bluuebunny/crossref_metadata_2025 huggingface dataset:
Auxin-degron system identifies immediate mechanisms of Oct4
Authors: Bates Lawrence E , Alves Mariana R P , Silva José C R
Published: September 2020

The pluripotency factor Oct4 is essential for the maintenance of naïve pluripotent stem cells in vitro and in vivo. However, the specific role of Oct4 in this process remains unknown. Here, we developed a rapid protein-level Oct4 depletion system that demonstrates that the immediate downstream response to loss of Oct4 is reduced expression of key pluripotency factors. Our data show a requirement for Oct4 for the efficient transcription of several key pluripotency factors, and suggest that expression of trophectoderm markers is a subsequent event. Additionally, we find that Nanog is competent to bind to the genome in the absence of Oct4, and this binding is in fact enhanced. Globally, however, active enhancer associated histone mark H3K27ac is depleted. Our work establishes that while Oct4 is required for the maintenance of the naïve transcription factor network, at a normal ESC level it antagonises this network through inhibition of Nanog binding.
Necrotizing enterocolitis-induced systemic immune suppression in neonatal preterm pigs
Authors: Ren Shuqiang , Pan Xiaoyu , Hui Yan , Kot Witold , Gao Fei , Sangild Per T. , Nguyen Duc Ninh
Published: September 2020

Objectives

Preterm infants are at high risks of sepsis and necrotising enterocolitis (NEC). Some develop sepsis shortly after suspected or confirmed NEC, implying that NEC may predispose to sepsis but the underlying mechanisms are unknown. Using NEC-sensitive preterm pigs as models, we investigated the immune status in animals with and without NEC.

Methods

Preterm pigs (n=113, caesarean delivered at day 106) were reared until day 5 or 9. Blood was analyzed for T cell subsets, neutrophil phagocytosis, trans criptomics and immune responses to LPS challenge. Gut tissues were used for histology and cytokine analyses. Pigs with/without macroscopic NEC lesions were scored as healthy, mild or severe NEC.

Results

Overall NEC incidence was similar on days 5 and 9 (61-62%) with less severe lesions on day 9, implying gradual mucosal repair following the early phase of NEC on day 5. Pigs with NEC, especially severe NEC, showed decreased goblet cell density and increased MPO+and CD3+cell density in the distal intestine or colon. Circulating parameters were minimally affected by NEC on day 5, but widely altered on day 9 in pigs with NEC, especially severe NEC, to the direction of immune suppression. These included elevated Treg frequency, impaired neutrophil phagocytosis, diminished LPS-induced cytokine secretions and immune gene responses, and consistently low expressions of genes related to innate immune signalling and Th1 polarization.

Conclusion

We shows evidence for NEC-induced systemic immune suppression, even with mild and sub-clinical NEC lesions, thereby suggesting mechanisms for increased secondary infections in infants with previous NEC diagnosis.
SingleChannelNet: A Model for Automatic Sleep Stage Classification with Raw Single-Channel EEG
Authors: Zhou Dongdong , Hu Guoqiang , Zhang Jiacheng , Wang Jian , Yan Rui , Li Fan , Xu Qi , Kettunen Lauri , Chang Zheng , Cong Fengyu
Published: September 2020

In diagnosing sleep disorders, sleep stage classification is a very essential yet time-consuming process. Most of the existing state-of-the-art approaches rely on hand-crafted features and multi-modality polysomnography (PSG) data, where prior knowledge is compulsory and high computation cost can be expected. Besides, few studies are able to obtain high accuracy sleep staging using raw single-channel electroencephalogram (EEG). To overcome these shortcomings, this paper proposes an end-to-end framework with a deep neural network, namely SingleChannelNet, for automatic sleep stage classification based on raw single-channel EEG. The proposed model utilizes a 90s epoch as the textual input and employs two multi-convolution blocks and several max-average pooling layers to learn different scales of feature representations. To demonstrate the efficiency of the proposed model, we evaluate our model using different raw single-channel EEGs (C4/A1 and Fpz-Cz) on two different datasets (CC-SHS and Sleep-EDF datasets). Experimental results show that the proposed architecture can achieve better over-all accuracy and Cohen’s kappa (CCSHS: 90.2%-86.5%, Sleep-EDF: 86.1%-80.5%) compared with state-of-the-art approaches. Additionally, the proposed model can learn features automatically for sleep stage classification using different single-channel EEGs with distinct sampling rates from different datasets without using any hand-engineered features.
Neonicotinoids stimulate H2-limited methane emission inPeriplaneta americanathrough the regulation of gut bacterium community
Authors: Bao Haibo , Gao Haoli , Zhang Jianhua , Lu Haiyan , Yu Na , Shao Xusheng , Zhang Yixi , Jin Wei , Li Shuqing , Xu Xiaoyong , Tian Jiahua , Xu Zhiping , Li Zhong , Liu Zewen
Published: September 2020

