bluuebunny/crossref_metadata_2025 huggingface dataset:
Cervicovaginal immune mediators increase when young women begin to have sexual intercourse: a prospective study and meta-analysis
Authors: Hughes Sean M. , Levy Claire N. , Calienes Fernanda L. , Martinez Katie A. , Selke Stacy , Tapia Kenneth , Chohan Bhavna H. , Oluoch Lynda , Kiptinness Catherine , Wald Anna , Ghosh Mimi , Hardy Liselotte , Ngure Kenneth , Mugo Nelly R. , Hladik Florian , Roxby Alison C.
Published: April 2022

Background

Adolescent girls and young women (AGYW) are at high risk of sexually transmitted infections (STIs). It is unknown whether beginning to have sexual intercourse causes changes to immune mediators in the cervicovaginal tract that contribute to this risk.

Methods

We collected cervicovaginal lavages from Kenyan AGYW in the months before and after first penile-vaginal sexual intercourse and measured the concentrations of 20 immune mediators. We compared concentrations pre- and post-first sex using mixed effects models. Secondary analyses included adjustment for possible confounding factors. We additionally performed a systematic review to identify similar studies and combined them with our results by meta-analysis of individual participant data.

Results

We included 180 samples from 95 AGYW, with 44% providing only pre-first sex samples, 35% matched pre and post, and 21% only post. We consistently detected 19/20 immune mediators, all of which increased post-first sex (median increase 54%; p<0.05 for 13/19; Holm-Bonferroni-adjusted p<0.05 for IL-1β, IL-2 and CXCL8). Effects remained similar after adjusting for confounding factors including STIs and Nugent score.

Our systematic review identified two eligible studies, one of 93 Belgian participants and the other of 18 American participants. Nine immune mediators were measured in at least 2/3 studies. Meta-analysis confirmed higher levels post-first sex for 8/9 immune mediators (median increase 47%; p<0.05 for six mediators, most prominently IL-1α, IL-1β and CXCL8).

Conclusions

Cervicovaginal immune mediator concentrations increased after the beginning of sexual activity independently of confounding factors including STIs. Results were consistent across three studies conducted on three different continents.
Late maturation of semantic control promotes conceptual development
Authors: Jackson Rebecca L. , Lambon Ralph Matthew A. , Rogers Timothy T.
Published: April 2022

Control processes underpinned by the prefrontal cortex are critical for generating task-appropriate behaviour across cognitive domains, yet this region develops extremely late. Traditionally, this developmental pattern is considered negative but necessary. However, an alternative (yet perhaps complementary) view suggests that a developmental period without control could support learning, particularly in the semantic domain. Here, we exploit a recent computational model to test formally whether late development of the context-sensitive use of conceptual knowledge, or ‘semantic control’, would promote concept acquisition. Simulations show that late maturation of semantic control and anatomical connectivity conspire to promote conceptual learning. Delayed control speeds conceptual learning without compromising conceptual representations, particularly when control connects to intermediate layers. To assess whether semantic control also develops late in human children, we conducted a meta-analysis of the classic triadic matching task where participants decide which of two options best matches a third. Matching can be based on taxonomic or thematic relations. When these conflict, participants must exert semantic control to determine which relation is task appropriate. Context-sensitivity develops later than conceptual knowledge with large increases between 3 and 6 years. Thus, the protracted PFC development leads to a delay in acquiring semantic control processes, benefiting conceptual learning.
Drug combination prediction for cancer treatment using disease-specific drug response profiles and single-cell transcriptional signatures
Authors: Osorio Daniel , Shahrouzi Parastoo , Tekpli Xavier , Kristensen Vessela N. , Kuijjer Marieke L.
Published: April 2022

Developing novel cancer treatments is a challenging task that can benefit from computational techniques matching transcriptional signatures to large-scale drug response data. Here, we present ‘retriever,’ a tool that extracts robust disease-specific transcriptional drug response profiles based on cellular response profiles to hundreds of compounds from the LINCS-L1000 project. We usedretrieverto extract transcriptional drug response signatures of triple-negative breast cancer (TNBC) cell lines and combined these with a single-cell RNA-seq breast cancer atlas to predict drug combinations that antagonize TNBC-specific disease signatures. After systematically testing 152 drug response profiles and 11,476 drug combinations, we identified the combination of kinase inhibitors QL-XII-47 and GSK-690693 as the topmost promising candidate for TNBC treatment. Our new computational approach allows the identification of drugs and drug combinations targeting specific tumor cell types and subpopulations in individual patients. It is, therefore, highly suitable for the development of new personalized cancer treatment strategies.
Informational Masking Constrains Vocal Communication in Nonhuman Animals
Authors: Gupta Saumya , Kalra Lata , Rose Gary J. , Bee Mark A.
Published: April 2022

Noisy social environments constrain human speech communication in two important ways: spectrotemporal overlap between signals and noise can reduce speech audibility (“energetic masking”) and noise can interfere with processing informative features of otherwise audible speech (“informational masking”). Whether and how informational masking impacts vocal communication in nonhuman animals remains unknown. In this study of a treefrog, in which females choose mates in noisy breeding choruses, we investigated whether informational masking disrupts the recognition of vocal signals that guide mating decisions. We observed significantly reduced rates of responding to the vocalizations of a potential mate when target signals were broadcast concurrently with other biologically relevant sounds that obscured signal information in the absence of energetic masking. These informational masking effects were evident across a broad range of signal levels and were more pronounced when competing sounds fell in a particularly salient frequency range for processing vocalizations. Our results confirm informational masking is a general communication problem among humans and other animals and identify a crucial yet understudied source of selection on animal communication systems.
Beneficial and Detrimental Effects of Nonspecific Binding During DNA Hybridization
Authors: Phan Tam T. M. , Phan Tien M. , Schmit Jeremy D.
Published: April 2022

