bluuebunny/crossref_metadata_2025 huggingface dataset:
Sexual experiences and information needs among patients with prostate cancer: a qualitative study
Authors: Haining Zhou , Xiaoli Zhang , Jiping Zhu , Beibei Zhang , Ping Meng , Yunfei Guo
Published: April 2024

Background

Less is known about the sexual life and information seeking of Chinese patients with prostate cancer (PCa) after androgen deprivation therapy (ADT) treatment.

Aim

To identify the experiences of sex and information needs among Chinese patients with PCa after ADT treatment.

Methods

This qualitative study included 15 Chinese patients with PCa in urology inpatient wards, selected via a purposive sampling method. Semistructured interviews were conducted face-to-face or by telephone regarding sexual experiences and information needs after ADT treatment.

Outcomes

Themes and subthemes were assessed among patients with PCa.

Results

Two themes and 5 subthemes emerged from the interview data. The first theme was “altered sexual life and attitude” with 3 subthemes: (1) undesirable sexual function and altered sexuality, (2) sexual attitudes and sociocultural cognition, and (3) behavior adjustment and intimacy. The second theme was “scarce information sources” with 2 subthemes: (1) uncertainty and lack of information support and (2) barriers to access sexual information.

Clinical Implications

The present findings suggest that the following may help patients with PCa manage treatment and develop appropriate sexual attitudes: a tailored sexual health education program, well-equipped consultations rooms, and information delivery innovations.

Strengths and Limitations

Strengths of this study included adding unique evidence among patients with PCa within an Asian context to reveal the understudied topic of sexual health and information needs after ADT treatment. This study was limited in being representative of all Chinese patients with PCa, with different marital statuses, treatment therapies, sexual orientations, and barriers of information seeking.

Conclusion

Sexual life and attitude among patients with PCa were affected by their sociocultural cognition and ADT treatment, and most patients received insufficient information and sexual health education from health care providers.
Effects of poor maternal diet during gestation are detected in F2 offspring
Authors: Tillquist N M , Reed S A , Reiter A S , Kawaida M Y , Lee E C , Zinn S A , Govoni K E
Published: April 2024

Poor maternal nutrition of F0 ewes impairs F1 offspring growth, with minimal differences in glucose tolerance or select metabolic circulating factors, and independent of differences in residual feed intake (RFI). To determine if poor maternal nutrition in F0 ewes alters F2 offspring growth, circulating leptin, feed efficiency, or glucose tolerance, F0 ewes (n = 46) pregnant with twins were fed 100% (control), 60% (restricted), or 140% (over) of National Research Council requirements from days 30 ± 0.02 of gestation until parturition. At 16 to 19 mo of age, female F1 (n = 36) offspring were bred to generate F2 offspring [CON-F2 (n = 12 ewes; 6 rams), RES-F2 (n = 7 ewes; 13 rams), or OVER-F2 (n = 13 ewes; 9 rams) corresponding to diets of the granddam (F0)]. Lamb body weights (BW) and blood samples were collected weekly from days 0 to 28 and every 14 d until day 252 of age. Circulating leptin was measured in serum at days 0, 7, 14, 56, 210, and 252. An intravenous glucose tolerance test was performed at days 133 ± 0.28. At days 167 ± 0.33, individual daily intake was recorded over a 77-d feeding period to determine RFI. Rams were euthanized at days 285 ± 0.93, and body morphometrics, loin eye area (LEA), back fat thickness, and organ weights were collected and bone mineral density (BMD) and length were determined in the right hind leg. During gestation, OVER-F1 ewes tended to be 8.6% smaller than CON-F1 ewes (P ≤ 0.06). F2 offspring were of similar BW from birth to day 70 (P ≥ 0.20). However, from days 84 to 252, RES-F2 offspring tended to be 7.3% smaller than CON-F2 (P ≤ 0.10). Granddam diet did not influence F2 ram body morphometrics, organ or muscle weights, LEA, adipose deposition, or leg BMD (P ≥ 0.84). RES-F2 (−0.20) and CON-F2 (−0.45) rams tended to be more feed efficient than CON-F2 ewes (0.31; P ≤ 0.08). No effects of granddam diet were observed on glucose or insulin average or baseline concentrations, area under the curve, first-phase response, or ratio (P ≥ 0.52). However, CON-F2 rams (297 mg/dL ± 16.5) had a greater glucose peak compared with RES-F2 rams (239 mg/dL ± 11.2; P = 0.05). Peak insulin concentrations were not influenced by granddam diet (P = 0.75). At d 56, RES-F2 and OVER-F2 offspring had 53.5% and 61.8% less leptin compared with CON-F2 offspring, respectively (P ≤ 0.02). These data indicate that poor maternal nutrition impacts offspring growth into the second generation with minimal impacts on offspring RFI, glucose tolerance, and circulating leptin.
Thirty-Year Experience Treating Syndromic Craniosynostosis: Long-Term Outcomes following Cranial Expansions
Authors: Fearon Jeffrey A. , Ditthakasem Kanlaya , Harrison Lucas , Herbert Morley
Published: April 2024

Background:

Children with syndromic craniosynostosis require multiple cranial expansion procedures. The purpose of this study was to determine how many expansions are typically performed through maturity, to assess complication rates, and to identify trends that might reduce the burden of care.

