Formation of brominated and chlorinated dioxins and its prevention during a pilot test of mechanochemical treatment of PCB and PBDE contaminated soil

Abstract

The destruction of persistent organic pollutants (POPs) is a large challenge in particular in developing and emerging economies. To date, a detailed assessment of non-combustion technologies with respect to formation of dioxins is lacking. In this study, an assessment of mechanochemical (MC) destruction technology for polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs) in contaminated soil remediation was conducted. Actual applied conditions of pilot-scale MC POPs destruction process indicates that the temperature increase inside the ball mills has the potential to form high levels of toxic polybrominated and polychlorinated dibenzo-p-dioxins and dibenzofurans (PXDD/Fs) when dioxin precursors are present. Therefore, the MC technology was modified for treatment of the PCB and PBDE containing soil including an efficient cooling system which could prevent the formation of PXDD/F during the destruction of PCBs and PBDEs. This is likely relevant for all contaminated soils containing relevant dioxin precursor and need to be considered for treatment of soils with MC and probably other non-combustion technologies.

Graphical abstract

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http://ift.tt/2td59HL

The antimicrobial peptide, human β-defensin-1, potentiates in vitro osteoclastogenesis via activation of the p44/42 mitogen-activated protein kinases

Publication date: Available online 11 July 2017
Source:Peptides
Author(s): Anupong Makeudom, Chayarop Supanchart, Pattanin Montreekachon, Sakornrat Khongkhunthian, Thanapat Sastraruji, Julaporn Krisanaprakornkit, Suttichai Krisanaprakornkit
Previous studies have demonstrated increased expression and raised levels of human β-defensin (hBD)-1 in gingival tissue and crevicular fluid of patients with chronic periodontitis and peri-implantitis, oral bone-resorbing diseases caused by enhanced osteoclastogenesis. Therefore, we aimed to investigate the effect of hBD-1 on osteoclast formation and function and to elucidate the involved signaling pathway in vitro. Human peripheral blood mononuclear cells (PBMCs) were first incubated with various doses of hBD-1 and cell viability was assayed by MTT. PBMCs were treated with macrophage-colony stimulating factor and receptor activator of nuclear factor kappa-B ligand (RANKL) in the presence or absence of non-toxic doses of hBD-1. In vitro osteoclastogenesis was analyzed by tartrate-resistant acid phosphatase (TRAP) staining, osteoclast-specific gene expression, and a resorption pit assay. Involvement of mitogen-activated protein kinases (MAPKs) was studied by immunoblotting and specific MAPK inhibitors. HBD-1 potentiated induction of in vitro osteoclastogenesis by RANKL, as shown by significantly increased number of TRAP-positive multinuclear cells and resorption areas on the dentin slices, and further up-regulated expressions of osteoclast-specific genes compared to those by RANKL treatment (p <0.05). However, hBD-1 treatment without RANKL failed to induce formation of osteoclast-like cells. A significant and further increase in transient phosphorylation of the p44/42 MAPKs was demonstrated by hBD-1 co-treatment (p<0.05), consistent with the inhibitory effect by pretreatment with U0126 or PD98059 on hBD-1-enhanced osteoclastogenesis. Collectively, hBD-1 potentiates the induction of in vitro osteoclastogenesis by RANKL via enhanced phosphorylation of the p44/42 MAPKs.



http://ift.tt/2vb4DLI

Short-term high fat diet increases the presence of astrocytes in the hypothalamus of C57BL6 mice without altering leptin sensitivity

Abstract

Diet-induced obesity is associated with hypothalamic inflammation and this phenomenon has been proposed to explain leptin resistance. In this study we used a short-term high fat diet (HFD) paradigm for 10days and analysed the cellular and physiological responses to leptin administration in C57BL6 mice. In parallel we performed GFAP immuno-staining to measure the presence of astrocytes in the arcuate nucleus of the hypothalamus (ARH) after 10 days and 20 weeks of HFD. Interestingly our results demonstrate that the presence of star-like astrocytes is significantly increased after 10 days of HFD but this is not associated with the absence of cellular and physiological response to leptin administration in mice. All together our study suggest that star-like astrocytes rapidly increase in numbers in the ARH in response to HFD but this phenomenon cannot explain the development of leptin resistance by itself.

This article is protected by copyright. All rights reserved.

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Enhancement of the LH surge by male olfactory signals is associated with AVPV Kiss1 cell activation in female rats

Abstract

Olfactory stimuli play an important role in regulating reproductive functions in mammals. The present study investigated the effect of olfactory signals derived from male rats on kisspeptin neuronal activity and luteinizing hormone (LH) secretion in female rats. Wistar-Imamichi strain female rats were ovariectomised (OVX) and implanted with preovulatory levels of oestradiol-17β (E2). OVX+E2 rats were sacrificed 1 hour after exposure to either: clean bedding, female-soiled bedding or male-soiled bedding. Dual staining for Kiss1 mRNA in situ hybridization and c-Fos immunohistochemistry revealed that the numbers of Kiss1-expressing cells and c-Fos-immunopositive Kiss1-expressing cells in the anteroventral periventricular nucleus (AVPV) were significantly higher in OVX+E2 rats exposed to male-soiled bedding than those of the other groups. No significant difference was found in the number of c-Fos-immunopositive Kiss1-expressing cells in the arcuate nucleus and c-Fos-immunopositive Gnrh1-expressing cells between the groups. The number of c-Fos-immunopositive cells was also significantly higher in the limbic system consisting of several nuclei, such as the bed nucleus of the stria terminalis, the cortical amygdala and the medial amygdala, in OVX+E2 rats exposed to male-soiled bedding than the other groups. OVX+E2 rats exposed to male-soiled bedding showed apparent LH surges, and the peak of the LH surge and area under the curve of LH concentrations in the OVX+E2 group were significantly higher than those of the other two groups. These results suggest that olfactory signals derived from male rats activate AVPV kisspeptin neurones, likely via the limbic system, resulting in enhancement of the peak of the LH surge in female rats. Taken together, the present study suggests that AVPV kisspeptin neurones are a target of olfactory signals to modulate LH release in female rats.

This article is protected by copyright. All rights reserved.

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Long Term Health Outcomes Of Adults With McCune Albright Syndrome

Summary

Context

McCune Albright Syndrome (MAS) is associated with numerous health problems. Comprehensive long term health problems of adults with MAS are less well defined in the literature.

Objective

Our objective is to report comprehensive health outcomes of adults with MAS (> 18 years).

Design

Retrospective case note review of 16 adults with MAS managed by one clinician. Results expressed as median (range)

Results

The study included 16 adults (7 males) with MAS. Median current age is 29 years (20, 46). Twelve out of 16 had craniofacial fibrous dysplasia with 5/12 (42%) with progressive facial asymmetry. Growth hormone excess was observed in 6/16 (38%) and T3-toxicosis in 5/16 (31.3%). Six of the 7 men (86%) had abnormalities on testicular ultrasound with one man exhibiting marked atrophy of germ and Sertoli cells with reduction in spermatogenesis. Six of the 16 (38%) had cardio-respiratory complications including high output cardiac failure (n,3) hypertension (n,2) and one man with congestive cardiac failure and restrictive lung disease. Six of 8 (66%) who had screening endoscopy for upper gastrointestinal polyps show increasing numbers of polyps, with benign histology to date. One woman with a previous history of early puberty presented with early aggressive breast carcinoma, which was positive for GNAS.Two patients had GNAS positive muscle myomas. Platelet dysfunction with bleeding tendency responsiveto platelet transfusion during surgery was seen in four.

Conclusion

A range of complex health problems is encountered in adults with MAS. These have important implications for transition of patients with MAS and adult care. Long term cancer risk is currently unknown but requires careful follow-up.

This article is protected by copyright. All rights reserved.

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Bacterial adhesins, the pathogenic weapons to trick host defense arsenal

Publication date: September 2017
Source:Biomedicine & Pharmacotherapy, Volume 93
Author(s): Seema Patel, Nithya Mathivanan, Arun Goyal
Adhesins are bacterial proteins with host cell adhesive properties. These proteins occur in diverse architectures, ranging from capsules, vesicles, pili, fimbri, to enzymes. These proteins interact with host cell surface receptor proteins, for cross-membrane- trafficking and the invasion of host cells. Thus, they lead to inflammation and pathogenesis, of chronic as well as acute type. Inhibition of adhesin-mediated immune activation can be possible by mannose supplementation, assembly disruption, and host receptor blockage, among other approaches. Almost all bacterial pathogenesis is mediated by adhesins, yet when elaborated by normal flora, they might also be important for the exclusion of pathogens. For their ubiquity in bacterial pathogenesis, these lectin-like virulence proteins have been drug targets and vaccine components. Adhesins hold the clue for bacterial persistence and drug resistance as well, which can be detected through the annotation of hypothetical genes, the coding genes with sparsely-characterized functionality. This work takes a unique perspective on adhesins for better management of infectious diseases.



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The changing epidemiology of invasive Haemophilus influenzae disease: Emergence and global presence of serotype a strains that may require a new vaccine for control

Publication date: 24 July 2017
Source:Vaccine, Volume 35, Issue 33
Author(s): Raymond S.W. Tsang, Marina Ulanova
BackgroundMore than two decades after the implementation of the Hib conjugate vaccine in North America, Haemophilus influenzae serotype a (Hia) has emerged as a significant cause of invasive disease in Indigenous communities. However, little is known about the global presence of this pathogen.MethodsWe interrogated the H. influenzae Multi-Locus Sequence Typing (MLST) website (http://ift.tt/2tA4PGX) by selecting for serotype a records. We also updated our previous literature review on this subject matter.ResultsHia has been reported from at least 35 countries on six major continents. However, most Hia diseases were associated with Indigenous communities. Clonal analysis identified two clonal populations with one typified as ST-23 responsible for most invasive disease in North America and being the predominant clone described on the H. influenzae MLST website. Incidence of invasive Hia disease in Indigenous communities in North America are similar to the rates of Hib disease reported prior to the Hib conjugate vaccine era. Hia causes severe clinical diseases, such as meningitis, septicaemia, pneumonia, and septic arthritis with case-fatality rates between 5.6% and 33% depending on the age of the patient and the genetic makeup of the Hia strain.ConclusionAlthough invasive Hia disease can be found globally, the current epidemiological data suggest that this infection predominantly affects Indigenous communities in North America. The clinical disease of Hia and the clonal nature of the bacteria resemble that of Hib. The high incidence of invasive Hia disease in Indigenous communities, along with potential fatality and severe sequelae causing long-term disability in survivors, may support the development of a new Hia conjugate vaccine for protection against this infection similar in design to the one introduced in the 1990s to control invasive Hib disease.



http://ift.tt/2uh7whC

Increasing seasonal influenza vaccination among high risk groups in China: Do community healthcare workers have a role to play?

Publication date: 24 July 2017
Source:Vaccine, Volume 35, Issue 33
Author(s): Ying Song, Tao Zhang, Liling Chen, Bo Yi, Xiaoning Hao, Suizan Zhou, Ran Zhang, Carolyn Greene
BackgroundSeasonal influenza vaccine uptake in China is low. This study aims to assess the role of community healthcare workers (HCWs) in increasing vaccination among high risk groups in China.MethodsWe analyzed data from four knowledge, attitude and practice (KAP) studies on seasonal influenza vaccination in China targeting guardians of young children, pregnant women, adults aged ≥60years, and HCWs from 2012 to 2014.ResultsThirty-one percent of pregnant women and 78% adults aged ≥60years reported willingness to follow HCWs' recommendations for influenza vaccination. Guardians were more likely to vaccinate their children if they received HCWs' recommendations (35% vs. 17%, p<0.001). Community HCWs were more likely to recommend seasonal influenza vaccination than hospital HCWs (58% vs. 28%, p<0.001).ConclusionStudy results suggest the value of incorporating community HCWs' recommendation for seasonal influenza vaccination into existing primary public health programs to increase vaccination coverage among high risk groups in China.



