bluuebunny/crossref_metadata_2025 huggingface dataset:
Nurses in Advanced Roles as a strategy for equitable access to health care in the WHO Western Pacific Region: A mixed methods study
Authors: Kim Sue , Lee Tae Wha , Kim Gwang Suk , Cho Eunhee , Jang Yeonsoo , Baek Seoyoung , Lindsay David , Chan Sally Wai-Chi , Lee Regina Lai Tong , Guo Aimin , Wong Frances Kam Yuet , Yu Doris , Chair Sek Ying , Shimpuku Yoko , Mashino Sonoe , Lim Anecita Gigi , Bonito Sheila , Rumsey Michele , Neill Amanda , Hazarika Indrajit , Choi Mona
Published: May 2020

Purpose: This study investigated the current responsibilities of nurses in advanced roles (NARs), future healthcare needs, and the implications of these components for professional development of nurses.
Design: This study employed a descriptive survey on the current status of NARs in the Western Pacific region (WPR), followed by a Delphi survey and exploratory interviews. Experts from WPR countries who were individuals with recognized national expertise on NARs from clinical, academic, and/or government-related backgrounds were invited to participate in this study from December 2017 to December 2018.
Methods: Fifteen experts from ten countries provided descriptive data on the current status of NARs in the WPR via email. The data were used to grasp the spectrum of NAR and construct a working definition of NARs. This formed the basis for the Delphi survey, in which 27 experts from 14 countries completed the following three sections via email: Areas in need of NARs; Strengths, Weakness, Opportunities, and Threats analysis; and the role of NARs in promoting universal health coverage. Descriptive statistics were used for the survey and Delphi survey. For the exploratory interviews, semi-structured individual interviews were conducted with 19 key informants from 12 countries. Content analysis was performed for interview data. Delphi and interview findings were integrated in the final stage.
Findings: Thirty-seven roles were identified and categorized according to the regulations for the specific roles. Emergency care, critical care, elderly health, child health, and rural/remote communities were identified as fields with particular need for NARs. Providing effective services, influencing government leadership, and advocating for health system sustainability were deemed necessary for NAR to improve equitable healthcare access.
Conclusions: Demand for NARs is high in the WPR and we presented 15 items across five core strategic areas within the nursing community to enhance NAR development. Governmental-level recommendations include establishing legislative protection, remuneration, supportive channels, and conducting national needs assessments.
Accelerated approval of non-cancer drugs by the US Food and Drug Administration: A protocol for a meta-epidemiological investigation
Authors: Omae Kenji , Onishi Akira , Sahker Ethan , Furukawa Toshi A
Published: May 2020

The US Food and Drug Administration (FDA)'s accelerated approval program, in which drugs are approved on the basis of surrogate endpoints, has been a source of controversy in the context of risk-benefit trade-offs. The FDA recently reported on the 25-year experience with the program and concluded that the low failure rate in post-approval confirmatory trials was evidence that the program was operating effectively. However, many studies have revealed manufacturers' poor adherence to obligation of conducting confirmatory trials, and also concerned the harm and cost of cancer drugs approved through this program based on the limited evidence. To date, few studies have investigated accelerated approval of non-cancer drugs. Therefore, the purpose of this study is to review trends in the FDA's utilization of its accelerated approval program for non-cancer drugs and clarify the status of fulfillment of social obligations by the FDA and sponsors in the program. The FDA' s documents will be reviewed at Drugs@FDA to identify pre-approval and confirmatory trials and regulatory updates for drug indications granted accelerated approval other than cancer treatments. We will further search PubMed, Google/Google Scholar, and the sponsors' websites to match each identified confirmatory trial to publications in the medical literature.
High seroreactivity against SARS-CoV-2 Spike epitopes in a pre SARS-CoV-2 cohort: implications for antibody testing and vaccine design
Authors: Palm Kaia , Jaago Mariliis , Rahni Annika , Pupina Nadezhda , Pihlak Arno , Sadam Helle , Avarlaid Annela , Planken Anu , Planken Margus , Haring Liina , Vasar Eero , Bacevic Miljana , Lambert France , Kalso Eija , Pussinen Pirkko , Tienari Pentti , Vaheri Antti , Lindholm Dan , Timmusk Tonis , Ghaemmaghami Amir M
Published: May 2020

Little is known about the quality of polyclonal antibody responses in COVID-19 patients, and how it correlates with disease severity or patients' prior exposure to other pathogens. The whole polyclonal antibody repertoire in a retrospective cohort of 538 individuals was mapped against SARS-CoV-2 spike (S) glycoprotein, the main target of antibody immune responses in SARS-CoV-2 infection. Bioinformatic predictions identified 15 major B cell epitopes for S of SARS-CoV-2. Several epitopes localised in RBD of S including those spanning the ACE2-binding site, the highly conserved cryptic epitope of the neutralizing antibody of SARS-CoV, and fusion/entry domains of HR1 and HR2 of S protein of SARS-CoV-2. Intriguingly, some of these epitopes have cross-reactivity to antigens of common pathogens, potentially affecting SARS-CoV-2 infection outcome. High level of anti-Spike SARS-CoV-2 seroreactivity in populations with no history of exposure to SARS-CoV-2 is of clinical relevance and could underpin better understanding of COVID-19 pathophysiology in different populations and provide a blueprint for design of effective vaccines and developing better strategies for antibody testing.
Risks to Children under-five in India from COVID-19
Authors: Frost Isabel , Tseng Katie , Hauck Stephanie , Kappor Geetanjali , Sriram Aditi , Nandi Arindam , Laxminarayan Ramanan
Published: May 2020

