bluuebunny/crossref_metadata_2025 huggingface dataset:
DNA fluctuations reveal the size and dynamics of topological domains
Authors: Vanderlinden Willem , Skoruppa Enrico , Kolbeck Pauline J , Carlon Enrico , Lipfert Jan
Published: November 2022

DNA supercoiling is a key regulatory mechanism that orchestrates DNA readout, recombination, and genome maintenance. DNA-binding proteins often mediate these processes by bringing two distant DNA sites together, thereby inducing (transient) topological domains. In order to understand the dynamics and molecular architecture of protein-induced topological domains in DNA, quantitative and time-resolved approaches are required. Here, we present a methodology to determine the size and dynamics of topological domains in supercoiled DNA in real time and at the single-molecule level. Our approach is based on quantifying the extension fluctuations—in addition to the mean extension—of supercoiled DNA in magnetic tweezers (MT). Using a combination of high-speed MT experiments, Monte Carlo simulations, and analytical theory, we map out the dependence of DNA extension fluctuations as a function of supercoiling density and external force. We find that in the plectonemic regime, the extension variance increases linearly with increasing supercoiling density and show how this enables us to determine the formation and size of topological domains. In addition, we demonstrate how the transient (partial) dissociation of DNA-bridging proteins results in the dynamic sampling of different topological states, which allows us to deduce the torsional stiffness of the plectonemic state and the kinetics of protein-plectoneme interactions. We expect our results to further the understanding and optimization of magnetic tweezer measurements and to enable quantification of the dynamics and reaction pathways of DNA processing enzymes in the context of physiologically relevant forces and supercoiling densities.
A new system to measure the gradient vector of the magnetic field on unmanned aerial vehicles – data processing and field experiment
Authors: Kulüke Christian , Virgil Christopher , Stoll Johannes , Hördt Andreas
Published: November 2022

We present a novel airborne magnetometer system deployed on an unmanned aerial vehicle (UAV) that is capable of measuring the horizontal gradient of the three components of the magnetic field. The system consists of two three-component fluxgate magnetometers (FGM) that are mounted on a transverse horizontal boom. The sensor attitude is determined with a low-cost inertial measurement unit. The estimation of the magnetic field components as well as its gradient is extremely sensitive to sensor movement and sensor rotation and requires sophisticated data processing and corrections. Here, we present four specific calibration and correction procedures we consider essential to achieve sufficient accuracy. First, we present a new in-flight calibration method for an FGM gradiometer. Second, we introduce a procedure that corrects for rotation-induced noise in the FGMs that has not been described previously in the literature. In a third step, we correct for mechanical vibrations, which induce high-frequency noise in the data. Finally, the gradient of each component is mathematically rotated into the geographical coordinate system. The performance of the system is evaluated on a test site where several metal objects of known magnetization were placed on the ground surface. For the first time, we show the gradients of magnetic field components measured on a UAV. The gradients agree with the results of a forward simulation within a few nT m−1. The accuracy will be sufficient for many practical applications, such as geological mapping, ore exploration, and the search for metallic bodies.
Delaying drought-driven leaf cell damage may be the key trait of invasive trees ensuring their success in the Mediterranean basin
Authors: Azzarà Maria , Abate Elisa , Chiofalo Maria T , Crisafulli Alessandro , Trifilò Patrizia
Published: November 2022

Invasive alien species (IAS) threaten the biodiversity richness of the Mediterranean basin, a drought-prone region. However, our knowledge on the adaptive strategies of IAS for facing Mediterranean drought summers is still incomplete. The aim of the present study is to compare the water relations and the critical relative water content (RWC) values leading to loss of cell rehydration capacity of two Mediterranean basin IAS (i.e., Ailanthus altissima (Mill.) Swingle and Robinia pseudoacacia L.) versus two co-occurring native species (i.e., Fraxinus ornus L. and Quercus pubescens Willd.). Study IAS showed higher values of water potential at turgor loss point and osmotic potential at full turgor, lower values of modulus of elasticity and leaf mass area but higher photosynthesis rate, even during the summer, with respect to the Mediterranean native species. These findings supported the hypothesis that IAS are characterized by a resource acquisitive strategy coupled with a safety-efficiency trade-off, compared with Mediterranean native species. However, similar leaf RWC thresholds leading to loss of cell rehydration capacity were recorded in the two groups of species. Moreover, IAS showed higher saturated water content and capacitance values compared with the co-occurring species. Overall, our results suggest that the success of Mediterranean IAS is driven by their ability to delay dehydration damage of mesophyll cells during Mediterranean summer drought, thereby supporting their distinctive high carbon assimilation rate.
Encapsulation Dynamics of Neuromuscular Blocking Drugs by Sugammadex
Authors: Irani Amir Hossein , Voss Logan , Whittle Nicola , Sleigh Jamie W.
Published: November 2022

Background

The clinical actions of sugammadex have been well studied, but the detailed molecular mechanism of the drug encapsulation process has not been systematically documented. The hypothesis was that sugammadex would attract rocuronium and vecuronium via interaction with the sugammadex side-chain “tentacles,” as previously suggested.