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Editorial Board/Aims and Scope

Publication date: 24 July 2017
Source:Vaccine, Volume 35, Issue 33





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Immunization of Zika virus envelope protein domain III induces specific and neutralizing immune responses against Zika virus

Publication date: 24 July 2017
Source:Vaccine, Volume 35, Issue 33
Author(s): Ming Yang, Matthew Dent, Huafang Lai, Haiyan Sun, Qiang Chen
In this study, we described the generation and immunogenicity of the Zika Virus (ZIKV) envelope protein (E) domain III (DIII) as a protein subunit vaccine candidate. ZIKV EDIII (zEDIII) was rapidly produced in E. coli in inclusion bodies. ZIKV EDIII was solubilized, refolded and purified to >95% homogeneity with a one-step Ni²⁺ affinity chromatography process. Further analysis revealed that zEDIII was refolded properly and demonstrated specific binding to an anti-zEDIII monoclonal antibody that recognizes a zEDIII conformational epitope. Subcutaneous immunization of mice with 25 and 50μg of zEDIII was performed over a period of 11weeks. zEDIII evoked ZIKV-specific and neutralizing antibody response with titers that exceed the threshold that correlates with protective immunity against ZIKV. The antigen-specific IgG isotypes were predominantly IgG1 and splenocyte cultures from immunized mice secreted IFN-gamma, IL-4 and IL-6. Notably, zEDIII-elicited antibodies did not enhance the infection of dengue virus in Fc gamma receptor (FcγR)-expressing cells. This study provided a proof of principle for the further development of recombinant protein-based subunit vaccines against ZIKV.



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Changes in pathogens and pneumococcal serotypes causing community-acquired pneumonia in The Netherlands

Publication date: 24 July 2017
Source:Vaccine, Volume 35, Issue 33
Author(s): Stefan M.T. Vestjens, Gertjan H.J. Wagenvoort, Jan C. Grutters, Bob Meek, Arnoud F. Aldenkamp, Bart J.M. Vlaminckx, Willem-Jan W. Bos, Ger T. Rijkers, Ewoudt M.W. van de Garde
BackgroundIn 2006 a 7-valent pneumococcal conjugate vaccine (PCV7) was introduced in the immunisation programme for infants in The Netherlands and replaced by PCV10 in 2011. Limited data exist about the impact of PCV on the aetiology of CAP as a whole. The aim of the present study is to describe the overall changes in microbial aetiology, pneumococcal burden (including non-bacteraemic pneumococcal pneumonia) and its serotypes in adult community-acquired pneumonia (CAP) after the introduction of these PCVs.MethodsHospitalised adult CAP patients who participated in three consecutive trials were studied (2004–2006 (n=201), 2007–2009 (n=304) and 2012–2016 (n=300) and considered as pre-PCV7, PCV7 and PCV10 period). Extensive conventional microbiological testing was applied for all patients. In addition, patients with a serotype-specific pneumococcal antibody response were diagnosed with pneumococcal CAP. Changes in proportions of causative pathogens and distributions of pneumococcal serotypes were calculated.ResultsThe proportion of pneumococcal CAP decreased from 37% (n=74/201) to 26% (n=77/300) comparing the pre-PCV7 period with the PCV10 period (p=0.01). For other pathogens, including Legionella spp., Mycoplasma pneumoniae, S. aureus, H. influenzae, and respiratory viruses, no sustained shifts were observed in their relative contribution to the aetiology of CAP. Within the pneumococcal CAP patients, we observed a decrease in PCV7 and an increase in non-PCV10 serotype disease. PCV10-extra type disease did not decrease significantly comparing the PCV10 period with the pre-PCV7 and PCV7 period, respectively. Notably, PCV7 type disease decreased both in bacteraemic and non-bacteraemic patients.ConclusionsOur findings confirm that PCV introduction in infants impact the microbial aetiology of adult CAP and suggest herd effects in adults with CAP after introduction of PCVs in children.



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Induction, treatment and prevention of eczema vaccinatum in atopic dermatitis mouse models

Publication date: 24 July 2017
Source:Vaccine, Volume 35, Issue 33
Author(s): Hagit Achdout, Shlomo Lustig, Tomer Israely, Noam Erez, Boaz Politi, Hadas Tamir, Ofir Israeli, Trevor Waner, Sharon Melamed, Nir Paran
Eczema vaccinatum is a severe and occasionally lethal complication of smallpox vaccine, characterized by systemic viral dissemination, distant from the initial inoculation site of the vaccine. A major risk factor for eczema vaccinatum is a background of atopic dermatitis, a chronic, common allergic, relapsing disorder, manifested by dry and inflamed skin, itchy rash, Th2 biased immune response and hypersensitivity to various antigens. Unlike the severe manifestations of eczema vaccinatum in humans, current models present only mild symptoms that limits examination of potential therapeutics for eczema vaccinatum.The atopic dermatitis and eczema vaccinatum models we present here, are the first to simulate the severity of the diseases in humans. Indeed, dermatitic mice display persistent severe dermatitis, characterized by dry and inflamed skin with barrier dysfunction, epidermal hyperplasia and significant elevation of serum IgE. By exposing atopic dermatitis mice to ectromelia virus, we generated eczema vaccinatum that mimic the human disease better than known eczema vaccinatum models. Similarly to humans, eczematous mice displayed enlarged and disseminated skin lesions, which correlated with elevated viral load. Cidofovir and antiviral antibodies conferred protection even when treatment started at a late eczematous stage. Moreover, we are the first to demonstrate that despite a severe background of atopic dermatitis, modified vaccinia Ankara virus (MVA) vaccination protects against lethal ectromelia virus exposure. We finally show that protection by MVA vaccination is dependent on CD4⁺ T cells and is associated with significant activation of CD8⁺ cytotoxic T cells and induction of humoral immunity.



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Protective efficacy of multivalent replication-abortive vaccine strains in horses against African horse sickness virus challenge

Publication date: 24 July 2017
Source:Vaccine, Volume 35, Issue 33
Author(s): Valeria Lulla, Andres Losada, Sylvie Lecollinet, Adeline Kerviel, Thomas Lilin, Corinne Sailleau, Cecile Beck, Stephan Zientara, Polly Roy
African horse sickness virus (AHSV) is an orbivirus, a member of the Reoviridae family. Nine different serotypes have been described so far. AHSV is vectored by Culicoides spp. to equids, causing high mortality, particularly in horses, with considerable economic impacts. For development of a safe attenuated vaccine, we previously established an efficient reverse genetics (RG) system to generate Entry Competent Replication-Abortive (ECRA) virus strains, for all nine serotypes and demonstrated the vaccine potential of these strains in type I interferon receptor (IFNAR)-knockout mice. Here, we evaluated the protective efficacies of these ECRA viruses in AHSV natural hosts. One monoserotype (ECRA.A4) vaccine and one multivalent cocktail (ECRA.A1/4/6/8) vaccine were tested in ponies and subsequently challenged with a virulent AHSV4. In contrast to control animals, all vaccinated ponies were protected and did not develop severe clinical symptoms of AHS. Furthermore, the multivalent cocktail vaccinated ponies produced neutralizing antibodies against all serotypes present in the cocktail, and a foal born during the trial was healthy and had no viremia. These results validate the suitability of these ECRA strains as a new generation of vaccines for AHSV.



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A short hairpin RNA-based adjuvant targeting NF-κB repressor IκBα promotes migration of dermal dendritic cells to draining lymph nodes and antitumor CTL responses induced by DNA vaccination

Publication date: 24 July 2017
Source:Vaccine, Volume 35, Issue 33
Author(s): Felipe Gálvez-Cancino, Jonathan Roco, Nicole Rojas-Colonelli, Camila Flores, Paola Murgas, Sebastián Cruz-Gómez, César Oyarce, Manuel Varas-Godoy, Daniela Sauma, Alvaro Lladser
DNA vaccination is an attractive approach to elicit tumor-specific cytotoxic CD8⁺ T lymphocytes (CTL), which can mediate protective immunity against tumors. To initiate CTL responses, antigen-encoding plasmids employed for DNA vaccination need to activate dendritic cells (DC) through the stimulation of DNA-sensing innate immune receptors that converge in the activation of the master transcription factor NF-κB. To this end, NF-κB repressor IκBα needs to be degraded, allowing NF-κB to translocate to the nucleus and transcribe proinflammatory target genes, as well as its repressor IκBα. Therefore, NF-κB activation is self-limited by de novo synthesis of IκBa, which sequesters NF-κB in the cytosol. Hence, we tested whether co-delivering a shRNA-based adjuvant able to silence IκBα expression would further promote DNA-induced NFκB activation, DC activation and tumor-protective CTL responses induced by DNA vaccination in a preclinical model. First, an IκBα-targeting shRNA plasmid (shIκBα) was shown to reduce IκBα expression and promote NFκB-driven transcription in vitro, as well as up-regulate inflammatory target genes in vivo. Then, we showed that intradermal DNA electroporation induced the migration of skin migratory dendritic cells to draining lymph nodes and maturation of dermal dendritic cells (dDC). Interestingly, shIκBα further promoted the migration of mature skin migratory dendritic cells, in particular dDC, which are specialized in antigen cross-presentation and activation of CD8⁺ T cells. Consistently, mice vaccinated with a plasmid encoding the melanoma-associated antigen tyrosinase-related protein 2 (TRP2) in combination with shIκBα enhanced TRP2-specific CTL responses and reduced the number of lung melanoma foci in mice challenged with intravenous injection of B16F10 cells. Moreover, therapeutic vaccination with pTRP2 and shIκBα delayed the growth of B16F10 melanoma subcutaneous tumors. Our data suggest that adjuvants promoting NF-κB activation represent an attractive strategy to boost DC activation and promote the generation of tumor-protective CTL responses elicited by DNA vaccines.



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Aims and Scope and Editorial Board

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Macrophage selective photodynamic therapy by meta-tetra(hydroxyphenyl)chlorin loaded polymeric micelles: A possible treatment for cardiovascular diseases

Publication date: 30 September 2017
Source:European Journal of Pharmaceutical Sciences, Volume 107
Author(s): Jos W.H. Wennink, Yanna Liu, Petri I. Mäkinen, Francesca Setaro, Andrès de la Escosura, Meriem Bourajjaj, Jari P. Lappalainen, Lari P. Holappa, Joep B. van den Dikkenberg, Mina al Fartousi, Panagiotis N. Trohopoulos, Seppo Ylä-Herttuala, Tomas Torres, Wim E. Hennink, Cornelus F. van Nostrum
Selective elimination of macrophages by photodynamic therapy (PDT) is a new and promising therapeutic modality for the reduction of atherosclerotic plaques. m-Tetra(hydroxyphenyl)chlorin (mTHPC, or Temoporfin) may be suitable as photosensitizer for this application, as it is currently used in the clinic for cancer PDT. In the present study, mTHPC was encapsulated in polymeric micelles based on benzyl-poly(ε-caprolactone)-b-methoxy poly(ethylene glycol) (Ben-PCL-mPEG) using a film hydration method, with loading capacity of 17%. Because of higher lipase activity in RAW264.7 macrophages than in C166 endothelial cells, the former cells degraded the polymers faster, resulting in faster photosensitizer release and higher in vitro photocytotoxicity of mTHPC-loaded micelles in those macrophages. However, we observed release of mTHPC from the micelles in 30min in blood plasma in vitro which explains the observed similar in vivo pharmacokinetics of the mTHPC micellar formulation and free mTHPC. Therefore, we could not translate the beneficial macrophage selectivity from in vitro to in vivo. Nevertheless, we observed accumulation of mTHPC in atherosclerotic lesions of mice aorta's which is probably the result of binding to lipoproteins upon release from the micelles. Therefore, future experiments will be dedicated to increase the stability and thus allow accumulation of intact mTHPC-loaded Ben-PCL-mPEG micelles to macrophages of atherosclerotic lesions.

