhibitors significantly reduced pulmonary inflammation during in vivo infection in mice.


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Clinical Thyroidology for the Public – Highlighted Article

From Clinical Thyroidology for the Public: Hypothyroidism is most often caused by an autoimmune process where the body makes antibodies that attack and destroy the thyroid. Read More….

The post Clinical Thyroidology for the Public – Highlighted Article appeared first on American Thyroid Association.

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Cutaneous squamous cell carcinoma: an epidemiological review

Summary

Cutaneous squamous cell carcinoma (SCC) is a common cancer in white populations and its disease burden is often substantially underestimated. SCC occurs more often in men than women and increases dramatically with age; those affected often develop multiple primaries over time, which increases the burden. The main external cause is solar ultraviolet radiation (UVR), with immunosuppression being the other established risk factor, shown by the high SCC rates in organ transplant recipients. Sunbed use and certain genetic disorders and medical conditions are also associated with SCC, while associations with human papillomavirus infection and high bodyweight are not established. The presence of actinic keratoses (AKs) on sun-damaged skin is one of the strongest predictors of SCC in unaffected people and a very small proportion of AKs are SCC precursors, although the true rate of malignant transformation of AKs is unknown. The mainstay of SCC prevention is protection of the skin from undue sun exposure by use of clothing cover and sunscreen during summer or in sunny places. Educational, behavioural and multicomponent interventions directed at individuals ranging from parents of newborns, to school children and adolescents, to outdoor workers, have repeatedly been shown to be effective in improving sun-protective behaviours. Health policies can facilitate SCC prevention by setting standards for relevant behaviours to reduce UVR exposure, for example, by legislated restriction of the tanning industry. Skin cancer prevention initiatives are generally highly cost-effective and public investment should be encouraged to control the growing public health problems caused by SCC.

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Astrocyte-induced Reelin expression drives proliferation of Her2 + breast cancer metastases

Abstract

Breast cancer metastasis to the brain develops after a clinical latency of years to even decades, suggesting that colonization of the brain is the most challenging step of the metastatic cascade. However, the underlying mechanisms used by breast cancer cells to successfully colonize the brain's microenvironment remain elusive. Reelin is an archetypal extracellular glycoprotein that regulates migration, proliferation, and lamination of neurons. It is epigenetically silenced in various cancers, and its expression in multiple myelomas is linked to poor patient survival. We found that Reelin expression was low in primary breast cancer tissue. However, its expression was significantly higher in Her2⁺ breast cancers metastasizing to the brain. In particular, Reelin was highly expressed in the tumor periphery adjacent to surrounding astrocytes. This augmented Reelin expression was seen in Her2⁺ metastases, but not in triple negative (TN) primary tumors or in TN breast to brain metastasis cells co-cultured with astrocytes. Furthermore, the elevated expression was sustained in Her2⁺ cells grown in the presence of the DNA methyltransferase inhibitor 5-azacytidine, indicating epigenetic regulation of Reelin expression. The relative growth and rate of spheroids formation derived from Her2⁺ primary and BBM cells co-cultured with astrocytes were higher than those of TN primary and BBM cells, and knockdown of both Reelin and Her2 suppressed the astrocyte-induced growth and spheroid forming ability of Her2⁺ cells. Collectively, our results indicate that within the neural niche, astrocytes epigenetically regulate Reelin expression and its interaction with Her2 leading to increased proliferation and survival fitness.

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Virus-host interactome: Putting the accent on how it changes

Publication date: 6 March 2017
Source:Journal of Proteomics, Volume 156
Author(s): Guillermo Rodrigo, José-Antonio Daròs, Santiago F. Elena
Viral infections are extremely complex processes that could only be well understood by precisely characterizing the interaction networks between the virus and the host components. In recent years, much effort has gone in this direction with the aim of unveiling the molecular basis of viral pathology. These networks are mostly formed by viral and host proteins, and are expected to be dynamic both with time and space (i.e., with the progression of infection, as well as with the virus and host genotypes; what we call plastodynamic). This largely overlooked spatio-temporal evolution urgently calls for a change both in the conceptual paradigms and experimental techniques used so far to characterize virus-host interactions. More generally, molecular plasticity and temporal dynamics are unavoidable components of the mechanisms that underlie any complex disease; components whose understanding will eventually enhance our ability to modulate those networks with the aim of improving disease treatments.