Methane emitted by insects is considered to be an important source of atmospheric methane. Here we report the stimulation of methane emission inPeriplaneta americana, an insect species with abundant methanogens, by neonicotinoids, insecticides widely used to control insect pests. The application of cycloxaprid (CYC) and imidacloprid (IMI) caused foregut expansion inP. americana, and increased the methane production and emission. Antibiotics could mostly eliminate the stimulatory effects. InP. americanagut, hydrogen levels increased and pH values decreased, which could be significantly explained by the gut bacterium community change. The proportion of several bacterium genera increased in guts following CYC treatment, and four genera from five with increased proportions could generate hydrogen at anaerobic conditions. Hydrogen is a central intermediate in methanogenesis. Gut methanogens could use the increased hydrogen to produce more methane, especially at acidic conditions. Following neonicotinoid applications, all increased methanogens in both foregut and hindgut used hydrogen as electron donor to produce methane. Besides, the up-regulation ofmcrA, encoding the enzyme that catalyzes the final step of methanogenesis, suggested an enhanced methane production ability in present methanogens. In the termiteCoptotermes chaohuensis, another methanogen-abundant insect species, hydrogen levels in gut and methane emission significantly increased after neonicotinoid treatment, which was similar to the results inP. americana. In summary, neonicotinoids changed bacterium community inP. americanagut to generate more hydrogen, which then stimulate gut methanogens to produce and emit more methane. The finding raised a new concern over neonicotinoid applications, and might be a potential environmental risk associated with global warming.
Electron flow through NDH-1 complexes is the major driver of cyclic electron flow-dependent proton pumping in cyanobacteria
Authors: Miller Neil T. , Vaughn Michael D. , Burnap Robert L.
Published: September 2020

Cyclic electron flow (CEF) around Photosystem I is vital to balancing the photosynthetic energy budget of cyanobacteria and other photosynthetic organisms. The coupling of CEF to proton pumping has long been hypothesized to occur, providing proton motive force (PMF) for the synthesis of ATP with no net cost to [NADPH]. This is thought to occur largely through the activity of NDH-1 complexes, of which cyanobacteria have four with different activities. While a much work has been done to understand the steady-state PMF in both the light and dark, and fluorescent probes have been developed to observe these fluxesin vivo, little has been done to understand the kinetics of these fluxes, particularly with regard to NDH-1 complexes. To monitor the kinetics of proton pumping inSynechocystissp. PCC 6803, the pH sensitive dye Acridine Orange was used alongside a suite of inhibitors in order to observe light-dependent proton pumping. The assay was demonstrated to measure photosynthetically driven proton pumping and used to measure the rates of proton pumping unimpeded by dark ΔpH. Here, the cyanobacterial NDH-1 complexes are shown to pump a sizable portion of proton flux when CEF-driven and LEF-driven proton pumping rates are observed and compared in mutants lacking some or all NDH-1 complexes. It is also demonstrated that PSII and LEF are responsible for the bulk of light induced proton pumping, though CEF and NDH-1 are capable of generating ∼40% of the proton pumping rate when LEF is inactivated.

Highlights statement

NDH-1 is essential for proton pumping during cyclic photosynthetic electron flow in cyanobacteria
Virulence evolution of multiple infections with vertically and horizontally transmitted fungal species in a natural plant system
Authors: Fang Kai , Zhou Jie , Chen Lin , Li Yu-Xuan , Yang Ai-Ling , Dong Xing-Fan , Zhang Han-Bo
Published: September 2020

The virulence evolution of multiple infections of parasites from the same species has been modelled widely in evolution theory, and the trajectories of evolution are relevant to parasite transmission mode, as well as to parasite and host population dynamics. However, experimental studies on this topic remain scarce, particularly regarding multiple infections by different parasite species. In this study, we employed the invasive plantAgeratina adenophorato verify the predictions made by the model. We observed thatA. adenophorawas a highly susceptible host to phylogenetically diverse foliar pathogens with mixed vertical and horizontal transmission within leaf spots. The pathogen community structure at the leaf spot level was determined by transmission mode. Over time, the pathogen community decreased in diversity; meanwhile, the vertically transmitted pathogens exhibited decreased virulence to the hostA. adenophora, but the horizontally transmitted pathogens exhibited increased virulence to the host. Our results demonstrate that the predictions of classical models are still valid in a complex environment. Moreover, we propose that it is very important to determine whether the primary foliar pathogen of a given plant host is relevant to seedborne fungi, as this characteristic is an important factor in understanding pathogen-host interactions.
Genetic Architecture of 11 Major Psychiatric Disorders at Biobehavioral, Functional Genomic, and Molecular Genetic Levels of Analysis
Authors: Grotzinger Andrew D. , Mallard Travis T. , Akingbuwa Wonuola A. , Ip Hill F. , Adams Mark J. , Lewis Cathryn M. , McIntosh Andrew M. , Grove Jakob , Dalsgaard Søren , Lesch Klaus-Peter , Strom Nora , Meier Sandra M. , Mattheisen Manuel , Børglum Anders D. , Mors Ole , Breen Gerome ,   iPSYCH, Tourette Syndrome and Obsessive Compulsive Disorder Working Group of the Psychiatric Genetics Consortium,   Bipolar Disorder Working Group of the Psychiatric Genetics Consortium,   Major Depressive Disorder Working Group of the Psychiatric Genetics Consortium,   Schizophrenia Working Group of the Psychiatric Genetics Consortium, Lee Phil H. , Kendler Kenneth S. , Smoller Jordan W. , Tucker-Drob Elliot M. , Nivard Michel G.
Published: September 2020

