bluuebunny/crossref_metadata_2025 huggingface dataset:
How does policy focus influence scientific research?
Authors: Kishi Naoko
Published: October 2019

Policy focus gives scientists an incentive to pursue specific research subjects and influences a trend of scientific research. This study examines how public grant is allocated for stem cell research in Japan and shows that scientists are likely to advance their research toward the direction led by policy. Since Japanese scientists discovered a method to generate induced pluripotent stem cell (iPSC) in 2006, public financial and institutional support has skewed toward iPSC. The 2012 Nobel Prize in Physiology or Medicine for iPSC has also had an impact on policy and scientists’ selection of stem cells. Scientists in the top universities are likely to select iPSC research. In addition, iPSC research obtains more amount of public grant funding than other stem cell research. However, scientists’ age has no relevant impact on selecting iPSC research. Finally, this study concludes that targeted public funding skews knowledge portfolio by scientists in a nascent field.
The costs of successful beneficiaries in proceedings brought under section 50 of the Administration of Justice Act 1985—Perry v Neupert
Authors: Grantham Andrew
Published: October 2019

In this article, Andrew Grantham reviews the recent decision of the Court in Perry v Neupert in which HHJ Eyre QC reviewed the entitlement of successful beneficiaries to recover their costs in proceedings to remove the executor named in the testator’s will and the extent to which in such circumstances the executor is entitled to an indemnity out of the assets of the estate.
Identification of Serum Biomarkers to Distinguish Hazardous and Benign Aminotransferase Elevations
Authors: Vazquez Joel H , Clemens Melissa M , Allard Felicia D , Yee Eric U , Kennon-McGill Stefanie , Mackintosh Samuel G , Jaeschke Hartmut , Hambuchen Michael D , McGill Mitchell R
Published: October 2019

The standard circulating biomarker of liver injury in both clinical settings and drug safety testing is alanine aminotransferase (ALT). However, ALT elevations sometimes lack specificity for tissue damage. To identify novel serum biomarkers with greater specificity for injury, we combined unique animal models with untargeted proteomics, followed by confirmation with immunoblotting. Using proteomics, we identified 109 proteins in serum from mice with acetaminophen (APAP)-induced liver injury that were not detectable in serum from mice with benign ALT elevations due to high-dose dexamethasone (Dex). We selected 4 (alcohol dehydrogenase 1A1 [Aldh1a1], aldehyde dehydrogenase 1 [Adh1], argininosuccinate synthetase 1 [Ass1], and adenosylhomocysteinase [Ahcy]) with high levels for further evaluation. Importantly, all 4 were specific for injury when using immunoblots to compare serum from Dex-treated mice and mice with similar lower ALT elevations due to milder models of APAP or bromobenzene-induced liver injury. Immunoblotting for ALDH1A1, ADH1, and ASS1 in serum from APAP overdose patients without liver injury and APAP overdose patients with mild liver injury revealed that these candidate biomarkers can be detected in humans with moderate liver injury as well. Interestingly, further experiments with serum from rats with bile duct ligation-induced liver disease indicated that Aldh1a1 and Adh1 are not detectable in serum in cholestasis and may therefore be specific for hepatocellular injury and possibly even drug-induced liver injury, in particular. Overall, our results strongly indicate that ALDH1A1, ADH1, and ASS1 are promising specific biomarkers for liver injury. Adoption of these biomarkers could improve preapproval drug safety assessment.
Genome Sequence Resource of ‘Candidatus Liberibacter asiaticus’ from Thailand
Authors: Li Tao , Thaochan Narit , Huang Jiaquan , Chen Jianchi , Deng Xiaoling , Zheng Zheng
Published: October 2019

‘Candidatus Liberibacter asiaticus’ (Las) is an unculturable α-proteobacterium associated with citrus huanglongbing (HLB), a devastating disease currently threatening the citrus industry worldwide. Here, we present the genome sequence of Las strain TaiYZ2 from an HLB-affected pomelo tree in Hat Yai district, Songkhla Province, Thailand. The TaiYZ2 genome is composed of 1,230,623 bp with G+C content of 36.4%. This is the first Las genome sequence from Thailand, which will enrich current Las genome resource and facilitate HLB research and management.
Endothelial cell‐specific redox gene modulation inhibits angiogenesis but promotes B16F0 tumor growth in mice
Authors: Yura Yoshimitsu , Chong Brian S. H. , Johnson Ryan D. , Watanabe Yosuke , Tsukahara Yuko , Ferran Beatriz , Murdoch Colin E. , Behring Jessica B. , McComb Mark E. , Costello Catherine E. , Janssen‐Heininger Yvonne M. W. , Cohen Richard A. , Bachschmid Markus M. , Matsui Reiko
Published: October 2019