Methods:

A retrospective chart review was conducted of all consecutive patients undergoing cranial vault enlargement procedures for syndromic craniosynostosis performed by a single surgeon.

Results:

Of 444 patients treated with Apert or Crouzon/Pfeiffer syndromes, 348 had complete long-term records. The mean age at last follow-up was 16.9 years. Initial cranial expansions were performed at a significantly younger age for those beginning care at outside centers: 7.7 months versus 25.7 months in Dallas; 26.4% had ventriculoperitoneal shunts (syndrome-specific incidences: Apert syndrome, 16%; Crouzon syndrome, 27%; and Pfeiffer syndrome, 54%). Of 498 procedures, 80% were anterior, 18% were posterior, and 2% were midvaults. The overall complication rate was 2%, with no differences found between anterior and posterior procedures. Those treated solely in Dallas underwent a mean of 1.9 expansions. Children with Pfeiffer syndrome underwent more expansions (2.7) than those with Apert or Crouzon syndrome. Factors correlating with more expansions included earlier surgical interventions, use of distraction, ventriculoperitoneal shunts, and treatment begun at outside centers (3.1 procedures).

Conclusions:

Children with syndromic craniosynostosis treated at a single center underwent an average of 2 skull expansion procedures with a 2% complication rate. Calvarial distraction, ventriculoperitoneal shunts, and earlier surgical interventions were all associated with higher numbers of expansion procedures. Further research is needed to determine whether these correlations are causal.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, IV.
A dynamic trap well model of hydrothermal shape-memory effect in amorphous polymers undergoing tailorable shape recovery behaviour
Authors: Shi Jiabin , Gorbacheva Galina , Lu Haibao , Lau Denvid
Published: April 2024

A dynamic trap well model is developed to describe the complex relaxations of functional segments, and explore the working principles behind the hydrothermal coupling effect in shape memory polymers (SMPs). A constitutive relationship among shape fixity strain, shape recovery strain and relaxation time has been formulated to characterize the hydrothermal coupling effect using geometrical parameters (i.e. width and height) of trap wells. Moreover, effects of temperature and solvent absorption on dynamic relaxation behaviours of SMPs have been formulated based on the Flory-Huggins theory and Fokker-Plank probability equation. The trap well model effectively analyzes the shape fixity ratio and shape recovery ratio within ranges of 50–100% and 0–100%, respectively. Finally, an extended Maxwell model is proposed to formulate the dynamic mechanical behaviours of SMPs with hydrothermal shape-memory effect (SME), and the analytical results have been verified using the experimental results reported in literature. A good agreement between the analytical results obtained from the proposed model and the experimental data is present, where the correlation coefficient (
R
2
) is 95%. The present study firstly introduces the dynamic trap well model for shape memory behaviours and intricate relaxations, and then accurately predicts the dynamic shape recovery of SMP in response to hydrothermal stimulus.
Leaf gene expression trajectories during the growing season are consistent between sites and years in American beech
Authors: Sezen U. Uzay , Shue Jessica E. , Worthy Samantha J. , Davies Stuart J. , McMahon Sean M. , Swenson Nathan G.
Published: April 2024

Transcriptomics provides a versatile tool for ecological monitoring. Here, through genome-guided profiling of transcripts mapping to 33 042 gene models, expression differences can be discerned among multi-year and seasonal leaf samples collected from American beech trees at two latitudinally separated sites. Despite a bottleneck due to post-Columbian deforestation, the single nucleotide polymorphism-based population genetic background analysis has yielded sufficient variation to account for differences between populations and among individuals. Our expression analyses during spring-summer and summer-autumn transitions for two consecutive years involved 4197 differentially expressed protein coding genes. Using
Populus
orthologues we reconstructed a protein-protein interactome representing leaf physiological states of trees during the seasonal transitions. Gene set enrichment analysis revealed gene ontology terms that highlight molecular functions and biological processes possibly influenced by abiotic forcings such as recovery from drought and response to excess precipitation. Further, based on 324 co-regulated transcripts, we focused on a subset of GO terms that could be putatively attributed to late spring phenological shifts. Our conservative results indicate that extended transcriptome-based monitoring of forests can capture diverse ranges of responses including air quality, chronic disease, as well as herbivore outbreaks that require activation and/or downregulation of genes collectively tuning reaction norms maintaining the survival of long living trees such as the American beech.
Wickerhamomyces corioli f.a., sp. nov., a novel yeast species discovered in two mushroom species
Authors: Liu Min , Ding Ruo-Xin , Zhang Yu-Xuan , Li Hao-Ze , Wang Qi-Ming
Published: April 2024

Two yeast strains, designated as 19-39-3 and 19-40-2, obtained from the fruiting bodies of Trametes versicolor and Marasmius siccus collected in Yunwu Mountain Forest Park, PR China, have been identified as representing a novel asexual ascomycetous yeast species. From the results of phylogenetic analyses of the sequences of the D1/D2 domains of the large subunit (LSU) rRNA, small subunit (SSU) rRNA and translation elongation factor 1-α (TEF1) genes, it was determined that these strains represent a member of the genus Wickerhamomyces, with Wickerhamomyces alni and Candida ulmi as the closest relatives. The novel species exhibited 6.6 and 6.7% differences in the D1/D2 domains compared with W. alni and C. ulmi, respectively. Additionally, distinct biochemical and physiological differences were observed between the novel species and its related counterparts. No sexual reproduction was observed in these strains, leading to the proposal of the name Wickerhamomyces corioli f.a., sp. nov. for this newly discovered species.
Stepwise Stiffening/Softening of and Cell Recovery from Reversibly Formulated Hydrogel Double Networks
Authors: Kopyeva Irina , Goldner Ethan C. , Hoye Jack W. , Yang Shiyu , Regier Mary C. , Vera Kaitlyn R. , Bretherton Ross C. , DeForest Cole A.
Published: April 2024