Methods

Computational molecular dynamics simulations were done to investigate docking of sugammadex with rocuronium and vecuronium. To validate these methods, strength of binding was assessed between sugammadex and a heterogeneous group of nine other drugs, the binding affinities of which have been experimentally determined. These observations hinted that high concentrations of unbound sugammadex could bind to propofol, potentially altering its pharmacokinetic profile. This was tested experimentally in in vitro cortical slices.

Results

Sugammadex encapsulation of rocuronium involved a sequential progression down a series of metastable states. After initially binding beside the sugammadex molecule (mean ± SD center-of-mass distance = 1.17 ± 0.13 nm), rocuronium then moved to the opposite side to that hypothesized, where it optimally aligned with the 16 hydroxyl groups (distance, 0.82 ± 0.04 nm) before entering the sugammadex cavity to achieve energetically stable encapsulation by approximately 120 ns (distance, 0.35 ± 0.12 nm). Vecuronium formed fewer hydrogen bonds with sugammadex than did rocuronium; hence, it was less avidly bound. For the other molecules, the computational results showed good agreement with the available experimental data, showing a clear bilogarithmic relation between the relative binding free energy and the association constant (R
2 = 0.98). Weaker binding was manifest by periodic unbinding. The brain slice results confirmed the presence of a weak propofol–sugammadex interaction.

Conclusions

Computational simulations demonstrate the dynamics of neuromuscular blocking drug encapsulation by sugammadex occurring from the opposite direction to that hypothesized and also how high concentrations of unbound sugammadex can potentially weakly bind to other drugs given during general anesthesia.

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Cardiac Surgery Unit Advanced Life Support Training
Authors: Whitlock John P.
Published: November 2022

Background

Although the body of knowledge related to Cardiac Surgery Unit Advanced Life Support (CSU-ALS) guideline has grown over the last 10 years, there is no existing literature examining the impact of this training on patient mortality outcomes.

Objectives

This article describes one institution's experience related to patient mortality outcomes following a rigorous training program following the CSU-ALS guideline. Because of the small numbers associated with cardiac arrests after cardiac surgery (0.7%-8%), statistical significance was not a goal.

Methods

A quasi-experimental design was used to compare mortality outcomes before and after CSU-ALS training. One hundred percent of the staff were trained in the initial year, and 85% to 90% of the staff maintained competency in the following years. The author used 10 years of retrospective data to compare mortality rates 4 years before and 6 years after the intervention.

Results

The retrospective data showed a decrease in the percentage of failure-to-rescue rate in the intervention group (control 16% vs intervention 2%). Fisher exact testing implies that the observed frequencies were not significantly different from the expected frequencies (P = .072 and P = .135). Because of the small sample size, statistical significance could not be established.

Discussion

This institution experienced an extremely positive track record in outcomes despite its inability to prove a statistically significant correlation to the CSU-ALS training. The overall observed and self-reported confidence level of the staff during the study period was outside the project scope but deserves mention and further research.
The Circle of Life
Authors: Lindsay Julie , Pautler Mary , Papesca James Thomas
Published: November 2022

Background

During the course of a baccalaureate education, nursing students may encounter patient situations that are unexpected and emergent, including death. The use of simulation can offer students the opportunity to practice their communication skills with family centered-care and their teamwork in a safe environment with these emotionally charged patient situations.

Objectives

The aim of this study was to provide students with a final summative simulation that could encompass as much of the curriculum as possible.

Methods

We developed a simulation experience involving a 32-week pregnant woman diagnosed with H1N1, who deteriorated and needed intubation and an emergency C-section. Students were required to care not only for the pregnant patient who was decompensating but also for the premature infant while working with two providers, a chaplain, and the “husband/father” in an intensive care environment.

Results

Around 94% of the students thought the simulation was beneficial and helped them improve clinical judgments, assessments, and interprofessional and patient/family communication. Students felt this simulation was challenging and recommended it to continue for other senior classes. Students found the debriefing and open discussion with all participants beneficial.

Discussion

The use of a summative simulation encompassing as much of the nursing curriculum as possible can be an effective tool to assess student learning and engagement.
Reimagining Healthcare to Meet Communities' Needs Outside Hospital Walls
Authors: Oostra Randy
Published: November 2022

Identifying and addressing the social determinants of health is an integral part of the mission at ProMedica as a health and well-being organization and an anchor institution in the communities we serve. For more than a decade, ProMedica has been on a progressive journey to integrate identification, screening, and interventions with important drivers of adverse outcomes to create a new model for healthcare, a model designed to bend the cost curve and enhance the health of our patients, clients, and communities. We are living our commitment to a healthier, thriving community by coupling high-quality care with community outreach and strategically implemented social care. Initiatives include job training, affordable housing initiatives, and financial coaching,
Recent Trends in the Incidence of Gastric Cancer in the United States
Authors: Liu Kyle S. , Raza Syed Ahsan , El-Serag Hashem B. , Thrift Aaron P.
Published: November 2022

Background:

Gastric cancer (GC) incidence rates overall in the United States have declined over recent decades and are predicted to continue declining. However, there have been mixed recent findings regarding the potential stabilization of rates and potential divergent trends by age group. We used the most recent cancer data for the United States and examined trends in GC between 1992 and 2019, overall and in important subgroups of the population.