Graphical abstract

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Selectively Impaired Endocannabinoid-Dependent Long-Term Depression in the Lateral Habenula in an Animal Model of Depression

Publication date: 11 July 2017
Source:Cell Reports, Volume 20, Issue 2
Author(s): Hoyong Park, Jeehae Rhee, Seongju Lee, ChiHye Chung
Abnormal potentiation in the lateral habenula (LHb) has been suggested to mediate depression-like behaviors. However, the underlying mechanisms of the synaptic efficacy regulation of LHb synapses and the potential for their modulation are only poorly understood. Here, we report that long-term synaptic depression (LTD) occurs in the LHb upon both low-frequency stimulation (LFS) and moderate-frequency stimulation (MFS). LFS-induced LTD (LFS-LTD) is accompanied by a reduction in presynaptic release probability, which is endocannabinoid (eCB) signaling dependent. Surprisingly, exposure to an acute stressor completely masks the induction of LFS-LTD in the LHb while leaving the MFS-induced LTD intact. Pharmacological activation of cannabinoid receptor 1 (CB1R) or blockade of αCaMKII successfully restored LTD in the LHb in an animal model of depression. Thus, our findings reveal a form of synaptic strength regulation and a stress-induced shift of synaptic plasticity in the LHb.

Graphical abstract

Teaser

Park et al. find that long-term synaptic depression occurs in the lateral habenula after low- or moderate-frequency stimulation and DHPG application. In a depression model, CB1R-dependent LFS- and DHPG-LTD, but not MFS-LTD, were completely abolished. Stress exposure impairs CB1R signaling, leading to the abnormal activation of CaMKII and PKA.


http://ift.tt/2uPG5Zn

Inhibition of RIF1 by SCAI Allows BRCA1-Mediated Repair

Publication date: 11 July 2017
Source:Cell Reports, Volume 20, Issue 2
Author(s): Shin-Ya Isobe, Koji Nagao, Naohito Nozaki, Hiroshi Kimura, Chikashi Obuse
DNA double-strand breaks (DSBs) are repaired by either the homology-directed repair (HDR) or the non-homologous end-joining (NHEJ) pathway. RIF1 (RAP1-interacting factor homolog) was recently shown to stimulate NHEJ through an interaction with 53BP1 (p53-binding protein 1) phosphorylated at S/TQ sites, but the molecular mechanism underlying pathway choice remains unclear. Here, we show that SCAI (suppressor of cancer cell invasion) binds to 53BP1 phosphorylated at S/TP sites and facilitates HDR. Upon DNA damage, RIF1 immediately accumulates at damage sites and then gradually dissociates from 53BP1 and is subsequently replaced with SCAI. Depletion of SCAI reduces both the accumulation of HDR factors, including BRCA1 (breast cancer susceptibility gene 1), at damage sites and the efficiency of HDR, as detected by a reporter assay system. These data suggest that SCAI inhibits RIF1 function to allow BRCA1-mediated repair, which possibly includes alt-NHEJ and resection-dependent NHEJ in G1, as well as HDR in S/G2.

Graphical abstract

Teaser

Following DNA double-strand breakage, 53BP1 accumulates at damaged chromatin and, together with RIF1, facilitates non-homologous end joining (NHEJ). Here, Isobe et al. find that SCAI binds to 53BP1, thus inhibiting RIF1 function. This facilitates BRCA1-mediated repair, such as homology-directed repair in S/G2, and alternative-NHEJ or resection-mediated NHEJ in G1.


http://ift.tt/2uPOb46

Parvalbumin-Expressing GABAergic Neurons in Primary Motor Cortex Signal Reaching

Publication date: 11 July 2017
Source:Cell Reports, Volume 20, Issue 2
Author(s): Luc Estebanez, Diana Hoffmann, Birgit C. Voigt, James F.A. Poulet
The control of targeted reaching is thought to be shaped by distinct subtypes of local GABAergic inhibitory neurons in primary forelimb motor cortex (M1). However, little is known about their action potential firing dynamics during reaching. To address this, we recorded the activity of parvalbumin-expressing (PV+) GABAergic neurons identified from a larger population of fast-spiking units and putative excitatory regular-spiking units in layer 5 of the mouse forelimb M1 during an M1-dependent, sensory-triggered reaching task. PV+ neurons showed short latency responses to the acoustic cue and vibrotactile trigger stimulus and an increase in firing at reaching onset that scaled with the amplitude of reaching. Unexpectedly, PV+ neurons fired before regular-spiking units at reach onset and showed high overall firing rates during both sensory-triggered and spontaneous reaches. Our data suggest that increasing M1 PV+ neuron firing rates may play a role in the initiation of voluntary reaching.

Graphical abstract

Teaser

Estebanez et al. use optogenetics and electrophysiology to study the activity of parvalbumin-expressing GABAergic neurons in the forelimb primary motor cortex during a reaching task in head-fixed mice. They report that PV+ neurons show robust increases in firing at reaching onset that occur before the activity of putative pyramidal neurons.


http://ift.tt/2uPQTqv

Deletion of Type 2 Metabotropic Glutamate Receptor Decreases Sensitivity to Cocaine Reward in Rats

Publication date: 11 July 2017
Source:Cell Reports, Volume 20, Issue 2
Author(s): Hong-Ju Yang, Hai-Ying Zhang, Guo-Hua Bi, Yi He, Jun-Tao Gao, Zheng-Xiong Xi
Cocaine users show reduced expression of the metabotropic glutamate receptor (mGluR2), but it is not clear whether this is a predisposing trait for addiction or a consequence of drug exposure. In this study, we found that a nonsense mutation at the mGluR2 gene decreased mGluR2 expression and altered the seeking and taking of cocaine. mGluR2 mutant rats show reduced sensitivity to cocaine reward, requiring more cocaine to reach satiation when it was freely available and ceasing their drug-seeking behavior sooner than controls when the response requirement was increased. mGluR2 mutant rats also show a lower propensity to relapse after a period of cocaine abstinence, an effect associated with reduced cocaine-induced dopamine and glutamate overflow in the nucleus accumbens. These findings suggest that mGluR2 polymorphisms or reduced availability of mGluR2 might be risk factors for the initial development of cocaine use but could actually protect against addiction by reducing sensitivity to cocaine reward.

Graphical abstract

Teaser

The etiology and pathophysiology of drug addiction remain poorly understood. Yang et al. show that genetic deletion of mGluR2, a presynaptic glutamate autoreceptor, decreases sensitivity to cocaine reward that causes a compensatory increase in cocaine taking and a decrease in relapse to cocaine-seeking behavior in rats.


http://ift.tt/2uPz2jd

Alternative Splicing of P/Q-Type Ca2+ Channels Shapes Presynaptic Plasticity

Publication date: 11 July 2017
Source:Cell Reports, Volume 20, Issue 2
Author(s): Agnes Thalhammer, Andrea Contestabile, Yaroslav S. Ermolyuk, Teclise Ng, Kirill E. Volynski, Tuck Wah Soong, Yukiko Goda, Lorenzo A. Cingolani
Alternative splicing of pre-mRNAs is prominent in the mammalian brain, where it is thought to expand proteome diversity. For example, alternative splicing of voltage-gated Ca²⁺ channel (VGCC) α1 subunits can generate thousands of isoforms with differential properties and expression patterns. However, the impact of this molecular diversity on brain function, particularly on synaptic transmission, which crucially depends on VGCCs, is unclear. Here, we investigate how two major splice isoforms of P/Q-type VGCCs (Cav2.1[EFa/b]) regulate presynaptic plasticity in hippocampal neurons. We find that the efficacy of P/Q-type VGCC isoforms in supporting synaptic transmission is markedly different, with Cav2.1[EFa] promoting synaptic depression and Cav2.1[EFb] synaptic facilitation. Following a reduction in network activity, hippocampal neurons upregulate selectively Cav2.1[EFa], the isoform exhibiting the higher synaptic efficacy, thus effectively supporting presynaptic homeostatic plasticity. Therefore, the balance between VGCC splice variants at the synapse is a key factor in controlling neurotransmitter release and presynaptic plasticity.

Graphical abstract

Teaser

Alternative splicing of Ca²⁺ channels has been hypothesized to contribute to functional diversity in the brain. Thalhammer et al. find that two splice isoforms of P/Q-type Ca²⁺ channels differentially regulate presynaptic plasticity. These results provide evidence that the balance between Ca²⁺ channel isoforms controls synaptic efficacy.


http://ift.tt/2uPZeKK

Feedback Inhibition of the Rag GTPase GAP Complex Lst4-Lst7 Safeguards TORC1 from Hyperactivation by Amino Acid Signals

Publication date: 11 July 2017
Source:Cell Reports, Volume 20, Issue 2
Author(s): Marie-Pierre Péli-Gulli, Serena Raucci, Zehan Hu, Jörn Dengjel, Claudio De Virgilio
Amino acids stimulate the eukaryotic target of rapamycin complex 1 (TORC1), and hence growth, through the Rag GTPases and their regulators. Among these, the yeast Lst4-Lst7 Rag GTPase GAP complex clusters, as we previously reported, at the vacuolar membrane upon amino acid starvation. In response to amino acid refeeding, it activates the Rag GTPase-TORC1 branch and is then dispersed from the vacuolar surface. Here, we show that the latter effect is driven by TORC1 itself, which directly phosphorylates several residues within the intra-DENN loop of Lst4 that, only in its non-phosphorylated state, tethers the Lst4-Lst7 complex to the vacuolar membrane. An Lst4 variant disrupting this feedback inhibition mechanism causes TORC1 hyperactivation and proliferation defects in cells grown on poor nitrogen sources. Thus, we identify Lst4 as a TORC1 target and key node of a homeostatic mechanism that adjusts TORC1 activity to the availability of amino acids.

Graphical abstract

Teaser

Amino acids activate Rag GTPase-TORC1 signaling in part through the conserved Lst4-Lst7 Rag GTPase GAP complex. Here, Péli-Gulli et al. show that the Lst4-Lst7 module is a direct TORC1 target and key node of a feedback mechanism that adjusts TORC1 activity to amino acid availability.


http://ift.tt/2uPu7Pj

ΔFosB Regulates Gene Expression and Cognitive Dysfunction in a Mouse Model of Alzheimer’s Disease

Publication date: 11 July 2017
Source:Cell Reports, Volume 20, Issue 2
Author(s): Brian F. Corbett, Jason C. You, Xiaohong Zhang, Mark S. Pyfer, Umberto Tosi, Daniel M. Iascone, Iraklis Petrof, Anupam Hazra, Chia-Hsuan Fu, Gabriel S. Stephens, Annie A. Ashok, Suzan Aschmies, Lijuan Zhao, Eric J. Nestler, Jeannie Chin
Alzheimer's disease (AD) is characterized by cognitive decline and 5- to 10-fold increased seizure incidence. How seizures contribute to cognitive decline in AD or other disorders is unclear. We show that spontaneous seizures increase expression of ΔFosB, a highly stable Fos-family transcription factor, in the hippocampus of an AD mouse model. ΔFosB suppressed expression of the immediate early gene c-Fos, which is critical for plasticity and cognition, by binding its promoter and triggering histone deacetylation. Acute histone deacetylase (HDAC) inhibition or inhibition of ΔFosB activity restored c-Fos induction and improved cognition in AD mice. Administration of seizure-inducing agents to nontransgenic mice also resulted in ΔFosB-mediated suppression of c-Fos, suggesting that this mechanism is not confined to AD mice. These results explain observations that c-Fos expression increases after acute neuronal activity but decreases with chronic activity. Moreover, these results indicate a general mechanism by which seizures contribute to persistent cognitive deficits, even during seizure-free periods.

