bluuebunny/crossref_metadata_2025 huggingface dataset:
Limited evidence of spill over of antimicrobial resistantKlebsiella pneumoniaefrom animal/environmental reservoirs to humans in India
Authors: Jacob Jobin John , V Aravind , Beresford-Jones Benjamin S. , Y Binesh Lal , Shankar Chaitra , M Yesudoss , Abdullah Fiza , Priya T Monisha , Kulkarni Sanika , Baker Stephen , Veeraraghavan Balaji , Walia Kamini
Published: March 2024

Background

Klebsiella pneumoniaeis a common opportunistic pathogen known for having virulent and antimicrobial resistance (AMR) phenotypes. In addition to accumulating AMR and virulence genes,K. pneumoniaeserves as a vehicle for broadly disseminating these elements into other species. Here, we applied genomic surveillance in a one-health framework to assess the impact of the human-animal-environment interface on AMR transmission.

Methods

We sequenced representative genomes ofKlebsiella pneumoniaeisolated from clinical specimens (n=59), livestock samples (n=71), and hospital sewage samples (n=16) from a two-year surveillance study. We compared the taxonomic and genomic distribution ofK. pneumoniae, the abundance of AMR, virulence genes, and mobile genetic elements between isolates from three sources.

Results

Klebsiellaspp. was the second most commonly isolated species (n=2,569). The clonal distribution ofK. pneumoniaesuggested isolates originating from livestock were clonally distinct from those derived from clinical/hospital effluent isolates. Clinical and hospital sewage isolates typically carried a higher number of resistance/virulence genes. There was limited overlap ofK. pneumoniaeclones, AMR genes, virulence determinants, and plasmids between the different settings.

Conclusion

Currently, the spread of XDR or hypervirulent clones ofK. pneumoniaeappears to be confined to humans with no clear linkage with non-clinical sources. Moreover, emerging convergent clones ofK. pneumoniaecarrying both resistance and virulence determinants (ST231, ST2096) are likely to have emerged in hospital settings rather than in animal or natural environments. These data challenge the current view of AMR transmission inK. pneumoniaein a One-Health context.
Tethering NDC80-NUF2 to microparticles is sufficient to enable their biorientation in the spindle
Authors: Asai Kohei , Zhou Yuanzhuo , Kitajima Tomoya S.
Published: March 2024

Faithful chromosome segregation requires biorientation, where the pair of kinetochores on the chromosome establish bipolar microtubule attachment. The integrity of the kinetochore, a macromolecular complex built on centromeric DNA, is required for biorientation, but components sufficient for biorientation remain unknown. In this study, we show that tethering the outer kinetochore heterodimer NDC80-NUF2 to the surface of microbeads with no bipolar cue is sufficient for them to establish a biorientation-like state in mouse oocytes. NDC80-NUF2 microbeads efficiently and stably align at the spindle equator, forming bipolar microtubule attachments. Furthermore, they can self-correct alignment errors. They align independently of the outer kinetochore proteins SPC24-SPC25, KNL1, the MIS12 complex, or inner kinetochore proteins. Aurora-mediated NDC80 phosphoregulation promoted microbead alignment under challenging conditions. Interestingly, larger microbeads align more rapidly, suggesting that large platform size enhances NDC80-NUF2-mediated biorientation. This study shows a biohybrid kinetochore design for synthetic biorientation of microscale particles in cells.
Deletion of Nrf1 exacerbates oxidative stress-induced cellular senescence by disrupting the cell homeostasis
Authors: Lyu Da , Wang Meng , Qiu Lu , Hu Shaofan , Zhang Yiguo
Published: March 2024

Cellular senescence has been accepted as a fundamental contributor to ageing and a variety of age-related diseases, in which oxidative stress has been further recognized to play a critical initiation role. However, the anti-senescence potential of antioxidant nuclear factor erythroid-derived 2-like 1 (Nrf1, encoded byNfe2l1) remains elusive to date, even though the hitherto accumulating evidence demonstrates that it is an indispensable redox-determining transcription factor for maintaining cellular homeostasis and organ integrity. Herein, we discovered that deletion of Nrf1 resulted in markedly elevated senescence characteristics inNrf1α−/−cells, as characterized by two distinct experimental models induced by oxidative stress, which are evinced by typically heightened activity of senescence-associated β-galactosidase and progressive senescence-associated secretory phenotype (SASP), along with decreased cell vitality and intensified cell cycle arrest. Further experimental investigation also uncovered that such acceleration of oxidative stress-induced senescence resulted from heightened disturbance in the cellular homeostasis, because deficiency of Nrf1α leads to the STAG2- and SMC3-dependent chromosomal stability disruption and autophagy dysfunction, though as accompanied by excessive accumulation of Nrf2 (encoded byNfe2l2). The aberrant hyperactive Nrf2 cannot effectively counteract the escalating disturbance of cellular homeostasis caused byNrf1α−/−. Overall, this study has provided a series of evidence supporting that Nrf1 indeed exerts an essential protective function against oxidative stress-induced cellular senescence, thereby, highlighting its primary indispensable contribution to maintaining robust cell homeostasis.
Sex-specific viability effects of mutations inDrosophila melanogaster
Authors: Melde Robert H. , Abraham JoHanna M. , Ugolini Maryn R. , Castle Madison P. , Fjalstad Molly M. , Blumstein Daniela M. , Sharp Nathaniel P.
Published: March 2024