Biomechanical contributions of the ECM underpin cell growth and proliferation, differentiation, signal transduction, and other fate decisions. As such, biomaterials whose mechanics can be spatiotemporally altered – particularly in a reversible manner – are extremely valuable for studying these mechanobiological phenomena. Herein, we introduce a poly(ethylene glycol) (PEG)-based hydrogel model consisting of two interpenetrating step-growth networks that are independently formed via largely orthogonal bioorthogonal chemistries and sequentially degraded with distinct bacterial transpeptidases, affording reversibly tunable stiffness ranges that span healthy and diseased soft tissues (e.g., 500 Pa – 6 kPa) alongside terminal cell recovery for pooled and/or single-cell analysis in a near “biologically invisible” manner. Spatiotemporal control of gelation within the primary supporting network was achieved via mask-based and two-photon lithography; these stiffened patterned regions could be subsequently returned to the original soft state following sortase-based secondary network degradation. Using this approach, we investigated the effects of 4D-triggered network mechanical changes on human mesenchymal stem cell (hMSC) morphology and Hippo signaling, as well as Caco-2 colorectal cancer cell mechanomemory at the global transcriptome level via RNAseq. We expect this platform to be of broad utility for studying and directing mechanobiological phenomena, patterned cell fate, as well as disease resolution in softer matrices.

TOC Description

Biomaterials that can dynamically change stiffnesses are essential in further understanding the role of extracellular matrix mechanics. Using independently formulated and subsequently degradable interpenetrating hydrogel networks, we reversibly and spatiotemporally trigger stiffening/softening of cell-laden matrices. Terminal cell recovery for pooled and/or single-cell analysis is permitted in a near “biologically invisible” manner.
Integrative Systems Immunology Analysis Reveals Elevated Anti-AGTR1 Levels with Accumulating COVID-19 Symptoms
Authors: Fonseca Dennyson Leandro M , Jäpel Maj , Filgueiras Igor Salerno , Baiochi Gabriela Crispim , Ostrinski Yuri , Halpert Gilad , Lavi Yael Bublil , Vojdani Elroy , Santos e Silva Juan Carlo , Usuda Júlia Nakanishi , Freire Paula P. , Nóbile Adriel Leal , Adri Anny Silva , Marçal Pedro Barcelos , Corrêa Yohan Lucas Gonçalves , Nery do Vale Fernando Yuri , Lopes Letícia Oliveira , Schmidt Solveig Lea , Wang Xiaoqing , Vahldieck Carl , Fels Benedikt , Schimke Lena F. , Hirata Mario Hiroyuki , Miranda Gustavo Cabral- , AKhan Taj Ali , Catar Rusan , Moll Guido , Silva-Sousa Thayna , Yu Yen-Rei A , Dalmolin Rodrigo JS , Amital Howard , Vojdani Aristo , Nakaya Helder , Ochs Hans D. , Silverberg Jonathan I. , Zimmerman Jason , Zyskind Israel , Rosenberg Avi Z , Schulze-Forster Kai , Heidecke Harald , Hackel Alexander , Kusche-Vihrog Kristina , Shoenfeld Yehuda , Riemekasten Gabriela , Akbarzadeh Reza , Marques Alexandre H.C , Cabral-Marques Otavio
Published: April 2024

The coronavirus disease 2019 (COVID-19) displays a broad spectrum of symptoms, with the underlying reasons for this variability still not fully elucidated. Our study investigates the potential association between specific autoantibodies (AABs), notably those that targeting G protein-coupled receptors (GPCRs) and renin-angiotensin system (RAS) related molecules, and the diverse clinical manifestations of COVID-19, commonly observed in patients with autoimmune conditions, including rheumatic diseases, such as systemic sclerosis. In a cross-sectional analysis, we explored the relationship between AAB levels and the presence of key COVID-19 symptoms. Hierarchical clustering analysis revealed a robust correlation between certain AABs and symptoms such as fever, muscle ache, anosmia, and dysgeusia, which emerged as significant predictors of disease severity. Specifically, AABs against CHRM5 and CXCR3 were strongly linked to fever, while AABs against CHRM5 and BDKRB1 correlated with muscle ache. Anosmia was predominantly associated with AABs against F2R and AGTR1, while dysgeusia was linked to AABs against BDKRB1 and AGTR1. Furthermore, we observed a rise in AAB levels with the accumulation of these symptoms, with the highest levels detected in patients presenting all four predictors. Multinomial regression analysis identified AABs targeting AGTR1 as a key predictor for one or more of these core symptoms. Additionally, our study indicated that anti-AGTR1 antibodies triggered a concentration-dependent degradation of eGC, which could be mitigated by the AGTR1 antagonist Losartan. This suggests a potential mechanistic connection between eGC degradation, the observed COVID-19 symptoms, and rheumatic diseases. In conclusion, our research underscores a substantial correlation between AABs, particularly those against GPCRs and RAS-related molecules, and the severity of COVID-19 symptoms. These findings open avenues for potential therapeutic interventions in the management of COVID-19.
Adoption of AI-Powered Chatbots with Large Language Models by Pathologists
Authors: Bychkov Andrey , Laohawetwanit Thiyaphat , Pinto Daniel Gomes
Published: April 2024

