bluuebunny/crossref_metadata_2025 huggingface dataset:
A re-evaluation of gender bias in receptiveness to scientific evidence of gender bias
Authors: Shanks David R. , Coles Hollie A. , Yeo Nadia
Published: September 2024

Gender bias has been documented in many aspects of Science, Technology, Engineering and Mathematics (STEM) careers, yet efforts to identify the underlying causes have been inconclusive. To what extent do cognitive biases, including unequal receptiveness in women and men to evidence of gender bias, contribute to gender bias in STEM? We investigated receptiveness in a STEM context among members of the general public, by undertaking a high-powered (total
N
= 1171) replication, including three experiments (2 pre-registered) of the prominent study by Handley
et al
. [22]. It was hypothesized that men would evaluate a research summary reporting evidence of gender bias less favourably than women but that there would be no difference between men and women’s evaluations of research summaries unrelated to gender bias. The results revealed no effect of the assessor’s gender on receptiveness to scientific evidence of gender bias. The different results compared to those of Handley
et al
. [22] suggest either that the gender bias they detected has diminished in the past decade or that their findings are a false positive. The present research adds to a growing body of evidence suggesting that some influential studies on cognitive ‘markers’ of gender bias warrant re-examination.
Seasonal variation of behavioural thermoregulation in a fossorial salamander (
Ambystoma maculatum
)
Authors: Giacometti Danilo , Tattersall Glenn J.
Published: September 2024

Temperature seasonality plays a pivotal role in shaping the thermal biology of ectotherms. However, we still have a limited understanding of how ectotherms maintain thermal balance in the face of varying temperatures, especially in fossorial species. Due to thermal buffering underground, thermal ecology theory predicts relaxed selection pressure over thermoregulation in fossorial ectotherms. As a result, fossorial ectotherms typically show low thermoregulatory precision and low evidence of thermotactic behaviours in laboratory thermal gradients. Here, we evaluated how temperature selection (
T
sel
) and associated behaviours differed between seasons in a fossorial amphibian, the spotted salamander (
Ambystoma maculatum
). By comparing thermoregulatory parameters between the active and overwintering seasons, we show that
A. maculatum
engages in active behavioural thermoregulation despite being fossorial. In both seasons,
T
sel
was consistently offset higher than acclimatization temperatures. Thermoregulation differed between seasons, with salamanders having higher
T
sel
and showing greater evidence of thermophilic behaviours in the active compared with the overwintering season. Additionally, our work lends support to experimental assumptions commonly made but seldom tested in thermal biology studies. Ultimately, our study demonstrates that the combination of careful behavioural and thermal biology measurements is a necessary step to better understand the mechanisms that underlie body temperature control in amphibians.
Targeting DLK1 improves survival in patient-derived xenograft models of myeloid leukemia associated with Down syndrome
Authors: Barwe Sonali P. , Tavenner Meredith , van Berkel Patrick , Sebastian Aimy , Ries Rhonda E , Meshinchi Soheil , Hitzler Johann , Pikman Yana , Kolb E. Anders , Gopalakrishnapillai Anilkumar
Published: September 2024

Myeloid leukemia associated with Down syndrome (ML-DS) is a rare pediatric cancer. Current standard-of-care includes cytotoxic chemotherapy. 10-20% of patients develop relapsed leukemia or have refractory disease. These patients have a 3-year event-free survival less than 21%. Novel therapy options are needed to improve survival in these patients with relapsed or refractory disease. Our transcriptome analysis to identify transmembrane proteins that are overexpressed in ML-DS compared to normal bone marrow specimens revealed DLK1 as one of the topmost modulated targets. We show that DLK1 knockout in ML-DS cells significantly reduced proliferationin vitroand delayed engraftmentin vivo. Furthermore, targeting DLK1 via antibody drug conjugates significantly prolonged survival compared to control isotype antibody drug conjugate in patient-derived xenograft models of refractory ML-DS. Taken together, targeting DLK1 may be a novel treatment option for refractory ML-DS patients.

Key Points

We identified DLK1 as a novel target differentially expressed in myeloid leukemia associated with Down syndrome (ML-DS).

DLK1-targeted antibody drug conjugate was effective in curbing leukemia progression in patient-derived xenograft models of refractory ML-DS
Freeze-dried porous collagen scaffolds for the repair of volumetric muscle loss injuries
Authors: Basurto Ivan M. , Boudreau Ryann D. , Bandara Geshani C. , Muhammad Samir A. , Christ George J. , Caliari Steven R.
Published: September 2024