We systematically interrogate the joint genetic architecture of 11 major psychiatric disorders at biobehavioral, functional genomic, and molecular genetic levels of analysis. We identify four broad factors (Neurodevelopmental, Compulsive, Psychotic, and Internalizing) that underlie genetic correlations among the disorders, and test whether these factors adequately explain their genetic correlations with biobehavioral traits. We introduce Stratified Genomic Structural Equation Modelling, which we use to identify gene sets and genomic regions that disproportionately contribute to pleiotropy, including protein-truncating variant intolerant genes expressed in excitatory and GABAergic brain cells that are enriched for pleiotropy between disorders with psychotic features. Multivariate association analyses detect a total of 152 (20 novel) independent loci which act on the four factors, and identify nine loci that act heterogeneously across disorders within a factor. Despite moderate to high genetic correlations across all 11 disorders, we find very little utility of, or evidence for, a single dimension of genetic risk across psychiatric disorders.
Knowledge, Attitude and Practice towards COVID-19 among people in Bangladesh during the pandemic: a cross-sectional study
Authors: Rabbani Md. Golam , Akter Orin , Hasan Md. Zahid , Samad Nandeeta , Mahmood Shehrin Shaila , Joarder Taufique
Published: September 2020

The world is grappling with Covid-19, a dire public health crisis. Preventive and control measures are adopted to reduce the spread of COVID-19. It is important to know the knowledge, attitude, and practice (KAP) of people towards this pandemic to suggest appropriate coping strategies. The aim of this study was to assess the KAP of Bangladeshi people towards Covid-19 and determinants of those KAPs. We conducted a cross-sectional survey of 492 Bangladeshi people aged above 18 years from May 7 to 29, 2020 throughout the country. Simple and multiple logistic regression analyses were conducted to identify the factors associated with KAP on COVID-19. About 45% of respondents had good knowledge, 49% of respondents expressed positive attitude towards controlling of COVID-19 and 24% of respondents had favorable practice towards COVID-19. Almost three fourths of the respondents went outside home during the lockdown period. Furthermore, the study found that good knowledge and attitude were associated with better practice of COVID-19 health measures. An evidence informed and context specific risk communication and community engagement, and a social and behavior change communication strategy against COVID-19 should be developed in Bangladesh, based on the findings of this study, targeting different socio-economic groups.
Increased resting-state functional connectivity within theta and alpha frequency bands in dysphoria: Towards a novel measure of depression risk
Authors: Dell’Acqua Carola , Ghiasi Shadi , Benvenuti Simone Messerotti , Greco Alberto , Gentili Claudio , Valenza Gaetano
Published: September 2020

Background

The understanding of neurophysiological correlates underlying the risk of developing depression may have a significant impact on its early and objective identification. Research has identified abnormal resting-state electroencephalography (EEG) power and functional connectivity patterns in major depression. However, the entity of dysfunctional EEG dynamics in dysphoria is yet unknown.

Methods

32-channel EEG was recorded in 26 female individuals with dysphoria and in 38 age-matched, female healthy controls. EEG power spectra and alpha asymmetry in frontal and posterior channels were calculated in a 4-minute resting condition. An EEG functional connectivity analysis was conducted through phase locking values, particularly mean phase coherence.

Results

While individuals with dysphoria did not differ from controls in EEG spectra and asymmetry, they exhibited dysfunctional brain connectivity. Particularly, in the theta band (4-8 Hz), participants with dysphoria showed increased connectivity between right frontal and central areas and right temporal and left occipital areas. Moreover, in the alpha band (8-12 Hz), dysphoria was associated with increased connectivity between right and left prefrontal cortex and between frontal and central-occipital areas bilaterally.

Limitations

All participants belonged to the female gender and were relatively young. Mean phase coherence did not allow to compute the causal and directional relation between brain areas.

Conclusions

An increased EEG functional connectivity in the theta and alpha bands characterizes dysphoria. These patterns may be associated with the excessive self-focus and ruminative thinking that typifies depressive symptoms. EEG connectivity patterns may represent a promising measure to identify individuals with a higher risk of developing depression.
Reduced heart rate variability is associated with vulnerability to depression
Authors: Dell’Acqua Carola , Bò Elisa Dal , Benvenuti Simone Messerotti , Palomba Daniela
Published: September 2020

Background

Heart rate variability (HRV) mirrors cardiac autonomic modulation, an index of well-being. Reduced HRV has been reported in depression, but few studies investigated HRV in individuals at-risk of or remitted from a full-blown depressive episode. The present study aimed at examining whether reduced HRV could be a potential indicator of vulnerability to depression.

Methods

Self-reported psychological measures and three-minute resting-state ECG were collected in two at-risk populations [group with dysphoria (n= 27), group with past depression (n= 16)] and in a control group (n= 25). Time- and frequency-domain HRV parameters were computed. Analysis of covariance was conducted to detect between-groups differences for each measure.

Results

Standard Deviation of Normal to Normal intervals (SDNN) and High Frequency (HF) power of HRV were found to be reduced both in individuals with dysphoria and in those with past depression as compared with controls. Whereas psychological measures did not significantly differ among individuals with past depression and controls, HRV was capable of discriminating between the two groups.

Limitations

Past depression was assessed retrospectively with self-reported information. The inclusion of a group with depression would provide an overview about HRV during the illness course.

