bluuebunny/crossref_metadata_2025 huggingface dataset:
Child marriage and adverse reproductive outcomes among young Afghan women: implication for policy and practice in Afghanistan
Authors: Dadras Omid , Nakayama Takeo
Published: November 2021

Background

Child marriage is defined as marriage before the age of 18 years and it has been linked to several adverse health and social outcomes. This study aimed to explore the prevalence and determinants of child marriage and its association with adverse reproductive outcomes among a nationally representative sample of young Afghan women.

Methods

This was a secondary analysis of the 2015 Afghanistan Demographic and Health Survey (DHS) data. Based on the UN recommendation on child marriage study, only women aged 20-24 years old were included. Descriptive statistics and binary logistic regression were employed to determine the distribution of respondents’ characteristics and prevalence and determinants of child marriage. Multivariate logistic models examined the association between child marriage and adverse reproductive outcomes accounting for the sociodemographic factors.

Results

An estimated 52% of the Afghan women aged 20-24 married at ages less than 18 years. Poor illiterate women were more likely to marry at early ages (<18). There was a significant negative relationship between child marriage and history of rapid repeat childbirth, delivery by skilled personnel, and institutional delivery. In both adjusted and unadjusted models, women married at age ≤14 were more likely to experience terminated or unintended pregnancy (AOR = 1.89, 95% CI: 1.31-2.75 and AOR = 2.20. 95% CI: 1.24-3.91, respectively), inadequate ANC (AOR = 1.71, 95% CI: 1.01-2.90), unmet need for family planning (AOR = 1.44, 95% CI: 1.05-1.98), fistula (AOR = 2.36, 95% CI: 1.22-4.57); While, for those married at age 15-17 years, only terminated or unintended pregnancy remained significant.

Conclusion

The younger age of marriage was associated with a higher prevalence of adverse reproductive outcomes among Afghan women. Moreover, poverty and illiteracy proved to be important predictors of child marriage in Afghan women. Strict international law enforcement and advocacy are a need in the current situation of Afghanistan to increase young women’s education, promote their civil rights, and improve their autonomy and role in decision-making concerning their health.
Second-Hand Smoke Exposure inside the House and Adverse Birth Outcomes in Indonesia: Evidence from Demographic and Health Survey 2017
Authors: Andriani Helen , Rahmawati Nurul Dina , Ahsan Abdillah , Kusuma Dian
Published: November 2021

Objectives

Second-hand Smoke (SHS) during pregnancy among non-smoking women associates with mortality and morbidity risks in their infants. However, little is known about the SHS inside the house and the adverse birth outcomes. This study aims to assess the prevalence, level, and frequency of SHS exposure inside the house and investigate their associations with birth outcomes.

Methods

We use the Indonesian Demographic and Health Survey (IDHS) 2017, a large-scale nationally representative survey. Women aged 15 to 49 years who had given birth in the last five years before the study and their husbands were interviewed (n=19,935). Three dependent variables included Low Birth Weight (LBW), size at birth, and birth weight.

Results

Seventy-eight percent of mothers exposed to SHS inside home, of whom 7.2% had LBW children. Compared to non-SHS exposure mothers, those exposed to SHS were younger, had first birth before 20 years old, married, lower educated, non-worker, lived in rural, grand multipara, had pollution from cooking fuel, cook in a separate building, had higher risk of delivering lower birth weight (aOR=1.16, 95% CI: 1.02, 1.33), and smaller baby (aOR=1.51, 95%CI: 1.35, 1.69), even after the controlling for the covariates. We identified the inverted U-shaped association for SHS exposure frequency. Similar risk was also observed among mothers exposed with SHS on a daily basis compared to those who are not exposed.

Conclusion for Practice

Exposure to SHS inside home was significantly associated with LBW and size at birth. Given the high smoking prevalence, relevant policy and health promotion are needed.

Significance Statement

Adverse birth outcomes, such as low birth weight and smaller size at birth, may not be clearly explained by the second-hand smoke (SHS) exposure from a smoking husband alone. Our findings show that the prevalence of SHS inside the house in Indonesia is 78.4%. Pregnant women exposed to anyone who smokes in the household may be linked to poor birth quality, including low birth weight and smaller size at birth in their babies, after adjustment for risk factors. The effects of SHS exposure on birth outcomes are further exacerbated by daily SHS exposure.
Immunogenicity of heterologous prime/boost inactivated and mRNA COVID-19 vaccine
Authors: Wanlapakorn Nasamon , Yorsaeng Ritthideach , Phowatthanasathian Harit , Suntronwong Nungruthai , Kanokudom Sitthichai , Sudhinaraset Natthinee , Poovorawan Yong
Published: November 2021

Introduction

In August 2021, Thailand imported the BNT162b2 mRNA COVID-19 vaccine. The prioritised group to receive the BNT162b2 vaccine were health professionals. The BNT162b2 vaccine scheduled for healthcare workers were two-dose regimen administered three weeks apart, the third dose booster in two-dose inactivated CoronaVac vaccine recipients or as a second dose in health professionals who had received the CoronaVac or adenoviral-vectored (ChAdOx1-S) vaccine as the first dose regardless of the interval between the first and second dose.

Methods

This study aims to evaluate the immunogenicity of the heterologous prime boost CoronaVac followed by BNT162b2 in health professionals.

Results

The CoronaVac/BNT162b2 vaccine recipients elicited higher neutralizing activity against the original Wuhan and all variants of concern than in the recipients of the two-dose CoronaVac.