Volumetric muscle loss (VML) injuries are characterized by the traumatic loss of skeletal muscle resulting in permanent damage to both tissue architecture and electrical excitability. To address this challenge, we previously developed a 3D aligned collagen-glycosaminoglycan (CG) scaffold platform that supportedin vitromyotube alignment and maturation. In this work, we assessed the ability of CG scaffolds to facilitate functional muscle recovery in a rat tibialis anterior (TA) model of VML. Functional muscle recovery was assessed following implantation of either non-conductive CG or electrically conductive CG-polypyrrole (PPy) scaffolds at 4, 8, and 12 weeks post-injury byin vivoelectrical stimulation of the peroneal nerve. After 12 weeks, scaffold-treated muscles produced maximum isometric torque that was significantly greater than non-treated tissues. Histological analysis further supported these reparative outcomes with evidence of regenerating muscle fibers at the material-tissue interface in scaffold-treated tissues that was not observed in non-repaired muscles. Scaffold-treated muscles possessed higher numbers of M1 and M2 macrophages at the injury while conductive CG-PPy scaffold-treated muscles showed significantly higher levels of neovascularization as indicated by the presence of pericytes and endothelial cells, suggesting a persistent wound repair response not observed in non-treated tissues. Finally, only tissues treated with non-conductive CG scaffolds displayed neurofilament staining similar to native muscle, further corroborating isometric contraction data. Together, these findings show that CG scaffolds can facilitate improved skeletal muscle function and endogenous cellular repair, highlighting their potential use as therapeutics for VML injuries.
Task-voting for schizophrenia spectrum disorders prediction using machine learning across linguistic feature domains
Authors: He Rui , de la Foz Víctor Ortiz-García , Cacho Luis Manuel Fernández , Homan Philipp , Sommer Iris , Ayesa-Arriola Rosa , Hinzen Wolfram
Published: September 2024

Background and Hypothesis

Identifying schizophrenia spectrum disorders (SSD) from spontaneous speech features is a key focus in computational psychiatry today.

Study Design

We present a task-voting procedure using different speech-elicitation tasks to predict SSD in Spanish, followed by ablation studies highlighting the roles of specific tasks and feature domains. Speech from five tasks was recorded from 92 subjects (49 with SSD and 41 controls). A total of 319 features were automatically extracted, from which 24 were pre-selected based on between-feature correlations and ANOVA F-values, covering acoustic-prosody, morphosyntax, and semantic similarity metrics.

Study Results

ExtraTrees-based classification using these features yielded an accuracy of 0.840 on hold-out data. Ablating picture descriptions impaired performance most, followed by story reading, retelling, and free speech. Removing morphosyntactic measures impaired performance most, followed by acoustic and semantic measures. Mixed-effect models suggested significant group differences on all 24 features. In SSD, speech patterns were slower and more variable temporally, while variations in pitch, amplitude, and sound intensity decreased. Semantic similarity between speech and prompts decreased, while minimal distances from embedding centroids to each word increased, and word-to-word similarity arrays became more predictable, all replicating patterns documented in other languages. Morphosyntactically, SSD patients used more first-person pronouns together with less third-person pronouns, and more punctuations and negations. Semantic metrics correlated with a range of positive symptoms, and multiple acoustic-prosodic features with negative symptoms.

Conclusions

This study highlights the importance of combining different speech tasks and features for SSD detection, and validates previously found patterns in psychosis for Spanish.
Pain distribution can be determined by classical conditioning
Authors: Nastaj Jakub , Skalski Jacek , Nowak Daria , Kruszyna Natalia , Bąbel Przemysław , Szikszay Tibor , Luedtke Kerstin , Gnat Rafał , Adamczyk Wacław M.
Published: September 2024

ABSTRACT

Chronic widespread pain (CWP) - as many other clinical presentations - manifests in ongoing pain without identifiable structural cause, with pain that spreads over multiple body areas. The development and maintenance of symptoms may involve learning mechanisms. Ninety-four healthy volunteers participated in this study and were randomly distributed to four groups. In the classical conditioning combined with verbal suggestion group, US-(small pain distribution) and US+ (large pain distribution) were paired with visual stimuli (CS+ and CS-) and participants were told about this association. In the verbal suggestion group, the conditioning was not performed, whereas in classical conditioning only group, learning was not combined with suggestion. In the control group, conditioning and suggestion did not take place. Ratings of perceived pain distribution (PD) were collected after each trial and ratings of pain intensity after each block of trials. During the testing phase, participants were exposed to electrocutaneous stimuli corresponding to only the small (US-) pain distribution. Results showed significant differences between CS+ and CS-pain distribution ratings across the experimental groups: conditioning + verbal suggestion (p<0.01), conditioning only group (p<0.05) and verbal suggestion only group (p<0.05), but not in the control group (p>0.05). Furthermore, significant differences in the perceived pain distribution were found between the control group and all experimental groups. This result supports our main hypothesis that the perceived pain distribution can be influenced by classical conditioning as well as verbal suggestion, although the effect is stronger when both are combined.
Distal super-enhancer drives aberrantCXCL13expression in Cancer cells driving growth and p53 dysregulation via CXCR5-CXCL13 axis
Authors: Gothwal Santosh Kumar , Mattila Pieta K. , Barlow Jacqueline H
Published: September 2024

