bluuebunny/crossref_metadata_2025 huggingface dataset:
PheMIME: An Interactive Web App and Knowledge Base for Phenome-Wide, Multi-Institutional Multimorbidity Analysis
Authors: Zhang Siwei , Strayer Nick , Vessels Tess , Choi Karmel , Wang Geoffrey W , Li Yajing , Bejan Cosmin A , Hsi Ryan S , Bick Alexander G. , Velez Edwards Digna R , Savona Michael R , Philips Elizabeth J , Pulley Jill , Self Wesley H , Hopkins Wilkins Consuelo , Roden Dan M , Smoller Jordan W. , Ruderfer Douglas M , Xu Yaomin
Published: July 2023

Motivation

Multimorbidity, characterized by the simultaneous occurrence of multiple diseases in an individual, is an increasing global health concern, posing substantial challenges to healthcare systems. Comprehensive understanding of disease-disease interactions and intrinsic mechanisms behind multimorbidity can offer opportunities for innovative prevention strategies, targeted interventions, and personalized treatments. Yet, there exist limited tools and datasets that characterize multimorbidity patterns across different populations. To bridge this gap, we used large-scale electronic health record (EHR) systems to develop the Phenome-wide Multi-Institutional Multimorbidity Explorer (PheMIME), which facilitates research in exploring and comparing multimorbidity patterns among multiple institutions, potentially leading to the discovery of novel and robust disease associations and patterns that are interoperable across different systems and organizations.

Results

PheMIME integrates summary statistics from phenome-wide analyses of disease multimorbidities. These are currently derived from three major institutions: Vanderbilt University Medical Center, Mass General Brigham, and the UK Biobank. PheMIME offers interactive exploration of multimorbidity through multi-faceted visualization. Incorporating an enhanced version of associationSubgraphs, PheMIME enables dynamic analysis and inference of disease clusters, promoting the discovery of multimorbidity patterns. Once a disease of interest is selected, the tool generates interactive visualizations and tables that users can delve into multimorbidities or multimorbidity networks within a single system or compare across multiple systems. The utility of PheMIME is demonstrated through a case study on schizophrenia.

Availability and implementation

The PheMIME knowledge base and web application are accessible athttps://prod.tbilab.org/PheMIME/. A comprehensive tutorial, including a use-case example, is available athttps://prod.tbilab.org/PheMIME_supplementary_materials/.

Furthermore, the source code for PheMIME can be freely downloaded fromhttps://github.com/tbilab/PheMIME.

Data availability statement

The data underlying this article are available in the article and in its online web application or supplementary material.
Facial Palsy and the eyes: Epidemiology, Tear Film, and Meibomian gland dysfunction; a comparative analysis
Authors: Guerrero-de Ferran Caroline , Rivera-Alvarado Jocelyn I. , Bastán-Fabián Daniel , Del Castillo-Morales Alfredo , Velázquez-Valenzuela Fabiola , Valdez García Jorge E.
Published: July 2023

Purpose

To describe the correlation between facial palsy of any etiology and Meibomian gland dysfunction and to report the tear film parameters found in patients with facial palsy diagnosis.

Design

Observational, longitudinal, and comparative study.

Methods

A sample of 20 patients with unilateral facial palsy was obtained its severity was staged using the House-Brackmann scale. A dry eye evaluation using an Oculus 5M keratograph was performed, which included infrared meibography, tear breakup time, and a dry eye questionnaire. Meibographies were analyzed using ImageJ software to determine the affected area.

Results

11 patients (55%) were female, mean age of diagnosis was 57.80 ± 18.28 (range of 22-80), 10 (50%) cases were due to Bell’s palsy. Tear breakup time was markedly reduced in the affected side but was statistically insignificant (p=0.2167) and tear meniscus height was much greater in the non-affected side (p=0.0199). Finally, Meibomian gland alterations were more evident in the affected side, with upper Meibomian glands having a loss of 29.55 ± 13.31 percent (p=0.0374) and lower glands presenting a loss 44.44 ± 16.9 percent (p=<0.001).