In populations with separate sexes, genetic load due to deleterious mutations may be expressed differently in males and females. Evidence from insect models suggests that selection against mutations is stronger in males, with a positive intersexual correlation for fitness. This pattern will reduce deleterious allele frequencies at the expense of males, such that female mean fitness is greater than expected, preserving population persistence in the face of high mutation rates. While previous studies focus on reproductive success, mutation load depends on total selection in each sex, including selection for viability. In fruit flies, we might expect minimal sex differences in viability effects, since male and female larvae behave similarly, but many genes show sex-biased expression in larvae. We measured the sex-specific viability effects of nine “marker” mutations and 33 mutagenized chromosomes. We find that both types of mutations generally reduce viability in both sexes. Among marker mutations we detect instances of sex biased selection in both directions, but mutagenized chromosomes show little sign of sex-specific mutational variance. We conclude that some mutations can indeed affect viability in a sex-specific manner, but that the pattern of male-biased mutational effects observed previously for reproductive success is not apparent at the pre-reproductive stage.
Evaluating the feasibility of study methods for a future trial-based economic evaluation of a multistage shared decision-making program for type 2 diabetes mellitus: protocol for a cluster-randomized controlled pilot study
Authors: Tichler A. , Hertroijs D.F.L. , van Mastrigt G.A.P.G. , Brouwers M.C.G.J. , Ruwaard D. , Elissen A.M.J.
Published: March 2024

Introduction

We developed a multistage shared decision-making program for type 2 diabetes that aims to support person-centered type 2 diabetes management in primary care. The program consists of an online patient decision aid, a preparatory consult for patients, and interprofessional training for healthcare professionals. The short– and long-term effectiveness of the multistage shared decision-making program needs to be researched in a trial-based economic evaluation. To evaluate the feasibility of study methods for future economic evaluation, we will conduct a pilot study that focuses on sample recruitment and retention, study management, and feasibility of outcome and cost measurements.

Methods and analysis

The multistage shared decision-making program will be pilot-tested in a cluster-randomized controlled trial in four primary care practices (located in the region of Gorinchem, the Netherlands) using a mixed-methods approach. The intervention practices will adopt the program, whereas the control practices provide usual care. Data collection will include recruitment, retention, and consent rates, patients’ sociodemographic and clinical characteristics, and the assessment of primary and secondary outcomes of the future trial-based economic evaluation. We will also collect data on the usage behavior of patients when completing questionnaires of the primary and secondary outcomes (i.e. time needed to complete questionnaires). Semi-structured interviews with patients will be conducted to obtain insights into the understandability and usability of measurement tools. Moreover, focus groups with healthcare professionals from participating practices will be organized to complement the quantitative data on sample representativeness and to assess the study management challenges of participating practices.

Discussion

The pilot will address uncertainties around the feasibility of a future trial-based economic evaluation, focusing on sample recruitment and retention, study management, and the feasibility of outcome and cost measurements. The results will guide the improvement of study procedures for the economic evaluation of our multistage shared decision-making program for type 2 diabetes.
The association between prolonged SARS-CoV-2 symptoms and work outcomes
Authors: Venkatesh Arjun , Yu Huihui , Malicki Caitlin , Gottlieb Michael , Elmore Joann G. , Hill Mandy J. , Idris Ahamed H. , Montoy Juan Carlos C. , O’Laughlin Kelli N. , Rising Kristin L. , Stephens Kari A. , Spatz Erica S. , Weinstein Robert A. ,   the INSPIRE Group
Published: March 2024

While the early effects of the COVID-19 pandemic on the United States labor market are well-established, less is known about the long-term impact of SARS-CoV-2 infection and Long COVID on employment. To address this gap, we analyzed self-reported data from a prospective, national cohort study to estimate the effects of SARS-CoV-2 symptoms at three months post-infection on missed workdays and return to work. The analysis included 2,939 adults in the Innovative Support for Patients with SARS-CoV-2 Infections Registry (INSPIRE) study who tested positive for their initial SARS-CoV-2 infection at the time of enrollment, were employed before the pandemic, and completed a baseline and three-month electronic survey. At three months post-infection, 40.8% of participants reported at least one SARS-CoV-2 symptom and 9.6% of participants reported five or more SARS-CoV-2 symptoms. When asked about missed work due to their SARS-CoV-2 infection at three months, 7.1% of participants reported missing ≥10 workdays and 13.9% of participants reported not returning to work since their infection. At three months, participants with ≥5 symptoms had a higher adjusted odds ratio (aOR) of missing ≥10 workdays (2.96, 95% CI 1.81-4.83) and not returning to work (2.44, 95% CI 1.58-3.76) compared to those with no symptoms. Prolonged SARS-CoV-2 symptoms were common, affecting 4-in-10 participants at three-months post-infection, and were associated with increased odds of work loss, most pronounced among adults with ≥5 symptoms at three months. Despite the end of the Federal COVID-19 Public Health Emergency and efforts to “return to normal”, policymakers must consider the clinical and economic implications of the COVID-19 pandemic on people’s employment status and work absenteeism, particularly as data characterizing the numerous health and well-being impacts of Long COVID continue to emerge. Improved understanding of risk factors for lost work time may guide efforts to support people in returning to work.
A fungal transcription factorBOT6facilitates the transition of a beneficial root fungus into an adapted anthracnose pathogen
Authors: Ujimatsu Ren , Takino Junya , Nakamura Masami , Haba Hiromi , Minami Atsushi , Hiruma Kei
Published: March 2024