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The protein expression landscape of mitosis and meiosis in diploid budding yeast

Publication date: 6 March 2017
Source:Journal of Proteomics, Volume 156
Author(s): Emmanuelle Becker, Emmanuelle Com, Régis Lavigne, Marie-Hélène Guilleux, Bertrand Evrard, Charles Pineau, Michael Primig
Saccharomyces cerevisiae is an established model organism for the molecular analysis of fundamental biological processes. The genomes of numerous strains have been sequenced, and the transcriptome and proteome ofmajor phases during the haploid and diploid yeast life cycle have been determined. However, much less is known about dynamic changes of the proteome when cells switch from mitotic growth to meiotic development. We report a quantitative protein profiling analysis of yeast cell division and differentiation based on mass spectrometry. Information about protein levels was integrated with strand-specific tiling array expression data. We identified a total of 2366 proteins in at least one condition, including 175 proteins showing a statistically significant>5-fold change across the sample set, and 136 proteins detectable in sporulating but not respiring cells. We correlate protein expression patterns with biological processes and molecular function by Gene Ontology term enrichment, chemoprofiling, transcription interference and the formation of double stranded RNAs by overlapping sense/antisense transcripts. Our work provides initial quantitative insight into protein expression in diploid respiring and differentiating yeast cells. Critically, it associates developmentally regulated induction of antisense long noncoding RNAs and double stranded RNAs with fluctuating protein concentrations during growth and development.Biological significanceThis integrated genomics analysis helps better understand how the transcriptome and the proteome correlate in diploid yeast cells undergoing mitotic growth in the presence of acetate (respiration) versus meiotic differentiation (Meiosis I and II). The study (i) provides quantitative expression data for 2366 proteins and their cognate mRNAs in at least one sample, (ii) shows strongly fluctuating protein levels during growth and differentiation for 175 cases, and (iii) identifies 136 proteins absent in mitotic but present in meiotic yeast cells. We have integrated protein profiling data using mass spectrometry with tiling array RNA profiling data and information on double-stranded RNAs (dsRNAs) by overlapping sense/antisense transcripts from an RNA-Sequencing experiment. This work therefore provides quantitative insight into protein expression during cell division and development and associates changing protein levels with developmental stage specific induction of antisense transcripts and the formation of dsRNAs.

Graphical abstract

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Quantitative proteome analysis of an antibiotic resistant Escherichia coli exposed to tetracycline reveals multiple affected metabolic and peptidoglycan processes

Publication date: 6 March 2017
Source:Journal of Proteomics, Volume 156
Author(s): Daniela Jones-Dias, Ana Sofia Carvalho, Inês Barata Moura, Vera Manageiro, Gilberto Igrejas, Manuela Caniça, Rune Matthiesen
Tetracyclines are among the most commonly used antibiotics administrated to farm animals for disease treatment and prevention, contributing to the worldwide increase in antibiotic resistance in animal and human pathogens. Although tetracycline mechanisms of resistance are well known, the role of metabolism in bacterial reaction to antibiotic stress is still an important assignment and could contribute to the understanding of tetracycline related stress response. In this study, spectral counts-based label free quantitative proteomics has been applied to study the response to tetracycline of the environmental-borne Escherichia coli EcAmb278 isolate soluble proteome. A total of 1484 proteins were identified by high resolution mass spectrometry at a false discovery rate threshold of 1%, of which 108 were uniquely identified under absence of tetracycline whereas 126 were uniquely identified in presence of tetracycline. These proteins revealed interesting difference in e.g. proteins involved in peptidoglycan-based cell wall proteins and energy metabolism. Upon treatment, 12 proteins were differentially regulated showing more than 2-fold change and p<0.05 (p value corrected for multiple testing). This integrated study using high resolution mass spectrometry based label-free quantitative proteomics to study tetracycline antibiotic response in the soluble proteome of resistant E. coli provides novel insight into tetracycline related stress.SignificanceThe lack of new antibiotics to fight infections caused by multidrug resistant microorganisms has motivated the use of old antibiotics, and the search for new drug targets. The evolution of antibiotic resistance is complex, but it is known that agroecosystems play an important part in the selection of antibiotic resistance bacteria. Tetracyclines are still used as phytopharmaceutical agents in crops, selecting resistant bacteria and changing the ecology of farm soil. Little is known about the metabolic response of genetically resistant populations to antibiotic exposure. Indeed, to date there are no quantitative tetracycline resistance studies performed with the latest generation of high resolution mass spectrometers allowing high mass accuracy in both MS and MS/MS scans. Here, we report the proteome profiling of a soil-borne Escherichia coli upon tetracycline stress, so that this new perspective could provide a broaden understanding of the metabolic responses of E. coli to a widely used antibiotic.

