bluuebunny/crossref_metadata_2025 huggingface dataset:
Symptoms, Psychosocial Factors, and Health-Related Quality of Life in Patients With Neuroendocrine Tumors
Authors: Haugland Trude , DeVon Holli A.
Published: May 2018

Background

Understanding the influence of psychosocial factors and symptoms on health-related quality of life (HRQoL) might help researchers develop interventions to optimize HRQoL in patients with neuroendocrine tumors (NETs).

Objective

The aim of this study was to characterize available evidence on symptoms, psychosocial factors, and HRQoL in patients with NET.

Methods

For this integrative literature review, the literature search was guided by the methodology proposed by Whittemore and Knafl. MEDLINE, CINAHL, PubMed, PsychINFO, and Google Scholar were searched for articles exploring symptoms, psychosocial factors, and HRQoL in patients living with gastrointestinal NETs.

Results

Combining keywords yielded 37 articles after removing 2 duplicates. Twenty-three articles were removed because they did not meet inclusion criteria. Two articles had a qualitative design. The final review included 15 studies. Geographically diverse studies indicate that patients with NET experience fatigue, nausea/vomiting, pain, dyspnea, and sleep disturbance. Anxiety, higher depression, and stress negatively influenced HRQoL. More social support, self-efficacy, and optimism were associated with better HRQoL. Findings from the qualitative studies emphasize that NET-related symptoms and adverse effects of the treatment influence the patients' HRQoL.

Conclusion

This review identified fatigue, nausea/vomiting, pain, dyspnea, and sleep disturbance as the most important symptoms. The most frequently reported psychosocial factors were anxiety and depression, which influenced HRQoL negatively. Social support and self-efficacy had a positive impact on HRQoL.

Implications for Practice

Researchers and clinicians must understand the importance of psychosocial factors and symptoms associated with HRQoL to develop targeted interventions to optimize HRQoL in patients with NET.
Periauricular Purse-String Reinforced with SMAS plication and Malaria Fat Pad Elevation for Mid-and Lower Facial Rejuvenation
Authors: Wang Rongrong , Yang Jie , Guo Ke , Zhong Aimei , Tong Jing , Xiong Lingyun , Sun Jiaming
Published: May 2018

Background

Facial aging is a complex process influencing every layer of the facial structure. Most accepted surgical techniques for facial rejuvenation involve certain manipulation of the superficial musculoaponeurotic system (SMAS). Out of these SMAS-based techniques, SMAS plication or suspension provides excellent outcomes with shorter convalescence and fewer potential complications. Herein, we would like to present our own technique combining SMAS plication, periauricular purse-string, and malar fat pad elevation technique for mid and lower facelift.

Methods

Through a classical periauricular and temporal incision, a periauricular permanent purse-string suture was woven into the SMAS to suspend sagging soft tissue of the mid and lower face after superficial undermining, then plication of inner and outer SMAS of the purse-string loop was performed to further secure suspension, and at last the malar fat pad was elevated for midface rejuvenation. The shape of the loop varies with patients' age; for younger patients, the loop is more vertical, and for older patients, the loop is more horizontal. Patient-reported outcomes were described using the FACE-Q questionnaire.

Results

From January 2010 to June 2015, a total of 138 patients were treated with this technique by a same surgeon. Follow-up duration ranged from 1 to 6 years. Preoperative and postoperative photographs were recorded and analyzed. The complications rates were low, and satisfaction rates were high. Patients felt that they appeared 7.3 years younger than their actual age on average and were most satisfied with the appearance of their lower face and jawline.

Conclusions

Periauricular purse-string reinforced with SMAS plication and malar fat pad elevation technique produces esthetically pleasing outcomes, besides being simple, safe, and personalized.
The Soleus Muscle Flap
Authors: Song Ping , Pu Lee L. Q.
Published: May 2018

Lower extremity reconstruction often poses several challenges for the reconstructive surgeon. Because of limited local tissue options, patients who sustain extensive middle to distal third tibia fractures used to be at higher risk of limb loss without adequate soft tissue coverage. The traditional principle of reconstructing middle and distal third leg wounds with free tissue transfer is being challenged by advances in understanding of local muscle flap anatomy and surgical techniques to improve the efficacy of local flaps. In this article, we examine contemporary considerations, developed by the authors, for the appropriate indications of free tissue transfer versus use of local flaps such as the soleus muscle flap. We review the versatility and reliability of the soleus muscle as a local muscle option once the technique is mastered on how to safely and effectively design and execute this flap. We highlight the importance of an algorithmic approach to soft-tissue reconstruction of the lower extremity based on the best surgical option for the patient. This includes factors such as medical history, appropriate surgical candidacy, as well as the size and mechanism of injury to decide the most viable option for lower extremity reconstruction. We show that the medial hemisoleus muscle flap is a reliable local option, both by itself or in conjunction with other local flaps, to reconstruct less extensive wounds in the middle to distal third of the leg. Ultimately, such a local muscle flap must be mastered by the reconstructive surgeon to augment his or her armamentarium to provide a well-rounded reconstructive plan in managing the soft-tissue wound, while minimizing donor-site morbidity and potentially be more cost-effective in nature.
Fatal Case of Metformin-Associated Lactic Acidosis Associated With Temporary Ileostomy
Authors: Tirelli Flavio , Biondi Alberto , Persiani Roberto
Published: May 2018

BACKGROUND:

Metformin is considered a first choice for oral treatment of patients with type 2 diabetes in the absence of contraindications. Colorectal cancer is the second most frequent cancer among the general population; low anterior resections and temporary diverting ileostomies are commonly performed in this population. As the incidence of type 2 diabetes increases, the use of metformin in patients with both type 2 diabetes and an ileostomy will most likely increase as well.