Conclusions

The heterologous CoronaVac/BNT162b2 could be used as an alternative regimen in countries experiencing the vaccine shortages and in individuals experiencing the adverse events following CoronaVac.
Non-invasive visualization of amyloid-beta deposits in Alzheimer amyloidosis mice using magnetic resonance imaging and fluorescence molecular tomography
Authors: Ren Wuwei , Ni Ruiqing , Vaas Markus , Klohs Jan , Ripoll Jorge , Wolf Martin , Rudin Markus
Published: November 2021

Abnormal cerebral accumulation of amyloid-beta peptide (Aβ) is a major hallmark of Alzheimer’s disease. Non-invasive monitoring of Aβ deposits enables assessing the disease burden in patients and animal models mimicking aspects of the human disease as well as evaluating the efficacy of Aβ-modulating therapies. Previous in vivo assessments of plaque load in mouse models of cerebral amyloidosis have been predominantly based on two-dimensional diffuse fluorescence reflectance imaging (2D-FRI) and two-photon microscopy (2PM) using Aβ-specific imaging agents. However, 2D-FRI lacks depth resolution, whereas 2PM is restricted by the limited field of view preventing coverage of large brain regions. Here, we utilized a magnetic resonance imaging (MRI) and fluorescence molecular tomography (FMT) pipeline with the curcumin derivative fluorescent probe CRANAD-2 to achieve full 3D brain coverage for detecting Aβ accumulation in the arcAβ mouse model of cerebral amyloidosis. A homebuilt FMT system was used for data acquisition in combination with a customized software platform enabling the integration of anatomical information derived from MRI as prior information for FMT image reconstruction. The results obtained from the FMT-MRI study were compared to data obtained from conventional 2D-FRI recorded under similar physiological conditions. The two methods yielded comparable time courses of the fluorescence intensity following intravenous injection of CRANAD-2 in a region of interest comprising the mouse brain. The depth resolution inherent to FMT allowed separation of signal contributions from the scalp and different brain regions, indicating preferential accumulation of the fluorescent tracer in the cerebral cortex, a region characterized by significant plaque deposition in arc Aβ mice. In conclusion, we have demonstrated the feasibility of visualizing Aβ deposition in 3D using a multimodal FMT-MRI method. This hybrid imaging method provides complementary anatomical, physiological and molecular information, thereby enabling the detailed characterization of the disease status in mouse models of cerebral amyloidosis, which is also important for monitoring the efficacy of putative treatments targeting Aβ.
RNA-Seq analysis identifies novel roles for the primary cilia gene SPAG17 and the SOX9 locus non-coding RNAs in systemic sclerosis
Authors: Roberson Elisha D.O. , Carns Mary , Cao Li , Aren Kathleen , Goldberg Isaac A. , Morales-Heil David J. , Korman Benjamin D. , Atkinson John P. , Varga John
Published: November 2021

Systemic sclerosis (SSc) is characterized by immune activation, vasculopathy, and unresolving fibrosis in the skin, lungs, and other organs. We performed RNA-Seq analysis on skin biopsies and peripheral blood mononuclear cells (PBMCs) from SSc patients and controls to better understand SSc pathogenesis. We analyzed these data to 1) test for case-control differences, and 2) identify genes whose expression levels correlate with SSc severity as measured by local skin score, modified Rodnan skin score (MRSS), forced vital capacity (FVC), or diffusion capacity for carbon monoxide (DLCO). We found that PBMCs from SSc patients showed a strong type 1 interferon signature. This signal replicated in the skin, with additional signals for increased extracellular matrix (ECM) genes, classical complement pathway activation, and the presence of B cells. Notably, we observed a marked decrease in the expression of SPAG17, a cilia component, in SSc skin. We identified genes that correlated with MRSS, DLCO, and FVC in SSc PBMCs and skin using weighted gene co-expression analysis (WGCNA). These genes were largely distinct from the case/control differentially expressed genes. In PBMCs, type 1 interferon signatures negatively correlated with DLCO. In SSc skin, ECM gene expression positively correlated with MRSS. Network analysis of SSc skin genes correlated with clinical features identified the non-coding RNAs SOX9-AS1 and ROCR, both near the SOX9 locus, as highly connected, “hub-like” genes in the network. These results identify non-coding RNAs and SPAG17 as novel factors potentially implicated in SSc pathogenesis.
A glycerol shunt functions as a glucose excess security valve in pancreatic β-cells
Authors: Al-Mass Anfal , Poursharifi Pegah , Peyot Marie-Line , Lussier Roxane , Levens Emily , Guida Julian , Mugabo Yves , Possik Elite , Ahmad Rasheed , Al-Mulla Fahd , Sladek Robert , Madiraju S.R.Murthy , Prentki Marc
Published: November 2021

