bluuebunny/crossref_metadata_2025 huggingface dataset:
Patterns and Predictors of HIV Status Disclosure in the 12 Months After Diagnosis in Mozambique
Authors: Taylor Kate , Lamb Matthew , Lahuerta Maria , Ahoua Laurence , Abacassamo Fatima , Elul Batya
Published: February 2020

Background:

HIV disclosure benefits people living with HIV, their partners, and HIV programs. However, data on the prevalence of disclosure and associated correlates have come largely from patients already in HIV care, potentially overestimating disclosure rates and precluding examination of the impact of disclosure on HIV care outcomes.

Setting:

We used data from an implementation study conducted in Maputo City and Inhambane Province, Mozambique. Adults were enrolled at HIV testing clinics after diagnosis and traced in the community 1 and 12 months later when they reported on disclosure and other outcomes.

Methods:

We examined patterns of participants' disclosure to their social networks (N = 1573) and sexual partners (N = 1024) at both follow-up assessments and used relative risk regression to identify correlates of nondisclosure.

Results:

Disclosure to one's social network and sexual partners was reported by 77.8% and 57.7% of participants, respectively, at 1 month and 92.9% and 72.4% of participants, respectively, at 12 months. At both time points, living in Inhambane Province, being single or not living with a partner, having high levels of anticipated stigma, and not initiating HIV treatment were associated with increased risks of nondisclosure to social networks. Nondisclosure to sexual partners at both follow-up assessments was associated with being women, living in Inhambane Province and in a household without other people living with HIV, and reporting that posttest counseling addressed disclosure.

Conclusions:

Although reported disclosure to social networks was high, disclosure to sexual partners was suboptimal. Effective and acceptable approaches to support partner disclosure, particularly for women, are needed.
Prehospital Mortality Due to Hemorrhagic Shock Remains High and Unchanged: A Summary of Current Civilian EMS Practices and New Military Changes
Authors: Duchesne Juan , Taghavi Sharven , Houghton August , Khan Mansoor , Perreira Bruno , Cotton Bryan , Tatum Danielle
Published: February 2020

Mortality secondary to trauma-related hemorrhagic shock has not improved for several decades. Underlying the stall in progress is the conundrum of effective prehospital interventions for hemorrhage control. As we know, neither pressing hard on the gas nor “stay and play” has changed mortality over the last 20 years. For this reason, when dealing with effective changes that will improve severe hemorrhage mortality outcomes, there is a need for the creation of a hybrid prehospital model. Improvements in mortality outcomes for patients with severe hemorrhage based on evidence for common civilian prehospital procedures such as in-field intubation and immediate fluid resuscitation with crystalloid solution are weak at best. The use of tourniquets, once considered too risky to use, however, has risen dramatically in large part due to success seen during their use in the military. Their use in the civilian setting shows promising results. Recently updated military Advanced Resuscitative Care guidelines propose the use of prehospital whole blood transfusion as well as in-field use of Zone 1 Resuscitative Endovascular Balloon Occlusion of the Aorta. Several case studies from Europe suggest these strategies are feasible for use in the civilian population, but could they be implemented in the US?
The Moral Status of Organ Donation and Transplantation Within Islamic Law: The Fiqh Council of North America’s Position
Authors: Padela Aasim I. , Auda Jasser
Published: February 2020

Background.

Muslim communities tend to hold more negative attitudes toward organ donation than other communities. These views, in part, reflect the diverse views of Islamic scholars who debate the conditions under which donation and transplantation is morally licit. In December 2018, the Fiqh Council of North America (FCNA) weighed in on the US context of donation and transplantation through an Islamic ethico-legal verdict (fatwa).

Methods.

Between 2016 and 2018, FCNA members engaged in multidisciplinary research using conventions of collective Islamic moral deliberation. They examined rulings on organ donation and transplantation issued by Islamic jurists and juridical councils abroad, convened with organ donation and transplantation professionals and stakeholders including families and patients, and consulted medical and bioethics experts.

Results.

FCNA judges organ donation to be morally permissible from the perspective of Islamic law and ethics, subject to several conditions. These include first-person authorization, that donation occur either while living or after circulatory declaration of death, harm to the donor is minimized, reproductive organs are not donated, among others. Organ transplantation, in general, was also deemed licit.

Conclusions.

FCNA’s verdict uniquely addresses American contexts and has several clinical practice implications. By sharing their perspective with academic and professional stakeholders, the council aims to provide nuanced guidance for assisting Muslims in making informed choices regarding these procedures and further societal dialogue on the ethics and practices of donation and transplantation.
Genetics and major depressive disorder: clinical implications for disease risk, prognosis and treatment
Authors: Fabbri Chiara , Montgomery Stuart , Lewis Cathryn M. , Serretti Alessandro
Published: February 2020