Conclusions

A clear difference in Meibomian gland and tear film dynamics can be observed in paretic vs non paretic sides in the same patients. Multiple mechanisms contribute to this ailment, such as an incomplete blinking pattern and Meibomian gland dysfunction due to orbicularis oculi weakness. Software based analysis also showed a greater glandular area loss when compared to clinician’s analysis, which may help aide in therapeutic decisions for patients with meibomian gland dysfunction.
One-Year Follow-up of Young People with ME/CFS Following Infectious Mononucleosis by Epstein-Barr Virus
Authors: Pricoco Rafael , Meidel Paulina , Hofberger Tim , Zietemann Hannah , Mueller Yvonne , Wiehler Katharina , Michel Kaja , Paulick Johannes , Leone Ariane , Haegele Matthias , Mayer-Huber Sandra , Gerrer Katrin , Mittelstrass Kirstin , Scheibenbogen Carmen , Renz-Polster Herbert , Mihatsch Lorenz , Behrends Uta
Published: July 2023

Background

Infectious mononucleosis, caused by the Epstein-Barr Virus (EBV-IM), has been linked to the development of myalgic encephalomyelitis/chronic fatigue-syndrome (ME/CFS) in children, adolescents, and young adults. Our study presents the first cohort of young individuals in Germany who were diagnosed with ME/CFS following EBV-IM.

Methods

We conducted a one-year follow-up of 25 young people diagnosed with ME/CFS at our specialized tertiary outpatient service by clinical criteria requiring post-exertional malaise and with documented EBV-IM as the triggering event. Demographic information, laboratory findings, frequency and severity of symptoms, physical functioning, and health-related quality of life (HRQoL) were assessed at first visit as well as 6 and 12 months later at follow-up visits.

Results

The physical functioning and HRQoL of the cohort were significantly impaired, with young adults displaying more severe symptoms, as well as worsening of fatigue, physical and mental functioning, and HRQoL throughout the study, compared to adolescents. After one year, we found that 6/12 (54%) adolescents no longer met the diagnostic criteria for ME/CFS, indicating partial remission, while all young adults continued to fulfill the Canadian consensus criteria. Improvement in children was evident in physical functioning, symptom frequency and severity, and HRQoL, while young adults had little improvement. EBV serology and EBV DNA load did not correlate with distinct clinical features of ME/CFS, and clinical chemistry showed no evidence of inflammation. Remarkably, the median time from symptom onset to ME/CFS diagnosis was 13.8 (IQR: 9.1–34.9) months.

Conclusions

ME/CFS following EBV-IM in young people is a severely debilitating disease with diagnoses protracted longer than one year in many patients and only limited responses to conventional symptom-oriented medical care. Although younger children may have a better prognosis, their condition can fluctuate and significantly impact their HRQoL. Our data emphasize that biomarkers and effective therapeutic options are also urgently needed for this very young age group to better manage their medical condition and pave the way to recovery.
Gut microbiota and faecal cytokine profiles of rural Cambodian infants and links to early life nutrition and diarrhoeal episodes
Authors: Dalby Matthew J , Kiu Raymond , Serghiou Iliana R , Miyazaki Asuka , Acford-Palmer Holly , Tung Rathavy , Caim Shabhonam , Phillips Sarah , Kujawska Magdalena , Matsui Mitsuaki , Iwamoto Azusa , Taking Bunsreng , Cox Sharon E , Hall Lindsay J
Published: July 2023