The infection strategies employed by plant endophytes are attributed to their ability to overcome durable nonhost resistance and adapt to the host environment. However, the regulatory genetic background underlying how they adapt to the host and determine their lifestyles remains enigmatic. Here, we show that theCtBOT6, a cluster-residing transcription factor in the root-associated fungusColletotrichum tofieldiae(Ct), plays a pivotal role in regulating virulence-related gene expression and in producing metabolites both not only within and but unexpectedly outside of the cluster. Genetic manipulation ofCtBOT6toward activation alone is sufficient to transition a root beneficial Ct along the mutualist-pathogen continuum even toward a leaf pathogen capable of overcoming nonhost resistance, partly dependent on the host abscisic acid and ethylene pathways. Our findings indicate that the status of CtBOT6 serves as a critical determinant for the endophytic fungus to adapt to the plant different environments and manifest diverse infection strategies.
Metabolomic analysis of the effect of endocannabinoid metabolism inhibition in ovalbumin-induced allergic airway inflammation in Guinea pigs
Authors: Abohalaka Reshed , Karaman Yasemin , Recber Tuba , Onder Sevgen Celik , Nemutlu Emirhan , Bozkurt Turgut Emrah
Published: March 2024

Background and aims

Asthma manifests as a multifaceted airway inflammation. The therapeutic potential of targeting endocannabinoids in mitigating asthma remains incompletely elucidated. Therefore, we aim to scrutinize metabolic alterations, deepen our comprehension of the endocannabinoids’ therapeutic role, and discern novel biomarkers for monitoring allergic airway inflammation.

Methods

Guinea pigs were sensitized with ovalbumin (150μg) or PBS on days 1, 4, and 7. On day 14, they were exposed to aerosols containing 0.3% ovalbumin or PBS. Treatment groups were administered inhibitors of fatty acid amide hydrolase (FAAH) and/or monoacylglycerol lipase (MAGL) one hour prior to aerosol exposure. Subsequently, bronchoalveolar lavage (BAL), blood, and lung samples were collected on the following day for analysis using GC-MS. Metabolites were meticulously categorized into 10 distinct classifications based on their chemical and biological functions. Subsequently, they were further organized into 5 principal metabolic pathways for a comprehensive metabolomic analysis.

Results

Ovalbumin exposure exclusively altered the metabolic profile in the lung. Conversely, inhibition of endocannabinoids metabolism induced a systemic shift in energy metabolites such as carbohydrates, amino and fatty acids.

Conclusions

Allergen exposure induced an elevation in metabolites associated with glycolytic metabolism particularly in the lungs, indicating enhanced activation and increased numbers of immune cells. Notably, inhibition of endocannabinoids mitigated these shifts, underscoring its anti-inflammatory efficacy.
Enhanced Place Specificity of the Parallel Auditory Brainstem Response: An Electrophysiological Study
Authors: Stoll Thomas J , Maddox Ross K
Published: March 2024

Purpose

This study investigates the effect of parallel stimulus presentation on the place specificity of the auditory brainstem response (ABR) in human listeners. Frequency-specific stimuli do not guarantee a response from the place on the cochlea corresponding only to that characteristic frequency – especially for brief and high-level stimuli. Adding masking noise yields responses that are more place specific, and a prior modeling study has suggested similar effects when multiple frequency-specific stimuli are presented in parallel. We tested this hypothesis experimentally here, comparing the place specificity of responses to serial and parallel stimuli at two stimulus frequencies and three stimulus rates.

Methods

Parallel ABR (pABR) stimuli were presented alongside high-pass filtered noise with a varied cutoff frequency. Serial presentation was also tested by isolating and presenting single-frequency stimulus trains from the pABR ensemble. Latencies of the ABRs were examined to assess place specificity of responses. Response bands were derived by subtracting responses from different high pass noise conditions. The response amplitude from each derived response band was then used to determine how much individual frequency regions of the auditory system were contributing to the overall response.

Results

We found that parallel presentation improves place specificity of ABRs for the lower stimulus frequency and at higher stimulus rates. At a higher stimulus frequency, serial and parallel presentation were equally place specific.

Conclusion

Parallel presentation can provide more place specific responses than serial for lower stimulus frequencies. The improvement increases with higher stimulus rates and is in addition to the pABR’s primary benefit of faster test times.
Lower limb joint Loading during high-impact activities: implication for bone health
Authors: Altai Zainab , Hayford Claude Fiifi , Phillips Andrew , Moran Jason , Zhai Xiaojun , Liew Bernard X.W.
Published: March 2024

Osteoporosis, a significant concern among the elderly, results in low-trauma fractures affecting millions globally. Despite the inclusion of physical activities in strategies to mitigate osteoporosis-related fractures, the optimal exercises for bone health remain uncertain. Determining exercises that enhance bone mass requires an understanding of loading on lower limb joints. This study investigates hip, knee, and ankle joint loading during walking, running, jumping, and hopping exercises, assessing impacts at various intensities (maximal, medium, and minimum efforts).

