bluuebunny/crossref_metadata_2025 huggingface dataset:
Eco-evolutionary dynamics of host–microbiome interactions in a natural population of closely related mouse subspecies and their hybrids
Authors: Ferreira Susana C. M. , Jarquín-Díaz Víctor Hugo , Planillo Aimara , Ďureje Ľudovít , Martincová Iva , Kramer-Schadt Stephanie , Forslund-Startceva Sofia K. , Heitlinger Emanuel
Published: December 2024

Closely related host species share similar symbionts, but the effects of host genetic admixture and environmental conditions on these communities remain largely unknown. We investigated the influence of host genetic admixture and environmental factors on the intestinal prokaryotic and eukaryotic communities (fungi, parasites) of two house mouse subspecies (
Mus musculus domesticus
and
M. m. musculus
) and their hybrids in two settings: (i) wild-caught mice from the European hybrid zone and (ii) wild-derived inbred mice in a controlled laboratory environment before and during a community perturbation (infection). In wild-caught mice, environmental factors strongly predicted the overall microbiome composition. Subspecies' genetic distance significantly influenced the overall microbiome composition, and each component (bacteria, parasites and fungi). While hybridization had a weak effect, it significantly impacted fungal composition. We observed similar patterns in wild-derived mice, where genetic distances and hybridization influenced microbiome composition, with fungi being more stable to infection-induced perturbations than other microbiome components. Subspecies' genetic distance has a stronger and consistent effect across microbiome components than differences in expected heterozygosity among hybrids, suggesting that host divergence and host filtering play a key role in microbiome divergence, influenced by environmental factors. Our findings offer new insights into the eco-evolutionary processes shaping host–microbiome interactions.
Behavioural context of call production in humpback whale calves: identification of potential begging calls in a mysticetes species
Authors: Ratsimbazafindranahaka Maevatiana Nokoloina , Huetz Chloé , Saloma Anjara , Andrianarimisa Aristide , Adam Olivier , Charrier Isabelle
Published: December 2024

Baleen whale calves vocalize, but the behavioural context and role of their social calls in mother–calf interactions are yet to be documented further. We investigated the context of call production in humpback whale (
Megaptera novaeangliae
) calves using camera-equipped animal-borne multi-sensor tags. Behavioural states, including suckling sessions, were identified using accelerometer, depth and video data. Call types were categorized through clustering techniques. We found that call types and rates predict the occurrence of a given state. Milling, resting and travelling were associated with a median call rate of 0 calls min
−1
, while surface play, tagging responses and suckling were associated with higher call rates, averaging up to a median of 0.5 calls min
−1
for suckling. Suckling sessions were mainly associated with two sets of low-frequency calls corresponding to previously described burping, barking and snorting sounds. Surface play sessions featured mid-frequency calls with whoop-like sounds and other call types. These results address the significance of vocal signalling in mother–calf communication and the calf’s development, including the first identification of potential begging calls. Overall, this study offers new insights into baleen whale behaviour, underscores the importance of social calls in mother–calf interactions and enhances our understanding of communication systems in aquatic mammalian mother–young pairs.
Sex predicts response to novelty and problem-solving in a wild bird with female-biased sexual dimorphism
Authors: Danel Samara , Rebout Nancy , Bonadonna Francesco , Biro Dora
Published: December 2024

A wide range of animals, including a number of bird, fish, mammal and reptile species, show sex differences in cognitive tests. Hardly anything is known, however, about whether and how sex-specific non-cognitive factors (e.g. response to novelty) affect the expression of cognition in the wild. We used a series of learning and problem-solving tasks in wild breeding skuas, a species in which females are the larger sex (female-biased sexual size dimorphism). We also evaluated the birds’ response to novelty (novel objects) before and after the tasks were administered. Both sexes performed equally well in learning (
Discrimination-learning task
) and re-learning (
Reversal-learning task
) food associations with colour and spatial cues, but female skuas outperformed males in problem-solving tasks (
String-pulling task
,
Box-opening task
). Females were also less neophobic than males: they were faster at accepting a food reward in novel situations. Better female performance may not imply higher cognition
per se
. Sex-specific size differences may translate into less or more neophobic behavioural types, which, in turn, predict females’ problem-solving success and response to novelty. Species with female-biased sexual dimorphism may present a useful model to assess the interactions between sex, non-cognitive factors and cognition in the wild.
Sox15is a novel retinal developmental gene that promotes cone photoreceptor differentiation through inhibition of alternative rod photoreceptor fates
Authors: Belair-Hickey Justin J. , Khalili Saeed , Coles Brenda L.K. , Ballios Brian G. , Liu Jeff C. , Bader Gary D. , van der Kooy Derek
Published: December 2024