The recently identified glycerol-3-phosphate (Gro3P) phosphatase (G3PP) in mammalian cells, encoded by thePGPgene, was shown to regulate intermediary metabolism by hydrolyzing Gro3P and to control glucose-stimulated insulin secretion (GSIS) in β-cells,in vitro. We now examined in inducible β-cell specific G3PP-KO (BKO) mice, the role of G3PP in the control of insulin secretionin vivo, β-cell function and glucotoxicity. BKO mice, compared toMCrecontrols, showed increased body weight, adiposity, fed insulinemia, GSIS, reduced plasma triglycerides and mildly altered glucose tolerance. Isolated BKO mouse islets at high (16.7 mM) but not low or intermediate glucose (3-8 mM) showed elevated GSIS, Gro3P, metabolites reflecting β-cell activation, O2consumption, ATP production and reduced glycerol release. BKO islets chronically exposed to elevated glucose showed increased apoptosis, reduced insulin content and expression ofPdx-1, MafAandIns-2genes. As G3PP channels glucose carbons towards glycerol formation and release, the results demonstrate that β-cell are endowed with a “glycerol shunt” acting as a glucose excess security valve. We propose that the glycerol shunt plays a role in glucodetoxification, the prevention of insulin hypersecretion, acts as a defense against excess body weight gain and contributes to β-cell mass preservation in the face of hyperglycemia.
Epigenetic changes in autoimmune monocytes contribute to disease and can be targeted by JAK inhibition
Authors: Peeters J.G.C. , Boltjes A. , Scholman R.C. , Vervoort S.J. , Coffer P.J. , Mokry M. , Vastert S.J. , van Wijk F. , van Loosdregt J.
Published: November 2021

How the local inflammatory environment regulates epigenetic changes in the context of autoimmune diseases remains unclear. Here we assessed the transcriptional and active enhancer profile of monocytes derived from the inflamed joints of Juvenile Idiopathic Arthritis (JIA) patients, a model well-suited for studying autoimmune diseases. RNA-sequencing analysis demonstrated that synovial-derived monocytes display an activated phenotype, characterized by increased expression of surface activation markers and multiple chemokines and cytokines. This increased expression is regulated on the epigenetic level, as ChIP-sequencing indicated increased H3K27 acetylation of genes upregulated in synovial monocytes. IFN signaling-associated genes are increased and epigenetically altered in synovial monocytes, suggesting a role for IFN in establishing the inflammatory phenotype. Treatment of human synovial monocytes with the Janus-associated kinase (JAK) inhibitor Ruxolitinib, which inhibits IFN signaling, transformed the activated enhancer landscape and reduced disease-associated gene expression, thereby inhibiting the inflammatory phenotype. Taken together, these data provide novel insight into epigenetic regulation of autoimmune disease-patient derived monocytes and suggest that altering the epigenetic profile can be a therapeutic approach for the treatment of autoimmune diseases.
cNap1 bridges centriole contact sites to maintain centrosome cohesion
Authors: Mahen Robert
Published: November 2021

Centrioles are non-membrane bound organelles that participate in fundamental cellular processes through their ability to form physical contacts with other structures. During interphase, two mature centrioles can associate to form a single centrosome - a phenomenon known as centrosome cohesion. Centrosome cohesion is important for processes such as cell migration, and yet how it is maintained is unclear. Current models indicate that pericentriolar fibres termed rootlets, also known as the centrosome linker, entangle to maintain centriole proximity. Here, I uncover a new centriole-centriole contact site and mechanism of centrosome cohesion, based on coalescence of the proximal centriole component cNap1. Using live-cell imaging of endogenously tagged cNap1, I show that proximal centrioles form dynamic contacts in response to physical force from the cytoskeleton. Expansion microscopy reveals that cNap1 bridges between these contact sites, physically linking proximal centrioles on the nanoscale. When ectopically tethered to organelles such as lysosomes, cNap1 forms viscous and cohesive condensates that promote organelle spatial proximity. Conversely, cNap1 mutants with reduced viscosity are unable to maintain centrosome cohesion. These results define a previously unrecognised mechanism of centrosome cohesion by cNap1 assemblies at the proximal centriole and illustrate how a non-membrane bound organelle forms dynamic organelle contact sites.
Conformational Changes in the Negative Arm of the Circadian Clock Correlate with Dynamic Interactomes Involved in Post-transcriptionally Regulated Processes
Authors: Pelham Jacqueline F. , Mosier Alexander E. , Altshuler Samuel C. , Kirchhoff Christopher L. , Fall William B. , Baik Lisa S. , Chiu Joanna C. , Hurley Jennifer M.
Published: November 2021

The circadian clock employs a transcriptional/translational negative feedback loop (TTFL) to anticipate environmental changes due to the Earth’s diurnal cycle, with regulation of organismal physiology believed to stem from temporal transcriptional activation by the positive arm. However, up to 80% of oscillating proteins do not have rhythmic mRNA, establishing circadian post-transcriptional regulation through unknown mechanisms. Given the pervasive conservation of the intrinsically disordered nature of negative-arm clock proteins, we hypothesized that post-transcriptional regulation may stem from conformational shifts in negative-arm proteins that time vacillations in the constituents of negative-arm macromolecular complexes to time cellular physiology. Our investigation of the negative arm clock protein in Neurospora crassa, FREQUENCY (FRQ), demonstrated temporal conformational fluidity correlated with daily changes in physiologically diverse macromolecular complex components. A parallel investigation of the macromolecular complexes centered around Drosophila melanogaster PERIOD (dPER) and human PERIOD (hPER2) found a similar number and physiological diversity of interacting partners in higher eukaryotes. Short linear motifs (SLiMs) associated with the interactors localized to disordered and phosphorylated regions on the PERs and FRQ, with disordered interactors oscillating in the macromolecular complexes over circadian time. This oscillation correlated with oscillations in post-transcriptionally regulated proteins, suggesting the negative arm may tune cellular physiology and proteostasis post-transcriptionally via vacillations in the circadian negative-arm macromolecular protein complexes.
A multiscale X-ray phase-contrast tomography dataset of whole human left lung
Authors: Xian R. Patrick , Walsh Claire L. , Verleden Stijn E. , Wagner Willi L. , Bellier Alexandre , Marussi Sebastian , Ackermann Maximilian , Jonigk Danny D. , Jacob Joseph , Lee Peter D. , Tafforeau Paul
Published: November 2021