In the post-genomic era, genetics has led to limited clinical applications in the diagnosis and treatment of major depressive disorder (MDD). Variants in genes coding for cytochrome enzymes are included in guidelines for assisting in antidepressant choice and dosing, but there are no recommendations involving genes responsible for antidepressant pharmacodynamics and no consensus applications for guiding diagnosis or prognosis. However, genetics has contributed to a better understanding of MDD pathogenesis and the mechanisms of antidepressant action, also thanks to recent methodological innovations that overcome the challenges posed by the polygenic architecture of these traits. Polygenic risk scores can be used to estimate the risk of disease at the individual level, which may have clinical relevance in cases with extremely high scores (e.g. top 1%). Genetic studies have also shed light on a wide genetic overlap between MDD and other psychiatric disorders. The relationships between genes/pathways associated with MDD and known drug targets are a promising tool for drug repurposing and identification of new pharmacological targets. Increase in power thanks to larger samples and methods integrating genetic data with gene expression, the integration of common variants and rare variants, are expected to advance our knowledge and assist in personalized psychiatry.
Impact of rare and common genetic variation in the Interleukin-1 pathway on human cytokine responses
Authors: van Deuren Rosanne C. , Arts Peer , Cavalli Giulio , Jaeger Martin , Steehouwer Marloes , van de Vorst Maartje , Gilissen Christian , Joosten Leo A.B. , Dinarello Charles A. , Mhlanga Musa M. , Kumar Vinod , Netea Mihai G. , van de Veerdonk Frank L. , Hoischen Alexander
Published: February 2020

Background

Interleukin(IL)-1 signaling is of major importance in human innate cytokine responses. Common variants in related genes have been linked to various inflammation-mediated diseases and stimulation-induced cytokine responses, but the role of rare variants remains to be elucidated.

Methods

In this study, we characterize the role of rare and common genetic variation, as identified by molecular inversion probe-based sequencing, in 48 genes related to the IL-1 pathway. Using a systems biology approach, we examined the inter-individual variability ofin vitrostimulation-specific human cytokine responses from 463 healthy individuals of the Human Functional Genomics Project and assessed the role of rare and common genetic variants, separately and combined, by means of the Sequence Kernel Association Test.

Results

We identified strong associations for rare genetic variants inNCF4(adjP=7.2E−05) andCASP1(adjP=3.0E−05) with IL-6 production in response to PHA and LPS stimulation, respectively. In addition, common variants inIL36AandIL38were associated to bothC. albicans-induced IL-1β (IL36AadjP=0.0442;IL38adjP=0.0092) and IL-6 production (IL36AadjP=0.0037;IL38adjP=0.0082), an effect that was stronger at the subpathway level both for IL-1β (adjP=0.0017) and IL-6 (adjP=1.8E−04). The common variant signature for the IL-1β and IL-6 response toC. albicanswas confirmed by an association with all anti-inflammatory genes (adjP=1.87E−03andadjP=5.75E−04), and we validated this finding for non-coding common variants. Lastly, we identified a burden of rare variants in pro-inflammatory genes and LPS-induced IL-6 production (adjP=2.42E−04), and a new role for anti-inflammatory rare variants onS. aureus-stimulated IL-6 production (adjP=6.71E−03).

Conclusions

In conclusion, we show that both common and rare genetic variation in genes of the IL-1 pathway, separately and combined, differentially influencein vitrocytokine responses to various stimuli in healthy individuals. This study therefore accentuates potential mechanisms that are translatable into new hypothesis-driven characterization of common and rare variant involvement in a wide variety of inflammatory and immunological mechanisms and diseases.
Single cell RNA sequencing of 13 human tissues identify cell types and receptors of human coronaviruses
Authors: Qi Furong , Qian Shen , Zhang Shuye , Zhang Zheng
Published: February 2020

The new coronavirus (2019-nCoV) outbreak from December 2019 in Wuhan, Hubei, China, has been declared a global public health emergency. Angiotensin I converting enzyme 2 (ACE2), is the host receptor by 2019-nCov to infect human cells. Although ACE2 is reported to be expressed in lung, liver, stomach, ileum, kidney and colon, its expressing levels are rather low, especially in the lung. 2019-nCoV may use co-receptors/auxiliary proteins as ACE2 partner to facilitate the virus entry. To identify the potential candidates, we explored the single cell gene expression atlas including 119 cell types of 13 human tissues and analyzed the single cell co-expression spectrum of 51 reported RNA virus receptors and 400 other membrane proteins. Consistent with other recent reports, we confirmed that ACE2 was mainly expressed in lung AT2, liver cholangiocyte, colon colonocytes, esophagus keratinocytes, ileum ECs, rectum ECs, stomach epithelial cells, and kidney proximal tubules. Intriguingly, we found that the candidate co-receptors, manifesting the most similar expression patterns with ACE2 across 13 human tissues, are all peptidases, including ANPEP, DPP4 and ENPEP. Among them, ANPEP and DPP4 are the known receptors for human CoVs, suggesting ENPEP as another potential receptor for human CoVs. We also conducted “CellPhoneDB” analysis to understand the cell crosstalk between CoV-targets and their surrounding cells across different tissues. We found that macrophages frequently communicate with the CoVs targets through chemokine and phagocytosis signaling, highlighting the importance of tissue macrophages in immune defense and immune pathogenesis.
Molecular mechanism of evolution and human infection with the novel coronavirus (2019-nCoV)
Authors: He Jiahua , Tao Huanyu , Yan Yumeng , Huang Sheng-You , Xiao Yi
Published: February 2020