The CXCL13 chemokine plays a crucial role in guiding B cell migration to the light zones (LZs) during the germinal center (GC) reaction. WhileCXCL13expression is absent in most cell types, aberrant amplification of the CXCR5-CXCL13 signaling is observed in various cancers, including germinal center-derived B-lymphomas (GCDBL), colorectal adenocarcinoma (COAD), and liver hepatocellular carcinoma (LIHC). However, the molecular mechanisms underlying abnormalCXCL13transcription in cancer cells and its functional consequences remain elusive. We identify DNA-CpG methylation binding protein 1 (MBD1) as a suppressor ofCXCL13expression. Chromosomal conformation capture (3C) analysis reveals a distal super-enhancer located nearCCNG2that interacts with theCXCL13promoter in GCDBL, suggesting that enhancer-hijacking drives the aberrant expression. Our functional validation demonstrates that CXCR5-CXCL13 signaling suppresses p53 and its target genes in GCDBLs, COAD, and LIHC. Notably, CXCL13 in the GCDBL cell line Raji disrupts CXCR5-mediated migration, a mechanism essential for (light zone) LZ-entry and affinity maturation of GC B cells. These findings highlight the dual role of the CXCR5-CXCL13 axis in immune response and cancer proliferation.

Key Points

Super-enhancer nearCCNG2region interacts withCXCL13-TSSdriving CXCL13 in cancers.

Aberrant CXCL13 prevents CXCR5-mediated migration of B-lymphomas and promotes growth and p53 dysregulation in CXCR5+ cells

CXCR5-CXCL13 axis impairs p53 target gene expression and promotes tumor growth

Abstract Figure

Highlights

AberrantCXCL13expression in hematological and solid cancers

Chemotherapeutic treatment of cancer cells promotesCXCL13andCXCR5expression

Distal super-enhancer onCCNG2interacts withCXCL13promoter

CXCL13 expression in B-lymphomas prevents CXCR5-dependent migration

CXCR5-CXCL13 axis encounters p53 function in hematological and solid cancer cells
Vision is not olfaction: impact on the insect Mushroom Bodies connectivity
Authors: Le Moël Florent , Wystrach Antoine
Published: September 2024

The Mushroom Bodies, a prominent and evolutionary conserved structure of the insect brain, are known to be the support of olfactory memory. There is now evidence that this structure is also required for visual learning, but the hypotheses about how the view memories are encoded are still largely based on what is known of the encoding of olfactory information. The different processing steps happening along the several relays before the Mushroom Bodies is still unclear, and how the visual memories actually may allow navigation is entirely unknown. Existing models of visual learning in the Mushroom Bodies quickly fall short when used in a navigational context. We discuss how the visual world differs from the olfactory world and what processing steps are likely needed in order to form memories useful for navigation, and demonstrate it using a computational model of the Mushroom Bodies embedded in an agent moving in through a virtual 3D world.
Pursuing reconsolidation in ethanol-CPP: memory reactivation in different conditions did not trigger destabilization
Authors: Zacouteguy Boos Flávia , Déo Sorigotto Beatriz , Favoretto Cristiane Aparecida , Cruz Fabio Cardoso , Quadros Isabel Marian Hartmann de
Published: September 2024

Consolidated memories can return to a labile state during retrieval, through destabilization, and must be reconsolidated to persist. Associative memories of contextual cues paired with hedonic effects of drugs of abuse exert a pivotal role in maintaining maladaptive behaviors in addiction. Thus, impairment of reconsolidation of drug-associated memories may provide a potential strategy to reduce drug-seeking and relapse in addiction. It is critical to understand the conditions under which a consolidated memory becomes labile and may undergo reconsolidation. After inducing ethanol Conditioned Place Preference (CPP; 2 g/kg ethanol, i.p.) in male mice, we examined different parameters during the reactivation session that could turn memory susceptible to disruption by systemic injection of the protein synthesis inhibitor cycloheximide (CHX, 100 mg/kg, i.p.). Reactivation with free access to the apparatus (similarly to a Test session, for 10, 5, or 3 min) or Reactivation sessions restricted to ethanol-paired compartment with no ethanol (for 10 or 5 min), or with the administration of a low dose of ethanol (5 min session), failed to reduced ethanol-preference after CHX administration. These findings suggest that boundary conditions constraint memory in ethanol-CPP to undergo reconsolidation.
Connectivity between supplementary motor complex and primary motor cortex: a dual-coil paired-pulse TMS study
Authors: Kim Hakjoo , Lei Yuming , Bao Shancheng , Huynh Angelina T. , Buchanan John J. , Bernard Jessica A. , Brown Joshua C. , Wright David L.
Published: September 2024

In recent years, dual-coil paired-pulse transcranial magnetic stimulation (ppTMS) has garnered interest for its potential in elucidating neural circuit dynamics. In this study, the dual-coil ppTMS was utilized to assess the effective connectivity between the supplementary motor complex (SMC) and the primary motor cortex (M1) in humans. A robust facilitatory connection between the SMC and M1 was observed, manifested as a 19% increase in mean peak-to-peak motor-evoked potentials following preconditioning of SMC 7 ms prior to M1 stimulation. Importantly, the facilitatory influence of SMC only occurred when the preconditioning stimulation was administered 4 cm anterior to Cz but not when applied at 5-cm, 6-cm, or 7-cm distance. While previous work has focused on demonstrating important temporal dynamics for SMC-M1 plasticity, the present findings highlight a critical contribution of spatial specificity for modulation of SMC-M1 circuitry.