Objective: The novel coronavirus, COVID-19, has rapidly emerged to become a global pandemic and is known to cause a high risk to patients over the age of 70 and those with co-morbidities, such as hypertension and diabetes. Though children are at comparatively lower risk compared to adults, the Indian population has a large young demographic that is likely to be at higher risk due to exposure to pollution, malnutrition and poor access to medical care. We aimed to quantify the potential impact of COVID-19 on Indias child population.

Methods: We combined district family household survey data with data from the COVID-19 outbreak in China to analyze the potential impact of COVID-19 on children under the age of 5, under three different scenarios; each of which assumed the prevalence of infection to be 0.5%, 1%, or 5%.

Results: We find that in the lowest prevalence scenario, across the most populous 18 Indian states, asymptomatic, non-hospitalized symptomatic and hospitalized symptomatic cases could reach 87,200, 412,900 and 31,900, respectively. In a moderate prevalence scenario, these figures reach 174,500, 825,800, and 63,800, and in the worst case, high prevalence scenario these cases could climb as high as 872,200, 4,128,900 and 319,700.

Conclusion: These estimates show COVID-19 has the potential to pose a substantial threat to Indias large population of children, particularly those suffering from malnutrition and exposure to indoor air pollution, who may have limited access to health services.
The COVID-19 Pandemic Predominantly Hits Poor Neighborhoods, or does it? Evidence from Germany
Authors: Pluemper Thomas , Neumayer Eric
Published: May 2020

Background
Reports from the UK and the USA suggest that COVID-19 predominantly affects poorer individuals and neighbourhoods. This article paints a more complex picture by distinguishing between a first and second phase of the pandemic. The initial spread of infections and its correlation with socio-economic factors largely depends on how the virus first entered a country. The second phase of the pandemic begins when individuals start taking precautionary measures and governments implement lockdowns. In this phase the further spread of the virus depends on the ability of individuals to socially distance themselves, which is to some extent socially stratified.

Methods
We analyze the geographical distribution of known cases per capita across 401 local districts in Germany, once for infections in the initial phase and for new infections during the second phase.

Results
In Germany, the virus first entered via individuals returning from skiing in the Alps and other international travel. In this first phase we find a positive association between the wealth of a district and infection rates and a negative association with indicators of social deprivation. During the second phase, richer districts and districts with a higher share of university-educated employees record fewer new infections, whilst the initial safety advantage of more socially deprived districts disappears.

Conclusion
The social stratification of Covid-19 changes substantively across the two phases of the pandemic in Germany. Only in the second phase does socio-economic advantage turn into a safety advantage. Thus, suggestions that the pandemic predominantly hits the poor needs to be qualified.
Almitrine as a non ventilatory strategy to improve intrapulmonary shunt in COVID-19 patients
Authors: LOSSER MARIE REINE , LAPOIX COLINE , CHAMPIGNEULLE BENOIT , DELANNOY MATTHIEU , PAYEN JEAN FRANCOIS , PAYEN DIDIER
Published: May 2020

In severe COVID-19 pulmonary failure, hypoxia is mainly related to pulmonary vasodilation with altered hypoxic pulmonary vasoconstriction (HPV). Besides prone positioning, other non-ventilatory strategies may reduce the intrapulmonary shunt. This study has investigated almitrine, a pharmacological option to improve oxygenation.
Patients and Method. A case control series of 17 confirmed COVID-19 mechanically ventilated patients in prone or supine positioning was collected: 10 patients received two doses of almitrine (4 and 12 mcg/kg/min) at 30-45 min interval each, and were compared to 7 control COVID-matched patients conventionally treated. The end-point was the reduction of intra-pulmonary shunt increasing the PaO2 and ScvO2.
Results Patients were male (59%) with median (25th, 75th percentiles) age of 70 (54-78) years and a BMI of 29 (23-34). At stable mechanical ventilatory settings, PaO2 (mmHg) at FiO2 1 (135 (85, 195) to 214 (121, 275); p = 0.06) tended to increase with almitrine. This difference was significant when the best PaO2 between the 2 doses was used : 215 (123,294) vs baseline (p = 0.01). A concomitant increase in ScvO2 occurred ((73 (72, 76) to 82 (80, 87); p = 0.02). Eight over 10 almitrine-treated patients increased their PaO2, with no clear dose-effect. During the same time, the controls did not change PaO2.
In conclusion, in early COVID-19 with severe hypoxemia, almitrine infusion is associated with improved oxygenation in prone or supine positioning. This pharmacological intervention may offer an alternative and/or an additional effect to proning and might delay or avoid more demanding modalities such as ECMO.
Plasma concentration and safety of lopinavir/ritonavir in patients with Covid-19: a short communication
Authors: Chouchana Laurent , Boujaafar Sana , Gana Ines , Laure-Hélène  , Regard Lucile , Legendre Paul , Azoulay Celia , Canouï Etienne , Zerbit Jeremie , Carlier Nicolas , Terrier Benjamin , Kernéis Solen , Batista Rui , Treluyer Jean-Marc , Zheng Yi , Benaboud Sihem
Published: May 2020

Background

Lopinavir/ritonavir has been proposed as off-label treatment for Covid-19, although efficacy have not been proven. It has previously been shown that lopinavir plasma concentration is dramatically increased in inflammatory settings. As Covid-19 may be associated with major inflammation, assessing lopinavir plasma concentration and its safety in Covid-19 patients is essential.