Conclusions

The findings suggest that reduced HRV is likely to be implicated in the risk of developing full-blown depression, rather than being a mere correlate of current depressive state. The results suggest that HRV may improve clinicians’ ability to early identify people at risk for depression who can benefit from targeted prevention by psychiatric and psychological interventions.
A statistical algorithm for outbreak detection in a multi-site setting: the case of sick leave monitoring
Authors: Duchemin Tom , Noufaily Angela , Hocine Mounia N.
Published: September 2020

Surveillance for infectious disease outbreak or for other processes should sometimes be implemented simultaneously on multiple sites to detect local events. Sick leave can be monitored accross companies to detect issues such as local outbreaks and identify companies-related issues as local spreading of infectious diseases or bad management practice. In this context, we proposed an adaptation of the Quasi-Poisson regression-based Farrington algorithm for multi-site surveillance. The proposed algorithm consists of a Negative-Binomial mixed effect regression with a new reweighting procedure to account for past outbreaks and increase sensitivity of the model. We perform a wide range simulations to assess the performance of the model in terms of False Positive Rate and Probability of Detection. We propose an application to sick leave rate in the context of COVID-19. The proposed algorithm provides good overall performance and opens up new opportunities for multi-site data surveillance.
Aerosol transmission of COVID-19 and infection risk in indoor environments
Authors: Lelieveld J. , Helleis F. , Borrmann S. , Cheng Y. , Drewnick F. , Haug G. , Klimach T. , Sciare J. , Su H. , Pöschl U.
Published: September 2020

The role of aerosolized SARS-CoV-2 viruses in airborne transmission of COVID-19 is debated. The transmitting aerosol particles are generated through the breathing and vocalization by infectious subjects. Some authors state that this represents the dominant route of spreading, while others dismiss the option. Public health organizations generally categorize it as a secondary transmission pathway. Here we present a simple, easy-to-use spreadsheet algorithm to estimate the infection risk for different indoor environments, constrained by published data on human aerosol emissions, SARS-CoV-2 viral loads, infective dose and other parameters. We evaluate typical indoor settings such as an office, a classroom, a choir practice room and reception/party environments. These are examples, and the reader is invited to use the algorithm for alternative situations and assumptions. Our results suggest that aerosols from highly infective subjects can effectively transmit COVID-19 in indoor environments. This “highly infective” category represents about one fifth of the patients tested positive for SARS-CoV-2. We find that “super infective” subjects, representing the top few percent of positive-tested ones, plus an unknown fraction of less, but still highly infective, high aerosol-emitting subjects, may cause COVID-19 clusters (>10 infections), e.g. in classrooms, during choir singing and at receptions. The highly infective ones also risk causing such events at parties, for example. In general, active room ventilation and the ubiquitous wearing of face masks (i.e. by all subjects) may reduce the individual infection risk by a factor of five to ten, similar to high-volume HEPA air filtering. The most effective mitigation measure studied is the use of high-quality masks, which can drastically reduce the indoor infection risk through aerosols.
A microplanning strategy to improve door-to-door health service delivery: The case of Seasonal Malaria Chemoprevention in Sub-Saharan African villages
Authors: Ouédraogo André Lin , Zhang Julie , Tinto Halidou , Valéa Innocent , Wenger Edward A.
Published: September 2020

Background

Malaria incidence has plateaued in Sub-Saharan Africa despite Seasonal Malaria Chemoprevention’s introduction. Community health workers use a door-to-door delivery strategy to treat children with SMC drugs, but for SMC to be as effective as in clinical trials, coverage must be high over successive seasons.

Methods

We developed and used a microplanning model that ‘utilizes raster to estimate population size, generates optimal households visit itinerary, and quantifies SMC coverage based on CHWs’ time investment for treatment and walking. CHWs’ performance under current SMC deployment mode was assessed using CHWs’ tracking data and compared to microplanning in villages with varying demographics and geographies.

Results

Estimates showed that microplanning significantly reduces CHWs’ walking distance by 25%, increases the number of visited households by 36% (p < 0.001) and increases SMC coverage by 21% from 37.3% under current SMC deployment mode up to 58.3% under microplanning (p < 0.001). Optimal visit itinerary alone increased SMC coverage up to 100% in small villages whereas in larger or hard-to-reach villages, filling the gap additionally needed an optimization of the CHW ratio.

Conclusion

We estimate that for a pair of CHWs, the daily optimal number of visited children (assuming 8.5mn of treatment duration per child) and walking distance should not exceed 45 and 5km respectively. Our work contributes to extend SMC coverage by 21-63% and may have broader applicability for other community health programs.
Risk of adverse COVID-19 outcomes for people living with HIV: a rapid review and meta-analysis
Authors: Mellor Maya M. , Bast Anne C. , Jones Nicholas R. , Roberts Nia W. , Ordóñez-Mena José M. , Reith Alastair J.M. , Butler Christopher C. , Matthews Philippa C. , Dorward Jienchi
Published: September 2020

Objective

To assess whether people living with HIV (PLWH) are at increased risk of COVID-19 mortality or adverse outcomes, and whether antiretroviral therapy (ART) influences this risk.

Design

Rapid review with meta-analysis and narrative synthesis.

Methods

We searched databases including Embase, Medline, medRxiv, and Google Scholar up to 26th August 2020 for studies describing COVID-19 outcomes in PLWH and conducted a meta-analysis of higher quality studies.