Methods:

Age-adjusted GC incidence rates and trends in adults 20 years or older were calculated using data from the Surveillance, Epidemiology, and End Results (SEER) 12 program. Secular trends were examined overall and by age group, sex, race/ethnicity, SEER registry, and tumor location. We used joinpoint regression to compute annual percent changes, average annual percent changes, and associated 95% CI.

Results:

GC rates decreased by 1.23% annually from 1992 to 2019. Despite overall decreases, GC incidence rates increased for age groups below 50 years, predominately driven by noncardia GC (74.3% of all GCs). Cardia GC (26.7% of GC) rates decreased in all age groups except for 80 to 84 years. Overall GC rates decreased for both sexes, all races, and for all SEER registry regions, with the largest decreases occurring in males, Asians and Pacific Islanders, and in Hawaii. Age-period-cohort analysis revealed that birth cohorts before 1940 and after 1980 both had increased rates of GC compared with the reference birth cohort of 1955.

Conclusion:

GC rates overall have continued to decline through 2019, despite increases in the rate of noncardia GC for younger age groups.
Pharmacogenomic Profiling of Pediatric Patients on Psychotropic Medications in an Emergency Department
Authors: Ghosh Pallavi , Martinez Jesse , Shah Nipam , Kenan Will , Fowler Andrew , Limdi Nita , Burns Lindsey , Cogan Elizabeth S. , Gardiner Anna , Hain Daniel , Johnson Holly , Lewis David , Shelton Richard , Liebelt Erica
Published: November 2022

Objective

The aim of the study was to evaluate the ability of a combinatorial pharmacogenomic test to predict medication blood levels and relative clinical improvements in a selected pediatric population.

Methods

This study enrolled patients between ages 3 to 18 years who presented to a pediatric emergency department with acute psychiatric, behavioral, or mental health crisis and/or concerns, and had previously been prescribed psychotropic medications. Patients received combinatorial pharmacogenomic testing with medications categorized according to gene-drug interactions (GDIs); medications with a GDI were considered “incongruent,” and medications without a GDI were considered “congruent.” Blood levels for escitalopram, fluoxetine, aripiprazole, and clonidine were evaluated according to level of GDI. Relative clinical improvements in response to the prescribed psychotropic medications were measured using a parent-rated Clinical Global Impression of Improvement (CGI-I) assessment, where lower scores corresponded with greater improvement.

Results

Of the 100 patients enrolled, 73% reported taking ≥1 incongruent medication. There was no significant difference in CGI-I scores between patients prescribed congruent versus incongruent medications (3.37 vs 3.68, P = 0.343). Among patients who presented for depression or suicidal ideation, those prescribed congruent medications had significantly lower CGI-I scores compared with those taking incongruent medications (P = 0.036 for depression, P = 0.018 for suicidal ideation). There was a significant association between medication GDI and blood levels for aripiprazole (n = 15, P = 0.01) and escitalopram (n = 10, P = 0.01).

Conclusions

Our preliminary findings suggest that combinatorial pharmacogenomic testing can predict medication blood levels and relative outcomes based on medication congruency in children presenting to an emergency department with acute psychiatric/behavioral crises. Additional studies will be needed to confirm these findings.
Efficacy, safety, and tolerability of isoniazid preventive therapy for tuberculosis in people living with HIV
Authors: Jagi Jaya Laxmi , Thomas Christy , Gudi Sai Krishna , Undela Krishna
Published: November 2022

Objective:

The aim of this study was to systematically assess the efficacy, safety, and tolerability of isoniazid preventive therapy (IPT) for tuberculosis (TB) in people with HIV (PWH).

Design:

A systematic review and meta-analysis.

Methods:

A thorough literature search was performed using PubMed, Cochrane CENTRAL, and Google Scholar from their inception to June 30, 2021. All randomized controlled trials (RCTs) investigating the efficacy, safety, or tolerability of IPT on PWH compared with placebo or active comparators were included in the study. The heterogeneity among the studies was identified by using the I
2 statistic and Cochran's Q test.

Results:

Out of the 924 nonduplicate RCTs identified through database searching and other sources, 26 studies comprising 38 005 patients were included. The overall effect estimate identified the reduction of active TB incidence [odds ratio (OR) 0.69; 95% confidence interval (95% CI) 0.57–0.84; P < 0.001], but not all-cause mortality (OR 0.91; 95% CI 0.82, 1.02; P = 0.10) with IPT compared with the control. In addition, no significant association was identified between the use of IPT and the risk of peripheral neuropathy (OR 1.50; 95% CI 0.96–2.36; P = 0.08) and hepatotoxicity (OR 1.21; 95% CI 0.97–1.52; P = 0.09).

Conclusion:

This systematic review and meta-analysis identified a significant reduction in the incidence of active TB, but not all-cause mortality, among PWH who received IPT compared with the control. Lesser number of outcomes may be the reason for nonsignificant results in terms of safety outcomes of IPT. Therefore, there is a need for extensive and long-term studies to address these issues further, especially in TB/HIV endemic areas.
Costal Cartilage Harvest Through a Small Incision in Asian Rhinoplasty After Breast Augmentation
Authors: Song Zhen , Zhang Xulong , You Jianjun , Wang Huan , Zheng Ruobing , Xu Yihao , Guo Junsheng , Tian Le , Fan Fei
Published: November 2022

Background:

The costal cartilage is widely used in rhinoplasty. Although different surgical methods of costal cartilage harvest have been developed, few studies have reported the method of costal cartilage harvest for patients after breast augmentation. This study aims to provide our experience of costal cartilage harvest through a small incision approach.