Graphical abstract

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Proteomic analysis to unravel the complex venom proteome of eastern India Naja naja: Correlation of venom composition with its biochemical and pharmacological properties

Publication date: 6 March 2017
Source:Journal of Proteomics, Volume 156
Author(s): Sumita Dutta, Abhishek Chanda, Bhargab Kalita, Taufikul Islam, Aparup Patra, Ashis K. Mukherjee
The complex venom proteome of the eastern India (EI) spectacled cobra (Naja naja) was analyzed using tandem mass spectrometry of cation-exchange venom fractions. About 75% of EI N. naja venom proteins were <18kDa and cationic at physiological pH of blood. SDS-PAGE (non-reduced) analysis indicated that in the native state venom proteins either interacted with each-other or self-aggregated resulting in the formation of higher molecular mass complexes. Proteomic analysis revealed that 43 enzymatic and non-enzymatic proteins in EI N. naja venom with a percent composition of about 28.4% and 71.6% respectively were distributed over 15 venom protein families. The three finger toxins (63.8%) and phospholipase A2s (11.4%) were the most abundant families of non-enzymatic and enzymatic proteins, respectively. nanoLC-ESI-MS/MS analysis demonstrated the occurrence of acetylcholinesterase, phosphodiesterase, cholinesterase and snake venom serine proteases in N. naja venom previously not detected by proteomic analysis. ATPase, ADPase, hyaluronidase, TAME, and BAEE-esterase activities were detected by biochemical analysis; however, due to a limitation in the protein database depository they were not identified in EI N. naja venom by proteomic analysis. The proteome composition of EI N. naja venom was well correlated with its in vitro and in vivo pharmacological properties in experimental animals and envenomed human.Biological significanceProteomic analysis reveals the complex and diverse protein profile of EI N. naja venom which collectively contributes to the severe pathophysiological manifestation upon cobra envenomation. The study has also aided in comprehending the compositional variation in venom proteins of N. naja within the Indian sub-continent. In addition, this study has also identified several enzymes in EI N. naja venom which were previously uncharacterized by proteomic analysis of Naja venom.

Graphical abstract

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A biotin enrichment strategy identifies novel carbonylated amino acids in proteins from human plasma

Publication date: 6 March 2017
Source:Journal of Proteomics, Volume 156
Author(s): Jesper F. Havelund, Katarzyna Wojdyla, Michael J. Davies, Ole N. Jensen, Ian Max Møller, Adelina Rogowska-Wrzesinska
Protein carbonylation is an irreversible protein oxidation correlated with oxidative stress, various diseases and ageing. Here we describe a peptide-centric approach for identification and characterisation of up to 14 different types of carbonylated amino acids in proteins. The modified residues are derivatised with biotin-hydrazide, enriched and characterised by tandem mass spectrometry. The strength of the method lies in an improved elution of biotinylated peptides from monomeric avidin resin using hot water (95°C) and increased sensitivity achieved by reduction of analyte losses during sample preparation and chromatography. For the first time MS/MS data analysis utilising diagnostic biotin fragment ions is used to pinpoint sites of biotin labelling and improve the confidence of carbonyl peptide assignments. We identified a total of 125 carbonylated residues in bovine serum albumin after extensive in vitro metal ion-catalysed oxidation. Furthermore, we assigned 133 carbonylated sites in 36 proteins in native human plasma protein samples. The optimised workflow enabled detection of 10 hitherto undetected types of carbonylated amino acids in proteins: aldehyde and ketone modifications of leucine, valine, alanine, isoleucine, glutamine, lysine and glutamic acid (+14Da), an oxidised form of methionine - aspartate semialdehyde (−32Da) - and decarboxylated glutamic acid and aspartic acid (−30Da).Biological significanceProteomic tools provide a promising way to decode disease mechanisms at the protein level and help to understand how carbonylation affects protein structure and function. The challenge for future research is to identify the type and nature of oxidised residues to gain a deeper understanding of the mechanism(s) governing carbonylation in cells and organisms and assess their role in disease.

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Editorial Board

Publication date: 6 March 2017
Source:Journal of Proteomics, Volume 156





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Casein phosphopeptides and CaCl2 increase penicillin production and cause an increment in microbody/peroxisome proteins in Penicillium chrysogenum