CASE:

We present the case of a patient affected by colorectal cancer who developed a severe metformin-associated lactic acidosis (MALA) after creation of a temporary ileostomy to protect a low colorectal anastomosis. High-volume output from his ileostomy led to significant fluid loss and electrolyte imbalance, his condition was complicated by MALA, resulting in death.

CONCLUSION:

The population of ileostomy patients who also have type 2 diabetic and taking metformin is at risk for MALA. High stomal output can lead to dehydration, with a loss of fluids and electrolytes and metformin could aggravate this condition, potentiating the risk of MALA.
The variability of amino acids sequences in hepatitis B virus
Authors: Cao Jianhao , Luo Shuhong , Xiong Yuanyan
Published: May 2018

Hepatitis B virus (HBV) is an important human pathogen belonging to theHepadnaviridaefamily,Orthohepadnavirusgenus. It infects over 240 million people globally. The reverse transcription during its genome replication leads to low fidelity DNA synthesis, which is the source of variability in the viral proteins. To investigate the variability quantitatively, we retrieved amino acid sequences of 5167 records of all available HBV genotypes (A-J) from the Genbank database. The amino acid sequences encoded by the open reading frames (ORF) S/C/P/X in the HBV genome were extracted and subjected to alignment respectively. We analyzed the variability of the lengths and the sequences of proteins as well as the frequencies of amino acids. Our study comprehensively characterized of the variability and conservation of HBV at the level of amino acids, especially for the structural proteins, hepatitis B surface antigens (HBsAg), to find out the potential sites critical for virus assembly and immune recognition. Interestingly, the preS1/S2 domains in HBsAg were variable at some positions of amino acid residues, which provides a potential mechanism of immune-escape for HBV, while the preS2 and S domains were conserved in the lengths of protein sequences. In the S domain, the cysteine residues and the secondary structures of the alpha-helix and beta-sheet were likely critical for the stable folding of the protein structure. The preC domain and C-terminal domain (CTD) of the core protein are highly conserved. And the polymerases HBpol and the HBx were highly variable at the amino acid level.
Toxicity of TiO2, SiO2, ZnO, CuO, Au and Ag engineered nanoparticles on hatching and early nauplii of Artemia sp.
Authors: Rohit R , Murthy Ch. Lakshmi N , Idris Mohammed M , Singh Shashi
Published: May 2018

The potential of environmental release enhances with increased commercial applications of the nanomaterials. A simple and efficient test to estimate the acute toxicity of nanoparticles is carried out in this work using Artemia species and their hatching rate. We have tested six different engineered nanoparticles (silver, gold, copper oxide, zinc oxide, titanium dioxide and silicon nanoparticles) and three soluble salts (CuSO4, ZnSO4 and AgNO3) on Artemia sp. The physiochemical properties of the nanoparticles involved in this study are estimated and their properties in normal water and marine water were analyzed. Hydrated and bleached Artemia cysts were allowed to hatch in continuously aerated, filtered sterile salt water containing nanoparticles; hatching of viable nauplii vs total hatchlings were recorded. In parallel, Standard Artemia toxicity test was conducted on the nauplii monitoring the viability. A comparison of results obtained in both experiments is discussed. The toxicity of the nanoparticles was compared and the order of toxicity is estimated as Ag>CuO>ZnO>Au>TiO2>SiO2.
Time Lags and Niche Shifts in a Biological Invasion of Hummingbirds
Authors: Battey C.J.
Published: May 2018

Shifts in a species’ realized niche can lead to rapid population growth by increasing the carrying capacity of local habitats and allowing colonization of new areas. This process is well known in “invasive” species introduced to novel ranges by humans, but can also occur when native species expand their range. In these cases expansions may be driven either by a shift in the available environment or by a shift in the species’ use of existing niche space, but identifying the specific environmental or behavioral changes involved is often hindered by time lags in the process of colonization. Here I document a century of range shifts in the Anna’s Hummingbird (Calypte anna) and show that recent abundance in the Pacific Northwest is the product of a series of range and niche expansions that started in the early 20thcentury following the spread of garden cultivation and introduced plant species in California. Demographic trends in the northwest have tracked simple models of exponential growth since populations became established in the 1960’s and 70’s, and nest records suggest that the species has delayed the beginning of the breeding season by at least 18 days in the north. Niche models trained on historic climate and occurrence data fail to predict the modern range, suggesting that climate change is not the primary cause of the expansion. Range expansions in the Anna’s Hummingbird thus closely track the dynamics of an invasive species spreading across a novel range, and were made possible by a mix of introduced plants, phenological acclimation, and an expansion of the realized climatic niche.
MTAP loss correlates with an immunosuppressive profile in GBM and its substrate MTA stimulates alternative macrophage polarization
Authors: Hansen Landon J. , Yang Rui , Woroniecka Karolina , Chen Lee , Yan Hai , He Yiping
Published: May 2018