Methods

Real-world Covid-19 experience based on a retrospective study.

Results

Of 31 patients treated by lopinavir/ritonavir for Covid-19, we observed very high lopinavir plasma concentrations, increased of 4.6-fold (IQR, 3.6-6.2) with regards to average plasma concentrations in HIV. All except one patient were above the upper limit of the concentration ranges of HIV treatment. About one over four to five patients prematurely stopped treatment mainly secondary an adverse drug reaction related to hepatic or gastrointestinal disorders.

Conclusion

Lopinavir plasma concentrations in patients with moderate to severe Covid-19 were higher than expected, associated with the occurrence of hepatic or gastrointestinal adverse drug reactions. However, owing that high plasma concentration may be required for in vivo antiviral activity against SARS-CoV-2 as suggested by previous studies, it appears that, in the absence of adverse drug reaction, lopinavir dosage should not be reduced. Cautious is necessary as off-label use can be associated with a new drug safety profile.
Gut microbiome diversity is an independent predictor of survival in cervical cancer patients receiving chemoradiation
Authors: Sims Travis T. , El Alam Molly B. , Karpinets Tatiana V. , Dorta-Estremera Stephanie , Hegde Venkatesh L. , Nookala Sita , Yoshida-Court Kyoko , Wu Xiaogang , Biegert Greyson W.G. , Delgado Medrano Andrea Y. , Solley Travis , Ahmed-Kaddar Mustapha , Chapman Bhavana V. , Sastry K. Jagannadha Jagannadha , Mezzari Melissa P. , Petrosino Joseph F. , Lin Lilie L. , Ramondetta Lois , Jhingran Anuja , Schmeler Kathleen M. , Ajami Nadim J. , Wargo Jennifer , Colbert Lauren E. , Klopp Ann H.
Published: May 2020

Diversity of the gut microbiome is associated with higher response rates for cancer patients receiving immunotherapy but has not been investigated in patients receiving radiation therapy. Additionally, current studies investigating the gut microbiome and outcomes in cancer patients may not adjusted for established risk factors. Here, we sought to determine if diversity and composition of the gut microbiome was independently associated with survival in cervical cancer patients receiving chemoradiation. Our study demonstrates that the diversity of gut microbiota is associated with a favorable response to chemoradiation. Additionally, compositional variation among patients correlated with short term and long-term survival. Short term survivor fecal samples were significantly enriched in Porphyromonas, Porphyromonadaceae, and Dialister, whereas long term survivor samples were significantly enriched in Escherichia Shigella, Enterobacteriaceae, and Enterobacteriales. Moreover, analysis of immune cells from cervical tumor brush samples by flow cytometry revealed that patients with a high microbiome diversity had increased tumor infiltration of CD4+ lymphocytes as well as activated subsets of CD4 cells expressing ki67+ and CD69+ over the course of radiation therapy. The modulation of gut microbiota before chemoradiation might provide an alternative way to enhance treatment efficacy and improve treatment outcomes in cervical cancer patients.
Acute cardiac injury in patients with COVID-19
Authors: De Lorenzo Andrea , Kasal Daniel , Tura Bernardo , Lamas Cristiane , Rey Helena
Published: May 2020

Introduction: Cardiac complications of COVID-19 are potentially life-threatening. The occurrence of myocardial injury in the context of COVID-19 is multifactorial and has generated increasing interest.
Methods: A systematic review with meta-analysis of the literature was performed. MEDLINE and EMBASE were searched. Two independente reviewers evaluated the selected manuscripts for the outcome myocardial injury, defined by troponin elevation above the 99th percentile. Study heterogeneity and risk of bias were evaluated.
Results: Eight studies, with a total of 1229 patients, were included. The frequency of myocardial injury was 16% (95% CI: 9% - 27%). The heterogeneity among studies was high (93%).
Conclusions: Myocardial injury may occur in patients with COVID-19, with a frequency of 16% among current studies. Continuous research is needed to update these findings, as the pandemic evolves, and to define the implications of myocardial injury in the context of this infection.
Efficient Prevalence Estimation and Population Screening for SARS-CoV-2
Authors: Gundersen Kenneth , Kvaloy Jan Terje , Gjessing Haakon K. , Lohr Iren Hoyand
Published: May 2020

The testing capacity for SARS-CoV-2 using RT-PCR analyses can be substantially increased by using pooling techniques. Here we discuss two important consequences of this. First, prevalence estimation can be done with a very limited number of RT-PCR analysis. Second, for screening purposes, the number of detected cases can largely increased.
Deep learning the collisional cross sections of the peptide universe from a million training samples
Authors: Meier Florian , Köhler Niklas D. , Brunner Andreas-David , Wanka Jean-Marc H. , Voytik Eugenia , Strauss Maximilian T. , Theis Fabian J. , Mann Matthias
Published: May 2020