DNA strands have to sample numerous states to find the alignment that maximizes Watson-Crick-Franklin base pairing. This process depends strongly on sequence, which affects the stability of the native duplex as well as the prevalence of non-native inter- and intra-molecular helices. We present a theory which describes DNA hybridization as a three stage process: diffusion, registry search, and zipping. We find that non-specific binding affects each of these stages in different ways. Mis-registered intermolecular binding in the registry search stage helps DNA strands sample different alignments and accelerates the hybridization rate. Non-native intramolecular structure affects all three stages by rendering portions of the molecule inert to intermolecular association, limiting mis-registered alignments to be sampled, and impeding the zipping process. Once inregister base-pairs are formed, the stability of the native structure is important to hold the molecules together long enough for non-native contacts to break.
Decision Tree Ensembles Utilizing Multivariate Splits Are Effective at Investigating Beta-Diversity in Medically Relevant 16S Amplicon Sequencing Data
Authors: Rudar Josip , Golding G. Brian , Kremer Stefan C. , Hajibabaei Mehrdad
Published: April 2022

Developing an understanding of how microbial communities vary across conditions is an important analytical step. We used 16S rRNA data isolated from human stool to investigate if learned dissimilarities, such as those produced using unsupervised decision tree ensembles, can be used to improve the analysis of the composition of bacterial communities in patients suffering from Crohn’s Disease and adenomas/colorectal cancers. We also introduce a workflow capable of learning dissimilarities, projecting them into a lower dimensional space, and identifying features that impact the location of samples in the projections. For example, when used with the centered log-ratio transformation, our new workflow (TreeOrdination) could identify differences in the microbial communities of Crohn’s Disease patients and healthy controls. Further investigation of our models elucidated the global impact ASVs had on the location of samples in the projected space and how each ASV impacted individual samples in this space. Furthermore, this approach can be used to integrate patient data easily into the model and results in models that generalize well to unseen data. Models employing multivariate splits can improve the analysis of complex high-throughput sequencing datasets since they are better able to learn about the underlying structure of the dataset.

Author Summary

There is an ever-increasing level of interest in accurately modeling and understanding the role that commensal organisms play in human health and disease. We show that learned representations can be used to create informative ordinations. We also demonstrate that the application of modern model introspection algorithms can be used to investigate and quantify the impact of taxa in these ordinations and that the taxa identified by these approaches have been associated with immune-mediated inflammatory diseases and colorectal cancer.
What factors converged to create a COVID-19 hot-spot? Lessons from the South Asian community in Ontario
Authors: Anand Sonia S , Arnold Corey , Bangdiwala Shrikant , Bolotin Shelly , Bowdish Dawn , Chanchlani Rahul , de Souza Russell , Desai Dipika , Kandasamy Sujane , Khan Farah , Khan Zainab , Langlois Marc-André , Limbachia Jayneel , Lear Scott , Loeb Mark , Loh Lawrence , Manoharan Baanu , Nakka Kiran , Pelchat Martin , Punthakee Zubin , Schulze Karleen , Williams Natalie , Wahi Gita
Published: April 2022

Background

South Asians represent the largest non-white ethnic group in Canada. The Greater Toronto Area (GTA), home to a high proportion of South Asians, emerged as a COVID-19 hot spot. Early in the pandemic, the South Asian community was identified as having risk factors for exposure and specific barriers to accessing testing and reliable health information, rendering them uniquely vulnerable to SARS-CoV-2 infection.

Objectives

To investigate the burden of SARS-CoV-2 infection among South Asians in the GTA, and to determine which demographic characteristics were most closely aligned with seropositivity, in this cross-sectional analysis of a prospective cohort study.

Methods

Participants from the GTA were enrolled between April and July 2021. Seropositivity for anti-spike and anti-nucleocapsid antibodies was determined from dried blood spots, and age and sex standardized to the Ontario South Asian population. Demographics, risk perceptions, and sources of COVID-19 information were collected via questionnaire in a subset.

Results

Among the 916 South Asians enrolled, mean age 41 years, the age and sex standardized seropositivity was 23.6% (95% CI: 20.8%-26.4%). Approximately one-third identified as essential workers, and 19% reported living in a multi-generational household. Over half perceived high COVID-19 risk due to their geographic location, and 36% due to their type of employment. The top three most trusted sources of COVID-related information included healthcare providers/public health, traditional media sources, and social media.

Conclusion

By the third wave of the COVID-19 pandemic, approximately one-quarter of a sample of South Asians in Ontario had serologic evidence of prior SARS-CoV-2 infection. Insight into factors that render certain populations at risk can help future pandemic planning and disease control efforts.
Effectiveness of COVID-19 vaccines against Omicron and Delta hospitalisation: test negative case-control study
Authors: Stowe Julia , Andrews Nick , Kirsebom Freja , Ramsay Mary , Bernal Jamie Lopez
Published: April 2022

Background

The omicron (B.1.1.529) variant has been associated with reduced vaccine effectiveness (VE) against infection and mild disease with rapid waning, even after a third dose, nevertheless omicron has also been associated with milder disease than previous variants. With previous variants protection against severe disease has been substantially higher than protection against infection.