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Teaser

Corbett et al. report that, in mouse models of Alzheimer's disease, spontaneous seizures induce expression of ΔFosB in the dentate gyrus, where it triggers histone modifications and suppresses gene expression important for memory. Due to its long half-life, ΔFosB may persistently affect gene expression and memory, even when seizures are infrequent.


http://ift.tt/2uPHEX2

Golgi Outpost Synthesis Impaired by Toxic Polyglutamine Proteins Contributes to Dendritic Pathology in Neurons

Publication date: 11 July 2017
Source:Cell Reports, Volume 20, Issue 2
Author(s): Chang Geon Chung, Min Jee Kwon, Keun Hye Jeon, Do Young Hyeon, Myeong Hoon Han, Jeong Hyang Park, In Jun Cha, Jae Ho Cho, Kunhyung Kim, Sangchul Rho, Gyu Ree Kim, Hyobin Jeong, Jae Won Lee, TaeSoo Kim, Keetae Kim, Kwang Pyo Kim, Michael D. Ehlers, Daehee Hwang, Sung Bae Lee
Dendrite aberration is a common feature of neurodegenerative diseases caused by protein toxicity, but the underlying mechanisms remain largely elusive. Here, we show that nuclear polyglutamine (polyQ) toxicity resulted in defective terminal dendrite elongation accompanied by a loss of Golgi outposts (GOPs) and a decreased supply of plasma membrane (PM) in Drosophila class IV dendritic arborization (da) (C4 da) neurons. mRNA sequencing revealed that genes downregulated by polyQ proteins included many secretory pathway-related genes, including COPII genes regulating GOP synthesis. Transcription factor enrichment analysis identified CREB3L1/CrebA, which regulates COPII gene expression. CrebA overexpression in C4 da neurons restores the dysregulation of COPII genes, GOP synthesis, and PM supply. Chromatin immunoprecipitation (ChIP)-PCR revealed that CrebA expression is regulated by CREB-binding protein (CBP), which is sequestered by polyQ proteins. Furthermore, co-overexpression of CrebA and Rac1 synergistically restores the polyQ-induced dendrite pathology. Collectively, our results suggest that GOPs impaired by polyQ proteins contribute to dendrite pathology through the CBP-CrebA-COPII pathway.

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Teaser

Chung et al. show that polyQ toxicity induces dendritic pathology involving loss of Golgi outposts (GOPs) in neurons. Genomic analysis reveals that polyQ inhibits expression of genes in the COPII pathway and GOP synthesis by blocking CBP and downregulating CREB3L1/CrebA expression. Enhancing CrebA restores COPII gene expression and GOP synthesis.


http://ift.tt/2uPHE9u

Neogenin Recruitment of the WAVE Regulatory Complex to Ependymal and Radial Progenitor Adherens Junctions Prevents Hydrocephalus

Publication date: 11 July 2017
Source:Cell Reports, Volume 20, Issue 2
Author(s): Conor J. O'Leary, Cathrin C. Nourse, Natalie K. Lee, Amanda White, Michael Langford, Kai Sempert, Stacey J. Cole, Helen M. Cooper
Denudation of the ependyma due to loss of cell adhesion mediated by cadherin-based adherens junctions is a common feature of perinatal hydrocephalus. Junctional stability depends on the interaction between cadherins and the actin cytoskeleton. However, the molecular mechanism responsible for recruiting the actin nucleation machinery to the ependymal junction is unknown. Here, we reveal that loss of the netrin/RGM receptor, Neogenin, leads to severe hydrocephalus. We show that Neogenin plays a critical role in actin nucleation in the ependyma by anchoring the WAVE regulatory complex (WRC) and Arp2/3 to the cadherin complex. Blocking Neogenin binding to the Cyfip1/Abi WRC subunit results in actin depolymerization, junctional collapse, and denudation of the postnatal ventricular zone. In the embryonic cortex, this leads to loss of radial progenitor adhesion, aberrant neuronal migration, and neuronal heterotopias. Therefore, Neogenin-WRC interactions play a fundamental role in ensuring the fidelity of the embryonic ventricular zone and maturing ependyma.

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Teaser

Loss of ependymal adhesion leads to hydrocephalus. O'Leary et al. show that adherens junction assembly relies on Neogenin recruitment of the WRC and Arp2/3 to promote actin polymerization and that its loss results in hydrocephalus. Neogenin therefore stabilizes ependymal junctions to buffer the forces generated by increasing CSF in the neonate.


http://ift.tt/2uQ7f23

In Vitro Modeling Using Ciliopathy-Patient-Derived Cells Reveals Distinct Cilia Dysfunctions Caused by CEP290 Mutations

Publication date: 11 July 2017
Source:Cell Reports, Volume 20, Issue 2
Author(s): Hiroko Shimada, Quanlong Lu, Christine Insinna-Kettenhofen, Kunio Nagashima, Milton A. English, Elizabeth M. Semler, Jacklyn Mahgerefteh, Artur V. Cideciyan, Tiansen Li, Brian P. Brooks, Meral Gunay-Aygun, Samuel G. Jacobson, Tiziana Cogliati, Christopher J. Westlake, Anand Swaroop
Mutations in CEP290, a transition zone protein in primary cilia, cause diverse ciliopathies, including Leber congenital amaurosis (LCA) and Joubert-syndrome and related disorders (JSRD). We examined cilia biogenesis and function in cells derived from CEP290-LCA and CEP290-JSRD patients. CEP290 protein was reduced in LCA fibroblasts with no detectable impact on cilia; however, optic cups derived from induced pluripotent stem cells (iPSCs) of CEP290-LCA patients displayed less developed photoreceptor cilia. Lack of CEP290 in JSRD fibroblasts resulted in abnormal cilia and decreased ciliogenesis. We observed selectively reduced localization of ADCY3 and ARL13B. Notably, Hedgehog signaling was augmented in CEP290-JSRD because of enhanced ciliary transport of Smoothened and GPR161. These results demonstrate a direct correlation between the extent of ciliogenesis defects in fibroblasts and photoreceptors with phenotypic severity in JSRD and LCA, respectively, and strengthen the role of CEP290 as a selective ciliary gatekeeper for transport of signaling molecules in and out of the cilium.

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Teaser

Using fibroblasts and iPSC-derived optic cups from patients with distinct CEP290 mutations, Shimada et al. show a concordance between ciliogenesis defects in different cell types and clinical severity in Leber congenital amaurosis and Joubert syndrome. These studies establish CEP290 as gatekeeper of signaling molecules in and out of the primary cilium.


http://ift.tt/2uPUJzG

Probing Mammalian Cell Size Homeostasis by Channel-Assisted Cell Reshaping

Publication date: 11 July 2017
Source:Cell Reports, Volume 20, Issue 2
Author(s): Giulia Varsano, Yuedi Wang, Min Wu
Cell size homeostasis can be achieved by size checkpoints that couple cell size to cell-cycle progression or by alternative mechanisms such as constant extension. In mammalian cells, the existence of strict size checkpoints remains controversial due to the technical limitations in determining cell size directly and accurately. We developed a microfabricated channel system that linearizes mammalian cell growth and facilitates cell size measurements. By tracking cell length, while directly visualizing cell-cycle progression in rat basophilic leukemia cells and RAW 264.7 macrophages, we examined the mechanisms of size homeostasis and the existence of a size checkpoint at the G1/S transition. Our analysis revealed a two-tier size homeostasis mechanism where a G1 "sizer" or "adder" could operate, depending on the birth size of the cells.

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Teaser

Varsano et al. have developed a direct approach for measuring cell size changes of individual growing mammalian cells in relation with cell-cycle progression. They discovered that mammalian cells could use either a G1/S size checkpoint or constant extension for size control, depending on their birth sizes.


http://ift.tt/2uPIcwg

A PML/Slit Axis Controls Physiological Cell Migration and Cancer Invasion in the CNS

Publication date: 11 July 2017
Source:Cell Reports, Volume 20, Issue 2
Author(s): Valeria Amodeo, Deli A, Joanne Betts, Stefano Bartesaghi, Ying Zhang, Angela Richard-Londt, Matthew Ellis, Rozita Roshani, Mikaella Vouri, Sara Galavotti, Sarah Oberndorfer, Ana Paula Leite, Alan Mackay, Aikaterini Lampada, Eva Wessel Stratford, Ningning Li, David Dinsdale, David Grimwade, Chris Jones, Pierluigi Nicotera, David Michod, Sebastian Brandner, Paolo Salomoni
Cell migration through the brain parenchyma underpins neurogenesis and glioblastoma (GBM) development. Since GBM cells and neuroblasts use the same migratory routes, mechanisms underlying migration during neurogenesis and brain cancer pathogenesis may be similar. Here, we identify a common pathway controlling cell migration in normal and neoplastic cells in the CNS. The nuclear scaffold protein promyelocytic leukemia (PML), a regulator of forebrain development, promotes neural progenitor/stem cell (NPC) and neuroblast migration in the adult mouse brain. The PML pro-migratory role is active also in transformed mouse NPCs and in human primary GBM cells. In both normal and neoplastic settings, PML controls cell migration via Polycomb repressive complex 2 (PRC2)-mediated repression of Slits, key regulators of axon guidance. Finally, a PML/SLIT1 axis regulates sensitivity to the PML-targeting drug arsenic trioxide in primary GBM cells. Taken together, these findings uncover a drug-targetable molecular axis controlling cell migration in both normal and neoplastic cells.

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Teaser

Amodeo et al. find that the growth suppressor PML regulates cell migration during adult neurogenesis and neoplastic transformation via PRC2-mediated repression of Slit genes. Changes in Slit transcription upon PML loss are caused by global reduction of the repressive H3K27me3 histone mark and are associated with its redistribution to nuclear lamina.


http://ift.tt/2uQ7cmT

A Role for Mitochondrial Translation in Promotion of Viability in K-Ras Mutant Cells

Publication date: 11 July 2017
Source:Cell Reports, Volume 20, Issue 2
Author(s): Timothy D. Martin, Danielle R. Cook, Mei Yuk Choi, Mamie Z. Li, Kevin M. Haigis, Stephen J. Elledge
Activating mutations in the KRAS oncogene are highly prevalent in tumors, especially those of the colon, lung, and pancreas. To better understand the genetic dependencies that K-Ras mutant cells rely upon for their growth, we employed whole-genome CRISPR loss-of-function screens in two isogenic pairs of cell lines. Since loss of essential genes is uniformly toxic in CRISPR-based screens, we also developed a small hairpin RNA (shRNA) library targeting essential genes. These approaches uncovered a large set of proteins whose loss results in the selective reduction of K-Ras mutant cell growth. Pathway analysis revealed that many of these genes function in the mitochondria. For validation, we generated isogenic pairs of cell lines using CRISPR-based genome engineering, which confirmed the dependency of K-Ras mutant cells on these mitochondrial pathways. Finally, we found that mitochondrial inhibitors reduce the growth of K-Ras mutant tumors in vivo, aiding in the advancement of strategies to target K-Ras-driven malignancy.