Graphical abstract

Highlights

The conditioned stimulus induced larger MEPs compared to the unconditioned stimulus

The connectivity between SMC and M1 diminished when the SMC coil was moved forward

Findings highlight the importance of spatial specificity for modulation of SMC-M1 circuitry
Developing an evaluation framework for public health environmental surveillance: Protocol for an international, multidisciplinary e-Delphi study
Authors: Manuel Douglas G. , Bennett Carol , Brown Emma , Buckeridge David L. , Freedhoff Yoni , Funnell Sarah , Ishtiaq Farah , Wade Matthew J. , Moher David
Published: September 2024

Introduction

Public health environmental surveillance has evolved, especially during the coronavirus disease pandemic, with wastewater-based surveillance being a prominent example. As surveillance methods diversify and expand, it is essential to have a robust evaluation of surveillance systems. This electronic Delphi study will propose an evaluation framework for public health environmental surveillance, informed by the expanding practice of wastewater-based surveillance during the pandemic.

Methods

The Public Health Environmental Surveillance Evaluation Framework (PHES-EF) will be developed in five steps. In Step 1, a multinational and multidisciplinary executive group will be formed to guide the framework development process. In Step 2, candidate items for Round 1 of the electronic Delphi will be generated by conducting relevant scoping reviews and consultation with the study executive group. In Step 3, an international electronic Delphi will be conducted over two rounds to develop consensus on items for the framework. In Step 4, the executive group will reconvene to finalize the evaluation framework, discuss standout items, and determine the dissemination strategies. Lastly, Step 5 will focus on disseminating the evaluation framework to all parties involved with or affected by wastewater-based surveillance using traditional and public-oriented methods.

Discussion

The electronic Delphi study will provide multidisciplinary and multinational consensus for the evaluation framework for public health environmental surveillance by providing a set of minimum criteria required for their evaluation. The evaluation framework is intended to support the sustainability of environmental surveillance and improve its implementation, reliability, credibility, and value.
Genetic diversity and differentiation of a mycoheterotrophic orchid (Cymbidium macrorhizon)under urbanization
Authors: Ishii Naohiro I. , Yamamoto Satoshi , Iwachido Yuki , Uchida Kei
Published: September 2024

Urbanization exerts substantial pressures on genetic diversity of plant species. However, depending on species-specific life history, the direction/magnitude of urbanization impacts can vary. To elucidate relationships between life history and urbanization effects, there are needs to accumulate the knowledge on genetic diversity/differentiation along urban-rural gradients for species with unique traits. We examined these facets based on genome-wide single nucleotide polymorphisms of a mycoheterotrophic and vegetative-dormant orchid,Cymbidium macrorhizon, for eleven populations in remnant forests along an urban gradient within the Tokyo metropolitan area, Japan. The reduced inbreeding coefficient and increased genetic differentiation were observed with increased proportion of surrounding urban land-use 50 years ago rather than in recent years. This pattern might reflect lowest heterozygosity under intensive urbanization due to population bottleneck and genetic drift due to habitat shrinkage and fragmentation. The significant impacts of past landscape on the indices might indicate time lags of genetic erosion, namely intra-specific extinction debt, due to longevity and dormancy. Therefore, 30% increase of urban land-use since 1970s has not yet affected genetic erosion, resulting in its progression in the future. We emphasize the importance not only to assess genetic diversity but also to connect the assessments with life history and spatiotemporal urbanization impacts.
SMARTER-database: a tool to integrate SNP array datasets for sheep and goat breeds
Authors: Cozzi Paolo , Manunza Arianna , Ramirez-Diaz Johanna , Tsartsianidou Valentina , Gkagkavouzis Konstantinos , Peraza Pablo , Johansson Anna Maria , Arranz Juan Jose , Freire Fernando , Kusza Szilvia , Biscarini Filippo , Peters Lucy , Tosser-Klopp Gwenola , Ciappesoni Gabriel , Triantafyllidis Alexandros , Rupp Rachel , Servin Bertrand , Stella Alessandra
Published: September 2024

Underutilized sheep and goat breeds have the ability to adapt to challenging environments due to their genetic composition. Integrating publicly available genomic datasets with new data will facilitate genetic diversity analyses; however, this process is complicated by important data discrepancies, such as outdated assembly versions or different data formats. Here we present the SMARTER-database, a collection of tools and scripts to standardize genomic data and metadata mainly from SNP chips arrays on global small ruminant populations with a focus on reproducibility. SMARTER-database harmonizes genotypes for about 12,000 sheep and 6,000 goats to a uniform coding and assembly version. Users can access the genotype data via FTP and interact with the metadata through a web interface or programmatically using their custom scripts, enabling efficient filtering and selection of samples. These tools will empower researchers to focus on the crucial aspects of adaptation and contribute to livestock sustainability, leveraging the rich dataset provided by the SMARTER-database.
Beats of the Brain: Mapping Neural Activation During Candombe Engagement
Authors: Agarwal Netra
Published: September 2024

This research delves into the complex connection between traditional music in Uruguay, specifically candombe, and its cognitive advantages. Relying on real-life studies, we explore the impact of involvement with candombe music on diverse cognitive abilities such as cognitive flexibility, emotional regulation, and social cognition. Our results show that playing music, especially drumming, activates certain brain pathways related to cognitive function and emotional regulation.

