Background: The visualization of the subthalamic nucleus (STN) on magnetic resonance imaging (MRI) is variable. Studies of the contribution of patient-related factors and intrinsic brain volumetrics to STN visualization have not been reported previously. Objective: To assess the visualization of the STN during deep brain stimulation (DBS) surgery in a clinical setting. Methods: Eighty-two patients undergoing pre-operative MRI to plan for STN DBS for Parkinson disease were retrospectively studied. The visualization of the STN and its borders was assessed and scored by 3 independent observers using a 4-point ordinal scale (from 0 = not seen to 3 = excellent visualization). This measure was then correlated with the patients' clinical information and brain volumes. Results: The mean STN visualization scores were 1.68 and 1.63 for the right and left STN, respectively, with a good interobserver reliability (intraclass correlation coefficient: 0.744). Older age and decreased white matter volume were negatively correlated with STN visualization (p #x3c; 0.05). Conclusion: STN visualization is only fair to good on routine MRI with good concordance of interindividual rating. Advancing age and decreased white matter are associated with poor visualization of the STN. Knowledge about factors contributing to poor visualization of the STN could alert a surgeon to modify the imaging strategy to optimize surgical targeting.
Stereotact Funct Neurosurg
https://ift.tt/2shZjH9
Τετάρτη 30 Μαΐου 2018
Predict value of adiponectin for coronary atherosclerosis plaques according to computed tomography angiography in an asymptomatic population
Publication date: September–October 2018
Source:Clinical Imaging, Volume 51
Author(s): Lu Gan, Li Yang, Guangtao Yan
BackgroundThe association between serum adiponectin levels and coronary atherosclerosis plaque characteristics in asymptomatic populations is unclear.ObjectivesTo examine the predictive value of serum adiponectin levels for coronary high risk plaques as detected by computed tomography angiography (CTA).MethodsThis was a cross-sectional study. All patients were divided into high risk plaque group and non high risk plaque group. The FRS was calculated for each patient. CTA was performed for each patient. Adiponectin levels were measured by flow fluorescence immunmicrobead assay (FFIA). Receiver-operating characteristic (ROC) curves and multivariate analysis was used to determine the predictive value of adiponectin for high risk plaques.ResultsThe high risk plaque group showed lower adiponectin levels than non high risk plaque group (median, 7.27 vs. 8.51 μg/ml, P = 0.003). The multivariate analysis showed that age (OR = 2.62, 95%CI: 1.51–4.56, P = 0.001), hyperlipidemia (OR = 1.89, 95%CI: 1.07–3.36, P = 0.029), high-density lipoprotein cholesterol (HDL-C) (OR = 0.46, 95%CI: 0.24–0.87, P = 0.02), the ratio of total cholesterol to high-density lipoproteincholesterol (TC/HDL-C) (OR = 0.69, 95%CI: 0.50–0.94, P = 0.02), apolipoprotein B (apoB) (OR = 3.08, 95%CI: 1.50–6.32, P = 0.002), and adiponectin (OR = 0.37, 95%CI: 0.19–0.74, P = 0.005) were independently associated with the presence of high risk plaques. AUC of the multivariate model for high-risk plaques was 0.728 (95%CI: 0.627–0.783). Sensitivity was 74.9%, specificity was 60.2%, the positive predictive value was 65.3%, and the negative predictive value was 70.6%.ConclusionsDecreased adiponectin levels were associated with the presence of high-risk plaques in asymptomatic populations at low to intermediate FRS. Adiponectin can play an important role in plaque screening before coronary CTA.
https://ift.tt/2JhAi8R
Breast-specific gamma imaging of invasive breast cancer: Clinicopathologic factors affecting detectability and correlation with mammographic findings
Publication date: September–October 2018
Source:Clinical Imaging, Volume 51
Author(s): Ji Yeon Park, Kyung Ah Chun, Hyuk Jai Shin, Seong Yoon Yi, Heon-Ju Kwon, Hee Jin Park
PurposeTo investigate the factors affecting detectability of invasive breast cancers on BSGI.Material and methodsWe evaluated BSGI, mammography and pathologic reports of 89 patients with invasive breast cancers.Results87.6% were visible on BSGI. Cancer in old or postmenopausal women were more visible on BSGI (p = 0.003, 0.046). Cancers ≥ 1.0 cm in size were significantly more visible on BSGI than those <1 cm in size (p = 0.002). Cancers in fatty breasts were more visible than those in dense breasts (p = 0.042).ConclusionInvasive cancers in older, postmenopausal patients, cancers with size ≥1.0 cm, and those with fatty breast are better visualized by BSGI, than those in younger, premenopausal patients, with size <1.0 cm and dense breast.
https://ift.tt/2L7JrhA
Concordant, non-atypical breast papillomas do not require surgical excision: A 10-year multi-institution study and review of the literature
Publication date: September–October 2018
Source:Clinical Imaging, Volume 51
Author(s): Lars J. Grimm, Christine E. Bookhout, Rex C. Bentley, Sheryl G. Jordan, Thomas J. Lawton
PurposeNon-atypical papillomas (NAPs) diagnosed on core needle biopsy (CNB) frequently undergo surgical excision due to highly variable upstaging rates. The purpose of this study is to document our dual-institution upgrade rates of NAPs diagnosed on core needle biopsy and review the upgrade rates reported in the literature.Materials and methodsFollowing IRB approval, CNB results from Duke University (7/1/2004–6/30/2014) and the University of North Carolina Chapel Hill (1/1/04–6/30/2013) were reviewed to identify non-atypical papillomas. All cases with surgical excision or 2 years of imaging follow up were included. In addition, a literature review identified 60 published studies on upgrades of NAPs diagnosed at CNB. Cases in our cohort and the published literature were reviewed for confounding factors: [1] missing radiologic-pathologic concordance and/or discordance, [2] papillomas included with high-risk lesions, [3] high risk lesions counted as upgrades, [4] review by a nonspecialized breast pathologist, and [5] cancer incidentally detected.ResultsOf the 388 CNBs in our dual-institution cohort, 136 (35%) patients underwent surgical excision and 252 (65%) patients had imaging follow up. After controlling for confounders, no cancers (0/388) were found at surgical excision or during follow up imaging. The literature review upstaging rate was 4.0% (166/4157) but 1.8% (4/227) after excluding studies with confounders. The combined upstaging rate from the literature and this study was 0.6% (4/615).ConclusionThe upstaging rate for CNB diagnosed NAPs was 0% in our cohort and 0.6% overall after adjusting for confounders. This low rate does not warrant reflexive surgical excision and diagnostic imaging follow up should be discretionary.
https://ift.tt/2JitmbI
Concentration characteristics, source apportionment, and oxidative damage of PM 2.5 -bound PAHs in petrochemical region in Xinjiang, NW China
Abstract
Polycyclic aromatic hydrocarbons (PAHs) are of considerable concern due to their potential as human carcinogens. Thus, determining the characteristics, potential source, and examining the oxidative capacity of PAHs to protect human health is essential. This study investigated the PM2.5-bound PAHs at Dushanzi, a large petrochemical region in Xinjiang as well as northwest China. A total of 33 PM2.5 samples with 13 PAHs, together with molecular tracers (levoglucosan, and element carbon), were analyzed during the non-heating and heating periods. The results showed that the PM2.5 concentrations were 70.22 ± 22.30 and 95.47 ± 61.73 μg/m3, while that of total PAHs were 4.07 ± 2.03 and 60.33 ± 30.80 ng/m3 in sampling period, respectively. The fluoranthene, pyrene, chrysene, benzo[b]fluoranthene, and benzo[k]fluoranthene were the most abundant (top five) PAHs, accounting for 71.74 and 72.80% of total PAH mass during non-heating and heating periods. The BaP equivalent (BaPeq) concentration exceeded 1 ng/m3 as recommended by National Ambient Air Quality Standards during heating period. The diagnostic ratios and positive matrix factorization indicated that oil industry, biomass burning, coal combustion, and vehicle emissions are the primary sources. The coal combustion remarkably increased during heating period. The plasmid scission assay (PSA) results showed that higher DNA damage rate was observed during heating period. PAHs in PM2.5 such as Chr, BaP, and IcdP were found to have significantly positive correlations with the plasmid DNA damage rates. Additionally, the relationship among BaPeq and DNA damage rate suggested that synergistic reaction may modify the toxicity of PAHs.
https://ift.tt/2L8Gz49
Novel urinary biomarkers for the detection of bladder cancer: A systematic review
Source:Cancer Treatment Reviews
Author(s): Wei Shen Tan, Wei Phin Tan, Mae-Yen Tan, Pramit Khetrapal, Liqin Dong, Patricia deWinter, Andrew Feber, John D Kelly
BackgroundUrinary biomarkers for the diagnosis of bladder cancer represents an area of considerable research which has been tested in both patients presenting with haematuria and non-muscle invasive bladder cancer patients requiring surveillance cystoscopy. In this systematic review, we identify and appraise the diagnostic sensitive and specificity of reported novel biomarkers of different 'omic' class and highlight promising biomarkers investigated to date.MethodsA MEDLINE/ Pubmed systematic search was performed between January 2013 and July 2017 using the following keywords: (bladder cancer OR transitional cell carcinoma OR urothelial cell carcinoma) AND (detection OR diagnosis) AND urine AND (biomarker OR assay). All studies had a minimum of 20 patients in both bladder cancer and control arms and reported sensitivity and/ or specificity and/ or receiver operating characteristics (ROC) curve. QUADAS-2 tool was used to assess risk of bias and applicability of studies. The search protocol was registered in the PROSPERO database (CRD42016049918).ResultsSystematic search yielded 115 reports were included for analysis. In single target biomarkers had a sensitivity of 2-94%, specificity of 46-100%, positive predictive value (PPV) of 47-100% and negative predictive value (NPV) of 21-94%. Multi-target biomarkers achieved a sensitivity of 24-100%, specificity of 48-100%, PPV of 42-95% and NPV of 32-100%. 50 studies achieved a sensitivity and specificity of ≥ 80%. Protein (n=59) and transcriptomic (n=21) biomarkers represents the most studied biomarkers. Multi-target biomarker panels had a better diagnostic accuracy compared to single biomarker targets. Urinary cytology with urinary biomarkers improved the diagnostic ability of the biomarker. The sensitivity and specificity of biomarkers were higher for primary diagnosis compared to patients in the surveillance setting. Most studies were case control studies and did not have a predefined threshold to determine a positive test result indicating a possible risk of bias.ConclusionThis comprehensive systematic review provides an update on urinary biomarkers of different 'omic' class and highlights promising biomarkers. Few biomarkers achieve a high sensitivity and negative predictive value. Such biomarkers will require external validation in a prospective observational setting before adoption in clinical practice.