Results

We identified 1,908 studies and included 19 in the review. In a meta-analysis of five studies, PLWH had a higher risk of COVID-19 mortality (hazard ratio (HR) 1.93, 95% Confidence Interval (CI): 1.59-2.34) compared to people without HIV. Risk of death remained elevated for PLWH in a subgroup analysis of hospitalised cohorts (HR 1.54, 95% CI: 1.05-2.24) and studies of PLWH across all settings (HR 2.08, 95%CI: 1.69-2.56). Eight other studies assessed the association between HIV and COVID-19 outcomes, but provided inconclusive, lower-quality evidence due to potential confounding and selection bias.

There were insufficient data on the effect of CD4+ T cell count and HIV viral load on COVID-19 outcomes. Eleven studies reported COVID-19 outcomes by ART-regimen. In the two largest studies, tenofovir-disoproxil-fumarate (TDF)-based regimens were associated with a lower risk of adverse COVID-19 outcomes, although these analyses are susceptible to confounding by comorbidities.

Conclusion

Evidence is emerging that suggests a moderately increased risk of COVID-19 mortality amongst PLWH. Further investigation into the relationship between COVID-19 outcomes and CD4+ T cell count, HIV viral load, ART and the use of TDF is warranted.
Autonomic/Central Coupling during Daytime Sleep Differs between Older and Younger People
Authors: Chen Pin-Chun , Simon Katharine N , Sattari Negin , Whitehurst Lauren N , Mednick Sara C
Published: September 2020

Age-dependent functional changes are mirrored by declines in both the central the autonomic nervous systems and have been related to pathological aging. Prior studies in our group have identified a temporal coupling of Autonomic and Central Events (ACEs) during sleep using electrocardiogram to measure heart rate and electroencephalography to measure brain rhythms, with heart rate bursts (HRBs) temporally coincided with increased slow-wave-activity (SWA, 0.5-1Hz) and sigma activity (12-15Hz), followed by parasympathetic surge (RRHF) during non-rapid eye movement (NREM) sleep. ACEs predicted working memory (WM) improvement in young adults. Given that there are paralleling age-related declines in both the ANS and CNS, the current study investigated differences in ACE activity during daytime sleep in older and younger adults and their functional impact on working memory. Compared to youngers, older adults showed lower amplitude of ACEs during NREM sleep, but no age-related difference during Wake. Furthermore, while younger adults demonstrated a parasympathetic surge after HRBs, older adults showed a different pattern, with a earlier rise and maintenance of the RRHF. Finally, we examined whether ACE predicted WM in older adults. We found that older adults with good WM show stronger coupling, whereas low WM performers had less robust ACE activity. Taken together, our results demonstrated that autonomic-central coupling declines with age, with possible links to deterioration in WM function. Given that age-related deterioration in autonomic and central nervous system activity is implicated in pathological decline, the current findings may facilitate novel insights to the cognitive neuroscience of aging.
Structural Mechanism Underlying Ligand Binding and Activation of PPARγ
Authors: Shang Jinsai , Kojetin Douglas J.
Published: September 2020

Ligands bind to an occluded orthosteric pocket within the nuclear receptor (NR) ligand-binding domain (LBD). Molecular simulations have revealed several theoretical ligand entry/exit pathways to the orthosteric pocket, but experimentally it remains unclear whether ligand binding proceeds through induced fit or conformational selection mechanisms. Using NMR spectroscopy lineshape analysis, we show that ligand binding to the peroxisome proliferator-activated receptor gamma (PPARγ) LBD involves a two-step induced fit mechanism including an initial fast step followed by slow conformational change. Surface plasmon resonance and isothermal titration calorimetry heat capacity analysis support the fast kinetic binding step and the conformational change after binding step, respectively. The putative initial ligand binding pose is suggested in several crystal structures of PPARγ LBD where a ligand is bound to a surface pore formed by helix 3, the β-sheet, and the Ω-loop—one of several ligand entry sites suggested in previous targeted and unbiased molecular simulations. These findings, when considered with a recent NMR study showing the activation function-2 (AF-2) helix 12 exchanges in and out of the orthosteric pocket in apo/ligand-free PPARγ, suggest an activation mechanism whereby agonist binding occurs through an initial encounter complex with the LBD followed by transition of the ligand into the orthosteric pocket concomitant with a conformational change resulting in a solvent-exposed active helix 12 conformation.
Intercontinental prediction of soybean phenology via hybrid ensemble of knowledge-based and data-driven models
Authors: McCormick Ryan F. , Truong Sandra K. , Rotundo Jose , Gaspar Adam P. , Kyle Don , van Eeuwijk Fred , Messina Carlos D.
Published: September 2020

The timing of crop development has significant impacts on management decisions and subsequent yield formation. A large intercontinental dataset recording the timing of soybean developmental stages was used to establish ensembling approaches that leverage both discrete-time dynamical system models of soybean phenology and data-driven, machine-learned models to achieve accurate and interpretable predictions. We demonstrate that the knowledge-based, dynamical models can improve machine learning by generating expert-engineered features. Combining the predictions of the diverse component models via super learning resulted in a mean absolute error of 4.12 and 4.55 days to flowering (R1) and physiological maturity (R7), providing an improvement relative to the best benchmark model error of 6.90 and 15.47 days, respectively. The hybrid intercontinental model applies to a much wider range of management and temperature conditions than previous mechanistic models, enabling improved decision support as alternative cropping systems arise, farm sizes increase, and changes in the global climate continue to accelerate.
First high-quality reference genome ofAmphicarpaea edgeworthii
Authors: Song Tingting , Zhou Mengyan , Yuan Yuying , Yu Jinqiu , Cai Hua , Li Jiawei , Chen Yajun , Bai Yan , Zhou Gang , Cui Guowen
Published: September 2020