Publication date: 6 March 2017
Source:Journal of Proteomics, Volume 156
Author(s): Rebeca Domínguez-Santos, Katarina Kosalková, Carlos García-Estrada, Carlos Barreiro, Ana Ibáñez, Alejandro Morales, Juan-Francisco Martín
Transport of penicillin intermediates and penicillin secretion are still poorly characterized in Penicillium chrysogenum (re-identified as Penicillium rubens). Calcium (Ca²⁺) plays an important role in the metabolism of filamentous fungi, and casein phosphopeptides (CPP) are involved in Ca²⁺ internalization. In this study we observe that the effect of CaCl2 and CPP is additive and promotes an increase in penicillin production of up to 10–12 fold. Combination of CaCl2 and CPP greatly promotes expression of the three penicillin biosynthetic genes. Comparative proteomic analysis by 2D-DIGE, identified 39 proteins differentially represented in P. chrysogenum Wisconsin 54-1255 after CPP/CaCl2 addition. The most interesting group of overrepresented proteins were a peroxisomal catalase, three proteins of the methylcitrate cycle, two aminotransferases and cystationine β-synthase, which are directly or indirectly related to the formation of penicillin amino acid precursors. Importantly, two of the enzymes of the penicillin pathway (isopenicillin N synthase and isopenicillin N acyltransferase) are clearly induced after CPP/CaCl2 addition. Most of these overrepresented proteins are either authentic peroxisomal proteins or microbody-associated proteins. This evidence suggests that addition of CPP/CaCl2 promotes the formation of penicillin precursors and the penicillin biosynthetic enzymes in peroxisomes and vesicles, which may be involved in transport and secretion of penicillin.SignificancePenicillin biosynthesis in Penicillium chrysogenum is one of the best characterized secondary metabolism processes. However, the mechanism by which penicillin is secreted still remains to be elucidated. Taking into account the role played by Ca²⁺ and CPP in the secretory pathway and considering the positive effect that Ca²⁺ exerts on penicillin production, the analysis of global protein changes produced after CPP/CaCl2 addition is very helpful to decipher the processes related to the biosynthesis and secretion of penicillin.

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Proteomic insights into mannan degradation and protein secretion by the forest floor bacterium Chitinophaga pinensis

Publication date: 6 March 2017
Source:Journal of Proteomics, Volume 156
Author(s): Johan Larsbrink, Tina R. Tuveng, Phillip B. Pope, Vincent Bulone, Vincent G.H. Eijsink, Harry Brumer, Lauren S. McKee
Together with fungi, saprophytic bacteria are central to the decomposition and recycling of biomass in forest environments. The Bacteroidetes phylum is abundant in diverse habitats, and several species have been shown to be able to deconstruct a wide variety of complex carbohydrates. The genus Chitinophaga is often enriched in hotspots of plant and microbial biomass degradation. We present a proteomic assessment of the ability of Chitinophaga pinensis to grow on and degrade mannan polysaccharides, using an agarose plate-based method of protein collection to minimise contamination with exopolysaccharides and proteins from lysed cells, and to reflect the realistic setting of growth on a solid surface. We show that select Polysaccharide Utilisation Loci (PULs) are expressed in different growth conditions, and identify enzymes that may be involved in mannan degradation. By comparing proteomic and enzymatic profiles, we show evidence for the induced expression of enzymes and PULs in cells grown on mannan polysaccharides compared with cells grown on glucose. In addition, we show that the secretion of putative biomass-degrading enzymes during growth on glucose comprises a system for nutrient scavenging, which employs constitutively produced enzymes.Significance of this studyChitinophaga pinensis belongs to a bacterial genus which is prominent in microbial communities in agricultural and forest environments, where plant and fungal biomass is intensively degraded. Such degradation is hugely significant in the recycling of carbon in the natural environment, and the enzymes responsible are of biotechnological relevance in emerging technologies involving the deconstruction of plant cell wall material. The bacterium has a comparatively large genome, which includes many uncharacterised carbohydrate-active enzymes. We present the first proteomic assessment of the biomass-degrading machinery of this species, focusing on mannan, an abundant plant cell wall hemicellulose. Our findings include the identification of several novel enzymes, which are promising targets for future biochemical characterisation. In addition, the data indicate the expression of specific Polysaccharide Utilisation Loci, induced in the presence of different growth substrates. We also highlight how a constitutive secretion of enzymes which deconstruct microbial biomass likely forms part of a nutrient scavenging process.

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iTRAQ-based quantitative proteome revealed metabolic changes of Flammulina velutipes mycelia in response to cold stress

Publication date: 6 March 2017
Source:Journal of Proteomics, Volume 156
Author(s): Jing-Yu Liu, Jun-long Men, Ming-chang Chang, Cui-ping Feng, Ling-Gang Yuan
Temperature is one of the pivotal factors influencing mycelium growth and fruit-body formation of Flammulina velutipes. To gain insights into hyphae growth and fruit-body formation events and facilitate the identification of potential stage-specific biomarker candidates, we investigated the proteome response of F. velutipes mycelia to cold stresses using iTRAQ-coupled two-dimensional liquid chromatography tandem mass spectrometry (2D LC-MS/MS) technique. Among 1198 proteins identified with high confidence, a total of 63 displayed altered expression level after cold stress treatments. In-depth data analysis reveals that differentially expressed proteins were involved in a variety of cellular processes, particularly metabolic processes. Among the 31 up-regulated proteins, 24 (77.42%) were associated with 22 specific KEGG pathways. These up-regulated proteins could possibly serve as potential biomarkers to study the molecular mechanisms of F. velutipes mycelia response to cold stresses. These data of the proteins might provide valuable evidences to better understand the molecular mechanisms of mycelium resistance to cold stress and fruit-body formation in fungi.Biological significanceLow-temperature is one of the pivotal factors in some Flammulina velutipes industrial processes influencing mycelium growth, inducing primordia and controlling fruit-body development. Preliminary study has indicated that effectively regulating cultivation could augment the yield by controlling optimal cold stress level on mycelia. However, we are still far from understanding the molecular and physiological mechanisms of adaptation of these fungi at cold stress. In the present study, the experiments reported above were undertaken to investigate chronological changes of protein expression during F. velutipes mycelia in response to cold stress by using iTRAQ-coupled 2D LC-MS/MS technique. This result would provide new insights to the underlying mycelium growth and fruit-body formation mechanisms of basidiomycetes under cold stress.