A total of 37 healthy, active participants were recruited, with a mean (SD) age of 40.3 (13.1) years, height of 1.7 (0.08) m, and mass of 68.4 (11.7) kg. Motion capture data were collected for each participant while performing six different exercises: a self-selected level of walking, running, counter-movement jump, squat jump, unilateral hopping, and bilateral hopping. A lower body musculoskeletal model was developed for each participant in OpenSim. The static optimization method was used to calculate muscle forces and hip joint contact forces.

The study reveals that running and hopping induce increased joint contact forces compared to walking, with increments of 83% and 21%, respectively, at the hip; 134% and 94%, respectively, at the knee; and 94% and 77%, respectively, at the ankle. Jump exercises exhibit less hip and ankle loading compared to walking, with reductions of 36% and 19%, respectively. Joint loading varies across exercises and intensities, running faster increases forces on all joints, especially the hip. Sprinting raises hip forces but lowers forces on the knee and ankle. Higher jumps intensify forces on the hip, knee, and ankle, whereas hopping faster reduces forces on all joints.

The study emphasizes the site-specific impact of exercises on lower limb joint loadings, highlighting the potential of running and hopping for bone formation compared to jumping alone. These findings offer insights for optimizing exercise routines to improve bone health, with potential implications for risk prevention, rehabilitation, and prosthetic development.
Real World Predictors of Response and 24-month survival in high-grade TP53-mutated Myeloid Neoplasms
Authors: Kaur Amandeep , Rojek Alexandra , Symes Emily , Patel Anand A , Nawas Mariam T , Patel Jay L , Sojitra Payal M , Aquil Barina , Sukhanova Madina , Mcnerney Megan E , Wu Leo , Akmatbekov Aibek , Segal Jeremy , Tjota Melissa , Gurbuxani Sandeep , Cheng Jason X. , Yeon Su-Yeon , Ravisankar Harini V. , Fitzpatrick Carrie , Lager Angela , Drazer Michael W. , Saygin Caner , Wanjari Pankhuri , Katsonis Panagiotis , Lichtarge Olivier , Churpek Jane E. , Ghosh Sharmila B. , Patel Ami B. , Menon Madhu P. , Arber Daniel A. , Wang Peng , Venkataraman Girish
Published: March 2024

Current therapies for high-grade TP53-mutated myeloid neoplasms (≥ 10% blasts) do not offer a meaningful survival benefit except allogeneic stem cell transplantation in the minority who achieve a complete response to first line therapy (CR1). To identify reliable pre-therapy predictors of response and outcomes, we assembled a cohort of 234 individuals with well-annotated clinical, molecular and pathology data, evaluating CR1 & 24-month survival (OS24). In this elderly cohort (median age 68.0 years) with 73.4% receiving frontline non-intensive regimens (hypomethylating agents with or without venetoclax), we identified several novel factors predictive of inferior CR1 including male gender (P = .019), ≥ 2 autosomal monosomies (P < .001), -17/17p (P = .008), multi-hit TP53 allelic state (P < .001) and CUX1 alterations (P = .009). Inferior OS24 was predicated by ≥ 2 monosomies (P = .004), TP53 VAF>25% (P < .001), and TP53 splice junction mutations (P = .007). In addition, mutations/deletions in any of six genes including CUX1, U2AF1, epigenetic regulators (EZH2, TET2), or RAS pathway genes (CBL, KRAS) (termed 'EPI6' signature) predicted inferior OS24 (HR = 2.0 [1.5-2.8]; P < .0001). A risk score incorporating these accessible binary factors in a multivariable model stratified 3 prognostic distinct groups: favorable, intermediate, and poor with significantly different median (15.4, 9.2, 3.5 months) and 24-month (48.4%, 14.3%, 0.5%) survival (OS24) (P < .0001). For the first time, in a seemingly monolithic high-risk cohort, our data provides means to tease out small subgroups at baseline with superior or very poor outcomes.
MuViSS : Muscle, Visceral and Subcutaneous Segmentation by an automatic evaluation method using Deep Learning
Authors: Wasielewski Edouard , Boudjema Karim , Sulpice Laurent , Pecot Thierry
Published: March 2024

Purpose

Patient body composition is a major factor in patient management. Indeed, assessment of SMI as well as VFA and, to a lesser extent, SFA is a major factor in patient survival, particularly in surgery. However, to date, there is no simple, rapid, open-access assessment method. The aim of this work is to provide a simple, rapid and accurate tool for assessing patients’ body composition.

Material and methods

A total of 343 patients underwent liver transplantation at the University Hospital of Rennes between January 1st, 2012 and December 31s, 2018. Image analysis was performed using the open source software ImageJ. Tissue distinction was based on Hounsfield density. The training dataset used 332 images (320 for training and 12 for validation). The model was evaluated on 11 patients. The complete software and video package is available athttps://github.com/tpecot/MuViSS.

Results

In total, the model was trained with 332 images and evaluated on 11 images. Model accuracy is 0.974 (SD 0.003), Jaccard’s index is 0.98 for visceral fat, 0.895 for muscle and 0.94 for subcutaneous fat. The Dice index is 0.958 (SD 0.003) for visceral fat, 0.944 (SD: 0.012) for muscle and 0.970 (SD: 0.013) for subcutaneous fat. Finally, the Normalized root mean square error is 0.007 for visceral fat, 0.0518 for muscle and 0.0124 for subcutaneous fat.