The gut microbiota of infants in low-middle income countries like Cambodia remain underrepresented in microbiome research. This study aimed to explore the faecal gut microbiota composition and faecal cytokine profiles in a cohort of infants living in a rural province of Cambodia and explore the impact of sample storage conditions and infant environment on microbiota composition. Faecal samples collected at three time points from 32 infants (96 samples in total) after 7 months of age were analysed using 16S rRNA amplicon sequencing to determine the composition of the microbiota. Bacterial strains were isolated and subjected to whole genome sequencing and genomic analysis and concentrations of faecal cytokines were also measured. Initially, we compared the effects of two sample collection methods due to the challenges of faecal sample collection and storage in a rural location. Storage of faecal samples in a DNA preservation solution retained a greater abundance ofBacteroides. Analyses of microbiota composition of samples stored in DNA preservation solution indicated thatBifidobacteriumwas the most abundant genus withBifidobacterium longumthe most abundant species, particularly in breastfed infants. Most infants had detectable pathogenic taxa indicating frequent pathogen exposure, withShigellaandKlebsiellamore abundant in infants with recent diarrheal illness. We did not detect antibiotic-associated perturbations in the gut microbiota, and no associations were found between the gut microbiota and infant growth. Genomic analysis of isolated strains indicated the presence of gene clusters encoding the ability to digest human milk oligosaccharides inB. longumandBifidobacterium breveisolates. The presence of antibiotic-resistant genes was also identified in potentially pathogenic species, as well as in beneficial genera includingBifidobacterium. Faecal cytokine analysis showed higher concentrations of Interlukin-1alpha and vascular endothelial growth factor in breastfed infants, which may influence the infant gut mucosal immune system. This study provides insights into an underrepresented population of rural Cambodian infants, emphasising the impact of pathogen exposure and breastfeeding on gut microbiota composition and faecal immune profiles.
A Versatile Tool for Precise Variant Calling in Mycobacterium tuberculosis Genetic Polymorphisms
Authors: Razzak Safina Abdul , Hasan Zahra , Azim M. Kamran , Kanji Akbar , Shakoor Sadia , Hasan Rumina
Published: July 2023

Background

Whole genome sequencing (WGS) facilitates the diagnosis of multidrug-resistant MDR-TB through the interpretation of sequence variations (SV) inMycobacterium tuberculosis(MTB) genes. Information on phenotypic and genotypic resistance associations continues to evolve, it is important to identify SV within genes of interest. We developed an MTB-VCF variant calling pipeline that can compare against the reference genome for any gene of interest. We demonstrate its utility for calling SV in genes associated with Rifampicin (RIF), Isoniazid (INH), Ethambutol (EM), and Streptomycin (SM) resistance.

Methods

MTB-VCF is a Python-based command line Variant Calling pipeline designed to streamline batch processing from raw reads (FastQ) files. SV called by MTB-VCF were compared with those identified by TBProfiler, KVARQ, CASTB, Mykrobe Predictor and Phy-ResSE pipelines. The sensitivity and Specificity of MTB-VCF SV calling were calculated against the drug susceptibility testing (DST) phenotype.

Results

MTB-VCF identified 868 SV present in 200 phenotypically resistant MDR-TB isolates. These were acrossrpsl, rrs, rpoB, inhA,katG,ahpC,gidB andembCAB genes. Of these, 684 SV were known to be associated with a resistance genotype, leading to a specificity of 97.75%. The SV called by the MTB-VCF was compared separately to resistance genotypes called by TB-Profiler, KvarQ, CASTB, Mykrobe Predictor, and PhyRes-SE pipelines, demonstrating a sensitivity of 99.5%.

