bluuebunny/crossref_metadata_2025 huggingface dataset:
Updated Prevalence of Urinary Incontinence in Women: 2015–2018 National Population-Based Survey Data
Authors: Patel Ushma J. , Godecker Amy L. , Giles Dobie L. , Brown Heidi W.
Published: January 2022

Objectives

This study aimed to update estimates of urinary incontinence (UI) prevalence and associated risk factors for adult women in the United States, using the National Health and Nutrition Examination Survey (NHANES).

Methods

We used descriptive analysis of 2015–2018 NHANES weighted data for women to estimate prevalence and characterize UI types and severity. Logistic regression modeling determined adjusted associations with UI.

Results

Complete data were available for 5,006 women. In weighted analyses, 61.8% had UI, corresponding to 78,297,094 adult U.S. women, with 32.4% of all women reporting symptoms at least monthly. Of those with UI, 37.5% had stress urinary incontinence, 22.0% had urgency urinary incontinence, 31.3% had mixed symptoms, and 9.2% had unspecified incontinence. The prevalence of moderate or more severe UI by Sandvik Severity Index was 22.1%, corresponding to 28,454,778 adult U.S. women. In multivariate models, increasing age, body mass index ≥25, prior vaginal birth, anxiety, depression, functional dependence, and non-Hispanic White ethnicity and race were associated with any and moderate UI. Urinary incontinence was not associated with diabetes, education level, prior hysterectomy, smoking status, physical activity level, or current pregnancy status.

Conclusions

More than 60% of community-dwelling adult women in the United States experience any UI and an increase from prior estimates (38%–49%) using NHANES data from 1999 to 2004; more than 20% experience moderate or more severe UI. Increases in UI prevalence may be related to population aging and increasing obesity prevalence. Age greater than 70 years, body mass index >40, and vaginal birth had the strongest association with UI in multivariate modeling.
Absolute Agranulocytosis After 9 Weeks of Clozapine 25 mg Daily
Authors: Friedman Joseph H.
Published: January 2022

Background

Clozapine has been shown to be an effective and well-tolerated treatment for Parkinson disease (PD) psychosis as well as for refractory tremor in PD. Doses used are generally less than one tenth those used in treating schizophrenia. While the risk of leukopenia and agranulocytosis are reported to be independent of dose, that belief is based on the use of doses used in refractory schizophrenia. There are no published data on the risk of agranulocytosis in patients taking extremely low doses of clozapine.

Case Report

This 87-year-old man with diabetes and PD experienced a granulocyte count drop from normal, 3900, at dose initiation, to 0, at the ninth week of treatment taking clozapine 12.5 mg twice daily for refractory tremor. He recovered without developing an infection.

Conclusions

This is the first known reported case of agranulocytosis due to clozapine used at an extremely low dose. This report underscores the importance of blood monitoring, even at extremely low doses, although the exact risk remains unknown.
β-Blockers for the Treatment of Misophonia and Misokinesia
Authors: Webb Jadon
Published: January 2022

Misophonia is an adverse physical and emotional reaction to certain repetitive trigger sounds, usually generated by other people. Misokinesia refers to visual triggers that are sometimes (but not always) related to trigger sounds. Despite how common and disabling these conditions can be, medication treatment of misophonia and misokinesia is largely unexplored. We present the first case of using a β-blocker (propranolol) to successfully treat a patient experiencing misophonia and misokinesia. A moderate dose (60 mg) of propranolol completely eliminated multiple auditory and visual trigger symptoms related to other people eating. His trigger response symptoms included overwhelming negative emotions and prominent sympathetic overactivity (fight-or-flight response). These symptoms were so severe that he had avoided most meals with friends and family for the past several years. Propranolol eliminated the emotional and physiological effects of both the auditory and visual triggers, with an Amsterdam Misophonia Scale score reduction from 15 to 2. This enabled him to resume eating meals with family and friends with no distress. The medication was well tolerated. In summary, we report the novel finding that β-blockers were markedly effective at treating the physical and emotional symptoms of a patient with misophonia and misokinesia. This suggests a novel treatment approach for these conditions.
Variation in US Drug Overdose Mortality Within and Between Hispanic/Latine Subgroups: A Disaggregation of National Data
Authors: Cano Manuel , Gelpí-Acosta Camila
Published: January 2022

This study examined differences across Latine heritage groups (i.e., Mexican, Puerto Rican, Cuban, Dominican, Central American, South American) in rates of US drug overdose mortality. The study utilized 2015-2019 mortality data from the National Center for Health Statistics for 29,137 Hispanic individuals who died of drug overdose. Using population estimates from the American Community Survey, age-standardized drug overdose mortality rates were calculated by specific Latine heritage and sex, nativity, educational attainment, and geographic region. Standardized rate ratios (SRRs), incidence rate ratios (IRRs) from negative binomial regression models, and 95% Confidence Intervals (CIs) were calculated, and multiple imputation was used for missing Latine heritage group in select models.