Aims

The study aimed to investigate the adoption and perception of artificial intelligence (AI) chatbots, particularly those powered by large language models (LLMs), among pathologists worldwide. It explored the extent of their engagement with these technologies, identifying potential impacts on their professional practices.

Methods

A cross-sectional survey was conducted, gathering data from pathologists on their usage and views concerning AI chatbots powered by LLMs. The survey, distributed globally via various digital platforms, included both quantitative and qualitative questions. Statistical analyses were performed to delineate patterns in the adoption and perspectives on these AI tools among the respondents.

Results

Of 215 respondents, 100 (46.5%) reported using LLMs, particularly ChatGPT, for professional purposes, predominantly for information retrieval, proofreading, and academic writing, highlighting a significant time-saving benefit. The adoption varied across demographics, with younger, male pathologists showing higher usage rates. While the technology was mainly utilized for drafting academic materials and programming tasks, users expressed concerns about information accuracy, privacy, and the need for regulatory approval. Despite recognizing occasional inaccuracies, respondents saw potential in advanced AI features, particularly in image analysis and speech-to-text functions.

Conclusions

The survey underscored pathologists’ cautious yet growing interest in leveraging LLMs to enhance information accessibility, efficiency, and medical education. While the potential benefits are recognized, significant apprehensions about the reliability, ethics, and security associated with these AI tools underscore the need for comprehensive regulation and standardized practices to ensure their responsible use in the medical field.
Deep Archetypal Analysis for interpretable multi-omic data integration based on biological principles
Authors: Milite Salvatore , Caravagna Giulio , Sottoriva Andrea
Published: April 2024

High-throughput multi-omic molecular profiling allows probing biological systems at unprecedented resolution. However, the integration and interpretation of high-dimensional, sparse, and noisy multimodal datasets remains challenging. Deriving new biology using current methods is particularly difficult because they are not based on biological principles, but instead focus exclusively on a dimensionality reduction task. Here we introduce MIDAA (Multiomic Integration with Deep Archetypal Analysis), a framework that combines archetypal analysis, an approach grounded in biological principles, with deep learning. Using the concept of archetypes that are based on evolutionary trade-offs and Pareto optimality – MIDAA finds extreme data points that define the geometry of the latent space, preserving the complexity of biological interactions while retaining an interpretable output. We demonstrate that indeed these extreme points represent cellular programmes reflecting the underlying biology. We show on real and simulated multi-omics data how MIDAA outperforms state-of-the-art methods in identifying parsimonious, interpretable, and biologically relevant patterns.
Genome-Wide Association Testing for Haemorrhagic Bowel Syndrome in a Swiss Large White Pig Population
Authors: Mehrotra Arnav , Leonard Alexander S. , Drögemüller Cord , Grahofer Alexander , Khayatzadeh Negar , Hofer Andreas , Neuenschwander Stefan , Pausch Hubert
Published: April 2024

Background

The porcine haemorrhagic bowel syndrome (HBS) is a multifactorial disease causing fatal gastrointestinal disturbances and sudden death in fattening pigs. HBS is the leading cause of deaths during fattening in Swiss pigs, with unclear etiology. Environmental and management factors are associated with HBS incidence, but recent findings also suggest a potential genetic predisposition. Pigs sired by a Swiss Large White (SLW) line appear more prone to HBS. Here we conduct genome-wide association studies (GWAS) for HBS between cases and controls to investigate potential genetic factors for the disease in Swiss fattening pigs.

Results

Our study included 1,036 HBS cases and 4,080 controls with available microarray genotypes or whole-genome sequencing data. Variant positions were determined according to the current porcine reference assembly (Sscrofa11.1) or a HiFi-based SLW haplotype assembly which we constructed using trio-binning. GWAS for HBS were conducted using 12.49 to 15.46 million biallelic variants in three mapping cohorts consisting of purebred animals from SLW sire and dam lines, or crosses between these two parental lines. The statistical model applied for the GWAS accounted for animal relatedness, population structure, and an imbalanced case/control ratio. No sequence variants significantly associated with HBS were identified, regardless of the cohort analysed and the reference sequence considered.