Glutaredoxin‐1 (Glrx) is a small cytosolic enzyme that removes S‐glutathionylation, glutathione adducts of protein cysteine residues, thus modulating redox signaling and gene transcription. Although Glrx up‐regulation prevented endothelial cell (EC) migration and global Glrx transgenic mice had impaired ischemic vascularization, the effects of cell‐specific Glrx overexpression remained unknown. Here, we examined the role of EC‐specific Glrx up‐regulation in distinct models of angiogenesis; namely, hind limb ischemia and tumor angiogenesis. EC‐specific Glrx transgenic (EC‐Glrx TG) overexpression in mice significantly impaired EC migration in Matrigel implants and hind limb revascularization after femoral artery ligation. Additionally, ECs migrated less into subcutaneously implanted B16F0 melanoma tumors as assessed by decreased staining of EC markers. Despite reduced angiogenesis, EC‐Glrx TG mice unexpectedly developed larger tumors compared with control mice. EC‐Glrx TG mice showed higher levels of VEGF‐A in the tumors, indicating hypoxia, which may stimulate tumor cells to form vascular channels without EC, referred to as vasculogenic mimicry. These data suggest that impaired ischemic vascularization does not necessarily associate with suppression of tumor growth, and that antiangiogenic therapies may be ineffective for melanoma tumors because of their ability to implement vasculogenic mimicry during hypoxia.—Yura, Y., Chong, B. S. H., Johnson, R. D., Watanabe, Y., Tsukahara, Y., Ferran, B., Murdoch, C. E., Behring, J. B., McComb, M. E., Costello, C. E., Janssen‐Heininger, Y. M. W., Cohen, R. A., Bachschmid, M. M., Matsui, R. Endothelial cell‐specific redox gene modulation inhibits angiogenesis but promotes B16F0 tumor growth in mice. FASEB J. 33, 14147‐14158 (2019). www.fasebj.org
Inhibiting repressive epigenetic modification promotes telomere rejuvenation in somatic cell reprogramming
Authors: Yang Lei , Liu Xuefei , Song Lishuang , Su Guanghua , Di Anqi , Bai Chunling , Wei Zhuying , Li Guangpeng
Published: October 2019

The efficiency of somatic cell nuclear transfer (SCNT) reprogramming is extremely low in terms of production of cloned animals. Here, we found that telomere rejuvenation is a critical event for SCNT reprogramming. Through small‐molecule screening, we identified that melatonin significantly improved the in vitro and in vivo developmental competence of SCNT‐derived embryos. Through use of embryonic biopsy, single‐cell RNA sequencing, and quantitative FISH experiments, we revealed that melatonin not only attenuated the zygotic genome activation defect but also facilitated telomere elongation in the SCNT embryos. Further investigation indicated that melatonin inhibited heterochromatic epigenetic modification related to gene silencing including DNA methylation and histone H3 lysine 9 trimethylation. In addition, melatonin could increase the level of activation markers such as acetylated histone H3. This is the first study to characterize melatonin‐treatment and telomere rejuvenation in SCNT‐mediated reprogramming. Moreover, combinational use of melatonin‐treated donor embryos and pseudopregnant recipients achieved synergistic enhancement of the production of cloned animals.—Yang, L., Liu, X., Song, L., Su, G., Di, A., Bai, C., Wei, Z., Li, G. Inhibiting repressive epigenetic modification promotes telomere rejuvenation in somatic cell reprogramming. FASEB J. 33, 13982‐13997 (2019). www.fasebj.org
The role of prison-based interventions for hepatitis C virus (HCV) micro-elimination among people who inject drugs in Montréal, Canada
Authors: Godin Arnaud , Kronfli Nadine , Cox Joseph , Alary Michel , Maheu-Giroux Mathieu
Published: October 2019

Background

In Canada, hepatitis C virus (HCV) transmission primarily occurs among people who inject drugs (PWID) and people with experience in the prison system bare a disproportionate HCV burden. These overlapping groups of individuals have been identified as a priority populations for HCV micro-elimination in Canada, a country currently not on track to achieve its elimination targets. Considering the missed opportunities to intervene in provincial prisons, this study aims to estimate the population-level impact of prison-based interventions and post-release risk reduction strategies on HCV transmission among PWID in high HCV-burdened Canadian city, Montréal.

Methods

A dynamic HCV transmission model among PWID was developed and calibrated to community and prison bio-behavioural surveys in Montréal. The, the relative impact of prison-based testing and treatment or post-release linkage to care, alone or in combination with risk reduction strategies, was estimated from 2018 to 2030, and compared to counterfactual status quo scenario.

Results

Testing and linkage to care interventions implemented over 2018-30 could lead to the greatest declines in prevalence (23%; 95% Credible interval(CrI):17–31%), incidence (20%; 95%CrI: 10–28%), and prevent the most new chronic infections (8%; 95%CrI: 4–11%). Testing and treatment in prison could decrease prevalence, incidence, and fraction of prevented new chronic infections. Combining test and linkage to care with risk reduction measures could further its epidemiological impact, preventing 10% (95%CrI: 5–16%) of new chronic infections. When implemented concomitantly with community-based treatment scale-up, both prison-based interventions had synergistic effects, averting a higher fraction of new chronic infections.

Conclusion

Offering HCV testing and post-release linkage to care in provincial prisons, where incarcerations are frequent and sentences short, could change the course of the HCV epidemic in Montréal. Integration of post-release risk reduction measures and community-based treatment scale-up could also increase the impact of these interventions.
Spatial versus angular resolution for tractography-assisted planning of deep brain stimulation
Authors: Liebrand Luka C. , van Wingen Guido A. , Vos Frans M. , Denys Damiaan , Caan Matthan W.A.
Published: October 2019

