bluuebunny/crossref_metadata_2025 huggingface dataset:
Steep increases in fentanyl-related mortality west of the Mississippi River: synthesizing recent evidence from county and state surveillance
Authors: Shover Chelsea L. , Falasinnu Titilola O. , Dwyer Candice L. , Santos Nayelie Benitez , Cunningham Nicole J. , Vest Noel A. , Humphreys Keith
Published: June 2020

Background and Aims

Overdose deaths from synthetic opioids (e.g., fentanyl), increased 10-fold in the United States from 2013-2018, despite 88% of deaths occurring east of the Mississippi River. Public health professionals have long feared that further spread of fentanyl could greatly exacerbate the opioid epidemic. We aimed to measure and characterize recent fentanyl deaths in jurisdictions west of the Mississippi River.

Design

Systematic search of states and counties in the Western U.S. for publicly available data on fentanyl-related deaths since the most recently published Centers for Disease Control and Prevention (CDC) statistics, which cover through December 2018. Longitudinal study using 2019 and 2020 mortality records to identify changes in fentanyl-involved mortality since most recent CDC statistics.

Settings

U.S. states west of the Mississippi River.

Measurements

Annual rate of fentanyl-involved deaths per 100,000 population. Proportion of fatal heroin-, stimulant, and prescription pill overdoses also involving fentanyl.

Findings

We identified nine jurisdictions with publicly available fentanyl death data through December 2019 or later - State of Arizona; Denver County, CO; Harris County, TX; Humboldt County, CA; King County, WA; Los Angeles County, CA; San Francisco County, CA; Siskiyou County, CA; Dallas-Fort Worth, TX metro area (Denton, Johnson, Parker, Tarrant counties. Fentanyl deaths increased in each jurisdiction. Their collective contribution to national synthetic narcotics mortality tripled from 2017 to 2019. First quarter 2020 data (available from all but San Francisco County) showed a 33% growth in fentanyl-mortality over 2019. Fentanyl-involvement in heroin, stimulant, and prescription pill deaths has grown substantially over time.

Conclusions

Fentanyl has spread westward, which could dramatically worsen the nation’s already severe opioid epidemic. Increasing standard-dose of naloxone, expanding Medicaid, improving coverage of addiction treatment, and public health educational campaigns should be prioritized.
A Digital Protein Microarray for COVID-19 Cytokine Storm Monitoring
Authors: Song Yujing , Ye Yuxuan , Su Shiuan-Haur , Stephens Andrew , Cai Tao , Chung Meng-Ting , Han Meilan , Newstead Michael W. , Frame David , Singer Benjamin H. , Kurabayashi Katsuo
Published: June 2020

Despite widespread concern for cytokine storms leading to severe morbidity in COVID-19, rapid cytokine assays are not routinely available for monitoring critically ill patients. We report the clinical application of a machine learning-based digital protein microarray platform for rapid multiplex quantification of cytokines from critically ill COVID-19 patients admitted to the intensive care unit (ICU) at the University of Michigan Hospital. The platform comprises two low-cost modules: (i) a semi-automated fluidic dispensing/mixing module that can be operated inside a biosafety cabinet to minimize the exposure of technician to the virus infection and (ii) a 12-12-15 inch compact fluorescence optical scanner for the potential near-bedside readout. The platform enabled daily cytokine analysis in clinical practice with high sensitivity (<0.4pg/mL), inter-assay repeatability (∼10% CV), and near-real-time operation with a 10min assay incubation. A cytokine profiling test with the platform allowed us to observe clear interleukin −6 (IL-6) elevations after receiving tocilizumab (IL-6 inhibitor) while significant cytokine profile variability exists across all critically ill COVID-19 patients and to discover a weak correlation between IL-6 to clinical biomarkers, such as Ferritin and CRP. Our data revealed large subject-to-subject variability in a patient’s response to anti-inflammatory treatment for COVID-19, reaffirming the need for a personalized strategy guided by rapid cytokine assays.
Mobility network modeling explains higher SARS-CoV-2 infection rates among disadvantaged groups and informs reopening strategies
Authors: Chang Serina , Pierson Emma , Koh Pang Wei , Gerardin Jaline , Redbird Beth , Grusky David , Leskovec Jure
Published: June 2020