Drug overdose mortality rates in the Puerto Rican heritage population were more than three times as high as in the Mexican heritage population (IRR 3.61 [95% CI 3.02-4.30] in unadjusted model; IRR 3.70 [95% CI 3.31-4.15] in model adjusting for age, sex, nativity, educational attainment, and region; SRR 3.23 [95% CI, 3.15-3.32] in age-standardized model with missing Hispanic heritage imputed). Higher age-standardized rates of drug overdose mortality were observed in males than females across all Latine groups, yet the magnitude of the sex differential varied by Latine heritage. The relationship between drug overdose mortality and nativity differed by Latine heritage; in all groups except Puerto Rican, overdose mortality rates were significantly higher in the US-born than those not US-born. In contrast, overdose mortality rates were significantly lower in US-born Puerto Ricans than in Puerto Ricans who were not US-born (e.g., born in Puerto Rico; SRR, 0.84 [95% CI 0.80-0.88]). The relationship between drug overdose mortality and educational attainment (for ages 25+) also varied between Latine groups.

The diverse subgroups comprising the US Latine population vary not only in rates of drug overdose mortality, but also in demographic risk factors for fatal drug overdose.
An ensemble prediction model for COVID-19 mortality risk
Authors: Li Jie , Li Xin , Hutchinson John , Asad Mohammad , Wang Yadong , Wang Edwin
Published: January 2022

Background

It’s critical to identify COVID-19 patients with a higher death risk at early stage to give them better hospitalization or intensive care. However, thus far, none of the machine learning models has been shown to be successful in an independent cohort. We aim to develop a machine learning model which could accurately predict death risk of COVID-19 patients at an early stage in other independent cohorts.

Methods

We used a cohort containing 4711 patients whose clinical features associated with patient physiological conditions or lab test data associated with inflammation, hepatorenal function, cardiovascular function and so on to identify key features. To do so, we first developed a novel data preprocessing approach to clean up clinical features and then developed an ensemble machine learning method to identify key features.

Results

Finally, we identified 14 key clinical features whose combination reached a good predictive performance of AUC 0.907. Most importantly, we successfully validated these key features in a large independent cohort containing 15,790 patients.

Conclusions

Our study shows that 14 key features are robust and useful in predicting the risk of death in patients confirmed SARS-CoV-2 infection at an early stage, and potentially useful in clinical settings to help in making clinical decisions.
qEEG Analysis in the Diagnosis of Alzheimer’s Disease; a Comparison of Functional Connectivity and Spectral Analysis
Authors: Frangopoulou Maria Semeli , Alimardani Maryam
Published: January 2022

Alzheimer’s disease (AD) is a brain disorder that is mainly characterized by a progressive degeneration of neurons in the brain, causing a decline in cognitive abilities and difficulties in engaging in day-to-day activities. This study compares an FFT-based spectral analysis against a functional connectivity analysis based on phase synchronization, for finding known differences between AD patients and Healthy Control (HC) subjects. Both of these quantitative analysis methods were applied on a dataset comprising bipolar EEG montages’ values from 20 diagnosed AD patients and 20 age-matched HC subjects. Additionally, an attempt was made to localize the identified AD-induced brain activity effects in AD patients. The obtained results showed the advantage of the functional connectivity analysis method compared to a simple spectral analysis. Specifically, while spectral analysis could not find any significant differences between the AD and HC groups, the functional connectivity analysis showed statistically higher synchronization levels in the AD group in the lower frequency bands (delta and theta), suggesting that the AD patients’ brains are in a ‘phase-locked’ state. Further comparison of functional connectivity between the homotopic regions confirmed that the traits of AD were localized in the centro-parietal and centro-temporal areas in the theta frequency band (4-8 Hz). The contribution of this study is that it applies a neural metric for Alzheimer’s detection from a data science perspective rather than from a neuroscience one. The study shows that the combination of bipolar derivations with phase synchronization yields similar results to comparable studies employing alternative analysis methods.
Post-traumatic stress symptoms in cancer patients during the COVID-19 pandemic: a one-year longitudinal study
Authors: Bastien Etienne , Lefèvre-Arbogast Sophie , Lequesne Justine , Gernier François , Cherifi François , Rigal Olivier , Guittet Lydia , Grellard Jean-Michel , Binarelli Giulia , Lange Marie , Fernette Marie , Tron Laure , Morel Adeline , Richard Doriane , Griffon Bénédicte , Leconte Alexandra , Quilan Florian , Pépin Louis-Ferdinand , Jardin Fabrice , Leheurteur Marianne , Faveyrial Audrey , Clarisse Bénédicte , Joly Florence
Published: January 2022

Background

Cancer patients may be particularly vulnerable to psychological consequences of the COVID-19 pandemic and successive lockdowns. We studied the prevalence and evolution of post-traumatic stress disorder (PTSD) symptoms in cancer patients during the pandemic waves, and investigated factors associated with high symptoms.

Methods

COVIPACT is a one-year longitudinal prospective study of French patients with solid/hematologic malignancy receiving treatment during the first nationwide lockdown. PTSD symptoms were measured every 3 months from April 2020 using the Impact of Event Scale-Revised. Patients also completed validated questionnaires on quality of life (QoL), cognitive complaints and insomnia, and a survey on their COVID-19 lockdown experience.

Results

Longitudinal analyses involved 386 patients with at least one PTSD assessment after baseline (median age 63, 76% female). Among them, 21.5% had moderate/severe PTSD symptoms during the first lockdown. The rate of patients reporting PTSD symptoms decreased at lockdown release (13.6%), increased again at second lockdown (23.2%), and slightly declined from the second release period (22.7%) to the third lockdown (17.5%). Patients were grouped into three trajectories of evolution. Most patients had stable low symptoms throughout the period, 6% had high baseline symptoms slowly decreasing over time, and 17.6% had moderate symptoms worsening during second lockdown. Female sex, feeling socially isolated, worrying about COVID-19 infection, and using psychotropic drugs were associated with PTSD symptoms. PTSD symptoms were associated with impaired QoL, sleep and cognition.