The sense of community and distinct rhythmic patterns found in candombe not only boost individual cognitive skills but also foster social bonding, ultimately leading to better mental well-being and strength. This study highlights how cultural heritage influences cognitive functions, showing that candombe is crucial for mental well-being in addition to being a significant cultural symbol.

In summary, our research supports incorporating traditional Uruguayan music in educational and therapeutic environments, offering a new framework for cognitive and emotional growth. This research focuses on how Uruguay’s diverse musical traditions can be used to enhance cognitive abilities and mental health, offering possibilities for application in different cultural settings globally.
A reliance on human habitats is key to the success of an introduced predatory reptile
Authors: Major Tom , Jeffrey Lauren , Russel Guillem Limia , Bracegirdle Rebecca , Gandini Antonio , Morgan Rhys , Marshall Benjamin Michael , Mulley John F. , Wüster Wolfgang
Published: September 2024

Understanding the success of animals in novel environments is increasingly important as human-mediated introductions continue to move species far beyond their natural ranges. Alongside these introductions, inhabited and agricultural areas are spreading, and correspondingly most animal introductions occur in populated areas. Commensal species which can live alongside humans by making use of specific conditions, structures, or prey, have a significant advantage. Introduced mammal species often use anthropogenic features in their environment and demonstrate a higher tolerance of human disturbance, but their importance remains understudied in ectotherms. The Aesculapian snake (Zamenis longissimus) is an ectotherm which has been introduced beyond the northern extremities of its natural range. To understand their persistence, we radio-tracked snakes daily over two active seasons, including high-frequency tracking of a subset of males. We investigated snake home range size using Autocorrelated Kernel Density Estimators (AKDE). Using AKDE-weighted Habitat Selection Functions we identified preferences for habitat features in a mosaic of habitats, and we used Integrated Step Selection Functions to further explore how these features influence movement. We revealed a particular preference for buildings in male snakes, while females preferred woodland. We demonstrate that the success of this ectothermic predator is likely tied to a willingness to use human features of the landscape.
Longitudinal trajectories of psychological resilience and cognitive impairment among older adults: evidence from a national cohort study
Authors: Wang Peicheng , Li Ruihua , Chen Yanhua
Published: September 2024

Background

The relationship between resilience trajectories and cognitive health is not well understood. This study aimed to identify subgroups of psychological resilience trajectories in a national sample of older adults and to examine the association with cognitive impairment over time.

Methods

This study used data from the Chinese Longitudinal Healthy Longevity Survey (CLHLS) from 2008 to 2018, and 2,788 respondents were included in this prospective analysis. Using a group□based trajectory modeling approach, we identified resilience trajectory groups within a 6-year period. Cox proportional hazards models were used to assess the relationship between the resilience trajectory groups and cognitive impairment.

Results

Three distinct trajectories of psychological resilience, including decreasing resilience group (n=131,7.1%), persistent middle resilience group (n=1,808, 58.1%), and persistent high resilience group (n=849, 34.8%). During the 6-year follow-up, compared to those with persistent high resilience, participants with persistent middle resilience (HR=1.43, 95% CI=1.14-1.79) and decreasing resilience (HR=2.46, 95% CI=1.76-3.43) remained consistent associated with a higher risk of cognitive impairment. The associations between resilience trajectories and cognitive impairment varied by lifestyle and health conditions.

Conclusions

Psychological resilience is a relatively stable trait among older adults in China, with most individuals maintaining a persistently high or middle level of resilience throughout the follow-up period; however, declining psychological resilience was significantly associated with the risk of cognitive impairment. Therefore, developing targeted interventions to strengthen psychological resilience in older adults is crucial for promoting cognitive health and successful aging, especially for those who have unhealthy lifestyles and with poorer health conditions.
The impact of burn trauma on glycocalyx derangement
Authors: Kühtreiber Hannes , Bormann Daniel , Salek Melanie , Haider Thomas , Mildner Caterina Selina , Lingitz Marie-Therese , Aigner Clemens , Radtke Christine , Ankersmit Hendrik Jan , Mildner Michael
Published: September 2024

Burn injuries often lead to severe complications, including acute respiratory distress syndrome (ARDS), driven in part by systemic inflammation and glycocalyx disruption. In this study, we analyzed the sera of 28 patients after burn trauma and utilized transcriptomic analyses to decipher the impact of burn injury on glycocalyx derangement. We observed significant upregulation of immune cell-derived degrading enzymes, particularly matrix metalloproteinase-8 (MMP8), which correlated with increased immune cell infiltration and glycocalyx derangement. Serum analysis of burn patients revealed significantly elevated levels of shed glycocalyx components and MMP8, both correlating with the presence of inhalation injury. Consequently, treatment of human in vitro lung tissue models with MMP8 induced significant glycocalyx shedding in both, the endothelium and epithelium. Together our data suggest MMP8 as a contributor of glycocalyx disruption and lung injury post-burn.
Causal effects of breast cancer risk factors across hormone receptor breast cancer subtypes: A two-sample Mendelian randomization study
Authors: Verdiesen Renée MG , Shokouhi Mehrnoosh , Burgess Stephen , Canisius Sander , Chang-Claude Jenny , Bojesen Stig E , Schmidt Marjanka K
Published: September 2024

Background

It is unclear if established breast cancer risk factors exert similar causal effects across hormone receptor breast cancer subtypes. We estimated and compared causal estimates of height, body mass index (BMI), type 2 diabetes, age at menarche, age at menopause, breast density, alcohol consumption, regular smoking, and physical activity across these subtypes.