Technological advancements in X-ray imaging using bright and coherent synchrotron sources now allows to decouple sample size and resolution, while maintaining high sensitivity to the microstructure of soft, partially dehydrated tissues. The recently developed imaging technique, hierarchical phase-contrast tomography, is a comprehensive approach to address the challenge of organ-scale (up to tens of centimeters) soft tissue imaging with resolution and sensitivity down to the cellular level. Using this technique, we imaged ex vivo an entire human left lung at an isotropic voxel size of 25.08 μm along with local zooms down to 6.05 - 6.5 μm and 2.45 - 2.5 μm in voxel size. The high tissue contrast offered by the fourth-generation synchrotron source at the European Synchrotron Radiation Facility reveals complex multiscale anatomical constitution of the human lung from the macroscopic (centimeter) down to the microscopic (micrometer) scale. The dataset provides complete organ-scale 3D information of the secondary pulmonary lobules and delineates the microstructure of lung nodules with unprecedented detail.
A ROS-Ca2+ signalling pathway identified from a chemical screen for modifiers of sugar-activated circadian gene expression
Authors: Li Xiang , Deng Dongjing , Cataltepe Gizem , Román Ángela , Monte-Bello Carolina Cassano , Skyricz Aleksandra , Caldana Camila , Haydon Michael J
Published: November 2021

Sugars are essential metabolites for energy and anabolism that can also act as signals to regulate plant physiology and development. Experimental tools to disrupt major sugar signalling pathways are limited. We have performed a chemical screen for modifiers of activation of circadian gene expression by sugars to discover pharmacological tools to investigate and manipulate plant sugar signalling. Using a library of commercially available bioactive compounds, we identified 75 confident hits that modified the response of a circadian luciferase reporter to sucrose in dark-adapted seedlings. We validated the transcriptional effect on a subset of the hits and measured their effects on a range of sugar-dependent phenotypes for 13 of these chemicals. Chemicals were identified that appear to influence known and unknown sugar signalling pathways. Pentamidine isethionate (PI) was identified as a modifier of a sugar-activated Ca2+ signal that acts downstream of superoxide in a metabolic signalling pathway affecting circadian rhythms, primary metabolism and plant growth. Our data provide a resource of new experimental tools to manipulate plant sugar signalling and identify novel components of these pathways.
Fast DNA-PAINT imaging using a deep neural network
Authors: Narayanasamy Kaarjel K. , Rahm Johanna V. , Tourani Siddharth , Heilemann Mike
Published: November 2021

DNA points accumulation for imaging in nanoscale topography (DNA-PAINT) is a super-resolution technique with relatively easy-to-implement multi-target imaging. However, image acquisition is slow as sufficient statistical data has to be generated from spatio-temporally isolated single emitters. Here, we trained the neural network (NN) DeepSTORM to predict fluorophore positions from high emitter density DNA-PAINT data. This achieves image acquisition in one minute. We demonstrate multi-color super-resolution imaging of structure-conserved semi-thin neuronal tissue and imaging of large samples. This improvement can be integrated into any single-molecule microscope and enables fast single-molecule super-resolution microscopy.
Heat activation and inactivation of bacterial spores. Is there an overlap?
Authors: Wen Juan , Smelt Jan P. P. M. , Vischer Norbert O.E. , de Vos Arend L. , Setlow Peter , Brul Stanley
Published: November 2021

Heat activation at a sublethal temperature is widely applied to promote Bacillus species spore germination. This treatment also has potential to be employed in food processing to eliminate undesired bacterial spores by enhancing their germination, and then inactivating the less heat resistant germinated spores at a milder temperature. However, incorrect heat treatment could also generate heat damage in spores, and lead to more heterogeneous spore germination. Here, the heat activation and heat damage profile of Bacillus subtilis spores was determined by testing spore germination and outgrowth at both population and single spore levels. The heat treatments used were 40-80°C, and for 0-300 min. The results were as follows. 1) Heat activation at 40-70°C promoted L-valine and L-asparagine-glucose-fructose-potassium (AGFK) induced germination in a time dependent manner. 2) The optimal heat activation temperatures for AGFK and L-valine germination via the GerB plus GerK or GerA germinant receptors were 65 and 50-65°C, respectively. 3) Heat inactivation of dormant spores appeared at 70°C, and the heat damage of molecules essential for germination and growth began at 70 and 65°C, respectively. 4) Heat treatment at 75°C resulted in both activation of germination and damage to the germination apparatus, and 80°C treatment caused more pronounced heat damage. 5) For the spores that should withstand adverse environmental temperatures in nature, heat activation seems functional for a subsequent optimal germination process, while heat damage affected both germination and outgrowth.
Circadian regulation of lung repair and regeneration
Authors: Naik Amruta , Forrest Kaitlyn , Issah Yasmine , Valekunja Utham , Reddy Akhilesh B , Hennessy Elizabeth , Brooks Thomas S. , Babu Apoorva , Morley Mike , Grant Gregory R. , FitzGerald Garret A. , Sehgal Amita , Worthen G. Scott , Frank David B. , Morrisey Edward E , Sengupta Shaon
Published: November 2021