Conclusions

Around a quarter of cancer patients presented high and persistent PTSD symptoms over the first year of the COVID-19 pandemic and may benefit from psychological support.
Extremely potent monoclonal antibodies neutralize Omicron and other SARS-CoV-2 variants
Authors: Chen Zhaochun , Zhang Peng , Matsuoka Yumiko , Tsybovsky Yaroslav , West Kamille , Santos Celia , Boyd Lisa F. , Nguyen Hanh , Pomerenke Anna , Stephens Tyler , Olia Adam S. , De Giorgi Valeria , Holbrook Michael R. , Gross Robin , Postnikova Elena , Garza Nicole L. , Johnson Reed F. , Margulies David H. , Kwong Peter D. , Alter Harvey J. , Buchholz Ursula J. , Lusso Paolo , Farci Patrizia
Published: January 2022

The ongoing coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has triggered a devastating global health, social and economic crisis. The RNA nature and broad circulation of this virus facilitate the accumulation of mutations, leading to the continuous emergence of variants of concern with increased transmissibility or pathogenicity1. This poses a major challenge to the effectiveness of current vaccines and therapeutic antibodies1, 2. Thus, there is an urgent need for effective therapeutic and preventive measures with a broad spectrum of action, especially against variants with an unparalleled number of mutations such as the recently emerged Omicron variant, which is rapidly spreading across the globe3. Here, we used combinatorial antibody phage-display libraries from convalescent COVID-19 patients to generate monoclonal antibodies against the receptor-binding domain of the SARS-CoV-2 spike protein with ultrapotent neutralizing activity. One such antibody, NE12, neutralizes an early isolate, the WA-1 strain, as well as the Alpha and Delta variants with half-maximal inhibitory concentrations at picomolar level. A second antibody, NA8, has an unusual breadth of neutralization, with picomolar activity against both the Beta and Omicron variants. The prophylactic and therapeutic efficacy of NE12 and NA8 was confirmed in preclinical studies in the golden Syrian hamster model. Analysis by cryo-EM illustrated the structural basis for the neutralization properties of NE12 and NA8. Potent and broadly neutralizing antibodies against conserved regions of the SARS-CoV-2 spike protein may play a key role against future variants of concern that evade immune control.
Ocimum sanctum, OscWRKY1, regulates phenylpropanoid pathway genes and promotes resistance to pathogen infection in Arabidopsis
Authors: Joshi Ashutosh , Jeena Gajendra Singh , Shikha  , Kumar Ravi , Pandey Alok , Shukla Rakesh Kumar
Published: January 2022

WRKY transcription factor (TF) family regulates various developmental and physiological functions in plants. PAL genes encode enzymes which are involved in plant defense responses, but the direct regulation of PAL genes and phenylpropanoid pathway through WRKY TF’s is not well characterized. In the present study, we have characterized an OscWRKY1 gene from O. sanctum which shows induced expression after methyl jasmonate (MeJA), salicylic acid (SA), and wounding. Recombinant OscWRKY1 protein binds to the W-box cis-element TTGAC[C/T] and activates the reporter gene in yeast. Overexpression of OscWRKY1 enhances Arabidopsis resistance towards Pseudomonas syringae pv. tomato Pst DC3000. Upstream activator sequences of PAL and C4H have identified the conserved W-box cis-element (TTGACC) in both O. sanctum and Arabidopsis. OscWRKY1 was found to interact with W-box cis-element present in the PAL and C4H promoters. Silencing of OscWRKY1 using VIGS resulted in reduced expression of PAL, C4H, COMT, F5H and 4CL transcripts. OscWRKY1 silenced plants exhibit reduced PAL activity, whereas, the overexpression lines of OscWRKY1 in Arabidopsis exhibit increased PAL activity. These results revealed that OscWRKY1 positively regulates the phenylpropanoid pathway genes and enhances the resistance against bacterial pathogen in Arabidopsis.
matOptimize: A parallel tree optimization method enables online phylogenetics for SARS-CoV-2
Authors: Ye Cheng , Thornlow Bryan , Hinrichs Angie , Torvi Devika , Lanfear Robert , Corbett-Detig Russell , Turakhia Yatish
Published: January 2022

Phylogenetic tree optimization is necessary for precise analysis of evolutionary and transmission dynamics, but existing tools are inadequate for handling the scale and pace of data produced during the COVID-19 pandemic. One transformative approach, online phylogenetics, aims to incrementally add samples to an ever-growing phylogeny, but there are no previously-existing approaches that can efficiently optimize this vast phylogeny under the time constraints of the pandemic. Here, we present matOptimize, a fast and memory-efficient phylogenetic tree optimization tool based on parsimony that can be parallelized across multiple CPU threads and nodes, and provides orders of magnitude improvement in runtime and peak memory usage compared to existing state-of-the-art methods. We have developed this method particularly to address the pressing need during the COVID-19 pandemic for daily maintenance and optimization of a comprehensive SARS-CoV-2 phylogeny. Thus, our approach addresses an important need for daily maintenance and refinement of a comprehensive SARS-CoV-2 phylogeny.