Glioblastoma (GBM) is a lethal brain cancer known for its potent immunosuppressive effects. Loss ofMethylthioadenosine Phosphorylase(MTAP) expression, via gene deletion or epigenetic silencing, is one of the most common alterations in GBM. Here, we show that MTAP loss in GBM cells is correlated with differential expression of immune regulatory genes. In silico analysis of gene expression profiles in GBM samples revealed that lowMTAPexpression is correlated with reduced proportions of γδT cells, fewer activated CD4 cells, and an increased proportion of M2 macrophages. Using in vitro macrophage models, we found that methylthioadenosine (MTA), the metabolite that accumulates as a result of MTAP loss in GBM cells, promotes the immunosuppressive alternative activation (M2) of macrophages. We show that this effect of MTA on macrophages is independent of IL4/IL3 signaling, is mediated by the adenosine A2Breceptor, and can be pharmacologically reversed. This study suggests that MTAP loss in GBM cells contributes to the immunosuppressive microenvironment, and thatMTAPstatus should be a factor for consideration in understanding GBM immune states and devising immunotherapy-based approaches for treatingMTAP-null GBM.
Alternative super-enhancers result in similar gene expression in different tissues
Authors: Bojcsuk Dora , Nagy Gergely , Balint Balint Laszlo
Published: May 2018

Super-enhancers (SEs) are clusters of highly active enhancers, regulating cell type-specific and disease-related genes, including oncogenes. The individual regulatory regions within SEs might be simultaneously bound by different transcription factors (TFs) and co-regulators such as P300, BRD4 and Mediator, which together establish a chromatin environment conducting to effective gene induction. While cells with distinct TF profiles can have different functions, an unanswered question is how different cells control overlapping genetic programmes. Here, we show that the construction of oestrogen receptor alpha (ERα)-driven SEs is tissue specific, and both the collaborating TFs and the active SE components are largely differing between human breast cancer-derived MCF-7 and endometrial cancer-derived Ishikawa cells; nonetheless, SEs common to both cell types have similar transcriptional outputs. In the MCF-7 cell line, ERα-dominated SEs are also driven by the well-known FoxA1 and AP2γ TFs, as described previously, whereas in Ishikawa cells, FoxM1, TCF12 and TEAD4 are as important as ERα for SE formation. Our results show that SEs can be constructed in several ways, but the overall activity of common SEs is the same between cells with a common master regulator. These findings may reshape our current understanding of how these regulatory units can fine-tune cell functions. From a broader perspective, we show that systems assembled from different components can perform similar tasks if a common functional trigger drives their assembly.
Relative value perception in an insect: positive and negative incentive contrasts in ants
Authors: Wendt Stephanie , Strunk Kim S. , Heinze Juergen , Roider Andreas , Czaczkes Tomer J.
Published: May 2018

Humans tend to value things not on their absolute values, but relative to reference points such as former experience or expectations. People rate the quality of a new salary relative to their previous salary and the salaries of their peers, instead of appreciating its absolute value. Here, we demonstrate a similar effect in an insect: ants, which had previously experienced a low quality food source, showed higher acceptance of medium quality food (e.g. 0.1M then 0.5M; positive contrast) than if they had received the medium food all along (e.g. 0.5M then 0.5M; control), and vice versa for high expectations. Further experiments demonstrate that these contrast effects arise from cognitive rather than mere sensory or pre-cognitive perceptual causes. Pheromone deposition also correlates with perceived reward value, and ants showed successive contrasts in their pheromone deposition. Relative value perception can therefore be expected to have strong effects not only on individual behaviour, but also on collective decision-making. Contrast effects were also social: the quality of food received from other ants affected the perceived value of food found later. Value judgement is a key element in decision making, and thus relative value perception will strongly influence how animals interact with their environment.
Genome Functional Annotation across Species using Deep Convolutional Neural Networks
Authors: Khodabandelou Ghazaleh , Routhier Etienne , Mozziconacci Julien
Published: May 2018

Deep neural network application is today a skyrocketing field in many disciplinary domains. In genomics the development of deep neural networks is expected to revolutionize current practice. Several approaches relying on convolutional neural networks have been developed to associate short genomic sequences with a functional role such as promoters, enhancers or protein binding sites along genomes. These approaches rely on the generation of sequences batches with known annotations for learning purpose. While they show good performance to predict annotations from a test subset of these batches, they usually perform poorly when applied genome-wide.