Conclusions

The lack of genetic associations despite a relatively large sample size suggests that susceptibility to HBS in the studied SLW population is not due to large effect variants but may be influenced by numerous small effect genetic variants, in addition to environmental and management factors.
Migration of endocrine and metabolism disrupting chemicals from plastic food packaging
Authors: Stevens Sarah , Bartosova Zdenka , Völker Johannes , Wagner Martin
Published: April 2024

Plastics constitute a vast array of substances, with over 16 000 known plastic chemicals, including intentionally and non-intentionally added substances. Toxicity and thousands of chemicals are extractable from plastics; however, the extent to which toxicity and chemicals migrate from everyday plastic products remains poorly understood. This study aims to characterize the endocrine and metabolism disrupting activity, as well as chemical composition of migrates from plastic food contact articles (FCAs) from four countries as significant sources of human exposure. Additionally, strategies for prioritization of chemicals were explored. Fourteen plastic FCAs covering seven polymer types with high global market shares were migrated into water and a water-ethanol mixture as food simulants according to European regulations. The migrates were analyzed using reporter gene assays for nuclear receptors relevant to human health and non-target chemical analysis to characterize the chemical composition of the migrates. All FCA migrates interfered with at least two nuclear receptors, predominantly targeting pregnane X receptor. Moreover, peroxisome proliferator receptor gamma was broadly activated by the migrates, though mostly with lower potencies, while estrogenic and antiandrogenic activities were more selectively induced by specific FCAs. Fewer chemicals and less toxicity migrated into water compared to the water-ethanol mixture. The latter exhibited similar toxicity and number of chemicals as methanol extracts of the same FCAs. Novel strategies were employed to address the chemical complexity of FCAs and narrow down the list of potential active chemicals. By comparing the composition of multiple leachates of one sample and using stepwise partial least squares regressions, we successfully reduced the chemical complexity, pinpointed potential endocrine disruptors such as triphenyl phosphate and prioritized chemicals for further identification efforts. This study demonstrates the migration of endocrine and metabolism disrupting chemicals from plastic FCAs into food simulants, rendering a migration of these compounds into food and beverages probable.
Mirror-assisted light-sheet microscopy: a simple upgrade to enable bi-directional sample excitation
Authors: Zylbertal Asaph , Bianco Isaac H.
Published: April 2024

Significance

Light-sheet microscopy is a powerful imaging technique that achieves optical sectioning via selective illumination of individual sample planes. However, when the sample contains opaque or scattering tissue, the incident light-sheet may not be able to uniformly excite the entire sample. For example, in the context of larval zebrafish whole-brain imaging, occlusion by the eyes prevents access to a significant portion of the brain during common implementations using unidirectional illumination.

Aim

We introduce mirror-assisted light-sheet microscopy (mLSM), a simple inexpensive method that can be implemented on existing digitally scanned light-sheet setups by adding a single optical element – a mirrored micro-prism. The prism is placed near the sample to generate a second excitation path for accessing previously obstructed regions.

Approach

Scanning the laser beam onto the mirror generates a second, reflected illumination path that circumvents the occlusion. Online tuning of the scanning and laser power waveforms enables near uniform sample excitation with dual illumination.

Results

mLSM produces cellular-resolution images of zebrafish brain regions inaccessible to unidirectional illumination. Imaging quality in regions illuminated by the direct or reflected sheet is adjustable by translating the excitation objective. The prism does not interfere with visually guided behaviour.

Conclusions

mLSM presents an easy to implement, cost-effective way to upgrade an existing light-sheet system to obtain more imaging data from a biological sample.
DNA isolation in bark beetles: reliability of extraction methods and application in downstream molecular procedures
Authors: Stazione Leonel , Lantschner Victoria , Corley Juan , Soliani Carolina
Published: April 2024

Molecular tools are increasingly used in entomology for several applications such as taxonomy, genetics, ecology and evolution. For these studies, DNA extraction from individual insects is a crucial step, since the yield and quality vary depending on the methods used. Finding an ideal balance between quality and yield is particularly difficult to reach and several constraints must be considered upon selecting the final protocol. Bark beetles (Coleoptera: Curculionidae, Scolytinae) are a diverse group of forest insects for which molecular studies at the individual level are important, given that many species are invasive and may become pests. However, DNA extraction in bark beetles is not easy, given their small size and complex molecules of diverse nature conforming their exoskeleton and present in their digestive tract. Here, we carried out a comparative analysis of DNA extraction performance in five bark beetle species:Hylurgus ligniperda, Hylastes ater, Orthotomicus erosus, Orthotomicus laricisandCyrtogenius luteus. By assessing the efficiency of two different protocols, our aim was to establish the best species-specific method for population-level studies. Our results showed that a method’s whole performance mainly depends on the species considered and translates into DNA quantity and quality variance. We also noted that the traditional method showed better PCR efficiency for the smallest species whereas the commercial kit performed better for the larger beetles. Our comparative analysis provides evidence that no single method for DNA isolation is best, and that each particular species requires optimization.
Meta-transcriptomic analysis of companion animal infectomes reveals their diversity and potential roles in animal and human disease
Authors: Wu Wei-Chen , Pan Yuan-Fei , Zhou Wu-Di , Liao Yu-Qi , Peng Min-Wu , Luo Geng-Yan , Xin Gen-Yang , Peng Ya-Ni , An Tongqing , Li Bo , Luo Huanle , Barrs Vanessa R. , Beatty Julia A. , Holmes Edward C. , Zhao Wenjing , Shu Yuelong
Published: April 2024