Methods

We used a test-negative case–control design to estimate VE against hospitalisation with the omicron and delta variants using community and in hospital testing linked to hospital records. As a milder disease, there may be an increasing proportion of hospitalised individuals with Omicron as an incidental finding. We therefore investigated the impact of using more specific and more severe hospitalisation indicators on VE.

Results

Among 18-64 year olds using all Covid-19 cases admitted via emergency care VE after a booster peaked at 82.4% and dropped to 53.6% by 15+ weeks after the booster; using all admissions for >= 2 days stay with a respiratory code in the primary diagnostic field VE ranged from 90.9% down to 67.4%; further restricting to those on oxygen/ventilated/on intensive care VE ranged from 97.1% down to 75.9%. Among 65+ year olds the equivalent VE estimates were 92.4% down to 76.9%; 91.3% down to 85.3% and 95.8% down to 86.8%.

Conclusions

With generally milder disease seen with Omicron, in particular in younger adults, contamination of hospitalisations with incidental cases is likely to reduce VE estimates against hospitalisation. VE estimates improve and waning and waning is more limited when definitions of hospitalisation that are more specific to severe respiratory disease are used.
Effects of Intravenous and Inhaled Anesthetics on the Postoperative Complications for the patients undergoing One Lung Ventilation
Authors: Yang Jing , Huang Qinghua , Cao Rong , Cui Yu
Published: April 2022

Introduction

With the widely used technique of One Lung Ventilation (OLV) in patients throughout thoracic surgery, it’s unclear whether inhaled or intravenous anesthetics were associated with postoperative complications. The purpose of the current study is to compare the effects of intravenous and inhaled anesthetics on the postoperative complications within the patients suffering OLV.

Methods

We searched the related randomized controlled trials in PubMed\EMBASE\Medline and the Cochrane library up to 09\2021.Inclusive criteria were as follows: We included all the randomized controlled trials which compared the effects of intravenous and inhaled anesthetics on the postoperative complications[listed as: (a) major complications; (b)postoperative pulmonary complications (PPCs); (c) postoperative cognitive function (MMSE score); (d) length of hospital stay; (e) 30-days mortality] for the patients undergoing one lung ventilation.

Results

Thirteen randomized controlled trials with 2522 patients were included for analysis. Overall, there were no significant differences in the postoperative major complications between inhaled and intravenous anesthetics groups (OR 0.78, 95%CI 0.54 to 1.13, p=0.19; I2=0%). However, more PPCs were detected in intravenous groups when compared to inhaled groups (OR 0.62, 95%CI 0.44 to 0.87, p=0.005; I2=37%). Both the postoperative MMSE scores (SMD -1.94, 95%CI -4.87 to 0.99, p=0.19; I2=100%) and the length of hospital stay (SMD 0.05, 95%CI -0.29 to 0.39, p=0.76; I2=73%) were comparable between two groups. Besides, the 30-day mortality didn’t differ significantly across groups either (OR 0.79, 95%CI 0.03 to 18, p=0.88; I2=63%).

Conclusions

In patients undergoing OLV, generous anesthesia with inhaled anesthetics could reduce PPCs compared with intravenous anesthetics, but no evident advantages were provided over other major complications, cognitive function, hospital stay or mortality.
Characteristics of Kenyan Women Enrolled in a Trial on Doxycycline Postexposure Prophylaxis for Sexually Transmitted Infection Prevention
Authors: Oware Kevin , Adiema Lydia , Rono Bernard , Violette Lauren R. , McClelland R. Scott , Donnell Deborah , Scoville Caitlin W. , Odoyo Josephine , Baeten Jared M. , Bukusi Elizabeth , Stewart Jenell
Published: April 2022

Introduction

The global incidence of sexually transmitted infections (STIs) has been rapidly increasing over the past decade, with more than one million curable STIs being acquired daily. Young women in sub-Saharan Africa have a high prevalence and incidence of both curable STIs and HIV. The use of doxycycline as a prophylaxis to prevent STI infections is promising; however, clinical trials, to date, have only been conducted among men who have sex with men (MSM) in high-income settings. We describe the characteristics of participants enrolled in the first trial to determine the efficacy of doxycycline post-exposure prophylaxis (PEP) to reduce STI incidence among women.

Methods

This is an open-label 1:1 randomized clinical trial of doxycycline PEP efficacy to reduce incident bacterial STIs – Neisseria gonorrhoeae, Chlamydia trachomatis, and Treponema pallidum – among Kenyan women aged ≥18 and ≤30 years. All were also taking HIV pre-exposure prophylaxis (PrEP). We describe the baseline characteristics of participants.

Results

Between February 2020 and November 2021, 449 women were enrolled. The median age was 24 years (IQR 21-27), the majority were never married (66.1%), 370 women (82.4%) reported having a primary sex partner, and 33% had sex with new partners in the 3 months prior to enrolment. Two-thirds (67.5%, 268 women) did not use condoms, 36.7% reported transactional sex, and 43.2% suspected their male partners of having sex with other women. Slightly less than half (45.9%, 206 women) were recently concerned about being exposed to an STI. The prevalence of STIs was 17.9%, with C. trachomatis accounting for the majority of infections.