In this study, we address this issue and propose an optimal strategy to train convolutional neural networks for this specific application. We use as a case study transcription start sites and show that a model trained on one organism can be used to predict transcription start sites in a different specie. This cross-species application of convolutional neural networks trained with genomic sequence data provides a new technique to annotate any genome from previously existing annotations in related species. It also provides a way to determine whether the sequence patterns recognized by chromatin associated proteins in different species are conserved or not.
Metagenomic analysis suggests broad metabolic potential in extracellular symbionts of the bivalveThyasiracf.gouldi
Authors: McCuaig Bonita , Peña-Castillo Lourdes , Dufour Suzanne C.
Published: May 2018

Next-generation sequencing has opened new avenues for studying metabolic capabilities of bacteria that cannot be cultured. Here, we provide a metagenomic description of a chemoautotrophic gammaproteobacterial symbiont associated withThyasiracf.gouldi, a sediment-dwelling bivalve from the family Thyasiridae. Symbionts of thyasirids differ from those of other bivalves by being located outside rather than inside gill epithelial cells, and recent work suggests that they are capable of living freely in the environment. TheT. cf.gouldisymbiont genome shows no signs of genomic reduction and contains many genes that would only be useful outside the host, including flagellar and chemotaxis genes. The thyasirid symbiont may be capable of sulfur oxidation via both the sulfur oxidation and dissimilatory sulfate reduction pathways, as observed in other bivalve symbionts. In addition, genes for hydrogen oxidation and dissimilatory nitrate reduction were found, suggesting varied metabolic capabilities under a range of redox conditions. The genes of the tricarboxylic acid cycle are also present, along with membrane bound sugar importer channels, suggesting that the bacteria may be mixotrophic. In this study, we have generated the first thyasirid symbiont genomic resources and lay the groundwork for further research in tracking the changes required for life as a bivalve symbiont.
Laboratory Validation of a Clinical Metagenomic Sequencing Assay for Pathogen Detection in Cerebrospinal Fluid
Authors: Miller S , Naccache SN , Samayoa E , Messacar K , Arevalo S , Federman S , Stryke D , Pham E , Fung B , Bolosky WJ , Ingebrigtsen D , Lorizio W , Paff SM , Leake JA , Pesano R , DeBiasi RL , Dominguez SR , Chiu CY
Published: May 2018

Metagenomic next-generation sequencing (mNGS) for pan-pathogen detection has been successfully tested in proof-of-concept case studies in patients with acute illness of unknown etiology, but to date has been largely confined to research settings. Here we developed and validated an mNGS assay for diagnosis of infectious causes of meningitis and encephalitis from cerebrospinal fluid (CSF) in a licensed clinical laboratory. A clinical bioinformatics pipeline, SURPI+, was developed to rapidly analyze mNGS data, automatically report detected pathogens, and provide a graphical user interface for evaluating and interpreting results. We established quality metrics, threshold values, and limits of detection of between 0.16 – 313 genomic copies or colony forming units per milliliter for each representative organism type. Gross hemolysis and excess host nucleic acid reduced assay sensitivity; however, a spiked phage used as an internal control was a reliable indicator of sensitivity loss. Diagnostic test accuracy was evaluated by blinded mNGS testing of 95 patient samples, revealing 73% sensitivity and 99% specificity compared to original clinical test results, with 81% positive percent agreement and 99% negative percent agreement after discrepancy analysis. Subsequent mNGS challenge testing of 20 positive CSF samples prospectively collected from a cohort of pediatric patients hospitalized with meningitis, myelitis, and/or encephalitis showed 92% sensitivity and 96% specificity relative to conventional microbiological testing of CSF in identifying the causative pathogen. These results demonstrate the analytic performance of a laboratory-validated mNGS assay for pan-pathogen detection, to be used clinically for diagnosis of neurological infections from CSF.
Transcriptional Network Analysis on Brains Reveals a Potential Regulatory Role of PPP1R3F in Autism Spectrum Disorders
Authors: Torshizi Abolfazl Doostparast , Duan Jubao , Wang Kai
Published: May 2018

Objective

This study aims at identifying master regulators of transcriptional networks in autism spectrum disorders (ASDs).

Results

With two sets of independent RNA-Seq data generated on cerebellum from patients with ASDs and control subjects (N=39 and 45 for set 1, N=24 and 38 for set 2, respectively), we carried out a network deconvolution of transcriptomic data, followed by virtual protein activity analysis. We identified PPP1R3F (Protein Phosphatase 1 Regulatory Subunit 3F) as a master regulator affecting a large body of downstream genes that are associated with the disease phenotype. Pathway enrichment analysis on the identified targets of PPP1R3F in both datasets indicated alteration of endocytosis pathway. This exploratory analysis is limited by sample size, but it illustrates a successful application of network deconvolution approaches in the analysis of brain gene expression data and generates a hypotheses that may be further validated by large-scale studies in the future.
Graded and bidirectional control of real-time reach kinematics by the cerebellum
Authors: Becker Matthew I. , Person Abigail L.
Published: May 2018

The rules governing the relationship between cerebellar output and movement production remain unknown despite the well-recognized importance of the cerebellum in motor learning and precision. In this study, we investigated how cerebellar output sculpts reach behavior in mice by manipulating neural activity in the anterior interposed nucleus (IntA) in closed-loop with ongoing behavior. Optogenetic modulation of cerebellar output revealed monotonically graded and bidirectional control of real-time reach velocity by IntA. Furthermore, kinematic effects were relatively context invariant, suggesting that cerebellar output summates with ongoing motor commands generated elsewhere throughout the reaching movement. These results characterize the relationship between cerebellar output modulation and reach behavior as a bidirectional and scalable kinematic command signal. Our findings illustrate how learned, predictive coding in the cerebellar cortex could be actuated through the cerebellar nuclei to contribute in real time to purposive motor control.
Integrated Molecular Profiling Studies to Characterize the Cellular Origins of High-Grade Serous Ovarian Cancer
Authors: Lawrenson Kate , Fonseca Marcos A.S. , Segato Felipe , Lee Janet M. , Corona Rosario I. , Seo Ji-Heui , Coetzee Simon , Lin Yvonne G. , Pejovic Tanja , Mhawech-Fauceglia Paulette , Drapkin Ronny , Karlan Beth Y. , Hazelett Dennis J. , Freedman Matthew L. , Gayther Simon A. , Noushmehr Houtan
Published: May 2018