Conclusion

The MTB-VCF pipeline offers a rapid and accurate solution for identifying SV in target genes for interpretation later. It can be run in large batches, proving flexible computing that allows for the customization of core bioinformatic pipelines, enabling the analysis of WGS data from different technologies.
Phytoplankton tune local pH to actively modulate circadian swimming behavior
Authors: Ghoshal Arkajyoti , Dhar Jayabrata , Grossart Hans-Peter , Sengupta Anupam
Published: July 2023

Diel vertical migration (DVM), the diurnal exodus of motile phytoplankton between the light- and nutrient-rich aquatic regions, is governed by endogenous biological clocks. Many species exhibit irregular DVM patterns wherein out-of-phase gravitactic swimming–relative to that expected due to the endogenous rhythm–is observed. How cells achieve and control this irregular swimming behavior, and its impact on biological fitness remain poorly understood. Combining local environmental monitoring with behavioral and physiological analyses of motile bloom-formingHeterosigma akashiwocells, we report that phytoplankton species modulate their DVM pattern by progressively tuning local pH, yielding physiologically equivalent yet behaviorally distinct gravitactic sub-populations which remain separated vertically within a visibly homogeneous cell distribution. Individual and population-scale tracking of the isolatedtopandbottomsub-populations revealed similar gravitactic (swimming speed and stability) and physiological traits (growth rate and maximum photosynthetic yield), suggesting that the sub-populations emerge due to mutual co-existence. Exposing the top (bottom) sub-population to the spent media of the bottom (top) counterpart recreates the emergent vertical distribution, while no such phenomenon was observed when the sub-populations were exposed to their own spent media. A model of swimming mechanics based on the quantitative analysis of cell morphologies confirms that the emergent sub-populations represent distinct swimming stabilities, resulting from morphological transformations after the cells are exposed to the spent media. Together with the corresponding night-time dataset, we present an integrated picture of the circadian swimming, wherein active chemo-regulation of the local environment underpins motility variations for potential ecological advantages via intraspecific division of labor over the day-night cycle. This chemo-regulated migratory trait offers mechanistic insights into the irregular diel migration, relevant particularly for modelling phytoplankton transport, fitness and adaptation as globally ocean waters see a persistent drop in the mean pH.

One sentence summary

Active regulation of local pH diversifies the diel vertical migration of motile phytoplankton.
Phenotypic effect ofGBA1variants in individuals with and without Parkinson disease: the RAPSODI study
Authors: Toffoli M , Chohan H , Mullin S , Jesuthasan A , Yalkic S , Koletsi S , Menozzi E , Rahall S , Limbachiya N , Loefflad N , Higgins A , Bestwick J , Lucas-Del-Pozo S , Fierli F , Farbos A , Mezabrovschi R , Lee-Yin C , Schrag A , Moreno-Martinez D , Hughes D , Noyce A , Colclough K , Jeffries AR , Proukakis C , Schapira AHV
Published: July 2023

Background

Variants in theGBA1gene cause the lysosomal storage disorder Gaucher disease (GD). They are also risk factors for Parkinson disease (PD), and modify the expression of the PD phenotype.

The penetrance ofGBA1variants in PD is incomplete, and the ability to determine who amongstGBA1variant carriers are at higher risk of developing PD, would represent an advantage for prognostic and trial design purposes.

Objectives

To compare the motor and non-motor phenotype ofGBA1carriers and non-carriers.

Methods

We present the cross-sectional results of the baseline assessment from the RAPSODI study, an online assessment tool for PD patients andGBA1variant carriers. The assessment includes clinically validated questionnaires, a tap-test, the University of Pennsyllvania Smell Identification Test and cognitive tests. Additional, homogeneous data from the PREDICT-PD cohort were included.

Results

A total of 379 participants completed all parts of the RAPSODI assessment (89GBA1-negative controls, 169GBA1-negative PD, 47GBA1-positive PD, 47 non-affectedGBA1carriers, 27 GD). Eightysix participants were were recruited through PREDICT-PD (43 non-affectedGBA1carriers and 43GBA1-negative controls).GBA1-positive PD showed worse performance in visual cognitive tasks and olfaction compared toGBA1-negative PD patients. No differences were detected between non-affectedGBA1carriers carriers andGBA1-negative controls. No phenotypic differences were observed between any of the non-PD groups.