Fine-grained epidemiological modeling of the spread of SARS-CoV-2—capturing who is infected at which locations—can aid the development of policy responses that account for heterogeneous risks of different locations as well as the disparities in infections among different demographic groups. Here, we develop a metapopulation SEIR disease model that uses dynamic mobility networks, derived from US cell phone data, to capture the hourly movements of millions of people from local neighborhoods (census block groups, or CBGs) to points of interest (POIs) such as restaurants, grocery stores, or religious establishments. We simulate the spread of SARS-CoV-2 from March 1–May 2, 2020 among a population of 98 million people in 10 of the largest US metropolitan statistical areas. We show that by integrating these mobility networks, which connect 57k CBGs to 553k POIs with a total of 5.4 billion hourly edges, even a relatively simple epidemiological model can accurately capture the case trajectory despite dramatic changes in population behavior due to the virus. Furthermore, by modeling detailed information about each POI, like visitor density and visit length, we can estimate the impacts of fine-grained reopening plans: we predict that a small minority of “superspreader” POIs account for a large majority of infections, that reopening some POI categories (like full-service restaurants) poses especially large risks, and that strategies restricting maximum occupancy at each POI are more effective than uniformly reducing mobility. Our models also predict higher infection rates among disadvantaged racial and socio-economic groups solely from differences in mobility: disadvantaged groups have not been able to reduce mobility as sharply, and the POIs they visit (even within the same category) tend to be smaller, more crowded, and therefore more dangerous. By modeling who is infected at which locations, our model supports fine-grained analyses that can inform more effective and equitable policy responses to SARS-CoV-2.
Prevalence of Chemosensory Dysfunction in COVID-19 Patients: A Systematic Review and Meta-analysis Reveals Significant Ethnic Differences
Authors: von Bartheld Christopher S. , Hagen Molly M. , Butowt Rafal
Published: June 2020

A significant fraction of people who test positive for COVID-19 have chemosensory deficits. However, the reported prevalence of these deficits in smell and/or taste varies widely, and the reason for the differences between studies is unclear. We determined the pooled prevalence of such chemosensory deficits in a systematic review. We searched the COVID-19 portfolio of the National Institutes of Health for all studies that reported the prevalence of smell and/or taste deficits in patients diagnosed with COVID-19. Forty-two studies reporting on 23,353 patients qualified and were subjected to a systematic review and meta-analysis. Estimated random prevalence of olfactory dysfunction was 38.5%, of taste dysfunction was 30.4% and of overall chemosensory dysfunction was 50.2%. We examined the effects of age, disease severity, and ethnicity on chemosensory dysfunction. The effect of age did not reach significance, but anosmia/hypogeusia decreased with disease severity, and ethnicity was highly significant: Caucasians had a 3-6 times higher prevalence of chemosensory deficits than East Asians. The finding of ethnic differences points to genetic, ethnicity-specific differences of the virus-binding entry proteins in the olfactory epithelium and taste buds as the most likely explanation, with major implications for infectivity, diagnosis and management of the COVID-19 pandemic.
Seroprevalence of Antibodies to SARS-CoV-2 in Healthcare Workers in Non-epidemic Region: A Hospital Report in Iwate Prefecture, Japan
Authors: Nakamura Akihiro , Sato Ryoichi , Ando Sanae , Oana Natsuko , Nozaki Eiji , Endo Hideaki , Miyate Yoshiharu , Soma Jun , Miyata Go
Published: June 2020

Background

As of June 18, 2020, Iwate is the only one of 47 prefectures in Japan with no confirmed coronavirus disease 2019 (COVID-19) cases. Serological survey for COVID-19 antibodies is crucial in area with low prevalence as well as epidemic area when addressing health and social issues caused by COVID-19.

Methods

Serum samples from healthcare workers (n = 1,000, mean 40 ± 11 years) of Iwate Prefectural Central Hospital, Iwate, Japan were tested for the prevalence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies. Two laboratory-based quantitative tests (Abbott’s and Roche’s immunoassays) and one point-of-care (POC) qualitative test performed simultaneously. Sensitivity and specificity were 100%, 99.6% in Abbott’s immunoassay; 100%, 99.8% in Roche’s immunoassay; 97.8%, 94.6% in Alfa POC test, respectively.

Results

The laboratory-based quantitative tests showed positive in 4 of 1,000 samples (0.4%) (95% CI: 0.01 to 0.79): 4/1,000 (0.4%) (95% CI: 0.01 to 0.79) in Abbott; 0/1,000 (0%) in Roche. Positive samples were not detected for both Abbott’s and Roche’s immunoassays. The POC qualitative test showed positive in 33 of 1,000 samples (3.3%) (95% CI: 2.19 to 4.41). There were no samples with simultaneous positive reaction for two quantitative tests and a POC test.

Conclusions

Infected COVID-2 cases were not confirmed by a retrospective serological study in healthcare workers of our hospital. The POC qualitative tests with lower specificity have the potential for higher false positive reactions than the laboratory-based quantitative tests in areas with very low prevalence of COVID-19.
Mapping the Algal Secret Genome: The small RNA Locus Map forChlamydomonas reinhardtii
Authors: Müller Sebastian Y. , Matthews Nicholas E. , Valli Adrian A. , Baulcombe David C.
Published: June 2020

Small (s)RNAs play crucial roles in the regulation of gene expression and genome stability across eukaryotes where they direct epigenetic modifications, post-transcriptional gene silencing, and defense against both endogenous and exogenous viruses. The green algaChlamydomonas reinhardtiiis a well-studied unicellular alga species with sRNA-based mechanisms that are distinct from those of land plants. It is, therefore, a good model to study sRNA evolution but a systematic classification of sRNA mechanisms is lacking in this and any other algae. Here, using data-driven machine learning approaches including Multiple Correspondence Analysis (MCA) and clustering, we have generated a comprehensively annotated and classified sRNA locus map for C. reinhardtii. This map shows some common characteristics with higher plants and animals, but it also reveals distinct features. These results are consistent with the idea that there was diversification in sRNA mechanisms after the evolutionary divergence of algae from higher plant lineages.
Joint nonparametric coalescent inference of mutation spectrum history and demography
Authors: DeWitt William S. , Harris Kameron Decker , Harris Kelley
Published: June 2020