Historically, high-grade serous ovarian cancers (HGSOCs) were thought to arise from ovarian surface epithelial cells (OSECs) but recent data implicate fallopian tube secretory epithelial cells (FTSECs) as the major precursor. We performed transcriptomic and epigenomic profiling to characterize molecular similarities between OSECs, FTSECs and HGSOCs. Transcriptomic signatures of FTSECs were preserved in most HGSOCs reinforcing FTSECs as the predominant cell-of-origin; though an OSEC-like signature was associated with increased chemosensitivity (Padj= 0.03) and was enriched in proliferative-type tumors, suggesting a dualistic model for HGSOC origins. More super-enhancers (SEs) were shared between FTSECs and HGSOCs than between OSECS and HGSOCs (P< 2.2 × 10−16). SOX18, ELF3 and EHF transcription factors (TFs) coincided with HGSOC SEs and represent putative novel drivers of tumor development. Our integrative analyses support a predominantly fallopian origin for HGSOCs and indicate tumorigenesis may be driven by different TFs according to cell-of-origin.
Partitioning protein ParP directly links chemotaxis to biofilm dispersal in Pseudomonas aeruginosa
Authors: Reinhardt Jesse M. , Bardy Sonia L.
Published: May 2018

The recent characterization of partitioning proteins in the localization of chemotaxis signal transduction systems was proposed to have broad implications for polarly-flagellated non-enterobacteriaceae gamma-proteobacteria. These studies showed that the loss of either partitioning protein resulted in equivalent reductions in swimming motility and chemotaxis protein localization and inheritance. However, the role of these chemotaxis partitioning proteins outside of Vibrio spp. remains untested. Our studies on the chemotaxis partitioning proteins in Pseudomonas aeruginosa revealed an unexpected role for the partitioning protein ParP. While the P. aeruginosa ParC and ParP homologs are needed for wild type swimming motility, the loss of ParP results in a greater swimming defect compared to the parC mutant. Our studies revealed that the Par-like proteins directly interact with each other and the chemotaxis system, and ParP interacts with DipA. Deletion of dipA results in a similar defect in swimming motility as the parP mutant. ParP has an interdependence for polar cluster formation, but not localization, with both CheA and DipA, and CheA cluster formation is partially dependent on ParP. Due to the direct interactions and interdependence of cluster formation of ParP and DipA, and the similar phenotypes of the parP and dipA mutants, further investigation into the role of ParP in biofilm dispersion is warranted.

Importance

Impaired chemotaxis protein cluster formation or inheritance reduces chemotaxis which can have an impact on of the virulence of a bacterium. In some gamma-proteobacteria there are systems in place to ensure that chemotaxis proteins, like chromosomes and plasmids, are localized for optimal chemotaxis and that daughter cells inherit their own clusters for use after cell division. Par-like proteins have been implicated in the partitioning and localization of chemotaxis proteins and the chemotactic ability of Vibrio spp. and Rhodobacter sphaeroides [1–3]. We propose that Par-like proteins can do more than localize chemotaxis proteins to the poles of the cells. In P. aeruginosa, they bring together other key proteins involved in regulating flagellar-based motility, and we propose they function as a critical link between biofilm dispersal and motility.
Susceptibility to Neutralization by Broadly Neutralizing Antibodies Correlates with Infected Cell Binding for a Panel of Clade B HIV Reactivated from Latent Reservoirs
Authors: Ren Yanqin , Korom Maria , Truong Ronald , Chan Dora , Huang Szu-han , Kovacs Colin C. , Benko Erika , Safrit Jeffrey T. , Lee John , Garbán Hermes , Apps Richard , Goldstein Harris , Lynch Rebecca M. , Jones R.Brad
Published: May 2018

Efforts to HIV cure are obstructed by reservoirs of latently infected CD4+T-cells that can re-establish viremia. Broadly neutralizing HIV-specific antibodies (bNAbs), defined by unusually high neutralization breadths against globally diverse viruses, may contribute to the elimination of these reservoirs by binding to reactivated cells, targeting them for immune clearance. However, the relationship between neutralization of reservoir isolates and binding to corresponding infected primary CD4+T-cells has not been determined. Thus, the extent to which neutralization breadths and potencies can be used to infer the corresponding parameters of infected-cell binding is currently unknown. We assessed the breadths and potencies of bNAbs against 36 viruses reactivated from peripheral blood CD4+T-cells of ARV-treated HIV-infected individuals, using paired neutralization and infected-cell binding assays. Single antibody breadths ranged from 0–64% for neutralization (IC80≤10μg/ml) and 0–89% for binding, with two-antibody combinations reaching 0-83% and 50-100%, respectively. Infected-cell binding correlated with virus neutralization for 10 out of 14 antibodies (e.g. 3BNC117, r=0.87, p<0.0001). Heterogeneity was observed, however, with a lack of significant correlations for 2G12, CAP256.VRC26.25, 2F5, and 4E10. Our results provide guidance on the selection of bNAbs for interventional cure studies; both by providing a direct assessment of intra-and inter-individual variability in neutralization and infected cell binding in a novel cohort, and by defining the relationships between these parameters for a panel of bNAbs.