Optimal lung repair and regeneration is essential for recovery from viral infections such as that induced by influenza A virus (IAV). We have previously demonstrated that lung inflammation induced by IAV is under circadian control. However, it is not known if the circadian clock exerts its influence on lung repair and regenerative processes independent of acute inflammation from IAV. Here, we demonstrate for the first time that lung organoids have a functional clock as they mature and that the absence of an intact circadian clock impairs regenerative capacity. Using several models of circadian disruption, we show that with the absence of an intact clock lung proliferation is disrupted. Further, we find that the circadian clock acts through direct control of the Wnt/β-catenin pathway. We speculate, that adding the circadian dimension to the critical process of lung repair and regeneration will lead to novel therapies and improve outcomes. Finally, we use data from UK Biobank to demonstrate at the population level, the role of poor circadian rhythms in mediating negative outcomes following lung infection.
Organization and dynamics of the SpoVAEa protein, and its surrounding inner membrane lipids upon germination of Bacillus subtilis spores
Authors: Wen Juan , Vischer Norbert O.E. , de Vos Arend L. , Manders Erik. M. M. , Setlow Peter , Brul Stanley
Published: November 2021

The SpoVA proteins make up a channel in the inner membrane (IM) of B. subtilis spore. This channel responds to signals from activated germinant receptors (GRs), and allows release of Ca2+-DPA from the spore core during germination. In the current work, we studied the location and dynamics of SpoVAEa in dormant spores. Notably, the SpoVAEa-SGFP2 proteins were present in a single spot in spores, similar to the complex formed by all GRs. However, while the GRs’ spot remains in one location, the SpoVAEa-SGFP2 spot in the IM moved randomly with high frequency. The dynamics of the SpoVAEa-SGFP2 and its surrounding IM region as stained by fluorescent dyes were also tracked during spore germination, as the dormant spore IM appeared to have an immobile germination related functional microdomain. This microdomain disappeared around the time of appearance of a germinated spore, the loss of fluorescence of the IM by fluorescent dyes, as well as the appearance of SpoVAEa-SGFP2 peak fluorescent intensity occurred in parallel. These observed events were highly related to the rapid phase darkening, which is considered as the Ca2+DPA rapid release. We also tested the response of SpoVAEa and the IM to thermal treatments at 40-80°C. Heat treatment triggered an increase of green autofluorescence, which is speculated to be due to coat protein denaturation, and 80°C treatments induce the appearance of phase-grey-like spores. These spores presumably have a similar intracellular physical state as the phase grey spores detected in the germination but lack the functional proteins for further germination events.
Regnase-1 deficiency restrains Klebsiella pneumoniae infection by regulation of a Type I interferon response
Authors: Trevejo-Nuñez Giraldina , Lin Becky , Fan Li , Aggor Felix E. Y. , Biswas Partha S. , Chen Kong , Gaffen Sarah L.
Published: November 2021

Excessive inflammatory responses can cause collateral tissue damage or autoimmune inflammation, sometimes with severe morbidity or mortality. During host defense responses, numerous negative feedback mechanisms are established to prevent excessive unchecked inflammation. However, this restraint can sometimes come at the cost of suboptimal infection control, and we do not fully understand how this balance is maintained during different infection settings. The endoribonuclease Regnase-1 (Reg1, Zc3h12a, MCPIP1) is an RNA binding protein (RBP) that binds and degrades many target mRNA transcripts. Reg1 is a potent feedback regulator of IL-17 and LPS signal transduction, among other stimuli. Consequently, Reg1 deficiency exacerbates autoimmune inflammation in multiple mouse models, but on the other hand, reduced Reg1 improves immunity to fungal infection. To date, the role of Reg1 in bacterial immunity is poorly defined. Here, we show that mice deficient in Reg1 are more resistant to pulmonary Klebsiella pneumoniae (KP) infection. Unexpectedly, effects of Reg1 deficiency were not due to accelerated eradication of bacteria or increased pro-inflammatory cytokine expression. Rather, alveolar macrophages from Reg1-deficient mice showed enrichment of Type I IFN-related genes upon KP infection, accompanied by increased Ifnb1 expression. Surprisingly, the stability of Ifnb1 mRNA was not altered by Reg1-deficiency; rather, mRNA encoding its upstream regulator IRF7 appeared to be a more prominent target. Blockade of IFNR during KP infection reversed disease improvement. Thus, impaired Reg1 induces Type I IFN and enhances resistance to KP, raising the possibility that Reg1 could be a potential clinical target in acute bacterial infections.

Graphical abstract
The Contributions of Eye Gaze Fixations and Target-Lure Similarity to Behavioral and fMRI Indices of Pattern Separation and Pattern Completion
Authors: Bjornn Daniel K. , Van Julie , Brock Kirwan C.
Published: November 2021

Pattern separation and pattern completion are generally studied in humans using mnemonic discrimination tasks such as the Mnemonic Similarity Task (MST) where participants identify similar lures and repeated items from a series of images. Failures to correctly discriminate lures are thought to reflect a failure of pattern separation and a propensity toward pattern completion. Recent research has challenged this perspective, suggesting that poor encoding rather than pattern completion accounts for the occurrence of false alarm responses to similar lures. In two experiments, participants completed a continuous recognition task version of the MST while eye movement (Experiments 1 and 2) and fMRI data (Experiment 2) were collected. In Experiment 1, we replicated the result that fixation counts at study predicted accuracy on lure trials (consistent with poor encoding predicting mnemonic discrimination performance), but this effect was not observed in our fMRI task. In both experiments we found that target-lure similarity was a strong predictor of accuracy on lure trials. Further, we found that fMRI activation changes in the hippocampus were significantly correlated with the number of fixations at study for correct but not incorrect mnemonic discrimination judgments when controlling for target-lure similarity. Our findings indicate that while eye movements during encoding predict subsequent hippocampal activation changes for correct mnemonic discriminations, the predictive power of eye movements for activation changes for incorrect mnemonic discrimination trials was modest at best.
Active Segregation Dynamics in the Living Cell
Authors: Bansal Ajay , Das Amit , Rao Madan
Published: November 2021