Companion animals such as cats and dogs harbor diverse microbial communities that can potentially impact human health due to close and frequent contact. To better characterize their total infectomes and assess zoonotic risks, we performed meta-transcriptomic profiling on 239 samples from cats and dogs collected across China, comparing the similarities and differences between animal species (cats or dogs), sampling sites (rectal or oropharyngeal), and health status (healthy or diseased). We identified 24 viral species, 270 bacterial genera, and two fungal genera, including many known pathogens such ascanine parvovirus,Clostridium difficile, andCandida albicans,as well as opportunistic pathogens such ascanine vesivirus. Microbial compositions differed mainly according to sampling site (i.e., rectal and oropharyngeal swabs), and less so between host species and health status. Notably, we detected 27 potential zoonotic pathogens, such asalphacoronavirus 1, among all sampling sites, hosts, and health status, underscoring substantial zoonotic risks requiring surveillance. Overall, our meta-transcriptomic analysis reveals a landscape of actively transcribing microorganisms in major companion animals, including key pathogens, those with the potential for cross-species transmission, and possible zoonotic threats.
Menopausal hormone therapy and the female brain: leveraging neuroimaging and prescription registry data from the UK Biobank cohort
Authors: Barth Claudia , Galea Liisa A.M. , Jacobs Emily G. , Lee Bonnie H. , Westlye Lars T. , de Lange Ann-Marie G.
Published: April 2024

Background and Objectives

Menopausal hormone therapy (MHT) is generally thought to be neuroprotective, yet results have been inconsistent. Here, we present a comprehensive study of MHT use and brain characteristics in middle-to older aged females from the UK Biobank, assessing detailed MHT data, APOE ε4 genotype, and tissue-specific gray (GM) and white matter (WM) brain age gap (BAG), as well as hippocampal and white matter hyperintensity (WMH) volumes.

Methods

A total of 19,846 females with magnetic resonance imaging data were included (current-users = 1,153, 60.1 ± 6.8 years; past-users = 6,681, 67.5 ± 6.2 years; never-users = 12,012, mean age 61.6 ± 7.1 years). For a sub-sample (n = 538), MHT prescription data was extracted from primary care records. Brain measures were derived from T1-, T2- and diffusion-weighted images. We fitted regression models to test for associations between the brain measures and MHT variables including user status, age at initiation, dosage and duration, formulation, route of administration, and type (i.e., bioidentical vs synthetic), as well as active ingredient (e.g., estradiol hemihydrate). We further tested for differences in brain measures among MHT users with and without a history of hysterectomy ± bilateral oophorectomy and examined associations by APOE ε4 status.

Results

We found significantly higher GM and WM BAG (i.e., older brain age relative to chronological age) as well as smaller left and right hippocampus volumes in current MHT users, not past users, compared to never-users. Effects were modest, with the largest effect size indicating a group difference of 0.77 years (∼9 months) for GM BAG. Among MHT users, we found no significant associations between age at MHT initiation and brain measures. Longer duration of use and older age at last use post menopause was associated with higher GM and WM BAG, larger WMH volume, and smaller left and right hippocampal volumes. MHT users with a history of hysterectomy ± bilateral oophorectomy showedlowerGM BAG relative to MHT users without such history. Although we found smaller hippocampus volumes in carriers of two APOE ε4 alleles compared to non-carriers, we found no interactions with MHT variables. In the sub-sample with prescription data, we found no significant associations between detailed MHT variables and brain measures after adjusting for multiple comparisons.

Discussion

Our results indicate that population-level associations between MHT use, and female brain health might vary depending on duration of use and past surgical history. Future research is crucial to establish causality, dissect interactions between menopause-related neurological changes and MHT use, and determine individual-level implications to advance precision medicine in female health care.
Prescription Trends of Initial Antihypertensive Medications among Treatment-Naïve Individuals in South Korea: A Retrospective Analysis
Authors: Joo Hajung , Chae Seung Eun , Eom Yeong Rok , Je Nam Kyung
Published: April 2024

Introduction

Managing hypertension effectively is crucial for preventing cardiovascular complications. This study investigates the prescribing trends of initial antihypertensive treatments in South Korea, focusing on the shift towards combination therapies, especially fixed-dose combinations, as recommended by current guidelines.

Methods

We retrospectively analyzed data from 59,950 treatment-naïve hypertension patients without significant comorbidities from the National Patient Sample of the Health Insurance Review and Assessment Service, spanning 2009 to 2020. The study examined the prevalence of monotherapy versus combination therapy and the preferred classes of antihypertensive drugs.

Results

Among the cohort, 55.7% received monotherapy, and 44.3% were initiated on combination therapy. There was a notable increase in the prescription of fixed-dose combinations from 73.8% in 2009 to 93.8% in 2020. ARBs and CCBs were the predominant choices, with a preference for ARBs over ACE inhibitors, possibly due to the lower risk of side effects such as cough. The trend towards fixed-dose combinations aligns with guidelines advocating for improved patient adherence and efficacy.