The size and shape of peptide ions in the gas phase are an under-explored dimension for mass spectrometry-based proteomics. To explore the nature and utility of the entire peptide collisional cross section (CCS) space, we measure more than a million data points from whole-proteome digests of five organisms with trapped ion mobility spectrometry (TIMS) and parallel accumulation – serial fragmentation (PASEF). The scale and precision (CV <1%) of our data is sufficient to train a deep recurrent neural network that accurately predicts CCS values solely based on the peptide sequence. Cross section predictions for the synthetic ProteomeTools library validate the model within a 1.3% median relative error (R > 0.99). Hydrophobicity, position of prolines and histidines are main determinants of the cross sections in addition to sequence-specific interactions. CCS values can now be predicted for any peptide and organism, forming a basis for advanced proteomics workflows that make full use of the additional information.
The choices we make and the impacts they have: Machine learning and species delimitation in North American box turtles (Terrapenespp.)
Authors: Martin Bradley T. , Chafin Tyler K. , Douglas Marlis R. , Placyk John S. , Birkhead Roger D. , Phillips Chris A. , Douglas Michael E.
Published: May 2020

Model-based approaches that attempt to delimit species are hampered by computational limitations as well as the unfortunate tendency by users to disregard algorithmic assumptions. Alternatives are clearly needed, and machine-learning (M-L) is attractive in this regard as it functions without the need to explicitly define a species concept. Unfortunately, its performance will vary according to which (of several) bioinformatic parameters are invoked. Herein, we gauge the effectiveness of M-L-based species-delimitation algorithms by parsing 64 variably-filtered versions of a ddRAD-derived SNP dataset collected from North American box turtles (Terrapenespp.). Our filtering strategies included: (A) minor allele frequencies (MAF) of 5%, 3%, 1%, and 0% (=none), and (B) maximum missing data per-individual/per-population at 25%, 50%, 75%, and 100% (=no filtering). We found that species-delimitation via unsupervised M-L impacted the signal-to-noise ratio in our data, as well as the discordance among resolved clades. The latter may also reflect biogeographic history, gene flow, incomplete lineage sorting, or combinations thereof (as corroborated from previously observed patterns of differential introgression). Our results substantiate M-L as a viable species-delimitation method, but also demonstrate how commonly observed patterns of phylogenetic discordance can seriously impact M-L-classification.
Individual differences in spatial learning are correlated across cognitive tasks but not associated with stress response behaviour in the Trinidadian guppy
Authors: Prentice Pamela M. , Mnatzaganian Chloe , Houslay Thomas M. , Thornton Alex , Wilson Alastair J.
Published: May 2020

Cognition is vital for carrying out behaviours required for survival and reproduction. In animals, we now know that cognitive performance varies not just among species, but also among individuals within populations. While this variation is a prerequisite for contemporary natural selection, it is also true that selection does not act on traits in isolation. The extent to which cognitive traits covary with other aspects of phenotype (e.g. personality traits) is therefore expected to be an important factor in shaping evolutionary dynamics. Here we adopt a multivariate approach to test for spatial learning ability in a captive population of male Trinidadian guppies (Poecilia reticulata), and ask whether differences in cognitive performance are associated with (repeatable) differences in stress response behaviour. We focus on stress response for two reasons. First, functional links between cognitive traits and ‘stress coping style’ have been hypothesised. Second, individual-level studies of cognitive performance typically rely on multiple testing paradigms that may themselves be a stressor. Thus, there is a risk that variation in stress responsiveness is itself a cause of apparent, but artefactual variance in cognitive ability. Using a set of fish exposed repeatedly to two distinct spatial learning tasks (maze layouts), and an acute stress response test (open field trial), we find differences among-individuals in task performance that are repeatable within- and across maze layouts. On average performance improves with experience in the first maze, consistent with spatial learning, but not in the second. In both mazes, there is among-individual variation in the trajectory of mean performance with trial number suggesting individuals differ in ‘learning rate’. Acute stress response behaviour is repeatable but predicts neither average time to solve the maze nor learning rate. We thus find no support for among-individual correlation between acute stress response and cognitive performance. However, we highlight the possibility that cumulative, chronic stress effects may nonetheless cause observed declines in performance across repeats for some individuals (leading to lack of improvement in mean time to solve the second maze). If so, this may represent a pervasive but difficult challenge for our ability to robustly estimate learning rates in studies of animal cognition.
Divergent CPEB prion-like domains reveal different assembly mechanisms for a generic amyloid-like fold
Authors: Hervás Rubén , Fernández-Ramírez María del Carmen , Galera-Prat Albert , Suzuki Mari , Nagai Yoshitaka , Bruix Marta , Menéndez Margarita , Laurents Douglas V. , Carrión-Vázquez Mariano
Published: May 2020