Graphical abstract

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Quantitative proteomics analysis of Caenorhabditis elegans upon germ cell loss

Publication date: 6 March 2017
Source:Journal of Proteomics, Volume 156
Author(s): Yuan-Zhu Pu, Qin-Li Wan, Ai-Jun Ding, Huai-Rong Luo, Gui-Sheng Wu
The abrogation of the germ cells in Caenorhabditis elegans (C. elegans) by either genetic means or cell ablation results in about 60% increase of longevity. Upon the inhibition of germline stem cell proliferation, certain signaling molecules inhibit the target of rapamycin (TOR), activate the transcription factors including DAF-16, DAF-12, and PHA-4, leading to altered fatty acid lipolysis, autophagy, stress resistance, and the extended lifespan. But the exact cascades and interactions of those signaling pathways are still obscure. To understand how the reproductive system affects aging at the protein level, we determined the protein expression profile of the long-lived temperature-sensitive mutant glp-1(e2141) and wild-type N2 using isobaric tags for relative and absolute quantitation (iTRAQ) technology. Our results showed that the abundance of proteins relevant to transcription, RNA processing, translation, protein folding, and proteolytic process were decreased, while collagen proteins and proteins involved in detoxification and innate immune responses were increased in C. elegans glp-1 mutant, these alterations of protein abundance might attenuate protein metabolism and enhance immune response and stress resistance, and finally contribute to germline-mediated longevity.Biological significanceThis study provides an overview of the altered protein expression upon germline ablation. Germ-cell loss results in decreased abundance of proteins involved in protein synthesis and breakdown, and increased abundance of proteins involved in detoxification and immune response, suggesting that protein synthesis and metabolism might be attenuated, while detoxification and immune responses might be increased. The altered protein abundance might result in physiological adaptations that contribute to extended longevity in germline-deficient C. elegans. This study brings new light on the role of reproductive control of lifespan.

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The impact of cruciferous vegetable isothiocyanates on histone acetylation and histone phosphorylation in bladder cancer

Publication date: 6 March 2017
Source:Journal of Proteomics, Volume 156
Author(s): Besma Abbaoui, Kelly H. Telu, Christopher R. Lucas, Jennifer M. Thomas-Ahner, Steven J. Schwartz, Steven K. Clinton, Michael A. Freitas, Amir Mortazavi
Cruciferous vegetable intake is associated with reduced risk of bladder cancer, yet mechanisms remain unclear. Cruciferous vegetable isothiocyanates (ITCs), namely sulforaphane (SFN) and erucin (ECN), significantly inhibit histone deacetylase (HDAC) activity in human bladder cancer cells representing superficial to invasive biology (59–83% inhibition with 20μM, 48h treatment), and in bladder cancer xenografts (59±3% ECN inhibition). Individual HDACs inhibited by SFN and ECN include HDACs 1, 2, 4 and 6. Interestingly, global acetylation status of histones H3 or H4 remain unaltered. The interplay between HDAC inhibition and modest modulation of AcH3 and AcH4 status is partially explained by decreased histone acetyl transferase activity (48.8±5.3%). In contrast, a significant decrease in phosphorylation status of all isoforms of histone H1 was observed, concomitant with increased phosphatase PP1β and PP2A activity. Together, these findings suggest that ITCs modulate histone status via HDAC inhibition and phosphatase enhancement. This allows for reduced levels of histone H1 phosphorylation, a marker correlated with human bladder cancer progression. Therefore, ITC-mediated inhibition of histone H1 phosphorylation presents a novel direction of research in elucidating epidemiological relationships and supports future food-based prevention strategies.SignificanceCollectively, our findings suggest that the cruciferous vegetable isothiocyanates: sulforaphane (SFN) and erucin (ECN), impact histones status in bladder cancer cells by modulating specific HDACs and HATs, and enhancing phosphatase activity, resulting in reduction of histone H1 phosphorylation. These findings are significant due to the fact that our previous work positively correlated histone H1 phosphorylation with bladder cancer carcinogenesis and progression. Therefore, we propose that SFN and ECN may inhibit bladder carcinogenesis via epigenetic modulation of gene expression associated with histone H1 phosphorylation. These efforts may elucidate biomarkers useful in epidemiologic studies related to cruciferous vegetable intake and cancer risk or provide intermediate biomarkers for food-based clinical intervention studies in high-risk cohorts.