The type of cell fate decisions a progenitor can make in the developing nervous system are dependent on a combination of cell intrinsic gene expression programs and cell extrinsic signaling molecules that influence expression programs. Moreover, both the progenitor’s spatial location in the tissue and time at which it exists during development can, to varying degrees, influence the competency of differentiation. Here, we use the developing mouse retina to understand how signaling factors in the retinal niche can influence a progenitor to become unipotentially-restricted to differentiate into cone photoreceptors, and how this competency changes over the course of retinal development. We show that the secreted inhibitory protein COCO causes progenitors to become cone-restricted, and that the competency for this restricted differentiation is maintained throughout retinal development. Using RNA-sequencing, we identify the transcription factorSox15as a potential novel marker of restricted progenitors in the developing retina, and that it acts in response to COCO’s effects. Knockdown experiments indicate that this novel retinal transcription factor promotes cone differentiation by inhibiting differentiation into alternative photoreceptor types.
Corticospinal excitability is facilitated during coordinative action observation and motor imagery of adapted single-leg sit-to-stand movements in young healthy adults
Authors: Valappil Ashika Chembila , Grilc Neža , Castelli Federico , Chye Samantha , Wright David , Tyler Christopher , Knight Ryan , Mian Omar , Tillin Neale , Bruton Adam
Published: December 2024

Combined action observation and motor imagery (AOMI) facilitates corticospinal excitability (CSE). This study used single-pulse transcranial magnetic stimulation (TMS) to explore changes in CSE for coordinative AOMI of a single-leg sit-to-stand (SL-STS) movement. Twenty-one healthy adults completed two testing sessions, where they engaged with baseline (BL), action observation (AO), and motor imagery (MI) control conditions, and three experimental conditions where they observed a slow-paced SL-STS while simultaneously imagining a slow- (AOMIHICO), medium- (AOMIMOCO), or fast-paced (AOMILOCO) SL-STS, with imagery guided through audio sonification. A TMS pulse was delivered to the right leg representation of the left primary motor cortex at three stimulation timepoints aligned with peak EMG activity of the knee extensor muscle group for the slow-, medium-, and fast-paced SL-STS during each condition. Motor evoked potential (MEP) amplitudes were recorded from the KE muscle group as a marker of CSE for all stimulation timepoints and conditions. A main effect for experimental condition was reported for all three stimulation timepoints. MEP amplitudes were significantly greater for AOMIHICO at T1 and T3, and AOMIMOCO and AOMILOCO at all stimulation timepoints, when compared with control conditions. The findings provide empirical support for the propositions of the Dual-Action Simulation Hypothesis and Visual Guidance Hypothesis accounts for coordinative AOMI. This study builds on existing neurophysiological support for the use of coordinative AOMI as an alternative method for movement (re)learning. Longitudinal research incorporating neurophysiological and behavioral measures is warranted to explore the efficacy of coordinative AOMI for this purpose.
A core set of neural states underlying memory reactivation of naturalistic events in the posterior medial cortex
Authors: Lee Yoonjung , Lee Hongmi , Chen Janice
Published: December 2024

In the posterior midline default mode network, spatial activity patterns similar to those during the initial experience are reactivated during the successful recall of past events. Prior studies have shown that these event-specific activity patterns are consistent across individuals recalling a shared experience, suggesting that common functional responses underlying episodic recall do exist. However, the spatial organization of function during episodic encoding and subsequent recall, especially in the absence of external stimuli, remains poorly understood. To address this, we leverage fMRI data collected during the encoding and recall of naturalistic movies to identify a core set of neural states in the posterior medial cortex. These states are stimulus-locked, reactivated during recall, and have a shared spatial organization across brains (i.e., individuals). We show that a surprisingly small number of these states (16 states across hemispheres) is sufficient to achieve the same levels of reactivation in the posterior medial cortex as when using the standard methods of the field. Additionally, these states are linked to actions and social-affective features of events in the movies. Our findings elucidate the properties of a common, spatially organized code within the posterior default mode network which appears during natural recollection of memories.
Exposure to low doses ofBatrachochytrium dendrobatidisreveals variation in resistance in the Critically Endangered southern corroboree frog
Authors: Davidson Mikaeylah J. , Berger Lee , Aquilina Amy , Poveda Melissa Hernandez , Guinto Daniel , McFadden Michael , Gilbert Deon , Goodall Damian , Zenger Kyall R. , Skerratt Lee F. , Kosch Tiffany A.
Published: December 2024

Chytridiomycosis poses a significant extinction threat to many amphibians, including the critically endangered southern corroboree frog (Pseudophryne corroboree). Captive breeding programs have become essential to maintain populations while effective long-term conservation strategies are developed. Understanding the variation in susceptibility to chytridiomycosis within this species is essential in exploring the potential for selective breeding to enhance disease resistance. In this study, we conducted a large-scaleBatrachochytrium dendrobatidis(Bd) exposure experiment involving 972 juvenileP. corroboreeselected to ensure a broad genetic representation of the species. Three replicate experiments were conducted under uniform conditions, to assess individual susceptibility and compare results across replicate experiments. Significant variation was observed within and between experiments, with individual survival rates ranging from 44-74% across experiments, influenced notably by the zoo in which frogs were bred. Remarkably, 21-47% of exposed frogs remainedBd-negative, suggesting potential innate resistance. Infection intensity correlated positively with body condition, in one experiment, while age and size showed inconsistent effects on survival and infection rates across experiments, but younger and smaller frogs were more susceptible to infection and had lower survival. Among frogs that became infected, none cleared infection, with most progressing to terminal stages within an average of 69 days (ranging from 33 to 97 days). However, a few individuals maintained stable infection loads without displaying clinical signs of chytridiomycosis. This observed phenotypic variation inP. corroboreeresponses toBdhighlights the potential for selective breeding to improve survival outcomes in this species. The dataset generated from this study will be instrumental in guiding breeding strategies that strengthen conservation efforts for this critically endangered species.
Comparative effectiveness of Mirror Therapy and Music Therapy on psychomotor rehabilitation of ischemic stroke: A Systematic Review and Meta-Analysis
Authors: Estévez Aída , Pérez-Nieto Miguel Ángel , Herrero Laura
Published: December 2024