Functional amyloids are present in a wide variety of organisms ranging from bacteria to humans. Experience-dependent aggregation of the cytoplasmic polyadenylation element-binding (CPEB) prion-like protein to a translationally active state has emerged as a plausible biochemical substrate of long-lasting memories. CPEB aggregation is driven by prion-like domains (PLD) that are highly divergent in sequence across species. Here, we describe the amyloid-like features of the neuronalAplysiaCPEB (ApCPEB) PLDin vitrousing single-molecule and bulk biophysical methods and compare them with those previously reported for neuronalDrosophilaCPEB, Orb2 PLD. The existence of transient oligomers and mature filaments suggests similarities in the late stages of the assembly pathway for both PLDs. However, while prior to aggregation the Orb2 PLD monomer remains as a random coil in solution,ApCPEB PLD adopts a diversity of conformations comprisingα-helical structures that evolve to coiled-coil species, suggesting structural differences at the beginning of their amyloid assembly pathways. Our results show how divergent PLDs of CPEB proteins from different species retain the ability to form a generic amyloid-like fold through different assembly mechanisms.
Deterministic scRNA-seq of individual intestinal organoids reveals new subtypes and coexisting distinct stem cell pools
Authors: Bues Johannes , Biočanin Marjan , Pezoldt Joern , Dainese Riccardo , Chrisnandy Antonius , Rezakhani Saba , Saelens Wouter , Gardeux Vincent , Gupta Revant , Russeil Julie , Saeys Yvan , Amstad Esther , Claassen Manfred , Lutolf Matthias , Deplancke Bart
Published: May 2020

Single-cell RNA-sequencing (scRNA-seq) has transformed our ability to resolve cellular properties across systems. However, current scRNA-seq platforms are one-size-fits-all approaches that are tailored toward large cell inputs (> 1,000 cells), rendering them inefficient and costly when processing small, individual tissue samples. This important drawback tends to be resolved by loading bulk samples, but this yields confounded mosaic cell population read-outs. To overcome these technological limitations, we developed adeterministic, mRNA-capture bead and cellco-encapsulation dropleting system, DisCo. We demonstrate that DisCo enables precise particle and cell positioning and droplet sorting control through combined machine-vision and multilayer microfluidics. In comparison to other microfluidics systems, the active flow control driving DisCo, enables continuous operation and processing of low-input samples (< 100 cells) at high capture efficiency (> 70%). To underscore the unique capabilities of our approach, we analyzed intestinal organoid development by “DisCo-ing” 31 individual organoids at varying developmental stages. This revealed extensive organoid heterogeneity, identifying distinct subtypes including a regenerative fetal-likeLy6a+stem cell population which persists as symmetrical cysts even under differentiation conditions. Furthermore, we uncovered a so far uncharacterized “gobloid” subtype consisting predominantly of precursor and mature (Muc2+) goblet cells. These findings demonstrate the unique power of DisCo in providing high-resolution snapshots of cellular heterogeneity among small, individual tissues.
Drug Repurposing Through a Bioinformatics Pipeline Applied on Fibrotic Diseases
Authors: Karatzas Evangelos , Kakouri Andrea , Kolios George , Delis Alex , Spyrou George M.
Published: May 2020

Subject

Fibrotic diseases cover a spectrum of systemic and organ-specific maladies that affect a large portion of the population, currently without cure. The shared characteristic these diseases feature is their uncontrollable fibrogenesis deemed responsible for the accumulated damage in the susceptible tissues.Idiopathic Pulmonary Fibrosis(IPF), an interstitial lung disease, is one of the most common and studied fibrotic diseases and still remains an active research target.

Objective

We highlight unique and common (i) genes, (ii) biological pathways and (iii) candidate repurposed drugs among nine fibrotic diseases. We bibliographically explore the resulting candidate substances for potential anti-fibrotic mode of action and focus on diseases that appear to be more similar toIPFso as to jointly examine potential treatments.

Methodology

We identify key genes for the 9 fibrotic diseases by analyzing transcriptomics datasets. We construct gene-to-gene networks for each disease and examine these networks to explore functional communities of biological pathways. We also use the most significant genes as input in Drug Repurposing (DR) tools and re-rank the resulting candidates according to their structural properties and functional relationship to each investigated disease.

Results

We identify 7 biological pathways involved in all 9 fibrotic diseases as well as pathways unique to some of these diseases. Based on our DR results, we suggest captopril and ibuprofen that both appear to slow the progression of fibrotic diseases according to existing bibliography. We also recommend nafcillin and memantine, which haven’t been studied against fibrosis yet, for further wet-lab experimentation. We also observe a group of cardiomyopathy-related pathways that are exclusively highlighted forOral Submucous Fibrosis(OSF). We suggest digoxin to be tested againstOSF, since we observe cardiomyopathy-related pathways implicated inOSFand there is bibliographic evidence that digoxin may potentially clear myocardial fibrosis. Finally, we establish thatIPFshares several involved genes, biological pathways and candidate inhibiting-drugs withDupuytren’s Disease,IgG4-related Disease,SScandCystic Fibrosis. We propose that treatments for these fibrotic diseases should be jointly pursued.
Sequencing and annotation of the endangered wild buffalo (Bubalus arnee) mitogenome for taxonomic and hybridization assessment
Authors: Pacha Ankit Shankar , Nigam Parag , Pandav Bivash , Mondol Samrat
Published: May 2020