Conclusion

Young cisgender women using HIV PrEP in Kenya and enrolled in a trial of doxycycline postexposure prophylaxis had a high prevalence of curable STIs and represent a target population for an STI prevention intervention.
Recurrent aphthous stomatitis affects quality of life
Authors: Rivera César , Muñoz-Pastén Mariagrazia , Muñoz-Núñez Esteban , Hernández-Olivos Romina
Published: April 2022

Recurrent aphthous stomatitis are recurrent oral ulcers that can affect important daily activities, such as oral hygiene and eating. In this prospective case-control study (n=62), we show that, during ulcer episodes, patients report a poorer quality of life compared to ulcer-free periods, and that this impact is positively associated with the number and size of lesions. Our results suggest that, if intervened locally, general relief of the condition could be achieved.
Metabolic Disturbances, Hemoglobin A1c, and Social Cognition Impairment in Schizophrenia Spectrum Disorders
Authors: Tang Sunny X. , Oliver Lindsay D. , Hänsel Katrin , DeRosse Pamela , John Majnu , Khairullah Ammar , Gold James M. , Buchanan Robert W. , Voineskos Aristotle , Malhotra Anil K.
Published: April 2022

Social cognitive impairments are core features of schizophrenia spectrum disorders (SSD) and are associated with greater functional impairment and decreased quality of life. Metabolic disturbances have been related to greater impairment in general neurocognition, but their relationship to social cognition has not been previously reported. In this study, metabolic measures and social cognition were assessed in 245 participants with SSD and 165 healthy comparison subjects (HC), excluding those with hemoglobin A1c (HA1c)>6.5%. Tasks assessed emotion processing, theory of mind, and social perception. Functional connectivity within and between social cognitive networks was measured during a naturalistic social task. Among SSD, a significant inverse relationship was found between social cognition and cumulative metabolic burden (β=-0.38,p<0.001) and HA1c (β=-0.37,p<0.001). The relationship between social cognition and HA1c was robust across domains and measures of social cognition and after accounting for age, sex, race, non-social neurocognition, hospitalization, and treatment with different antipsychotic medications. Negative connectivity between affect sharing and motor resonance networks was a partial mediator of this relationship across SSD and HC groups (β=-0.05,p=0.008). There was a group x HA1c effect indicating that SSD participants were more adversely affected by increasing HA1c. Thus, we provide the first report of a robust relationship in SSD between social cognition and abnormal glucose metabolism. If replicated and found to be causal, insulin sensitivity and blood glucose may present as promising targets for improving social cognition, functional outcomes, and quality of life in SSD.
Automated development of clinical prediction models enables real-time risk stratification with exemplar application to hypoxic-ischaemic encephalopathy
Authors: Lyon Matthew S. , White Heather , Gaunt Tom R. , Lawlor Deborah , Odd David
Published: April 2022

Real-time updated risk prediction of disease outcomes could lead to improvements in patient care and better resource management. Established monitoring during pregnancy at antenatal and intrapartum periods could be particularly amenable to benefits of this approach. This proof-of-concept study compared automated and manual prediction modelling approaches using data from the Collaborative Perinatal Project with exemplar application to hypoxic-ischaemic encephalopathy (HIE). Using manually selected predictors identified from previously published studies we obtained high HIE discrimination with logistic regression applied to antenatal only (0.71 AUC [95% CI 0.64-0.77]), antenatal and intrapartum (0.70 AUC [95% CI 0.64-0.77]), and antenatal, intrapartum and birthweight (0.73 AUC [95% CI 0.67-0.79]) data. In parallel, we applied a range of automated modelling methods and found penalised logistic regression had best discrimination and was equivalent to the manual approach but required little human input giving 0.75 AUC for antenatal only (95% CI 0.69, 0.81), 0.70 AUC for antenatal and intrapartum (95% CI 0.63, 0.78), and 0.74 AUC using antenatal, intrapartum, and infant birthweight (95% CI 0.65, 0.81). These results demonstrate the feasibility of developing automated prediction models which could be applied to produce disease risk estimates in real-time. This approach may be especially useful in pregnancy care but could be applied to any disease.
Modeling and Global Sensitivity Analysis of Strategies to Mitigate Covid-19 Transmission on a Structured College Campus
Authors: Zhao Lihong , Santiago Fabian , Rutter Erica M. , Khatri Shilpa , Sindi Suzanne
Published: April 2022

In response to the COVID-19 pandemic, many higher educational institutions moved their courses on-line in hopes of slowing disease spread. The advent of multiple highly-effective vaccines offers the promise of a return to “normal” in-person operations, but it is not clear if—or for how long—campuses should employ non-pharmaceutical interventions such as requiring masks or capping the size of in-person courses. In this study, we develop and fine-tune a model of COVID-19 spread to UC Merced’s student and faculty population. We perform a global sensitivity analysis to consider how both pharmaceutical and non-pharmaceutical interventions impact disease spread. Our work reveals that vaccines alone may not be sufficient to eradicate disease dynamics and that significant contact with an infectious surrounding community will maintain infections on-campus. Our work provides a foundation for higher-education planning allowing campuses to balance the benefits of in-person instruction with the ability to quarantine/isolate infectious individuals.
In vivoprenylomic profiling in the brain of a transgenic mouse model of Alzheimer’s disease reveals increased prenylation of a key set of proteins
Authors: Jeong Angela , Auger Shelby A. , Maity Sanjay , Li Ling , Distefano Mark D.
Published: April 2022