https://ift.tt/2kzxnKF
The Dutch national guideline on metastases and hematological malignancies localized within the spine; a multidisciplinary collaboration towards timely and proactive management
Source:Cancer Treatment Reviews
Author(s): Karlijn H.J. Groenen, Yvette M. van der Linden, Thea Brouwer, Sander P.D. Dijkstra, Alexander de Graeff, Paul R. Algra, Jos M.A. Kuijlen, Monique C. Minnema, Claudia Nijboer, Davey L.H. Poelma, Christa Rolf, Tebbe Sluis, Michel A.M.B. Terheggen, Alexandra C.M. van der Togt-van Leeuwen, Ronald H.M.A. Bartels, Walter Taal
Here, we describe the development of a Dutch national guideline on metastases and hematological malignancies localized within the spine. The aim was to create a comprehensive guideline focusing on proactive management of these diseases, enabling healthcare professionals to weigh patient perspectives, life expectancy, and expected outcomes to make informed treatment recommendations. A national multidisciplinary panel consisting of clinicians, a nurse, a patient advocate, an epidemiologist, and a methodologist drafted the guideline. The important role of patients in the realization of the guideline enabled us to identify and address perceived shortcomings in patient care. The guideline covers not only metastatic epidural spinal cord compression, but also the treatment of uncomplicated metastases and hematological malignancies localized within the spine. The guideline is applicable in daily practice and provides an up-to-date and concise overview of the diagnostic and treatment possibilities for patients suffering from a disease that can have a serious impact on their quality of life. Suggestions for the practical implementation of patient care in hospitals are also provided, including approaches for pursuing proactive management. The crucial role of the patient in decision making is emphasized in this guideline.
https://ift.tt/2sojFxO
Involvement of Mossy Cells in Sharp Wave-Ripple Activity In Vitro
Publication date: 29 May 2018
Source:Cell Reports, Volume 23, Issue 9
Author(s): Aarti Swaminathan, Ines Wichert, Dietmar Schmitz, Nikolaus Maier
The role of mossy cells (MCs) of the hippocampal dentate area has long remained mysterious. Recent research has begun to unveil their significance in spatial computation of the hippocampus. Here, we used an in vitro model of sharp wave-ripple complexes (SWRs), which contribute to hippocampal memory formation, to investigate MC involvement in this fundamental population activity. We find that a significant fraction of MCs (∼47%) is recruited into the active neuronal network during SWRs in the CA3 area. Moreover, MCs receive pronounced, ripple-coherent, excitatory and inhibitory synaptic input. Finally, we find evidence for SWR-related synaptic activity in granule cells that is mediated by MCs. Given the widespread connectivity of MCs within and between hippocampi, our data suggest a role for MCs as a hub functionally coupling the CA3 and the DG during ripple-associated computations.
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The functional implication of hippocampal mossy cells (MCs) is thus far poorly understood. Swaminathan et al. demonstrate sub-threshold activity and recruitment of MCs during ripples that are fast neuronal oscillations involved in memory consolidation. These results suggest a pivotal role for MCs in computations occurring during ripple-related brain states.https://ift.tt/2JdU4C5
Mitochondrial Aging Defects Emerge in Directly Reprogrammed Human Neurons due to Their Metabolic Profile
Publication date: 29 May 2018
Source:Cell Reports, Volume 23, Issue 9
Author(s): Yongsung Kim, Xinde Zheng, Zoya Ansari, Mark C. Bunnell, Joseph R. Herdy, Larissa Traxler, Hyungjun Lee, Apua C.M. Paquola, Chrysanthi Blithikioti, Manching Ku, Johannes C.M. Schlachetzki, Jürgen Winkler, Frank Edenhofer, Christopher K. Glass, Andres A. Paucar, Baptiste N. Jaeger, Son Pham, Leah Boyer, Benjamin C. Campbell, Tony Hunter, Jerome Mertens, Fred H. Gage
Mitochondria are a major target for aging and are instrumental in the age-dependent deterioration of the human brain, but studying mitochondria in aging human neurons has been challenging. Direct fibroblast-to-induced neuron (iN) conversion yields functional neurons that retain important signs of aging, in contrast to iPSC differentiation. Here, we analyzed mitochondrial features in iNs from individuals of different ages. iNs from old donors display decreased oxidative phosphorylation (OXPHOS)-related gene expression, impaired axonal mitochondrial morphologies, lower mitochondrial membrane potentials, reduced energy production, and increased oxidized proteins levels. In contrast, the fibroblasts from which iNs were generated show only mild age-dependent changes, consistent with a metabolic shift from glycolysis-dependent fibroblasts to OXPHOS-dependent iNs. Indeed, OXPHOS-induced old fibroblasts show increased mitochondrial aging features similar to iNs. Our data indicate that iNs are a valuable tool for studying mitochondrial aging and support a bioenergetic explanation for the high susceptibility of the brain to aging.
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Kim et al. compared mitochondrial features in aging human fibroblasts and directly induced neurons (iNs). They find that only iNs display severe signs of mitochondrial aging defects and show that the metabolic shift during fibroblast-to-neuron conversion renders iNs particularly vulnerable to mitochondrial aging.https://ift.tt/2L6IVjX
The Anti-Warburg Effect Elicited by the cAMP-PGC1α Pathway Drives Differentiation of Glioblastoma Cells into Astrocytes
Publication date: 29 May 2018
Source:Cell Reports, Volume 23, Issue 9
Author(s): Fan Xing, Yizhao Luan, Jing Cai, Sihan Wu, Jialuo Mai, Jiayu Gu, Haipeng Zhang, Kai Li, Yuan Lin, Xiao Xiao, Jiankai Liang, Yuan Li, Wenli Chen, Yaqian Tan, Longxiang Sheng, Bingzheng Lu, Wanjun Lu, Mingshi Gao, Pengxin Qiu, Xingwen Su, Wei Yin, Jun Hu, Zhongping Chen, Ke Sai, Jing Wang, Furong Chen, Yinsheng Chen, Shida Zhu, Dongbing Liu, Shiyuan Cheng, Zhi Xie, Wenbo Zhu, Guangmei Yan
https://ift.tt/2L9ivhE
IMP3 Stabilization of WNT5B mRNA Facilitates TAZ Activation in Breast Cancer
Publication date: 29 May 2018
Source:Cell Reports, Volume 23, Issue 9
Author(s): Sanjoy Samanta, Santosh Guru, Ameer L. Elaimy, John J. Amante, Jianhong Ou, Jun Yu, Lihua J. Zhu, Arthur M. Mercurio
Insulin-like growth factor-2 mRNA-binding protein 3 (IMP3) is an oncofetal protein associated with many aggressive cancers and implicated in the function of breast cancer stem cells (CSCs). The mechanisms involved, however, are poorly understood. We observed that IMP3 facilitates the activation of TAZ, a transcriptional co-activator of Hippo signaling that is necessary for the function of breast CSCs. The mechanism by which IMP3 activates TAZ involves both mRNA stability and transcriptional regulation. IMP3 stabilizes the mRNA of an alternative WNT ligand (WNT5B) indirectly by repressing miR145-5p, which targets WNT5B, resulting in TAZ activation by alternative WNT signaling. IMP3 also facilitates the transcription of SLUG, which is necessary for TAZ nuclear localization and activation, by a mechanism that is also mediated by WNT5B. These results demonstrate that TAZ can be regulated by an mRNA-binding protein and that this regulation involves the integration of Hippo and alternative WNT-signaling pathways.
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Mechanisms that regulate TAZ are critical for understanding the biology and improving the therapy of breast and other cancers. Samanta et al. demonstrate that insulin-like growth factor-2 mRNA-binding protein 3 (IMP3) contributes to TAZ activation in breast cancer stem cells by stabilizing WNT5B mRNA and facilitating alternative Wnt signaling. IMP3 and WNT5B also function together to promote the transcription of SLUG, which is necessary for TAZ nuclear localization and activation.https://ift.tt/2JiYcRi
Conformational Plasticity in Broadly Neutralizing HIV-1 Antibodies Triggers Polyreactivity
Publication date: 29 May 2018
Source:Cell Reports, Volume 23, Issue 9
Author(s): Julie Prigent, Annaëlle Jarossay, Cyril Planchais, Caroline Eden, Jérémy Dufloo, Ayrin Kök, Valérie Lorin, Oxana Vratskikh, Thérèse Couderc, Timothée Bruel, Olivier Schwartz, Michael S. Seaman, Oliver Ohlenschläger, Jordan D. Dimitrov, Hugo Mouquet
Human high-affinity antibodies to pathogens often recognize unrelated ligands. The molecular origin and the role of this polyreactivity are largely unknown. Here, we report that HIV-1 broadly neutralizing antibodies (bNAbs) are frequently polyreactive, cross-reacting with non-HIV-1 molecules, including self-antigens. Mutating bNAb genes to increase HIV-1 binding and neutralization also results in de novo polyreactivity. Unliganded paratopes of polyreactive bNAbs with improved HIV-1 neutralization exhibit a conformational flexibility, which contributes to enhanced affinity of bNAbs to various HIV-1 envelope glycoproteins and non-HIV antigens. Binding adaptation of polyreactive bNAbs to the divergent ligands mainly involves hydrophophic interactions. Plasticity of bNAbs' paratopes may, therefore, facilitate accommodating divergent viral variants, but it simultaneously triggers promiscuous binding to non-HIV-1 antigens. Thus, a certain level of polyreactivity can be a mark of adaptable antibodies displaying optimal pathogens' recognition.
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HIV-1 bNAbs are frequently polyreactive and bind to self-antigens. Prigent et al. show that specific mutations in bNAbs that enhance their neutralizing capacity create an intrinsic structural flexibility of the antibody paratope. This promotes the conformational adaptation that facilitates binding to HIV-1 variants and polyreactivity to topologically distinct non-HIV-1 molecules.https://ift.tt/2L9iwSK
A Batf3/Nlrp3/IL-18 Axis Promotes Natural Killer Cell IL-10 Production during Listeria monocytogenes Infection
Publication date: 29 May 2018
Source:Cell Reports, Volume 23, Issue 9
Author(s): Sarah E. Clark, Rebecca L. Schmidt, Daniel S. McDermott, Laurel L. Lenz
The bacterial pathogen Listeria monocytogenes (Lm) capitalizes on natural killer (NK) cell production of regulatory interleukin (IL)-10 to establish severe systemic infections. Here, we identify regulators of this IL-10 secretion. We show that IL-18 signals to NK cells license their ability to produce IL-10. IL-18 acts independent of IL-12 and STAT4, which co-stimulate IFNγ secretion. Dendritic cell (DC) expression of Nlrp3 is required for IL-18 release in response to the Lm p60 virulence protein. Therefore, mice lacking Nlrp3, Il18, or Il18R fail to accumulate serum IL-10 and are highly resistant to systemic Lm infection. We further show that cells expressing or dependent on Batf3 are required for IL-18-inducing IL-10 production observed in infected mice. These findings explain how Il18 and Batf3 promote susceptibility to bacterial infection and demonstrate the ability of Lm to exploit NLRP3 for the promotion of regulatory NK cell activity.