Conclusions

Our results support previous evidence thatGBA1-positive PD has a specific phenotype with more severe non-motor symptoms. However, we did not reproduce previous findings of more frequent prodromal PD signs in non-affectedGBA1carriers.
Remote Digital Cognitive Assessment Reveals Cognitive Deficits Related to Hippocampal Atrophy in Autoimmune Limbic Encephalitis
Authors: Shibata Kengo , Attaallah Bahaaeddin , Tai Xin-You , Trender William , Hellyer Peter J. , Hampshire Adam , Irani Sarosh R , Manohar Sanjay G , Husain Masud
Published: July 2023

Autoimmune Limbic Encephalitis (ALE) is a neurological disease characterised by inflammation of the limbic regions of the brain, mediated by pathogenic autoantibodies. Because cognitive deficits persist following acute treatment of ALE, the accurate assessment of long-term cognitive outcomes is important for clinical assessments and trials. However, evaluating cognition is costly and an unmet need for validated digital methods exists. We investigated whether remote digital methods could identify previously characterised cognitive impairments in ALE patients and would correlate with standard neuropsychological assessment and hippocampal volume. The cognitive performance of 21 chronic ALE patients along with 54 age-matched healthy controls was assessed with a battery of 12 cognitive tasks from the Cognitron online platform. ALE patients performed significantly worse in memory, visuospatial abilities, executive function, and language. No impairments in digit & spatial span, target detection (attention) and emotion discrimination were observed. The global score on the online cognitive tasks correlated significantly with the established Addenbrooke’s Cognitive Examination III (ACE) pen-and-paper test. Deficits in visuospatial processing and language were identified in ALE compared to controls using remote digital testing but not the ACE, highlighting higher sensitivity of computerised testing to residual cognitive impairment. Finally, the hippocampal volume of ALE patients and healthy controls correlated with online cognitive scores. Overall, these findings demonstrate that remote, online testing may facilitate the characterisation of cognitive profiles in complex neurological diseases.
US Exceptionalism? International Trends in Midlife Mortality
Authors: Dowd Jennifer Beam , Doniec Katarzyna , Zhang Luyin , Tilstra Andrea
Published: July 2023

Background

Rising midlife mortality in the United States (US) has raised concerns, particularly the increase in “deaths of despair” (due to drugs, alcohol, and suicide). While life expectancy is also stalling in other countries such as the UK, whether midlife mortality is rising outside the US is not known.

Methods

We document trends in midlife mortality in the US, UK and a group of 16 high-income countries in Western Europe, Australia, Canada, New Zealand, and Japan, as well as 7 Central and Eastern European (CEE) countries from 1990-2019. We use annual mortality data from the World Health Organization Mortality Database to analyze sex and age-specific (25-44, 45-54, and 55-64) age-standardized death rates across 13 major cause-of-death categories.

Findings

US midlife mortality rates worsened since 1990 for several causes of death including drug- related, alcohol-related, suicide, metabolic disease, nervous system disease, respiratory disease, and infectious/parasitic diseases. Deaths due to homicide, transport accidents, and cardiovascular disease declined overall since 1990 but saw recent increases or stalling of improvements. Midlife mortality has also recently increased in the UK for 45-54-year-olds, and in Canada, Poland, and Sweden among 25-44-year-olds.

Conclusion

The US is increasingly falling behind not only high-income but also CEE countries heavily impacted by the post-Soviet mortality crisis of the 1990s. While levels of midlife mortality in the UK are substantially lower than in the US overall, there are signs that UK midlife mortality is worsening relative to the rest of Europe.
LigaNET: A multi-modal deep learning approach to predict the risk of subsequent anterior cruciate ligament injury after surgery
Authors: Han Mo , Singh Mallika , Karimi Davood , Kim Jin Young , Flannery Sean W. ,   BEAR Trial Team, Ecklund Kirsten , Murray Martha M. , Fleming Braden C. , Gholipour Ali , Kiapour Ata M.
Published: July 2023