Booming and busting populations modulate the accumulation of genetic diversity, encoding histories of living populations in present-day variation. Many methods exist to decode these histories, and all must make strong model assumptions. It is typical to assume that mutations accumulate uniformly across the genome at a constant rate that does not vary between closely related populations. However, recent work shows that mutational processes in human and great ape populations vary across genomic regions and evolve over time. This perturbs themutation spectrum: the relative mutation rates in different local nucleotide contexts. Here, we develop theoretical tools in the framework of Kingman’s coalescent to accommodate mutation spectrum dynamics. We describemushi: a method to perform fast, nonparametric joint inference of demographic and mutation spectrum histories from allele frequency data. We usemushito reconstruct trajectories of effective population size and mutation spectrum divergence between human populations, identify mutation signatures and their dynamics in different human populations, and produce more accurate time calibration for a previously-reported mutational pulse in the ancestors of Europeans. We show that mutation spectrum histories can be productively incorporated in a well-studied theoretical setting, and rigorously inferred from genomic variation data like other features of evolutionary history.
Population genomic time series data of a natural population suggests adaptive tracking of environmental changes
Authors: Pfenninger Markus , Foucault Quentin
Published: June 2020

Natural populations are constantly exposed to fluctuating environmental changes that negatively affect their fitness in unpredictable ways. While theoretical models show the possibility of counteracting these environmental changes through rapid evolutionary adaptations, there have been few empirical studies demonstrating such adaptive tracking in natural populations.

Here, we analysed environmental data, fitness-related phenotyping and genomic time-series data sampled over three years from a natural Chironomus riparius (Diptera, Insecta) population to address this question. We show that the population’s environment varied significantly on the time scale of the sampling in many selectively relevant dimensions, independently of each other. Similarly, phenotypic fitness components evolved significantly on the same temporal scale (mean 0.32 Haldanes), likewise independent from each other. The allele frequencies of 367,446 SNPs across the genome showed evidence of positive selection. Using temporal correlation of spatially coherent allele frequency changes revealed 35,574 haplotypes with more than one selected SNP. The mean selection coefficient for these haplotypes was 0.30 (s.d. = 0.68). The frequency changes of these haplotypes clustered in 46 different temporal patterns, indicating concerted, independent evolution of many polygenic traits. Nine of these patterns were strongly correlated with measured environmental variables.

Thus, our results suggest that the natural population of C. riparius tracks environmental change through rapid polygenic adaptation in many independent dimensions. This is further evidence that natural selection is pervasive at the genomic level and that evolutionary and ecological time scales may not differ at all, at least in some organisms.
Experimental methodologies can affect pathogenicity ofBatrachochytrium salamandrivoransinfections
Authors: Kumar Rajeev , Malagon Daniel A. , Carter Edward Davis , Miller Debra L. , Bohanon Markese L. , Cusaac Joseph Patrick W. , Peterson Anna C. , Gray Matthew J.
Published: June 2020

Controlled experiments are one approach to understanding the pathogenicity of etiologic agents to susceptible hosts. The recently discovered fungal pathogen,Batrachochytrium salamandrivorans(Bsal), has resulted in a surge of experimental investigations because of its potential to impact global salamander biodiversity. However, variation in experimental methodologies could thwart knowledge advancement by introducing confounding factors that make comparisons difficult among studies. Thus, our objective was to evaluate if variation in experimental methods changed inferences made on the pathogenicity ofBsal. We tested whether passage duration ofBsalculture, exposure method of the host toBsal(water bath vs. skin inoculation),Bsalculturing method (liquid vs. plated), host husbandry conditions (aquatic vs. terrestrial), and skin swabbing frequency influenced diseased-induced mortality in a susceptible host species, the eastern newt (Notophthalmus viridescens). We found that disease-induced mortality was faster for eastern newts when exposed to a low passage isolate, when newts were housed in terrestrial environments, and if exposure to zoospores occurred via water bath. We did not detect differences in disease-induced mortality between culturing methods or swabbing frequencies. Our results illustrate the need to standardize methods amongBsalexperiments; we provide suggestions for future experiments in the context of hypothesis testing.
Development of a sensitive molecular diagnostic assay for detectingBorrelia burgdorferiDNA from blood of Lyme disease patients by digital PCR
Authors: Das Srirupa , Hammond-McKibben Denise , Guralski Donna , Lobo Sandra , Fiedler Paul N.
Published: June 2020