Significance Statement

Phylogenetic trees have been central to genomic surveillance, epidemiology, and contact tracing efforts during the COVD-19 pandemic. With over 6 million SARS-CoV-2 genome sequences now available, maintaining an accurate, comprehensive phylogenetic tree of all available SARS-CoV-2 sequences is becoming computationally infeasible with existing software, but is essential for getting a detailed picture of the virus’ evolution and transmission. Our novel phylogenetic software, matOptimize, is helping refine possibly the largest-ever phylogenetic tree, containing millions of SARS-CoV-2 sequences, thus providing an unprecedented resolution for studying the pathogen’s evolutionary and transmission dynamics.
Role of Yap1 in adult neural stem cell activation
Authors: Fan Wenqiang , Jurado-Arjona Jerónimo , Alanis-Lobato Gregorio , Péron Sophie , Berger Christian , Andrade-Navarro Miguel A. , Falk Sven , Berninger Benedikt
Published: January 2022

Most adult hippocampal neural stem cells (NSCs) remain quiescent with only a minor portion undergoing active proliferation and neurogenesis. The molecular mechanisms that trigger eventually the transition from quiescence to activation are still poorly understood. Here, we found the activity of the transcriptional activator Yap1 to be enriched in active NSCs. Genetic deletion of Yap1 led to a significant reduction in the relative proportion of active NSCs supporting a physiological role of Yap1 in regulating the transition from quiescence to activation. Overexpression of wild type Yap1 in adult NSCs did not induce NSC activation suggesting tight upstream control mechanisms, but overexpression of a gain-of-function mutant (Yap1-5SA) elicited cell cycle entry in NSCs and hilar astrocytes. Consistent with a role of Yap1 in NSC activation, single cell RNA sequencing revealed the partial induction of an activated NSC gene expression program. Yet, Yap1-5SA expression also induced Taz and other key components of the Yap/Taz regulon previously identified in glioblastoma stem cell-like cells. Consequently, dysregulated Yap1 activity led to repression of hippocampal neurogenesis, promoting aberrant differentiation instead.
Effectiveness of psychosocial interventions for hypertensive disorders in pregnancy: A systematic review and meta-analysis
Authors: Nnate Daniel A. , Ajayi Kobi V. , Hossain Md Mahbub , Guerby Paul
Published: January 2022

Objective

Studies on psychosocial interventions for perinatal mental health and wellbeing are mostly limited to the postpartum period. However, the physiological changes associated with hypertensive disorders in pregnancy predisposes women to severe psychological distress and adverse birth outcomes. This review investigated the effectiveness of psychosocial interventions for hypertensive disorders during pregnancy.

Methods

Cochrane CENTRAL, Embase, MEDLINE, MIDIRS, CINAHL, PsycINFO, PsycArticles, and Web of Science were searched up to 22nd August 2021. Effect sizes on relevant health outcomes were pooled in a meta-analysis using STATA software.

Results

Eight randomised trials involving 460 participants met the inclusion criteria. Included studies adopted several interventions ranging from music, exercise, cognitive behavioural therapy (CBT), spiritual care education and psychoeducation. The pooled effect showed a significant reduction in anxiety (d= −0.35 [−0.58, −0.11], p=0.004) and depression (d= −0.37 [−0.57, −0.17], p=0.0003). Spiritual care education significantly reduced postpartum stress disorder (d= −62.00 [−93.10, −30.90], p= 0.0001). However, CBT showed no effect on gestational stress (d= −2.20 [-4.89, 0.48], p= 0.11).

Conclusion

This study provides satisfactory evidence that psychosocial interventions may likely reduce anxiety and depression associated with hypertensive disorders in pregnancy. However, the evidence is very uncertain about its effect on neonatal outcomes.

Summary of findings
Estimating the relative proportions of SARS-CoV-2 strains from wastewater samples
Authors: Pipes Lenore , Chen Zihao , Afanaseva Svetlana , Nielsen Rasmus
Published: January 2022

Wastewater surveillance has become essential for monitoring the spread of SARS-CoV-2. The quantification of SARS-CoV-2 RNA in wastewater correlates with the Covid-19 caseload in a community. However, estimating the proportions of different SARS-CoV-2 strains has remained technically difficult. We present a method for estimating the relative proportions of SARS-CoV-2 strains from wastewater samples. The method uses an initial step to remove unlikely strains, imputation of missing nucleotides using the global SARS-CoV-2 phylogeny, and an Expectation-Maximization (EM) algorithm for obtaining maximum likelihood estimates of the proportions of different strains in a sample. Using simulations with a reference database of >3 million SARS-CoV-2 genomes, we show that the estimated proportions accurately reflect the true proportions given sufficiently high sequencing depth and that the phylogenetic imputation is highly accurate and substantially improves the reference database.
Inhibition of the JAK/STAT pathway with baricitinib reduces the multiple organ dysfunction caused by hemorrhagic shock in rats
Authors: Patel Nikita Mayur , Collotta Debora , Aimaretti Eleonora , Alves Gustavo Ferreira , Kröller Sarah , Coldewey Sina Maren , Collino Massimo , Thiemermann Christoph
Published: January 2022

Objective

The aim of this study was to investigate (a) the effects of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway inhibitor (baricitinib) on the multiple organ dysfunction syndrome (MODS) in a rat model of hemorrhagic shock (HS) and (b) whether treatment with baricitinib attenuates the activation of JAK/STAT, NF-κB and NLRP3 caused by HS.