The wild water buffalo (Bubalus arnee) is one of the most endangered and least studied large bovid in the Indian subcontinent. India retains 90% of the global population as two fragmented populations in Assam and Chhattisgarh, both threatened by habitat loss and degradation, hunting, disease from livestock, and hybridization with the domestic buffalos. For the first time, we sequenced the 16,357 bp long mitogenome of pure wild water buffalo from both populations. The annotated genes included 13 protein-coding genes, 22 tRNA, two ribosomal genes, and a non-coding control region. Comparative mitogenome analyses showed both populations are genetically similar but significantly different from domestic buffalo. We also identified structural differences in seven tRNA secondary structures between both species. Both wild and domestic water buffalo formed sister clades which were paraphyletic to genus Bos. This study provides baseline information on wild buffalo mitogenome for further research on phylogeny, phylogeography and hybrid assessment and help conserving this endangered species.
Medial Prefrontal Cortex Interacts with the Anteromedial Thalamus in Motivation and Dopaminergic Activity
Authors: Yang Chen , Hu Yuzheng , Talishinsky Aleksandr D. , Potter Christian T. , Ramsey Leslie A. , Kesner Andrew J. , Don Reuben F. , Junn Sue , Tan Aaron , Pierce Anne F. , Nicolas Celine , Calva Coleman B. , Su Conghui , Mejia-Aponte Carlos A. , Wang Dong V. , Lu Hanbing , Yang Yihong , Ikemoto Satoshi
Published: May 2020

How does the prefrontal cortex (PFC) regulate motivated behavior? Our experiments characterize the circuits of the PFC regulating motivation, reinforcement and dopamine activity, revealing a novel cortico-thalamic loop. The stimulation of medial PFC (mPFC) neurons activated many downstream regions, as shown by functional MRI. Axonal terminal stimulation of mPFC neurons in downstream regions, including the anteromedial thalamic nucleus (AM), reinforced behavior and activated midbrain dopaminergic neurons. The stimulation of AM neurons projecting to the mPFC also reinforced behavior and activated dopamine neurons, and mPFC and AM showed a positive-feedback loop organization. Reciprocal excitatory functional connectivity, as well as co-activation of the two regions, was found in human participants who watched reinforcing videos. Our results suggest that this cortico-thalamic loop regulates motivation, reinforcement and dopaminergic neuron activity.
The role of microglia membrane potential in chemotaxis
Authors: Laprell Laura , Schulze Christian , Brehme Marie-Luise , Oertner Thomas G.
Published: May 2020

Microglia react to danger signals by rapid and targeted extension of cellular processes towards the source of the signal. This positive chemotactic response is accompanied by a hyperpolarization of the microglia membrane. Here we show that optogenetic depolarization of microglia has little effect on baseline motility, but significantly slows down the chemotactic response. Reducing the extracellular Ca2+concentration mimics the effect of optogenetic depolarization. As the membrane potential sets the driving force for Ca2+entry, hyperpolarization is an integral part of rapid stimulus-response coupling in microglia. Compared to typical excitable cells such as neurons, the sign of the activating response is inverted in microglia, leading to inhibition by depolarizing channelrhodopsins.
THE IMPACT OF MISTRANSLATION ON PHENOTYPIC VARIABILITY AND FITNESS
Authors: Samhita Laasya , Raval Parth K , Stephenson Godwin , Thutupalli Shashi , Agashe Deepa
Published: May 2020

Phenotypic variation is widespread in natural populations, and can significantly alter their ecology and evolution. Phenotypic variation often reflects underlying genetic variation, but also manifests via non-heritable mechanisms. For instance, translation errors result in about 10% of cellular proteins carrying altered sequences. Thus, proteome diversification arising from translation errors can potentially generate phenotypic variability, in turn increasing variability in the fate of cells or of populations. However, this link remains unverified. We manipulated mistranslation levels inEscherichia coli, and measured phenotypic variability between single cells (individual level variation), as well as replicate populations (population level variation). Monitoring growth and survival, we find that mistranslation indeed increases variation acrossE. colicells, but does not consistently increase variability in growth parameters across replicate populations. Interestingly, although any deviation from the wild type (WT) level of mistranslation reduces fitness in an optimal environment, the increased variation is associated with a survival benefit under stress. Hence, we suggest that mistranslation-induced phenotypic variation can impact growth and survival and has the potential to alter evolutionary trajectories.
Genome-wide analysis identifies genetic effects on reproductive success and ongoing natural selection at theFADSlocus
Authors: Mathieson Iain , Day Felix R. , Barban Nicola , Tropf Felix C. , Brazel David M. ,   eQTLGen Consortium,   BIOS Consortium, Vaez Ahmad , van Zuydam Natalie , Bitarello Bárbara D. , Snieder Harold , den Hoed Marcel , Ong Ken K. , Mills Melinda C. , Perry John R.B. ,   on behalf of the Human Reproductive Behaviour Consortium
Published: May 2020