Dysregulation of protein prenylation has been implicated in many diseases, including Alzheimer’s disease (AD). Prenylomic analysis, the combination of metabolic incorporation of an isoprenoid analogue (C15AlkOPP) into prenylated proteins with a bottom-up proteomic analysis, has allowed identification of prenylated proteins in various cellular models. Here, transgenic AD mice were administered with C15AlkOPP through intracerebroventricular (ICV) infusion over 13 days. Using prenylomic analysis, 36 prenylated proteins were enriched in the brains of AD mice. Importantly, the prenylated forms of 15 proteins were consistently upregulated in AD mice compared to non-transgenic wild-type controls. These results highlight the power of this in vivo metabolic labeling approach to identify multiple post-translationally modified proteins that may serve as potential therapeutic targets for a disease that has proved refractory to treatment thus far. Moreover, this method should be applicable to many other types of protein modifications, significantly broadening its scope.
Overexpression of the WAPO-A1 gene increases the number of spikelets per spike in bread wheat
Authors: Wittern Lukas M. , Barrero Jose M. , Bovill William D. , Verbyla Klara L. , Hughes Trijntje , Swain Steve M. , Steed Gareth , Webb Alex A.R. , Gardner Keith , Greenland Andy , Jacobs John , Frohberg Claus , Schmidt Ralf-Christian , Cavanagh Colin , Rohde Antje , Davey Mark , Hannah Matthew A.
Published: April 2022

Two homoeologous QTLs for number of spikelets per spike (SPS) were mapped on chromosomes 7AL and 7BL using two wheat MAGIC populations. Sets of lines contrasting for the QTL on 7AL were developed which allowed for the validation and fine mapping of the 7AL QTL and for the identification of a previously described candidate gene, WHEAT ORTHOLOG OF APO1 (WAPO1). Using transgenic overexpression in both a low and a high SPS line, we provide a functional validation for the role of this gene in determining SPS also in hexaploid wheat. We show that the expression levels of this gene positively correlate with SPS in multiple MAGIC founder lines under field conditions as well as in transgenic lines grown in the greenhouse. This work highlights the potential use of WAPO1 in hexaploid wheat for further yield increases. The impact of WAPO1 and SPS on yield depends on other genetic and environmental factors, hence, will require a finely balanced expression level to avoid the development of detrimental pleiotropic phenotypes.
Feedback linking cell envelope stiffness, curvature, and synthesis enables robust rod-shaped bacterial growth
Authors: al-Mosleh Salem , Gopinathan Ajay , Santangelo Christian , Huang Kerwyn Casey , Rojas Enrique
Published: April 2022

Bacterial growth is remarkably robust to environmental fluctuations, yet the mechanisms of growth-rate homeostasis are poorly understood. Here, we combine theory and experiment to infer mechanisms by which Escherichia coli adapts its growth rate in response to changes in osmolarity, a fundamental physicochemical property of the environment. The central tenet of our theoretical model is that cell-envelope expansion is only sensitive to local information such as enzyme concentrations, cell-envelope curvature, and mechanical strain in the envelope. We constrained this model with quantitative measurements of the dynamics of E. coli elongation rate and cell width after hyperosmotic shock. Our analysis demonstrated that adaptive cell-envelope softening is a key process underlying growth-rate homeostasis. Furthermore, our model correctly predicted that softening does not occur above a critical hyperosmotic shock magnitude and precisely recapitulated the elongation-rate dynamics in response to shocks with magnitude larger than this threshold. Finally, we found that to coordinately achieve growth-rate and cell-width homeostasis, cells employ direct feedback between cell-envelope curvature and envelope expansion. In sum, our analysis points to new cellular mechanisms of bacterial growth-rate homeostasis and provides a practical theoretical framework for understanding this process.

Significance Statement

The bacterial cell envelope is the critical structure that defines cell size and shape, and its expansion therefore defines cell growth. Although size, shape, and growth rate are important cellular variables that are robust to environmental fluctuations, the feedback mechanisms by which these variables influence cell-envelope expansion are unknown. Here, we explore how E. coli cells achieve growth-rate and cell-width homeostasis during fluctuations in osmolarity, a key environmental property. A biophysical model in which the cell envelope softens after an osmotic shock and envelope expansion depends directly on local curvature quantitatively recapitulated all experimental observations. Our study elucidates new mechanisms of bacterial cell morphogenesis and highlights the deep interplay between global cellular variables and the mechanisms of cell-envelope expansion.
HSD3B1 is an Oxysterol 3β-Hydroxysteroid Dehydrogenase in Human Placenta
Authors: Dickson Alison , Yutuc Eylan , Thornton Catherine A , Dunford James E , Oppermann Udo , Wang Yuqin , Griffiths William J
Published: April 2022