Methods

We used a two-sample Mendelian randomization approach and selected genetic instrumental variables from large-scale risk factor GWAS. Publicly available summary-level data for the following subtypes were included: luminal A-like; luminal B/HER2-negative-like; luminal B-like; HER2-enriched-like; triple negative. We employed multiple methods to evaluate the strength of causal evidence for each risk factor-subtype association.

Results

Collectively, our analyses indicated that increased height and decreased BMI are probable causal risk factors for all five subtypes. For the other risk factors, the strength of evidence for causal effects differed across subtypes. Heterogeneity in the magnitude of causal effect estimates for age at menopause and breast density was explained by null findings for triple negative tumours. Regular smoking was the sole risk factor for which there was no evidence for a causal effect on any subtype.

Conclusions

This study suggests that established breast cancer risk factors differ across hormone receptor subtypes.
Hyperbaric Oxygen Therapy for Long COVID: 3-Month Follow up Results from a Prospective Registry of 232 patients
Authors: van Berkel J. , Lalieu R.C , Joseph D. , Hellemons M. , Lansdorp C.A.
Published: September 2024

A potential beneficial effect of hyperbaric oxygen therapy (HBOT) on complaints of long COVID was found, leading to increased demand for this treatment despite many remaining clinical questions and lack of formal guideline recommendations and reimbursement. A registry was set up in order to gain more insight into patient characteristics and (long-term) outcomes of long COVID patients undergoing HBOT. Patient-reported outcome measures were collected at baseline, after treatment and at 3-month follow up. The primary outcome measures were the mental and physical component score (MCS/PCS) of the SF-36 questionnaire 3 months after HBOT. A clinically relevant positive or negative response was defined as an increase or decrease of ≥10% in MCS and/or PCS after 3 months. Secondary outcomes included the EQ-5D, severity of complaints and ability to work. In this prospective registry of 232 long COVID patients, 65% of long term-ill patients had a clinically relevant increase in quality of life. However, 15% of the patients experienced deterioration in quality of life. Symptoms that showed most improvement were predominantly in the cognitive domain. This indicates that HBOT may have a positive effect on complaints of long COVID, but alertness for worsening of the condition should be exercised.
Pulmonary inflammation in severe pneumonia is characterised by compartmentalised and mechanistically distinct sub-phenotypes
Authors: Jeffrey M , Bartholdson Scott J , White RJ , Higginson E , Maes M , Forrest S , Pereira-Dias J , Parmar S , Heasman-Hunt E , Curran MD , Polgarova P , Herre J , Davenport EE , Baker S , Dougan G , Navapurkar V , Conway Morris A
Published: September 2024

Pneumonia is the leading infectious disease killer worldwide and commonly requires admission to critical care. Despite its prevalence, the underpinning biology of severe pneumonia remains incompletely understood. We performed multifaceted assessments of bronchoalveolar transcriptome, cytokines, microbiology, and clinical features to biologically dissect a cohort of patients with suspected severe pneumonia. Our data revealed three lung-restricted transcriptionally defined severe pneumonia endotypes (termed ‘Pneumotypes’ (Pn)). All three Pneumotypes had comparable clinical presentations and severity of respiratory failure but critically had divergent outcomes. Pn1, the most common, was characterised by low alveolar cytokines, expanded tolerogenic macrophages and epithelial damage. Pn3 was characterised by neutrophil-monocyte infiltration, IL-6-STAT3 activation and longer duration of mechanical ventilation. Pn2 displayed the fastest resolution, exhibiting a balanced immune response and epithelial-endothelial repair signatures. Our work has identified mechanistically distinct phenotypes in the lungs of patients with suspected pneumonia and acute lung injury, providing new targets for personalised therapy.
Mature leaves produce a multi-layered wound periderm by integrating phytohormone signaling with ATML1-mediated epidermal specification
Authors: Lee Jung-Min , Jeon Woo-Taek , Han Minsoo , Kwon Myung , Kim Kyungyoon , Je Sujeong , Jung Hoon , Heo Geon , Yamaoka Yasuyo , Lee Yuree
Published: September 2024