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Glycation inhibitors extend yeast chronological lifespan by reducing advanced glycation end products and by back regulation of proteins involved in mitochondrial respiration

Publication date: 6 March 2017
Source:Journal of Proteomics, Volume 156
Author(s): Rubina S. Kazi, Reema M. Banarjee, Arati B. Deshmukh, Gouri V. Patil, Mashanipalya G. Jagadeeshaprasad, Mahesh J. Kulkarni
Advanced Glycation End products (AGEs) are implicated in aging process. Thus, reducing AGEs by using glycation inhibitors may help in attenuating the aging process. In this study using Saccharomyces cerevisiae yeast system, we show that Aminoguanidine (AMG), a well-known glycation inhibitor, decreases the AGE modification of proteins in non-calorie restriction (NR) (2% glucose) and extends chronological lifespan (CLS) similar to that of calorie restriction (CR) condition (0.5% glucose). Proteomic analysis revealed that AMG back regulates the expression of differentially expressed proteins especially those involved in mitochondrial respiration in NR condition, suggesting that it switches metabolism from fermentation to respiration, mimicking CR. AMG induced back regulation of differentially expressed proteins could be possibly due to its chemical effect or indirectly by glycation inhibition. To delineate this, Metformin (MET), a structural analog of AMG and a mild glycation inhibitor and Hydralazine (HYD), another potent glycation inhibitor but not structural analog of AMG were used. HYD was more effective than MET in mimicking AMG suggesting that glycation inhibition was responsible for restoration of differentially expressed proteins. Thus glycation inhibitors particularly AMG, HYD and MET extend yeast CLS by reducing AGEs, modulating the expression of proteins involved in mitochondrial respiration and possibly by scavenging glucose.SignificanceThis study reports the role of glycation in aging process. In the non-caloric restriction condition, carbohydrates such as glucose promote protein glycation and reduce CLS. While, the inhibitors of glycation such as AMG, HYD, MET mimic the caloric restriction condition by back regulating deregulated proteins involved in mitochondrial respiration which could facilitate shift of metabolism from fermentation to respiration and extend yeast CLS. These findings suggest that glycation inhibitors can be potential molecules that can be used in management of aging.

Graphical abstract

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Downregulation of GNA13-ERK network in prefrontal cortex of schizophrenia brain identified by combined focused and targeted quantitative proteomics

Publication date: Available online 16 February 2017
Source:Journal of Proteomics
Author(s): Mio Hirayama-Kurogi, Yohei Takizawa, Yasuto Kunii, Junya Matsumoto, Akira Wada, Mizuki Hino, Hiroyasu Akatsu, Yoshio Hashizume, Sakon Yamamoto, Takeshi Kondo, Shingo Ito, Masanori Tachikawa, Shin-ichi Niwa, Hirooki Yabe, Tetsuya Terasaki, Mitsutoshi Setou, Sumio Ohtsuki
Schizophrenia is a disabling mental illness associated with dysfunction of the prefrontal cortex, which affects cognition and emotion. The purpose of the present study was to identify altered molecular networks in the prefrontal cortex of schizophrenia patients by comparing protein expression levels in autopsied brains of patients and controls, using a combination of targeted and focused quantitative proteomics. We selected 125 molecules possibly related to schizophrenia for quantification by knowledge-based targeted proteomics. Among the quantified molecules, GRIK4 and MAO-B were significantly decreased in plasma membrane and cytosolic fractions, respectively, of prefrontal cortex. Focused quantitative proteomics identified 15 increased and 39 decreased proteins. Network analysis identified "GNA13-ERK1-eIF4G2 signaling" as a downregulated network, and proteins involved in this network were significantly decreased. Furthermore, searching downstream of eIF4G2 revealed that eIF4A1/2 and CYFIP1 were decreased, suggesting that downregulation of the network suppresses expression of CYFIP1, which regulates actin remodeling and is involved in axon outgrowth and spine formation. Downregulation of this signaling seems likely to impair axon formation and synapse plasticity of neuronal cells, and could be associated with development of cognitive impairment in the pathology of schizophrenia.Biological significanceThe present study compared the proteome of the prefrontal cortex between schizophrenia patients and healthy controls by means of targeted proteomics and global quantitative proteomics. Targeted proteomics revealed that GRIK4 and MAOB were significantly decreased among 125 putatively schizophrenia-related proteins in prefrontal cortex of schizophrenia patients. Global quantitative proteomics identified 54 differentially expressed proteins in schizophrenia brains. The protein profile indicates attenuation of "GNA13-ERK signaling" in schizophrenia brain. In particular, EIF4G2 and CYFIP1, which are located downstream of the GNA13-ERK network, were decreased, suggesting that the attenuation of this signal network may cause impairment of axon formation and synapse plasticity in the brain of schizophrenia patients. Our results provide a novel insight into schizophrenia pathology, and could be helpful for drug development.