Background

Post-traumatic MODS, which is in part due to excessive systemic inflammation, is associated with high morbidity and mortality. The JAK/STAT pathway is a regulator of numerous growth factor and cytokine receptors and, hence, is considered a potential master regulator of many inflammatory signaling processes. However, its role in trauma-hemorrhage is unknown.

Methods

An acute HS rat model was performed to determine the effect of baricitinib on MODS. The activation of JAK/STAT, NF-κB and NLRP3 pathways were analyzed by western blotting in the kidney and liver.

Results

We demonstrate here for the first time that treatment with baricitinib (during resuscitation following severe hemorrhage) attenuates the organ injury and dysfunction and the activation of JAK/STAT, NF-κB and NLRP3 pathways caused by HS in the rat.

Conclusions

Our results point to a role of the JAK/STAT pathway in the pathophysiology of the organ injury and dysfunction caused by trauma/hemorrhage and indicate that JAK inhibitors, such as baricitinib, may be repurposed for the treatment of the MODS after trauma and/or hemorrhage.
Population demography maintains biogeographic boundaries
Authors: Schmidt Chloé , Muñoz Gabriel , Lancaster Lesley T. , Lessard JP , Marske Katharine A. , Marshall Katie E. , Garroway Colin J.
Published: January 2022

Global biodiversity is organized into biogeographic regions that comprise distinct biotas. The contemporary factors maintaining differences in species composition between biogeographic regions are poorly understood. Given the evidence that populations with sufficient genetic variation can adapt to fill new habitats, it is surprising that we do not see more homogenization of species assemblages among regions. Theory suggests that the expansion of populations across biogeographic transition zones could be limited by environmental gradients that affect population demography in ways that could limit adaptive capacity, but this has not been empirically explored. Using three independently curated data sets describing continental patterns of mammalian demography and population genetics, we show that populations closer to biogeographic transition zones have lower effective population sizes and genetic diversity, and are more genetically differentiated. These patterns are consistent with reduced adaptive capacity near biogeographic transition zones. The consistency of these patterns across mammalian species suggests they are stable, predictable, and generalizable in their contribution to long-term limits on expansion and homogenization of biodiversity across biogeographic transition zones. Understanding the contemporary processes acting on populations that maintain differences in the composition of regional biotas is crucial for our basic understanding of the current and future organization of global biodiversity. The importance of contemporary, population-level processes on the maintenance of global biogeographic regions suggests that biogeographic boundaries are susceptible to environmental perturbation associated with human-caused global change.
Single cell mutant selection for metabolic engineering of actinomycetes
Authors: Akhgari Amir , Baral Bikash , Koroleva Arina , Siitonen Vilja , Fewer David P. , Melançon Charles E. , Rahkila Jani , Metsä-Ketelä Mikko
Published: January 2022

Actinomycetes are important producers of pharmaceuticals and industrial enzymes. However, wild type strains require laborious development prior to industrial usage. Here we present a generally applicable reporter-guided metabolic engineering tool based on random mutagenesis, selective pressure, and single-cell sorting. We developed fluorescence-activated cell sorting (FACS) methodology capable of reproducibly identifying high-performing individual cells from a mutant population directly from liquid cultures. Genome-mining based drug discovery is a promising source of bioactive compounds, which is complicated by the observation that target metabolic pathways may be silent under laboratory conditions. We demonstrate our technology for drug discovery by activating a silent mutaxanthene metabolic pathway in Amycolatopsis. We apply the method for industrial strain development and increase mutaxanthene yields 9-fold to 99 mg l−1 in a second round of mutant selection. Actinomycetes are an important source of catabolic enzymes, where product yields determine industrial viability. We demonstrate 5-fold yield improvement with an industrial cholesterol oxidase ChoD producer Streptomyces lavendulae to 20.4 U g−1 in three rounds. Strain development is traditionally followed by production medium optimization, which is a time-consuming multi-parameter problem that may require hard to source ingredients. Ultra-high throughput screening allowed us to circumvent medium optimization and we identified high ChoD yield production strains directly from mutant libraries grown under preset culture conditions. In summary, the ability to screen tens of millions of mutants in a single cell format offers broad applicability for metabolic engineering of actinomycetes for activation of silent metabolic pathways and to increase yields of proteins and natural products.
Histone chaperones exhibit conserved functionality in nucleosome remodeling
Authors: Buzón P. , Velázquez-Cruz A. , González-Arzola K. , Díaz-Quintana A. , Díaz-Moreno I. , Roos W.H.
Published: January 2022

Chromatin homeostasis mediates some of the most fundamental processes in the eukaryotic cell. In this regard, histone chaperones have emerged as major regulatory factors during DNA replication, repair, and transcription. However, the dynamic nature of these processes has severely impeded their characterization at the molecular level. Here we apply single-molecule probing by fluorescence optical tweezers to follow histone chaperone dynamics in real-time. The molecular action of SET/template-activating factor-Iβ and nucleophosmin 1—representing the two most common histone chaperone folds—were examined using both nucleosomes and isolated core histones. We show that these chaperones present binding specificity for partially dismantled nucleosomes and are able to recognize and disrupt non-native histone-DNA interactions. Furthermore, we reveal that cytochrome c inhibition of histone chaperones is coupled to chaperone accumulation on DNA-bound histones. Our single-molecule approach shows that despite the drastically different structures of these chaperones, they present conserved modes of action mediating nucleosome remodeling.
Overexpression of miR5505 enhanced drought and salt resistance in rice (Orayza sativa)
Authors: Fan Yuanwei , Xie Jiankun , Zhang Fantao
Published: January 2022