Identifying genetic determinants of reproductive success may highlight mechanisms underlying fertility and also identify alleles under present-day selection. Using data in 785,604 individuals of European ancestry, we identify 43 genomic loci associated with either number of children ever born (NEB) or childlessness. These loci span diverse aspects of reproductive biology across the life course, including puberty timing, age at first birth, sex hormone regulation and age at menopause. Missense alleles inARHGAP27were associated with increased NEB but reduced reproductive lifespan, suggesting a trade-off between reproductive ageing and intensity. As NEB is one component of evolutionary fitness, our identified associations indicate loci under present-day natural selection. Accordingly, we find that NEB-increasing alleles have increased in frequency over the past two generations. Furthermore, integration with data from ancient selection scans identifies a unique example of an allele—FADS1/2gene locus—that has been under selection for thousands of years and remains under selection today. Collectively, our findings demonstrate that diverse biological mechanisms contribute to reproductive success, implicating both neuro-endocrine and behavioural influences.
Global quantitative analysis of the human brain proteome and phosphoproteome in Alzheimer’s disease
Authors: Ping Lingyan , Kundinger Sean R. , Duong Duc M. , Yin Luming , Gearing Marla , Lah James J. , Levey Allan I. , Seyfried Nicholas T.
Published: May 2020

Alzheimer’s disease (AD) is characterized by an early, asymptomatic phase (AsymAD) in which individuals exhibit amyloid-beta (Aβ) plaque accumulation in the absence of clinically detectable cognitive decline. Here we report an unbiased multiplex quantitative proteomic and phosphoproteomic analysis using tandem mass tag (TMT) isobaric labeling of human post-mortem cortex (n=27) across pathology-free controls, AsymAD and symptomatic AD individuals. With off-line high-pH fractionation and liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) on an Orbitrap Lumos mass spectrometer, we identified 11,378 protein groups across three TMT 11-plex batches. Immobilized metal affinity chromatography (IMAC) was used to enrich for phosphopeptides from the same TMT-labeled cases and 51,736 phosphopeptides were identified. Of these, 48,992 were quantified by TMT reporter ions representing 33,652 unique phosphosites. Two reference standards in each TMT 11-plex were included to assess intra- and inter-batch variance at the protein and peptide level. This comprehensive human brain proteome and phosphoproteome dataset will serve as a valuable resource for the identification of biochemical, cellular and signaling pathways altered during AD progression.
Dramatic reduction of psychiatric emergency consultations during lockdown linked to COVID-19 in Paris and suburbs
Authors: Pignon Baptiste , Gourevitch Raphaël , Tebeka Sarah , Dubertret Caroline , Cardot Hélène , Masson Valérie Dauriac-Le , Trebalag Anne-Kristelle , Barruel David , Yon Liova , Hemery François , Loric Marie , Rabu Corentin , Pelissolo Antoine , Leboyer Marion , Schürhoff Franck , Pham-Scottez Alexandra
Published: May 2020

Aims

The COVID-19 pandemic and associated lockdown may have psychiatric consequences and increase the number of psychiatric emergency consultations. This study aimed to compare the number and characteristics of emergency psychiatric consultations during the four first weeks of the lockdown in three psychiatric emergency services from Paris and its suburbs, and to compare them to the same period in 2019.

Methods

Three psychiatric centers in Paris and its suburbs took part in the study. We compared the number of total psychiatric emergency consultations during the 4 first weeks of the lockdown in France to the corresponding 4 weeks in 2019. We also compared the number of consultations during these 4-week time periods in 2020 and 2019 across different diagnostic categories.

Results

In the 4 first weeks of the lockdown in France, 553 emergency psychiatry consultations were carried out, compared to 1224 consultations during the corresponding period of 2019, representing a 54.8 % decrease. This decrease was evident across all psychiatric disorders, including anxiety (number of consultations in 2020 representing 36.1 % of 2019), mood (41.1 %), and psychotic disorders (57.3 %). The number of suicide attempts also decreased (number of suicide attempts in 2020 representing 42.6 % of 2019). In comparison to 2019, the proportion of total consultations for anxiety disorders also decreased (16.6 % vs. 20.8 %), whilst the proportion of total consultations increased for psychotic disorders (31.1 % vs. 24.1 %).

Conclusions

The total number of psychiatric emergency consultations during lockdown dramatically decreased. The psychological consequences of lockdown may be delayed, indicating that psychiatric services should be prepared for a secondary increase in emergency presentations.
Normal Childhood Brain Growth and a Universal Sex and Anthropomorphic Relationship to Cerebrospinal Fluid
Authors: Peterson Mallory R. , Cherukuri Venkateswararao , Paulson Joseph N. , Ssentongo Paddy , Kulkarni Abhaya V. , Warf Benjamin C. , Monga Vishal , Schiff Steven J.
Published: May 2020

Object

The study of brain size and growth has a long and contentious history, yet normal brain volume development has yet to be fully described. In particular, the normal brain growth and cerebrospinal fluid (CSF) accumulation relationship is critical to characterize because it is impacted in numerous conditions of early childhood where brain growth and fluid accumulation are affected such as infection, hemorrhage, hydrocephalus, and a broad range of congenital disorders. This study aims to describe normal brain volume growth, particularly in the setting of cerebrospinal fluid accumulation.

Methods

We analyzed 1067 magnetic resonance imaging (MRI) scans from 505 healthy pediatric subjects from birth to age 18 to quantify component and regional brain volumes. The volume trajectories were compared between the sexes and hemispheres using Smoothing Spline ANOVA. Population growth curves were developed using Generalized Additive Models for Location, Scale, and Shape.