Given the restricted total scanning time for clinical neuroimaging, it is unclear whether clinical diffusion MRI protocols would benefit more from higher spatial resolution or higher angular resolution. In this work, we investigated the relative benefit of improving spatial or angular resolution in diffusion MRI to separate two parallel running white matter tracts that are targets for deep brain stimulation: the anterior thalamic radiation and the supero-lateral branch of the medial forebrain bundle. Both these tracts are situated in the ventral anterior limb of the internal capsule, and recent studies suggest that targeting a specific tract could improve treatment efficacy. Therefore, we scanned 19 healthy volunteers at 3T and 7T according to three diffusion MRI protocols with respectively standard clinical settings, increased spatial resolution of 1.4 mm, and increased angular resolution (64 additional gradient directions at b=2200s/mm2). We performed probabilistic tractography for all protocols and quantified the separability of both tracts. The higher spatial resolution protocol improved separability by 41% with respect to the clinical standard, presumably due to decreased partial voluming. The higher angular resolution protocol resulted in increased apparent tract volumes and overlap, which is disadvantageous for application in precise treatment planning. We thus recommend to increase the spatial resolution for deep brain stimulation planning to 1.4 mm while maintaining angular resolution. This recommendation complements the general advice to aim for high angular resolution to resolve crossing fibers, confirming that the specific application and anatomical considerations are leading in clinical diffusion MRI protocol optimization.
A Comprehensive Typing System for Information Extraction from Clinical Narratives
Authors: Caufield J. Harry , Zhou Yichao , Bai Yunsheng , Liem David A. , Garlid Anders O. , Chang Kai-Wei , Sun Yizhou , Ping Peipei , Wang Wei
Published: October 2019

We have developed ACROBAT (Annotation for Case Reports using Open Biomedical Annotation Terms), a typing system for detailed information extraction from clinical text. This resource supports detailed identification and categorization of entities, events, and relations within clinical text documents, including clincal case reports (CCRs) and the free-text components of electronic health records. Using ACROBAT and the text of 200 CCRs, we annotated a wide variety of real-world clinical disease presentations. The resulting dataset, MACCROBAT2018, is a rich collection of annotated clinical language appropriate for training biomedical natural language processing systems.
Evaluation of a brief intervention to reduce cell phone use in college students
Authors: Piper Brian J. , Daily Shay M. , Martin Sarah L. , Martin Maurice W.
Published: October 2019

Background

Excessive cell phone use contributes to distracted driving, may increase risk for automobile accidents, and a minority of mobile phone users exhibit behaviors consistent with technological addiction. The purpose of this study was to determine whether cell phone beliefs and behaviors could be changed by a brief educational encounter. The Theory of Reasoned Action provided a lens for viewing attitudes and behavior.

Methods

A one-week pre-post design with a thirty-day follow-up was used with participants (N = 215, 67.0% female, age = 20.0 + 1.6) assigned to a peer led intervention or comparison groups. The intervention included cell-phone educational materials. A short index of cell phone behavior was developed which showed good internal consistency with a Cronbach’s alpha of .81.

Results

The intervention group “agreed” or “strongly-agreed” more than the comparison group on five of the seven areas of cell phone beliefs and behaviors (p < 0.05, item Cohen’s d = .32 to .47, total d = .50) at one-week following receipt of informational materials.

Discussion

We conclude that attitudes and behaviors regarding cell phones are malleable and susceptible to change in young-adults following a brief psychoeducational intervention.
Increased Mortality in Patients with Standard EEG Findings of “Diffuse Slowing”
Authors: Wanzek Rob , Bormann Nicholas , Shabbir Yaseen , Saito Taku , Yamada Thoru , Shinozaki Gen
Published: October 2019

Background/Objectives

We aim to confirm the association between the high risk score on bispectral electroencephalogram (BSEEG) and mortality by comparing outcomes for those with “diffuse slowing” and normal findings on standard EEG.

Design

This is a retrospective study conducted with patient chart data from March 2015 to March 2017.

Setting

Single center study at a tertiary care academic hospital in the Midwest region of the USA.

Participants

1069 subjects aged 55 years and older who were on an inpatient floor or intensive care unit and received a standard 24-hour EEG.

Measurements

Primary outcome was all-cause mortality at 30-, 90-, 180-, and 365-days. Secondary outcomes were time-to-discharge, and discharge to home.

Results

Patients with “diffuse slowing” on standard EEG was significantly associated with 30-, 90-, 180-, and 365-day mortality (P < .001) compared to those with normal EEG findings when controlling for age, sex, and Carlson Comorbidity Index. Those with diffuse slowing also had a longer time to discharge (P < 0.001) and were less likely to discharge to home (P < 0.001) when controlling for the same factors. Findings were similar when limiting the study to only patients whose clinical status indicated “awake” at time of EEG, except for 30-day mortality.

Conclusion

Our findings show that a standard EEG finding of “diffuse slowing” for inpatients 55 year or older is associated with greater mortality. This study strengthens the importance of the association found between high BSEEG score and mortality.
Micro-costing Diagnostics in Oncology: From Single-Gene Testing to Whole Genome Sequencing
Authors: Pasmans Clémence TB , Tops Bastiaan BJ , Steeghs Elisabeth MP , Coupé Veerle MH , Grünberg Katrien , de Jong Eiko K , Schuuring Ed MD , Willems Stefan M , Ligtenberg Marjolijn JL , Retèl Valesca P. , van Snellenberg Hans , de Bruijn Ewart , Cuppen Edwin , Frederix Geert WJ
Published: October 2019

Purpose

Predictive diagnostics play an increasingly important role in personalized medicine for cancer treatment. Whole genome sequencing (WGS) based treatment selection is expected to rapidly increase worldwide. Detailed and comparative cost analyses of diagnostic techniques are an essential element in decision-making. This study aimed to calculate and compare the total cost of currently used diagnostic techniques and of WGS in treatment of non-small cell lung carcinoma (NSCLC), melanoma, colorectal cancer (CRC) and gastrointestinal stromal tumor (GIST) in the Netherlands.