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Flower-like Brushite structures on Mg

Publication date: Available online 16 February 2017
Source:Materials Today
Author(s): Sridevi Brundavanam, Ravi Krishna Brundavanam, Gérrard Eddy Jai Poinern, Derek Fawcett




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Nano-formulation enhances insecticidal activity of natural pyrethrins against Aphis gossypii (Hemiptera: Aphididae) and retains their harmless effect to non-target predators

Abstract

The insecticidal activity of a new nano-formulated natural pyrethrin was examined on the cotton aphid, Aphis gossypii Glover (Hemiptera: Aphididae), and the predators Coccinella septempunctata L. (Coleoptera: Coccinellidae) and Macrolophus pygmaeus Rambur (Hemiptera: Miridae), in respect with the nano-scale potential to create more effective and environmentally responsible pesticides. Pyrethrin was nano-formulated in two water-in-oil micro-emulsions based on safe biocompatible materials, i.e., lemon oil terpenes as dispersant, polysorbates as stabilizers, and mixtures of water with glycerol as the dispersed aqueous phase. Laboratory bioassays showed a superior insecticidal effect of the pyrethrin micro-emulsions compared to two commercial suspension concentrates of natural pyrethrins against the aphid. The nano-formulated pyrethrins were harmless, in terms of caused mortality and survival time, to L3 larvae and four-instar nymphs of the predators C. septempunctata and M. pygmaeus, respectively. We expect that these results can contribute to the application of nano-technology in optimization of pesticide formulation, with further opportunities in the development of effective plant protection products compatible with integrated pest management practices.

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An online SPE LC-MS/MS method for the analysis of antibiotics in environmental water

Abstract

A fast and simple method for the analysis of 17 commonly used antibiotics in Finland in water samples was developed. The method combines online solid phase extraction using a reusable online trapping column combined with analytical separation on a C₁₈ analytical column and detection by a triple quadrupole mass spectrometer. The method was fully validated for detection and quantification limits as well as linearity, repeatability, and matrix effects. The method gave an excellent linear response (r ² > 0.99) and detection limits for all compounds (1–10 ng⁻¹), except for tetracycline (20 ng l⁻¹) and roxithromycin (50 ng l⁻¹). The repeatability was evaluated at two concentrations, and the values at 5 ng l⁻¹ ranged from 5 to 39% and at 100 ng l⁻¹ ranged from 3 to 19%. To test the method on real samples at low environmental concentrations, water samples collected from a river receiving discharges from two wastewater treatment plants were analyzed as well as samples from a pristine river. Seven antibiotics as well as carbamazepine were detected in the samples. The concentration of the compounds ranged from 5 to 81 ng l⁻¹.

http://ift.tt/2kYfWV3

Distributed mixed-integer fuzzy hierarchical programming for municipal solid waste management. Part II: scheme analysis and mechanism revelation.

Abstract

As presented in the first companion paper, distributed mixed-integer fuzzy hierarchical programming (DMIFHP) was developed for municipal solid waste management (MSWM) under complexities of heterogeneities, hierarchy, discreteness, and interactions. Beijing was selected as a representative case. This paper focuses on presenting the obtained schemes and the revealed mechanisms of the Beijing MSWM system. The optimal MSWM schemes for Beijing under various solid waste treatment policies and their differences are deliberated. The impacts of facility expansion, hierarchy, and spatial heterogeneities and potential extensions of DMIFHP are also discussed. A few of findings are revealed from the results and a series of comparisons and analyses. For instance, DMIFHP is capable of robustly reflecting these complexities in MSWM systems, especially for Beijing. The optimal MSWM schemes are of fragmented patterns due to the dominant role of the proximity principle in allocating solid waste treatment resources, and they are closely related to regulated ratios of landfilling, incineration, and composting. Communities without significant differences among distances to different types of treatment facilities are more sensitive to these ratios than others. The complexities of hierarchy and heterogeneities pose significant impacts on MSWM practices. Spatial dislocation of MSW generation rates and facility capacities caused by unreasonable planning in the past may result in insufficient utilization of treatment capacities under substantial influences of transportation costs. The problems of unreasonable MSWM planning, e.g., severe imbalance among different technologies and complete vacancy of ten facilities, should be gained deliberation of the public and the municipal or local governments in Beijing. These findings are helpful for gaining insights into MSWM systems under these complexities, mitigating key challenges in the planning of these systems, improving the related management practices, and eliminating potential socio-economic and eco-environmental issues resulting from unreasonable management.