Conclusion

To our knowledge, this is the first freely available model for assessing body composition. The model is fast, simple and accurate, based on Deep Learning.

Statements and declarations

All authors declare no conflict of interest
What do we have here? A Systematic Review of Mental Health Policy in Colombia
Authors: Juan Norha Vera San , Garavito German Alarcón , Gort Monica Gonzalez , Sanguinetti Maria Cecilia Dedios , Burgess Rochelle , Lucumí Diego
Published: March 2024

Background

Colombia’s mental health policy is currently under the spotlight due to the global call of prioritising mental health services quality and innovation and the Colombian vision of having an articulated mental health system based on inclusion and community participation. Despite the interest in this topic and proliferation of policy documents, there is no clarity around mental health concepts underlying the compendium of mental health policies, plans and legislation, which are crucial for successful development and implementation of public mental health.

Method

This study is a novel Systematic Collaborative Policy Review which includes a structured approach to identifying and synthesising relevant institutional documents, alongside a realist approach including consultations with experts throughout the review process to increase the applicability of results.

Results

295 records were screened at title and main content stage, 66 were assessed in full text and 46 were included in this review. Most documents identified were created by the Ministry of Health, the Unit for the Attention and Integral Reparation to the Victims, and regional governments.

We found Colombian institutional documents had a holistic understanding of mental health, including considerations around the importance of prevention through the creation of healthy protective environments, as well as protecting right to receive a diagnosis, treatment and rehabilitation for people who require mental health care. There was a strong focus on childhood wellbeing and addressing issues related to illegal drug use. Numerous preventive programmes were listed such as specific programmes for LGTB+ and indigenous communities.

Conclusion

Colombia has a strong mental health legal and programmatic baseline, with ample coverage of aspects ranging from prevention and promotion to quality treatment. However, the extent to which these plans are implemented is unclear. There is a need for clear implementation paths to be included in policy plans, and identification of measurable outputs to monitor success.
Subcellular mRNA kinetic modeling reveals nuclear retention as rate-limiting
Authors: Steinbrecht David , Minia Igor , Milek Miha , Meisig Johannes , Blüthgen Nils , Landthaler Markus
Published: March 2024

Eukaryotic mRNAs are transcribed, processed, translated, and degraded in different subcellular compartments. Here, we measured mRNA flow rates between subcellular compartments in mouse embryonic stem cells. By combining metabolic RNA labeling, biochemical fractionation, mRNA sequencing, and mathematical modeling, we determined the half-lives of nuclear pre-, nuclear mature, cytosolic, and membrane-associated mRNAs from over 9000 genes. In addition, we estimated transcript elongation rates. Many matured mRNAs have long nuclear half-lives, indicating nuclear retention as the rate-limiting step in the flow of mRNAs. In contrast, mRNA transcripts coding for transcription factors show fast kinetic rates, and in particular short nuclear half-lives. Differentially localized mRNAs have distinct rate constant combinations, implying modular regulation. Membrane stability is high for membrane-localized mRNA and cytosolic stability is high for cytosol-localized mRNA. mRNAs encoding target signals for membranes have low cytosolic and high membrane half-lives with minor differences between signals. Transcripts of nuclear-encoded mitochondrial proteins have long nuclear retention and cytoplasmic kinetics that do not reflect co-translational targeting. Our data and analyses provide a useful resource to study spatiotemporal gene expression regulation.
Spatial distribution of poultry farms using point pattern modelling: a method to address livestock environmental impacts and disease transmission risks
Authors: Dupas Marie-Cécile , Pinotti Francesco , Joshi Chaitanya , Joshi Madhvi , Blake Damer , Tomley Fiona , Gilbert Marius , Fournie Guillaume
Published: March 2024

The distribution of farm locations and sizes is paramount to characterize patterns of disease spread. With some regions undergoing rapid intensification of livestock production, resulting in increased clustering of farms in peri-urban areas, measuring changes in the spatial distribution of farms is crucial to design effective interventions. However, those data are not available in many countries, their generation being resource-consuming. Here, we develop a farm distribution model (FDM), which allows the prediction of locations and sizes of poultry farms in countries with scarce data. The model combines (i) a Log-Gaussian Cox process model to simulate the farm distribution as a spatial Poisson point process, and (ii) a random forest model to simulate farm sizes (i.e. the number of animals per farm). Spatial predictors were used to calibrate the FDM on intensive broiler and layer farm distributions in Bangladesh, Gujarat (Indian state) and Thailand. We found that the FDM yielded realistic farm distributions in terms of spatial clustering, farm locations and sizes, while providing insights on the factors influencing these distributions. Finally, we illustrate the relevance of modelling realistic farm distributions in the context of epidemic spread by simulating pathogen transmission on an array of spatial distributions of farms. We found that farm distributions generated from the FDM yielded spreading patterns consistent with simulations using observed data, while random point patterns underestimated vulnerability to epidemics. Indeed, spatial clustering increases vulnerability to epidemics, highlighting the relevance of spatial clustering and farm sizes to study epidemic spread. As the FDM maintains a realistic distribution of farms and their size, its use to inform mathematical models of disease transmission is very relevant for regions where these data are not available.
Environmental similarity between relatives reduces heritability of reproductive timing in wild great tits
Authors: Jones Carys V. , Regan Charlotte E. , Firth Josh A. , Cole Eleanor F. , Sheldon Ben C.
Published: March 2024