Methods

The activity-based costing (ABC) method was conducted to calculate the total cost of included diagnostic techniques based on data provided by Dutch pathology laboratories and the Dutch centralized cancer WGS facility. Costs were allocated to four categories: capital costs, maintenance costs, software costs and operational costs. Outcome measures were total cost per cancer patient per included technique, and the total cost per cancer patient per most commonly applied technique (combination) for each cancer type.

Results

The total cost per cancer patient per technique varied from € 58 (Sanger sequencing, 3 amplicons) to € 4738 (paired tumor-normal WGS). The operational costs accounted for the vast majority over 90 % of the total per cancer patient technique costs. The most important operational cost drivers were consumables followed by personnel (for sample preparation and primary data analysis).

Conclusion

This study outlined in detail all costing aspects and cost prices of current and new diagnostic modalities used in treatment of NSCLC, melanoma, CRC and GIST in the Netherlands. Detailed cost differences and value comparisons between these diagnostic techniques enable future economic evaluations to support decision-making on implementation of WGS and other diagnostic modalities in routine clinical practice.
Yolk-Sac-Derived Macrophages Progressively Expand in the Mouse Kidney with Age
Authors: Ide Shintaro , Yahara Yasuhito , Kobayashi Yoshihiko , Strausser Sarah A. , Watwe Anisha , Pivratsky Jamie R. , Crowley Steven D. , Shinohara Mari L. , Alman Benjamin A. , Souma Tomokazu
Published: October 2019

Renal macrophages represent a highly heterogeneous and specialized population of myeloid cells with mixed developmental origins from the yolk-sac and hematopoietic stem cells (HSC). They promote both injury and repair by regulating inflammation, angiogenesis, and tissue remodeling. Recent reports highlight differential roles for ontogenically distinct renal macrophage populations in disease. However, little is known about how these populations change over time in normal, uninjured kidneys. Prior reports demonstrated a high proportion of HSC-derived macrophages in the young adult kidney. Unexpectedly, using genetic fate-mapping and parabiosis studies, we find that yolk-sac-derived macrophages progressively expand in number with age and become a major contributor to the renal macrophage population in older mice. This chronological shift in macrophage composition involves cellular proliferation and recruitment from circulating progenitors and may contribute to the distinct immune responses, limited reparative capacity, and increased disease susceptibility of kidneys in the elderly population.
Identification of a Central Neural Circuit that Regulates Anxiety-induced Bone Loss
Authors: Yang Fan , Liu Yunhui , Chen Shanping , Dai Zhongquan , Yang Dazhi , Gao Dashuang , Shao Jie , Wang Yuyao , Wang Ting , Zhang Zhijian , Zhang Lu , Lu William W , Tu Jie , Li Yinghui , Wang Liping
Published: October 2019

The homeostasis of bone metabolism is finely regulated by the central nervous system and recent studies have suggested that mood disorders, such as anxiety, are closely related to bone metabolic abnormalities; however, our understanding of central neural circuits regulating bone metabolism is still largely limited. In this study, we first demonstrate that confined isolation of human participants under normal gravity resulted in decreased bone density and elevated anxiety levels. We then used an established mouse model to dissect the neural circuitry regulating anxiety-induced bone loss. Combining electrophysiological, optogenetic and chemogenetic approaches, we demonstrate that GABAergic neural circuitry in ventromedial hypothalamus (VMH) modulates anxiety-induced bone loss; importantly, the GABAergic input in VMHdm arose from a specific group of somatostatin neurons in the bed nucleus of the stria terminalis (BNST), which is both indispensable for anxiety-induced bone loss and able to trigger bone loss in the absence of stressors. VGLUT2 neurons in Nucleus tractus solitaries (NTS) and peripheral sympathetic system were employed by this BNST-VMH neural circuit to regulate anxiety-induced bone loss. Overall, we uncovered new GABAergic neural circuitry from the forebrain to hypothalamus, used in the regulation of anxiety-induced bone loss, and revealed a population of somatostatin neurons in BNST not previously implicated in bone mass regulation. These findings thus identify the underlying central neural mechanism of psychiatric disorders, such as anxiety, that influences bone metabolism at the circuit level.

One Sentence Summary

Identification of a new GABAergic neural circuit from forebrain to hypothalamus used for regulation of anxiety-induced bone loss.
Transcriptome reconstruction and functional analysis of eukaryotic marine plankton communities via high-throughput metagenomics and metatranscriptomics
Authors: Vorobev Alexey , Dupouy Marion , Carradec Quentin , Delmont Tom O. , Annamalé Anita , Wincker Patrick , Pelletier Eric
Published: October 2019

Large scale metagenomic and metatranscriptomic data analyses are often restricted by their genecentric approach, limiting the ability to understand organismal and community biology. De novo assembly of large and mosaic eukaryotic genomes from complex meta -omics data remains a challenging task, especially in comparison with more straightforward bacterial and archaeal systems. Here we use a transcriptome reconstruction method based on clustering co-abundant genes across a series of metagenomic samples. We investigated the co-abundance patterns of ~37 million eukaryotic unigenes across 365 metagenomic samples collected during the Tara Oceans expeditions to assess the diversity and functional profiles of marine plankton. We identified ~12 thousand co-abundant gene groups (CAGs), encompassing ~7 million unigenes, including 924 metagenomics based transcriptomes (MGTs, CAGs larger than 500 unigenes). We demonstrated the biological validity of the MGT collection by comparing individual MGTs with available references. We identified several key eukaryotic organisms involved in dimethylsulfoniopropionate (DMSP) biosynthesis and catabolism in different oceanic provinces, thus demonstrating the potential of the MGT collection to provide functional insights on eukaryotic plankton. We established the ability of the MGT approach to capture interspecies associations through the analysis of a nitrogen-fixing haptophyte-cyanobacterial symbiotic association. This MGT collection provides a valuable resource for an exhaustive analysis of eukaryotic plankton in the open ocean by giving access to the genomic content and functional potential of many ecologically relevant eukaryotic species.
Multi-modality neuroimaging brain-age in UK Biobank: relationship to biomedical, lifestyle and cognitive factors
Authors: Cole James H
Published: October 2019