In this paper, we bring together our efforts in identifying and understanding nonequilibrium phase segregation driven by active processes in the living cell, with special focus on the segregation of cell membrane components driven by active contractile stresses arising from cortical actomyosin. This also has implications for active segregation dynamics in membraneless regions within the cytoplasm and nucleus (3d). We formulate an active version of the Flory-Huggins theory that incorporates a contribution from fluctuating active stresses. Apart from knitting together some of our past theoretical work in a comprehensive narrative, we highlight some new results, and establish a correspondence with recent studies on Active Model B/B+. We point to the many unusual aspects of the dynamics of active phase segregation, such as (i) anomalous growth dynamics, (ii) coarsening accompanied by propulsion and coalescence of domains that exhibit nonreciprocal effects, (iii) segregation into mesoscale domains, (iv) emergence of a nonequilibrium phase segregated steady state characterised by strong macroscopic fluctuations (fluctuation dominated phase ordering (FDPO)), and (v) mesoscale segregation even above the equilibriumTc. Apart from its implications for actively driven segregation of binary fluids, these ideas are at the heart of anActive Emulsiondescription of the lateral organisation of molecules on the plasma membrane of living cells, whose full molecular elaboration appears elsewhere.
Artificial Intelligence uncovers carcinogenic human metabolites
Authors: Mittal Aayushi , Mohanty Sanjay Kumar , Gautam Vishakha , Arora Sakshi , Saproo Sheetanshu , Gupta Ria , S Roshan , Garg Prakriti , Aggarwal Anmol , R Padmasini , Dixit Nilesh Kumar , Pal Singh Vijay , Mehta Anurag , Tayal Juhi , Naidu Srivatsava , Sengupta Debarka , Ahuja Gaurav
Published: November 2021

The genome of a eukaryotic cell is often vulnerable to both intrinsic and extrinsic threats due to its constant exposure to a myriad of heterogeneous compounds. Despite the availability of innate DNA damage response pathways, some genomic lesions trigger cells for malignant transformation. Accurate prediction of carcinogens is an ever-challenging task due to the limited information aboutbona fide(non)carcinogens. We developed Metabokiller, an ensemble classifier that accurately recognizes carcinogens by quantitatively assessing their electrophilicity as well as their potential to induce proliferation, oxidative stress, genomic instability, alterations in the epigenome, and anti-apoptotic response. Concomitant with the carcinogenicity prediction, Metabokiller is fully interpretable since it reveals the contribution of the aforementioned biochemical properties in imparting carcinogenicity. Metabokiller outperforms existing best-practice methods for carcinogenicity prediction. We used Metabokiller to unravel cells’ endogenous metabolic threats by screening a large pool of human metabolites and predicted a subset of these metabolites that could potentially trigger malignancy in normal cells. To cross-validate Metabokiller predictions, we performed a range of functional assays usingSaccharomyces cerevisiaeand human cells with two Metabokiller-flagged human metabolites namely 4-Nitrocatechol and 3,4-Dihydroxyphenylacetic acid and observed high synergy between Metabokiller predictions and experimental validations.
Determining international spread of novel B.1.1.523 SARS-CoV-2 lineage
Authors: Zemaitis Lukas , Alzbutas Gediminas , Gecys Dovydas , Komissarov Andrey , Pautienius Arnoldas , Ugenskiene Rasa , Sukys Marius , Lesauskaite Vaiva
Published: November 2021

Here we report the emergence of variant lineage B.1.1.523 that contains a set of mutations including 156_158del, E484K and S494P in Spike protein. E484K and S494P are known to significantly reduce SARS-CoV-2 neutralization by convalescent and vaccinee sera and are considered as mutations of concern. Lineage B.1.1.523 has presumably originated in Russian Federation and spread across European countries with the peak of transmission in April – May 2021. The B.1.1.523 lineage has now been reported from 27 countries.
Re-evaluating the actin-dependence of spectraplakin functions during axon growth and maintenance
Authors: Qu Yue , Alves-Silva Juliana , Gupta Kriti , Hahn Ines , Parkin Jill , Sánchez-Soriano Natalia , Prokop Andreas
Published: November 2021