Since December, 2019, an outbreak of pneumonia caused by the new coronavirus (2019-nCoV) has hit the city of Wuhan in the Hubei Province. With the continuous development of the epidemic, it has become a national public health crisis and calls for urgent antiviral treatments or vaccines. The spike protein on the coronavirus envelope is critical for host cell infection and virus vitality. Previous studies showed that 2019-nCoV is highly homologous to human SARS-CoV and attaches host cells though the binding of the spike receptor binding domain (RBD) domain to the angiotensin-converting enzyme II (ACE2). However, the molecular mechanisms of 2019-nCoV binding to human ACE2 and evolution of 2019-nCoV remain unclear. In this study, we have extensively studied the RBD-ACE2 complex, spike protein, and free RBD systems of 2019-nCoV and SARS-CoV using protein-protein docking and molecular dynamics (MD) simulations. It was shown that the RBD-ACE2 binding free energy for 2019-nCoV is significantly lower than that for SARS-CoV, which is consistent with the fact that 2019-nCoV is much more infectious than SARS-CoV. In addition, the spike protein of 2019-nCoV shows a significantly lower free energy than that of SARS-CoV, suggesting that 2019-nCoV is more stable and able to survive a higher temperature than SARS-CoV. This may also provide insights into the evolution of 2019-nCoV because SARS-like coronaviruses are thought to have originated in bats that are known to have a higher body-temperature than humans. It was also revealed that the RBD of 2019-nCoV is much more flexible especially near the binding site and thus will have a higher entropy penalty upon binding ACE2, compared to the RBD of SARS-CoV. That means that 2019-nCoV will be much more temperature-sensitive in terms of human infection than SARS-CoV. With the rising temperature, 2019-nCoV is expected to decrease its infection ability much faster than SARS-CoV, and get controlled more easily. The present findings are expected to be helpful for the disease prevention and control as well as drug and vaccine development of 2019-nCoV.
Ecological niche models as hypothesis generators of functional genetic differentiation and potential local adaptation in a Mediterranean alpine ecosystem
Authors: Morente-López Javier , Kass Jamie M. , Lara-Romero Carlos , Serra-Diaz Josep María , Soto-Correa José Carmen , Anderson Robert P. , Iriondo José María
Published: February 2020

Geographically disparate populations within a species’ range may show important differences including variation in ecological, demographic, genetic and phenotypic characteristics. Based on the Center-Periphery Hypothesis, it is often assumed that environmental conditions are optimal in the geographic center of the range and stressful or suboptimal at the periphery, implying ecological marginality is concordant with geographic periphery. But this assumption has been challenged as geographical and ecological gradients are not necessarily concordant. The conservation value of populations inhabiting environmentally marginal areas is still under debate and is closely related with their evolutionary potential. Strong selective pressures caused by stressful conditions may generate novel adaptations in marginal areas, conferring these populations distinct evolutionary potential. But populations inhabiting marginal areas may also show reductions in neutral and adaptive genetic diversity via drift and inbreeding.

In this work we explore the potential of ecological niche models (ENMs) to identify environmentally optimal and marginal areas, as well as the principal putative selective pressures likely to act. To do so, we built a carefully parameterized ENM ofSilene ciliata, a dominant plant species of Mediterranean alpine habitats. Complementarily, we selected wild populations inhabiting contrasting environmental conditions and carried out common garden experiments to detect genetic differentiation among populations associated with functional traits. With the resulting information, we tested whether environmentally marginal populations defined by the ENM had genetically differentiated phenotypes that are potentially adaptive and, thus, of conservation value.

We found genetically based phenotypic differentiation of phenological traits between populations inhabiting areas identified by the ENM as marginal and optimal, as well as between populations with different habitat suitability values. Results supported ENMs as powerful tools for determining environmental marginality and identifying selection pressures, and thus also as hypothesis generators for divergent selection. Furthermore, genetically based phenotypic differentiation found underlines the potential adaptive value of populations inhabiting marginal areas. The approach developed here provides a theoretically justified and practical way to study adaptive processes and provide insights about the conservation value of marginal populations.
A causal role for estradiol in human reinforcement learning
Authors: Veselic Sebastijan , Jocham Gerhard , Gausterer Christian , Wagner Bernhard , Ernhoefer-Reßler Miriam , Lanzenberger Rupert , Lamm Claus , Eisenegger Christoph , Vermeer Annabel Losecaat
Published: February 2020

The sex hormone estrogen is hypothesized to play a key role in human cognition via its interactions with the dopaminergic system. Work in rodents has shown that estrogen’s most potent form, estradiol, impacts striatal dopamine functioning predominately via increased D1-receptor signalling, while human work has suggested that high estradiol levels are associated with altered reward sensitivity. Here, we addressed two fundamental questions: 1) whether estradiol causally alters reward sensitivity in men, and 2) whether this effect of estradiol is moderated by individual variation in polymorphisms of dopaminergic genes. To test this, we performed a double-blind placebo-controlled administration study in which hundred men received either a single dose of estradiol (2 mg) or placebo. We found that estradiol administration increased reward sensitivity, which was moderated by baseline dopamine. This was observed in choice behaviour and increased learning rates. These results confirm a causal role of estradiol in reinforcement learning in men that is moderated by the striatal dopaminergic pathway.
Pangolin homology associated with 2019-nCoV
Authors: Zhang Tao , Wu Qunfu , Zhang Zhigang
Published: February 2020