The epidermis of plants forms a protective barrier against various stress, but how breaches in the epidermis are repaired is not well understood. Here, we investigated wound healing in the mature leaves ofArabidopsis. We discover a novel type of wound periderm comprising a multi-layered ligno-suberized barrier covered with cuticular wax, which is formed by mesophyll cells that adopt an epidermal fate. Mesophyll cells of protective layer 1 (P1), just beneath the wound, transition into epidermal cells, which seal the wound by depositing cuticle. As P1 undergoes cell death, protective layer 2 (P2), which underlies P1, takes the place of P1 and undergoes ligno-suberization. This multi-layered periderm involves integration of ethylene and jasmonic acid signaling with ATML1, a key transcription factor in epidermal specification, to coordinate cell layer-specific functions. This novel wound periderm also occurs in the leaves of tobacco andCapsella, suggesting it is a widespread phenomenon.
Lower-Limb Muscle Synergies in Musician’s Dystonia: A Case Study of a Drummer
Authors: Sata Shizuka , Honda Kazuaki , Yamaguchi Satoshi , Komine Mizuki , Kim SungHyek , Kashino Makio , Hagio Shota , Fujii Shinya
Published: September 2024

Musician’s dystonia (MD) is a movement disorder characterized by involuntary muscle contractions specifically triggered by playing an instrument. This condition often leads to a loss of fine motor control, threatening the careers of affected musicians. While MD is commonly associated with the hands, it can also affect the lower limbs, particularly in drummers. Understanding the muscle coordination involved in MD is crucial for comprehending its neurological mechanisms, yet the muscle coordination of lower-limb dystonia has not been thoroughly explored. This study aimed to investigate the differences in lower-limb muscle synergies in a drummer with MD, utilizing Non-negative Matrix Factorization (NMF) to analyze coordinated muscle activity patterns during drumming tasks. A 36-year-old male professional drummer with lower-limb MD was instructed to play a drum set in time with a metronome set at 80 beats per minute. The task involved striking the bass drum pedal in time with the downbeat. Electromyographic (EMG) data were collected from ten muscles in the right lower limb. The data were analyzed using NMF to extract muscle synergies and compare the number of synergies, spatial modules, and temporal modules between the data with and without dystonia symptoms. The number of muscle synergies did not differ significantly between the data with and without symptoms. Notably, changes were observed in both the spatial and temporal modules of muscle synergies. Spatial modules revealed the appearance of dystonia-specific muscle synergy, which is considered related to compensatory movement. Temporal modules showed significant earlier overactivation in timing, which is considered the direct manifestation of dystonia symptoms. These findings indicate that lower-limb dystonia in drummers affects the spatial and temporal profiles of muscle synergies. This study underscores the importance of considering both spatial and temporal modules of muscle synergy in understanding and treating lower-limb dystonia in drummers. Further research is needed to validate these findings and apply muscle synergy analysis for the clinical assessment of lower-limb dystonia in drummers.
Self-organized coexistence of phage and a population of host colonies
Authors: Yadav Anjali , Mitarai Namiko , Sneppen Kim
Published: September 2024

Phages and bacteria coexist under widely different conditions, ranging from liquid cultures to oceans, soil, and the human gut. However, our models are typically limited to well-mixed liquid cultures governed by mass-action kinetics. Here, we suggest a modification to the Lotka-Volterra dynamics by including the formation of microcolonies. By analyzing the model in an open system with a steady influx of bacteria, we predict that the colony size distribution is power-low distributed with steeper exponents for the stronger external influx. In the realistic case where the phage attack rate to individual colonies is proportional to their radius, we obtain self-organization to a steady state where the maximal colony size is smaller for stronger external driving.
Contractile forces direct the chiral swirling of minimal cell collectives
Authors: Badih Ghina , Schaeffer Alexandre , Vianay Benoît , Smilovici Pauline , Blanchoin Laurent , Thery Manuel , Kurzawa Laëtitia
Published: September 2024

Chirality is a conserved biological feature with critical implications in tissue morphogenesis and embryonic development. In culture, large multicellular groups exhibit spontaneous chiral symmetry break when moving collectively on micropatterned surfaces. Although several studies have shown that actin network integrity and acto-myosin network contractility participate to the establishment of the chirality of the movement, the exact contribution of contractile forces to the directionality of the chiral bias in collectives remains to be elucidated. Here we studied the contractile forces produced by a minimal collective constituted of a pair of endothelial cells. We first show that cell doublets confined on disk-shaped micropatterns undergo spontaneous and persistent chiral swirling, displaying a mild but robust clockwise (CW) bias, as the one observed in bigger collectives. This bias could be amplified or reversed by modulating contractile forces. Traction force measurements revealed that large forces tend to drive counter-clockwise (CCW) rotation whereas low forces rather favor a CW rotation. Furthermore, the study of heterotypic doublets indicates that the speed and direction of the rotation is determined by the more contractile cells within the doublets. These results thus revealed that contractile leader cells could drive the chiral motion of minimal collectives.