The blockage of cerebral vessels is one of the most common strokes. The consequences may vary according to the location of the lesion, but psychomotor abilities are usually affected. Together with specific neurorehabilitation programs and pharmacological treatments some novel non-pharmacological therapies are emerging in recent years. In this context, the impact of both Mirror and Music therapies has been separately analyzed in different studies. However, it is not clear at a what point their true effects are similar or not. The main aim of this study was to carry out a systematic review and meta-analysis to analyze the effects of MiT and MuT over matched controls on the psychomotor recovery of ischemic stroke patients as well as to explore whether the benefits of one of them may outpace the other by using network meta-analytical technics. A total of 28 observations (Mirror therapy, N = 15; Music therapy, N = 13), from 11 randomized trials’ studies we included in the network approach analysis which includes both direct and indirect comparisons. The systematic review revealed interesting similarities in the implementation of the therapies. The results of the meta- analysis showed small to moderate significant effect sizes of both Mirror and Music therapies over paired controls and non-significant differences between them.
Temperature-driven biogeography of marine giant viruses infecting the picoeukaryoteMicromonas
Authors: Demory David , Endo Hisashi , Baudoux Anne-Claire , Bigeard Estelle , Grimsley Nigel , Simon Nathalie , Ogata Hiroyuki , Weitz Joshua S.
Published: December 2024

Climate shapes the biogeography of microbial and viral communities in the ocean. Among abiotic factors, temperature is one of the main drivers of microbial community distribution. However, we lack knowledge on how temperature shapes the life history traits, population dynamics, and the biogeography of marine viruses. This study integrates mathematical modeling with in situ observations to investigate the temperature-driven biogeography of marine viruses. We focused on prasinoviruses, a group of giant viruses that infect the picoeukaryoteMicromonas, a widespread phytoplankton with thermotypes adapted from poles to tropics. Analyzing the Tara Oceans and Polar Circle databases, we found that temperature is the primary determinant ofMicromonasvirus (MicV) distribution in the surface ocean. Phylogenetic reconstruction of MicV-s revealed that these viruses form several groups with cryophile or cryo-mesophile preferences. We applied a mechanistic model to describe temperature-driven population dynamics, allowing us to predict the global presence and absence of MicV-s. Lysis and infection emerged as reliable predictors of MicV distribution, indicating that temperature-driven cellular mechanisms significantly shape viral community structure and distribution. This study provides new insights into the role of temperature in regulating viral populations, emphasizing the importance of integrating modeling with observations to understand marine viral ecology.
Incomplete lineage sorting of segmental duplications defines the human chromosome 2 fusion site early during African great ape speciation
Authors: Jiang Xinrui , Zhang Lu , Yang Zikun , Yang Xiangyu , Ma Kaiyue , Yoo DongAhn , Lu Yong , Zhang Shilong , Chen Jieyi , Nie Yanhong , Bian Xinyan , Han Junmin , Fu Lianting , Zhang Juan , Zhang Guojie , Sun Qiang , Eichler Evan E. , Mao Yafei
Published: December 2024

All great apes differ karyotypically from humans due to the fusion of chromosomes 2a and 2b, resulting in human chromosome 2. Yet, the structure, function, and evolutionary history of the genomic regions associated with this fusion remain poorly understood. Here, we analyze finished telomere-to-telomere chromosomes in great apes and macaques to show that the fusion was associated with multiple pericentric inversions, segmental duplications (SDs), and the rapid turnover of subterminal repetitive DNA. We characterized the fusion site at single-base-pair resolution and identified three distinct SDs that originated more than 5 million years ago. These three distinct SDs were differentially distributed among African great apes as a result of incomplete lineage sorting (ILS) and lineage-specific duplication. Most conspicuously, one of these SDs shares homology to a hypomethylated SD spacer sequence present in hundreds of copies in the subterminal heterochromatin of chimpanzees and bonobos. The fusion in human was accompanied by a systematic degradation of the three divergent α-satellite arrays representing the ancestral centromere creating five distinct structural haplotypes in humans. CRISPR/Cas9-mediated depletion of the fusion site in human cell lines significantly alters the expression of 108 genes, indicating a potential regulatory consequence to this human-specific karyotypic change.
Cytokinesis-dependent twisting of HMR-1/Cadherin regulates the first left-right symmetry-breaking event inCaenorhabditis elegans
Authors: Khor Mi Jing , Sangha Gaganpreet , Sugioka Kenji
Published: December 2024