Methods:

A retrospective review was performed for patients undergoing esthetic rhinoplasty with costal cartilage after breast augmentation between May 2019 and May 2021. Postoperative pain was evaluated with the Visual Analog Scale, and the scars at the donor site were assessed 1 year postoperatively with the Modified Vancouver Scar Scale.

Results:

A total of 23 female patients were included. The average follow-up time was 21.4 months. No complications of massive bleeding, pleural injury, or breast implant injury during the surgery, wound dehiscence, or wound infection in the harvested site were observed. No patients complained of changes in breast morphology or breast asymmetry after costal cartilage harvest. Results of Visual Analog Scale for donor-site pain indicated pain in donor-site peaked at 12 hours after surgery and gradually decreased. All patients were satisfied with the scarring of the donor sites after surgery.

Conclusion:

The better scar performance, low complication rates, and high satisfaction among patients suggest that this is a safe technique to harvest costal cartilage with a small incision in rhinoplasty for patients after breast augmentation.
Infectious droplet exposure is an inefficient route for SARS-CoV-2 infection in the ferret model
Authors: James Joe , Byrne Alexander M. P. , Goharriz Hooman , Golding Megan , Cuesta Joan M. A. , Mollett Benjamin C. , Shipley Rebecca , M. McElhinney Lorraine , Fooks Anthony R. , Brookes Sharon M.
Published: November 2022

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19) in humans, has a wide host range, naturally infecting felids, canids, cervids, rodents and mustelids. Transmission of SARS-CoV-2 is universally accepted to occur via contact with contaminated secretions from the respiratory epithelium, either directly or indirectly. Transmission via droplet nuclei, generated from a cough or sneeze, has also been reported in several human and experimental animal scenarios. However, the role of droplet transmission at the human–animal interface remains to be fully elucidated. Here, the ferret infection model was used to investigate the routes of infection for the SARS-CoV-2 beta variant (B.1.351). Ferrets were exposed to droplets containing infectious SARS-CoV-2, ranging between 4 and 106 µm in diameter, simulating larger droplets produced by a cough from an infected person. Following exposure, viral RNA was detected on the fur of ferrets, and was deposited onto environmental surfaces, as well as the fur of ferrets placed in direct contact; SARS-CoV-2 remained infectious on the fur for at least 48 h. Low levels of viral RNA were detected in the nasal washes early post-exposure, yet none of the directly exposed, or direct-contact ferrets, became robustly infected or seroconverted to SARS-CoV-2. In comparison, ferrets intranasally inoculated with the SARS-CoV-2 beta variant became robustly infected, shedding viral RNA and infectious virus from the nasal cavity, with transmission to 75 % of naive ferrets placed in direct contact. These data suggest that larger infectious droplet nuclei and contaminated fur play minor roles in SARS-CoV-2 transmission among mustelids and potentially other companion animals.
Plastid Genome Assembly Using Long-read Data (ptGAUL)
Authors: Zhou Wenbin , Armijos Carolina E. , Lee Chaehee , Lu Ruisen , Wang Jeremy , Ruhlman Tracey A. , Jansen Robert K. , Jones Alan M. , Jones Corbin D.
Published: November 2022

Although plastid genome (plastome) structure is highly conserved across most seed plants, investigations during the past two decades revealed several disparately related lineages that experienced substantial rearrangements. Most plastomes contain a large, inverted repeat and two single-copy regions and few dispersed repeats, however the plastomes of some taxa harbor long repeat sequences (>300 bp). These long repeats make it difficult to assemble complete plastomes using short-read data leading to misassemblies and consensus sequences that have spurious rearrangements. Single-molecule, long-read sequencing has the potential to overcome these challenges, yet there is no consensus on the most effective method for accurately assembling plastomes using long-read data. We generated a pipeline,plastidGenomeAssemblyUsingLong-read data (ptGAUL), to address the problem of plastome assembly using long-read data from Oxford Nanopore Technologies (ONT) or Pacific Biosciences platforms. We demonstrated the efficacy of the ptGAUL pipeline using 16 published long-read datasets. We showed that ptGAUL produces accurate and unbiased assemblies. Additionally, we employed ptGAUL to assemble four newJuncus(Juncaceae) plastomes using ONT long reads. Our results revealed many long repeats and rearrangements inJuncusplastomes compared with basal lineages of Poales.
Updated benchmarking of variant effect predictors using deep mutational scanning
Authors: Livesey Benjamin J. , Marsh Joseph A.
Published: November 2022