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Clark et al. show that a bacterial pathogen suppresses protective immunity through an inflammasome-dependent pathway. Stimulation of NLRP3-dependent interleukin (IL)-18 release licenses NK cells to produce the anti-inflammatory molecule IL-10. Batf3-dependent cells are vital for IL-18 release, which drives this regulatory natural killer cell activity.https://ift.tt/2JdU0lP
Early Seizures Prematurely Unsilence Auditory Synapses to Disrupt Thalamocortical Critical Period Plasticity
Publication date: 29 May 2018
Source:Cell Reports, Volume 23, Issue 9
Author(s): Hongyu Sun, Anne E. Takesian, Ting Ting Wang, Jocelyn J. Lippman-Bell, Takao K. Hensch, Frances E. Jensen
Heightened neural excitability in infancy and childhood results in increased susceptibility to seizures. Such early-life seizures are associated with language deficits and autism that can result from aberrant development of the auditory cortex. Here, we show that early-life seizures disrupt a critical period (CP) for tonotopic map plasticity in primary auditory cortex (A1). We show that this CP is characterized by a prevalence of "silent," NMDA-receptor (NMDAR)-only, glutamate receptor synapses in auditory cortex that become "unsilenced" due to activity-dependent AMPA receptor (AMPAR) insertion. Induction of seizures prior to this CP occludes tonotopic map plasticity by prematurely unsilencing NMDAR-only synapses. Further, brief treatment with the AMPAR antagonist NBQX following seizures, prior to the CP, prevents synapse unsilencing and permits subsequent A1 plasticity. These findings reveal that early-life seizures modify CP regulators and suggest that therapeutic targets for early post-seizure treatment can rescue CP plasticity.
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Early-life seizures are often associated with intellectual disability and/or autism. Sun et al. show that seizures prematurely unsilence synapses to disrupt tonotopic plasticity in auditory cortex, revealing a mechanism for the relationship between seizures and later cognitive impairment.https://ift.tt/2L9iw5c
Antigenic Variation in the Lyme Spirochete: Insights into Recombinational Switching with a Suggested Role for Error-Prone Repair
Publication date: 29 May 2018
Source:Cell Reports, Volume 23, Issue 9
Author(s): Theodore B. Verhey, Mildred Castellanos, George Chaconas
The Lyme disease spirochete, Borrelia burgdorferi, uses antigenic variation as a strategy to evade the host's acquired immune response. New variants of surface-localized VlsE are generated efficiently by unidirectional recombination from 15 unexpressed vls cassettes into the vlsE locus. Using algorithms to analyze switching from vlsE sequencing data, we characterize a population of over 45,000 inferred recombination events generated during mouse infection. We present evidence for clustering of these recombination events within the population and along the vlsE gene, a role for the direct repeats flanking the variable region in vlsE, and the importance of sequence homology in determining the location of recombination, despite RecA's dispensability. Finally, we report that non-templated sequence variation is strongly associated with recombinational switching and occurs predominantly at the 5′ end of conversion tracts. This likely results from an error-prone repair mechanism operational during recombinational switching that elevates the mutation rate > 5,000-fold in switched regions.
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The Lyme disease spirochete is a master of disguise and escapes the host immune system by continually changing a major surface lipoprotein, VlsE. Using next- generation sequencing and by designing a computer algorithm, Verhey et al. reveal insights into the mechanism of the recombination reaction that drives antigenic variation.https://ift.tt/2L2smp6
Site-Specific Gene Editing of Human Hematopoietic Stem Cells for X-Linked Hyper-IgM Syndrome
Publication date: 29 May 2018
Source:Cell Reports, Volume 23, Issue 9
Author(s): Caroline Y. Kuo, Joseph D. Long, Beatriz Campo-Fernandez, Satiro de Oliveira, Aaron R. Cooper, Zulema Romero, Megan D. Hoban, Alok V. Joglekar, Georgia R. Lill, Michael L. Kaufman, Sorel Fitz-Gibbon, Xiaoyan Wang, Roger P. Hollis, Donald B. Kohn
X-linked hyper-immunoglobulin M (hyper-IgM) syndrome (XHIM) is a primary immunodeficiency due to mutations in CD40 ligand that affect immunoglobulin class-switch recombination and somatic hypermutation. The disease is amenable to gene therapy using retroviral vectors, but dysregulated gene expression results in abnormal lymphoproliferation in mouse models, highlighting the need for alternative strategies. Here, we demonstrate the ability of both the transcription activator-like effector nuclease (TALEN) and clustered regularly interspaced short palindromic repeats-associated protein 9 (CRISPR/Cas9) platforms to efficiently drive integration of a normal copy of the CD40L cDNA delivered by Adeno-Associated Virus. Site-specific insertion of the donor sequence downstream of the endogenous CD40L promoter maintained physiologic expression of CD40L while overriding all reported downstream mutations. High levels of gene modification were achieved in primary human hematopoietic stem cells (HSCs), as well as in cell lines and XHIM-patient-derived T cells. Notably, gene-corrected HSCs engrafted in immunodeficient mice at clinically relevant frequencies. These studies provide the foundation for a permanent curative therapy in XHIM.
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Kuo et al. demonstrate that both TALEN and CRISPR/Cas9 platforms combined with a corrective AAV donor can mediate site-specific gene editing at the CD40 ligand locus. High levels of gene modification were achieved in human hematopoietic stem cells, which engraft in immunodeficient mice at clinically relevant frequencies.https://ift.tt/2JiY8Ry
Accumulation of Succinate in Cardiac Ischemia Primarily Occurs via Canonical Krebs Cycle Activity
Publication date: 29 May 2018
Source:Cell Reports, Volume 23, Issue 9
Author(s): Jimmy Zhang, Yves T. Wang, James H. Miller, Mary M. Day, Joshua C. Munger, Paul S. Brookes
Succinate accumulates during ischemia, and its oxidation at reperfusion drives injury. The mechanism of ischemic succinate accumulation is controversial and is proposed to involve reversal of mitochondrial complex II. Herein, using stable-isotope-resolved metabolomics, we demonstrate that complex II reversal is possible in hypoxic mitochondria but is not the primary succinate source in hypoxic cardiomyocytes or ischemic hearts. Rather, in these intact systems succinate primarily originates from canonical Krebs cycle activity, partly supported by aminotransferase anaplerosis and glycolysis from glycogen. Augmentation of canonical Krebs cycle activity with dimethyl-α-ketoglutarate both increases ischemic succinate accumulation and drives substrate-level phosphorylation by succinyl-CoA synthetase, improving ischemic energetics. Although two-thirds of ischemic succinate accumulation is extracellular, the remaining one-third is metabolized during early reperfusion, wherein acute complex II inhibition is protective. These results highlight a bifunctional role for succinate: its complex-II-independent accumulation being beneficial in ischemia and its complex-II-dependent oxidation being detrimental at reperfusion.
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Although succinate drives reperfusion injury, its ischemic accumulation mechanism is controversial. Herein, Zhang et al. show that ischemic succinate is generated by canonical Krebs cycle activity, rather than by mitochondrial complex II reversal, and improves ischemic energetics. At reperfusion, most succinate is washed out and may serve a signaling role.https://ift.tt/2L9tY0H
Aerobic Glycolysis Is Essential for Normal Rod Function and Controls Secondary Cone Death in Retinitis Pigmentosa
Publication date: 29 May 2018
Source:Cell Reports, Volume 23, Issue 9
Author(s): Lolita Petit, Shan Ma, Joris Cipi, Shun-Yun Cheng, Marina Zieger, Nissim Hay, Claudio Punzo
Aerobic glycolysis accounts for ∼80%–90% of glucose used by adult photoreceptors (PRs); yet, the importance of aerobic glycolysis for PR function or survival remains unclear. Here, we further established the role of aerobic glycolysis in murine rod and cone PRs. We show that loss of hexokinase-2 (HK2), a key aerobic glycolysis enzyme, does not affect PR survival or structure but is required for normal rod function. Rods with HK2 loss increase their mitochondrial number, suggesting an adaptation to the inhibition of aerobic glycolysis. In contrast, cones adapt without increased mitochondrial number but require HK2 to adapt to metabolic stress conditions such as those encountered in retinitis pigmentosa, where the loss of rods causes a nutrient shortage in cones. The data support a model where aerobic glycolysis in PRs is not a necessity but rather a metabolic choice that maximizes PR function and adaptability to nutrient stress conditions.
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Photoreceptors are terminal differentiated neurons using aerobic glycolysis to meet their metabolic needs. Using a hexokinase-2 conditional mouse, Petit et al. show that photoreceptors do not need hexokinase-2 for survival but rather for function and adaptation to metabolic stress.https://ift.tt/2JiY6Jq
Maternal Inheritance of a Recessive RBP4 Defect in Canine Congenital Eye Disease
Publication date: 29 May 2018
Source:Cell Reports, Volume 23, Issue 9
Author(s): Maria Kaukonen, Sean Woods, Saija Ahonen, Seppo Lemberg, Maarit Hellman, Marjo K. Hytönen, Perttu Permi, Tom Glaser, Hannes Lohi
Maternally skewed transmission of traits has been associated with genomic imprinting and oocyte-derived mRNA. We report canine congenital eye malformations, caused by an amino acid deletion (K12del) near the N terminus of retinol-binding protein (RBP4). The disease is only expressed when both dam and offspring are deletion homozygotes. RBP carries vitamin A (retinol) from hepatic stores to peripheral tissues, including the placenta and developing eye, where it is required to synthesize retinoic acid. Gestational vitamin A deficiency is a known risk factor for ocular birth defects. The K12del mutation disrupts RBP folding in vivo, decreasing its secretion from hepatocytes to serum. The maternal penetrance effect arises from an impairment in the sequential transfer of retinol across the placenta, via RBP encoded by maternal and fetal genomes. Our results demonstrate a mode of recessive maternal inheritance, with a physiological basis, and they extend previous observations on dominant-negative RBP4 alleles in humans.