Diverse mechanisms for establishing cellular- and organismal-level left-right (L-R) asymmetry emerged during the evolution of bilateral animals, including cilia-based and actomyosin-dependent mechanisms. In pond snails andCaenorhabditis elegans, cell division plays a critical role in regulating both levels of L-R asymmetries. However, the precise mechanism by which cell division breaks cellular-level L-R symmetry remains elusive. Here, we show that cytokinesis-induced cortical flow twists the cell-cell adhesion pattern, which in turn controls the L-R asymmetrical constriction of the contractile ring, thereby breaking the first L-R body symmetry inC. elegans. During the second mitosis ofC. elegansembryos, we discovered the twisting of the HMR-1/cadherin patch at the cell-cell contact site. The HMR-1 patch twisting occurs within a few minutes upon cytokinesis onset, with individual cadherin foci within the patch exhibits directional flow and coalescence. This cell type exhibits chiral cortical flow, characterized by counter-rotational surface flows in the two halves of the dividing cell. We found that this chiral cortical flow plays a critical role in regulating HMR-1 patch twisting by inducing cadherin flow. As the HMR-1 patch twists, the contractile ring preferentially associates with HMR-1 on the right side of the embryo. We demonstrate that HMR-1 patch twisting regulates the L-R asymmetric ring closure. This study uncovers an interplay between three fundamental cellular processes—cell-cell adhesion, cytokinesis, and cell polarity— mediated by cadherin flow, shedding light on cadherin flow’s role in cellular patterning during development.
Men with long-term conditions in the Game of Stones text messaging and financial incentives trial: an exploratory mixed methods study
Authors: Macaulay Lisa , O’Dolan Catriona , Swingler James , Torrens Claire , MacLean Alice , Turner Katrina , Avenell Alison , Cotton Seonaidh , Dombrowski Stephan U , Gray Cindy M , Hunt Kate , Kee Frank , McKinley Michelle C , MacLennan Graeme , Hoddinott Pat
Published: December 2024

Men living with multiple long-term conditions and obesity are under-represented in behavioural weight management trials. Within an effective text messaging and financial incentives trial, our aim was to explore retention, secondary mental health and wellbeing outcomes, and experiences of men with multiple long-term conditions.

Methods

Mixed methods process evaluation within a 3-group randomised controlled trial: behavioural text messages with financial incentives, texts alone and waiting-list control, for 583 of 585 men with obesity. Trial retention, mental health and wellbeing outcomes, and experiences were compared for 235 (40%) participants with multiple long-term conditions, 181 (31%) with single conditions, 167 (29%) with no conditions, and for 165 (29%) with disability. Semi-structured interviews, analysed using the Framework method, explored experiences with weight trajectories. Concurrent descriptive and qualitative analyses were undertaken.

Results

Of the 235 (40%) trial participants with multiple long-term conditions, 99 were disabled and 93 were living in deprived areas. Participants with multiple long-term conditions and/or disability were older, fewer had a degree level qualification, and fewer were in full time work. Retention at 12 months was higher for men with disability (76%) or no long-term conditions (75%), and lower for men with diabetes (65%). Self-reported weight stigma, wellbeing and quality of life scores improved or stayed the same for men living with multiple long-term conditions in the intervention groups, however, results for anxiety and depression screening scores were inconsistent. Participant experiences indicated complex dynamic health, social and life situations which could provide motivation to lose weight for some but not others. Hospitalisation and poor mobility, with inability to exercise, was de-motivating for making changes to reach weight loss targets.

Conclusion

Men with multiple long-term conditions varied from very successful weight loss and improved health, to not prioritising or feeling helped by the programme or disengagement due to immobility or diabetes.
‘It would nearly put the life back into you’ Older adults’ experiences of a Community Specialist Team for Older People (CSTOP) service model in Ireland: A Qualitative Descriptive Study
Authors: Condon Brian , Griffin Anne , Delvin Collette , Fitzgerald Christine , Shanahan Elaine , Glynn Liam , Couturier Yves , O’Connor Margaret , Hayes Christina , Manning Molly , Galvin Rose , Leahy Aoife , Robinson Katie
Published: December 2024

Introduction

In Ireland, there has been a substantial recent investment in the Community Specialist Team for Older People (CST OP) service model. This approach provides timely integrated assessment and intervention for older adults in the community by a specialist multidisciplinary team. To inform the ongoing development and refinement of the CST OP service model, and ensure it is responsive to the needs and preferences of older adults, it is important to understand how older adults experience this new model of care. This qualitative descriptive study aims to resolve a research gap by exploring older adults’ experiences of the CST OP service model.

Methods

A qualitative descriptive study design was employed to explore older adults’ experiences of the CST OP service model. Purposive non-probability sampling was used to recruit 13 older adults who had completed intervention with a CST OP intervention. All interviews were completed in participants own homes, audio recorded and transcribed verbatim. A reflexive approach to thematic analysis guided data analysis.

Findings

Three themes were identified; older adults were uncertain about what to expect from the CST OP service and encountered accessibility barriers (theme1); the CST OP team provided coordinated, comprehensive care and built strong relationships with older adults (theme 2); CST OP intervention enabled older adults to better manage everyday activities and long-term conditions, thereby improving their wellbeing (theme 3).