Conclusions

The evolving prescription trends in South Korea towards combination therapy, particularly fixed-dose combinations, reflect a commitment to aligning with international hypertension management guidelines. This adaptation underscores the importance of evidence-based practice in enhancing hypertension care.
Dynamic self-association of archaeal tubulin-like protein CetZ1 drivesHaloferax volcaniimorphogenesis
Authors: de Silva Roshali T. , Shinde Vinaya , Brown Hannah J. , Liao Yan , Duggin Iain G.
Published: April 2024

Tubulin superfamily (TSF) proteins include the well-known eukaryotic tubulin and bacterial FtsZ families, and lesser-known archaeal CetZ family. In eukaryotes and bacteria, GTP-dependent polymerization and self-association of tubulin and FtsZ protofilaments are integral to the formation of cytoskeletal structures with essential roles in cell division, growth, and morphology. Archaeal CetZs are implicated in the control of cell shape and motility through unknown mechanisms. Here, we reveal a sequence of subcellular localization patterns of CetZ1, the prototypical member of the CetZ family, during stages ofHaloferax volcaniirod cell development, in which it plays an essential role. Like tubulin and FtsZ, we found that CetZ1 formed GTP-dependent polymers in vitro, which appear to associate laterally as irregular polymer bundles. Mutations targeting regions predicted to mediate self-association and dynamic turnover of CetZ1, including the longitudinal (GTPase T7 and T4 loops) and lateral assembly interfaces, perturbed or altered rod shape development and subcellular assembly and dynamics, and caused corresponding effects on polymerization in vitro. Remarkably, a conspicuous amphipathic protrusion in the large microtubule (M-) loop, a characteristic of the CetZ1 subfamily, also strongly influenced function and assembly. Our findings reveal the importance of dynamic CetZ1 self-association in cellular morphogenesis involving multiple regions of the TSF fold, including tubulin- and FtsZ-like structural characteristics and CetZ1-specific features. Furthermore, they support a mechanism involving CetZ1 dynamic guidance of cell envelope-associated structures that reshape the cell during morphogenesis.
Microdroplet screening rapidly profiles a biocatalyst to enable its AI-assisted engineering
Authors: Gantz Maximilian , Mathis Simon V. , Nintzel Friederike E. H. , Zurek Paul J. , Knaus Tanja , Patel Elie , Boros Daniel , Weberling Friedrich-Maximilian , Kenneth Matthew R. A. , Klein Oskar J. , Medcalf Elliot J. , Moss Jacob , Herger Michael , Kaminski Tomasz S. , Mutti Francesco G. , Lio Pietro , Hollfelder Florian
Published: April 2024

Engineering enzyme biocatalysts for higher efficiency is key to enabling sustainable, ‘green’ production processes for the chemical and pharmaceutical industry. This challenge can be tackled from two angles: by directed evolution, based on labor-intensive experimental testing of enzyme variant libraries, or by computational methods, where sequence-function data are used to predict biocatalyst improvements. Here, we combine both approaches into a two-week workflow, where ultra-high throughput screening of a library of imine reductases (IREDs) in microfluidic devices provides not only selected ‘hits’, but also long-read sequence data linked to fitness scores of >17 thousand enzyme variants. We demonstrate engineering of an IRED for chiral amine synthesis by mapping functional information in one go, ready to be used for interpretation and extrapolation by protein engineers with the help of machine learning (ML). We calculate position-dependent mutability and combinability scores of mutations and comprehensively illuminate a complex interplay of mutations driven by synergistic, often positively epistatic effects. Interpreted by easy-to-use regression and tree-based ML algorithms designed to suit the evaluation of random whole-gene mutagenesis data, 3-fold improved ‘hits’ obtained from experimental screening are extrapolated further to give up to 23-fold improvements in catalytic rate after testing only a handful of designed mutants. Our campaign is paradigmatic for future enzyme engineering that will rely on access to large sequence-function maps as profiles of the way a biocatalyst responds to mutation. These maps will chart the way to improved function by exploiting the synergy of rapid experimental screening combined with ML evaluation and extrapolation.
Maturation-informed synthetic Magnetic Resonance Images of the Developing Human Fetal Brain
Authors: Lajous Hélène , Boeuf Fló Andrés le , Gordaliza Pedro M. , Esteban Oscar , Marqués Ferran , Dunet Vincent , Koob Mériam , Cuadra Meritxell Bach
Published: April 2024

Magnetic resonance imaging is a powerful modality to investigate abnormal developmental patternsin utero. However, since it is not the first-line diagnostic tool in this sensitive population, data remain scarce and heterogeneous between scanners and centers. In addressing the data scarcity issue while generating data representative of real fetal brain MRI, we proposedFaBiAN, a ‘Fetal Brain magnetic resonance Acquisition Numerical phantom. Here, we present a novel synthetic dataset of 594 two-dimensional, low-resolution series of T2-weighted images corresponding to 78 developing human fetal brains between 20.0 and 34.8 weeks of gestational age. Data are generated with substantive improvements from the originalFaBiANto account for local heterogeneities within white matter tissues throughout maturation. These synthetic-yet-highly-realistic images cover both healthy and pathological development trajectories simulated with standard clinical settings and anatomically informed by the Fetal Tissue Annotations (FeTA) dataset. Two independent radiologists qualitatively assessed the realism of the simulated images. We also quantitatively demonstrate the simulated data’s increased fidelity to real data compared to the previousFaBiANversion. The reuse potential of the proposed dataset was also evaluated in the context of automated fetal brain tissue segmentation. Besides, our dataset that combines images generated from various clinical scenarios has been made publicly available to support the continuous endeavor of the community to develop advanced post-processing methods aswell as cutting-edge artificial intelligence models.
Histones are exosome membrane proteins regulated by cell stress
Authors: Singh Birendra , Sundbom Marcus Fredriksson , Muthukrishnan Uma , Natarajan Balasubramanian , Stransky Stephanie , Görgens André , Nordin Joel Z. , Wiklander Oscar P. B. , Sandblad Linda , Sidoli Simone , Andaloussi Samir EL , Haney Michael , Gilthorpe Jonathan D.
Published: April 2024