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Maternal inheritance distinctive from imprinting and oocyte-derived mRNA mechanisms has been regarded as a rare exception unique to humans. Kaukonen et al. describe a canine model with a recessive maternally transmitted RBP4 defect, suggesting that this mechanism is more common in developmental defects.https://ift.tt/2L3dcjB
Modeling Late-Onset Sporadic Alzheimer’s Disease through BMI1 Deficiency
Publication date: 29 May 2018
Source:Cell Reports, Volume 23, Issue 9
Author(s): Anthony Flamier, Jida El Hajjar, James Adjaye, Karl J. Fernandes, Mohamed Abdouh, Gilbert Bernier
Late-onset sporadic Alzheimer's disease (AD) is the most prevalent form of dementia, but its origin remains poorly understood. The Bmi1/Ring1 protein complex maintains transcriptional repression of developmental genes through histone H2A mono-ubiquitination, and Bmi1 deficiency in mice results in growth retardation, progeria, and neurodegeneration. Here, we demonstrate that BMI1 is silenced in AD brains, but not in those with early-onset familial AD, frontotemporal dementia, or Lewy body dementia. BMI1 expression was also reduced in cortical neurons from AD patient-derived induced pluripotent stem cells but not in neurons overexpressing mutant APP and PSEN1. BMI1 knockout in human post-mitotic neurons resulted in amyloid beta peptide secretion and deposition, p-Tau accumulation, and neurodegeneration. Mechanistically, BMI1 was required to repress microtubule associated protein tau (MAPT) transcription and prevent GSK3beta and p53 stabilization, which otherwise resulted in neurodegeneration. Restoration of BMI1 activity through genetic or pharmaceutical approaches could represent a therapeutic strategy against AD.
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Flamier et al. report on a role of BMI1 in sporadic Alzheimer's disease (AD) pathogenesis. They show reduced BMI1 expression in AD brains and cortical neurons compared to non-demented controls, familial AD, frontotemporal dementia, and Lewy body dementia. Human neurons deficient for BMI1 display pathological hallmarks of AD. Their work suggests that BMI1 reduction results in AD pathology through de-repression of MAPT and stabilization of GSK3beta and p53.https://ift.tt/2JdTTGV
Inhibition of Neuroinflammation by AIBP: Spinal Effects upon Facilitated Pain States
Publication date: 29 May 2018
Source:Cell Reports, Volume 23, Issue 9
Author(s): Sarah A. Woller, Soo-Ho Choi, Eun Jung An, Hann Low, Dina A. Schneider, Roshni Ramachandran, Jungsu Kim, Yun Soo Bae, Dmitri Sviridov, Maripat Corr, Tony L. Yaksh, Yury I. Miller
Apolipoprotein A-I binding protein (AIBP) reduces lipid raft abundance by augmenting the removal of excess cholesterol from the plasma membrane. Here, we report that AIBP prevents and reverses processes associated with neuroinflammatory-mediated spinal nociceptive processing. The mechanism involves AIBP binding to Toll-like receptor-4 (TLR4) and increased binding of AIBP to activated microglia, which mediates selective regulation of lipid rafts in inflammatory cells. AIBP-mediated lipid raft reductions downregulate LPS-induced TLR4 dimerization, inflammatory signaling, and expression of cytokines in microglia. In mice, intrathecal injections of AIBP reduce spinal myeloid cell lipid rafts, TLR4 dimerization, neuroinflammation, and glial activation. Intrathecal AIBP reverses established allodynia in mice in which pain states were induced by the chemotherapeutic cisplatin, intraplantar formalin, or intrathecal LPS, all of which are pro-nociceptive interventions known to be regulated by TLR4 signaling. These findings demonstrate a mechanism by which AIBP regulates neuroinflammation and suggest the therapeutic potential of AIBP in treating preexisting pain states.
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Woller et al. report that ApoA-I binding protein (AIBP) selectively regulates, via TLR4 binding, cholesterol removal and normalization of lipid rafts in inflamed microglia. Spinal delivery of AIBP reduces neuroinflammation and prevents and reverses neuropathic pain states, such as chemotherapy-induced peripheral neuropathy, with an effect sustained for >2 months.https://ift.tt/2L7FwBo
Power Grid Protection of the Muscle Mitochondrial Reticulum
Publication date: 29 May 2018
Source:Cell Reports, Volume 23, Issue 9
Author(s): Brian Glancy, Lisa M. Hartnell, Christian A. Combs, Armel Femnou, Junhui Sun, Elizabeth Murphy, Sriram Subramaniam, Robert S. Balaban
https://ift.tt/2JdTEeZ
NMDA Receptor Activation Underlies the Loss of Spinal Dorsal Horn Neurons and the Transition to Persistent Pain after Peripheral Nerve Injury
Publication date: 29 May 2018
Source:Cell Reports, Volume 23, Issue 9
Author(s): Perrine Inquimbert, Martin Moll, Alban Latremoliere, Chi-Kun Tong, John Whang, Gregory F. Sheehan, Brendan M. Smith, Erica Korb, Maria C.P. Athié, Olusegun Babaniyi, Nader Ghasemlou, Yuchio Yanagawa, C. David Allis, Patrick R. Hof, Joachim Scholz
Peripheral nerve lesions provoke apoptosis in the dorsal horn of the spinal cord. The cause of cell death, the involvement of neurons, and the relevance for the processing of somatosensory information are controversial. Here, we demonstrate in a mouse model of sciatic nerve injury that glutamate-induced neurodegeneration and loss of γ-aminobutyric acid (GABA)ergic interneurons in the superficial dorsal horn promote the transition from acute to chronic neuropathic pain. Conditional deletion of Grin1, the essential subunit of N-methyl-d-aspartate-type glutamate receptors (NMDARs), protects dorsal horn neurons from excitotoxicity and preserves GABAergic inhibition. Mice deficient in functional NMDARs exhibit normal nociceptive responses and acute pain after nerve injury, but this initial increase in pain sensitivity is reversible. Eliminating NMDARs fully prevents persistent pain-like behavior. Reduced pain in mice lacking proapoptotic Bax confirmed the significance of neurodegeneration. We conclude that NMDAR-mediated neuron death contributes to the development of chronic neuropathic pain.
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Dorsal horn neurons process somatosensory information, including pain. Inquimbert et al. utilized spatially restricted Grin1 knockout to show that NMDA-receptor-mediated excitatory input causes the degeneration of some dorsal horn neurons after nerve injury. Irreversible loss of GABAergic interneurons leads to a deficit in inhibition that promotes persistent pain hypersensitivity.https://ift.tt/2JdTRyN
Differentiating Cerebellar Impact on Thalamic Nuclei
Publication date: 29 May 2018
Source:Cell Reports, Volume 23, Issue 9
Author(s): Simona V. Gornati, Carmen B. Schäfer, Oscar H.J. Eelkman Rooda, Alex L. Nigg, Chris I. De Zeeuw, Freek E. Hoebeek
The cerebellum plays a role in coordination of movements and non-motor functions. Cerebellar nuclei (CN) axons connect to various parts of the thalamo-cortical network, but detailed information on the characteristics of cerebello-thalamic connections is lacking. Here, we assessed the cerebellar input to the ventrolateral (VL), ventromedial (VM), and centrolateral (CL) thalamus. Confocal and electron microscopy showed an increased density and size of CN axon terminals in VL compared to VM or CL. Electrophysiological recordings in vitro revealed that optogenetic CN stimulation resulted in enhanced charge transfer and action potential firing in VL neurons compared to VM or CL neurons, despite that the paired-pulse ratio was not significantly different. Together, these findings indicate that the impact of CN input onto neurons of different thalamic nuclei varies substantially, which highlights the possibility that cerebellar output differentially controls various parts of the thalamo-cortical network.
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In this study, Gornati et al. demonstrate that the impact of cerebellar nuclei axons on thalamic neurons varies per thalamic region. These findings provide insights into how the versatile cerebellum can have a differential effect on the many brain regions that it connects to.https://ift.tt/2L7vkZK
Neurobeachin and the Kinesin KIF21B Are Critical for Endocytic Recycling of NMDA Receptors and Regulate Social Behavior
Publication date: 29 May 2018
Source:Cell Reports, Volume 23, Issue 9
Author(s): Kira V. Gromova, Mary Muhia, Nicola Rothammer, Christine E. Gee, Edda Thies, Irina Schaefer, Sabrina Kress, Manfred W. Kilimann, Olga Shevchuk, Thomas G. Oertner, Matthias Kneussel
Autism spectrum disorders (ASDs) are associated with mutations affecting synaptic components, including GluN2B-NMDA receptors (NMDARs) and neurobeachin (NBEA). NBEA participates in biosynthetic pathways to regulate synapse receptor targeting, synaptic function, cognition, and social behavior. However, the role of NBEA-mediated transport in specific trafficking routes is unclear. Here, we highlight an additional function for NBEA in the local delivery and surface re-insertion of synaptic receptors in mouse neurons. NBEA dynamically interacts with Rab4-positive recycling endosomes, transiently enters spines in an activity-dependent manner, and regulates GluN2B-NMDAR recycling. Furthermore, we show that the microtubule growth inhibitor kinesin KIF21B constrains NBEA dynamics and is present in the NBEA-recycling endosome-NMDAR complex. Notably, Kif21b knockout decreases NMDAR surface expression and alters social behavior in mice, consistent with reported social deficits in Nbea mutants. The influence of NBEA-KIF21B interactions on GluN2B-NMDAR local recycling may be relevant to mechanisms underlying ASD etiology.
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Gromova et al. functionally link the autism risk factor neurobeachin with KIF21B and endosomal pathways. Dynamic NBEA localizes at recycling endosomes and enters synapses in an activity-dependent manner. NBEA and KIF21B regulate NMDAR cell surface expression, and similar to NBEA mutants, KIF21B depletion induces social abnormalities linked to autism.https://ift.tt/2JdTQed
A Non-canonical Feedback Circuit for Rapid Interactions between Somatosensory Cortices
Publication date: 29 May 2018
Source:Cell Reports, Volume 23, Issue 9
Author(s): Genki Minamisawa, Sung Eun Kwon, Maxime Chevée, Solange P. Brown, Daniel H. O'Connor
Sensory perception depends on interactions among cortical areas. These interactions are mediated by canonical patterns of connectivity in which higher areas send feedback projections to lower areas via neurons in superficial and deep layers. Here, we probed the circuit basis of interactions among two areas critical for touch perception in mice, whisker primary (wS1) and secondary (wS2) somatosensory cortices. Neurons in layer 4 of wS2 (S2L4) formed a major feedback pathway to wS1. Feedback from wS2 to wS1 was organized somatotopically. Spikes evoked by whisker deflections occurred nearly as rapidly in wS2 as in wS1, including among putative S2L4 → S1 feedback neurons. Axons from S2L4 → S1 neurons sent stimulus orientation-specific activity to wS1. Optogenetic excitation of S2L4 neurons modulated activity across both wS2 and wS1, while inhibition of S2L4 reduced orientation tuning among wS1 neurons. Thus, a non-canonical feedback circuit, originating in layer 4 of S2, rapidly modulates early tactile processing.