The brain-age paradigm is proving increasingly useful for exploring ageing-related disease and can predict important future health outcomes. Most brain-age research utilises structural neuroimaging to index brain volume. However, ageing affects multiple aspects of brain structure and function, which can be examined using multi-modality neuroimaging. Using UK Biobank, brain-age was modelled in n=2,205 healthy people with T1-weighted MRI, T2-FLAIR, T2*, diffusion-MRI, task fMRI and resting-state fMRI. In a held-out healthy validation set (n=520), chronological age was accurately predicted (r=0.79, mean absolute error=3.52 years) using LASSO regression, higher than using any modality separately. Thirty-four neuroimaging phenotypes were deemed informative by the regression (after bootstrapping); predominantly grey-matter volume and white-matter microstructure measures. When applied to new individuals from UK Biobank (n=14,701), significant associations with multi-modality brain-predicted age difference (brain-PAD) were found for: stroke history, diabetes diagnosis, smoking, alcohol intake and some, but not all, cognitive measures (corrected p<0.05). Multi-modality neuroimaging can improve brain-age prediction, and derived brain-PAD values are sensitive to biomedical and lifestyle factors that negatively impact brain and cognitive health.
Promoter proximal pausing limits Yki-induced tumorous growth in Drosophila
Authors: Nagarkar Sanket , Wasnik Ruchi , Govada Pravallika , Cohen Stephen , Shashidhara LS
Published: October 2019

Promoter proximal pausing (PPP) of RNA Polymerase II has emerged as a crucial rate-limiting-step in the regulation of gene expression. Regulation of PPP is brought about by complexes 7SK snRNP, P-TEFb (Cdk9/cycT) and the Negative Elongation Factor (NELF) which are highly conserved from Drosophila to humans. Here we show that RNAi-mediated depletion of bin3 or Hexim of the 7SK snRNP complex or depletion of individual components of the NELF complex enhance Yki-driven growth leading to neoplastic transformation of Drosophila wing imaginal discs. We also show that increased CDK9 expression cooperates with Yki, in driving neoplastic growth. Interestingly, over-expression of CDK9 on its own or in the background of depletion of one of the components of 7SK snRNP or the NELF complex necessarily and specifically needed Yki over-expression to cause tumorous growth. Genome-wide gene expression analyses suggested that deregulation of protein homeostasis is associated with tumorous growth of wing imaginal discs. As both Fat/Hippo/Yki pathway and PPP are highly conserved, our observations may provide insights into mechanisms of oncogenic function of YAP, the orthologue of Yki in human.
Quantitative properties of a feedback circuit predict frequency-dependent pattern separation
Authors: Braganza Oliver , Müller-Komorowska Daniel , Kelly Tony , Beck Heinz
Published: October 2019

Feedback inhibitory motifs are thought to be important for pattern separation across species. How feedback circuits may implement pattern separation of biologically plausible, temporally structured input in mammals is, however, poorly understood. We have quantitatively determined key properties of net feedback inhibition in the mouse dentate gyrus, a region critically involved in pattern separation. Feedback inhibition is recruited steeply with a low dynamic range (0 to 4% of active GCs), and with a non-uniform spatial profile. Additionally, net feedback inhibition shows frequency-dependent facilitation, driven by strongly facilitating mossy fiber inputs. Computational analyses show a significant contribution of the feedback circuit to pattern separation of theta modulated inputs, even within individual theta cycles. Moreover, pattern separation was selectively boosted at gamma frequencies, in particular for highly similar inputs. This effect was highly robust, suggesting that frequency dependent pattern separation is a key feature of the feedback inhibitory microcircuit.
Genome Sequence of Segmented Filamentous Bacteria Present in the Human Intestine
Authors: Jonsson Hans , Hugerth Luisa W. , Sundh John , Andersson Anders F.
Published: October 2019

Segmented filamentous bacteria (SFB) colonize the small intestine of a variety of animals in a host-specific manner. SFB are physically attached to the host’s intestinal epithelium and affect several functions related to the immune system, among them IgA production and T-cell maturation. Until now, no human-specific SFB genome had been described. Here, we report the metagenomic reconstruction of an SFB genome from a human ileostomy sample. Phylogenomic analysis clusters the genome with the SFB genomes from mouse, rat and turkey, but the genome is genetically distinct, displaying 65-71% average amino acid identity to the other genomes, and is tentatively unique for the human small intestine. By screening human faecal metagenomic datasets, we identified individuals carrying sequences identical to the new SFB-genome. We thus conclude that a unique SFB variant exists in humans and we foresee a renewed interest in the elucidation of SFB functionality in this environment.
Impact of intensive care unit admission during handover on mortality: a propensity matched cohort study
Authors: Midega Thais Dias , Filho Newton Carlos Viana Leite , Nassar Antônio Paulo , Alencar Roger Monteiro , Neto Antônio Capone , Ferraz Leonardo Rolim , Corrêa Thiago Domingos
Published: October 2019

Introduction

Handover is a process of transferring information, responsibility and authority for providing care of critically ill patients from a departing intensivist to an oncoming intensivist. The effect of i admission during a medical handover on clinical outcomes is unknown.