Anterior cruciate ligament (ACL) injuries are a common cause of soft tissue injuries in young active individuals, leading to a significant risk of premature joint degeneration. Postoperative management of such injuries, in particular returning patients to athletic activities, is a challenge with immediate and long-term implications including the risk of subsequent injury. In this study, we present LigaNET, a multi-modal deep learning pipeline that predicts the risk of subsequent ACL injury following surgical treatment. Postoperative MRIs (n=1,762) obtained longitudinally between 3 to 24 months after ACL surgery from a cohort of 159 patients along with 11 non-imaging outcomes were used to train and test: 1) a 3D CNN to predict subsequent ACL injury from segmented ACLs, 2) a 3D CNN to predict injury from the whole MRI, 3) a logistic regression classifier predict injury from non-imaging data, and 4) a multi-modal pipeline by fusing the predictions of each classifier. The CNN using the segmented ACL achieved an accuracy of 77.6% and AUROC of 0.84, which was significantly better than the CNN using the whole knee MRI (accuracy: 66.6%, AUROC: 0.70; P<.001) and the non-imaging classifier (accuracy: 70.1%, AUROC: 0.75; P=.039). The fusion of all three classifiers resulted in highest classification performance (accuracy: 80.6%, AUROC: 0.89), which was significantly better than each individual classifier (P<.001). The developed multi-modal approach had similar performance in predicting the risk of subsequent ACL injury from any of the imaging sequences (P>.10). Our results demonstrate that a deep learning approach can achieve high performance in identifying patients at high risk of subsequent ACL injury after surgery and may be used in clinical decision making to improve postoperative management (e.g., safe return to sports) of ACL injured patients.
Methodological approach to sleep state misperception in insomnia disorder: comparison between multiple nights of actigraphy recordings and a single night of polysomnography recording
Authors: Maltezos Antonia , Perrault Aurore A. , Walsh Nyissa A. , Phillips Emma-Maria , Gong Kirsten , Tarelli Lukia , Smith Dylan , Cross Nathan E. , Pomares Florence B. , Gouin Jean-Philippe , Dang-Vu Thien Thanh
Published: July 2023

Rationale

Sleep state misperception (SSM) represents the discrepancy between objectively recorded and subjectively perceived measures of sleep, including sleep onset latency (SOL), sleep duration (TST) and wake duration (WASO). The severity of SSM is higher in insomnia disorder (INS) compared to other populations. SSM is typically assessed in-lab during one night with polysomnographic (PSG) recording or at-home with actigraphy recordings over multiple days, both complemented by subjective sleep reports. Both methods of data collection have their specific strengths and weaknesses, and provide sleep measures that may differ, especially in individuals with sleep disorders. The extent to which the methods and environment of data collection impact measures of sleep misperception remains unclear. This study aimed at providing a comprehensive assessment of SSM in INS and good sleepers (GS) by comparing recordings performed for one night in-lab (PSG and night review) and during several nights at-home (actigraphy and sleep diaries).

Methods

Fifty-seven INS and 29 GS wore an actigraphy device and filled a sleep diary for two weeks at-home. They subsequently completed a PSG recording and filled a night review the next morning in-lab. Sleep perception index (subjective/objective × 100; in %) of SOL, WASO and TST were computed and compared between methods and groups.

Results

We found that GS and INS exhibit opposite patterns of sleep misperception. GS displayed a tendency to overestimate TST and WASO but correctly perceived SOL. The degree of misperception was similar across methods within the GS group. In contrast, INS underestimated their TST and overestimated their SOL both in-lab and at-home, yet the severity of misperception (i.e., degree of mismatch) of SOL was larger at-home than in-lab. Finally, INS overestimated WASO only in-lab while correctly perceiving it at-home. While only the degree of TST misperception was stable across methods in INS, misperception of SOL and WASO were dependent on the method used.