Variant effect predictors (VEPs) provide a potential solution to the influx of variants of uncertain clinical significance produced by genome sequencing studies. However, the assessment of VEP performance is fraught with biases introduced by benchmarking against clinical observations. In this study, building on our previous work, we use independently generated measurements of protein function from deep mutational scanning (DMS) experiments for 26 human proteins to benchmark 55 different VEPs, while introducing minimum data circularity. The top VEPs are dominated by unsupervised methods including EVE, DeepSequence and ESM-1v, a new protein language model that ranked first overall. However, the strong performance of recent supervised VEPs, in particular VARITY, shows that developers are taking data circularity and bias issues seriously. We also assess the performance of DMS and unsupervised VEPs for discriminating between known pathogenic and putatively benign missense variants. Our findings are mixed, demonstrating that some DMS datasets perform exceptionally at variant classification, while others are poor. Notably, we observe a striking correlation between VEP agreement with DMS data and performance in identifying clinically relevant variants, with EVE, DeepSequence and ESM-1v performing best, further supporting the utility of DMS as an independent benchmark.
OpenFold: Retraining AlphaFold2 yields new insights into its learning mechanisms and capacity for generalization
Authors: Ahdritz Gustaf , Bouatta Nazim , Floristean Christina , Kadyan Sachin , Xia Qinghui , Gerecke William , O’Donnell Timothy J , Berenberg Daniel , Fisk Ian , Zanichelli Niccolò , Zhang Bo , Nowaczynski Arkadiusz , Wang Bei , Stepniewska-Dziubinska Marta M , Zhang Shang , Ojewole Adegoke , Guney Murat Efe , Biderman Stella , Watkins Andrew M , Ra Stephen , Lorenzo Pablo Ribalta , Nivon Lucas , Weitzner Brian , Ban Yih-En Andrew , Sorger Peter K , Mostaque Emad , Zhang Zhao , Bonneau Richard , AlQuraishi Mohammed
Published: November 2022

AlphaFold2 revolutionized structural biology with the ability to predict protein structures with exceptionally high accuracy. Its implementation, however, lacks the code and data required to train new models. These are necessary to (i) tackle new tasks, like protein-ligand complex structure prediction, (ii) investigate the process by which the model learns, which remains poorly understood, and (iii) assess the model’s generalization capacity to unseen regions of fold space. Here we report OpenFold, a fast, memory-efficient, and trainable implementation of AlphaFold2. We train OpenFold from scratch, fully matching the accuracy of AlphaFold2. Having established parity, we assess OpenFold’s capacity to generalize across fold space by retraining it using carefully designed datasets. We find that OpenFold is remarkably robust at generalizing despite extreme reductions in training set size and diversity, including near-complete elisions of classes of secondary structure elements. By analyzing intermediate structures produced by OpenFold during training, we also gain surprising insights into the manner in which the model learns to fold proteins, discovering that spatial dimensions are learned sequentially. Taken together, our studies demonstrate the power and utility of OpenFold, which we believe will prove to be a crucial new resource for the protein modeling community.
Genome editing of an African elite rice variety confers resistance against endemic and emergingXanthomonas oryzaepv.oryzaestrains
Authors: Schepler-Luu Van , Sciallano Coline , Stiebner Melissa , Ji Chonghui , Boulard Gabriel , Diallo Amadou , Auguy Florence , Char Si Nian , Arra Yugander , Schenstnyi Kyrylo , Buchholzer Marcel , Loo Eliza P.I. , Bilaro Atugonza L. , Lihepanyama David , Mkuya Mohammed , Murori Rosemary , Oliva Ricardo , Cunnac Sebastien , Yang Bing , Szurek Boris , Frommer Wolf B.
Published: November 2022

Bacterial leaf blight (BB) of rice, caused byXanthomonas oryzaepv.oryzae(Xoo), threatens global food security and the livelihood of small-scale rice producers. Analyses ofXoocollections from Asia, Africa and the Americas demonstrated surprising continental segregation, despite robust global rice trade. Here, we report unprecedented BB outbreaks in Tanzania. The causative strains, unlike endemicXoo, carry Asian-type TAL effectors targeting the sucrose transporterSWEET11aand suppressingXa1. Phylogenomics clustered these strains withXoostrains from China. African rice varieties do not carry suitable resistance genes. To protect African rice production against this emerging threat, we developed a hybrid CRISPR-Cas9/Cpf1 system to edit six TALe-binding elements in threeSWEETpromoters of the East African elite variety Komboka. The edited lines show broad-spectrum resistance against Asian and African strains ofXoo, including strains recently discovered in Tanzania. This strategy could help to protect global rice crops from BB pandemics.
Longitudinal dynamics of the human vaginal ecosystem across the reproductive cycle
Authors: Costello Elizabeth K. , DiGiulio Daniel B. , Robaczewska Anna , Symul Laura , Wong Ronald J. , Shaw Gary M. , Stevenson David K. , Holmes Susan P. , Kwon Douglas S. , Relman David A.
Published: November 2022