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Minamisawa et al. uncover a rapid feedback pathway between secondary and primary somatosensory cortices that arises from layer 4 and acts to enhance sensory feature representation.https://ift.tt/2L336iL
Human Pluripotent Stem-Cell-Derived Cortical Neurons Integrate Functionally into the Lesioned Adult Murine Visual Cortex in an Area-Specific Way
Publication date: 29 May 2018
Source:Cell Reports, Volume 23, Issue 9
Author(s): Ira Espuny-Camacho, Kimmo A. Michelsen, Daniele Linaro, Angéline Bilheu, Sandra Acosta-Verdugo, Adèle Herpoel, Michele Giugliano, Afsaneh Gaillard, Pierre Vanderhaeghen
The transplantation of pluripotent stem-cell-derived neurons constitutes a promising avenue for the treatment of several brain diseases. However, their potential for the repair of the cerebral cortex remains unclear, given its complexity and neuronal diversity. Here, we show that human visual cortical cells differentiated from embryonic stem cells can be transplanted and can integrate successfully into the lesioned mouse adult visual cortex. The transplanted human neurons expressed the appropriate repertoire of markers of six cortical layers, projected axons to specific visual cortical targets, and were synaptically active within the adult brain. Moreover, transplant maturation and integration were much less efficient following transplantation into the lesioned motor cortex, as previously observed for transplanted mouse cortical neurons. These data constitute an important milestone for the potential use of human PSC-derived cortical cells for the reassembly of cortical circuits and emphasize the importance of cortical areal identity for successful transplantation.
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Espuny-Camacho et al. show that transplanted ESC-derived human cortical neurons integrate functionally into the lesioned adult mouse brain. Transplanted neurons display visual cortical identity and show specific restoration of damaged cortical pathways following transplantation into the visual but not the motor cortex, suggesting the importance of areal-identity match for successful cortical repair.https://ift.tt/2JiXZgY
Scholar : Human–Computer Interaction, Volume 33, Issue 4, 2018 is now available online on Taylor & Francis Online
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Who were the Nataruk people? Mandibular morphology among late Pleistocene and early Holocene fisher-forager populations of West Turkana (Kenya)
Source:Journal of Human Evolution
Author(s): Aurélien Mounier, Maria Correia, Frances Rivera, Federica Crivellaro, Ronika Power, Joe Jeffery, Alex Wilshaw, Robert A. Foley, Marta Mirazón Lahr
Africa is the birthplace of the species Homo sapiens, and Africans today are genetically more diverse than other populations of the world. However, the processes that underpinned the evolution of African populations remain largely obscure. Only a handful of late Pleistocene African fossils (∼50-12 Ka) are known, while the more numerous sites with human fossils of early Holocene age are patchily distributed. In particular, late Pleistocene and early Holocene human diversity in Eastern Africa remains little studied, precluding any analysis of the potential factors that shaped human diversity in the region, and more broadly throughout the continent. These periods include the Last Glacial Maximum (LGM), a moment of extreme aridity in Africa that caused the fragmentation of population ranges and localised extinctions, as well as the 'African Humid Period', a moment of abrupt climate change and enhanced connectivity throughout Africa. East Africa, with its range of environments, may have acted as a refugium during the LGM, and may have played a critical biogeographic role during the heterogene`ous environmental recovery that followed. This environmental context raises a number of questions about the relationships among early Holocene African populations, and about the role played by East Africa in shaping late hunter-gatherer biological diversity. Here, we describe eight mandibles from Nataruk, an early Holocene site (∼10 Ka) in West Turkana, offering the opportunity of exploring population diversity in Africa at the height of the 'African Humid Period'. We use 3D geometric morphometric techniques to analyze the phenotypic variation of a large mandibular sample. Our results show that (i) the Nataruk mandibles are most similar to other African hunter-fisher-gatherer populations, especially to the fossils from Lothagam, another West Turkana locality, and to other early Holocene fossils from the Central Rift Valley (Kenya); and (ii) a phylogenetic connection may have existed between these Eastern African populations and some Nile Valley and Maghrebian groups, who lived at a time when a Green Sahara may have allowed substantial contact, and potential gene flow, across a vast expanse of Northern and Eastern Africa.
https://ift.tt/2H1DOz2
Glycosylated superparamagnetic nanoparticle gradients for osteochondral tissue engineering
Publication date: September 2018
Source:Biomaterials, Volume 176
Author(s): Chunching Li, James PK. Armstrong, Isaac J. Pence, Worrapong Kit-Anan, Jennifer L. Puetzer, Sara Correia Carreira, Axel C. Moore, Molly M. Stevens
In developmental biology, gradients of bioactive signals direct the formation of structural transitions in tissue that are key to physiological function. Failure to reproduce these native features in an in vitro setting can severely limit the success of bioengineered tissue constructs. In this report, we introduce a facile and rapid platform that uses magnetic field alignment of glycosylated superparamagnetic iron oxide nanoparticles, pre-loaded with growth factors, to pattern biochemical gradients into a range of biomaterial systems. Gradients of bone morphogenetic protein 2 in agarose hydrogels were used to spatially direct the osteogenesis of human mesenchymal stem cells and generate robust osteochondral tissue constructs exhibiting a clear mineral transition from bone to cartilage. Interestingly, the smooth gradients in growth factor concentration gave rise to biologically-relevant, emergent structural features, including a tidemark transition demarcating mineralized and non-mineralized tissue and an osteochondral interface rich in hypertrophic chondrocytes. This platform technology offers great versatility and provides an exciting new opportunity for overcoming a range of interfacial tissue engineering challenges.
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https://ift.tt/2soXQ17
Glycogen-nucleic acid constructs for gene silencing in multicellular tumor spheroids
Publication date: September 2018
Source:Biomaterials, Volume 176
Author(s): Marcin Wojnilowicz, Quinn A. Besford, Yun-Long Wu, Xian Jun Loh, Julia A. Braunger, Agata Glab, Christina Cortez-Jugo, Frank Caruso, Francesca Cavalieri
The poor penetration of nanocarrier-siRNA constructs into tumor tissue is a major hurdle for the in vivo efficacy of siRNA therapeutics, where the ability of the constructs to permeate the 3D multicellular matrix is determined by their physicochemical properties. Herein, we optimized the use of soft glycogen nanoparticles for the engineering of glycogen-siRNA constructs that can efficiently penetrate multicellular tumor spheroids and exert a significant gene silencing effect. Glycogen nanoparticles from different bio-sources and with different structural features were investigated. We show that larger glycogen nanoparticles ranging from 50 to 80 nm are suboptimal systems for complexation of nucleic acids if fine control of the size of constructs is required. Our studies suggest that 20 nm glycogen nanoparticles are optimal for complexation and efficient delivery of siRNA. The chemical composition, surface charge, and size of glycogen-siRNA constructs were finely controlled to minimize interactions with serum proteins and allow penetration into 3D multicellular spheroids of human kidney epithelial cells and human prostate cancer cells. We introduced pH sensitive moieties within the construct to enhance early endosome escape and efficiently improve the silencing effect in vitro. Glycogen-siRNA constructs were found to mediate gene silencing in 3D multicellular spheroids causing ∼60% specific gene silencing. The optimized construct exhibited an in vivo circulation lifetime of 8 h in mice, with preferential accumulation in the liver. No accumulation in the kidney, lung, spleen, heart or brain, or signs of toxicity in mice were observed. Our results highlight the potential for screening siRNA nanocarriers in 3D cultured prostate tumor models, thereby improving the predictive therapeutic efficacy of glycogen-based platforms in human physiological conditions.
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https://ift.tt/2kBcHSN
A bioactive implant in situ and long-term releases combined drugs for treatment of osteoarticular tuberculosis
Publication date: September 2018
Source:Biomaterials, Volume 176
Author(s): Chao-Xi Zhou, Litao Li, Yi-Guang Ma, Bing-Nan Li, Guang Li, Zhihang Zhou, Feng Shi, Jie Weng, Cong Zhang, Fenghua Wang, Xu Cui, Lei Wang, Hao Wang
Anti-tuberculosis chemotherapy with a long duration and adequate dosing is the mainstay for treatment of osteoarticular tuberculosis (TB). However, it is difficult for systemic administration to reach adequate local drug concentrations and achieve effective treatment. Herein, a hydroxyapatite (HA) scaffold implant combined with a drug-releasing system was designed to achieve in situ and long-term anti-TB drug release and highly efficient therapeutic activity in vitro and in vivo. The clinical anti-TB drugs hydrophilic isoniazid (INH) and hydrophobic rifampicin (RFP) were molecularly dispersed into polyvinyl alcohol (PVA) through immersion-curing techniques and were steadily adhered onto the surfaces of HA scaffolds (HA-drug@PVA). The HA-drug@PVA scaffolds showed a long-term, sustained drug release profile and killed proliferating Mycobacteriumin vitro. In vivo experimental results revealed that the HA-drug@PVA scaffolds provided over 10- and 100-fold higher concentrations in muscles and bones, respectively, as well as a much lower concentration (<0.025) in blood. Furthermore, the HA-drug@PVA scaffold implanted in an osteoarticular TB rabbit model showed obvious bone regeneration and fusion due to the inhibition of TB-associated inflammatory changes. The excellent therapeutic effects indicate that in situ implant materials combined with a long-term drug release system are promising for the treatment of osteoarticular TB and other osteoarticular infections.
https://ift.tt/2H2kO3n
Neighboring cells override 3D hydrogel matrix cues to drive human MSC quiescence
Publication date: September 2018
Source:Biomaterials, Volume 176
Author(s): Silvia A. Ferreira, Peter A. Faull, Alexis J. Seymour, Tracy T.L. Yu, Sandra Loaiza, Holger W. Auner, Ambrosius P. Snijders, Eileen Gentleman
Physical properties of modifiable hydrogels can be tuned to direct stem cell differentiation in a role akin to that played by the extracellular matrix in native stem cell niches. However, stem cells do not respond to matrix cues in isolation, but rather integrate soluble and non-soluble signals to balance quiescence, self-renewal and differentiation. Here, we encapsulated single cell suspensions of human mesenchymal stem cells (hMSC) in hyaluronic acid-based hydrogels at high and low densities to unravel the contributions of matrix- and non-matrix-mediated cues in directing stem cell response. We show that in high-density (HD) cultures, hMSC do not rely on hydrogel cues to guide their fate. Instead, they take on characteristics of quiescent cells and secrete a glycoprotein-rich pericellular matrix (PCM) in response to signaling from neighboring cells. Preventing quiescence precluded the formation of a glycoprotein-rich PCM and forced HD cultures to differentiate in response to hydrogel composition. Our observations may have important implications for tissue engineering as neighboring cells may act counter to matrix cues provided by scaffolds. Moreover, as stem cells are most regenerative if activated from a quiescent state, our results suggest that ex vivo native-like niches that incorporate signaling from neighboring cells may enable the production of clinically relevant, highly regenerative cells.