Discussion/ conclusion

Our findings highlight the importance of CGA in community-based care for older adults. Further research is needed to address access barriers and evaluate older adults’ experiences with case management and care coordination in the CST OP service model.
Nitrogen response and growth trajectory of sorghum CRISPR-Cas9 mutants using high-throughput phenotyping
Authors: Jin Hongyu , Park Alexa , Sreedasyam Avinash , Li Guangyong , Ge Yufeng , Swaminathan Kankshita , Schmutz Jeremy , Clemente Thomas E. , Schnable James C. , Yang Jinliang
Published: December 2024

Inorganic nitrogen (N) fertilizer has emerged as one of the key factors driving increased crop yields in the past several decades; however, the overuse of chemical N fertilizer has led to severe ecological and environmental burdens. Understanding how crops respond to N fertilizer has become a central topic in plant science and plant genetics, with the ultimate goal of enhancing N use efficiency (NUE) in crop production. As one of the most essential macronutrients, N significantly influences crop performance across different developmental stages of plant, phenotypic traits result from the accumulative effects of genetic factors, prevailing environmental conditions (specifically N availability), and their complex interactions. To characterize the targeting N-responsiveness and growth trajectory, we employed CRISPR-Cas9 technique to generate sorghum mutants using CRISPR technology. Using a LemnaTec plant imaging system, we obtained time series imagery data from 29 to 130 days after sowing (DAS) for these CRISPR-edited mutants under high N and low N greenhouse conditions. After imagery data analysis, we extracted a number of morphological and greenness index traits as a proxy of plant growth and N responses. Subsequently, we employed two different methods to model the temporal N-responsive traits, allowing us to estimate seven key parameters from the growth curve. Our findings revealed that the wildtype and the edited sorghum lines exhibited differences in N responses for several of the key growth-related parameters. The high-throughput N phenotyping pipeline paves the way for a better understanding of the N responses of edited lines in a dynamic manner and sheds light on further improvements in crop NUE.
Emergence ofCandida aurisin Minas Gerais, Brazil: Genomic Surveillance to inform Rapid Public Health Responses
Authors: Tomé Luiz Marcelo Ribeiro , Camargo Dhian Renato Almeida , Bastos Rafael Wesley , dos Santos Sara Cândida Ferreira , Guimarães Natália Rocha , Pedroso Sílvia Helena Sousa Pietra , de Souza da Silva Paulo Eduardo , Góes-Neto Aristóteles , de Assis Figueredo Lida Jouca , da Côrte Castro Gabriella , Rodrigues Ana Maria Ribeiro Nunes , Cruzeiro Flavia Ribeiro Soares , Dutra Nádia Aparecida Campos , Moura Josiane Barbosa Piedade , de Carvalho Pereira Glauco , Faria Carmem Dolores , Giovanetti Marta , de Melo Iani Felipe Campos , Alcantara Luiz Carlos Júnior , Adelino Talita Émile Ribeiro
Published: December 2024

Candida aurisposes a significant global health threat due to its multidrug-resistance and outbreak potential. In this study, we report its emergence in Minas Gerais, Brazil, supported by genomic surveillance that identified Clade-IV isolates, suggested a potential introduction from Colombia, and detected a missense mutation associated with azole resistance.
Global lymphatic filariasis post-validation surveillance activities in 2024: A systematic review protocol
Authors: Jian Holly , Lawford Harriet , McLure Angus , Lau Colleen , Craig Adam
Published: December 2024

Introduction

Lymphatic filariasis (LF) is a neglected tropical disease caused by infection with parasitic worms, spread by mosquitoes. In countries where LF is validated as eliminated as a public health problem by the World Health Organization (WHO), post-validation surveillance (PVS) is required to ensure recrudescence has not occurred and verify the sustained elimination of transmission. However, it is unclear what PVS strategies should be applied, how PVS strategies should be tailored to meet country capacity and need, and whether currently used approaches align with upcoming WHO guidelines.

Objectives

This study will aim to review available evidence on PVS implementation in countries previously endemic for LF; examine barriers and facilitators to PVS implementation; critique alignment in PVS activities with international guidelines; and identify knowledge gaps in PVS implementation that may be addressed through further research.

Methods

We will search four databases (PubMed, Scopus, Embase and Web of Science) for peer-reviewed literature and the WHO Institutional Repository for Information Sharing (IRIS) database for grey literature. Documents published between January 1, 2007 and November 5, 2024 will be included. Two reviewers will independently screen studies based on a priori inclusion and exclusion criteria. The quality of included studies will be assessed using the Joanna Briggs Institute Critical Appraisal Checklist, and deductive content analysis will be conducted to synthesise data. The study will also examine alignment with upcoming WHO PVS guidelines.

Conclusion

This review will systematically collate and analyse available literature on PVS of LF, which, to our knowledge, has not yet been conducted. Our study will synthesise knowledge in this field and provide an evidence base which may be used to guide the design of future PVS strategies.

This protocol has been registered in PROSPERO (registration ID:CRD42024618436).
Sepsis induces long-term reprogramming of human HSPCs and drives myeloid dysregulation in sepsis survivors
Authors: De Zuani Marco , Lázničková Petra , Hortová Kohoutková Marcela , Bosáková Veronika , Andrejčinová Ivana , Vadovičová Natália , Tomášková Veronika , Mýtniková Alexandra , Štíchová Julie , Tomáš Tomáš , Hrdý Jiří , Boráková Kristýna , Uldrijan Stjepan , Vlková Marcela , Šrámek Vladimír , Helán Martin , Bendíčková Kamila , Frič Jan
Published: December 2024