Most biologically active oxysterols have a 3β-hydroxy-5-ene function in the ring system with an additional site of oxidation at C-7 or on the side-chain. In blood plasma oxysterols with a 7α-hydroxy group are also observed with the alternative 3-oxo-4-ene function in the ring system formed by ubiquitously expressed 3β-hydroxy-Δ5-C27-steroid oxidoreductase Δ5-isomerase, HSD3B7. However, oxysterols without a 7α-hydroxy group are not substrates for HSD3B7 and are not usually observed with the 3-oxo-4-ene function. Here we report the unexpected identification of oxysterols in plasma derived from umbilical cord blood and blood from pregnant women taken before delivery at 37+ weeks of gestation, of side-chain oxysterols with a 3-oxo-4-ene function but no 7α-hydroxy group. These 3-oxo-4-ene oxysterols were also identified in placenta, leading to the hypothesis that they may be formed by a previously unrecognised 3β-hydroxy-Δ5-C27-steroid oxidoreductase Δ5-isomerase activity of HSD3B1, an enzyme which is highly expressed in placenta. Proof of principle experiments confirmed that HSD3B1 has this activity. We speculate that HSD3B1 in placenta is the source of the unexpected 3-oxo-4-ene oxysterols in cord and pregnant women’s plasma and may have a role in controlling the abundance of biologically active oxysterols delivered to the fetus.
GTP-bound E. coli FtsZ filaments are composed of Tense monomers: A DNP NMR study using interface detection
Authors: McCoy Kelsey M. , McDermott Ann E.
Published: April 2022

FtsZ filaments are the major structural component of the bacterial Z-ring and are drivers of bacterial division. While crystal structures for FtsZ from some gram positive bacteria in the presence of GTP-analog like compounds suggest the possibility of a high energy “Tense” conformation, to date it remains an important question to elucidate whether this Tense form is the dominant form in filaments. Using dynamic nuclear polarization (DNP) solid-state NMR and differential isotopic labelling, we directly detect residues located at the inter-monomer interface of GTP-bound WT Escherichia coli FtsZ filaments. We combine chemical shift prediction, homology modelling, and heteronuclear dipolar recoupling techniques to characterize the E. coli FtsZ filament interface and demonstrate that the monomers in active filaments assume a Tense conformation.
Rapid loss of fine motor skills after low dose space radiation exposure
Authors: Blackwell Ashley A , Fesshaye Arriyam , Tidmore Alyssa , Lake Rami I , Wallace Douglas G , Britten Richard A
Published: April 2022

Sensorimotor function, motivation, and attentional processes are fundamental aspects of behavioral organization during skilled tasks. NASA’s planned expedition to Mars will expose astronauts to space radiation (SR) that has the potential to impair performance in mission critical tasks. Impairments in task accuracy and movement kinematics have been previously reported during string-pulling behavior ~7 months after SR exposure. If similar SR-induced sensorimotor deficits emerge at earlier times, then astronauts may have compromised in-flight performance disruptions while performing skilled tasks in critical situations, such as when manipulating controls or performing seat egress. Due to the possibility that such performance losses may compromise mission success, it is critical to determine if sensorimotor, motivation, or attentional deficits occur acutely after SR exposure at a time point that corresponds to in-flight performance. Male Wistar rats were thus exposed to either 10 cGy simplified galactic cosmic radiation (GCRsim), 10 cGy 4Helium (4He), or no radiation at all (Sham), and string-pulling behavior was assessed approximately 72 hours later. Following exposure to SR, rats (4He) took more time to approach the string to initiate string-pulling behavior and to pull in the string to reach the Cheerio (4He and GCRsim) relative to Sham rats. 4He-exposed rats also exhibited a greater number of misses and less contacts relative to both Sham and GCRsim-exposed rats. Further, rats exposed to 4He demonstrated less concentrated reach endpoints with both the left and right hands compared to GCR-exposed rats. This work suggests that sensorimotor function and motivation and/or attentional processes were impaired 72 hours after 4He-radiation exposure.
New broad-spectrum anti-Flavivirus human antibodies with Zika virus-neutralizing potential
Authors: de Oliveira França Renato Kaylan Alves , Silva Jacyelle Medeiros , Rodrigues Lucas Silva , Maranhão Andrea Queiroz , Brigido Marcelo Macedo
Published: April 2022

Flavivirus infections show recurrent outbreaks and can be responsible for disease complications such as Hemorrhagic Dengue Fever and Congenital Zika Virus Syndrome. Effective therapeutic interventions are still a challenge. Antibodies can provide significant protection, although antibody response may fail due to ADE (Antibody-Dependent Enhancement) reactions or immune escape mutations. To generate effective neutralizing antibodies, the choice of the target antigen is a crucial part of the process. Human anti-Flavivirus antibodies were selected from a combinatorial library displayed on a phage surface. The antibodies were selected against a mimetic peptide based on the fusion loop region in Domain II of the protein E, which is highly conserved among different Flavivirus. Four rounds of selection were performed using the synthetic peptide in two strategies: the first was using acidic elution of bound phages, and the second was applying a competing procedure. After panning, the selected VH and VL domains were determined by combining NGS and bioinformatic approaches. Three different human monoclonal antibodies were expressed as scFvs and further characterized. All showed binding capacity to Zika (ZIKV), Yellow Fever (YFV), and Dengue (DENV) viruses. Two of these antibodies, AZ1p and AZ6m, could neutralize the ZIKV infection in a PRNT assay. These new antibodies have the potential to be used in therapeutic intervention against different Flavivirus illnesses and, due to the conservation of the fusion loop region, they may be resistant to scape mutations.