https://ift.tt/2kC3J7L
The effect of size and polymer architecture of doxorubicin–poly(ethylene) glycol conjugate nanocarriers on breast duct retention, potency and toxicity
Publication date: 30 August 2018
Source:European Journal of Pharmaceutical Sciences, Volume 121
Author(s): Zichao Gu, Dayuan Gao, Firas Al-Zubaydi, Shike Li, Yashveer Singh, Kristia Rivera, Jennifer Holloway, Zoltan Szekely, Susan Love, Patrick J. Sinko
Although systemic administration of chemotherapeutic agents is routinely used for treating invasive breast cancer, the only therapeutic options for ductal carcinoma in situ (DCIS) are surgery and radiation. Treating DCIS by delivering drugs locally to the affected milk duct offers significant advantages over systemic administration, including reduced systemic and breast toxicities, as well as a greatly reduced need for surgery and radiation. In this study, mammary gland retention and toxicity of intraductally administered poly(ethylene) glycol-doxorubicin (PEG-DOX) polymeric conjugate nanocarriers of varying molecular sizes and architectures were investigated. Nanocarriers were formed by conjugating one or more copies of doxorubicin to PEG polymers, of varying molecular weights (5, 10, 20, and 40 kDa) and architectures (linear, four-arm and eight-arm). Cytotoxicity against MCF7 cells, a human breast cancer cell line, was assessed, and IC50 values were calculated. The nanocarriers were intraductally administered into the mammary glands of female retired breeder Sprague-Dawley rats. Whole body images were captured using in vivo optical imaging, and changes in ductal structure as well local inflammation were monitored. Fluorescence intensities were monitored, over time, to evaluate nanocarrier mammary gland retention half-lives (t1/2). The IC50 values of PEG-DOX nanocarriers against MCF7 cells were 40 kDa PEG-(DOX)4 (1.23 μM) < 5 kDa PEG-DOX (1.76 μM) < 40 kDa PEG-(DOX)8 (3.49 μM) < 10 kDa PEG-DOX (3.86 μM) < 20 kDa PEG-DOX (8.96 μM) < 40 kDa PEG-DOX (18.11 μM), whereas the IC50 of free DOX was only 0.14 μM. The t1/2 of linear 5, 20, and 40 kDa nanocarriers were 2.2 ± 0.3, 3.6 ± 0.6, and 13.1 ± 3.4 h, whereas the retention t1/2 of 4- and 8-arm 40 kDa nanocarriers were 14.9 ± 5.6 h and 11.9 ± 2.9 h, respectively. The retention t1/2 of free doxorubicin was 2.0 ± 0.4 h, which was significantly shorter than that of the linear and branched 40 kDa PEG-DOX nanocarriers. Increased molecular weight and decreased branching both demonstrated a strong correlation to enhanced mammary gland retention. Intraductally administered free doxorubicin resulted in ductal damage, severe inflammation and generation of atypical cell neoplasms, whereas PEG-DOX nanocarriers induced only minor and transient inflammation (i.e., damaged epithelial cells and detached cellular debris). The 40 kDa 4-arm PEG-DOX nanocarrier demonstrated the longest ductal retention half-life, the lowest IC50 (i.e., most potent), and minimal ductal damage and inflammation. The current results suggest that PEG-DOX nanocarriers with prolonged ductal retention may present the best option for intraductal treatment of DCIS, due to their low local toxicity and potential for sustained therapeutic effect.
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https://ift.tt/2IZwwOd
Effect of formulation and process variables on lipid based sustained release tablets via continuous twin screw granulation: A comparative study
Publication date: 30 August 2018
Source:European Journal of Pharmaceutical Sciences, Volume 121
Author(s): Venkata Raman Kallakunta, Roshan Tiwari, Sandeep Sarabu, Suresh Bandari, Michael A. Repka
The current study's aim is to prepare lipid based sustained release tablets via a twin-screw granulation technique and compare those dosage forms with conventional techniques, namely wet granulation and direct compression. The granules were successfully manufactured in a single-step, continuous twin-screw granulation process with a low proportion of binder (Klucel™ EF, HPC SSL) using Compritol® 888 ATO, Precirol® ATO 5 and Geleol™ as sustained release agents. The granules prepared showed good flow characteristics and compaction properties. DSC and XRD studies were conducted to characterize the granules prepared via a twin-screw granulation method and the results demonstrated the crystalline nature of lipids within the granules. FTIR data indicated that there were no interactions with the formulation components investigated. The formulations developed by all three methods were compressed into tablets with a mechanical strength of 14–16 KP. The tablets formulated were characterized for physicochemical properties, in vitro drug release studies, water uptake and erosion studies. These results showed that the drug was not completely released after 24 h for tablets developed by the wet granulation process using all three lipids. The tablets prepared by the direct compression method demonstrated a burst release within 8 to 10 h from Precirol ATO 5® and Geleol™ formulations compared to Compritol® 888 ATO. However, tablets prepared using twin-screw granulation exhibited sustained release of the drug over 24 h and the water uptake and erosion results were in accordance with dissolution data. Stability data for 45 days at accelerated conditions (40 °C/75% RH) showed similar release profiles with ƒ2 values above 50 for all of the twin screw granulation formulations, indicating the suitability of the process for formulating sustained release tablets. These findings of a single-step, continuous twin-screw granulation process are novel and demonstrate new opportunities for development of sustained release tablets.
Graphical abstract
https://ift.tt/2LKbBjY
Characterization of solution stress degradation products of aliskiren and prediction of their physicochemical and ADMET properties
Publication date: 30 August 2018
Source:European Journal of Pharmaceutical Sciences, Volume 121
Author(s): Bhoopendra Singh Kushwah, Jugal Gupta, Dilip Kumar Singh, Moolchand Kurmi, Archana Sahu, Saranjit Singh
Forced degradation studies on aliskiren were carried out according to ICH and WHO guidelines. Six degradation products were formed in total in the solution state. Their separation among themselves and from the drug was successfully achieved on a C-18 column utilizing acetonitrile and phosphate buffer (pH 3.0) in the mobile phase, which was run in a gradient mode. To characterize them, a complete mass fragmentation pathway of the drug was first established with the help of MS/TOF and MSn data. This was followed by LC-MS/TOF studies on the degradation products. Some of the degradation products were also isolated and subjected to 1D (1H, 13C and DEPT-135) and 2D (COSY, HSQC and HMBC) NMR studies for confirmation of their structures. An interesting observation was hydrolysis followed by cyclization in case of three degradation products. Also, acetonitrile was found to react with aliskiren, leading to formation of a pseudo degradation product. Additionally, comparative ADMET properties of the drug and degradation products were established using ADMET Predictor™.
Graphical abstract
https://ift.tt/2xrzF7V
Do new N-substituted 3-amino-4-phenyl-5-oxo-pyrazolinecarboxamide derivatives exhibit antitubercular potential?
Publication date: 30 August 2018
Source:European Journal of Pharmaceutical Sciences, Volume 121
Author(s): Marta Swatko-Ossor, Katarzyna Klimek, Anna Belcarz, Agnieszka Anna Kaczor, Monika Pitucha, Grazyna Ginalska
As a continuation of previous tests concerning new N-substituted 3-amino-4-phenyl-5-oxo-pyrazolinecarboxamide derivatives (R3, R4 and R8) of notable antibacterial activity, their antitubercular potential against different mycobacterial strains was estimated. Tests performed on virulent (reference and clinical) strains of Mycobacterium bovis and Mycobacterium tuberculosis revealed the highest therapeutic potential of R8 derivative: MIC within the range 7.8–15.6 μg/ml and TI (therapeutic index) within the range 46.5–93. Moreover, the synergistic interaction was found between R3, R4 and R8 derivatives and rifampicin, one of the front-line antitubercular drugs. R8/rifampicin mixture in concentrations effective in inhibition of Mycobacterium tuberculosis strain was non-cytotoxic against GMK cells, displaying cell viability approximately 88–97% when compared to control. Molecular docking study enabled to conclude that enoyl acyl carrier protein reductase (InhA) can be considered as a potential molecular target of tested pyrazole derivatives. Although further modifications of chemical structure of the investigated pyrazole derivatives is required, in order to increase their antitubercular efficacy and therapeutic safety, these compounds, in particular R8 compound, can be promising for the treatment of human and bovine tuberculosis.