Conclusions

We found that GS and INS exhibit opposite patterns and severity of sleep misperception. While the degree of misperception in GS was similar across methods, we found that only sleep duration misperception was reliably detected by both in-lab and at-home methods in INS. Our results highlight that, when assessing sleep misperception in individuals with insomnia disorder, the method of data collection should be carefully considered in relation to the main sleep outcomes of interest.
Evaluating steroid hormone receptor interactions using the live-cell NanoBRET proximity assay
Authors: Huggins Rosemary J , Hosfield David , Ishag-Osman Amira , Lee Keemin , Ton-That Elia , Greene Geoffrey L.
Published: July 2023

Steroid hormone receptors play a crucial role in the development and characterization of the majority of breast cancers. These receptors canonically function through homodimerization, but physical interactions between different hormone receptors play a key role in cell functions as well. The estrogen receptor (ERα) and progesterone receptor (PR), for example, are involved in a complex set of interactions known as ERα/PR crosstalk. Here, we developed a valuable panel of nuclear receptor expression plasmids specifically for use in NanoBRET assays to assess nuclear receptor homo- and heterodimerization. We demonstrate the utility of this assay system by assessing ERα/PR physical interaction in the context of the endocrine therapy resistance- associated ERα Y537S mutation. We identify a role of the ERα Y537S mutation beyond that of constitutive activity of the receptor; it also increases ERα/PR crosstalk. In total, the NanoBRET assay provides a novel avenue for investigating hormone receptor crosstalk. Future research may use this system to assess the effects of other clinically significant hormone receptor mutations on hormone receptor crosstalk.
Energy allocation explains how protozoan phenotypic traits adapt to temperature and nutrient supply
Authors: Perna Andrea , Rivoli Enrico S. , Reiss Julia , Perkins Daniel M.
Published: July 2023

To survive and reproduce, living organisms need to maintain an efficient balance between energy intake and energy expenditure. When the environment changes, a previously efficient energy allocation strategy may become inefficient in the new environment, and organisms are required to change their physiology, morphology, and behaviour. However, how multiple phenotypic traits interact with each other and with the characteristics of the environment to determine energy allocation is poorly understood. To address this knowledge gap, we develop a predictive framework, based on energetic and biophysical principles, to characterise phenotype-environment interactions. We tested this by adapting axenic populations of the ciliateTetrahymena pyriformisto different environmental conditions of temperature and resource levels, and measured population growth, cell size, respiration, and movement. Movement speed and respiration rate increased with acute changes in environmental temperature in a way that could be predicted from simple physical scaling relations such as the Boltzmann-Arrhenius equation and the ‘viscous drag’ impacting movement. Based on theoretical arguments, we argue that these short-term changes of metabolic rate and movement speed introduce a mismatch between energy intake and energy expenditure and are not sustainable on the long-term. In fact, by around 3.5 days after the introduction ofTetrahymenainto a novel environment, all measured quantities were further modulated in a direction that likely restored the energy allocation balance of the cells. Changes in cell size played a substantial role in mediating these adaptations, by simultaneously affecting multiple phenotypic traits, such as metabolic rate and the energetic costs of movement. In a small microbial consumer likeTetrahymena, size changes can happen over rapid timescales, relative to the timescales of ecological changes and of seasonal environmental fluctuations. Changes in body size can therefore be effectively leveraged – alongside physiological and biochemical regulations – to cope with environmental changes.
Mechanical Hand Synergies during Dynamic Hand Movements are Mostly Controlled in a Non-Synergistic Way by Spinal Motor Neurons
Authors: Oßwald Marius , Cakici Andre L. , Oliveira Daniela Souza de , Braun Dominik I. , Vecchio Alessandro Del
Published: July 2023

Precise control of spinal motor neurons is crucial for voluntary hand and digit movements. However, the specific mechanisms by which motor unit ensembles govern dynamic synergistic and individual digit tasks remain poorly understood. We recorded synchronized 3D hand kinematics and high-density surface EMG (HD-sEMG) data from extrinsic hand muscles of twelve participants during 13 dynamic hand and digit movement tasks, consisting of single-digit flexion/extension and mechanically synergistic grasping tasks.