Lyme disease patients would benefit greatly from a timely, sensitive and specific molecular diagnostic test that can detect the causal agent,Borrelia burgdorferi, at the onset of symptoms. Currently available diagnostic methods recommended by the Centers for Disease Control and Prevention for Lyme disease, involve indirect serological tests that rely on the detection of a host-antibody response which often takes more than three weeks to develop. This results in non-detection of many genuine cases on a timely basis, preventing complete cure. In this study we have developed a digital PCR (polymerase chain reaction) assay that detects Lyme disease on clinical presentation at twice the sensitivity of the currently available diagnostic methods, using a cohort of patient samples collected from the Lyme disease endemic state of Connecticut, USA in 2016-2018. Digital PCR technology was chosen as it is more advanced and sensitive than other PCR techniques in detecting rare targets and the lower limit of detection of this diagnostic assay was found to be three genome copies ofB. burgdorferi. The paucity of spirochetes in the bloodstream of Lyme disease patients that hinders the clinical adoption of PCR-based diagnostic tests, was overcome by using a comparatively larger sample volume, pre-analytical processing of blood samples and a pre-amplification step to enrich forB. burgdorferi-specific gene targets before using the digital PCR technology to analyze patient samples. Pre-analytical processing of blood samples from acute patients revealed that the best sample type for Lyme disease detection is platelet-rich plasma and not whole blood. If detected on time, Lyme disease can be cured completely limiting the overuse of antibiotics and associated morbidities.
Conditional Protein Rescue (CPR) by Binding-Induced Protective Shielding
Authors: Gaynor Andrew S. , Chen Wilfred
Published: June 2020

An effective method to modulate the stability of proteins is essential to biological research. Herein, we describe a new technology that allows conditional stabilization of proteins based on masking of a degron tag by a specific intracellular protein cue. A target protein is fused to a degron tag and an affinity sensor domain. When the sensor detects its target protein, the degron is effectively concealed and the target protein is rescued. By introducing nanobodies as the sensor, we allow for virtually any endogenous protein to be targeted. In a model system using yeast cytosine deaminase, we demonstrate low cell death background yet maintain the ability to elicit strong activation and prodrug-mediated cell killing using GFP as the rescue protein. The flexibility in choosing different masking targets provides a straightforward method to generalize the strategy for conditional protein rescue in a wide range of biological contexts, including oncoprotein detection.
Cortico-hippocampal morphology and behavioural indices improved in maternal deprivation model of schizophrenia following vitamin B complex supplementation
Authors: Omotoso Gabriel Olaiya , Abdulsalam Fatimah Adeola , Mutholib Nafisat Yetunde , Bature Abdulkabir , Gbadamosi Ismail Temitayo
Published: June 2020

Maternal deprivation (MD) during early life development has been documented to culminate in long-term alterations in brain function and behavioural manifestations that mimic schizophrenia. This study elucidated the putative neuroprotective roles of vitamin B complex in MD-induced behavioural and neurochemical modifications in hippocampus and prefrontal cortex of Wistar rats. Rat pups were maternally deprived on postnatal day 9 for 24 hours and then treated with or without vitamin B complex for 15 days while a control group was undisturbed during the experimental period. The rats were then subjected to behavioural paradigms to measure memory indices and anxiety levels. The rats were sacrificed to obtain the PFC and hippocampus for histomorphological and biochemical analysis. Behavioural analysis of the animals revealed that MD induced a declination in long- and short-term memory in addition to anxiety-like behaviour in the open field test. Cortico-hippocampal histomorphology of these animals showed an increased astrocytic density and chromatolysis, which were accompanied by reduced levels of superoxide dismutase and catalase enzymes. Vitamin B complex mitigated MD-induced behavioural decline, histomorphological perturbation and oxidative stress by enhancing the intrinsic antioxidant defence, thereby culminating in nootropic behaviour and reduced anxiety. In conclusion, we confirmed the hypothesis that vitamin B complex is neuroprotective against neuropathological alterations induced by maternal deprivation.
Simulating a Primary Visual Cortex at the Front of CNNs Improves Robustness to Image Perturbations
Authors: Dapello Joel , Marques Tiago , Schrimpf Martin , Geiger Franziska , Cox David D. , DiCarlo James J.
Published: June 2020

Current state-of-the-art object recognition models are largely based on convolutional neural network (CNN) architectures, which are loosely inspired by the primate visual system. However, these CNNs can be fooled by imperceptibly small, explicitly crafted perturbations, and struggle to recognize objects in corrupted images that are easily recognized by humans. Here, by making comparisons with primate neural data, we first observed that CNN models with a neural hidden layer that better matches primate primary visual cortex (V1) are also more robust to adversarial attacks. Inspired by this observation, we developed VOneNets, a new class of hybrid CNN vision models. Each VOneNet contains a fixed weight neural network front-end that simulates primate V1, called the VOneBlock, followed by a neural network back-end adapted from current CNN vision models. The VOneBlock is based on a classical neuroscientific model of V1: the linear-nonlinear-Poisson model, consisting of a biologically-constrained Gabor filter bank, simple and complex cell nonlinearities, and a V1 neuronal stochasticity generator. After training, VOneNets retain high ImageNet performance, but each is substantially more robust, outperforming the base CNNs and state-of-the-art methods by 18% and 3%, respectively, on a conglomerate benchmark of perturbations comprised of white box adversarial attacks and common image corruptions. Finally, we show that all components of the VOneBlock work in synergy to improve robustness. While current CNN architectures are arguably brain-inspired, the results presented here demonstrate that more precisely mimicking just one stage of the primate visual system leads to new gains in ImageNet-level computer vision applications.
Ermin deficiency as an inside-out model of inflammatory dysmyelination
Authors: Ziaei Amin , Garcia-Miralles Marta , Radulescu Carola I. , Sidik Harwin , Silvin Aymeric , Bae Han-Gyu , Bonnard Carine , Mohammad Yusof Nur Amirah Binte , Bardile Costanza Ferrari , Tan Liang Juin , Ng Alvin Yu Jin , Tohari Sumanty , Dehghani Leila , Venkatesh Byrappa , Langley Sarah R. , Shaygannejad Vahid , Reversade Bruno , Jung Sangyong , Ginhoux Florent , Pouladi Mahmoud A.
Published: June 2020