The vaginal ecosystem is closely tied to human health and reproductive outcomes. However, its dynamics in the wake of childbirth remain poorly characterized. Here, we profiled the vaginal microbiota and cytokine milieu of subjects sampled throughout pregnancy (two cohorts;n= 196 pregnancies) and, in a subset, for one year postpartum (one cohort;n= 72 pregnancies). Delivery was associated with a vaginal pro-inflammatory cytokine response and the depletion of dominant taxa – typically,Lactobacillusspecies. By contrast, neither the progression of gestation nor the approach of labor strongly altered the vaginal ecosystem. At ~9.5 months postpartum (the latest timepoint at which cytokines were analyzed), elevated inflammation was associated with vaginal bacterial communities that had remained perturbed (i.e., highly diverse) from the time of delivery. Using time-to-event analysis, we found that the one-year postpartum probability of transitioning toLactobacillusdominance was 49.4% (95% confidence interval (CI) [33.6%, 61.5%];n= 58 at-risk cases, 86.2% of whom experienced this state prior to delivery). As diversity and inflammation declined postpartum, dominance byL. crispatus, the quintessential health-associated state, failed to recover: its prevalence before, immediately after, and one year after delivery was 41%, 4%, and 9%, respectively. Over the same period, states quasi-dominated by non-Lactobacillusspecies grew more common. Prompted by these findings, we revisited our pre-delivery data, discovering that a history of prior live birth was associated with a lower odds ofL. crispatusdominance in pregnant subjects (odds ratio (OR) 0.14; 95% CI [0.06, 0.32];P< 0.001) – an outcome modestly tempered by a longer (>18-month) interpregnancy interval. Our results suggest that reproductive history and childbirth in particular remodel the vaginal ecosystem and that the timing and degree of recovery from delivery may help determine the subsequent health of the woman and of future pregnancies.
Unexpected genetic and microbial diversity for arsenic cycling in deep sea cold seep sediments
Authors: Zhang Chuwen , Liu Xinyue , Shi Ling-Dong , Li Jiwei , Xiao Xi , Shao Zongze , Dong Xiyang
Published: November 2022

Cold seeps, where cold hydrocarbon-rich fluid escapes from the seafloor, showed strong enrichment of toxic metalloid arsenic (As). The toxicity and mobility of As can be greatly altered by microbial processes that play an important role in global As biogeochemical cycling. However, a global overview of genes and microbes involved in As transformation at seeps remains to be fully unveiled. Using 87 sediment metagenomes and 33 metatranscriptomes derived from 13 globally distributed cold seeps, we show that As detoxification genes (arsM, arsP, arsC1/arsC2,acr3) were prevalent at seeps and more phylogenetically diverse than previously expected. Asgardarchaeota and a variety of unidentified bacterial phyla (e.g. 4484-113, AABM5-125-24 and RBG-13-66-14) may also function as the key players in As transformation. The abundances of As-cycling genes and the compositions of As-associated microbiome shifted across different sediment depths or types of cold seep. The energy-conserving arsenate reduction or arsenite oxidation could impact biogeochemical cycling of carbon and nitrogen, via supporting carbon fixation, hydrocarbon degradation and nitrogen fixation. Overall, this study provides a comprehensive overview of As-cycling genes and microbes at As-enriched cold seeps, laying a solid foundation for further studies of As cycling in deep sea microbiome at the enzymatic and processual levels.
A Framework for Designing Efficient Deep Learning-Based Genomic Basecallers
Authors: Singh Gagandeep , Alser Mohammed , Denolf Kristof , Firtina Can , Khodamoradi Alireza , Cavlak Meryem Banu , Corporaal Henk , Mutlu Onur
Published: November 2022

Nanopore sequencing generates noisy electrical signals that need to be converted into a standard string of DNA nucleotide bases using a computational step called basecalling. The performance of basecalling has critical implications for all later steps in genome analysis. Therefore, there is a need to reduce the computation and memory cost of basecalling while maintaining accuracy. We presentRUBICON, a framework to develop efficient hardware-optimized basecallers. We demonstrate the effectiveness ofRUBICONby developingRUBICALL, the first hardware-optimized mixed-precision basecaller that performs efficient basecalling, outperforming the state-of-the-art basecallers. We believeRUBICONoffers a promising path to develop future hardware-optimized basecallers.
A simple framework for agent-based modeling with extracellular matrix
Authors: Metzcar John , Duggan Ben S. , Fischer Brandon , Murphy Matthew , Heiland Randy , Macklin Paul
Published: November 2022

Extracellular matrix (ECM) is a key component of the cellular microenvironment and critical in multiple disease and developmental processes. Representing ECM and cell-ECM interactions is a challenging multiscale problem as they span molecular-level details to tissue-level dynamics. While several computational frameworks exist for ECM modeling, they often focus on very detailed modeling of individual ECM fibers or represent only a single aspect of the ECM. Using the PhysiCell agent-based modeling platform, we developed a framework of intermediate detail with the ability to capture bidirectional cell-ECM interactions. We represent a small region of ECM, an ECM element, with three variables describing its local microstructure: anisotropy, density, and overall fiber orientation. To spatially model the ECM, we use an array of ECM elements. Cells remodel local ECM microstructure and in turn, local microstructure impacts cellular motility. We demonstrate the utility of this framework and reusability of its core cell-ECM interaction model through examples in cellular invasion, wound healing, basement membrane degradation, and leader-follower collective migration. Despite the relative simplicity of the framework, it is able to capture a broad range of cell-ECM interactions of interest to the modeling community. Furthermore, variables representing the ECM microstructure are accessible through simple programming interfaces. This allows them to impact cell behaviors, such as proliferation and death, without requiring custom code for each interaction, particularly through PhysiCell’s modeling grammar, enabling rapid modeling of a diverse range of cell-matrix biology. We make this framework available as a free and open source software package athttps://github.com/PhysiCell-Models/collective-invasion.
SMARCB1 loss creates patient-specificMYCtopologies that drive malignant rhabdoid tumor growth
Authors: Liu Ning Qing , Paassen Irene , Custers Lars , Teunissen Hans , Ayyildiz Dilara , He Jiayou , Hoving Eelco W. , de Wit Elzo , Drost Jarno
Published: November 2022