Author summary

The central idea of this work is to present a possible unique therapeutic approach to combat different diseases that cause health problems annually, such as Dengue and yellow fever infections and Zika congenital syndromes. The viruses that cause these diseases, of the Flavivirus genus, typically have disease amplification reactions and evasion mechanisms of the immune response that hinder the success of specific therapies and vaccines and require new forms of effective and safe treatments. We have developed new neutralizing human antibodies so that they bind to a highly conserved region of Flavivirus, called the fusion loop, and in such a way as to avoid adverse effects associated with anti-Flavivirus antibodies. We showed that the antibodies have high cross-reactivity against different Flaviviruses and we exemplified their neutralizing capacity for Zika virus infection in an ex vivo assay. New monoclonal antibodies such as those presented here may contribute to the control of important tropical diseases in a safer and more efficient way.
Identification and receptor mechanism of TIR-catalyzed small molecules in plant immunity
Authors: Huang Shijia , Jia Aolin , Song Wen , Hessler Giuliana , Meng Yonggang , Sun Yue , Xu Lina , Laessle Henriette , Jirschitzka Jan , Ma Shoucai , Xiao Yu , Yu Dongli , Hou Jiao , Liu Ruiqi , Sun Huanhuan , Liu Xiaohui , Han Zhifu , Chang Junbiao , Parker Jane E. , Chai Jijie
Published: April 2022

Plant nucleotide-binding leucine-rich-repeat receptors (NLRs) with an N-terminal toll/interleukin-1 receptor (TIR) domain sense pathogen effectors to enable TIR-encoded NADase activity for immune signaling. TIR-NLR (TNL) signaling requires conserved helper NLRs NRG1 and ADR1 and the lipase-like protein EDS1 that functions as a heterodimer with each of its paralogs PAD4 and SAG101. We show that TIR-containing proteins catalyze production of 2’-(5’’-phosphoribosyl)-5’-adenosine mono-/di-phosphate (pRib-AMP/ADP)in vitroandin planta. Biochemical and structural data demonstrate that EDS1-PAD4 is a receptor complex for pRib-AMP/ADP. pRib-ADP binding triggers a conformational change in the PAD4 C-terminal domain to allosterically promote EDS1-PAD4 interaction with ADR1-L1 but not NRG1A. Our study identifies TIR-catalyzed pRib-AMP/ADP as a missing link in TIR signaling via EDS1-PAD4 and as likely second messengers for plant immunity.
Explaining flexible continuous speech comprehension from individual motor rhythms
Authors: Lubinus Christina , Keitel Anne , Obleser Jonas , Poeppel David , Rimmele Johanna M.
Published: April 2022

When speech is too fast, the tracking of the acoustic signal along the auditory pathway deteriorates, leading to suboptimal speech segmentation and decoding of speech information. Thus, speech comprehension is limited by the temporal constraints of the auditory system. Here we ask whether individual differences in auditory-motor coupling strength in part shape these temporal constraints. In two behavioral experiments, we characterize individual differences in the comprehension of naturalistic speech as function of the individual synchronization between the auditory and motor systems and the preferred frequencies of the systems. Obviously, speech comprehension declined at higher speech rates. Importantly, however, both higher auditory-motor synchronization and higher spontaneous speech motor production rates were predictive of better speech-comprehension performance. Furthermore, performance increased with higher working memory capacity (Digit Span) and higher linguistic, model-based sentence predictability – particularly so at higher speech rates and for individuals with high auditory-motor synchronization. These findings support the notion of an individual preferred auditory– motor regime that allows for optimal speech processing. The data provide evidence for a model that assigns a central role to motor-system-dependent individual flexibility in continuous speech comprehension.
Omicron breakthrough infection drives cross-variant neutralization and memory B cell formation
Authors: Quandt Jasmin , Muik Alexander , Salisch Nadine , Lui Bonny Gaby , Lutz Sebastian , Krüger Kimberly , Wallisch Ann-Kathrin , Adams-Quack Petra , Bacher Maren , Finlayson Andrew , Ozhelvaci Orkun , Vogler Isabel , Grikscheit Katharina , Hoehl Sebastian , Goetsch Udo , Ciesek Sandra , Türeci Özlem , Sahin Ugur
Published: April 2022

Omicron is the evolutionarily most distinct SARS-CoV-2 variant (VOC) to date and displays multiple amino acid alterations located in neutralizing antibody sites of the spike (S) protein. We report here that Omicron breakthrough infection in BNT162b2 vaccinated individuals results in strong neutralizing activity not only against Omicron, but also broadly against previous SARS-CoV-2 VOCs and against SARS-CoV-1. We found that Omicron breakthrough infection mediates a robust B cell recall response, and primarily expands preformed memory B cells that recognize epitopes shared broadly by different variants, rather than inducing new B cells against strictly Omicron-specific epitopes. Our data suggest that, despite imprinting of the immune response by previous vaccination, the preformed B cell memory pool has sufficient plasticity for being refocused and quantitatively remodeled by exposure to heterologous S protein, thus allowing effective neutralization of variants that evade a previously established neutralizing antibody response.