Ermin is an actin-binding protein found almost exclusively in the central nervous system (CNS) as a component of myelin sheaths. Although Ermin has been predicted to play a role in the formation and stability of myelin sheaths, this has not been directly examinedin vivo. Here we show that Ermin is essential for myelin sheath integrity and normal saltatory conduction. Loss of Ermin in mice caused de-compacted and fragmented myelin sheaths and led to slower conduction along with progressive neurological deficits. RNA sequencing of the corpus callosum, the largest white matter structure in the CNS, pointed to inflammatory activation in aged Ermin-deficient mice, which was corroborated by increased levels of microgliosis and astrogliosis. The inflammatory milieu and myelin abnormalities were further associated with increased susceptibility to immune-mediated demyelination insult in Ermin knockout mice. Supporting a possible role of Ermin deficiency in inflammatory white matter disorders, a rare inactivating mutation in theERMNgene was identified in multiple sclerosis patients. Our findings demonstrate a critical role for Ermin in maintaining myelin integrity. Given its near exclusive expression in myelinating oligodendrocytes, Ermin deficiency represents a compelling “inside-out” model of inflammatory dysmyelination and may offer a new paradigm for the development of myelin stability-targeted therapies.
Maternal cortisol is associated with neonatal amygdala microstructure and connectivity in a sexually dimorphic manner
Authors: Stoye David Q , Blesa Manuel , Sullivan Gemma , Galdi Paola , Lamb Gillian J , Black Gill S , Quigley Alan J , Thrippleton Michael J , Bastin Mark E , Reynolds Rebecca M , Boardman James P
Published: June 2020

The mechanisms linking maternal stress in pregnancy with infant neurodevelopment in a sexually dimorphic manner are poorly understood. We tested the hypothesis that maternal hypothalamic-pituitary-adrenal axis activity, measured by hair cortisol concentration, is associated with microstructure, structural connectivity and volume of the infant amygdala. In 78 human mother-infant dyads, maternal hair was sampled postnatally, and infants underwent magnetic resonance imaging at term-equivalent age. Higher hair cortisol concentration was associated with higher left amygdala fractional anisotropy (β=0.677, p=0.010), lower left amygdala orientation dispersion index (β=-0.597, p=0.034), and higher fractional anisotropy in connections between the right amygdala and putamen (β=0.475, p=0.007) in girls compared to boys. Maternal cortisol during pregnancy is related to newborn amygdala architecture and connectivity in a sexually dimorphic manner. Given the fundamental role of the amygdala in the emergence of emotion regulation, these findings offer new insights into mechanisms linking maternal stress with adverse neuropsychiatric outcomes of children.

Impact Statement

Prenatal stress is transmitted to infant development through cortisol, which imparts sex-specific effects on the development and connectivity of the amygdalae.
A reference-guided approach for epigenetic characterization of single cells
Authors: Chen Shengquan , Yan Guanao , Zhang Wenyu , Li Jinzhao , Jiang Rui , Lin Zhixiang
Published: June 2020

The recent advancements in single-cell technologies, including single-cell chromatin accessibility sequencing (scCAS), have enabled profiling the epigenetic landscapes for thousands of individual cells. However, the characteristics of scCAS data, including high dimensionality, high degree of sparsity and high technical variation, make the computational analysis challenging. Reference-guided approach, which utilizes the information in existing datasets, may facilitate the analysis of scCAS data. We present RA3 (Reference-guided Approach for the Analysis of single-cell chromatin Acessibility data), which utilizes the information in massive existing bulk chromatin accessibility and annotated scCAS data. RA3 simultaneously models 1) the shared biological variation among scCAS data and the reference data, and 2) the unique biological variation in scCAS data that identifies distinct subpopulations. We show that RA3 achieves superior performance in many scCAS datasets. We also present several approaches to construct the reference data to demonstrate the wide applicability of RA3.
Disruption of the gut microbiota attenuates epithelial ovarian cancer sensitivity to cisplatin therapy
Authors: Chambers Laura M. , Esakov Emily L. , Braley Chad , Trestan Lexie , Alali Zahraa , Bayik Defne , Lathia Justin D. , Sangwan Naseer , Bazeley Peter , Joehlin-Price Amy S. , Dwidar Mohammed , Hajjar Adeline , Ahern Philip P. , Claesen Jan , Rose Peter , Vargas Roberto , Brown J. Mark , Michener Chad , Reizes Ofer
Published: June 2020