Importance

Although anti-retroviral therapies have improved the lives of people who are living with HIV, they do not cure infection. Efforts are being directed towards harnessing the immune system to eliminate the virus that persists, potentially resulting in virus-free remission without medication. HIV-specific antibodies hold promise for such therapies owing to their abilities to both prevent the infection of new cells (neutralization), and also to direct the killing of infected cells. We isolated 36 HIV strains from individuals whose virus was suppressed by medication, and tested 14 different antibodies for neutralization of these viruses and for binding to cells infected with the same viruses (critical for engaging natural killer cells). For both neutralization and infected-cell binding, we observed variation both between individuals, and amongst different viruses within an individual. For most antibodies, neutralization activity correlated with infected cell binding. These data provide guidance on the selection of antibodies for clinical trials.
Characterisation of Antibody Interactions with the G Protein of Vesicular Stomatitis Virus Indiana Strain and Other Vesiculovirus G Proteins
Authors: Munis Altar M , Tijani Maha , Hassall Mark , Mattiuzzo Giada , Collins Mary K , Takeuchi Yasuhiro
Published: May 2018

Vesicular stomatitis virus Indiana strain G protein (VSVind.G) is the most commonly used envelope glycoprotein to pseudotype lentiviral vectors (LV) for experimental and clinical applications. Recently, G proteins derived from other vesiculoviruses (VesG), for example Cocal virus, have been proposed as alternative LV envelopes with possible advantages compared to VSVind.G. Well-characterised antibodies that recognise VesG will be useful for vesiculovirus research, development of G protein-containing advanced therapy medicinal products (ATMPs), and deployment of VSVind-based vaccine vectors. Here we show that one commercially available monoclonal antibody, 8G5F11, binds to and neutralises G proteins from three strains of VSV as well as Cocal, and Maraba viruses, whereas the other commercially available monoclonal anti-VSVind.G antibody, IE9F9, binds to and neutralises only VSVind.G. Using a combination of G protein chimeras and site-directed mutations, we mapped the binding epitopes of IE9F9 and 8G5F11 on VSVind.G. IE9F9 binds close to the receptor binding site and competes with soluble low-density lipoprotein receptor (LDLR) for binding to VSVind.G, explaining its mechanism of neutralisation. In contrast, 8G5F11 binds close to a region known to undergo conformational changes when the G protein moves to its post-fusion structure, and we propose that 8G5F11 cross-neutralises VesGs by inhibiting this.

IMPORTANCE

VSVind.G is currently regarded as the gold-standard envelope to pseudotype lentiviral vectors. However, recently other G proteins derived from vesiculoviruses have been proposed as alternative envelopes. Here, we investigated two anti-VSVind.G monoclonal antibodies for their ability to cross-react with other vesiculovirus G proteins, and identified the epitopes they recognise, and explored the mechanisms behind their neutralisation activity. Understanding how cross-neutralising antibodies interact with other G proteins may be of interest in the context of host-pathogen interaction and co-evolution as well as providing the opportunity to modify the G proteins and improve G protein-containing medicinal products and vaccine vectors.
The Gut Microbiome of the Eastern Spruce Budworm Does Not Influence Larval Growth or Survival
Authors: Schwarz Melbert T. , Kneeshaw Daniel , Kembel Steven W.
Published: May 2018

Microbial communities have been shown to play an important role for host health in mammals, especially humans. It is thought that microbes could play an equally important role in other animal hosts such as insects. A growing body of evidence seems to support this, however most of the research effort in understanding host-microbe interactions in insects has been focused on a few well-studied groups such as bees, cockroaches and termites. We studied the effects of the gut-associated microbial community on the growth and survival of the eastern spruce budworm Choristoneura fumiferana, an economically important lepidopteran forest pest in eastern Canada and the northeastern United States. Contrary to our expectations, the gut microbial community of spruce budworm larvae does not appear to influence host growth or survival. Our results agree with the hypothesis that lepidopteran larvae lack resident microbial communities and are not nutritionally dependent on bacterial symbionts.
TRPV4 interacts with mitochondrial proteins and acts as a mitochondrial structure-function regulator
Authors: Kumar Ashutosh , Majhi Rakesh Kumar , Acharya Tusar Kanta , Smalla Karl-Heinz , Gundelfinger Eckart D , Goswami Chandan
Published: May 2018