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Treatment of Arctic wastewater by chemical coagulation, UV and peracetic acid disinfection

Abstract

Conventional wastewater treatment is challenging in the Arctic region due to the cold climate and scattered population. Thus, no wastewater treatment plant exists in Greenland, and raw wastewater is discharged directly to nearby waterbodies without treatment. We investigated the efficiency of physicochemical wastewater treatment, in Kangerlussuaq, Greenland. Raw wastewater from Kangerlussuaq was treated by chemical coagulation and UV disinfection. By applying 7.5 mg Al/L polyaluminium chloride (PAX XL100), 73% of turbidity and 28% phosphate was removed from raw wastewater. E. coli and Enterococcus were removed by 4 and 2.5 log, respectively, when UV irradiation of 0.70 kWh/m³ was applied to coagulated wastewater. Furthermore, coagulated raw wastewater in Denmark, which has a chemical quality similar to Greenlandic wastewater, was disinfected by peracetic acid or UV irradiation. Removal of heterotrophic bacteria by applying 6 and 12 mg/L peracetic acid was 2.8 and 3.1 log, respectively. Similarly, removal of heterotrophic bacteria by applying 0.21 and 2.10 kWh/m³ for UV irradiation was 2.1 and greater than 4 log, respectively. Physicochemical treatment of raw wastewater followed by UV irradiation and/or peracetic acid disinfection showed the potential for treatment of arctic wastewater.

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Combined toxicity of imidacloprid and three insecticides to the earthworm, Eisenia fetida (Annelida, Oligochaeta)

Abstract

Although the earthworm Eisenia fetida has been used in many ecotoxicological studies in recent years, most of these studies have only focused on assessing the effects of individual insecticides. In the present study, we aimed to compare the individual and combined toxic effects of imidacloprid and three insecticides (phoxim, chlorpyrifos, and lambda-cyhalothrin) on E. fetida. We showed that imidacloprid had the highest intrinsic toxicity to the worms in filter paper contact test, followed by phoxim and lambda-cyhalothrin, while the least toxicity was found from chlorpyrifos. Moreover, 14-day soil toxicity test revealed that the highest toxicity was still detected for imidacloprid with an LC₅₀ value of 2.82 (2.61∼3.17) mg a.i. kg⁻¹ dry weight (DW), followed by chlorpyrifos with an LC₅₀ value of 384.9 (353.5∼440.3) mg a.i. kg⁻¹ DW. Meanwhile, a relatively less toxicity was found for lambda-cyhalothrin with an LC₅₀ value of 560.3 (475.9∼718.5) mg a.i. kg⁻¹ DW, while the lowest toxicity to E. fetida was observed for phoxim with an LC₅₀ value of 901.5 (821.3∼1017) mg a.i. kg⁻¹ DW. In addition, significant synergistic responses were found from the ternary mixture of imidacloprid-phoxim-lambda-cyhalothrin and quaternary mixture of imidacloprid-phoxim-chlorpyrifos-lambda-cyhalothrin in both bioassay systems. Therefore, our findings highlighted that the simultaneous presence of several insecticides in the soil environment might lead to increased toxicity, resulting in serious damage to the nontarget organisms compared with individual insecticides.

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The effect of iron nanoparticles on performance of cognitive tasks in rats

Abstract

To assess the influence of 62.5 ± 0.6 nm iron nanoparticles on the status of central nervous system, a study was conducted on Wistar rats, which were subjected to abdominal injection of the studied nanoparticles at doses of 2 and 14 mg/kg. Based on the analysis of the structural and functional status of the cerebral cortex of rats, behavioral reactions of animals, and the elemental composition of the cerebral cortex, we investigated the nanoparticles' neurotoxic effect, whose degree and nature varied depending on the dosage and the time elapsed after the injection. We identified pathological changes in motor and somatosensory areas of the rats' cerebral cortex and established pronounced changes in the elemental homeostasis of the animals' cerebral cortex in experimental groups. Identified structural changes were accompanied by an increase in exploratory activity, locomotor activity, and emotional status of the animals. At that, these activities were more pronounced in rats, which were administered iron nanoparticles at a dose of 14 mg/kg. By the end of the experiment, the excitation processes prevailed over the inhibition processes that have led to the inhibition of central nervous system activity in experimental animals against the adaptation to stress in rats of the control group.

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