Malignant rhabdoid tumor (MRT) is a highly malignant and often lethal childhood cancer. MRTs are genetically defined by bi-allelic inactivating mutations inSMARCB1, a member of the BRG1/BRM-associated factors (BAF) chromatin remodeling complex. Mutations in BAF complex members are common in human cancer, yet their contribution to tumorigenesis remains in many cases poorly understood. Here, we studied derailed regulatory landscapes as a consequence ofSMARCB1loss in the context of MRT. Our multi-omics approach on patient-derived MRT organoids revealed a dramatic reshaping of the regulatory landscape uponSMARCB1reconstitution. Chromosome conformation capture experiments subsequently revealed patient-specific looping of distal enhancer regions with the promoter of theMYConcogene. This intertumoral heterogeneity inMYCenhancer utilization is also present in patient MRT tissues as shown by combined single-cell RNA-seq and ATAC-seq. We show that loss ofSMARCB1drives patient-specific epigenetic reprogramming underlying MRT tumorigenesis.
Flow cytometry-based biomarker assay forin vitroidentification of heat tolerance conferring coral symbionts
Authors: Buerger Patrick , Buler Marcin , Yeap Heng Lin , Edwards Owain R , van Oppen Madeleine JH , Oakeshott John G , Court Leon
Published: November 2022

Corals’ tolerance to high temperature stress largely depends on their symbiotic microalgae (Symbiodiniaceae). However, the contributing microalgal traits are largely unclear. Here we compare thein vitrocellular profiles of sevenCladocopium C1acromicroalgal strains (derived from the same ancestral strain) during a four-week exposure to 27°C or 31°C. One was an unselected wild-type strain (WT), three were selected at 31°C for nine years and shown to confer thermal tolerance on the coral host (SS+) and three others were similarly selected but did not confer tolerance (SS-). Flow cytometry was used to measure the intracellular stress indicators reactive oxygen species (ROS), reduced glutathione (rGSH) and mitochondrial-membrane potential (ΔΨm), as well as cell size/shape and photosynthetic pigments. Cell densities and photosynthetic efficiency (ΦPSII, Fv/Fm) were also measured. WT showed the highest levels of intracellular ROS and ΔΨm, lowest rGSH and largest cell sizes at both temperatures. SS+ strains had the lowest ROS and highest rGSH values and a unique pattern of correlations among parameters at 31°C. Our results support previous reports implicating the role of microalgal ROS, ΔΨm and rGSH in holobiont thermal tolerance and suggest flow cytometry is a useful pre-screening tool for identifying microalgal strains with enhanced thermal tolerance.
An SNF2 helicase-like protein links mitotic transcription termination to sister chromatid resolution
Authors: Carmo Catarina , Coelho João , Silva Rui , Tavares Alexandra , Boavida Ana , Gaetani Paola , Martinho Rui Gonçalo , Oliveira Raquel A.
Published: November 2022

Abstract

Mitotic chromatin is largely assumed incompatible with transcription due to changes in the transcription machinery and chromosome architecture. However, the mechanisms of mitotic transcriptional inactivation and their interplay with chromosome assembly remain largely unknown. By monitoring ongoing transcription inDrosophilaearly embryos, we reveal that eviction of nascent mRNAs from mitotic chromatin occurs after substantial chromosome compaction and is not promoted by condensin I. Instead, we show that the timely removal of transcripts from mitotic chromatin is driven by the SNF2 helicase-like protein Lodestar (Lds), identified here as a modulator of sister chromatid cohesion defects. In addition to transcriptional termination, we uncovered that Lds cooperates with Topoisomerase 2 to ensure efficient sister chromatid resolution and mitotic fidelity. We conclude that mitotic transcriptional termination is not a passive consequence of cell cycle progression and/or chromosome compaction but occurs via dedicated mechanisms with functional parallelisms to sister chromatid resolution.
Curli amyloid fibers inEscherichia colibiofilms: the influence of water availability on their structure and functional properties
Authors: Siri Macarena , Mangiarotti Agustín , Vázquez-Dávila Mónica , Bidan Cécile M.
Published: November 2022

E. colibiofilms consist of bacteria embedded in a self-produced matrix mainly made of protein fibers and polysaccharides. The curli amyloid fibers found in the biofilm matrix are promising versatile building blocks to design sustainable bio-sourced materials. To exploit this potential, it is crucial to understand i) how environmental cues during biofilm growth influence the molecular structure of these amyloid fibers, and ii) how this translates at higher length scales. To explore these questions, we studied the effect of water availability during biofilm growth on the conformation and functions of curli. We used microscopy and spectroscopy to characterize the amyloid fibers purified from biofilms grown on nutritive substrates with different water contents, and micro-indentation to measure the rigidity of the respective biofilms. The purified curli amyloid fibers present differences in the yield, structure and functional properties upon biofilm growth conditions. Fiber packing and β-sheets content correlate with their hydrophobicity and chemical stability, and with the rigidity of the biofilms. Our study highlights howE. colibiofilm growth conditions impact curli structure and functions contributing to macroscopic materials properties. These fundamental findings infer an alternative strategy to tune curli structure, which will ultimately benefit to engineer hierarchical and functional curli-based materials.