TRPV4 has been linked with the development of sensory defects, neuropathic pain, neurodegenerative disorders such as Charcot Marie Tooth disease and various muscular dystrophies. In all these cases mitochondrial abnormalities were tagged as cellular hallmarks and such abnormalities have been reported as key factor for the pathophysiological conditions. Mitochondria also have the unique ability to sense and regulate their own temperature. Here, we demonstrate that TRPV4, a thermosensitive ion channels, localizes to a subpopulation of mitochondria in various cell lines, in primary cells and also in sperm cells. Improper expression and/or function of TRPV4 induce several mitochondrial abnormalities such as low oxidative potential, high Ca2+-influx and changes in electron transport chain functions. TRPV4 is also involved in regulation of mitochondrial morphology, smoothness, and fusion-fission events. The C-terminal cytoplasmic region of TRPV4 can localize it to mitochondria and interacts with mitochondrial proteins including Hsp60, Mfn1 and Mfn2. Regulation of mitochondria by TRPV4 may contribute to previously uncharacterized mitochondria-specific functions observed in various cell types. This discovery may help to link TRPV4-mediated channelopathies with mitochondria-mediated diseases.
Mapping DNA sequence to transcription factor binding energy in vivo
Authors: Barnes Stephanie L. , Belliveau Nathan M. , Ireland William T. , Kinney Justin B. , Phillips Rob
Published: May 2018

Despite the central importance of transcriptional regulation in systems biology, it has proven difficult to determine the regulatory mechanisms of individual genes, let alone entire gene networks. It is particularly difficult to analyze a promoter sequence and identify the locations, regulatory roles, and energetic properties of binding sites for transcription factors and RNA polymerase. In this work, we present a strategy for interpreting transcriptional regulatory sequences using in vivo methods (i.e. the massively parallel reporter assay Sort-Seq) to formulate quantitative models that map a transcription factor binding site’s DNA sequence to transcription factor-DNA binding energy. We use these models to predict the binding energies of transcription factor binding sites to within 1 kBT of their measured values. We further explore how such a sequence-energy mapping relates to the mechanisms of trancriptional regulation in various promoter contexts. Specifically, we show that our models can be used to design specific induction responses, analyze the effects of amino acid mutations on DNA sequence preference, and determine how regulatory context affects a transcription factor’s sequence specificity.
Cryo-EM structure of the volume-regulated anion channel LRRC8
Authors: Kasuya Go , Nakane Takanori , Yokoyama Takeshi , Jia Yanyan , Inoue Masato , Watanabe Kengo , Nakamura Ryoki , Nishizawa Tomohiro , Kusakizako Tsukasa , Tsutsumi Akihisa , Yanagisawa Haruaki , Dohmae Naoshi , Hattori Motoyuki , Ichijo Hidenori , Yan Zhiqiang , Kikkawa Masahide , Shirouzu Mikako , Ishitani Ryuichiro , Nureki Osamu
Published: May 2018

Maintenance of cell volume against osmotic change is crucial for proper cell functions, such as cell proliferation and migration. The leucine-rich repeat-containing 8 (LRRC8) proteins are anion selective channels, and were recently identified as pore components of the volume-regulated anion channels (VRACs), which extrude anions to decrease the cell volume upon cell-swelling. Here, we present the human LRRC8A structure, determined by a single-particle cryo-electron microscopy analysis. The sea anemone-like structure represents a trimer of dimers assembly, rather than a symmetrical hexameric assembly. The four-spanning transmembrane region has a gap junction channel-like membrane topology, while the LRR region containing 15 leucine-rich repeats forms a long twisted arc. The channel pore is along the central axis and constricted on the extracellular side, where the highly conserved polar and charged residues at the tip of the extracellular helix contribute to the anion and other osmolyte permeability. Comparing the two structural populations facilitated the identification of both compact and relaxed conformations, suggesting that the LRR region is flexible and mobile with rigid-body motions, which might be implicated in structural transitions upon pore opening. Overall, our structure provides a framework for understanding the molecular mechanisms of this unique class of ion channels.
A Cell Cycle Switch Dictates Organ Repair and Tissue Growth Responses in TheDrosophilaHindgut
Authors: Cohen Erez , Allen Scott R , Sawyer Jessica K , Fox Donald T
Published: May 2018

Ploidy-increasing cell cycles drive tissue growth in many developing organs. Such cycles, including endocycles, are increasingly appreciated to drive tissue growth following injury or activated growth signaling in mature organs. In these organs, the regulation and distinct roles of different cell cycles remains unclear. Here, we uncover a programmed switch between cell cycles in theDrosophilahindgut pylorus. Using an acute injury model, we identify mitosis as the response in larval pyloric cells, whereas endocycles occur in adult pyloric cells. By developing a novel genetic method, DEMISE (Dual-Expression-Method-for-Induced-Site-specific-Eradication), we show the cell cycle regulator Fizzy-related dictates the decision between mitosis and endocycles. After injury, both cycles accurately restore tissue mass and genome content. However, in response to sustained growth signaling, only endocycles preserve epithelial architecture. Our data reveal distinct cell cycle programming in response to similar stimuli in mature vs. developmental states and reveal a tissue-protective role of endocycles.
Effectiveness of Demand creation promotions and demand creation personnel in creating demand for Voluntary Medical Male Circumcision in Chitungwiza district, Zimbabwe in 2016
Authors: Matikiti Taurai , Juru Tsitsi P , Gombe Notion , Nsubuga Peter , Tshimanga Mufuta
Published: May 2018