Graphical abstract

Teaser

Using CRISPR and shRNA-based screening approaches in isogenic cell lines, Martin et al. identify a requirement for mitochondrial translation in K-Ras mutant cell viability.


http://ift.tt/2uQ5rq6

Viral Activation of Heparanase Drives Pathogenesis of Herpes Simplex Virus-1

Publication date: 11 July 2017
Source:Cell Reports, Volume 20, Issue 2
Author(s): Alex M. Agelidis, Satvik R. Hadigal, Dinesh Jaishankar, Deepak Shukla
Herpes simplex virus-1 (HSV-1) causes lifelong recurrent pathologies without a cure. How infection by HSV-1 triggers disease processes, especially in the immune-privileged avascular human cornea, remains a major unresolved puzzle. It has been speculated that a cornea-resident molecule must tip the balance in favor of pro-inflammatory and pro-angiogenic conditions observed with herpetic, as well as non-herpetic, ailments of the cornea. Here, we demonstrate that heparanase (HPSE), a host enzyme, is the molecular trigger for multiple pathologies associated with HSV-1 infection. In human corneal epithelial cells, HSV-1 infection upregulates HPSE in a manner dependent on HSV-1 infected cell protein 34.5. HPSE then relocates to the nucleus to regulate cytokine production, inhibits wound closure, enhances viral spread, and thus generates a toxic local environment. Overall, our findings implicate activated HPSE as a driver of viral pathogenesis and call for further attention to this host protein in infection and other inflammatory disorders.

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Teaser

Agelidis et al. demonstrate that herpes simplex virus-1 (HSV-1) infection activates the host protein heparanase (HPSE), which drives key processes in herpes pathogenesis. These results shed light on the mechanisms by which HSV-1 disrupts homeostasis and breaks immune tolerance in the case of the human cornea.


http://ift.tt/2uPZedI

Reduced Circulating Insulin Enhances Insulin Sensitivity in Old Mice and Extends Lifespan

Publication date: 11 July 2017
Source:Cell Reports, Volume 20, Issue 2
Author(s): Nicole M. Templeman, Stephane Flibotte, Jenny H.L. Chik, Sunita Sinha, Gareth E. Lim, Leonard J. Foster, Corey Nislow, James D. Johnson
The causal relationships between insulin levels, insulin resistance, and longevity are not fully elucidated. Genetic downregulation of insulin/insulin-like growth factor 1 (Igf1) signaling components can extend invertebrate and mammalian lifespan, but insulin resistance, a natural form of decreased insulin signaling, is associated with greater risk of age-related disease in mammals. We compared Ins2^+/− mice to Ins2^+/+ littermate controls, on a genetically stable Ins1 null background. Proteomic and transcriptomic analyses of livers from 25-week-old mice suggested potential for healthier aging and altered insulin sensitivity in Ins2^+/− mice. Halving Ins2 lowered circulating insulin by 25%–34% in aged female mice, without altering Igf1 or circulating Igf1. Remarkably, decreased insulin led to lower fasting glucose and improved insulin sensitivity in aged mice. Moreover, lowered insulin caused significant lifespan extension, observed across two diverse diets. Our study indicates that elevated insulin contributes to age-dependent insulin resistance and that limiting basal insulin levels can extend lifespan.

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Teaser

In a study examining the life-long effects of lowering insulin levels in mice, Templeman et al. provide evidence that elevated insulin levels contribute to age-dependent insulin resistance. Moreover, they show that slightly reducing circulating insulin is sufficient to extend mammalian lifespan, independently of Igf1.


http://ift.tt/2uPZdGG

SIFamide Translates Hunger Signals into Appetitive and Feeding Behavior in Drosophila

Publication date: 11 July 2017
Source:Cell Reports, Volume 20, Issue 2
Author(s): Carlotta Martelli, Ulrike Pech, Simon Kobbenbring, Dennis Pauls, Britta Bahl, Mirjam Vanessa Sommer, Atefeh Pooryasin, Jonas Barth, Carmina Warth Perez Arias, Chrystalleni Vassiliou, Abud Jose Farca Luna, Haiko Poppinga, Florian Gerhard Richter, Christian Wegener, André Fiala, Thomas Riemensperger
Animal behavior is, on the one hand, controlled by neuronal circuits that integrate external sensory stimuli and induce appropriate motor responses. On the other hand, stimulus-evoked or internally generated behavior can be influenced by motivational conditions, e.g., the metabolic state. Motivational states are determined by physiological parameters whose homeostatic imbalances are signaled to and processed within the brain, often mediated by modulatory peptides. Here, we investigate the regulation of appetitive and feeding behavior in the fruit fly, Drosophila melanogaster. We report that four neurons in the fly brain that release SIFamide are integral elements of a complex neuropeptide network that regulates feeding. We show that SIFamidergic cells integrate feeding stimulating (orexigenic) and feeding suppressant (anorexigenic) signals to appropriately sensitize sensory circuits, promote appetitive behavior, and enhance food intake. Our study advances the cellular dissection of evolutionarily conserved signaling pathways that convert peripheral metabolic signals into feeding-related behavior.

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Teaser

As in vertebrates, feeding and feeding-related behavior in Drosophila is regulated by a complex neuronal signaling network. Martelli et al. now report that four SIFamidergic neurons in the fly brain receive signals from hunger- and satiety-signaling neurons to regulate the responsiveness of odor-processing neurons, orchestrate appetitive behavior, and induce feeding.


http://ift.tt/2uPBPJ8

Acute Dietary Restriction Acts via TOR, PP2A, and Myc Signaling to Boost Innate Immunity in Drosophila

Publication date: 11 July 2017
Source:Cell Reports, Volume 20, Issue 2
Author(s): Jung-Eun Lee, Morsi Rayyan, Allison Liao, Isaac Edery, Scott D. Pletcher
Dietary restriction promotes health and longevity across taxa through mechanisms that are largely unknown. Here, we show that acute yeast restriction significantly improves the ability of adult female Drosophila melanogaster to resist pathogenic bacterial infections through an immune pathway involving downregulation of target of rapamycin (TOR) signaling, which stabilizes the transcription factor Myc by increasing the steady-state level of its phosphorylated forms through decreased activity of protein phosphatase 2A. Upregulation of Myc through genetic and pharmacological means mimicked the effects of yeast restriction in fully fed flies, identifying Myc as a pro-immune molecule. Short-term dietary or pharmacological interventions that modulate TOR-PP2A-Myc signaling may provide an effective method to enhance immunity in vulnerable human populations.

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Teaser

Lee et al. reveal how dietary restriction boosts the innate immune response against pathogenic bacterial infection via a signaling mechanism in which reduced TOR signaling results in stabilization of Myc through its suppressor protein phosphatase 2A.


http://ift.tt/2tHd57G

Peripartum Antibiotics Promote Gut Dysbiosis, Loss of Immune Tolerance, and Inflammatory Bowel Disease in Genetically Prone Offspring

Publication date: 11 July 2017
Source:Cell Reports, Volume 20, Issue 2
Author(s): Jun Miyoshi, Alexandria M. Bobe, Sawako Miyoshi, Yong Huang, Nathaniel Hubert, Tom O. Delmont, A. Murat Eren, Vanessa Leone, Eugene B. Chang
Factors affecting the developing neonatal gut microbiome and immune networks may increase the risk of developing complex immune disorders such as inflammatory bowel diseases (IBD). In particular, peripartum antibiotics have been suggested as risk factors for human IBD, although direct evidence is lacking. Therefore, we examined the temporal impact of the commonly used antibiotic cefoperazone on both maternal and offspring microbiota when administered to dams during the peripartum period in the IL-10-deficient murine colitis model. By rigorously controlling for cage, gender, generational, and murine pathobiont confounders, we observed that offspring from cefoperazone-exposed dams develop a persistent gut dysbiosis into adulthood associated with skewing of the host immune system and increased susceptibility to spontaneous and chemically dextran sodium sulfate (DSS)-induced colitis. Thus, early life exposure to antibiotic-induced maternal dysbiosis during a critical developmental window for gut microbial assemblage and immune programming elicits a lasting impact of increased IBD risk on genetically susceptible offspring.

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Teaser

Miyoshi et al. show that maternal and neonatal exposure to antibiotics can cause enduring changes in the gut microbiome that adversely affect the development of the immune system. In genetically susceptible individuals, the persistence of intestinal dysbiosis and immune imbalance may increase risk for immune disorders like inflammatory bowel diseases.


http://ift.tt/2tGPUtP

Two Sets of Piwi Proteins Are Involved in Distinct sRNA Pathways Leading to Elimination of Germline-Specific DNA

Publication date: 11 July 2017
Source:Cell Reports, Volume 20, Issue 2
Author(s): Dominique I. Furrer, Estienne C. Swart, Matthias F. Kraft, Pamela Y. Sandoval, Mariusz Nowacki
Piwi proteins and piRNAs protect eukaryotic germlines against the spread of transposons. During development in the ciliate Paramecium, two Piwi-dependent sRNA classes are involved in the elimination of transposons and transposon-derived DNA: scan RNAs (scnRNAs), associated with Ptiwi01 and Ptiwi09, and iesRNAs, whose binding partners we now identify as Ptiwi10 and Ptiwi11. scnRNAs derive from the maternal genome and initiate DNA elimination during development, whereas iesRNAs continue DNA targeting until the removal process is complete. Here, we show that scnRNAs and iesRNAs are processed by distinct Dicer-like proteins and bind Piwi proteins in a mutually exclusive manner, suggesting separate biogenesis pathways. We also demonstrate that the PTIWI10 gene is transcribed from the developing nucleus and that its transcription depends on prior DNA excision, suggesting a mechanism of gene expression control triggered by the removal of short DNA segments interrupting the gene.

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Teaser

Furrer et al. show that two small RNA classes are bound by different Piwi proteins to mediate two functionally separate DNA elimination pathways in Paramecium.


http://ift.tt/2tGZRaO

Identification of tumor-autonomous and indirect effects of vitamin D action that inhibit breast cancer growth and tumor progression

Publication date: Available online 11 July 2017
Source:The Journal of Steroid Biochemistry and Molecular Biology
Author(s): Abhishek Aggarwal, David Feldman, Brian J. Feldman
Several epidemiological studies have found that low vitamin D levels are associated with worse prognosis and poorer outcomes in patients with breast cancer (BCa), although some studies have failed to find this association. In addition, prior research has found that BCa patients with vitamin D deficiency have a more aggressive molecular phenotype and worse prognostic biomarkers. As vitamin D deficiency is common in patients diagnosed with BCa, elucidating the cause of the association between poor outcomes and vitamin D deficiency promises to have a significant impact on improving care for patients with BCa including enabling the development of novel therapeutic approaches. Here we review our recent findings in this area, including our data revealing that reduction of the expression of the vitamin D receptor (Vdr) within BCa cells accelerates primary tumor growth and enables the development of metastases, demonstrating a tumor autonomous effect of vitamin D signaling to suppress BCa metastases. We believe that these findings are likely relevant to humans as we discovered evidence that a mechanism of VDR regulation identified in our mouse models is conserved in human BCa. In particular, we identified a negative correlation between serum 25(OH)D concentration and the level of expression of the tumor progression factor ID1 in primary tumors from patients with breast cancer.



http://ift.tt/2uPttRT

Overcoming barriers to treating iron overload in patients with lower-risk myelodysplastic syndrome

Publication date: Available online 12 July 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): Amer M. Zeidan, Vinod A. Pullarkat, Rami S. Komrokji
Myelodysplastic syndromes (MDS) constitute a group of heterogeneous hematopoietic neoplasms characterized by ineffective erythropoiesis, anemia, and/or cytopenias. Supportive care for patients with MDS involves frequent red blood cell transfusions, which places patients with ongoing transfusional dependence (TD) at risk for iron overload (IO). Development of IO and tissue iron deposition can increase the risk of cardiac, hepatic, and endocrine toxicities, infection, and progression to acute myeloid leukemia. Iron chelation therapy (ICT) is an option for lower-risk MDS patients to reduce their degree of IO and possibly improve survival; use of these agents in thalassemia patients with TD and IO has been associated with reduced IO-associated complications and better survival. At present, there are several barriers to the regular use of ICT, such as a lack of randomized trial evidence and consistent guidance on diagnosis of IO and when to implement ICT, as well as barriers in adherence to/tolerability of ICT.