To explore potential intermediate host of a novel coronavirus is vital to rapidly control continuous COVID-19 spread. We found genomic and evolutionary evidences of the occurrence of 2019-nCoV-like coronavirus (named as Pangolin-CoV) from dead Malayan Pangolins. Pangolin-CoV is 91.02% and 90.55% identical at the whole genome level to 2019-nCoV and BatCoV RaTG13, respectively. Pangolin-CoV is the lowest common ancestor of 2019-nCoV and RaTG13. The S1 protein of Pangolin-CoV is much more closely related to 2019-nCoV than RaTG13. Five key amino-acid residues involved in the interaction with human ACE2 are completely consistent between Pangolin-CoV and 2019-nCoV but four amino-acid mutations occur in RaTG13. It indicates Pangolin-CoV has similar pathogenic potential to 2019-nCoV, and would be helpful to trace the origin and probable intermediate host of 2019-nCoV.
Is FAM19A5 an adipokine? Peripheral FAM19A5 in wild-type, FAM19A5 knockout, and LacZ knockin mice
Authors: Kwak Hoyun , Cho Eun-Ho , Cho Eun Bee , Lee Yoo-Na , Shahapal Anu , Yong Hyo Jeong , Reyes-Alcaraz Arfaxad , Jeong Yongwoo , Lee Yerim , Lee Minhyeok , Ha Nui , Oh Sitaek , Lee Jae Keun , Lee Won Suk , Kim Won Kyum , Hwang Jong-Ik , Seong Jae Young
Published: February 2020

FAM19A5 is a novel secretory protein primarily expressed in the brain. However, a recent study reported that FAM19A5 is an adipocyte-derived adipokine that regulates vascular smooth muscle function through sphingosine-1-phosphate receptor 2 (S1PR2). In our study, we investigated FAM19A5 transcript and protein levels in peripheral tissues, including adipose tissues, from wild-type, FAM19A5 knockout, and FAM19A5 LacZ knockin mice. We found that FAM19A5 transcript levels in the central nervous system were much greater than those in any of the peripheral tissues, including adipose tissues. Furthermore, the FAM19A5 protein levels in adipose and reproductive tissues were below detectable limits for Western blot analysis. Additionally, we found that the FAM19A5 protein did not interact with S1PR2 in terms of G protein-mediated signal transduction, β-arrestin recruitment, or ligand-mediated internalization. Taken together, our findings revealed basal levels of FAM19A5 transcripts and proteins in peripheral tissues, confirming its primary expression in the central nervous system and lack of significant interaction with S1PR2.
Molecular classification of the placebo effect in nausea
Authors: Meissner Karin , Lutter Dominik , Toerne Christine von , Haile Anja , Woods Stephen C. , Hoffmann Verena , Ohmayer Uli , Hauck Stefanie M. , Tschöp Matthias
Published: February 2020

Numerous studies have shown that the mere expectation improvement can alleviate symptoms in various conditions. These ‘placebo effects’ often include reliable changes in central and peripheral organ systems. Here, we tested for the first time whether placebo effects can be monitored and predicted by plasma proteins. In a randomized controlled design, 90 healthy participants were exposed to a 20-min vection stimulus on two separate days and were randomly allocated to placebo treatment or no treatment on the second day. Significant placebo effects on nausea, motion sickness, and gastric activity could be verified. Using state-of-the-art proteomics, 74 differentially regulated proteins were identified in placebo-treated participants as compared to no-treatment controls. Gene ontology (GO) enrichment analyses of these proteins revealed acute-phase proteins as well as microinflammatory proteins to be reliable plasma correlates of the placebo effect. Regression analyses showed that day-adjusted scores of nausea indices in the placebo group were predictable by the identified GO protein signatures. We next identified specific plasma proteins, for which a significant amount of variance could be explained by the experimental factors ‘sex’, ‘group’, ‘nausea’, or their interactions. GO enrichment analyses of these proteins identified ‘grooming behavior’ as a prominent hit, based on ‘neurexin-1’ (NRXN1) and ‘contactin-associated protein-like 4’ (CNTNAP4). Finally, Receiver Operator Characteristics (ROC) allowed to identify specific plasma proteins differentiating placebo responders from non-responders. These comprised immunoglobulins (IGHM, IGKV1D-16, IGHV3-23, IGHG1) and MASP2, related to regulation of complement activation, as well as proteins involved in oxidation reduction processes (QSOX1, CP TXN). This proof-of-concept study indicates that plasma proteomics are a promising tool to identify molecular correlates and predictors of the placebo effect in humans.
Improved daylight vision following AAV-mediated expression ofR9APin murine rod photoreceptors
Authors: Nishiguchi Koji M. , Fujita Kosuke , Cristante Enrico , Bainbridge James W. , Douglas Ronald H. , Nakazawa Toru , Smith Alexander J. , Ali Robin R.
Published: February 2020

Cone photoreceptors mediate daylight vision and are the primary cells responsible for vision in humans. Cone dysfunction leads to poor quality daylight vision because rod photoreceptors become saturated and non-functional at high light levels. Here we demonstrate that in mice lacking cone function, AAV-mediated over-expression of Rgs9-anchor protein (R9AP), a critical component of the GTPase complex that mediates the deactivation of the phototransduction cascade, results in desensitization of rod function and a “photopic shift” of the rod-driven electroretinogram. This treatment enables rods to respond to brighter light (up to ∼2.0 log) with increased visually-evoked cortical responses to high intensity stimulation. These results suggest that AAV-mediated transfer ofR9apinto rods might be used to improve daylight vision in humans visually handicapped by cone dysfunction.
Modeling microbial cross-feeding at intermediate scale portrays community dynamics and species coexistence
Authors: Liao Chen , Wang Tong , Maslov Sergei , Xavier Joao B.
Published: February 2020