Intraspecific variation is necessary for evolutionary change and population resilience, but the extent to which it contributes to either depends on the causes of this variation. Understanding the causes of individual variation in traits involved with reproductive timing is important in the face of environmental change, especially in systems where reproduction must coincide with seasonal resource availability. However, separating the genetic and environmental causes of variation is not straightforward, and there has been limited consideration of how small-scale environmental effects might lead to similarities between individuals that occupy similar environments, potentially biasing estimates of genetic heritability. In ecological systems, environments can often be complex in their spatial structure, and it may therefore be important to account for similarities in the environments experienced by individuals within a population beyond considering spatial distances alone. Here, we construct multi-matrix quantitative genetic animal models using over 11,000 breeding records (spanning 35 generations) of individually-marked great tits (Parus major) and information about breeding proximity and habitat characteristics to quantify the drivers of variability in two key seasonal reproductive timing traits. We show that the environment experienced by related individuals explains around a fifth of the variation seen in reproductive timing, and accounting for this leads to decreased estimates of heritability. Our results thus demonstrate that environmental sharing between relatives can strongly affect estimates of heritability and therefore alter our expectations of the evolutionary response to selection.
Multiomics Analysis Reveals Extensive Remodeling of the Extracellular Matrix and Cellular Metabolism Due to Plakophilin-2 Knockdown in Guinea Pigs
Authors: Song Rui , Wu Haiyan , Yu Lihui , Yu Jingning , Yang WenHui , Wu WenJun , Sun Fei , Wang Haizhen
Published: March 2024

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a leading cause of sudden cardiac death (SCD) in young individuals, yet the mechanisms underlying its pathogenesis, particularly the role of plakophilin-2 (PKP2), remain incompletely understood. This study aimed to elucidate the profile of molecular and metabolic consequences of PKP2 knockdown in a guinea pig model of ARVC. We employed adeno-associated virus serotype 9 (AAV9) to deliver PKP2 shRNA, establishing a model that recapitulates key features of human ARVC, including right ventricular (RV) enlargement, sudden death, and cardiac lipid accumulation. Proteomic analysis revealed significant dysregulation of extracellular matrix (ECM) proteins, PI3K-Akt signaling, and energy metabolism in PKP2-deficient RVs. Metabolomic profiling further highlighted alterations in lipid metabolism and inter-metabolites of TCA cycle, with a notable shift towards fatty acid oxidation. These findings suggest that PKP2 deficiency triggers a cascade of molecular events leading to ECM remodeling, metabolic reconfiguration, and potential mitochondrial dysfunction, which may contribute to the development of ARVC. Our study provides novel insights into the early molecular mechanisms of ARVC and identifies potential therapeutic targets for this underexplored disease.
Chemoproteomic profiling of serine hydrolases reveals the dynamic role of lipases inPhaeodactylum tricornutum
Authors: Dolui Achintya Kumar , Yaakov Beery , Jasinska Weronika , Barak Simon , Brotman Yariv , Khozin-Goldberg Inna
Published: March 2024

Phaeodactylum tricornutumis a model oleaginous pennate diatom, widely investigated for the accumulation of triacylglycerols (TAG) in lipid droplets during nitrogen (N) starvation. However, lipid droplet breakdown, TAG catabolism, and remobilization upon N replenishment during growth restoration are less studied. Serine hydrolases (SH) constitute a diverse family encompassing proteases, amidases, esterases, and lipases. In this report, we adopted a chemoproteomic approach called Activity-Based Protein Profiling (ABPP) to explore the repertoire of active serine hydrolases to elucidate the mechanisms of lipid metabolism inP. tricornutum(strain Pt4). A superfamily-wide profile of serine hydrolases revealed a differentially active proteome (activome) during N starvation and after nutrient replenishment. We report 30 active serine hydrolases, which were broadly categorized into metabolic serine hydrolases and serine proteases. Lipases appeared to be the major metabolic linchpins prevalent during lipid remobilization. Global transcriptomics analysis provided a complementary insight into the gene expression level of the detected serine hydrolases. It revealed putative phospholipases as central players in membrane lipid turnover and remodeling involved in cellular lipid homeostasis and TAG accumulation. TAG remobilization and lipid droplet breakdown were impaired in the presence of phenyl mercuric acetate (PMA), whose activity as an SH inhibitor was validated by competitive ABPP. Lipid species profiling corroborated the impairment in TAG degradation and the buildup of structural lipids in the presence of PMA after nutrient replenishment. Collectively, our functional proteome approach, coupled with the transcriptome and lipidome data, provides a comprehensive landscape ofbona fideactive serine hydrolases, including lipases in this model diatom.
NEMO: Improved and accurate models for identification of 6mA using Nanopore sequencing
Authors: Kulkarni Onkar , Zaveri Lamuk , Mathew Reuben Jacob , Singh Nitesh Kumar , Ara Sreenivas , Garde Shambhavi , Reddy Manjula , Tallapaka Karthik Bharadwaj , Sowpati Divya Tej
Published: March 2024