Axons are the long and slender processes of neurons constituting the biological cables that wire the nervous system. The growth and maintenance of axons require bundles of microtubules that extend through their entire length. Understanding microtubule regulation is therefore an essential aspect of axon biology. Key regulators of neuronal microtubules are the spectraplakins, a well-conserved family of cytoskeletal cross-linkers that underlie neuropathies in mouse and humans. Spectraplakin deficiency in mouse orDrosophilacauses severe decay of microtubule bundles and axon growth inhibition. The underlying mechanisms are best understood forDrosophilaShort stop (Shot) and believed to involve cytoskeletal cross-linkage: the N-terminal calponin homology (CH) domains bind to F-actin, and the C-terminus to microtubules and Eb1. Here we have gained new understanding by showing that the F-actin interaction must be finely balanced: altering the properties of F-actin networks or deleting/exchanging Shot’s CH domains induces changes in Shot function - with a Lifeact-containing Shot variant causing remarkable remodelling of neuronal microtubules. In addition to actin-MT cross-linkage, we find strong indications that Shot executes redundant MT bundle-promoting roles that are F-actin-independent. We argue that these likely involve the neuronal Shot-PH isoform, which is characterised by a large, unexplored central plakin repeat region (PRR). Work on PRRs might therefore pave the way towards important new mechanisms of axon biology and architecture that might similarly apply to central PRRs in mammalian spectraplakins.
Transcriptomic Analysis of 3D Vasculature-On-A-Chip Reveals Paracrine Factors Affecting Vasculature Growth and Maturation
Authors: Tan Sin Yen , Jing Qiuyu , Leung Ziuwin , Xu Ying , Wu Angela R
Published: November 2021

In vitro models of vasculature are of great importance for modelling vascular physiology and pathology. However, there is usually a lack of proper spatial patterning of interacting heterotypic cells in conventional vasculature dish models, which might confound results between contact and non-contact interactions. We use a microfluidic platform with structurally defined separation between human microvasculature and fibroblasts to probe their dynamic, paracrine interactions. We also develop a novel, versatile technique to retrieve cells embedded in extracellular matrix from the microfluidic device for downstream transcriptomic analysis, and uncover growth factor and cytokine expression profiles associated with improved vasculature growth. Paired receptor-ligand analysis further reveals paracrine signaling molecules that could be supplemented into the medium for vasculatures models where fibroblast co-culture is undesirable or infeasible. These findings also provide deeper insights into the molecular cues for more physiologically relevant vascular mimicry and vascularized organoid model for clinical applications such as drug screening and disease modeling.
Vibrio cholerae El Tor strains linked to global cholera are homogeneous by pulsed-field gel electrophoresis
Authors: Johura Fatema-Tuz , Biswas Sahitya Ranjan , Rashed Shah M , Islam Mohammad Tarequl , Islam Saiful , Sultana Marzia , Huq Anwar , Thomson Nicholas R , Colwell Rita R. , Watanabe Haruo , Alam Munirul
Published: November 2021

Vibrio cholerae O1 El Tor, causative agent of the ongoing seventh cholera pandemic, is native to the aquatic environment of the Ganges Delta, Bay of Bengal (GDBB). Recent studies traced pandemic strains to the GDBB and proposed global spread of cholera had occurred via intercontinental transmission. In the research presented here, NotI-digested genomic DNA extracted from V. cholerae O1 clinical and environmental strains isolated in Bangladesh during 2004 – 2014 was analyzed by pulsed-field gel electrophoresis (PFGE). Results of cluster analysis showed 94.67% of the V. cholerae isolates belonged to clade A and included the majority of clinical isolates of spatio-temporal origin and representing different cholera endemic foci. The rest of the strains were estuarine, all environmental isolates from Mathbaria, Bangladesh, and occurred as singletons, clustered in clades B and C, or in the small clades D and E. Cluster analysis of the Bangladeshi strains and including 157 El Tor strains from thirteen countries in Asia, Africa, and the Americas revealed 85% of the total set of isolates belonged to clade A, indicating all were related, yet did not form an homogeneous cluster. Overall, 15% of the global strains comprised multiple small clades or segregated as singletons. Three sub-clades could be discerned within the major clade A, reflecting distinct lineages of V. cholerae El Tor associated with cholera in Asia, Africa, and the Americas. The presence in Asia and the Americas of non-pandemic V. cholerae El Tor populations differing by PFGE and from strains associated with cholera globally suggests different ecotypes are resident in distant geographies.

Author Summary

Cholera is a major health threat, especially in the Ganges Delta, Bay of Bengal (GDBB). Vibrio cholerae, causative agent of cholera, is native to the GDBB aquatic environment. Recent genomic studies suggest GDBB is the cholera hotspot where the disease spreads globally via human activity. Pulsed-field gel electrophoresis (PFGE) of NotI-digested genomic DNA from V. cholerae El Tor endemic cholera strains was done, including Bangladesh aquatic environment and clinical strains from distant geographical regions representing three cholera-prone continents. Results showed the majority of pandemic strains belonged to a major cluster, suggesting clonal relatedness. Ecotypes were detected, indicating geographically specific lineages. It is concluded that epidemic strains in Bangladesh and thirteen countries of Asia, Africa, and the Americas are geographically adapted, with independent evolution of the bacterium in respective geographical regions.
SmdA is a novel cell morphology determinant in Staphylococcus aureus
Authors: Myrbråten Ine Storaker , Stamsås Gro Anita , Chan Helena , Angeles Danae Morales , Knutsen Tiril Mathiesen , Salehian Zhian , Shapaval Volha , Straume Daniel , Kjos Morten
Published: November 2021

Cell division and cell wall synthesis in staphylococci need to be precisely coordinated and controlled to allow the cell to multiply while maintaining their nearly spherical shape. The mechanisms ensuring correct placement of the division plane and synthesis of new cell wall have been studied intensively, however, hitherto unknown factors and proteins are likely to play key roles in this complex interplay. We here identified and investigated a protein with major influence on cell morphology in Staphylococcus aureus. The protein, named SmdA (for staphylococcal morphology determinant A), is a membrane-protein with septum-enriched localization. By CRISPRi knockdown and overexpression combined with different microscopy techniques, we demonstrate that proper levels of SmdA is necessary for cell division, including septum formation and cell splitting. We also identified conserved residues in SmdA that are critical for its functionality. Pulldown- and bacterial two-hybrid interaction experiments showed that SmdA interacts with several known cell division- and cell wall synthesis proteins, including penicillin binding proteins (PBPs) and EzrA. Notably, SmdA also affects susceptibility to cell wall targeting antibiotics, particularly in methicillin-resistant S. aureus (MRSA). Together, our results show that S. aureus is dependent on balanced amounts of membrane-attached SmdA in order to carry out proper cell division.