Histones are conserved nuclear proteins that function as part of the nucleosome in the regulation of chromatin structure and gene expression. Interestingly, extracellular histones populate biofluids from healthy individuals and when elevated may contribute to various acute and chronic diseases. It is generally assumed that most extracellular histones exist as nucleosomes, as components of extracellular chromatin. We analysed cell culture models under normal and stressed conditions to identify pathways of histone secretion. We report that core and linker histones localize to extracellular vesicles (EVs) and are secreted via the multivesicular body/exosome pathway. Upregulation of histone EV secretion occurs in response to cellular stress, with enhanced vesicle secretion and a shift towards a population of smaller EVs. Most histones were membrane associated with the outer surface of EVs. Degradation of EV-DNA did not impact significantly on EV-histone association. Individual histones or histone octamers bound strongly to liposomes and EVs, but nucleosomes did not, showing histones do not require DNA for EV binding. EV histones colocalized most frequently with the tetraspanin CD63 but using genetic or pharmacological intervention, we found that all known pathways of exosome biogenesis acted positively on histone secretion. Inhibition of autophagy and lysosomal degradation had a strong positive effect on EV histone release. Unexpectedly, EV-associated histones lacked the extensive post-translational modification of their nuclear counterparts, suggesting loss of PTMs may be involved in their trafficking or secretion. Our data does not support a significant role for EV-histones existing as nucleosomes. We show for the first time that histones are secreted from cells as membrane proteins via EVs/exosomes. This fundamental discovery provides support for further investigation of the biological activity of exosome associated histones and their role in disease.
Topological confinement by a membrane anchor suppresses phase separation into protein aggregates: implications for prion diseases
Authors: Gogte Kalpshree , Kriegler Simon , Bader Verian , Kamps Janine , Grover Prerna , Winter Roland , Winklhofer Konstanze F. , Tatzelt Jörg
Published: April 2024

Protein misfolding and aggregation are a hallmark of various neurodegenerative disorders. However, the underlying mechanisms driving protein misfolding in the cellular context are incompletely understood. Here we show that the restriction of conformational degrees of freedom by a membrane anchor stabilizes the native protein conformation and suppresses liquid-liquid phase separation and protein aggregation. Inherited prion diseases in humans and neurodegeneration in transgenic mice are linked to the expression of anchorless prion protein (PrP), suggesting that the C-terminal glycosylphosphatidylinositol (GPI) anchor of native PrP impedes spontaneous formation of neurotoxic and infectious PrP species. Combining novelin vitroandin vivoapproaches, we show that anchoring to membranes prevents spontaneous aggregation of PrP. Upon release from the membrane, PrP undergoes a rapid conformational transition to detergent-insoluble aggregates. Our study supports an essential role of the GPI anchor in preventing spontaneous misfolding of PrPC.
Searching for enhancement in coalescence of in-jet (anti-)deuterons in proton-proton collisions
Authors: Bailung Yoshini , Shah Neha , Roy Ankhi
Published: April 2024

Recent measurements from ALICE report that “in-jet” nucleons carry a higher probability of forming a deuteron via coalescence than the nucleons from the underlying event (UE). This study makes use of an event shape classifier to separate the “in-jet” deuterons and the deuterons in the UE produced in high multiplicity proton-proton collisions at s=13 TeV. Event shape variables such as transverse spherocity allow the categorization of hard and soft components of an event, which can be divided into two respective classes; “jetty” and “isotropic”. The “jetty” deuterons minus the contribution of the deuterons from the “isotropic” event are taken as “in-jet” deuterons, and the coalescence mechanism is tested. The coalescence is performed with a Wigner function formalism, augmented as an afterburner to . The possible enhancement of the coalescence probability of “in-jet” deuterons is investigated by calculating the coalescence parameter (B2) in different spherocity classes in high-multiplicity pp collisions.

Published by the American Physical Society
2024
Wrinkling instabilities of swelling hydrogels
Authors: Webber Joseph J. , Worster M. Grae
Published: April 2024

We investigate the formation of wrinkling instabilities at the interface between layers of hydrogel and water, which arise to relieve horizontal compressive stresses caused by either differential swelling or confinement. Modelling the gel using a linear-elastic-nonlinear-swelling approach, we determine both a criterion for marginal stability and the growth rates of normal modes. Furthermore, our formalism allows us to understand the influence of differential swelling on the stability of hydrogels brought into contact with water, and we find three distinct phases of the instability. Initially, when only a thin skin layer of gel has swollen, buckles grow rapidly and the gel deforms as an incompressible material. A balance between normal elastic stress and pore pressure selects a wavelength for these buckles that increases with the square root of time. At late times, when the gel approaches a uniformly swollen state, buckles can only grow by differential swelling on much slower timescales determined by solvent transport. At intermediate times, growth is driven by the same fluid transport process as at late times but gradients in fluid pressure in the gel as it swells destabilize the interface, driving faster growth of wrinkles. We also explain why some instabilities can be transient, “healing” as time progresses, while others must remain for all time.

Published by the American Physical Society
2024