DNA methylation plays a key role in epigenetic regulation across lifeforms. Nanopore sequencing enables direct detection of base modifications. While multiple tools are currently available for studying 5-methylcytosine (5mC), there is a paucity of models that can detect 6-methyladenine (6mA) from raw nanopore data. Leveraging the motif-driven nature of bacterial methylation systems, we generated 6mA identification models that vastly surpass the accuracy of the current best model. Our work enables the study of 6mA at a single-base resolution in new as well as existing nanopore datasets.
Border-zone cardiomyocytes and macrophages contribute to remodeling of the extracellular matrix to promote cardiomyocyte invasion during zebrafish cardiac regeneration
Authors: Constanty Florian , Wu Bailin , Wei Ke-Hsuan , Lin I-Ting , Dallmann Julia , Guenther Stefan , Lautenschlaeger Till , Priya Rashmi , Lai Shih-Lei , Stainier Didier Y.R. , Beisaw Arica
Published: March 2024

Despite numerous advances in our understanding of zebrafish cardiac regeneration, an aspect that remains less studied is how regenerating cardiomyocytes invade, and eventually replace, the collagen-containing fibrotic tissue following injury. Here, we provide an in-depth analysis of the process of cardiomyocyte invasion using live-imaging and histological approaches. We observed close interactions between protruding cardiomyocytes and macrophages at the wound border zone, and macrophage-deficientirf8mutant zebrafish exhibited defects in extracellular matrix (ECM) remodeling and cardiomyocyte protrusion into the injured area. Using a resident macrophage ablation model, we show that defects in ECM remodeling at the border zone and subsequent cardiomyocyte protrusion can be partly attributed to a population of resident macrophages. Single-cell RNA-sequencing analysis of cells at the wound border revealed a population of cardiomyocytes and macrophages with fibroblast-like gene expression signatures, including the expression of genes encoding ECM structural proteins and ECM-remodeling proteins. The expression ofmmp14b, which encodes a membrane-anchored matrix metalloproteinase, was restricted to cells in the border zone, including cardiomyocytes, macrophages, fibroblasts, and endocardial/endothelial cells. Genetic deletion ofmmp14bled to a decrease in 1) macrophage recruitment to the border zone, 2) collagen degradation at the border zone, and 3) subsequent cardiomyocyte invasion. Furthermore, cardiomyocyte-specific overexpression ofmmp14bwas sufficient to enhance cardiomyocyte invasion into the injured tissue and along the apical surface of the wound. Altogether, our data shed important insights into the process of cardiomyocyte invasion of the collagen-containing injured tissue during cardiac regeneration. They further suggest that cardiomyocytes and resident macrophages contribute to ECM remodeling at the border zone to promote cardiomyocyte replenishment of the fibrotic injured tissue.
Mesenchymal stromal cell chondrogenesis under ALK1/2/3-specific BMP inhibition: A revision of the prohypertrophic signalling network concept
Authors: Diederichs Solvig , Dreher Simon I. , Nüesch Sarah-Anna , Schmidt Sven , Merle Christian , Richter Wiltrud
Published: March 2024

Background

In vitro chondrogenesis of mesenchymal stromal cells (MSCs) driven by the essential chondro-inducer transforming growth factor (TGF)-β is instable and yields undesired hypertrophic cartilage predisposed to bone formation in vivo. TGF-β can non-canonically activate bone morphogenetic protein-associated ALK1/2/3 receptors. These have been accused of driving hypertrophic MSC misdifferentiation, but data remained conflicting. We here tested the antihypertrophic capacity of two highly specific ALK1/2/3 inhibitors – compound A (CompA) and LDN 212854 (LDN21) – in order to reveal potential prohypertrophic contributions of these BMP/non-canonical TGF-β receptors during MSC in vitro chondrogenesis.

Methods

Standard chondrogenic pellet cultures of human bone marrow-derived MSCs were treated with TGF-β and CompA (500 nM) or LDN21 (500 nM). Daily 6-hour pulses of parathyroid hormone-related peptide (PTHrP[1–34], 2.5 nM, from day 7) served as potent antihypertrophic control treatment. Day 28 samples were subcutaneously implanted into immunodeficient mice.

Results

All groups underwent strong chondrogenesis, but GAG/DNA deposition andACANexpression were slightly but significantly reduced by ALK inhibition compared to solvent controls along with a mild decrease of the hypertrophy markersIHH-, SPP1-mRNA, and Alkaline phosphatase (ALP) activity. When corrected for the degree of chondrogenesis (COL2A1expression), only pulsed PTHrP but not ALK1/2/3 inhibition qualified as antihypertrophic treatment. In vivo, all subcutaneous cartilaginous implants mineralized within 8 weeks, but PTHrP pretreated samples formed less bone and attracted significantly less haematopoietic marrow than ALK1/2/3 inhibitor groups.