Sepsis is a life-threatening condition characterised by an overwhelming immune response and high fatality. While most research has focused on its acute phase, many sepsis survivors remain immunologically weakened leaving them susceptible to serious complications from even mild infections. The mechanisms underlying this prolonged immune dysregulation remain unclear, limiting effective interventions. Here, we analysed whether sepsis induced long-term “training” in hematopoietic stem and progenitor cells (HSPCs), imprinting changes that persist in their myeloid progeny. Peripheral blood analysis of 8 sepsis survivors, 12 patients with septic shock, and 10 healthy donors revealed a significant expansion of CD38+ progenitors in survivors, with increases in megakaryocyte-erythroid and granulocyte-monocyte progenitors, and reduced mature neutrophil counts. This shift suggests impaired granulopoiesis, favouring immature, immunosuppressive granulocytes. Differentiated macrophages from survivors’ HSPCs exhibited impaired metabolic pathways after lipopolysaccharide stimulation, with downregulation of tricarboxylic acid cycle and glycolysis genes, indicating altered immune metabolism. Pathway analysis revealed enhanced type-I interferon (IFN) and JAK-STAT signalling in survivors’ macrophages, reflective of potentially tolerance-prone reprogramming. Finally, exposing healthy donor HSPCs to IFNβ during macrophage differentiation reduced HSPC proliferation, increased apoptosis, and induced a metabolic shift towards glycolysis over mitochondrial respiration. Together, these findings suggest that sepsis induces lasting reprogramming in HSPCs leading to myeloid progeny with altered immune memory that might drive immune dysregulation in survivors. These data open avenues to explore potential targets to better manage long-term immune alterations in sepsis survivors.

KEY POINTS

Sepsis induces long-term alterations in HSPCs, leading to the expansion of immature progenitors and metabolic dysregulation of their progeny.

Type-I IFN signalling reprograms macrophage differentiation, affecting their metabolic function and reducing cell proliferation.
Controlled by disorder: phosphorylation modulates SRSF1 domain availability for spliceosome maturation
Authors: Fargason Talia , Powell Erin , De Silva Naiduwadura Ivon Upekala , Paul Trenton , Prevelige Peter , Zhang Jun
Published: December 2024

Serine/arginine-rich splicing factor 1 (SRSF1) is key in the mRNA lifecycle including transcription, splicing, nonsense-mediated decay, and nuclear export. Consequently, its dysfunction is linked to cancers, viral evasion, and developmental disorders. The functionality of SRSF1 relies on its interactions with other proteins and RNA molecules. These processes are regulated by phosphorylation of its unstructured arginine/serine-rich tail (RS). Here, we characterize how phosphorylation affects SRSF1’s protein and RNA interaction and phase separation. Using NMR paramagnetic relaxation enhancement and chemical shift perturbation, we find that when unphosphorylated, SRSF1’s RS interacts with its first RNA-recognition motif (RRM1). Phosphorylation of RS decreases its interactions with RRM1 and increases its interactions with the RNA-binding site. This change in SRSF1’s intramolecular interactions increases the availability of protein-interacting sites on RRM1 and weakens RNA binding of SRSF1. Phosphorylation alters the phase separation of SRSF1 by diminishing the role of arginine in intermolecular interactions. These findings provide an unprecedented view of how SRSF1 influences the early-stage spliceosome assembly.

Phosphorylation of SRSF1 is pivotal in pre-mRNA processing and is dysregulated in various pathologies. Modeling of SRSF1 based on NMR restraints reveals phosphorylation alters the accessibility of protein-protein and protein-RNA interaction sites on SRSF1’s RRM1 domain, altering its binding preferences
Modeling Bias Toward Binding Sites in PDB Structural Models
Authors: Wankowicz Stephanie A.
Published: December 2024

The protein data bank (PDB) is one of the richest databases in biology. The structural models deposited have provided insights into protein folds, relationships to evolution, energy functions of structures, and most recently, protein structure prediction, connecting sequence to structure. However, the X-ray crystallography (and cryo-EM) models deposited in the PDB are determined by a combination of refinement algorithms and manual modeling. The intervention of human modeling leads to the possibility that within a single structure, there can be differences in how well parts of a structure are modeled and/or fit the underlying experimental data. We identified that small molecule binding sites are more carefully modeled and better match the underlying experimental data than the rest of the protein structural model. This trend persisted irrespective of the structure’s resolution or its overall agreement with the experimental data. The variation of modeling has implications for how we interpret protein structural models and use structural models in explaining mechanisms, structural bioinformatics, simulations, docking, and structure prediction, especially when drawing conclusions about binding sites compared to the rest of the protein.
Effects of a Water, Sanitation, and Hygiene Program on Diarrhea and Child Growth in the Democratic Republic of the Congo: A Cluster-Randomized Controlled Trial of the Preventative-Intervention-for-Cholera-for-7-Days (PICHA7) Program
Authors: George Christine Marie , Sanvura Presence , Bisimwa Jean-Claude , Endres Kelly , Namunesha Alves , Felicien Willy , Banywesize Blessing Muderhwa , Williams Camille , Perin Jamie , Sack David A , Boroto Raissa , Nsimire Gisèle , Rugusha Feza , Endeleya Freddy , Kitumaini Pacifique , Lunyelunye Claude , Buhendwa Emmanuel , Bujiriri Pascal Kitumaini , Tumusifu Jessy , Munyerenkana Brigitte , Caulfield Laura E. , Bengehya Justin , Maheshe Ghislain , Cikomola Cirhuza , Mwishingo Alain , Bisimwa Lucien
Published: December 2024

Background

We assessed whether the Preventative-Intervention-for-Cholera-for-7-Days (PICHA7) program reduced diarrhea and improved child growth in the Democratic Republic of the Congo (DRC).