Epithelial Ovarian Cancer (EOC) is the leading cause of gynecologic cancer death. Despite many patients achieving remission with first-line therapy, up to 80% of patients will recur and require additional treatment. Retrospective clinical analysis of OC patients indicates antibiotic use during chemotherapy treatment is associated with poor overall survival. We assessed whether antibiotic (ABX) therapy would impact growth of EOC and sensitivity to cisplatin in murine models. Immune competent or compromised mice were given control or ABX containing water (metronidazole, ampicillin, vancomycin, and neomycin) before being intraperitoneally injected with murine EOC cells. Stool was collected to confirm microbiome disruption and tumors were monitored, and cisplatin therapy was administered weekly until endpoint. EOC tumor-bearing mice demonstrate accelerated tumor growth and resistance to cisplatin therapy in ABX treated compared with nonABX treatment. Stool analysis indicated most gut microbial species were disrupted by ABX treatment except for ABX resistant bacteria. To test for role of the gut microbiome, cecal microbiome transplants (CMTs) of microbiota derived from ABX or nonABX treated mice were used torecolonize the microbiome of ABX treated mice. nonABX cecal microbiome was sufficient to ameliorate the chemoresistance and survival of ABX treated mice indicative of a gut derived tumor suppressor. Mechanistically, tumors from ABX treated compared to nonABX treated mice contained a high frequency of cancer stem cells that were augmented by cisplatin. These studies indicate an intact microbiome provides a gut derived tumor suppressor and maintains chemosensitivity that is disrupted by ABX treatment.

Significance

Platinum resistance is associated with poor prognosis and reduced therapeutic options for ovarian cancer patients. We identifed a tumor suppressive role of the gut microbiome that is disrupted upon antibiotic therapy.
TranSPHIRE: Automated and feedback-optimized on-the-fly processing for cryo-EM
Authors: Stabrin Markus , Schoenfeld Fabian , Wagner Thorsten , Pospich Sabrina , Gatsogiannis Christos , Raunser Stefan
Published: June 2020

Single particle electron cryomicroscopy (cryo-EM) requires full automation to allow high-throughput structure determination which is especially important for drug discovery research. Although several software packages exist where parts of the cryo-EM pipeline are automated, a complete solution that offers reliable, quality-optimized on-the-fly processing, resulting in a high-resolution three-dimensional reconstruction does not exist. Here we present TranSPHIRE: A software package for fully automated processing of cryo-EM data sets during data acquisition. TranSPHIRE transfers data from the microscope, automatically applies the common pre-processing steps, picks particles, performs 2D clustering, and 3D refinement parallel to image recording. Importantly, TranSPHIRE introduces a machine learning-based feedback loop to re-train its internally used picking model to adapt to any given data set live during processing. This elegant approach enables TranSPHIRE to process data more effectively, producing high-quality particle stacks. TranSPHIRE collects, and displays all microscope settings and metrics generated by its individual tools, in order to allow users to quickly evaluate data during acquisition. TranSPHIRE can run on a single work station and also includes the automated processing of filaments.
Spatiotemporal expression of regulatory kinases directs the transition from mitosis to cellular morphogenesis
Authors: Yang Shuo , McAdow Jennifer , Du Yingqiu , Trigg Jennifer , Taghert Paul H. , Johnson Aaron N.
Published: June 2020

Embryogenesis depends on a tightly regulated balance between mitosis, differentiation, and morphogenesis. Understanding how the embryo uses a relatively small number of proteins to transition between growth and morphogenesis is a central question of developmental biology, but the mechanisms controlling mitosis and differentiation are considered to be fundamentally distinct. Here we show the mitotic kinase Polo, which regulates all steps of mitosis [1–3], also directs cellular morphogenesis after cell cycle exit. In mitotic cells, the Aurora kinases activate Polo to control a cytoskeletal regulatory module that directs cytokinesis [4–6]. We show that in the post-mitotic mesoderm, the control of Polo activity transitions from the Aurora kinases to the uncharacterized kinase Back Seat Driver (Bsd), where Bsd and Polo cooperate to regulate muscle morphogenesis. Polo and its effectors therefore direct mitosis and cellular morphogenesis, but the transition from growth to morphogenesis is determined by the spatiotemporal expression of upstream activating kinases.
Aerobic metabolism inVibrio choleraeis required for population expansion during infection
Authors: Van Alst Andrew J. , DiRita Victor J.
Published: June 2020