Rice is one of the most important crops in the world and half of the world population consumes it as their staple food. The abiotic stresses caused by drought, salt and other stresses have severely impacted rice production. MicroRNAs (miRNAs) are a type of small non-coding RNAs which widely reported as gene regulators, suppressing genes expression by degradation mRNA or translation inhibition. Previously, high-throughput sequencing has found a conserved miRNA miR5505 responding to drought stress in Dongxiang wild rice (DXWR). Several other studies also revealed that miR5505 was involved in rice stress responses. We further studied the effect of miRNA in drought and salt tolerance by overexpression it in rice. 2 in 18 successfully transformed transgenic lines with higher miR5505 expression were selected and then drought and salt resistance ability were evaluated. Both transgenic lines showed stronger drought and salt tolerance than wild-type (WT). Putative targets of miR5505 were identified by psRNATarget and several of them were found stress-related. RNA-seq found 1,980 differentially expressed genes (DEGs) in transgenic lines. Among them, 978 genes were down-regulated. Three genes were predicted by psRNATarget and two of them might be stress-related. We also found various environmental stresscis-acting elements in upstream of miR5505 promoter through Software PlantCARE. In all, we improved rice drought and salt tolerance by overexpressing miR5505, and the generated putative targets andcis-acting elements also suggested miR5505 might play important roles in the regulation of drought and salt responses.
Transatlantic spread of highly pathogenic avian influenza H5N1 by wild birds from Europe to North America in 2021
Authors: Caliendo V. , Lewis N. S. , Pohlmann A. , Baillie S.R. , Banyard A.C. , Beer M. , Brown I.H. , Fouchier R.A.M. , Hansen R.D.E. , Lameris T.K. , Lang A.S. , Laurendeau S. , Lung O. , Robertson G. , van der Jeugd H. , Alkie T.N. , Thorup K. , van Toor M.L. , Waldenström J. , Yason C. , Kuiken T. , Berhane Y.
Published: January 2022

Highly pathogenic avian influenza (HPAI) viruses of the A/Goose/Guangdong/1/1996 lineage (GsGd), which threaten the health of poultry, wildlife and humans, are spreading across Asia, Europe and Africa, but are currently absent from Oceania and the Americas. In December 2021, H5N1 HPAI viruses were detected in poultry and a free-living gull in St. John’s, Newfoundland and Labrador, Canada. Phylogenetic analysis showed that these viruses were most closely related to HPAI GsGd viruses circulating in northwestern Europe in spring 2021. Analysis of wild bird migration suggested that these viruses may have been carried across the Atlantic via Iceland, Greenland/Arctic or pelagic routes. The here documented incursion of HPAI GsGd viruses into North America raises concern for further virus spread across the Americas by wild bird migration.

One-Sentence Summary

Detection of H5N1 highly pathogenic avian influenza in Canada raises concern for spread in the Americas by migratory birds.
Standard selection treatments with sulfadiazine limit Plasmodium yoelii host-to-vector transmission
Authors: Rios Kelly T. , Dickson Taylor M. , Lindner Scott E.
Published: January 2022

Some early antimalarial drugs have been repurposed for experimental applications, thus extending their utility well beyond the point when resistance becomes prevalent in circulating parasite populations. One such drug is sulfadiazine, which is an analog of p-aminobenzoic acid (pABA), and acts as a competitive inhibitor of dihydropteroate synthase, which is an essential enzyme in the parasite’s folate synthesis pathway that is required for DNA synthesis. Sulfadiazine treatment of mice infected with P. yoelii and P. berghei is routinely used to enrich for gametocytes by killing asexual blood stage parasites, but it is not well known if the exposed gametocytes are perturbed or if there is a detrimental effect on transmission. To determine if there was a significant effect of sulfadiazine exposure upon host-to-vector transmission, we transmitted Plasmodium yoelii (17XNL strain) parasites to Anopheles stephensi mosquitoes and evaluated the prevalence of infection (percent of mosquitoes infected) and intensity of infection (number of oocysts per infected mosquito) under different sulfadiazine treatment conditions of the mouse or of the mosquitoes. We observed that parasites exposed to sulfadiazine either in the mouse host or in the mosquito vector had a reduction in both the number of mosquitoes that became infected and in the intensity of infection compared to untreated controls. We also observed that provision of freshly prepared pABA in the mosquito sugar water could only marginally overcome the defects caused by sulfadiazine treatment. In contrast, we determined that gametocytes exposed to sulfadiazine were able to be fertilized and develop into morphologically mature ookinetes in vitro, and thus that sulfadiazine exposure in the host may be reversible if the drug is washed out and the parasites are supplemented with pABA in the culture media. Overall, this indicates that sulfadiazine dampens host-to-vector transmission, and that this inhibition can only be partially overcome by exposure to fresh pABA in vivo and in vitro. Because gametocytes are of great interest for developing transmission blocking interventions, we recommend that less disruptive approaches for gametocyte enrichment be used in order to study minimally perturbed parasites.
cGAS recruitment to micronuclei is dictated by pre-existing nuclear chromatin status
Authors: MacDonald Kate M. , Nicholson-Puthenveedu Shirony , Tageldein Maha M. , Arrowsmith Cheryl , Harding Shane M.
Published: January 2022