Importance

Staphylococcus aureus is an important human and animal pathogen. Antibiotic resistance is a major problem in treatment of staphylococcal infections, and cell division and cell wall synthesis factors have previously been shown to modulate susceptibility to antibiotics in this species. In the current work we investigated the function of an essential protein named SmdA, which was identified based on its septal localization and knockdown phenotype resulting in defective cellular morphologies. We demonstrate that this protein is critical for normal cell division in S. aureus. Depletion of SmdA sensitize resistant staphylococci to β-lactam antibiotics. This work thus reveals a new staphylococcal cell division factor and a potential future target for narrow spectrum antimicrobials or compounds to resensitize antibiotic resistant staphylococcal strains.
KEEPING IN TOUCH WITH OUR HIDDEN SIDE
Authors: Mathieu Benjamin , Abillama Antonin , Martinez Malvina , Mouchnino Laurence , Blouin Jean
Published: November 2021

Previous studies have shown that the sensory modality used to identify the position of proprioceptive targets hidden from sight, but frequently viewed, influences the type of the body representation employed for reaching them with the finger. The question then arises as to whether this observation also applies to proprioceptive targets which are hidden from sight, and rarely, if ever, viewed. We used an established technique for pinpointing the type of body representation used for the spatial encoding of targets which consisted of assessing the effect of peripheral gaze fixation on the pointing accuracy. More precisely, an exteroceptive, visually dependent, body representation is thought to be used if gaze deviation induces a deviation of the pointing movement. Three light-emitting diodes (LEDs) were positioned at the participants’ eye level at −25 deg, 0 deg and +25 deg with respect to the cyclopean eye. Without moving the head, the participant fixated the lit LED before the experimenter indicated one of the three target head positions: topmost point of the head (vertex) and two other points located at the front and back of the head. These targets were either verbal-cued or tactile-cued. The goal of the subjects (n=27) was to reach the target with their index finger. We analysed the accuracy of the movements directed to the topmost point of the head, which is a well-defined, yet out of view anatomical point. Based on the possibility of the brain to create visual representations of the body areas that remain out of view, we hypothesized that the position of the vertex is encoded using an exteroceptive body representation, both when verbally or tactile-cued. Results revealed that the pointing errors were biased in the opposite direction of gaze fixation for both verbal-cued and tactile-cued targets, suggesting the use of a vision-dependent exteroceptive body representation. The enhancement of the visual body representations by sensorimotor processes was suggested by the greater pointing accuracy when the vertex was identified by tactile stimulation compared to verbal instruction. Moreover, we found in a control condition that participants were more accurate in indicating the position of their own vertex than the vertex of other people. This result supports the idea that sensorimotor experiences increase the spatial resolution of the exteroceptive body representation. Together, our results suggest that the position of rarely viewed body parts are spatially encoded by an exteroceptive body representation and that non-visual sensorimotor processes are involved in the constructing of this representation.
Using light-sheet microscopy to study spontaneous activity in the developing lateral-line system
Authors: Zhang Qiuxiang , Kindt Katie
Published: November 2021

Hair cells are the sensory receptors in the auditory and vestibular systems of all vertebrates, and in the lateral-line system of aquatic vertebrates. During development, spontaneous activity in hair cells shapes the formation of these sensory systems. In auditory hair cells of mice, coordinated waves of spontaneous activity can be triggered by concomitant activity in nearby supporting cells. But in mammals, developing auditory and vestibular hair cells can also autonomously generate spontaneous events independent of supporting cell activity. To date, significant progress has been made studying spontaneous activity in the auditory and vestibular systems of mammals, in isolated cultures. The purpose of this work is to explore the zebrafish lateral-line system as a model to study and understand spontaneous activity in vivo. Our work applies genetically encoded calcium indicators along with light-sheet fluorescence microscopy to visualize spontaneous calcium activity in the developing lateral-line system. Consistent with our previous work, we show that spontaneous calcium activity is present in developing lateral-line hair cells. We now show that supporting cells that surround hair cells, and cholinergic efferent terminals that directly contact hair cells are also spontaneously active. Using two-color functional imaging we demonstrate that spontaneous activity in hair cells does not correlate with activity in either supporting cells or cholinergic terminals. We find that during lateral-line development, hair cells autonomously generate spontaneous events. Using localized calcium indicators, we show that within hair cells, spontaneous calcium activity occurs in two distinct domains–the mechanosensory bundle and the presynapse. Further, spontaneous activity in the mechanosensory bundle ultimately drives spontaneous calcium influx at the presynapse. Comprehensively, our results indicate that in developing lateral-line hair cells, autonomously generated spontaneous activity originates with spontaneous mechanosensory events. Overall, with robust spontaneous activity three different cell types, the developing lateral line is a rich model to study these activities in an intact sensory organ. Future work studying this model may further our understanding of these activities and their role in sensory system formation, function and regeneration.