Objectives

Our purpose was to evaluate the impact of ICU admission during a medical handover on clinical outcomes.

Methods

Post hoc analysis of a cohort study addressing the effect of ICU admissions during the handover on outcomes. This retrospective, single center, propensity matched cohort study was conducted in a 41-bed open general ICU located in a private tertiary care hospital in São Paulo, Brazil. Based on time of ICU admission, patients were categorized into two cohorts: handover group (ICU admission between 6:30 am to 7:30 or 6:30 pm to 7:30 pm) or control group (admission between 7:31 am to 6:29 pm or 7:31 pm to 6:29 am). Patients in the handover group were propensity matched to patients in the control group at 1:2 ratio. Our primary outcome was hospital mortality.

Results

Between June 1, 2013 and May 31, 2015, 6,650 adult patients were admitted to the ICU. Following exclusion of ineligible participants, 5,779 patients [389 (6.7%) in handover group and 5390 (93.3%) in control group] were eligible for propensity score matching, of whom 1,166 were successfully matched [389 (33.4%) handover group and 777 (66.6%) in control group]. Before matching, hospital mortality was 14.1% (55/389 patients) in handover group compared to 11.7% (628/5,390) in control group (p=0.142). After propensity-score matching, ICU admission during handover was not associated with increased risk of ICU (OR, 1.40; 95% CI, 0.92 to 2.11; p=0.11) and hospital (OR, 1.23; 95%CI, 0.85 to 1.75; p=0.26) mortality. ICU and hospital length of stay did not differ between the groups.

Conclusion

In this propensity-matched single center cohort study, ICU admission during medical handover did not affect clinical outcomes.
Heritability and relationship of oxytocin receptor gene variants with social behavior and central oxytocin in colony-reared adult female rhesus macaques
Authors: De Leon Desirée , Walum Hasse , McCormack Kai M. , LaPrairie Jamie L. , Lindell Stephen G. , Firesryche Ashley , Johnson Zach , Wilson Mark E. , Barr Christina S. , Sanchez Mar M. , Young Larry J.
Published: October 2019

The genetic contributions to sociality are an important research focus for understanding individual variation in social function and risk of social deficits in neurodevelopmental disorders (e.g. autism). The neuropeptide oxytocin (OXT) and its receptor, OXTR, influence social behavior across species. In humans and animals, common variants within the OXTR gene (OXTR) have been associated with varying socio-behavioral traits. However, the reported magnitude of influence of individual variants on complex behavior has been inconsistent. Compared to human studies, non-human primate (NHP) studies in controlled environments have the potential to result in robust effects detectable in relatively small samples. Here we estimate heritability of social behavior and central OXT concentrations in 214 socially-housed adult female rhesus macaques, a species sharing high similarity with humans in genetics, physiology, brain and social complexity. We present a bioinformatically-informed approach for identifying single nucleotide polymorphisms (SNPs) with likely biological relevance. We tested 13 common SNPs in regulatory and coding regions ofOXTRfor associations with behavior (pro-social, anxiety-like, and aggressive) and OXT concentration in cerebrospinal fluid (CSF). We found moderate rates of heritability for both social behavior and CSF OXT concentrations. No tested SNPs showed significant associations with behaviors or CSF in this sample. Associations between OXT CSF and social behavior were not significant either. SNP effect sizes were generally comparable to those reported in human studies of complex traits. While environmental control and a socio-biological similarity with humans is an advantage of rhesus models for detecting smaller genetic effects, it is insufficient to obviate large sample sizes necessary for appropriate statistical power.
Effects of initial microbial biomass abundance on respiration during pine litter decomposition
Authors: Albright Michaeline B.N. , Runde Andreas , Lopez Deanna , Gans Jason , Sevanto Sanna , Woolf Dominic , Dunbar John
Published: October 2019

Microbial biomass is increasingly used to predict respiration in soil organic carbon (SOC) models. Its increased use combined with the difficulty of accurately measuring this variable points a need to directly assess the importance of microbial biomass abundance for carbon (C) cycling. To test the hypothesis that the initial microbial biomass abundance (i.e. biomass abundance on new plant litter) is a strong driver of plant litter C cycling, we manipulated biomass abundance by 10 and 100-fold dilution and composition using 12 source communities on sterile pine litter and measured respiration in microcosms for 30 days. In the first two days of microbial growth on fresh litter, a 100-fold difference in initial biomass abundance caused an average difference in respiration of nearly 300%, but the effect rapidly declined to less than 30% in 10 days and to 14% in 30 days. Parallel simulations with a soil carbon model, SOMIC 1.0, also predicted a 14% difference over 30 days, consistent with the experimental results. Model simulations predicted convergence of cumulative CO2 to within 10% in three months and within 4% in three years. Rapid microbial growth likely attenuates the effects of large initial differences in biomass abundance. In contrast, the persistence of source community as an explanatory factor in driving differences in respiration across microcosms supports the importance of microbial composition in C cycling. Overall, the results suggest that the initial abundance of microbial biomass on litter is a weak driver of C flux from litter decomposition over long timescales (months to years) when litter communities have equal nutrient availability. By extension, slight variation in the timing of microbial dispersal to fresh litter is likely to be a minor factor in long-term C flux.