Micronuclei (MN) are aberrant cytosolic compartments containing broken genomic fragments or whole lagging chromosomes. MN envelopes irreversibly rupture, allowing the viral receptor cGAS to localize to MN and initiate an inflammatory signalling cascade. Here, we demonstrate that MN envelope rupture is not sufficient for cGAS localization. Unlike MN that arise following ionizing radiation (IR), ruptured MN generated from acute transcription stressors DRB or siSRSF1 are refractory to cGAS localization. Recruitment of cGAS to MN is blocked by inhibiting the histone methyltransferase DOT1L prior to IR exposure, demonstrating that cGAS recruitment to MN is dictated by nuclear chromatin organization at the time of DNA damage. Loss of cGAS+ MN, caused either by acute transcription stressors or by preventing DOT1L-deposited histone methylation, corresponded to significantly decreased cGAS-dependent inflammatory signalling. These results implicate nuclear chromatin organization in micronuclear composition and activity, influencing the ability of damage-induced MN to retain cytosolic proteins upon rupture.
Von Willebrand factor A1 domain affinity for GPIbα and stability are differentially regulated by its O-glycosylated N-linker and C-linker
Authors: Bonazza Klaus , Iacob Roxana E. , Hudson Nathan E. , Li Jing , Lu Chafen , Engen John R. , Springer Timothy A.
Published: January 2022

Hemostasis in the arterial circulation is mediated by binding of the A1 domain of the ultralong protein von Willebrand factor to GPIbα on platelets to form a platelet plug. A1 is activated by tensile force on VWF concatemers imparted by hydrodynamic drag force. The A1 core is protected from force-induced unfolding by a long-range disulfide that links cysteines near its N and C-termini. The O-glycosylated linkers between A1 and its neighboring domains, which transmit tensile force to A1, are reported to regulate A1 activation for binding to GPIb, but the mechanism is controversial and incompletely defined. Here, we study how these linkers, and their polypeptide and O-glycan moieties, regulate A1 affinity by measuring affinity, kinetics, thermodynamics, hydrogen deuterium exchange (HDX), and unfolding by temperature and urea. The N-linker lowers A1 affinity 40-fold with a stronger contribution from its O-glycan than polypeptide moiety. The N-linker also decreases HDX in specific regions of A1 and increases thermal stability and the energy gap between its native state and an intermediate state, which is observed in urea-induced unfolding. The C-linker also decreases affinity of A1 for GPIbα, but in contrast to the N-linker, has no significant effect on HDX or A1 stability. Among different models for A1 activation, our data are consistent with the model that the intermediate state has high affinity for GPIbα, which is induced by tensile force physiologically and regulated allosterically by the N-linker.

Impact Statement

Both the polypeptide and attached O-glycans N-terminal to the A1 domain in von Willebrand factor lower its affinity for its ligand GPIbα on platelets, its stability, and structural dynamics and decrease population of a high-affinity, intermediate state in unfolding.

Key points

Ligand-binding affinity of A1 and the stability of its native state is regulated by an N-terminal interdomain, O-glycosylated linker
Detailed measurements and simulations of electric field distribution of two TMS coils cleared for obsessive compulsive disorder in the brain and in specific regions associated with OCD
Authors: Tzirini Marietta , Roth Yiftach , Harmelech Tal , Zibman Samuel , Pell Gaby S , Kimiskidis Vasilios k. , Tendler Aron , Zangen Abraham , Samaras Theodoros
Published: January 2022

The FDA cleared deep transcranial magnetic stimulation (Deep TMS) with the H7 coil for obsessive-compulsive disorder (OCD) treatment, following a double-blinded placebo-controlled multicenter trial. Two years later the FDA cleared TMS with the D-B80 coil on the basis of substantial equivalence. In order to investigate the induced electric field characteristics of the two coils, these were placed at the treatment position for OCD over the prefrontal cortex of a head phantom, and the field distribution was measured. Additionally, numerical simulations were performed in eight Population Head Model repository models with two sets of conductivity values and three Virtual Population anatomical head models and their homogeneous versions. The H7 was found to induce significantly higher maximal electric fields (p<0.0001, t=11.08) and to stimulate two to five times larger volumes in the brain (p<0.0001, t=6.71). The rate of decay of electric field with distance is significantly slower for the H7 coil (p < 0.0001, Wilcoxon matched-pairs test). The field at the scalp is 306% of the field at a 3 cm depth with the D-B80, and 155% with the H7 coil. The H7 induces significantly higher intensities in broader volumes within the brain and in specific brain regions known to be implicated in OCD (dorsal anterior cingulate cortex (dACC), dorsolateral prefrontal cortex (dlPFC), inferior frontal gyrus (IFG), orbitofrontal cortex (OFC) and pre-supplementary motor area (pre-SMA)) compared to the D-B80. Significant field ≥ 80 V/m is induced by the H7 (D-B80) in 15% (1%) of the dACC, 78% (29%) of the pre-SMA, 50% (20%) of the dlPFC, 30% (12%) of the OFC and 15% (1%) of the IFG. Considering the substantial differences between the two coils, the clinical efficacy in OCD should be tested and verified separately for each coil.
Lateral entorhinal cortex inputs modulate hippocampal dendritic excitability by recruiting a local disinhibitory microcircuit
Authors: Bilash Olesia M. , Chavlis Spyridon , Poirazi Panayiota , Basu Jayeeta
Published: January 2022