Graphical abstract
https://ift.tt/2LFxHUC
How Areal Specification Shapes the Local and Interareal Circuits in a Macaque Model of Congenital Blindness
Abstract
There is little understanding of the structural underpinnings of the functional reorganization of the cortex in the congenitally blind human. Taking advantage of the extensive characterization of the macaque visual system, we examine in macaque the influence of congenital blindness resulting from the removal of the retina during in utero development. This effectively removes the normal influence of the thalamus on cortical development leading to an induced hybrid cortex (HC) combining features of primary visual and extrastriate cortex. Retrograde tracers injected in HC reveal a local, intrinsic connectivity characteristic of higher order areas and show that the HC receives a uniquely strong, purely feedforward projection from striate cortex but no ectopic inputs, except from subiculum, and entorhinal cortex. Statistical modeling of quantitative connectivity data shows that HC is relatively high in the cortical hierarchy and receives a reinforced input from ventral stream areas while the overall organization of the functional streams are conserved. The directed and weighted anophthalmic cortical graph from the present study can be used to construct dynamic and structural models. These findings show how the sensory periphery governs cortical phenotype and reveal the importance of developmental arealization for understanding the functional reorganization in congenital blindness.https://ift.tt/2so971K
Human Pregenual Anterior Cingulate Cortex: Structural, Functional, and Connectional Heterogeneity
Abstract
The human pregenual anterior cingulate cortex (pACC) encompasses 7 distinct cyto- and receptorarchitectonic areas. We lack a detailed understanding of the functions in which they are involved, and stereotaxic maps are not available. We present an integrated structural/functional map of pACC based on probabilistic cytoarchitectonic mapping and meta-analytic connectivity modeling and quantitative functional decoding. Due to the restricted spatial resolution of functional imaging data relative to the microstructural parcellation, areas p24a of the callosal sulcus and p24b on the surface of the cingulate gyrus were merged into a "gyral component" (p24ab) of area p24, and areas pv24c, pd24cv, and pd24cd, located within the cingulate sulcus were merged into a "sulcal component" (p24c) for meta-analytic analysis. Area p24ab was specifically associated with interoception, p24c with the inhibition of action, and p32, which was also activated by emotion induction tasks pertaining negatively valenced stimuli, with the ability to experience empathy. Thus, area p32 could be classified as cingulate association cortex playing a crucial role in the cognitive regulation of emotion. By this spectrum of functions, pACC is a structurally and functionally heterogeneous region, clearly differing from other parts of the anterior and middle cingulate cortex.https://ift.tt/2IWD6cf
A Longitudinal Study of Local Gyrification Index in Young Boys With Autism Spectrum Disorder
Abstract
Local gyrification index (LGI), a metric quantifying cortical folding, was evaluated in 105 boys with autism spectrum disorder (ASD) and 49 typically developing (TD) boys at 3 and 5 years-of-age. At 3 years-of-age, boys with ASD had reduced gyrification in the fusiform gyrus compared with TD boys. A longitudinal evaluation from 3 to 5 years revealed that while TD boys had stable/decreasing LGI, boys with ASD had increasing LGI in right inferior temporal gyrus, right inferior frontal gyrus, right inferior parietal lobule, and stable LGI in left lingual gyrus. LGI was also examined in a previously defined neurophenotype of boys with ASD and disproportionate megalencephaly. At 3 years-of-age, this subgroup exhibited increased LGI in right dorsomedial prefrontal cortex, cingulate cortex, and paracentral cortex, and left cingulate cortex and superior frontal gyrus relative to TD boys and increased LGI in right paracentral lobule and parahippocampal gyrus, and left precentral gyrus compared with boys with ASD and normal brain size. In summary, this study identified alterations in the pattern and development of LGI during early childhood in ASD. Distinct patterns of alterations in subgroups of boys with ASD suggests that multiple neurophenotypes exist and boys with ASD and disproportionate megalencephaly should be evaluated separately.https://ift.tt/2snsY13
Functional Fractionation of the Cingulo-opercular Network: Alerting Insula and Updating Cingulate
Abstract
The anterior insula (AI) and dorsal anterior cingulate cortex (dACC) are engaged in various cognitive and affective processes. An influential account posits that the AI and dACC's ubiquitous engagements reflect their role in the transient capture of attention by salient stimuli. Using fMRI here we tested this claim and functionally dissociated these regions. In the first experiment, we compared these regions' responses to emotion-laden and emotion-neutral salient "oddball" movie events. We found that while the AI only responded transiently to the onset and offset of neutral events, its response to affective events was sustained, challenging the transient attention capture account. By contrast, dACC remained transient regardless of event type. A second experiment distinguished the information encoded by these brain regions with the presentation of behaviorally salient events that require either maintaining the current task set or updating to a different one; the AI was found to signal the presence of the behaviorally relevant events, while the dACC was associated with switching of attention settings in response to the events. We conclude that AI and dACC are involved in signaling the presence of potentially or de facto behaviorally significant events and updating internal attention settings in response to these events, respectively.https://ift.tt/2IWD4RF
Evaluating the Prediction of Brain Maturity From Functional Connectivity After Motion Artifact Denoising
Abstract
The ability to make individual-level predictions from neuroanatomy has the potential to be particularly useful in child development. Previously, resting-state functional connectivity (RSFC) MRI has been used to successfully predict maturity and diagnosis of typically and atypically developing individuals. Unfortunately, submillimeter head motion in the scanner produces systematic, distance-dependent differences in RSFC and may contaminate, and potentially facilitate, these predictions. Here, we evaluated individual age prediction with RSFC after stringent motion denoising. Using multivariate machine learning, we found that 57% of the variance in individual RSFC after motion artifact denoising was explained by age, while 4% was explained by residual effects of head motion. When RSFC data were not adequately denoised, 50% of the variance was explained by motion. Reducing motion-related artifact also revealed that prediction did not depend upon characteristics of functional connections previously hypothesized to mediate development (e.g., connection distance). Instead, successful age prediction relied upon sampling functional connections across multiple functional systems with strong, reliable RSFC within an individual. Our results demonstrate that RSFC across the brain is sufficiently robust to make individual-level predictions of maturity in typical development, and hence, may have clinical utility for the diagnosis and prognosis of individuals with atypical developmental trajectories.https://ift.tt/2spAsRg
Cell-Specific Loss of SNAP25 from Cortical Projection Neurons Allows Normal Development but Causes Subsequent Neurodegeneration
Abstract
Synaptosomal associated protein 25 kDa (SNAP25) is an essential component of the SNARE complex regulating synaptic vesicle fusion. SNAP25 deficiency has been implicated in a variety of cognitive disorders. We ablated SNAP25 from selected neuronal populations by generating a transgenic mouse (B6-Snap25tm3mcw (Snap25-flox)) with LoxP sites flanking exon5a/5b. In the presence of Cre-recombinase, Snap25-flox is recombined to a truncated transcript. Evoked synaptic vesicle release is severely reduced in Snap25 conditional knockout (cKO) neurons as shown by live cell imaging of synaptic vesicle fusion and whole cell patch clamp recordings in cultured hippocampal neurons. We studied Snap25 cKO in subsets of cortical projection neurons in vivo (L5—Rbp4-Cre; L6—Ntsr1-Cre; L6b—Drd1a-Cre). cKO neurons develop normal axonal projections, but axons are not maintained appropriately, showing signs of swelling, fragmentation and eventually complete absence. Onset and progression of degeneration are dependent on the neuron type, with L5 cells showing the earliest and most severe axonal loss. Ultrastructural examination revealed that cKO neurites contain autophagosome/lysosome-like structures. Markers of inflammation such as Iba1 and lipofuscin are increased only in adult cKO cortex. Snap25 cKO can provide a model to study genetic interactions with environmental influences in several disorders.https://ift.tt/2IWD18r
Ingested d-Aspartate Facilitates the Functional Connectivity and Modifies Dendritic Spine Morphology in Rat Hippocampus
Abstract
d-Aspartate (d-Asp), the stereoisomer of l-aspartate, has a role in memory function in rodents. However, the mechanism of the effect of d-Asp has not been fully understood. In this study, we hypothesized that ingested d-Asp directly reaches the hippocampal tissues via the blood circulation and modifies the functional connectivity between hippocampus and other regions through spinogenesis in hippocampal CA1 neurons. The spinogenesis induced by the application of d-Asp was investigated using rat acute hippocampal slices. The density of CA1 spines was increased following 21 and 100 μM d-Asp application. The nongenomic spine increase pathway involved LIM kinase. In parallel to the acute slice study, brain activation was investigated in awake rats using functional MRI following the intragastric administration of 5 mM d-Asp. Furthermore, the concentration of d-Asp in the blood serum and hippocampus was significantly increased 15 min after intragastric administration of d-Asp. A functional connectivity by awake rat fMRI demonstrated increased slow-frequency synchronization in the hippocampus and other regions, including the somatosensory cortex, striatum, and the nucleus accumbens, 10–20 min after the start of d-Asp administration. These results suggest that ingested d-Asp reaches the brain through the blood circulation and modulates hippocampal neural networks through the modulation of spines.https://ift.tt/2H3SCNs
Role of autophagy in sevoflurane-induced neurotoxicity in neonatal rat hippocampal cells
Source:Brain Research Bulletin
Author(s): Lili Xu, Jianjun Shen, Lina Yu, Jianliang Sun, Patrick M. McQuillan, Zhiyong Hu, Min Yan
BackgroundSevoflurane has been extensively employed for induction and maintenance of general anesthesia. The effect of sevoflurane-induced apoptosis in developmental neurotoxicity has been appreciated for some time now, but the underlying mechanism of developmental neurotoxicity has not been established. The aim of our study is to evaluate the role of autophagy in sevoflurane-induced neurotoxicity through observing changes in the levels of autophagy in hippocampal neurons after exposure to sevoflurane.Methods/MaterialsPrimary cultured hippocampus neuronal cells were exposed to either 3.4% sevoflurane for 1 h (S1h group), 3 h (S3h group), 5 h (S5h group), or air (control group). We observed changes in autophagy proteins Beclin-1, LC3-II, p62, and Beclin-1mRNA, LC3mRNA and SQSTM1mRNA using Western Blot and QRT-PCR. We also determined the expression of LC3 using immunofluorescence staining, monitored the occurrence of autophagy using RFP-GFP-LC3 expression plasmid transient transfected hippocampal neuronal cells, detected the expression of LC3-II using siRNA Knockdown Beclin-1 and Atg5, and determined changes in cell apoptosis using Annexin V/PI staining and flow cytometry.ResultsAfter primary cultured hippocampal neuronal cells were exposed to 3.4% sevoflurane for 5 h, the expression level of Beclin-1 and LC3-II increased and p62 decreased in Western blotting. The expression of Beclin-1mRNA, LC3mRNA increased and SQSTM1mRNA decreased in QRT-PCR. LC3 increased with cell immunofluorescence staining, LC3 expression plasmid increased after mRFP-GFP-LC3 expression plasmid transient transfection and LC3-II decreased after transfection with siRNA Beclin-1 and siRNA Atg5. The apoptosis rate of primary cultured hippocampal neuronal cells increased in Annexin V/PI staining and flow cytometry analysis.ConclusionThis study demonstrates that sevoflurane may induce hippocampal neuron autophagy in primary cultured hippocampal neuronal cell and that Beclin-1 and Atg5 are involved in the process of sevoflurane-induced autophagy. Exposure of sevoflurane may not only induce autophagy of hippocampal neurons but also activate the apoptosis of hippocampal neurons. Autophagy may play an important role in sevoflurane-induced neurotoxicity in primary cultured hippocampal neuronal cells.
https://ift.tt/2xpoxZj
Detection of RO2 radicals and other products from cyclohexene ozonolysis with NH4+ and acetate chemical ionization mass spectrometry
Publication date: August 2018
Source:Atmospheric Environment, Volume 186
Author(s): Armin Hansel, Wiebke Scholz, Bernhard Mentler, Lukas Fischer, Torsten Berndt
The performance of the novel ammonium chemical ionization time of flight mass spectrometer (NH4+-CI3–TOF) utilizing NH4+ adduct ion chemistry to measure first generation oxidized product molecules (OMs) as well as highly oxidized organic molecules (HOMs) was investigated for the first time. The gas-phase ozonolysis of cyclohexene served as a first test system. Experiments have been carried out in the TROPOS free-jet flow system at close to atmospheric conditions. Product ion signals were simultaneously observed by the NH4+-CI3-TOF and the acetate chemical ionization atmospheric pressure interface time of flight mass spectrometer (acetate-CI-API-TOF). Both instruments are in remarkable good agreement within a factor of two for HOMs. For OMs not containing an OOH group the acetate technique can considerably underestimate OM concentrations by 2–3 orders of magnitude. First steps of cyclohexene ozonolysis generate ten different main products, detected with the ammonium-CI3-TOF, comprising 93% of observed OMs. The remaining 7% are distributed over several minor products that can be attributed to HOMs, predominately to highly oxidized RO2 radicals. Summing up, observed ammonium-CI3-TOF products yield 5.6 × 109 molecules cm−³ in excellent agreement with the amount of reacted cyclohexene of 4.5 × 109 molecules cm−³ for reactant concentrations of [O3] = 2.25 × 1012 molecules cm−³ and [cyclohexene] = 2.0 × 1012 molecules cm−³ and a reaction time of 7.9 s. NH4+ adduct ion chemistry is a promising CIMS technology for achieving carbon-closure due to the unique opportunity for complete detection of the whole product distribution including also peroxy radicals, and consequently, for a much better understanding of oxidation processes.