Social interaction between microbes can be described at many levels of details: from the biochemistry of cell-cell interactions to the ecological dynamics of populations. Choosing an appropriate level to model microbial communities without losing generality remains a challenge. Here we show that modeling cross-feeding interactions at an intermediate level between genome-scale metabolic models of individual species and consumer-resource models of ecosystems is suitable to experimental data. We applied our modeling framework to three published examples of multi-strainEscherichia colicommunities with increasing complexity: uni-, bi-, and multi-directional cross-feeding of either substitutable metabolic byproducts or essential nutrients. The intermediate-scale model accurately fit empirical data and quantified metabolic exchange rates that are hard to measure experimentally, even for a complex community of 14 amino acid auxotrophies. By studying the conditions of species coexistence, the ecological outcomes of cross-feeding interactions, and each community’s robustness to perturbations, we extracted new quantitative insights from these three published experimental datasets. Our analysis provides a foundation to quantify cross-feeding interactions from experimental data, and highlights the importance of metabolic exchanges in the dynamics and stability of microbial communities.

Author summary

The behavior of microbial communities such as the human microbiome is hard to predict by its species composition alone. Our efforts to engineer microbiomes—for example to improve human health—would benefit from mathematical models that accurately describe how microbes exchange metabolites with each other and how their environment shapes these exchanges. But what is an appropriate level of details for those models? We propose an intermediate level to model metabolic exchanges between microbes. We show that these models can accurately describe population dynamics in three laboratory communities and predicts their stability in response to perturbations such as changes in the nutrients available in the medium that they grow on. Our work suggests that a highly detailed metabolic network model is unnecessary for extracting ecological insights from experimental data and improves mathematical models so that one day we may be able to predict the behavior of real-world communities such as the human microbiome.
Histo-molecular differentiation of renal cancer subtypes by mass spectrometry imaging and rapid proteome profiling of formalin-fixed paraffin-embedded tumor tissue sections
Authors: Möginger Uwe , Marcussen Niels , Jensen Ole N.
Published: February 2020

Pathology differentiation of renal cancer types is challenging due to tissue similarities or overlapping histological features of various tumor (sub)types. As assessment is often manually conducted outcomes can be prone to human error and therefore require high-level expertise and experience. Mass spectrometry can provide detailed histo-molecular information on tissue and is becoming increasingly popular in clinical settings. Spatially resolving technologies such as mass spectrometry imaging and quantitative microproteomics profiling in combination with machine learning approaches provide promising tools for automated tumor classification of clinical tissue sections.

In this proof of concept study we used MALDI-MS imaging (MSI) and rapid LC-MS/MS-based microproteomics technologies (15 min/sample) to analyze formalin-fixed paraffin embedded (FFPE) tissue sections and classify renal oncocytoma (RO, n=11), clear cell renal cell carcinoma (ccRCC, n=12) and chromophobe renal cell carcinoma (ChRCC, n=5). Both methods were able to distinguish ccRCC, RO and ChRCC in cross-validation experiments. MSI correctly classified 87% of the patients whereas the rapid LC-MS/MS-based microproteomics approach correctly classified 100% of the patients.

This strategy involving MSI and rapid proteome profiling by LC-MS/MS reveals molecular features of tumor sections and enables cancer subtype classification. Mass spectrometry provides a promising complementary approach to current pathological technologies for precise digitized diagnosis of diseases.
Continuous regimens of cortico-motor integration calibrate levels of arousal during emergence from anesthesia
Authors: Gao Sijia , Calderon Diany Paola
Published: February 2020

Background

Recovery to a conscious state when emerging from anesthesia requires full cortical desynchronization, initiation of movement and behavioral reactivity to sensory stimuli. However, the variety of cortical electroencephalogram (EEG) patterns associated with specific anesthetics and the paucity of behavioral descriptions during emergence from anesthesia have prevented EEG and behavior as feasible tracking methods to assess emerging from anesthesia. We propose a detailed combined analysis of motor and cortical activity to determine levels of arousal in rodents.

Methods

Using decreasing anesthetic concentrations, we simultaneously recorded local field potentials (LFPs) and movement in mice. We delineated cortical dynamics and sub-states during emergence from anesthesia by applying a smoothed-Z score to extract dominant frequencies from spectrogram. Then, we implemented KMeans to obtain cortical sub-states. Finally, we used density estimation and an abrupt change detection algorithm to segment cortical activity into periods. We used cortical sub-states obtained during isoflurane traces to supervise sub-states in sevoflurane and a pharmacologically induced-arousal model. This information together with examining videos were used to categorize behavior.

Results

We identified five cortical periods with restored motor behavior during emergence from isoflurane anesthetic. Periods of structured sub-states denoted when specific motor behaviors occurred. No significant differences were found when comparing the combined cortical features and motor behavior using isoflurane, sevoflurane and our arousal-rodent model. We describe graded regimens of cortico-motor activity during emergence from anesthesia to assess arousal levels.