Conclusions

Overall, our data show that BMP-ALK1/2/3 inhibition cannot program mesenchymal stromal cells toward stable chondrogenesis. BMP-ALK1/2/3 signalling is no driver of hypertrophic MSC misdifferentiation and BMP receptor induction is not an adverse prohypertrophic side effect of TGF-β that leads to endochondral MSC misdifferentiation. Instead, the prohypertrophic network comprises misregulated PTHrP/hedgehog signalling and WNT activity, and a potential contribution of TGF-β-ALK4/5-mediated SMAD1/5/9 signalling should be further investigated to decide about its postulated prohypertrophic activity. This will help to successfully engineer cartilage replacement tissues from MSCs in vitro and translate these into clinical cartilage regenerative therapies.
Dissection of core promoter syntax through single nucleotide resolution modeling of transcription initiation
Authors: He Adam Y. , Danko Charles G.
Published: March 2024

How the DNA sequence ofcis-regulatory elements encode transcription initiation patterns remains poorly understood. Here we introduce CLIPNET, a deep learning model trained on population-scale PRO-cap data that predicts the position and quantity of transcription initiation with single nucleotide resolution from DNA sequence more accurately than existing approaches. Interpretation of CLIPNET revealed a complex regulatory syntax consisting of DNA-protein interactions in five major positions between−200 and+50 bp relative to the transcription start site, as well as more subtle positional preferences among transcriptional activators. Transcriptional activator and core promoter motifs work non-additively to encode distinct aspects of initiation, with the former driving initiation quantity and the latter initiation position. We identified core promoter motifs that explain initiation patterns in the majority of promoters and enhancers, including DPR motifs and AT-rich TBP binding sequences in TATA-less promoters. Our results provide insights into the sequence architecture governing transcription initiation.
Chemical inhibition of the integrated stress response impairs the ubiquitin-proteasome system
Authors: Xu Shanshan , Gierisch Maria E. , Barchi Enrica , Poser Ina , Alberti Simon , Salomons Florian A. , Dantuma Nico P.
Published: March 2024

The Integrated Stress Response Inhibitor (ISRIB) is an experimental compound that has been used to explore the potential beneficial effects of reducing the activation of the integrated stress response (ISR). As the ISR is a protective response, there is, however, a risk that its inhibition may compromise the cell’s ability to restore protein homeostasis. Here, we show that ISRIB treatment impairs degradation of proteins by the ubiquitin-proteasome system (UPS) during proteotoxic stress in the cytosolic, but not nuclear, compartment. Degradation of proteins intercepted by ribosome quality control (RQC) was particularly affected as accumulation of a UPS reporter substrate for ribosome quality control (RQC) was comparable to the level observed after proteasome inhibition. Consistent with impaired RQC, ISRIB treatment caused an accumulation of polyubiquitylated and detergent insoluble defective ribosome products (DRiPs) in the presence of puromycin. As depletion of the RQC ubiquitin ligase listerin partially restored ubiquitin-dependent proteasomal degradation, these data suggest that the persistent protein translation during proteotoxic stress in ISRIB-treated cells increases the pool of newly synthesized proteins targeted by RQC, which aggravates UPS dysfunction by overloading the cytosolic UPS.
Time-dependent backgrounds from marginal deformations of minimal strings in
AdS3
Authors: Dowd Eoin , Giribet Gaston
Published: March 2024

We study a class of time-dependent backgrounds in string theory which consist of marginal deformations of minimal strings on AdS3. For such backgrounds, we compute the three-point amplitudes and analyze their properties.

Published by the American Physical Society
2024
Scalable Fault-Tolerant Quantum Technologies with Silicon Color Centers
Authors: Simmons Stephanie
Published: March 2024

The scaling barriers currently faced by both quantum networking and quantum computing technologies ultimately amount to the same core challenge of distributing high-quality entanglement at scale. In this Perspective, a novel quantum information-processing architecture based on optically active spins in silicon is proposed that offers a combined single technological platform for scalable fault-tolerant quantum computing and networking. The architecture is optimized for overall entanglement distribution and leverages color-center spins in silicon (T centers) for their manufacturability, photonic interface, and high-fidelity information-processing properties. Silicon nanophotonic optical circuits allow for photonic links between T centers, which are networked via telecom-band optical photons in a highly connected graph. This high connectivity unlocks the use of low-overhead quantum error-correcting codes, significantly accelerating the time line for modular scalable fault-tolerant quantum repeaters and quantum processors.

Published by the American Physical Society
2024
Factors influencing online health information credibility: a meta-analysis
Authors: Zhao Yuehua , Zhang Linyi , Zeng Chenxi , Chen Yidan , Lu Wenrui , Song Ningyuan
Published: March 2024

Purpose

This study aims to address the growing importance of online health information (OHI) and the associated uncertainty. Although previous research has explored factors influencing the credibility of OHI, results have been inconsistent. Therefore, this study aims to identify the essential factors that influence the perceived credibility of OHI by conducting a meta-analysis of articles published from 2010 to 2022. The study also aims to examine the moderating effects of demographic characteristics, study design and the platforms where health information is located.

Design/methodology/approach

Based on the Prominence-Interpretation Theory (PIT), a meta-analysis of 25 empirical studies was conducted to explore 12 factors related to information content and source, social interaction, individual and media affordance. Moderators such as age, education level, gender of participants, sample size, platforms and research design were also examined.

Findings

Results suggest that all factors, except social support, have significant effects on the credibility of OHI. Among them, argument quality had the strongest correlation with credibility and individual factors were also found to be relevant. Moderating effects indicate that social support was significantly moderated by age and education level. Different sample sizes may lead to variations in the role of social endorsement, while personal involvement was moderated by sample size, platform and study design.

Originality/value

This study enriches the application of PIT in the health domain and provides guidance for scholars to expand the scope of research on factors influencing OHI credibility.