Graphical Abstract
Nirmatrelvir treatment blunts the development of antiviral adaptive immune responses in SARS-CoV-2 infected mice
Authors: Fumagalli Valeria , Di Lucia Pietro , Ravà Micol , Marotta Davide , Bono Elisa , Grassi Stefano , Donnici Lorena , Cannalire Rolando , Stefanelli Irina , Ferraro Anastasia , Esposito Francesca , Pariani Elena , Inverso Donato , Montesano Camilla , Delbue Serena , Tramontano Enzo , De Francesco Raffaele , Summa Vincenzo , Guidotti Luca G. , Iannacone Matteo
Published: November 2022

Alongside vaccines, antiviral drugs are becoming an integral part of our response to the SARS-CoV-2 pandemic. Nirmatrelvir – an orally available inhibitor of the 3-chymotrypsin-like cysteine protease – has been shown to reduce the risk of progression to severe COVID-19. However, the impact of nirmatrelvir treatment on the development of SARS-CoV-2-specific adaptive immune responses is unknown. Here, by using a mouse model of SARS-CoV-2 infection, we show that nirmatrelvir administration early after infection blunts the development of SARS-CoV-2-specific antibody and T cell responses. Accordingly, upon secondary challenge, nirmatrelvir-treated mice recruited significantly fewer memory T and B cells to the infected lungs and to mediastinal lymph nodes, respectively. Together, the data highlight a potential negative impact of nirmatrelvir treatment with important implications for clinical management and might help explain the virological and/or symptomatic relapse after treatment completion reported in some individuals.
The determinants of profitability in non-financial UK SMEs
Authors: Youssef Iman S. , Salloum Charbel , Al Sayah Maher
Published: November 2022

Purpose

The purpose of this study is to examine determinants of profitability of non-financial firms listed small- and medium-sized enterprises (SMEs) in the UK from 2012 till 2020. It has been argued that profitability plays a key role in economic development and growth. Despite the important role that SMEs play in developed economies like UK, academic research into SMEs profitability determinants in developed countries is not extensive.

Design/methodology/approach

The methodologies used include dynamic panel data estimation techniques. Relationship of nine independent variables with profitability was examined. Two models are created using return on assets (ROA) and return on equity (ROE) as dependent variables. Size, age, efficiency, working capital, liquidity, leverage and volatility of the firm represent firm-specific independent variables. Two macroeconomic variables, namely, gross domestic product and inflation are also used as independent variables. Data obtained from Thomson Reuters Data Stream for 93 listed SMEs companies in the UK from 2012 to 2020. Fixed effects, random effects and generalized method of moments were used in data analysis.

Findings

All variables showed significant influence on profitability, except liquidity reflecting insignificant impact on profitability in two regression models conducted for 93 firms under study. Efficiency, liquidity and leverage are the only three independent variables with similar impact on both ROA and ROE.

Practical implications

Identifying determinants of profitability will help stakeholders and corporate executive make sound decisions to ensure sustainability and stability at the firm level. This is particularly important given the key role played by SMEs in economic development and growth. The findings of this study would help direct financial management practices to ensure a favorable sustainable organizational performance.

Originality/value

This study differs from previous studies that focused mainly on developing countries; with limited research conducted on profitability of SMEs in developed economies. To the best of the author’s knowledge, this is the first study to examine factors influencing profitability of SMEs in UK. Previous studies concentrated on service sector like insurance and hotel firms.
An investigation of how stakeholders influence construction project performance: a small and medium sized contractor’s perspective in the Jordanian construction industry
Authors: Alkilani Suhair , Loosemore Martin
Published: November 2022

Purpose

This research uses contingency theory and Venkatraman’s concept of moderating fit to explore how key project stakeholders (clients, consultants and suppliers) influence project performance from the perspective of small and medium contractors in the Jordanian construction industry.

Design/methodology/approach

An anonymous structured survey was performed comprising 200 key informants including senior project managers, construction managers, engineers and general managers working for small- and medium-sized contractors in the Jordanian construction industry. The Partial Least Squares Structural Equation Modelling (PLS-SEM) was used to analyse the data.

Findings

The results of this study show that consultant-related factors (quality of documentation produced, ability to communicate and technical competencies) are perceived to have the most significant direct effect on project performance, followed by client-related factors (payment promptness, decision certainty and documentation control) and supplier-related factors (supplier performance, defects control and logistics management).

Originality/value

The results contribute new theoretical, empirical and practical insights to existing construction project performance research by highlighting the key performance factors which need to be managed for each stakeholder group to ensure effective project performance from a small- and medium-sized contractor perspective.