Conclusion

We show cortical patterns denote gradual motor behaviors when emerging from anesthesia. Restoring motor behavior is a dynamic process that begins tens of minutes earlier than the righting reflex. Combining cortical activity and motor behavior unveils novel biomarkers to accurately track emerging from general anesthesia in rodents and likely other species.
Structural basis for the recognition of the 2019-nCoV by human ACE2
Authors: Yan Renhong , Zhang Yuanyuan , Guo Yingying , Xia Lu , Zhou Qiang
Published: February 2020

Angiotensin-converting enzyme 2 (ACE2) has been suggested to be the cellular receptor for the new coronavirus (2019-nCoV) that is causing the coronavirus disease 2019 (COVID-19). Like other coronaviruses such as the SARS-CoV, the 2019-nCoV uses the receptor binding domain (RBD) of the surface spike glycoprotein (S protein) to engage ACE2. We most recently determined the structure of the full-length human ACE2 in complex with a neutral amino acid transporter B0AT1. Here we report the cryo-EM structure of the full-length human ACE2 bound to the RBD of the 2019-nCoV at an overall resolution of 2.9 Å in the presence of B0AT1. The local resolution at the ACE2-RBD interface is 3.5 Å, allowing analysis of the detailed interactions between the RBD and the receptor. Similar to that for the SARS-CoV, the RBD of the 2019-nCoV is recognized by the extracellular peptidase domain (PD) of ACE2 mainly through polar residues. Pairwise comparison reveals a number of variations that may determine the different affinities between ACE2 and the RBDs from these two related viruses.
Theory of Neuronal Perturbome: Linking Connectivity to Coding via Perturbations
Authors: Sadeh Sadra , Clopath Claudia
Published: February 2020

To unravel the functional properties of the brain, we need to untangle how neurons interact with each other and coordinate in large-scale recurrent networks. One way to address this question is to measure the functional influence of individual neurons on each other by perturbing themin vivo. Application of such single-neuron perturbations in mouse visual cortex has recently revealed feature-specificsuppressionbetween excitatory neurons, despite the presence of highly specific excitatory connectivity, which was deemed to underlie feature-specificamplification. Here, we studied which connectivity profiles are consistent with these seemingly contradictory observations, by modelling the effect of single-neuron perturbations in large-scale neuronal networks. Our numerical simulations and mathematical analysis revealed that, contrary to the prima facie assumption, neither inhibition-dominance nor broad inhibition alone were sufficient to explain the experimental findings; instead, strong and functionally specific excitatory-inhibitory connectivity was necessary, consistent with recent findings in the primary visual cortex of rodents. Such networks had a higher capacity to encode and decode natural images in turn, which was accompanied by the emergence of response gain nonlinearities at the population level. Our study provides a general computational framework to investigate how single-neuron perturbations are linked to cortical connectivity and sensory coding, and paves the road to map theperturbomeof neuronal networks in future studies.
CK1 Delta Is an mRNA Cap-Associated Protein That Drives Translation Initiation and Tumor Growth
Authors: Pal Ipsita , Grilo Andre M. Sardinha , Berchowitz Luke E. , Das Sharma Sohani , Mundi Prabhjot S. , Ali Abdullah M. , Martin M. Laura , Safari Maryam , Scotto Luigi , Malkovskiy Eli , Sawas Ahmed , Mukherjee Siddhartha , O’Connor Owen A. , Jovanovic Marko , Deng Changchun
Published: February 2020

Whether translation is differentially regulated across liquid and solid tumors remains poorly understood. Here we report the discovery that Casein Kinase 1 delta (CK1δ) plays a key role in regulating translation initiation in blood cancers, but interestingly, not in solid tumors. In lymphomas CK1δ is a key positive regulator of 4E-BP1 and p70S6K phosphorylation, assembly of eIF4F, and translation initiation. Furthermore, CK1δ is pulled down by m7GTP-agarose that mimics the mRNA m7G cap, consistent with the regulatory role of CK1δ in translation initiation. Targeting CK1δ using a small molecule inhibitor, namely SR-3029, potently kills lymphoma cell lines and primary lymphoma cells across histology subtypes. While SR-3029 shares with mTORC1 inhibitors the overlapping mechanism of repressing 4E-BP1 and p70S6K/RPS6 phosphorylation, the kinetics of repression is slow with SR-3029 and fast with mTORC1 inhibitors such as Torin-1. Remarkably, it is slower-acting SR-3029, but not fast-acting Torin-1, that kills lymphoma cells consistently across multiple histology subtypes. Proteomics and RNA sequencing studies show that SR-3029 represses the expression of many genes preferentially at the translation step, such as genes in the reactome translation initiation pathway. SR-3029 markedly represses the protein level of the C-MYC oncogene without decreasing its mRNA level. In contrast, Torin-1 fails to reduce the protein level of C-MYC in the same lymphoma cells. While SR-3029 also demonstrates potent activity in select solid tumors, its mechanism of action in the solid tumors is different. In breast cancer cells SR-3029 inhibits nuclear localization of β-catenin but at the same concentrations does not inhibit 4E-BP1 and p70S6K phosphorylation or global protein synthesis. Likewise, SR-3029 does not inhibit nuclear localization of β-catenin in lymphoma cells. Our results indicate that CK1δ is an mRNA cap-associated protein and an upstream kinase required for 4E-BP1 and p70S6K phosphorylation. CK1δ stimulates assembly of eIF4F and translation initiation, and is a critical driver for tumor growth in blood cancers across multiple histology types. CK1δ invokes the alternative mechanism of regulating β-catenin in select solid tumors. Our results indicate that CK1δ inhibition is a promising therapeutic strategy in both liquid and solid tumors, and the distinct roles of CK1δ in these malignancies may serve as biomarkers to enable precision cancer treatment.
A family of contact-dependent nuclease effectors contain an exchangeable, species-identifying domain
Authors: Sirias Denise , Utter Daniel R. , Gibbs Karine A.
Published: February 2020