Vibrio choleraeis a bacterial pathogen that replicates to high cell density in the small intestine of human hosts leading to the diarrheal disease cholera. During infection,V. choleraesenses and responds to environmental signals that govern cellular responses. Spatial localization ofV. choleraewithin the intestine affects nutrient availability and therefore the metabolic pathways required for the replicative success of the pathogen. Metabolic processes used byV. choleraeto reach such high cell densities are not fully known. Here we seek to better define the metabolic traits that contribute to high levels ofV. choleraeduring infection by investigating mutant strains in key carbohydrate metabolism pathways. By disrupting the pyruvate dehydrogenase (PDH) complex and pyruvate formate-lyase (PFL), we could differentiate aerobic and anaerobic metabolic pathway involvement inV. choleraeproliferation. We demonstrate that oxidative metabolism is a key contributor to the replicative success ofV. cholerae in vivousing an infant mouse model where PDH mutants were attenuated 100-fold relative to wild type for colonization. Additionally, metabolism of host substrates such as mucin were determined to supportV. choleraegrowthin vitroas a sole carbon source primarily in aerobic growth conditions. Mucin likely contributes to population expansion during human infection as it is a ubiquitous source of carbohydrates. These data highlight the importance of oxidative metabolism in the intestinal environment and warrants further investigation of how oxygen and other host substrates shape the intestinal landscape that ultimately influences bacterial disease. We conclude from our results that oxidative metabolism of host substrates such as mucin is a key driver ofV. choleraegrowth and proliferation during infection, leading to the substantial bacterial burden exhibited in cholera patients.

Importance

Vibrio choleraeremains a challenge in the developing world and incidence of the disease it causes, cholera, is anticipated to increase with rising global temperatures and with emergent, highly infectious strains. At present, the underlying metabolic processes that supportV. choleraegrowth during infection are less well understood than specific virulence traits such as production of a toxin or pilus. In this study we determined that oxidative metabolism of host substrates such as mucin contribute significantly toV. choleraepopulation expansionin vivo. Identifying metabolic pathways critical for growth can provide avenues for controllingV. choleraeinfection and the knowledge may be translatable to other pathogens of the gastrointestinal tract.
Rostrocaudal patterning and neural crest differentiation of human pre-neural spinal cord progenitors in vitro
Authors: Cooper Fay , Gentsch George E , Mitter Richard , Bouissou Camille , Healy Lyn , Rodriguez Ana Hernandez , Smith James C , Bernardo Andreia S
Published: June 2020

The spinal cord emerges from a niche of neuromesodermal progenitors (NMPs) formed and maintained by Wnt/FGF signals at the posterior end of the embryo. NMPs can be generated from human pluripotent stem cells and hold promise for spinal cord replacement therapies. However, NMPs are transient, which complicates the full range production of rostrocaudal spinal cord identitiesin vitro. Here we report the generation of NMP-derived pre-neural progenitors (PNPs) with stem cell-like self-renewal capacity. PNPs maintain pre-spinal cord identity by co-expressing the transcription factors SOX2 and CDX2, and lose mesodermal potential by downregulating TBXT. For 7 to 10 passages PNPs divide to self-renew and to make trunk neural crest (NC), while gradually adopting a more posterior identity by activating colinearHOXgene expression. This HOX clock can be halted at the thoracic level for up to 30 passages by blocking the trunk-to-tail transition through GDF11-mediated signal inhibition.
Dynamics of hydraulic and contractile wave-mediated fluid transport duringDrosophilaoogenesis
Authors: Alsous Jasmin Imran , Romeo Nicolas , Jackson Jonathan A. , Mason Frank , Dunkel Jörn , Martin Adam C.
Published: June 2020

From insects to mice, oocytes develop within cysts alongside nurse-like sister germ cells. Prior to fertilization, the nurse cells’ cytoplasmic contents are transported into the oocyte, which grows as its sister cells regress and die. Although critical for fertility, the biological and physical mechanisms underlying this transport process are poorly understood. Here, we combined live imaging of germline cysts, genetic perturbations, and mathematical modeling to investigate the dynamics and mechanisms that enable directional and complete cytoplasmic transport inDrosophila melanogasteregg chambers. We discovered that during ‘nurse cell (NC) dumping’, most cytoplasm is transported into the oocyte independently of changes in myosin-II contractility, with dynamics instead explained by an effective Young-Laplace’s law, suggesting hydraulic transport induced by baseline cell surface tension. A minimal flow network model inspired by the famous two-balloon experiment and genetic analysis of a myosin mutant correctly predicts the directionality of transport time scale, as well as its intercellular pattern. Long thought to trigger transport through ‘squeezing’, changes in actomyosin contractility are required only once cell volume is reduced by ∼75%, in the form of surface contractile waves that drive NC dumping to completion. Our work thus demonstrates how biological and physical mechanisms cooperate to enable a critical developmental process that, until now, was thought to be a mainly biochemically regulated phenomenon.
AMPlify: attentive deep learning model for discovery of novel antimicrobial peptides effective against WHO priority pathogens
Authors: Li Chenkai , Sutherland Darcy , Hammond S. Austin , Yang Chen , Taho Figali , Bergman Lauren , Houston Simon , Warren René L. , Wong Titus , Hoang Linda M.N. , Cameron Caroline E. , Helbing Caren C. , Birol Inanc
Published: June 2020