http://ift.tt/2uci94r

Mitochondrial dysfunctions in bladder cancer: exploring their role as disease markers and potential therapeutic targets

Publication date: Available online 11 July 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): Antonella Cormio, Francesca Sanguedolce, Clara Musicco, Vito Pesce, Giuseppe Calò, Pantaleo Bufo, Giuseppe Carrieri, Luigi Cormio
Bladder cancer (BC) is a major cause of mortality worldwide as it currently lacks fully reliable markers of disease outcome and effective molecular targets for therapy. Mitochondria play a key role in cell metabolism but the role of mitochondrial dysfunctions in BC has been scarcely investigated. In this review, we explored current evidence for the potential role of mitochondrial DNA (mtDNA) alterations (point mutations and copy number) as disease markers in BC. Some germline mtDNA mutations detectable in blood could represent a non-invasive tool to predict the risk of developing BC. MtDNA copy number and tumor specific mtDNA mutations and RNAs showed encouraging results as novel molecular markers for early detection of BC in body fluids. Moreover, mitochondrial proteins Lon protease, Mitofusin-2, and TFAM may have prognostic/predictive value and may represent potential therapeutic targets. A deeper understanding of mitochondrial dysfunctions in BC could therefore provide novel opportunities for targeted therapeutic strategies.



http://ift.tt/2vb92yh

CNVbase: Batch identification of novel and rare copy number variations based on multi-ethnic population data

Publication date: Available online 11 July 2017
Source:Journal of Genetics and Genomics
Author(s): Cheng Zhang, Jianqi Lu, Haiyi Lou, Renqian Du, Shuhua Xu, Yiping Shen, Feng Zhang, Haiyi Lou, Li Jin




http://ift.tt/2uh3DZQ

Comparing electro- and mechano-myographic muscle activation patterns in self-paced pediatric gait

Publication date: Available online 11 July 2017
Source:Journal of Electromyography and Kinesiology
Author(s): Katherine Plewa, Ali Samadani, Tom Chau
Electromyography (EMG) is the standard modality for measuring muscle activity. However, the convenience and availability of low-cost accelerometer-based wearables makes mechanomyography (MMG) an increasingly attractive alternative modality for clinical applications. Literature to date has demonstrated a strong association between EMG and MMG temporal alignment in isometric and isokinetic contractions. However, the EMG-MMG relationship has not been studied in gait. In this study, the concurrence of EMG- and MMG-detected contractions in the tibialis anterior, lateral gastrocnemius, vastus lateralis, and biceps femoris muscles were investigated in children during self-paced gait. Furthermore, the distribution of signal power over the gait cycle was statistically compared between EMG-MMG modalities. With EMG as the reference, muscular contractions were detected based on MMG with balanced accuracies between 88-94% for all muscles except the gastrocnemius. MMG signal power differed from that of EMG during certain phases of the gait cycle in all muscles except the biceps femoris. These timing and power distribution differences between the two modalities may in part be related to muscle fascicle length changes that are unique to muscle motion during gait. Our findings suggest that the relationship between EMG and MMG appears to be more complex during gait than in isometric and isokinetic contractions.



http://ift.tt/2uPKnj8

Induction and maintenance of regulatory T cells by transcription factors and epigenetic modifications

Publication date: Available online 11 July 2017
Source:Journal of Autoimmunity
Author(s): Mana Iizuka-Koga, Hiroko Nakatsukasa, Minako Ito, Takashi Akanuma, Qianjin Lu, Akihiko Yoshimura
Regulatory T cells (Tregs) are an essential cell subset for the maintenance of immune homeostasis. Foxp3 (Forkhead box P3) is the Treg master gene which is essential for immune suppressing activity. In addition, Tregs are characterized by a distinct pattern of gene expression, including upregulation of immune-suppressive genes and silencing of inflammatory genes. The molecular mechanisms of Treg development and maintenance have been intensively investigated. Tregs are characterized by expression of the transcription factor Foxp3. Several intronic enhancers and a promoter at the Foxp3 gene locus were shown to play important roles in Treg differentiation. The enhancers have been designated as conserved non-coding sequences (CNSs) 0, 1, 2, and 3. We showed that the transcription factors Nr4a and Smad2/3 are essential for the development of thymic Tregs and induced Tregs, respectively. Recently, Treg-specific DNA demethylation has been shown to play an important role in Treg stability. DNA demethylation of CNS2 has been implicated in Treg stability, and recent reports have revealed that the ten-eleven translocation (Tet) family of demethylation factor plays an important role in CpG demethylation at CNS2. This article reviews the recent progress on the roles of transcription factors and epigenetic modifications in the differentiation, maintenance, and function of Tregs.



http://ift.tt/2sOuhF4

Changes in the Executive Editorial Team

Publication date: Available online 11 July 2017
Source:Pathology - Research and Practice
Author(s): Albert Roessner




http://ift.tt/2t2nNqo

Metabolism and antioxidant effect of malaxinic acid and its corresponding aglycone in rat blood plasma

Publication date: September 2017
Source:Free Radical Biology and Medicine, Volume 110
Author(s): Hyun Joo Lee, Hang Yeon Jeong, Mi Rim Jin, Hyoung Jae Lee, Jeong-Yong Cho, Jae-Hak Moon
Malaxinic acid (MA) is a phenolic acid compound, found mainly in pear fruits (Pyrus pyrifolia N.), that is isoprenylated on the C-3 position of benzoic acid. Recently, the effects of prenylated phenolics on health have received much interest owing to their reported potent beneficial biological effects. We conducted a comparative study in rats to determine the metabolism, pharmacokinetics, and antioxidative activities of MA and its corresponding aglycone (MAA). MA and MAA were orally administered to rats (Sprague-Dawley, male, 6 weeks old) and their metabolites in plasma were analyzed. In addition, the MA metabolites in plasma were separated and the structures were confirmed via NMR and HR-MS analyses. The antioxidative activities of MA and MAA were evaluated by measuring their inhibitory effects on the 2,2′-azobis(2-amidinopropane)dihydrochloride- or copper ion-induced lipid peroxidation of rat plasma. MA was not absorbed in the intact form (the glucoside); both MA and MAA were absorbed as MAA and its metabolite form (glucuronide or sulfate). Moreover, the observed metabolite was the glucuronate of MAA rather than the glucuronide or sulfate. Concentrations of the free form of aglycone (MA administration, 4.6 ± 2.2μM; MAA administration, 7.2 ± 2.3μM) and total MAA (MA administration, 19.6 ± 4.4μM; MAA administration, 21.7 ± 3.3μM) in plasma reached a maximum at 15min after the oral administration of MA and MAA, respectively. The relative inhibitory effects on the formation of cholesteryl ester hydroperoxides in plasma collected at 15min after the oral administration of MA, MAA, and p-hydroxybenzoic acid (p-HBA) were as follows: MAA > MA ≥ p-HBA > control. Although the majority of MA and MAA is metabolized to conjugates, the compounds may contribute to the antioxidant defenses in the blood circulation owing to the presence of a phenolic hydroxyl group in the free form.

Graphical abstract

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Punicalagin, a PTP1B inhibitor, induces M2c phenotype polarization via up-regulation of HO-1 in murine macrophages

Publication date: September 2017
Source:Free Radical Biology and Medicine, Volume 110
Author(s): Xiaolong Xu, Yuhong Guo, Jingxia Zhao, Shasha He, Yan Wang, Yan Lin, Ning Wang, Qingquan Liu
Current data have shown that punicalagin (PUN), an ellagitannin isolated from pomegranate, possesses anti-inflammatory and anti-oxidant properties; however, its direct targets have not yet been reported. This is the first report that PTP1B serves as a direct target of PUN, with IC50 value of 1.04μM. Results from NPOI further showed that the Kon and Koff of PUN-PTP1B complex were 3.38e2M⁻¹s⁻¹ and 4.13e-3s⁻¹, respectively. The active site Arg24 of PTP1B was identified as a key binding site of PUN by computation simulation and point mutation. Moreover, inhibition of PTP1B by PUN promoted an M2c-like macrophage polarization and enhanced anti-inflammatory cytokines expression, including IL-10 and M-CSF. Based on gene expression profile, we elucidated that PUN treatment significantly up-regulated 275 genes and down-regulated 1059 genes. M1-like macrophage marker genes, such as Tlr4, Irf1/2, Hmgb1, and Stat1 were down-regulated, while M2 marker genes, including Tmem171, Gpr35, Csf1, Il1rn, Cebpb, Fos, Vegfα, Slc11a1, and Bhlhe40 were up-regulated in PUN-treated macrophages. Hmox-1, a gene encoding HO-1 protein, was preferentially expressed with 16-fold change. Inhibition of HO-1 obviously restored PUN-induced M2 polarization and IL-10 secretion. In addition, phosphorylation of both Akt and STAT3 contributed to PUN-induced HO-1 expression. This study provided new insights into the mechanisms of PUN-mediated anti-inflammatory and anti-oxidant activities and provided new therapeutic strategies for inflammatory diseases.

Graphical abstract

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Does cognitive behavioural therapy for insomnia improve cognitive performance? A systematic review and narrative synthesis

Individuals with insomnia report difficulties pertaining to their cognitive functioning. Cognitive behavioural therapy for insomnia (CBT-I) is associated with robust, long-term improvements in sleep parameters, however less is known about the impact of CBT-I on the daytime correlates of the disorder. A systematic review and narrative synthesis was conducted in order to summarise and evaluate the evidence regarding the impact of CBT-I on cognitive functioning. Reference databases were searched and studies were included if they assessed cognitive performance as an outcome of CBT-I, using either self-report questionnaires or cognitive tests.

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Volatiles emitted by Bacillus sp. BCT9 act as growth modulating agents on Lactuca sativa seedlings

Publication date: Available online 11 July 2017
Source:Microbiological Research
Author(s): Paola Fincheira, Leonardo Parra, Ana Mutis, Maribel Parada, Andrés Quiroz
Chemical products are applied during horticulture to increase food production, but the environmental problems resulting from these applications have led to a search for more sustainable products. Volatile organic compounds (VOCs) demonstrating plant growth promoter (PGP) activity released by bacterial species have emerged as alternatives, but their effects on Lactuca sativa growth are unknown. In this study, VOCs released by Bacillus sp. BCT9 cultures grown in different media (Methyl Red & Voges Proskauer, Murashige & Skoog and nutrient media) at concentrations of 0.1, 0.2, 0.5 and 0.7 (measured as the absorbance, λ=600nm) were tested to evaluate their activity as growth inducers of L. sativa after 10days of exposure. Lower concentrations of BCT9 increased root length, and higher concentrations induced shoot length and lateral root length. The dry weight and number of lateral roots increased similarly, independent of concentration, for VOCs produced in all culture media. BCT9 cultures grown in Methyl Red & Voges Proskauer medium as bioactive compounds with or without lanolin. These VOCs increased shoot length, root length and dry weight at low concentrations, independent of the presence of lanolin. Lateral root length increased with the application of 2-nonanone (50ppm) and 2-undecanone (0.05ppm). Based on these results, the use of bioactive volatiles as growth inducers of horticultural species represents an alternative or complementary strategy.



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Personal sleep pattern visualization using sequence-based kernel self-organizing map on sound data

Publication date: Available online 11 July 2017
Source:Artificial Intelligence in Medicine
Author(s): Hongle Wu, Takafumi Kato, Tomomi Yamada, Masayuki Numao, Ken-ichi Fukui
We propose a method to discover sleep patterns via clustering of sound events recorded during sleep. The proposed method extends the conventional self-organizing map algorithm by kernelization and sequence-based technologies to obtain a fine-grained map that visualizes the distribution and changes of sleep-related events. We introduced features widely applied in sound processing and popular kernel functions to the proposed method to evaluate and compare performance. The proposed method provides a new aspect of sleep monitoring because the results demonstrate that sound events can be directly correlated to an individual's sleep patterns. In addition, by visualizing the transition of cluster dynamics, sleep-related sound events were found to relate to the various stages of sleep. Therefore, these results empirically warrant future study into the assessment of personal sleep quality using sound data.