Zimbabwe is one of the 14 countries in eastern and southern Africa that have adopted Voluntary Medical Male Circumcision (VMMC) as an HIV prevention intervention in response to WHO’s recommendation for countries with generalised high HIV epidemics and low VMMC prevalence. However, since 2013 when VMMC was scalled up in Zimbabwe, there was a general low uptake of the VMMC programme particularly on the target age group 20-29 years which has an immediate reduction in the HIV burden. The failure of VMMC uptake in the priority age group prompted the need to analyse the effectiveness of demand creation promotions and personnel used in creating demand for VMMC in Chitungwiza district, Zimbabwe. We employed judgmental sampling, a non-probability sampling technique where we interviewed VMMC clients (n=50) and service providers (n=10) using self administered questions, and community mobilisers (n=10) and demand creation teams (n=3) using face-to-face interviews based on their experience, knowledge and professional judgment. We also randomly analysed client records in the form of 50 Client Intake Forms (CIF) books. We found out that Community mobilisers and Demand creation officers were effective in mobilising clients in the age group 10-15 years and 16-30 years respectively. The use of clinicians (nurses) was also found to be useful in creating demand for VMMC. We also found out that intensifying campaigns during school holidays, the use of tent-based/caravan campaigns and the door to door campaigns were most effective strategies under demand creation promotions. We concluded that there is need to increase demand creation officers and qualified community mobilisers. To regulary train and motivate current community mobilisers as well as increasing the use of clinicians(nurses) in demand creation. We recommended the need to increase the number of mobile caravans and intensifying on the door to door campaigns in the district.
Co-occurrence of a maternally inherited DNMT3A duplication and a paternally inherited pathogenic variant in EZH2 in a child with growth retardation and severe short stature: atypical Weaver syndrome or evidence of a DNMT3A dosage effect?
Authors: Polonis Katarzyna , Blackburn Patrick R. , Urrutia Raul A. , Lomberk Gwen A. , Kruisselbrink Teresa , Cousin Margot A. , Boczek Nicole J. , Hoppman Nicole L. , Babovic-Vuksanovic Dusica , Klee Eric W. , Pichurin Pavel N.
Published: May 2018

Overgrowth syndromes are a clinically heterogeneous group of disorders characterized by localized or generalized tissue overgrowth and varying degrees of developmental and intellectual disability. An expanding list of genes associated with overgrowth syndromes include the histone methyltransferase genes EZH2 and NSD1, which cause Weaver and Sotos syndrome, respectively, and the DNA methyltransferase (DNMT3A) gene that results in Tatton-Brown–Rahman syndrome (TBRS). Here, we describe a 5-year-old female with a paternally inherited pathogenic mutation in EZH2 (c.2050C>T, p.Arg684Cys) and a maternally inherited 505-kb duplication of uncertain significance at 2p23.3 (encompassing five genes, including DNMT3A) who presented with intrauterine growth restriction, slow postnatal growth, short stature, hypotonia, developmental delay, and neuroblastoma diagnosed at the age of 8 mo. Her father had tall stature, dysmorphic facial features, and intellectual disability consistent with Weaver syndrome, whereas her mother had short stature, cognitive delays, and chronic nonprogressive leukocytosis. It has been previously shown that EZH2 directly controls DNA methylation through physical association with DNMTs, including DNMT3A, with concomitant H3K27 methylation and CpG promoter methylation leading to repression of EZH2 target genes. Interestingly, NSD1 is involved in H3K36 methylation, a mark associated with transcriptional activation, and exhibits exquisite dosage sensitivity leading to overgrowth when deleted and severe undergrowth when duplicated in vivo. Although there is currently no evidence of dosage effects for DNMT3A, the co-occurrence of a duplication involving this gene and a pathogenic alteration in EZH2 in a patient with severe undergrowth is suggestive of a similar paradigm and further study is warranted.
How HR practice, work engagement and job crafting influence employee performance
Authors: Guan Xiaoyu , Frenkel Stephen
Published: May 2018

Purpose

Scholars have adopted different theoretical perspectives to explain the influence of HR practice on employee outcomes. However, few studies have investigated the role of human resource (HR) practice in fostering higher in-role and extra-role employee performance by encouraging employee participation in job design, a process referred to as job crafting. Drawing on human resource management (HRM) process theory and the job crafting literature, this study aims to examine how work engagement and job crafting mediate the relationship between employee perceptions of HR practice and employee performance.

Design/methodology/approach

The authors use survey on a sample of 455 employees working in five Chinese manufacturing firms to test their theoretical model.

Findings

This study finds that where management maintains a strong HR system, employees are more likely to be engaged in their work and participate in job crafting. In addition, job crafting on its own, and work engagement and job crafting together, are shown to mediate the HRM–performance relationship.

Research limitations/implications

In a Chinese context, line managers (including supervisors) are both important implementers of HR policy and vary in their adoption of particular roles. Yet our research did not consider the role of these persons in facilitating work engagement or job crafting. Future studies could usefully explore how these managers vary in their attitudes towards job crafting and the roles they play in encouraging this important activity.

Practical implications

One important implication is that strong HR system with distinctive, consistent and consensus HR practices should be used by managers to motivate employees to encourage work engagement and job crafting behaviours.

Originality/value

This study enriches the theoretical framework to explain the underlying mechanism between HRM and employee performance from job crafting perspective.