Results

Brain volume peaked at 10-12 years of age. Males exhibited larger age-adjusted total brain volumes than females, and body size normalization procedures did not eliminate this difference. The ratio of brain to CSF volume, however, revealed a universal age-dependent relationship independent of sex or body size.

Conclusions

These findings enable the application of normative growth curves in managing a broad range of childhood disease where cognitive development, brain growth, and fluid accumulation are interrelated.
Multifocal transient cortical brain lesions: a consistent MRI finding in neuro-COVID-19 patients
Authors: Anzalone Nicoletta , Castellano Antonella , Scotti Roberta , Scandroglio Anna Mara , Filippi Massimo , Ciceri Fabio , Tresoldi Moreno , Falini Andrea
Published: May 2020

We report four cases of subacute encephalopathy occurring in patients with SARS-CoV-2 infection. All patients have been intubated in the first week from onset of ARDS and presented neurological signs of agitation and spatial disorientation after weaning from mechanical ventilation. The MRI picture and the clinical features are described. MRI lesions characteristics are unusual but demonstrate a highly consistent pattern through all the four patients with similar neurological symptoms. They do not fulfill any typical criteria for a definite neuroradiological entity. Their predominantly parieto-occipital distribution recalls posterior reversible encephalopathy syndrome (PRES), although the prevalent cortical involvement and diffusion MRI pattern are not typical of PRES. We speculate that this pattern may be related to a possible transient dysregulation of vasomotor reactivity.
Retrospective analysis of the clinical characteristics of Candida auris infection cases over a 10-year period
Authors: Hu Shan , Wang Yuehua , Jiang Weiwei , Zhu Feilong , Quan Yongqiang , Zhang Guoming , Gu Feng , Gu Bing , Yang Ying
Published: May 2020

Candida auris is an emerging multidrug-resistant fungus with a high mortality rate. The first case of Candida auris infection was reported in 2009 and since then infections have been reported in nearly 40 countries. The fungus now represents a major global public health threat. We analyzed cases from the emergence of Candida auris infections up until the end of 2019. PubMed and Web of Science databases were searched for all papers related to Candida auris infections up until 31 December 2019. We organized these data into the following categories: date of publication, patient age and gender, underlying diseases, risk factors for infection, patient mortality information, drug sensitivity information of Candida auris isolates, and genetic classification. The χ2 test was used to screen for factors that may affect patient mortality before logistic regression analysis was used to further assess the suspected influencing factors to determine if they represent independent factors for patient mortality. Information pertaining to 542 patients was included. There were more male patients than female patients and the mortality rate was higher in males than females. A high proportion of patients were premature babies and elderly people. The proportions of patients with underlying diseases such as diabetes, kidney disease, and ear disease were also high. 65% of patients had a history in ICU and 60% were given broad-spectrum antibiotics. Logistic regression analysis revealed that kidney disease (P<0.05) and tumors (P<0.05) are independent factors that affect mortality in Candida auris infected patients. Patients infected with echinocandin-resistant Candida auris ultimately die.
Contiguous Erosion of the Inactive X in Human Pluripotency Concludes With Global DNA Hypomethylation
Authors: Bansal Prakhar , Pinter Stefan F.
Published: May 2020

Female human pluripotent stem cells (hPSCs) are prone to undergoing X chromosome erosion (XCE), a progressive loss of key epigenetic features on the inactive X that initiates with repression ofXIST, the long non-coding RNA required for X inactivation. As a result, previously silenced genes on the eroding X (Xe) reactivate, some of which are thought to provide selective advantages. To-date, the sporadic and progressive nature of XCE has largely obscured its scale, dynamics, and key transition events.

To address this knowledge gap, we performed an integrated analysis of DNA methylation (DNAme), chromatin accessibility, and gene expression across hundreds of hPSC samples. Differential methylation across the Xe enables ordering female hPSCs across a trajectory of XCE from initiation to terminal stages. Our results identify a crucialcis-regulatory element forXISTexpression, trace contiguously growing domains of reactivation to a few euchromatic origins on the Xi, and indicate that the late-stage Xe impairs DNAme genome-wide. Surprisingly, from this altered epigenetic landscape emerge select features of naïve pluripotency, suggesting its link to X chromosome dosage may be partially conserved in human embryonic development.
Single Molecule Light Field Microscopy
Authors: Sims Ruth R. , Abdul Rehman Sohaib , Lenz Martin O. , Clark Adam , Sanders Edward W. , Ponjavic Aleks , Muresan Leila , Lee Steven F. , O’Holleran Kevin
Published: May 2020

We introduce single molecule light field microscopy (SMLFM), a novel 3D single molecule localization technique that is capable of up to 20 nm isotropic precision across a 6μm depth of field. SMLFM can be readily implemented by installing a refractive microlens array into the conjugate back focal plane of any widefield single molecule localization system. We demonstrate that 3D localization can be performed by post-processing 2D localization data generated by common, widely-used, algorithms. In this work we benchmark the performance of SMLFM and finally showcase its capabilities by imaging fluorescently labeled membranes of fixed eukaryotic cells below the diffraction limit.