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Anti-proliferative activity of Gum kondagogu (Cochlospermum gossypium)-gold nanoparticle constructs on B16F10 melanoma cells: an in vitro model

Publication date: Available online 11 July 2017
Source:Bioactive Carbohydrates and Dietary Fibre
Author(s): S. Kalaignana Selvi, M.J. Mahesh Kumar, R.B. Sashidhar
The present study has explored the reducing and capping potentials of gum kondagogu (GK) for the synthesis of gold nanoparticle constructs. The formation of gold nanoparticles was confirmed by UV- absorption, FTIR, AFM, SEM and TEM. The GK-AuNPs showed a characteristic absorption peak at 534nm in UV spectra with the size range of 4.08–12.73 ±0.75nm. As a result of wide screening on the application of newly synthesized GK-AuNPs their anticancer potential were discovered by MTT assay, confocal microscopy, flow cytometry and quantitative real time PCR techniques. MTT assay of synthesized GK-AuNPs exhibited IC50 concentration of 1.7µgL⁻¹ after 48h. FACS analysis revealed that cell cycle gets arrested at G1 to S phase, with up-regulation of p53, caspase-3, caspase-9, PPARa and PPARb, genes and down regulation of Bcl-2 and Bcl-x(K) genes, in B16F10 cells treated with GK-AuNPs confirming the anti-proliferative properties of the nanoparticles.

Graphical abstract

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Immunological evaluation of Gum kondagogu (Cochlospermum gossypium): A tree gum with potential applications in food and pharma industry

Publication date: Available online 11 July 2017
Source:Bioactive Carbohydrates and Dietary Fibre
Author(s): Janaki Puskuri, Vani Katukam, R.B. Sashidhar
Gum kondagogu (KG) is a natural polysaccharide derived as an exudate from the bark of the tree Cochlospermum gossypium (Bixaceae family). The toxicological assessment of KG established that this gum to be nontoxic, while the immunological response to KG was yet to be explored, as the protein content of KG has been reported to be 5.0 − 6.3% (w/w). The current investigation evaluates immunogenic aspects of three grades of gum (KG-I, II and III) in a rodent model. The immunogenicity of KG was evaluated in comparison with ovalbumin, which is a known food allergen. As a measure of immunological response, delayed-type hypersensitivity (DTH) reaction, blood histamine levels and antibody (IgG) response were assessed. The DTH reaction of KG-III gum was found to be similar to that of ovalbumin, as measured by mean skin fold thickness of each ear sensitised with test and reference immunogens. KG-I and II did not elicit any DTH reaction. Statistically significant difference in histamine and IgG levels were observed between the control (PBS), ovalbumin and KG-III rat groups (p < 0.05). The experimental observations showed similar immune response between KG-III and ovalbumin in experimental groups sensitised with respective immunogens. Immune response to KG-III gum could be attributed to the impurities originating from the bark during the process of exudation. As there is no statistical significant immunological response to KG-I and II, these grades of gum may find potential applications in food and pharmaceutical industry.

Graphical abstract

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Dietary Fibre for Glycaemia Control: Towards a Mechanistic Understanding

Publication date: Available online 12 July 2017
Source:Bioactive Carbohydrates and Dietary Fibre
Author(s): H. Douglas Goff, Nikolay Repin, Hrvoje Fabek, Dalia El Khoury, Michael J. Gidley
One of the many functional benefits of dietary fibre when present in the human diet is its ability to reduce the rate of absorption of glucose after consumption of high glycaemic carbohydrate-containing foods, leading to a blunted blood glucose response curve and less demand for insulin. Glycaemia control through dietary intervention is of significant importance to those at high risk for Type 2 Diabetes Mellitus (T2D), or those with Impaired Glucose Tolerance or with T2D, populations that are growing globally at an alarming rate. The soluble polysaccharide gums are well known to induce viscosity and/or gelation in solution, and their physiological function is often related to this rheological behaviour. However, gastrointestinal secretions and dilution, and acidification and re-neutralization, can affect the rheological properties of the polysaccharides in vivo. When one considers the physiology of starch and sugar digestion and glucose absorption, it is possible to elucidate several plausible mechanisms by which both soluble and insoluble fibres might contribute to Glycaemia control: reduction in gastric emptying, modification of release of digestion- and fermentation-related hormones, inhibition of amylase activity and delayed starch hydrolysis, reduction in diffusion of amylolytic products to the small intestinal microvilli, and/or the development of an absorptive barrier layer through interactions with the mucosa. Scientific evidence suggests that all of these mechanisms are involved to some extent. Understanding the relationships between molecular structure, physical functionality and physiological functionality of dietary fibres should enable the food industry to deliver more fibre-enriched functional food products to consumers, especially for Glycaemia control.

Graphical abstract

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Artifacts in histology: A 1-year retrospective study

Odokuma Emmanuel Igho, Aifuobhokhan Aimakhume

Annals of Bioanthropology 2017 5(1):34-39

Introduction: Histology is a science of the analysis of tissue architecture; however, the presence of artifacts in microscopic sections may result in misdiagnosis. Despite documented common occurrences, studies on the patterns of artifacts in Nigeria are however scant. The rarity of descriptions in this clumsy but important component of histology stimulated our interest in demonstrating the various patterns of artifacts in a laboratory. This 1-year retrospective study was conducted in Federal Medical Centre, Asaba, Delta State. Materials and Methods: Tissue sections were viewed and with the aid of a microscope to check for the various patterns of artifacts. These artifacts were seen as artificial structures or tissue alternations on the prepared slide. Histological images were captured using eyepiece Scopetek DCM 500, 5.0 Megapixel connected USB 2.0 computer. Data were obtained by standard microscopic techniques in which the various patterns of tissue alterations were described. Permission for this study was obtained from the hospital Ethics Committee (ethical number FMC/ASB/T/A81/198). Results: This review of patterns of artifacts showed that during the 1-year period, of the 388 slides reviewed, 94.59% had the presence of artifacts. The results also revealed that fold artifacts were the most prevalent patterns constituting about 33.00% of the total tissue sections observed, followed by artifacts attributed to microtomy which accounted for 18.47% and formalin pigment artifacts, 14.78%. The least was heat and hemorrhagic artifacts which contributed to about 0.25%. Conclusion: In conclusion, fold artifacts were the most prevalent patterns observed in this study due to the thin sections which easily stretch around other structures having different constituencies if the tissue is not carefully lifted from the water bath.

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Body mass index of male and female Wistar rats following administration of leptin hormone after a dietary regime

Ahmed Muhammed Rabiu, H Wale, K Garba, AM Sabo, Z Hassan, AI Shugaba, UG Egesie, SO Odeh

Annals of Bioanthropology 2017 5(1):22-26

Introduction: Obesity is a problem affecting people of all ages and socioeconomic status. Leptin hormone (LH), a product of the obesity gene, is a key regulator of feeding and energy expenditure. Aim: The study is aimed at determining the effect of LH on body mass index (BMI) in Wistar rats after a diet regime. Materials and Methods: Forty rats (male [M], n = 20; female [F], n = 20), aged 9 weeks and weighing 77.2–123.0 g, were randomly divided into two Groups A (M) and B (F) and further divided into four subgroups of n = 5. They were maintained ad libitum on different diet and water for 10 weeks. Group 1; control (standard rat feed), Group 2 (high fat diet), Group 3 (protein diet), and Group 4 (carbohydrate diet). BMI was calculated weekly for 10 weeks (pretest). LH was injected for 2 weeks; the BMI was then calculated (posttest). Paired t-test was used to analyze the differences between the BMI pre- and post-test periods and also to analyze for sexual dimorphism for the pre- and post-test periods. Level of significance was at P < 0.05. Results: The results revealed no significant difference (P > 0.05) in the BMI for the pre- and post-test period and no sexual dimorphism for BMI during the pretest period. However, there was a significant difference (P < 0.05) and sexual dimorphism for BMI during the posttest period. Conclusion: This result implies that the LH is more effective in the male gender than the female when considering BMI and hence may reduce the risk associated with obesity.

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Histomorphological effects of nicotine on the kidney

Emmanuel Igho Odokuma, Joan Eseoghene Adogbeji

Annals of Bioanthropology 2017 5(1):9-13

Introduction: This experimental animal study was designed to investigate the histomorphological effects of nicotine on the kidneys of matured adult Wistar rats. Materials and Methods: Permission for the study was obtained from the Department of Human Anatomy and Cell Biology Ethics Committee (DELSU/CHS/ANA/68/43), and it involved 36 rats which were randomly assigned into three test and one control group. While animals in the control group (Group A) received only water and feed, 2 mg/day, 4 mg/day, and 6 mg/day of pure nicotine in solution was orally administered to test Groups B, C, and D, respectively (dose: 50 mg/kg/day). At the end of 7, 21, and 42 days, one experimental animal was selected from each of the groups at random, euthanized, and the harvested kidneys processed by standard techniques The obtained tissue samples were viewed with a digital light microscope (Scopetek DCM 500, 20.0 mega pixel) connected through a USB to an HP computer. Results: The control group showed normal histomorphologic features, but the test groups which were dose and time dependent showed progressive histological alterations. Glomerulosclerosis and widening of the glomerular space were observed following acute and subacute exposure unlike with the chronically exposed rats in which an intact renal structural integrity was documented. Conclusion: This study that prolonged exposure to orally administered nicotine within normal doses had minimal effects on the kidneys of adult Wistar rats.

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Evaluation of the lumbar-sacral configuration: A radiographic study of young adults in Southern Nigeria

Michael Omonkheoa Oyakhire, Alaba Udoaka

Annals of Bioanthropology 2017 5(1):1-8

Introduction: Compared with other populations, African spines, have not been adequately studied and consequently, surgical interventions on the spine rely on assumptions and data from studies done on non-Nigerians. Materials and Methods: Lateral lumbosacral X-ray films of 120 informed volunteers who met relevant inclusion criteria were studied. Three parameters frequently employed to characterize the lumbosacral region in the assessment of spinal health; Lumbar Lordotic Angle (LLA), Lumbar Lordotic Depth (LLD) and Lumbosacral Angle (LSA),were measured using standard radiographic procedures. Statistical Analysis: Data were analyzed using SPSS version 17. Confidence interval was set at 95% defining P ≤ 0.05 of statistical significance. Results: On the average, the subjects were 27 years old (males 28 and females 24). Mean (SE) of weight was 66.59 (1.06) kg; males 65.71 (1.18) kg, females 67.80 (2.04) kg. Mean (SE) of height was 1.66 (0.01) m, females 1.6 (0.01) m, males 1.69 (0.01). Mean (SE) of BMI was 24.32 (0.41); males 23.04 (0.39), females 26.45 (0.79). Mean (SE) of LSA was 31.12 (0.46) 0; females 32.04 (0.91) 0, males 30.56 (0.50) 0.Mean (SE) LLA 51.34 (0.76) 0; females 49.84 (1.23) 0, males 52.24 (0.96) 0.Mean (SE) LLD 3.23 (0.04) cm; males 3.15 (0.05) cm, females 3. 36 (0.07) cm. Significant associations were found between the following variables; age and LLA (r2= 0.158, P < 0.001), age and LLD (r2 = 0.224, P < 0.001), LSA and LLA (r2 = 0.034, P = 0.044), LSA and LLD (r2 = 0.042, P = 0.024), LLA and LLD (r2 = 0.555, P < 0.001). Conclusion: This study is probably the first to be carried out on living subjects in Nigeria and the data it provides will be useful for further research and will also add to existing knowledge on African spines.