Methods

The PICHA7 cluster-randomized controlled trial enrolled diarrhea patient households in urban Bukavu, DRC. Households were randomized into two arms: single in-person visit for the DRC government’s diarrhea patient standard message on oral rehydration solution use and a basic WASH message (standard arm); or this standard message and the PICHA7 program with quarterly in-person visits and weekly voice and text mobile health messages (mHealth) (PICHA7 arm). The primary outcome was diarrhea in the past two weeks assessed monthly for 12 months. Secondary outcomes were diarrhea with rice water stool, healthcare facility visits for diarrhea, stunting, underweight, and wasting over 12 months. Generalized estimating equations were used for regression models to account for clustering at the individual and household level.

Results

Between December 2021 and December 2022, 2334 participants in 359 households were randomly allocated to two arms: 1138 standard arm and 1196 PICHA7 arm. Diarrhea prevalence during the 12 month surveillance period was significantly lower among PICHA7 arm participants (Prevalence Ratio: 0.39 (95% Confidence Interval (CI): 0.32, 0.48). PICHA7 arm participants had lower odds of diarrhea with rice water stool (Odds Ratio (OR): 0.48 (95% CI: 0.27, 0.86)), and lower odds of visiting a healthcare facility for diarrhea during the 12 month surveillance period (OR: 0.44 (95% CI: 0.25, 0.77)). PICHA7 arm children 0-4 were significantly less likely to be stunted (52% vs. 63% standard arm) (OR: 0.65 (95% CI: 0.43, 0.98)) at the 12 month follow-up. All WASH components had high adherence.

Conclusion

The PICHA7 program which combines mHealth with quarterly in-person visits lowered diarrhea prevalence and stunting in the DRC.

Clinical Trials Registration

NCT05166850.

Key Points

The PICHA7 program combines mHealth with in-person visits and was assessed with a randomized controlled trial. Compared to the standard arm, the PICHA7 program lowered diarrhea prevalence for all ages and reduced stunting in children 0-4 years in the DRC.
Early brain changes in Lyme disease are associated with clinical outcomes
Authors: Marvel Cherie L. , Rebman Alison W. , Alm Kylie H. , Touradji Pegah , Bakker Arnold , Nadkarni Prianca A. , Bhattacharya Deeya , Morgan Owen P. , Mistri Amy , Sandino Christopher C. , Ecker Jonathan A. , Kozero Erica A. , Venkatesan Arun , Moghekar Abhay , Keeys Ashar A. , Aucott John N.
Published: December 2024

Background and Objectives

In Lyme disease (LD), 10-20% of patients develop persistent symptoms following antibiotic treatment (i.e., post-treatment Lyme disease (PTLD)), which often includes neurological symptoms. Little is known about how the brain is affected by LD. This study tested the hypothesis that brain changes occur early in LD and influence clinical outcomes.

Methods

In this case-control study, a working memory task was administered during functional MRI (fMRI), in conjunction with cognitive assessments and health surveys, in people with acute LD after antibiotic treatment [i.e., “baseline”] and six months later. A healthy control (HC) group was also assessed six months apart. The LD group was retrospectively categorized into those who returned to health (RTH) and those who reported persistent symptoms (sPTLD). FMRI data from both LD subgroups were compared to the HC group at both time points. Brain regions of interest (ROI) values were obtained from the fMRI results and correlated to cognitive performance and health survey scores.

Results

There were no differences in demographic characteristics [n, % male, mean age (range), mean days after end of initial antibiotic treatment (range)] among RTH [11, 45%, 56.5 (28.4- 78.2), 16.9 (-1.0-51.0)], sPTLD (9, 67%, 47.1 (26.2-66.6), 13.0 (6.0-20.0), and HC [19, 32%, 46.5 (19.4-59.9)]. Baseline brain activity in RTH increased relative to sPTLD and HC, p <.0025 and p <.001, respectively. Notably, 64% of the RTH group’s activation clusters were in white matter, confirmed by segmentation analysis. ROIs created from the RTH vs. HC fMRI results, including white matter regions, correlated with higher (better) health survey scores. At the 6-month follow-up, most of the RTH group’s activity had normalized compared to HC. The sPTLD group showed few fMRI activation differences versus the HC group at either time point, and no significant associations were observed between ROI values and health survey scores.

Discussion

Increased brain activity in early LD was associated with better health survey scores and RTH status six months later. The absence of such brain changes was associated with persistent symptoms. Understanding how increased brain activity contributes to RTH in LD will aid early identification of those most vulnerable to developing PTLD and guide treatment intervention.
A Hot-Swappable Genetic Switch: Building an inducible and trackable functional assay for the essential gene MEDIATOR 21
Authors: Watson Isabella J. , Maranas Cassandra , Nemhauser Jennifer L , Leydon Alexander R
Published: December 2024