Antibiotic resistance is a growing global health concern prompting researchers to seek alternatives to conventional antibiotics. Antimicrobial peptides (AMPs) are emerging therapeutic agents with promising utility in this domain and usingin silicomethods to discover novel AMPs is a strategy that is gaining interest. Such methods can filter through large volumes of candidate sequences and reduce lab screening costs. Here we introduce AMPlify, an attentive deep learning model for AMP prediction, and demonstrate its utility in prioritizing peptide sequences derived from theRana [Lithobates] catesbeiana(bullfrog) genome. We tested the bioactivity of our predicted peptides against a panel of bacterial species, including representatives from the World Health Organization’s “priority pathogens” list. Four of our novel AMPs were active against multiple species of bacteria, including a multi-drug resistant isolate of carbapenemase-producingEscherichia coli, demonstrating the utility of tools like AMPlify in our fight against antibiotic resistance.
Ventral hippocampus-lateral septum circuitry promotes foraging-related memory
Authors: Décarie-Spain Léa , Liu Clarissa M. , Lauer Logan Tierno , Subramanian Keshav , Bashaw Alexander G. , Klug Molly E. , Gianatiempo Isabella H. , Suarez Andrea N. , Noble Emily E. , Donohue Kristen N. , Cortella Alyssa M. , Hahn Joel D. , Davis Elizabeth A. , Kanoski Scott E.
Published: June 2020

Remembering the location of a food or water source is essential for survival. Here we demonstrate that spatial memory for food location is reflected in ventral hippocampus (HPCv) neuron activity and is impaired by HPCv lesion. HPCv mediation of foraging-related memory involves downstream lateral septum (LS) signaling, as both reversible and chronic disconnection of HPCv (field CA1) to LS signaling impairs spatial memory retention for the location of either food or water reinforcement. This neural pathway selectively encodes appetitive spatial memory, as HPCv-LS disconnection does not affect aversive reinforcement-based spatial memory in an escape task using the same apparatus. The selectivity of this pathway in promoting foraging-related memory is further supported by results showing that CA1v-LS disconnection does not affect food intake, motivated operant responses for food, anxiety-like behavior, locomotor activity, or social and olfactory-based appetitive learning. Fluorescent in situ hybridization reveals that LS neurons recruited during the appetitive spatial memory task are primarily GABAergic, and multisynaptic anterograde neural pathway tracing and immediate early gene mapping identify the lateral hypothalamic area as a functional downstream target of this pathway. Collective results reveal a novel neural circuit through which the hippocampus selectively mediates memory for the location of appetitive (food or water) but not aversive (escape) reinforcement.
A method to map and interpret pleiotropic loci using summary statistics of multiple traits
Authors: Lee Cue Hyunkyu , Shi Huwenbo , Pasaniuc Bogdan , Eskin Eleazar , Han Buhm
Published: June 2020

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The identification of pleiotropic loci and the interpretation of the associations at these loci are essential to understand the shared etiology of related traits. A common approach to map pleiotropic loci is to use an existing meta-analysis method to combine summary statistics of multiple traits. This strategy does not take into account the complex genetic architectures of traits such as genetic correlations and heritabilities. Furthermore, the interpretation is challenging because phenotypes often have different characteristics and units. We propose PLEIO, a summary-statistic-based framework to map and interpret pleiotropic loci in a joint analysis of multiple traits. Our method maximizes power by systematically accounting for the genetic correlations and heritabilities of the traits in the association test. Any set of related phenotypes, binary or quantitative traits with differing units, can be combined seamlessly. In addition, our framework offers interpretation and visualization tools to help downstream analyses. Using our method, we combined 18 traits related to cardiovascular disease and identified 20 novel pleiotropic loci, which showed five different patterns of associations. Our method is available athttps://github.com/hanlab-SNU/PLEIO.
Characterization of the evolutionary dynamics of influenza A H3N2 hemagglutinin
Authors: Wang Maggie Haitian , Lou Jingzhi , Cao Lirong , Zhao Shi , Chan Paul KS , Chan Martin Chi-Wai , Chong Marc KC , Wu William KK , Chan Renee WY , Wei Yuchen , Zhang Haoyang , Zee Benny CY , Yeoh Eng-kiong
Published: June 2020

Virus evolution drives the annual influenza epidemics in human population worldwide. However, it has been challenging to evaluate the mutation effect of the influenza virus on evading the population immunity. In this study, we introduce a novel statistical and computational approach to measure the dynamic molecular determinants underlying epidemics by the effective mutations (EMs), and account for the time of waning mutation advantage against herd immunity by the effective mutation periods (EMPs). Extensive analysis is performed on the genome and epidemiology data of 13-year worldwide H3N2 epidemics involving nine regions in four continents. We showed that the identified EM processed similar profile in geographically adjacent regions, while only 40% are common to Europe, North America, Asia and Oceania, indicating that the regional specific mutations also contributed significantly to the global H3N2 epidemics. The mutation dynamics calibrated that around 90% of the common EMs underlying global epidemics were originated from South East Asia, led by Thailand and India, and the rest were originated from North America. New Zealand was found to be the dominate sink region of H3N2 circulation, followed by UK. All regions might act as the intersection in the H3N2 transmission network. The proposed methodology provided a way to characterize key amino acids from the genetic epidemiology point of view. This approach is not restricted by the genomic region or type of the virus, and will find broad applications in identifying therapeutic targets for combating infectious diseases.