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Sexual dimorphism in frontal sinus of Southeast Nigerians

Uchenna Kenneth Ezemagu, C I. P Anibeze, Frank Chinedu Akpuaka

Annals of Bioanthropology 2017 5(1):14-17

Background: The functional and adaptive significance of frontal sinus is still very poorly understood and attempt to link frontal sinus patterns with specific influences such as sex or biological affinity have been inconclusive. Purpose: The study aims to demonstrate the influence and this relationship between the variation in frontal sinus dimensions and sex. Materials and Method: In this study, lateral and anteroposterior radiographs of 74 males and 46 females of Southeast Nigerians taken from August 18, 2003 to July 12, 2004 were measured (age 9–75). Data were analyzed using excel package of a desktop computer, employing Chi-square test to determine the association between sinus dimensions and sex. Result: The result showed that variation in frontal sinus breadth and depth may not depend on sex while variation in height slightly depends on sex (P < 0.05). Thus, establishing the fact that some metric and morphologic characteristics of the frontal sinus depend on sex. Conclusion: This finding depicts a sexual dimorphism in frontal sinus dimension. Moreover, it adds an additional factor to the puzzle of the meaning of the supra orbital development and morphologic characteristics.

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Role of volatile organic compounds from gloss paint, emulsion, and thinner on the testes of wistar rats (Rattus norvegicus)

Adeoye Oyetunji Oyewopo, Joseph Babatunde Dare, Olugbemi Tope Olaniyan, Akunna Godson Gabriel

Annals of Bioanthropology 2017 5(1):27-33

Introduction: Volatile organic compounds (VOCs) in paint are considered harmful to the environment, especially for people who work with them on a regular basis. Aim: In this study, we investigated the effect of VOCs in gloss paint, emulsion, and thinner on the testes of male Wistar rats. Materials and Methods: Twenty adult Wistar rats (100–200 g) were assigned to four (4) groups (A–D) of five rats each. Groups A (thinner), B (emulsion paint), and C (gloss paint) were exposed to fumes from one coating of an improvised chamber for 1 h daily for 21 days while Group D was the control group exposed to fresh air. The rats were exposed to the test chemicals using an improvised chamber of a carton with dimensions 37 cm × 25 cm × 25 cm and had a cross-ventilation (aeration) with six triangular holes of base 4 cm with spaces approximately 1 cm apart and 2 cm on each side. The rats were usually brought out of the animal house, placed in the carton coated with their respective paints for a period of 1 h daily, and then returned to the animal house under normal standard room temperature for 21 days. The rats were sacrificed 24 h after the last exposure day, by cervical dislocation. Results: In this study, the t-test for the body weight of the animal showed no statistical significance (P > 0.05). There was a significant decrease in sperm count and motility and deranged testicular profile in the groups exposed to nitrocellulose thinner, emulsion paint, and gloss paint. The follicle-stimulating hormone (FSH) values increased from those exposed to gloss paint, control thinner, and emulsion. The luteinizing hormone (LH) values increased from emulsion, control, gloss, and thinner. The testosterone (TT) values increased from gloss, emulsion, control, and thinner. Conclusion: We concluded that the exposure to VOCs present in paint has a deleterious effect on the reproductive potentials of an adult male Wistar rat.

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Determination of the palmar ridge counts and angles in acquired idiopathic blindness in some selected schools for the blind in Nigeria

JN Paul, EA Osunwoke, CW Paul

Annals of Bioanthropology 2017 5(1):18-21

Background: Ridges are delicately sculpted skin surface and their configural arrangements present on human fingers, toes, and soles. Aim: This study was aimed at determining the palmar ridge counts and palmar angles in acquired idiopathic blindness. Materials and Methods: The study had 72 subjects comprising 36 blind (14 females and 22 males) and 36 nonblind (18 females and 18 males). Palmar prints were obtained using print scanner (HP G3110 Photo Scanner). Results: The mean and standard deviation of the ridge counts for the total blind subjects: on the right hand, A–B was 26.02 ± 2.96, B–C was 27.04 ± 2.81, C–D was 33.16 ± 3.55; and on the left hand, A–B was 26.51 ± 2.38, B–C was 26.99 ± 2.89, and C–D was 33.20 ± 3.44. Considering the total ridge counts for the nonblind subjects on the right hand: A-B was 35.53 ± 1.99, B-C was 22.83 ± 1.87, and C-D was 41.20 ± 2.75; and on the left hand: A-B was 32.72 ± 2.54, B-C was 22.89 ± 2.24, and C-D was 41.30 ± 2.57. The palmar angles had the following values for the blind: on the right hand, ATD angle was 38.69° ± 3.65°, DAT angle was 60.11° ± 4.45°, and TDA angle was 81.19° ± 4.06°, while on the left hand: ATD angle was 38.47° ± 4.14°, DAT angle was 60.28° ± 4.49°, and TDA angle was 81.19° ± 4.50°. Conclusion: This study provides baseline information for researchers who will find it relevant in the course of their research with respect to palmar ridge counts and angles.

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Anomalous renal vasculature

Chike Ikechukwu Patrick Anibeze, Christian Chiemeka Ozor, Ogugua Augustine Egwu, Jude Ikechukwu Nnaji, Bright Ozuroke Enyinda, Blessing Amara Iwunze

Annals of Bioanthropology 2017 5(1):40-42

Presence of anomalous structures has been continually observed in human body specimens. Such variations have been observed in renal vasculature. During routine dissection of a young adult male cadaver at the Dissection Hall of the Anatomy Department of Enugu State University of Science and Technology, College of Medicine, Parklane, GRA, Enugu, Nigeria, we found multiple renal vasculatures. There were four separate renal arteries arising directly from abdominal aorta on the left. On the right, one major artery gives an early branch and three branches close to the hilum before separately entering the renal parenchyma. The venous vasculature also displays an obvious variation of a bifurcated vein on the right and a normal single vein on the left. These may predispose to easy factors of partial occlusion or compression of renal vasculature resulting in varicocele or hypertension. Similarly, blood circulation through the renal arteries, in case of multiple branching pattern, may result in altered hemodynamics. The knowledge of these anomalous vasculatures is significant since it is known that microvascular techniques for renal transplantation surgeries require a thorough anatomical knowledge of accessory or multiple vasculatures for better outcomes.

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Taxifolin reduces the cholesterol oxidation product-induced neuronal apoptosis by suppressing the Akt and NF-κB activation-mediated cell death

Publication date: Available online 11 July 2017
Source:Brain Research Bulletin
Author(s): Arum Kim, Yoon Jeong Nam, Chung Soo Lee
The taxifolin effect on the cholesterol oxidation product-induced neuronal apoptosis was investigated using differentiated PC12 cells and human neuroblastoma SH-SY5Y cells. 7-ketocholesterol induced phosphorylation of Akt, and increase in the levels of cytosolic and nuclear NF-κB p65, cytosolic NF-κB p50 and cytosolic phosphorylated-IκB-α levels in PC12 cells. The cholesterol oxidation products also induced a decrease in the levels of Bid and Bcl-2, increase in the levels of p53 and Bax, loss of the mitochondrial transmembrane potential, release of cytochrome c, activation of caspases (−8, −9 and −3), production of reactive oxygen species, depletion of GSH and cell death in both cell lines. Taxifolin, N-acetylcysteine, trolox, Akt inhibitor and Bay11-7085 attenuated the cholesterol oxidation product-induced changes in the apoptosis-related protein levels, activation of the Akt and NF-κB, reactive oxygen species production, GSH depletion and cell death. These results show that taxifolin may reduce the cholesterol oxidation product-induced neuronal apoptosis by suppressing the Akt and NF-κB activation-mediated cell death. The suppressive effect appears to be attributed to the inhibition of reactive oxygen species production and GSH depletion.



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Inhibitory effects of tetramethylpyrazine on pain transmission of trigeminal neuralgia in CCI-ION rats

Publication date: Available online 11 July 2017
Source:Brain Research Bulletin
Author(s): Wei Xiong, Mengxia Tan, Linkun He, Xiaoyan Ou, Youhong Jin, Guo Yang, Liping Huang, Yuling Shen, Shu Guan, Changshui Xu, Guilin Li, Shuangmei Liu, Hong Xu, Shangdong Liang, Yun Gao
Tetramethylpyrazine (TMP) has anti-inflammatory effects and is used to treat cerebral ischemic injury, but the mechanism of TMP on neural protection is not clear. Trigeminal neuralgia (TN) is a facial pain syndrome that is characterized by paroxysmal, shock-like pain attacks located in the somatosensory distribution of the trigeminal nerve. P2X3 receptor plays a crucial role in facilitating pain transmission. The present study investigates the effects of TMP on trigeminal neuralgia transmission mediated by P2X3 receptor of the trigeminal ganglia (TG). Chronic constriction injury of the infraorbital branch of the trigeminal nerve (CCI-ION) was used as a trigeminal neuralgia model. On day 15 after surgery, there was a significant decline in the mechanical hyperalgesia threshold in the territory of the ligated infraorbital nerve in the TN group, and an increase in expression of P2X3 receptor in the TG of the TN group compared with the Sham group. After treatment with TMP or A-317491, the mechanical hyperalgesia threshold of TN rats was significantly higher, and expression of P2X3 receptor in the TG noticeably declined compared with the TN group. Phosphorylation of p38 and ERK1/2 in the TN group was stronger than in the Sham group. However, the phosphorylation of p38 and ERK1/2 in the TN+TMP group and TN+A-317491 group was much lower than in the TN group. TMP significantly inhibited the ATP activated currents in HEK293 cells transfected with a P2X3 plasmid. Thus, TMP might have inhibitory effects on trigeminal neuralgia by suppressing the expression of P2X3 receptor in the TG and the phosphorylation of p38 and ERK1/2 in the TG.



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Transient brain hypothermia reduces the reperfusion injury of delayed tissue plasminogen activator and extends its therapeutic time window in a focal embolic stroke model

Publication date: Available online 11 July 2017
Source:Brain Research Bulletin
Author(s): Mohammadreza Zarisfi, Fatemeh Allahtavakoli, Mahsa Hassanipour, Mohammad Khaksari, Hosain Rezazadeh, Mohammad Allahtavakoli, Mohammad Mohsen Taghavi
It has been reported that restriction of reperfusion after thrombolytic therapy in ischemic stroke may reduce tissue plasminogen activator (tPA) adverse effects and extend its time window. We examined whether short-term and mild local brain cooling can prevent hyperemia and/or adverse effects of delayed tPA in rat embolic stroke model. Male animals were subjected to embolic stroke and then randomly classified into control (saline), tPA (1mg/kg; i.v.), local hypothermia (LH), and tPA+LH. The drug was injected at 6h after ischemia. LH was conducted by direct ipsilateral (injured) hemisphere cooling at 6.5h after stroke and maintained for approximately 30minutes. Cerebral blood flow was monitored in a duration of 60minute after tPA administration and hyperemic response was measured. Infarct volume, blood–brain barrier (BBB) disruption, edema formation, neurological deficits, and matrix metalloproteinase-9 (MMP-9) level were measured 48h later. A combination of tPA+LH significantly diminished infarct volume in comparison with the tPA (P <0.001) and control (P <0.05) groups. Combination therapy also decreased BBB leakage (P <0.001), MMP-9 level or edema (P <0.01) and improved neurological functions at 48h after the stroke. LH caused a gradual decrease in hyperemic response after thrombolysis compared to the control (P <0.05) or tPA (P <0.001) groups. LH alone also reduced infarct volume, BBB leakage or edema (P <0.01). The short-term local brain hypothermia may mitigate reperfusion injury following delayed tPA therapy and extend its time window up to 6h.



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