Importance

Microbial biomass is one of the most common microbial parameters used in land carbon (C) cycle models, however, it is notoriously difficult to measure accurately. To understand the consequences of mismeasurement, as well as the broader importance of microbial biomass abundance as a direct driver of ecological phenomena, greater quantitative understanding of the role of microbial biomass abundance in environmental processes is needed. Using microcosms, we manipulated the initial biomass of numerous microbial communities across a 100-fold range and measured effects on CO2 production during plant litter decomposition. We found that the effects of initial biomass abundance on CO2 production was largely attenuated within a week, while the effects of community type remained significant over the course of the experiment. Overall, our results suggest that initial microbial biomass abundance in litter decomposition within an ecosystem is a weak driver of long-term C cycling dynamics.
Transcriptomic profiling of PBDE-exposed HepaRG cells unveils critical lncRNA-PCG pairs involved in intermediary metabolism
Authors: Zhang Angela , Li Cindy Yanfei , Kelly Edward J. , Sheppard Lianne , Cui Julia Yue
Published: October 2019

Polybrominated diphenyl ethers (PBDEs) were formally used as flame-retardants and are chemically stable, lipophlic persistent organic pollutants which are known to bioaccumulate in humans. Although its toxicities are well characterized, little is known about the changes in transcriptional regulation caused by PBDE exposure. Long non-coding RNAs (lncRNAs) are increasingly recognized as key regulators of transcriptional and translational processes. It is hypothesized that lncRNAs can regulate nearby protein-coding genes (PCGs) and changes in the transcription of lncRNAs may act incisto perturb gene expression of its neighboring PCGs. The goals of this study were to 1) characterize PCGs and lncRNAs that are differentially regulated from exposure to PBDEs; 2) identify PCG-lncRNA pairs through genome annotation and predictive binding tools; and 3) determine enriched canonical pathways caused by differentially expressed lncRNA-PCGs pairs. HepaRG cells, which are human-derived hepatic cells that accurately represent gene expression profiles of human liver tissue, were exposed to BDE-47 and BDE-99 at a dose of 25 μM for 24 hours. Differentially expressed lncRNA-PCG pairs were identified through DESeq2 and HOMER; significant canonical pathways were determined through Ingenuity Pathway Analysis (IPA). LncTar was used to predict the binding of 19 lncRNA-PCG pairs with known roles in drug-processing pathways. Genome annotation revealed that the majority of the differentially expressed lncRNAs map to PCG introns. PBDEs regulated overlapping pathways with PXR and CAR such as protein ubiqutination pathway and PPARα-RXRα activation but also regulate distinctive pathways involved in intermediary metabolism. BDE-47 uniquely regulated signaling by Rho Family GTPases and PBDE-99 uniquely regulates JAK/Stat signaling, bile acid biosynthesis, sirtuin signaling pathway, and autophagy. In conclusion, lncRNAs play essential roles in modifying important pathways involved in intermediary metabolism such as carbohydrate and lipid metabolism.
THAP11F80Lcobalamin disorder-associated mutation reveals normal and pathogenic THAP11 functions in gene expression and cell proliferation
Authors: Dehaene Harmonie , Praz Viviane , Lhôte Philippe , Lopes Maykel , Herr Winship
Published: October 2019

Twelve human THAP proteins share the THAP domain, an evolutionary conserved zinc-finger DNA-binding domain. Studies of different THAP proteins have indicated roles in gene transcription, cell proliferation and development. We have analyzed this protein family, focusing on THAP7 and THAP11. We show that human THAP proteins possess differing homo- and heterodimer formation properties and interaction abilities with the transcriptional co-regulator HCF-1. HEK-293 cells lacking THAP7 were viable but proliferated more slowly. In contrast, HEK-293 cells were very sensitive to THAP11 alteration. Nevertheless, HEK-293 cells bearing a THAP11 mutation identified in a patient suffering from cobalamin disorder (THAP11F80L) were viable although proliferated more slowly. Cobalamin disorder is an inborn vitamin deficiency characterized by neurodevelopmental abnormalities, most often owing to biallelic mutations in theMMACHCgene, whose gene product MMACHC is a key enzyme in the cobalamin (vitamin B12) metabolic pathway. We show that THAP11F80Lselectively affected promoter binding by THAP11, having more deleterious effects on a subset of THAP11 targets, and resulting in altered patterns of gene expression. In particular, THAP11F80Lexhibited a strong effect on association with theMMACHCpromoter and led to a decrease inMMACHCgene transcription, suggesting that the THAP11F80Lmutation is directly responsible for the observed cobalamin disorder.
Dementia is Associated with a Syndrome of Global Neuropsychiatric Disturbance
Authors: Royall Donald R. , Palmer Raymond F. ,   the Alzheimer’s Disease Neuroimaging Initiative
Published: October 2019

Objective

Global factors have been identified in measures of cognitive performance (i.e., Spearman’s g) and psychopathology (i.e., “General Psychopathology”, “p”). Dementia is also strongly determined by the latent phenotype “δ”, derived from g. We wondered if the Behavior and Psychological Symptoms of Dementia (BPSD) might arise from an association between δ and p.

Methods

δ and p were constructed by confirmatory factor analyses in data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). δ and orthogonal factors representing “domain-specific” variance in memory (MEM) and executive function (EF) were regressed onto p and orthogonal factors representing “domain-specific” variance in positive (+) and negative (-) symptoms rated by the Neuropsychiatric Inventory Nursing Home Questionnaire (NPI-Q) by multiple regression in a structural equation model (SAM) framework.