Essential genes, estimated at approximately 20% of theArabidopsisgenome, are broadly expressed and required for reproductive success. They are difficult to study, as interfering with their function leads to premature death. Transcription is one of the essential functions of life, and the multi-protein Mediator complex coordinates the regulation of gene expression at nearly every eukaryotic promoter. In this study, we focused on a core Mediator component called MEDIATOR21 (MED21), which is required for activation of transcription. Our previous work has also shown a role for MED21 in repression of gene expression through its interaction with a corepressor protein. Here, we sought to differentiate the role MED21 plays in activation versus repression using the model plantArabidopsis. As mutations in MED21 lead to embryo lethal phenotypes, we constructed a set of synthetic switches using PhiC31 serine integrases to create an “on-to-off” inducible loss of function MED21 in a non-essential tissue. Our technology, which we call Integrase Erasers, made it possible formed21mutant plants to survive into adulthood by ablating protein expression selectively in lateral root primordia, allowing quantification and characterization ofmed21mutant phenotypes in a post-embryonic context. In addition, we engineered chemical induction of the Integrase Eraser to ablate MED21 expression in whole seedlings at a user-specified timepoint. Finally, we extended this technology to build a hot swappable Integrase Isoform Switch where expression of the integrase toggled cells from expressing wildtype MED21 to expressing MED21 sequence variants. Our analysis of the entire set of new integrase-based tools demonstrates that this is a highly efficient and robust approach to the study of essential genes.
Reanalysis of metabolomics data reveals that microbiota transfer therapy modulates important fecal and plasma metabolite profiles in children with autism spectrum disorders
Authors: Nirmalkar Khemlal , Qureshi Fatir , Kang Dae-Wook , Hahn Juergen , Adams James B. , Krajmalnik-Brown Rosa
Published: December 2024

While Autism Spectrum Disorder (ASD) is diagnosed through behavioral symptoms and psychometric evaluations, it has also been associated with distinct metabolomic patterns. A previous clinical trial of Microbiome Transfer Therapy (MTT) in children with ASD and gastrointestinal (GI) issues revealed significant differences in plasma metabolomics between children with ASD and their typically developing (TD) counterparts, which diminished after MTT. The objective of this study was to reanalyze the plasma and fecal samples using updated metabolomics libraries at Metabolon, applying a comprehensive panel of statistical methods. This approach aimed to provide deeper insights into ASD-related metabolic differences and the impact of MTT. The reanalysis identified more statistically significant metabolites and highlighted specific metabolites whose relative intensities differed between the ASD and TD groups, as well as metabolites with significant changes in intensity post-MTT. Several plasma metabolites, including sarcosine, iminodiacetate, caproate, and caprylate, initially showed significant differences between the ASD and TD groups but shifted to resemble TD levels after MTT treatment. In fecal samples, p-cresol sulfate and sphingolipids emerged as metabolites with altered intensities following MTT treatment. Multivariate Fisher’s Discriminant Analysis (FDA) with leave-one-out cross-validation revealed that a set of metabolites—including p-cresol sulfate, hydroxyproline, and caprylate—could robustly classify the ASD and TD cohort’s pre-treatment. However, after treatment, the same FDA model could not distinguish the two groups, as the FDA scores became similar to those of the TD cohort. Our findings enhance the understanding of ASD-associated metabolic changes and highlight the potential of MTT to influence these profiles. This underscores the importance of reanalysis using updated databases and robust statistical methods for comparative analysis. Further studies with larger cohorts and placebo-controlled trials are necessary to validate these results and explore the biochemical pathways involved, paving the way for personalized treatment approaches.
Frequent gastrointestinal cancer complications in Japanese patients with coronary syndromes undergoing percutaneous coronary intervention
Authors: Chiba Yasuyuki , Imagawa Shogo , Takahashi Yuki , Kubo Kimitoshi , Otsuka Kenta , Shimazu Kyo , Anzai Teisuke , Yonezawa Kazuya , Kato Mototsugu , Anzai Toshihisa
Published: December 2024

Background

Gastrointestinal bleeding is a major complication of dual antiplatelet therapy (DAPT) in patients undergoing percutaneous coronary intervention (PCI). Malignancy may be detected due to gastrointestinal bleeding, necessitating critical decisions regarding treatment selection and influencing patient prognosis. This study investigated the frequency of gastrointestinal malignancies, associated factors, and prognoses in patients undergoing perioperative PCI through upper and lower gastrointestinal endoscopy.

Methods

This single-center, retrospective, observational study included 501 Japanese patients who underwent initial PCI between January 2019 and January 2023. Of these patients, 393 who underwent perioperative upper and lower gastrointestinal endoscopy were evaluated for the presence of gastrointestinal malignancy.

Results

Of the total patients, 36% presented with acute coronary syndrome (ACS). Gastrointestinal malignancies were identified in 30 patients (8%), including 18 cases of colorectal cancer and eight cases of gastric cancer. No difference in the frequency of malignancies was observed between patients with ACS and chronic coronary syndrome (CCS) (p = 0.7398). Malignancies were significantly more common in patients with positive faecal immunochemical testing (FIT) (p < 0.0001); however, FIT did not detect all malignancies. The 1500-day survival rate for patients with gastrointestinal malignancies was 64%, with no difference in overall survival between treatment modalities.

Conclusions

A considerable proportion of Japanese patients undergoing PCI had gastrointestinal malignancies, regardless of whether they had ACS or CCS, and their prognosis was poor. Upper and lower gastrointestinal endoscopic evaluations should be conducted, including for ACS cases, to prevent DAPT-induced gastrointestinal bleeding and improve prognosis.