The lateral entorhinal cortex (LEC) provides information about multi-sensory environmental cues to the hippocampus through direct inputs to the distal dendrites of CA1 pyramidal neurons. A growing body of work suggests that LEC neurons perform important functions for episodic memory processing, coding for contextually-salient elements of an environment or the experience within it. However, we know little about the functional circuit interactions between LEC and the hippocampus. In this study, we combine functional circuit mapping and computational modeling to examine how long-range glutamatergic LEC projections modulate compartment-specific excitation-inhibition dynamics in hippocampal area CA1. We demonstrate that glutamatergic LEC inputs can drive local dendritic spikes in CA1 pyramidal neurons, aided by the recruitment of a disinhibitory vasoactive intestinal peptide (VIP)-expressing inhibitory neuron microcircuit. Our circuit mapping further reveals that, in parallel, LEC also recruits cholecystokinin (CCK)-expressing inhibitory neurons, which our model predicts act as a strong suppressor of dendritic spikes. These results provide new insight into a cortically-driven GABAergic microcircuit mechanism that gates non-linear dendritic computations, which may support compartment-specific coding of multi-sensory contextual features within the hippocampus.

HIGHLIGHTS

Slice electrophysiology experiments investigate how lateral entorhinal cortex influences hippocampal area CA1

LEC drives local spikes in distal dendrites but not in somata of CA1 pyramidal neurons

LEC inputs recruit VIP IN and CCK IN populations in CA1, but not SST INs

Computational modeling and circuit manipulation experiments identify a VIP IN-mediated disinhibitory microcircuit for gating local dendritic spike generation

IN BRIEF

Bilash et al. found that a distal cortical input is capable of driving local dendritic spikes in hippocampal pyramidal neurons. This dendritic spike generation is promoted by cortical recruitment of a local VIP interneuron-mediated disinhibitory microcircuit. Their results highlight new circuit mechanisms by which dynamic interaction of excitation, inhibition, and disinhibition support supralinear single-cell computations.
Chemical control and herbicide resistance of hairy fleabane [Conyza bonariensis (L.) Cronquist] in Jordan
Authors: Qasem Jamal R.
Published: January 2022

Two field experiments were conducted to evaluate the effectiveness of 12 herbicides in controlling hairy fleabane [Conyza bonariensis (L.) Cronquist] in a date palm orchard located in the central Jordan valley during the spring of 2017. Results showed that C. bonariensis resists paraquat (2.5, 5 and 7.5kgha-1), oxadiazon (5kgha-1) and oxyflourfen (3.3kgha-1) herbicides applied at normal or higher than the recommended rates. None of the three herbicides was significantly effective against the weed and treated plants continued growing normally similar to those of untreated control. Higher rates (10-fold of the recommended rates) of the same herbicides failed to control the weed. The effect of other tested herbicides on the weed was varied with bromoxynil plus MCPA (buctril®M), 2,4-D-iso-octyl ester, glyphosate, glyphosate trimesium and triclopyr were most effective and completely controlled the weed at recommended rates of application. Testing paraquat, oxadiazon and oxyflourfen using the normal recommended and 10-fold higher rates on two populations of C. bonariensis grown from seeds of the date palm and al-Twal (another site in the Jordan Valley) weed populations and grown in pots under glasshouse conditions showed that Date palm population was resistant to the three herbicides at both application rates while al-Twal site population was highly susceptible and completely controlled at normal and high rates of the three herbicides. It is concluded that certain populations of C. bonariensis developed resistance to paraquat, oxadiazon and oxyflourfen but control of this weed was possible using other herbicides of different mechanism of action. Herbicide rotation or other nonchemical weed control methods have been suggested to prevent or reduce the buildup and spread of resistant populations of this weed species. These results represent the first report on herbicide resistance of C. bonariensis in Jordan.
PolarMorphism enables discovery of shared genetic variants across multiple traits from GWAS summary statistics
Authors: von Berg Joanna , ten Dam Michelle , van der Laan Sander W. , de Ridder Jeroen
Published: January 2022

Pleiotropic SNPs are associated with multiple traits. Such SNPs can help pinpoint biological processes with an effect on multiple traits or point to a shared etiology between traits. We present PolarMorphism, a new method for the identification of pleiotropic SNPs from GWAS summary statistics. PolarMorphism can be readily applied to more than two traits or whole trait domains. PolarMorphism makes use of the fact that trait-specific SNP effect sizes can be seen as Cartesian coordinates and can thus be converted to polar coordinates r (distance from the origin) and theta (angle with the Cartesian x-axis). r describes the overall effect of a SNP, while theta describes the extent to which a SNP is shared. r and theta are used to determine the significance of SNP sharedness, resulting in a p-value per SNP that can be used for further analysis. We apply PolarMorphism to a large collection of publicly available GWAS summary statistics enabling the construction of a pleiotropy network that shows the extent to which traits share SNPs. This network shows how PolarMorphism can be used to gain insight into relationships between traits and trait domains. Furthermore, pathway analysis of the newly discovered pleiotropic SNPs demonstrates that analysis of more than two traits simultaneously yields more biologically relevant results than the combined results of pairwise analysis of the same traits. Finally, we show that PolarMorphism is more efficient and more powerful than previously published methods.