Graphical abstract
https://ift.tt/2xtLLh2
Alterations in apparent diffusion coefficient values of the kidney during the cardiac cycle: Evaluation with ECG-triggered diffusion-weighted MR imaging
Publication date: October 2018
Source:Magnetic Resonance Imaging, Volume 52
Author(s): Katsuyoshi Ito, Minoru Hayashida, Akihiko Kanki, Akira Yamamoto, Tsutomu Tamada, Koji Yoshida, Masahiro Tanabe
PurposeTo evaluate dynamic changes in apparent diffusion coefficient (ADC) values of the kidney at different time points during the cardiac cycle using electrocardiographic (ECG)-triggered diffusion-weighted MR imaging in normal subjects, and to elucidate the differences in ADC values between the right and left kidneys during a cardiac cycle.Materials and methodsThe study was approved by our institutional review board and informed consent was obtained from subjects. Twenty healthy volunteers who underwent ECG-triggered diffusion-weighted MR imaging of the kidney were included. The differences in ADC values of each kidney during different cardiac phases were compared. Additionally, the differences in maximum and minimum ADC values between the right and left kidney were also evaluated.ResultsADC values in the right and left kidney changed significantly during the cardiac cycle (P < 0.00001). Maximum and minimum ADC values during the cardiac cycle of the left kidney were significantly higher (P = 0.026 and 0.017, respectively) than those of the right kidney. Maximum ADC value in the left kidney had a significantly strong positive correlation with the left renal vein ratio (r = 0.83, P < 0.00001). In the right kidney, maximum ADC showed a weakly positive correlation with the diameter of the right renal vein (r = 0.45, P = 0.048).ConclusionADC values of the kidney obtained using ECG-triggered diffusion-weighted MR imaging change significantly during the cardiac cycle. Maximum (systolic) ADC during the cardiac cycle of the left kidney was significantly higher than that of the right kidney, probably due to the anatomical difference in the renal vein.
https://ift.tt/2IWAqvi
Application of cationized magnetoferritin for magnetic field-assisted delivery of short interfering RNA in vitro
Abstract
Cationized magnetoferritin is used for development of a simple, efficient, and fast delivery of short interference RNA into cells using combination of magnetophoresis for pre-concentration of siRNA-magnetoferritin complex on the surface of plated cells with subsequent application of nanosecond laser pulses producing stress waves in transfection chamber, which permeabilize cell membrane for the facilitated delivery of siRNA into the cell interior. As has been quantified using siRNA inducing cell death assay, by combination of these two physical factors we have obtained high efficiency for tested three different human carcinoma cells. Proposed method of gene silencing based on cationized magnetoferritin is a versatile and easily accessible platform with many possible applications in gene therapy.
https://ift.tt/2kBQx2J
A randomized controlled trial comparing helium-neon laser therapy and infrared laser therapy in patients with diabetic foot ulcer
Abstract
This study aimed to compare the effects of (HNLT) and (ILT) on diabetic foot ulcer. Sixty-five patients with diabetic foot ulcer (51 males and 14 females) aged 50–60 years. The participants were classified randomly to two groups, groups I and II. Group I received helium-neon laser therapy (HNLT) and conventional therapy with and group II received infrared laser therapy (ILT) and conventional therapy with for 8 weeks. Ulcer surface area was assessed using a sheet of cellophane paper at the beginning of the study, after 4 weeks, and after 8 weeks at the end of the study. At the beginning of the study, baseline clinical characteristics showed non-significant differences between the two groups (p > 0.05). After 4 weeks intervention, there were significant improvements in ulcer surface area in the two groups (p < 0.05). At the end of the study, after 8 weeks intervention, there were higher reduction in ulcer area in HNLT group more than ILT group, but this difference was statistically non- significant between the two groups (p > 0.05). The present study demonstrates that HNLT and ILT have similar effects to control diabetic foot ulcer in a short-term (up to 8 weeks). Eight weeks of laser therapy have beneficial impacts in diabetic foot ulcer.
https://ift.tt/2H26ckD
LA-ICP-MS U-Pb zircon geochronology data of the Early to Mid-Miocene syn-extensional massive silicic volcanism in the Pannonian Basin (East-Central Europe)
Source:Data in Brief, Volume 19
Author(s): Réka Lukács, Marcel Guillong, Jakub Sliwinski, István Dunkl, Olivier Bachmann, Szabolcs Harangi
This article provides LA-ICP-MS in-situ U-Pb zircon dates performed on single crystals from dacitic to rhyolitic ignimbrites of the Bükkalja Volcanic Field (Hungary, East-Central Europe) temporally covering the main period of the Neogene silicic volcanic activity in the Pannonian Basin. The data include drift-corrected, alpha dose-corrected, Th-disequilibrium-corrected, and filtered data for geochronological use. The data presented in this article are interpreted and discussed in the research article entitled "Early to Mid-Miocene syn-extensional massive silicic volcanism in the Pannonian Basin (East-Central Europe): eruption chronology, correlation potential and geodynamic implications" by Lukács et al. (2018) [1].
https://ift.tt/2xwFDVo
Metagenomic data on Anadara granosa associated bacterial communities using culture dependent approaches and 16S rRNA sequencing
Source:Data in Brief, Volume 19
Author(s): Kamarul Zaman Zarkasi, Mardani Abdul Halim, Teh Faridah Nazari, Feizal Daud
This article contains data on the bacterial communities and its diversity associated with Anadara granosa. The A. granosa samples were obtained from two major estuaries in Penang, Malaysia using a culture dependent and 16S rRNA Illumina sequencing approaches. A. granosa, a commercial blood cockles and popular seafoods, is fragile to the surrounding environments. Thus, our research focused to better understand the bacterial communities and it diversity in the A. granosa, as well as on the generation of a metagenomic library from A. granosa to further understanding on it diversity. The bacteria Vibrionaceae (34.1%) was predominant in the A. granosa from both environments followed by Enterobacteriaceae (33.3%) and Bacillaceae (16.75%). Vibrio sp., Klebsiella sp., and Bacillus subtilis were the most abundant species present. The data generated in this research is the first metagenomic examination of A. granosa and will provide as a baseline to understand the bacterial communities associated with A. granosa and its surrounding natural environments.
https://ift.tt/2sjhM6q
Dataset and analysis of editorial board composition of 165 Hindawi journals indexed and abstracted in PubMed based on affiliations
Source:Data in Brief, Volume 19
Author(s): Hilary I. Okagbue, Aderemi A. Atayero, Muminu O. Adamu, Pelumi E. Oguntunde, Abiodun A. Opanuga, Sheila A. Bishop
This article explores the editorial board composition (across the six continents) of Hindawi journals indexed in PubMed. The dataset used is the official affiliation of the board members available at the various webpages of Hindawi journal website and not the countries of origin of the editorial board members. Summary statistics were presented and the raw dataset was provided for further analysis by interested scholars. The percentage of the editorial board composition across the continents was presented, the dataset of Hindawi journals indexed in both Hindawi and Scopus were also presented and measured in terms of Citescore and percentiles. The dataset can be used in journal evaluation, auditing, bibliometric analysis, management of smart campus; ranking and the analysis can be extended to other journal indexations.
https://ift.tt/2IXm4GR
Microbes and Infection turns 20
Source:Microbes and Infection
Author(s): Sophia J. Häfner, David M. Ojcius
The journal Microbes and Infection is celebrating its vigintennial anniversary and has reunited for this occasion two dozen reviews illustrating achievements of the past as well as future challenges in the field of infectious diseases. From top-notch vaccine development strategies, to high-throughput powered analysis of complex host-pathogen interactions, to innovative therapeutic designs, this issue covers the entire spectrum of pathogens and areas of their confrontation with the host.
https://ift.tt/2spf9iv
Emerging Trends in Biomarker Discovery: Ease of Prognosis and Prediction in Cancer
Source:Seminars in Cancer Biology
Author(s): Anil K. Sharma
https://ift.tt/2IUgSYd
Implementing Precision Cancer Medicine in the Genomic Era
Source:Seminars in Cancer Biology
Author(s): Hui-Zi Chen, Russell Bonneville, Sameek Roychowdhury
The utilization of genomic data to direct treatment for cancer patients represents the central tenet in precision oncology, in which a patient is matched to a specific drug or therapy based on the genetic drivers detected in his or her tumor rather than the tumor's histologic classification. The expected but not always realized outcomes of molecularly matched therapies include increased response rates, more durable responses, deeper responses, and decreased number of therapy-related side effects. In this review, we will discuss different facets of utilizing genomic data to direct the increasingly complex care of cancer patients. We discuss the enlarging compendium of actionable genomic alterations and the development of novel molecular diagnostic assays for clinical application. Finally, we present an overview of the growing number of genomics-driven clinical trials and conclude with a discussion of future challenges in the implementation of precision oncology.
https://ift.tt/2H2WIWc
Τρίτη 29 Μαΐου 2018
Highly sensitive electrochemiluminescence immunosensor based on ABEI/H2O2 system with PFO dots as enhancer for detection of kidney injury molecule-1
Publication date: 30 September 2018
Source:Biosensors and Bioelectronics, Volume 116
Author(s): Huiyun Yang, Haijun Wang, Chengyi Xiong, Yaqin Chai, Ruo Yuan
In this work, poly[9,9-dioctylfluorenyl-2,7-diyl] (PFO) dots is discovered to display an appealing dual enhancement effect for the electrochemiluminescence (ECL) system of N-(aminobutyl)-N-(ethylisoluminol)/hydrogen peroxide (ABEI/H2O2), which not only enhances the ECL intensity of ABEI but also catalyzes decomposition of H2O2 to further amplify the ECL signal of ABEI. Owing to the electronegative property of PFO dots, electropositive ABEI-PEI as ECL reagent could be adsorbed on their surface and thus form a novel luminescence emitter (ABEI-PEI-PFO dots) with high ECL efficiency based on electrostatic attraction. Meanwhile, the water solubility and stability of this emitter are improved in virtue of the amine-rich property of ECL reagent (ABEI-PEI), which could increase the luminous efficiency of ECL reaction in aqueous solution. To increase the electron transfer efficiency, Pt nanoparticles (PtNPs) supported on reduced graphene oxide nanosheets (RGOs) via a onepot synthetic strategy are chosen as immobilizing platform for the ECL emitter (ABEI-PEI-PFO dots). Herein, the obtained dual-amplifed ABEI-PEI-PFO dots-RGOs/PtNPs complex is served as an ideal nanocarrier to capture detection antibody (Ab2). According to sandwiched immunoreaction, a highly sensitive ECL immunosensor is constructed for the detection of kidney injury molecule-1 (KIM-1) with a linearity from 50 fg mL−1 to 1 ng mL−1 and a detection limit of 16.7 fg mL−1. The developed ECL emitter combining dual amplified property for signal enhancement purpose would provide new thought and potential for sensitive bioanalysis and clinical application.
https://ift.tt/2sitXk1
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Publication date: September 2017 Source: Free Radical Biology and Medicine, Volume 110 Author(s): Lucía Fernández-del-Río, Anish Nag, Elen...