Amphicarpaea edgeworthii, an annual twining herb, is a widely distributed species and an ideal model for studying complex flowering types and evolutionary mechanisms of species. Herein, we generated a high-quality assembly ofA. edgeworthiiby using a combination of PacBio, 10× Genomics libraries, and Hi-C mapping technologies. The final 11 chromosome-level scaffolds covered 90.61% of the estimated genome (343.78 Mb), which is the first chromosome-scale assembled genome of an amphicarpic plant. These data will be beneficial for the discovery of genes that control major agronomic traits, spur genetic improvement of and functional genetic studies in legumes, and supply comparative genetic resources for other amphicarpic plants.
A novel small molecule LLL12B inhibits STAT3 signaling and sensitizes ovarian cancer cell to paclitaxel and cisplatin
Authors: Zhang Ruijie , Yang Xiaozhi , Roque Dana M. , Li Chenglong , Lin Jiayuh
Published: September 2020

Ovarian cancer is the fifth most common cause of cancer deaths among American women. Platinum and taxane combination chemotherapy represents the first-line approach for ovarian cancer, but treatment success is often limited by chemoresistance. Therefore, it is necessary to find new drugs to sensitize ovarian cancer cells to chemotherapy. Persistent activation of Signal Transducer and Activator of Transcription 3 (STAT3) signaling plays an important role in oncogenesis. Using a novel approach called advanced multiple ligand simultaneous docking (AMLSD), we developed a novel nonpeptide small molecule, LLL12B, which targets the STAT3 pathway. In this study, LLL12B inhibited STAT3 phosphorylation (tyrosine 705) and the expression of its downstream targets, which are associated with cancer cell proliferation and survival. We showed that LLL12B also inhibits cell viability, migration, and proliferation in human ovarian cancer cells. LLL12B combined with either paclitaxel or with cisplatin demonstrated synergistic inhibitory effects relative to monotherapy in inhibiting cell viability and LLL12B-paclitaxel or LLL12B-cisplatin combination exhibited greater inhibitory effects than cisplatin- paclitaxel combination in ovarian cancer cells. Furthermore, LLL12B-paclitaxel or LLL12B-cisplatin combination showed more significant in inhibiting cell migration and growth than monotherapy in ovarian cancer cells. In summary, our results support the novel small molecule LLL12B as a potent STAT3 inhibitor in human ovarian cancer cellsand suggest that LLL12B in combination with the current front-line chemotherapeutic drugs cisplatin and paclitaxel may represent a promising approach for ovarian cancer therapy.
MANF regulates unfolded protein response and neuronal survival through its ER-located receptor IRE1α
Authors: Kovaleva Vera , Yu Li-Ying , Ivanova Larisa , Nam Jinhan , Eesmaa Ave , Kumpula Esa-Pekka , Huiskonen Juha , Lindholm Päivi , Voutilainen Merja , Karelson Mati , Saarma Mart
Published: September 2020

Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER)-located protein with cytoprotective effects in numerous cell typesin vitroand in models of neurodegeneration and diabetesin vivo. So far, the exact mode of its action has remained elusive and plasma membrane or ER-located receptors of MANF have not been identified. We have found that MANF can directly interact with transmembrane unfolded protein response (UPR) receptor IRE1α and compete with the major ER chaperone BiP (GRP78) for the interaction with IRE1α. With lower affinities MANF can also interact with other UPR receptors, PERK and ATF6. Using molecular modeling and mutagenesis analysis, we have identified the exact structural MANF regions involved in its binding to the luminal domain of IRE1α. MANF attenuates UPR signaling by decreasing IRE1α oligomerization and IRE1α phosphorylation. MANF mutant deficient in IRE1α binding cannot regulate IRE1α oligomerization and fails to protect neurons from ER stress induced death. Importantly, we found that MANF-IRE1α interaction is also crucial for the survival promoting action of MANF for dopamine neurons in an animal model of Parkinson’s disease. Our data reveal a novel mechanism of IRE1α regulation during ER stress and demonstrate the intracellular mode of action of MANF as a modulator of UPR and neuronal cell survival through the direct interaction with IRE1α and regulation of its activity. Furthermore, our data explain why MANF in contrast to other growth factors has no effects on naive cells and rescues only ER stressed or injured cells.
Amplicons and isolates:Rhizobiumdiversity in fields under conventional and organic management
Authors: Moeskjær Sara , Tausen Marni , Andersen Stig U. , Young J. Peter W.
Published: September 2020

Background

The influence of farming on plant, animal and microbial biodiversity has been carefully studied and much debated. Here, we compare an isolate-based study of 196Rhizobiumstrains to amplicon-based MAUI-seq analysis of rhizobia from 17,000 white clover root nodules. We use these data to investigate the influence of soil properties, geographic distance, and field management onRhizobiumnodule populations.