Significance Statement

Chirality, which represents a fundamental property of living systems, manifests in cell collectives by their persistent biased directional swirling. Despite the clear identification of the implication of actomyosin cytoskeleton in driving the internal chiral symmetry break occurring in cells, little is known about the actual role of cellular forces produced by this network in the development of handedness in collectives. Our findings establish that the level of mechanical energy developed by pairs of confined endothelial cells regulates the strength and direction of their rotation. Our results also identify the more contractile cell of the doublet as the cell driving the direction and speed of rotation of the pair. This study thus sheds new light on the importance of the generation and integration of mechanical forces within a small collective in the determination of its chiral rotation.
Pangenomics to understand prophage dynamics in thePectobacteriumgenus and the radiating lineages ofP. Brasiliense
Authors: Pardeshi Lakhansing A. , van Duivenbode Inge , Pel Michiel J. C. , Jonkheer Eef M. , Kupczok Anne , de Ridder Dick , Smit Sandra , van der Lee Theo A. J.
Published: September 2024

Bacterial pathogens of the genusPectobacteriumare responsible for soft rot and blackleg disease in a wide range of crops and have a global impact on food production. The emergence of new lineages and their competitive succession is frequently observed inPectobacteriumspecies, in particular inP. brasiliense. With a focus on one such recently emergedP. brasilienselineage in the Netherlands that causes blackleg in potatoes, we studied genome evolution in this genus using a reference-free graph-based pangenome approach. We clustered 1,977,865 proteins from 454Pectobacteriumspp. genomes into 30,156 homology groups. ThePectobacteriumgenus pangenome is open and its growth is mainly contributed by the accessory genome. Bacteriophage genes were enriched in the accessory genome and contributed 16% of the pangenome. Blackleg-causingP. brasilienseisolates had increased genome size with high levels of prophage integration. To study the diversity and dynamics of these prophages across the pangenome, we developed an approach to trace prophages across genomes using pangenome homology group signatures. We identified lineage-specific as well as generalist bacteriophages infectingPectobacteriumspecies. Our results capture the ongoing dynamics of mobile genetic elements, even in the clonal lineages. The observed lineage-specific prophage dynamics provide mechanistic insights intoPectobacteriumpangenome growth and contribution to the radiating lineages ofP. brasiliense.
Evolutionary conserved RLF, a plant cytochromeb5-like heme-binding protein, is essential for organ development inMarchantia polymorpha
Authors: Iwata Kentaro P. , Shimizu Takayuki , Sakai Yuuki , Furuya Tomoyuki , Fukumura Hinatamaru , Kondo Yuki , Masuda Tatsuru , Ishizaki Kimitsune , Fukaki Hidehiro
Published: September 2024

InArabidopsis thaliana, REDUCED LATERAL ROOT FORMATION (RLF), a cytochromeb5-like heme-binding domain (Cytb5-HBD) protein, is necessary for proper lateral root formation. Whereas the other Cytb5-HBD proteins inA. thalianaregulate different metabolic reactions, RLF is unique as it specifically regulates organ development. However, it remains unknown whether heme binding to RLF is necessary for its function, and whetherRLForthologs in different plant species also regulate organ development. We demonstrate that RLF binds to hemein vitroand that the two histidine residues, which are conserved among Cytb5-HBD, are crucial for both heme binding and its biological function inA. thaliana. In addition, MpRLF, aRLFortholog inMarchantia polymorpha, rescues the lateral root formation phenotype of theA. thaliana rlfmutant. Mprlfge, the loss-of-function mutation in the MpRLF, resulted in delayed thallus growth and inhibited both gemma cup and antheridiophore formation. Transcriptome analysis using Mprlfgerevealed that MpRLFaffects several metabolic pathways. Our findings indicate that MpRLFis essential for vegetative and reproductive development inM. polymorpha, suggesting that the RLF-dependent redox reaction systems are evolutionarily conserved as crucial mechanisms for organ development across diverse plant species.
Deep contrastive learning enables genome-wide virtual screening
Authors: Jia Yinjun , Gao Bowen , Tan Jiaxin , Hong Xin , Zhu Wenyu , Tan Haichuan , Xiao Yuan , Huang Yanwen , Jin Yue , Yuan Yafei , Tian Jiekang , Ma Weiying , Zhang Yaqin , Yan Chuangye , Zhang Wei , Lan Yanyan
Published: September 2024

Numerous protein-coding genes are associated with human diseases, yet approximately 90% of them lack targeted therapeutic intervention. While conventional computational methods such as molecular docking have facilitated the discovery of potential hit compounds, the development of genome-wide virtual screening against the expansive chemical space remains a formidable challenge. Here we introduce DrugCLIP, a novel framework that combines contrastive learning and dense retrieval to achieve rapid and accurate virtual screening. Compared to traditional docking methods, DrugCLIP improves the speed of virtual screening by several orders of magnitude. In terms of performance, DrugCLIP not only surpasses docking and other deep learning-based methods across two standard benchmark datasets but also demonstrates high efficacy in wet-lab experiments. Specifically, DrugCLIP successfully identified agonists with < 100 nM affinities for 5HT2AR, a key target in psychiatric diseases. For another target NET, whose structure is newly solved and not included in the training set, our method achieved a hit rate of 15%, with 12 diverse molecules exhibiting affinities better than Bupropion. Additionally, two chemically novel inhibitors were validated by structure determination with Cryo-EM. Building on this foundation, we present the results of a pioneering trillion-scale genome-wide virtual screening, encompassing approximately 10,000 AlphaFold2 predicted proteins within the human genome and 500 million molecules from the ZINC and Enamine REAL database. This work provides an innovative perspective on drug discovery in the post-AlphaFold era, where comprehensive targeting of all disease-related proteins is within reach.