Results

Model fit was excellent (CFI = 0.98, RMSEA = 0.03). δ was strongly associated with p, (+) and (-) and strongly associated with p (r = −0.57, p<0.001). All three associations were inverse (adverse). Independently of δ, MEM was uniquely associated with (+), while ECF was associated with (-). Both associations were moderately strong. ECF was also weakly associated with p.

Conclusions

Dementia severity (δ) derived from general intelligence (g) is specifically associated with general psychopathology (p). This is p’s first demonstration in an elderly sample and the first to distinguish the global behavioral and psychological symptoms specific to dementia (BPSSD) from behavioral disturbances arising by way of non-dementing, albeit likely disease-specific, processes affecting domain-specific cognitive and behavioral constructs. Our findings call into question the utility of proposed regional interventions in BPSSD, and point to the need to explore global interventions against dementia-specific behavioral features.
Pangenomic read mapping
Authors: Anari Siavash Sheikhizadeh , de Ridder Dick , Schranz M. Eric , Smit Sandra
Published: October 2019

In modern genomics, mapping reads to a single reference genome is common practice. However, a reference genome does not necessarily accurately represent a population or species and as a result a substantial percentage of reads often cannot be mapped. A number of graph-based variation-aware mapping methods have recently been proposed to remedy this. Here, we propose an alternative multi-reference approach, which aligns reads to large collections of genomes simultaneously. Our approach, an extension to our pangenomics suite PanTools (https://git.wur.nl/bioinformatics/pantools), is as accurate as state-of the-art tools but more efficient on large numbers of genomes. We successfully applied PanTools to map genomic and metagenomic reads to large collections of viral, archaeal, bacterial, fungal and plant genomes.
Transcription-independent TFIIIC-bound sites cluster near heterochromatin boundaries within lamina-associated domains in C. elegans
Authors: Stutzman Alexis V. , Liang April S. , Beilinson Vera , Ikegami Kohta
Published: October 2019

BACKGROUND

Chromatin organization is central to precise control of gene expression. In various eukaryotic spieces, domains of pervasive cis-chromatin interactions demarcate functional domains of the genomes. In nematode C. elegans, however, pervasive chromatin contact domains are limited to the dosage-compensated sex chromosome, leaving the principle of C. elegans chromatin organization unclear. Transcription Factor III C (TFIIIC) is a basal transcription factor complex for RNA Polymerase III, and is implicated in chromatin organization. TFIIIC binding without RNA Polymerase III co-occupancy, referred to as extra-TFIIIC binding, has been implicated in insulating active and inactive chromatin domains in yeasts, flies, and mammalian cells. Whether extra-TFIIIC sites are present and contribute to chromatin organization in C. elegans remains unknown.

RESULTS

We identified 504 TFIIIC-bound sites absent of RNA Polymerase III and TATA-binding protein co-occupancy characteristic of extra-TFIIIC sites in C. elegans embryos. Extra-TFIIIC sites constituted half of all identified TFIIIC binding sites in the genome. Extra-TFIIIC sites formed dense clusters in cis. The clusters of extra-TFIIIC sites were highly over-represented within the distal arm domains of the autosomes that presented a high level of heterochromatin-associated histone H3K9 trimethylation (H3K9me3). Furthermore, extra-TFIIIC clusters were embedded in the lamina-associated domains. Despite the heterochromatin environment of extra-TFIIIC sites, the individual clusters of extra-TFIIIC sites were devoid of and resided near the individual H3K9me3-marked regions.

CONCLUSION

Clusters of extra-TFIIIC sites were pervasive in the arm domains of C. elegans autosomes, near the outer boundaries of H3K9me3-marked regions. Given the reported activity of extra-TFIIIC sites in heterochromatin insulation in yeasts, our observation raised the possibility that TFIIIC may also demarcate heterochromatin in C. elegans.
A cucumber green mottle mosaic virus vector for virus-induced gene silencing in cucurbit plants
Authors: Liu Mei , Liang Zhiling , Aranda Miguel A. , Hong Ni , Liu Liming , Kang Baoshan , Gu Qinsheng
Published: October 2019

Cucurbits produce fruits or vegetables that have great dietary importance and economic significance worldwide. The published genomes of at least 11 cucurbit species are boosting gene mining and novel breeding strategies, however genetic transformation in cucurbits is impractical as a tool for gene function validation due to low transformation efficiencies. Virus-induced gene silencing (VIGS) is a potential alternative tool. So far, very few ideal VIGS vectors are available for cucurbits. Here, we describe a new VIGS vector derived from cucumber green mottle mosaic virus (CGMMV), a monopartite virus that infects cucurbits naturally. We show that the CGMMV vector is competent to induce efficient silencing of the phytoene desaturase (PDS) gene in the model plant Nicotiana benthamiana and in cucurbits, including watermelon, melon, cucumber and bottle gourd. Infection with the CGMMV vector harboring PDS sequences of 69-300 bp in length in the form of sense-oriented or hairpin cDNAs resulted in photobleaching phenotypes in N. benthamiana and cucurbits by PDS silencing. Additional results reflect that silencing of the PDS gene could persist for over two months and the silencing effect of CGMMV-based vectors could be passaged. These results demonstrate that CGMMV vector could serve as a powerful and easy-to-use tool for characterizing gene function in cucurbits.

One sentence summary

A CGMMV-based vector enables gene function studies in cucurbits, an extremely low efficiency species for genetic transformation.