Results

Overall, there was good agreement between the two approaches and the precise allele frequency estimates from the large-scale MAUI-seq amplicon data allowed detailed comparisons of rhizobium populations between individual plots and fields. A few specific chromosomal core-gene alleles were significantly correlated with soil clay content, and core-gene allele profiles became increasingly distinct with geographic distance. Field management was associated with striking differences inRhizobiumdiversity, where organic fields showed significantly higher diversity levels than conventionally managed trials.

Conclusions

Our results indicate that MAUI-seq is suitable and robust for assessing noduleRhizobiumdiversity. We further observe possible profound effects of field management on microbial diversity, which could impact plant health and productivity and warrant further investigation.
HiCRes: a computational method to estimate and predict the resolution of HiC libraries
Authors: Marchal Claire , Singh Nivedita , Corso-Díaz Ximena , Swaroop Anand
Published: September 2020

Three-dimensional (3D) conformation of the chromatin is crucial to stringently regulate gene expression patterns and DNA replication in a cell-type specific manner. HiC is a key technique for measuring 3D chromatin interactions genome wide. Estimating and predicting the resolution of a library is an essential step in any HiC experimental design. Here, we present the mathematical concepts to estimate the resolution of a library and predict whether deeper sequencing would enhance the resolution. We have developed HiCRes, a docker pipeline, by applying these concepts to human and mouse HiC libraries.
Mass cytometry and artificial intelligence define CD169 as a specific marker of SARS-CoV2-induced acute respiratory distress syndrome
Authors: Roussel M. , Ferrant J. , Reizine F. , Le Gallou S. , Dulong J. , Carl S. , Lesouhaitier M. , Gregoire M. , Bescher N. , Verdy C. , Latour M. , Bézier I. , Cornic M. , Leonard S. , Feuillard J. , Tiwari V.K. , Tadié J.M. , Cogné M. , Tarte K.
Published: September 2020

Acute respiratory distress syndrome (ARDS) is the main complication of COVID-19, requiring admission to Intensive Care Unit (ICU). Despite recent immune profiling of COVID-19 patients, to what extent COVID-19-associated ARDS specifically differs from other causes of ARDS remains unknown, To address this question, we built 3 cohorts of patients categorized in COVID-19negARDSpos, COVID-19posARDSpos, and COVID-19posARDSneg, and compared their immune landscape analyzed by high-dimensional mass cytometry on peripheral blood followed by artificial intelligence analysis. A cell signature associating S100A9/calprotectin-producing CD169posmonocytes, plasmablasts, and Th1 cells was specifically found in COVID-19posARDSpos, unlike COVID-19negARDSpospatients. Moreover, this signature was shared by COVID-19posARDSnegpatients, suggesting severe COVID-19 patients, whatever they experienced or not ARDS, displayed similar immune dysfunctions. We also showed an increase in CD14posHLA-DRlowand CD14lowCD16posmonocytes correlated to the occurrence of adverse events during ICU stay. Our study demonstrates that COVID-19-associated ARDS display a specific immune profile, and might benefit from personalized therapy in addition to standard ARDS management.

One Sentence Summary

COVID-19-associated ARDS is biologically distinct from other causes of ARDS.
Multilocus phylogeny and historical biogeography ofHypostomusshed light on the processes of fish diversification in La Plata Basin
Authors: Cardoso Yamila P. , de Queiroz Luiz Jardim , Bahechar Ilham A. , Posadas Paula E. , Montoya-Burgos Juan I.
Published: September 2020

Distribution history of the widespread Neotropical genusHypostomusto shed light on the processes that shaped species diversity. We inferred a calibrated phylogeny; ancestral habitat preference, ancestral areas distribution, and the history of dispersal and vicariance events of this genus. The phylogenetic and distributional analyses indicate thatHypostomusspecies inhabiting La Plata Basin do not form a monophyletic clade, suggesting that several unrelated ancestral species colonized this basin in the Miocene (∼17 Mya). Dispersal to other rivers of La Plata Basin started about 8 Mya, followed by habitat shifts and an increased rate of cladogenesis. AmazonianHypostomusspecies colonized La Plata Basin several times in the Middle Miocene, probably via the Upper Paraná and the Paraguay rivers that acted as biogeographic corridors. During the Miocene, La Plata Basin experienced marine incursions; and geomorphological and climatic changes that reconfigured its drainage pattern, driving the dispersal and diversification ofHypostomus. The Miocene marine incursion was a strong barrier and its retraction triggeredHypostomusdispersal, increased speciation rate and ecological diversification. The timing of hydrogeological changes in La Plata Basin coincides well withHypostomuscladogenetic events, indicating that the history of this basin has acted on the diversification of its biota.
Higher-order sensorimotor circuit of the brain’s global network supports human consciousness
Authors: Qin Pengmin , Wu Xuehai , Wu Changwei , Wu Hang , Zhang Jun , Huang Zirui , Weng Xuchu , Qi Zengxin , Tang Weijun , Hiromi Tanikawa , Tan Jiaxing , Tanabe Sean , Fogel Stuart , Hudetz Anthony G. , Yang Yihong , Stamatakis Emmanuel A , Mao Ying , Northoff Georg
Published: September 2020