In mixed-species communities, bacteria can deploy contact-dependent effectors to compete with other organisms, often directly injecting these proteins into neighboring cells. One current hypothesis is that the entire protein contains information specific for a single species; emergence of new effectors comes from acquiring genes. Here we have characterized a family of DNA-degrading effectors that are nucleases which cause death. Like other families of chimeric nucleases, these effectors contain two domains. One is a PD-(D/E)XK-containing domain necessary for DNA cleavage. The other domain, which does not contain known DNA-binding structures, encodes species-identifying information. We capitalized on the species-identifying domain to differentiate among low-abundance species, as well as to reveal domain architectures within these proteins, in human gut and oral microbiomes. Emerging are questions about how low-abundance strains use effectors for survival and how strain-identifying effectors evolve.
High standing genetic variation in an invasive plant allows immediate evolutionary response to climate warming
Authors: Sun Yan , Bossdorf Oliver , Grados Ramon Diaz , Liao ZhiYong , Müller-Schärer Heinz
Published: February 2020

Abstract

Predicting plant distributions under climate change is constrained by our limited understanding of potential rapid adaptive evolution. In an experimental evolution study with the invasive common ragweed, we subjected replicated populations of the same initial genetic composition to simulated climate warming. Pooled DNA sequencing of parental and offspring populations showed that warming populations experienced a greater loss of genetic diversity, and greater genetic divergence from their parents, than control populations. In a common environment, offspring from warming populations showed more convergent phenotypes in seven out of nine plant traits, with later flowering and larger biomass, than plants from control populations. For both traits, we also found a significant higher ratio of phenotypic to genetic differentiation across generations for warming than for control populations, indicating stronger selection under warming conditions. Our findings demonstrate that ragweed populations can rapidly evolve in response to climate change within a single generation.
Limited evolution despite years of measurable viremia in a cART-treated seronegative HIV-1 positive individual
Authors: Fryer Helen R. , Raghwani Jayna , Gill M John , van Marle Guido , Golbchik Tanya , Grove Joe , Lythgoe Katrina A.
Published: February 2020

Understanding the role that antibodies play in controlling HIV-1 infection and in the dynamics that underpin the formation of the HIV-1 reservoir are important steps towards combatting this global disease. To address these gaps, we performed whole-genome, deep sequence analysis of longitudinal plasma HIV-1 samples from an individual who failed to develop detectable anti-HIV-1 antibodies for 4 years post infection. These analyses reveal limited evolution despite months of measurable viremia during treatment with cART. We used a mathematical model to simultaneously analyse the viral and evolutionary dynamics of this unique individual. We propose a role for antibodies in reducing viral infectivity and demonstrate how our data are consistent with a theory of rapid activation of latently infected cells prior to effective viral suppression. Our study supports and elucidates a recent finding that although the latent reservoir persists for years once virus is effectively suppressed, prior to suppression, viral strains within the reservoir turn over rapidly. The implications for a cure are significant.
Improving Metagenomic Classification using Discriminative k-mers from Sequencing Data
Authors: Storato D. , Comin M.
Published: February 2020

The major problem when analyzing a metagenomic sample is to taxonomically annotate its reads in order to identify the species they contain. Most of the methods currently available focus on the classification of reads using a set of reference genomes and their k-mers. While in terms of precision these methods have reached percentages of correctness close to perfection, in terms of recall (the actual number of classified reads) the performances fall at around 50%. One of the reasons is the fact that the sequences in a sample can be very different from the corresponding reference genome, e.g. viral genomes are highly mutated. To address this issue, in this paper we study the problem of metagenomic reads classification by improving the reference k-mers library with novel discriminative k-mers from the input sequencing reads. We evaluated the performance in different conditions against several other tools and the results showed an improved F-measure, especially when close reference genomes are not available.

Availability

https://github.com/davide92/K2Mem.git
Characterization of the dimeric interactions of dimeric and tetrameric conformations of the PvNV protrusion-domain using a mixed DFT/QTAIM approach
Authors: Astani Elahe K. , Chen Nai-Chi , Huang Yen-Chieh , Ersali Sara , Lin Pei-Ju , Guan Hong-Hsiang , Lin Chien-Chih , Chuankhayan Phimonphan , Chen Chun-Jung
Published: February 2020