One Sentence Summary

Breakthrough infection in individuals double- and triple-vaccinated with BNT162b2 drives cross-variant neutralization and memory B cell formation.
Evidence that Nek1 does not phosphorylate Rad54-S572 during recovery from IR
Authors: Ghosh Ishita , Khalil Md Imtiaz , De Benedetti Arrigo
Published: April 2022

A main focus of the work in our lab is on the activity of Tousled Like Kinase 1 (TLK1) in the area of DNA Damage and Repair. As one of its key interactor, TLK1 phosphorylates NIMA related kinase 1 (Nek1), and Nek1 was reported by Spies et al. to phosphorylate and regulate the activity of the key HRR protein Rad541, which suggested an intriguing signal transduction pathway: TLK1>Nek1>Rad54. In an effort to confirm such relations, we now report that we have not been able to reproduce key findings from that study. Specifically, we found that Nek1 does not phosphorylate RAD54-S572 as was reported. We generated Nek1-KO mouse NT1 cells2 and Nek1-Knock-down in Hek293 (same cells as in Spies et al.), and the pRAD54-S572 signal does not change with our custom Ab, with or w/o IR. When we used an Ab from the Lobrich lab, it detected an immunoreactive band of wrong size for RAD54, which also did not change after IR even in synchronized G2 cells, contrary to their report. We also note that their P-assignment was based on guessing a weak consensus Nek1 sequence, and that site-directed mutagenesis of RAD54-S572 failed to yield biological effects in their in in vitro studies1. To conclusively establish that S572 is not a site of phosphorylation of Nek1, we carried out a IVK with purified Nek1 and RAD54 followed by MS analysis of the phosphatides, which revealed several but not S572. We also could not reproduce their copurification of Nek1-RAD54 by coIP, calling into question this interaction. Neither we could reproduce their results demonstrating the importance of Nek1 for HRR using the same SceI-mediated DR-GFP conversion assays.
Actin turnover required for adhesion-independent bleb migration
Authors: Copos Calina , Strychalski Wanda
Published: April 2022

Cell migration is critical for many vital processes, such as wound healing, as well as harmful processes, like cancer metastasis. Experiments have highlighted the diversity in migration strategies employed by cells in physiologically relevant environments. In 3D fibrous matrices and confinement between two surfaces, some cells migrate using round membrane protrusions, called blebs. In bleb-based migration, the role of substrate adhesion is thought to be minimal, and it remains unclear if a cell can migrate without any adhesion complexes. We present a 2D computational fluid-structure model of a cell using cycles of bleb expansion and retraction in a channel with several geometries. The cell model consists of a plasma membrane, an underlying actin cortex, and viscous cytoplasm. Cellular structures are immersed in viscous fluid which permeates them, and the fluid equations are solved using the method of regularized Stokeslets. Simulations show that the cell cannot effectively migrate when the actin cortex is modeled as a purely elastic material. We find that cells do migrate in rigid channels if actin turnover is included with a viscoelastic description for the cortex. Our study highlights the non-trivial relationship between cell rheology and its external environment during migration with cytoplasmic streaming.
Topographically distinct adaptive landscapes for teeth, skeletons, and size explain the adaptive radiation of Carnivora (Mammalia)
Authors: Slater Graham J.
Published: April 2022

Abstract

Models of adaptive radiation were originally developed to explain the early, rapid appearance of distinct modes of life within diversifying clades. Phylogenetic tests of this hypothesis have yielded limited support for temporally declining rates of phenotypic evolution across diverse clades, but the concept of an adaptive landscape that links form to fitness, while also crucial to these models, has received more limited attention. Using methods that assess the temporal accumulation of morphological variation and estimate the topography of the underlying adaptive landscape, I found evidence of an early partitioning of mandibulo-dental morphological variation in Carnivora (Mammalia) that occurs on an adaptive landscape with multiple peaks, consistent with classic ideas about adaptive radiation. Although strong support for this mode of adaptive radiation is present in traits related to diet, its signal is not present in body mass data or for traits related to locomotor behavior and substrate use. These findings suggest that adaptive radiations may occur along some axes of ecomorphological variation without leaving a signal in others and that their dynamics are more complex than simple univariate tests might suggest.
Frequency of change determines effectiveness of microbial response strategies in sulfidic stream microbiomes
Authors: Li Shengjie , Mosier Damon , Dong Xiaoli , Kouris Angela , Ji Guodong , Strous Marc , Diao Muhe
Published: April 2022

Nature challenges microbes with change at different frequencies and demands an effective response for survival. Here, we used controlled laboratory experiments to investigate the ecological success of different response strategies, such as post-translational modification, transcriptional regulation, and specialized versus adaptable metabolisms. For this, we inoculated replicated chemostats with an enrichment culture obtained from sulfidic stream microbiomes 16 weeks prior. The chemostats were submitted to alternatingly oxic and anoxic conditions at three frequencies, with periods of 1 day, 4 days and 16 days. The microbial response was recorded with 16S rRNA gene amplicon sequencing, shotgun metagenomics, transcriptomics and proteomics. Metagenomics resolved 26 nearly complete genomes of bacterial populations, mainly affiliated with Proteobacteria and Bacteroidetes. Almost all these populations maintained a steady growth rate under both redox conditions at all three frequencies of change. Apparently, oscillating oxic/anoxic conditions selected for generalistic species, rather than species specializing in only a single condition. Rapid (1-day) dynamics yielded more stochasticity, both in community dynamics and gene expression, indicating that bet-hedging might be an effective coping strategy for relatively rapid environmental change. Codon-usage bias, previously associated with copiotrophic and oligotrophic lifestyles, was found to be a powerful predictor of ecological success at different frequencies, with copiotrophs and oligotrophs more successful at a rapid and a slow pace of change, respectively, independent of growth rate.