The neural correlates of consciousness, defined as the minimum neuronal mechanisms sufficient for any conscious percept, are usually subject to different interpretations depending on whether one uses measures of local or global brain activities. We argue that the local regions may support consciousness by serving as hubs within the brain’s global network. We adopt a unique functional magnetic resonance imaging resting state dataset that encompasses various conscious states, including non-rapid eye movement (NREM)-sleep, rapid eye movement (REM)-sleep, anesthesia, and brain injury patients. Using a graph-theoretical measure for detecting local hubs within the brain’s global network, we identify various higher-order sensory and motor regions as hubs with significantly reduced degree centrality during unconsciousness. Additionally, these regions form a sensorimotor circuit which correlates with levels of consciousness. Our findings suggest that integration of higher-order sensorimotor function may be a key mechanism of consciousness. This opens novel perspectives for therapeutic modulation of unconsciousness.
A Modular Approach to Active Focus Stabilization for Fluorescence Microscopy
Authors: van den Berg Birthe , Van den Eynde Robin , Amouroux Baptiste , Müller Marcel , Dedecker Peter , Vandenberg Wim
Published: September 2020

Fluorescent time-lapse experiments often suffer from focus drift, regularly rendering long measurements partially unusable. Frequently, this instability can be traced back to the specific mechanical components of the setup, but even in highly robust implementations z-drift occurs due to small temperature fluctuations which are hard to avoid. To resolve this issue, microscope manufacturers often offer their own interpretation of out-of-focus correction modules for their flagship instruments. However, self-assembled or older systems typically have to fend for their own or adapt their measurements to circumvent drift effects. In this manuscript, we propose a cost-efficient z-drift detection- and correction system that, due to its modular design, can be attached to any fluorescence microscope with an actuated stage or objective, be it in a custom or commercial setup. The reason for this wide applicability is specific to the design, which has a straightforward alignment procedure and allows sharing optics with the fluorescent emission path. Our system employs an infrared (IR) laser that is passed through a double-hole mask to achieve two parallel beams which are made to reflect on the coverslip and subsequently detected on an industrial sCMOS camera. The relative position of these beams is then uniquely linked to the z-position of a microscope-mounted sample. The system was benchmarked by introducing temperature perturbations, where it was shown to achieve a stable focus, and by scanning different positions while simulating a perturbation in the z-position of the stage, where we show that a lost focus can be recovered within seconds.
ADAR2 deaminase activity promotes Th17 effector function and protects against intestine inflammation
Authors: Ma Shengyun , Hao Yajing , Cho Benjamin S. , Chen Nicholas , Zheng Anna , Zhang Shuyang , Sun Ge , Patel Parth R. , Li Yuxin , Yee Brian A , Yeo Gene W , Zhou Bing , Fu Xiang-Dong , Huang Wendy Jia Men
Published: September 2020

ADAR1 and ADAR2 catalyze adenosine-to-inosine (A-to-I) editing, the most common post-transcriptional modification in RNA. While ADAR1 is ubiquitously expressed and plays a critical role in preventing activation of the host immune system, ADAR2 exhibits tissue-specific and inducible expression patterns, and its function in the immune system is not known. Here, we identify an intragenic super-enhancer involved in the dramatic induction of ADAR2 when naïve helper T cells differentiate toward the Th17 lineage. By editing the inverted repeat sequences at the 3’ untranslated region (UTR) ofMalt1, which encodes a component of the NF-κB activation complex, ADAR2 promotes MALT1 expression and Th17 effector function. Interference with the ADAR2-MALT1 pathway dampens the production of Th17 cytokines and promotes T cell-mediated colitis. This study expands our understanding of RNA editing in adaptive immunity and identifies the ADAR2-MALT1-IL-17A axis as a potential therapeutic target for inflammatory conditions in the intestine.
Integrative genomic strategies applied to a lymphoblast cell line model reveal specific transcriptomic signatures associated with clozapine response
Authors: de With SAJ , Ori APS , Wang T , Pulit SL , Strengman E , Viana J , Mill J , de Jong S , Ophoff RA
Published: September 2020

Clozapine is an important antipsychotic drug. However, its use is often accompanied by metabolic adverse effects and, in rare instances, agranulocytosis. The molecular mechanisms underlying these adverse events are unclear. To gain more insights into the response to clozapine at the molecular level, we exposed lymphoblastoid cell lines (LCLs) to increasing concentrations of clozapine and measured genome-wide gene expression and DNA methylation profiles. We observed robust and significant changes in gene expression levels due to clozapine (n = 463 genes at FDR < 0.05) affecting cholesterol and cell cycle pathways. At the level of DNA methylation, we find significant changes upstream of the LDL receptor, in addition to global enrichments of regulatory, immune and developmental pathways. By integrating these data with human tissue gene expression levels obtained from the Genotype-Tissue Expression project (GTEx), we identified specific tissues, including liver and several tissues involved in immune, endocrine and metabolic functions, that clozapine treatment may disproportionately affect. Notably, differentially expressed genes were not enriched for genome-wide disease risk of schizophrenia or for known psychotropic drug targets. However, we did observe a nominally significant association of genetic signals related to total cholesterol and low-density lipoprotein levels. Together, these results shed light on the biological mechanisms through which clozapine functions. The observed associations with cholesterol pathways, its genetic architecture and specific tissue effects may be indicative of the metabolic adverse effects observed in clozapine users. LCLs may thus serve as a useful tool to study these molecular mechanisms further.