The protrusion-domain (P-domain) ofPenaeus vannameinodavirus (PvNV) exists as two dimer-dimer conformations: one is a protein dimer and the other is a protein tetramer. We undertook a theoretical study to gain a clear understanding of the nature of the stabilizing interactions at the dimeric interfaces of the dimeric and tetrameric conformations of the PvNV P-domain (PvNVPd) using the quantum theory of atoms in molecules (QTAIM) and natural-bond orbital (NBO) analyses in the framework of the density-functional theory (DFT) approach. The QTAIM analysis characterized the presence of multiple hydrogen bonds of common types with strength ranging from electrostatic to the covalent limit inside the PvNVPd dimer-dimer interfaces. Val257-Lys335, Phe294-Val330, Gln296-Thr328, Glu296-Thr329, Thr328-Gln297, Val330-Ala293, Lys335-Asp256 and Lys335-Val257 pairs are critical residue pairs of all three dimeric interfaces of PvNVPd. They preserve these dimeric interfaces through charge-charge, charge-dipole, dipole-dipole, hydrophobic and hydrogen bond interactions. The strongest intermolecular dimer–dimer interactions belong to the dimeric interface between subunits A and B of PvNVPd in the tetrameric conformation.
The DrosophilaTARTtransposon manipulates the piRNA pathway as a counter-defense strategy to limit host silencing
Authors: Ellison Christopher E. , Kagda Meenakshi S. , Cao Weihuan
Published: February 2020

Co-evolution between transposable elements (TEs) and their hosts can be antagonistic, where TEs evolve to avoid silencing and the host responds by reestablishing TE suppression, or mutualistic, where TEs are co-opted to benefit their host. TheTART-ATE functions as an important component of Drosophila telomeres, but has also reportedly inserted into theD. melanogasternuclear export factor genenxf2. We find that, rather than inserting intonxf2, TART-Ahas actually captured a portion ofnxf2sequence. We show that Nxf2 is involved in suppressingTART-Aactivity via the piRNA pathway and thatTART-Aproduces abundant piRNAs, some of which are antisense to thenxf2transcript. We propose that capturingnxf2sequence allowedTART-Ato target thenxf2gene for piRNA-mediated repression and that these two elements are engaged in antagonistic co-evolution despite the fact thatTART-Ais serving a critical role for its host genome.
Novel phenotype of Wolbachia strain wPip in Aedes aegypti challenges assumptions on mechanisms of Wolbachia-mediated dengue virus inhibition
Authors: Fraser Johanna E. , O’Donnell Tanya B. , Duyvestyn Johanna M. , O’Neill Scott L. , Simmons Cameron P. , Flores Heather A.
Published: February 2020

The bacterial endosymbiontWolbachiais a biocontrol tool that inhibits the ability of theAedes aegyptimosquito to transmit positive-sense RNA viruses such as dengue and Zika. Growing evidence indicates that whenWolbachiastrainswMel orwAlbB are introduced into local mosquito populations, human dengue incidence is reduced. Despite the success of this novel intervention, we still do not fully understand howWolbachiaprotects mosquitoes from viral infection. Here, we demonstrate that theWolbachiastrainwPip does not inhibit virus infection inAe. aegypti. We have leveraged this novel finding, and a panel ofAe. aegyptilines carrying virus-inhibitory (wMel andwAlbB) and non-inhibitory (wPip) strains in a common genetic background, to rigorously test a number of hypotheses about the mechanism ofWolbachia-mediated virus inhibition. We demonstrate that, contrary to previous suggestions, there is no association between a strain’s ability to inhibit dengue infection in the mosquito and either its typical density in the midgut or salivary glands, or the degree to which it elevates innate immune response pathways in the mosquito. These findings, and the experimental platform provided by this panel of genetically comparable mosquito lines, clear the way for future investigations to define howWolbachiapreventsAe. aegyptifrom transmitting viruses.

Author summary

Dengue virus, transmitted by theAedes aegyptimosquito, is one of the fastest-growing infectious diseases, causing an estimated 390 million human infections per year worldwide. Vaccines have limited efficacy and there are no approved therapeutics. This has driven the rise of novel vector control programs, in particular those that use the bacterium,Wolbachia, which prevents transmission of dengue and other human pathogenic viruses when stably introduced intoAe. aegyptipopulations. Although this is proving to be a highly effective method, the details of how this biocontrol tool works are not well understood. Here we characterise a newWolbachiastrain,wPip, and find thatAe. aegypticarryingwPip are still able to transmit dengue similar to mosquitoes that do not carryWolbachia. This finding has allowed us to begin a rigorous program of comparative studies to determine which features of aWolbachiastrain determine whether it is antiviral. Understanding these mechanisms will enable us to predict the risk of viral resistance arising againstWolbachiaand facilitate preparation of second-generation field release lines.
The Development of Active Binocular Vision under Normal and Alternate Rearing Conditions
Authors: Klimmasch Lukas , Schneider Johann , Lelais Alexander , Shi Bertram E. , Triesch Jochen
Published: February 2020

The development of binocular vision is an active learning process comprising the development of disparity tuned neurons in visual cortex and the establishment of precise vergence control of the eyes. We present a computational model for the learning and self-calibration of active binocular vision based on the Active Efficient Coding framework, an extension of classic efficient coding ideas to active perception. Under normal rearing conditions, the model develops disparity tuned neurons and precise vergence control, allowing it to correctly interpret random dot stereogramms. Under altered rearing conditions modeled after neurophysiological experiments, the model qualitatively reproduces key experimental findings on changes in binocularity and disparity tuning. Furthermore, the model makes testable predictions regarding how altered rearing conditions impede the learning of precise vergence control. Finally, the model predicts a surprising new effect that impaired vergence control affects the statistics of orientation tuning in visual cortical neurons.