We extracted single motor unit (MU) activity and identified identical MUs across tasks. We extracted 7.8 ± 1.8 MUs per task and participant and found 182 out of 554 total MUs active during multiple movements. Analysis of the MU discharge patterns revealed two groups of motor units that were categorized intoprime mover MUs, showing strong correlation between firing rate modulation and digit kinematics, andpostural MUswith little modulated activity. We found these motor units could switch between the two modes, showing either postural or movement encoding activation depending on the task. However, MUs acted as prime mover only for one specific digit. We further observed highly task specific recruitment ofprime moverMUs. Across participants, we found only 9 ± 8.2 % ofprime moverMUs active during a grasp task and any single digit task involved in the grasp motion.

We draw three conclusions: (1) Single digits are controlled by distinct groups of MUs. (2) Unexpectedly, mechanically synergistic grasp movements are mostly controlled in a non-synergistic way by distinct groups of MUs. 3) Multiple manifolds construct the movement of the human hand, and each motor unit can flexibly switch between postural and dynamic modes.

Significance Statement

We investigated the neural control of motor unit ensembles during single-digit and synergistic grasping tasks in dynamic conditions. We found that motor units exhibited strong movement-correlated activity only for one specific digit. We further observed highly task specific recruitment of motor units during mechanically synergistic grasp movements, showing that on a motor unit level, mechanically synergistic movements are controlled in a non-synergistic way. The findings extend the knowledge of motor unit recruitment strategies in natural movements and have strong implications in the field of neurorehabilitation and control of assistive devices.
EPINEST, an agent-based model to simulate epidemic dynamics in large-scale poultry production and distribution networks
Authors: Pinotti Francesco , Lourenço José , Gupta Sunetra , Das Gupta Suman , Henning Joerg , Blake Damer , Tomley Fiona , Barnett Tony , Pfeiffer Dirk , Hoque Md. Ahasanul , Fournié Guillaume
Published: July 2023

The rapid intensification of poultry production raises important concerns about the associated risks of zoonotic infections. Here, we introduce EPINEST (EPI-demic NEtwork Simulation in poultry Transportation systems): an agent-based modelling designed to simulate pathogen transmission within realistic poultry production and distribution networks. The modular structure of the model allows for easy parameterization to suit specific countries and system configurations. Moreover, the framework enables the replication of a wide range of eco-epidemiological scenarios by incorporating diverse pathogen life-history traits, modes of transmission and interactions between multiple strains and/or pathogens. EPINEST was developed in the context of an interdisciplinary multicentre study conducted in Bangladesh, India, Vietnam and Sri Lanka, and will facilitate the investigation of the spreading patterns of various health hazards such as avian influenza,Campylobacter, Salmonellaand antimicrobial resistance in these countries. Furthermore, this modelling framework holds potential for broader application in veterinary epidemiology and One Health research, extending its relevance beyond poultry to encompass other livestock species and disease systems.
Influenza A virus infection alters lipid packing and surface electrostatic potential of the host plasma membrane
Authors: Petrich Annett , Chiantia Salvatore
Published: July 2023

The pathogenesis of influenza A viruses (IAVs) is influenced by several factors, including IAV strain origin and reassortment, tissue tropism and host type. While such factors were mostly investigated in the context of virus entry, fusion and replication, little is known about the viral-induced changes to the host lipid membranes which might be relevant in the context of virion assembly. In this work, we applied several biophysical fluorescence microscope techniques (i.e., Förster energy resonance transfer, generalized polarization imaging and scanning fluorescence correlation spectroscopy) to quantify the effect of infection by two IAV strains of different origin on the plasma membrane (PM) of avian and human cell lines. We found that IAV infection affects the membrane charge of the inner leaflet of the PM. Moreover, we showed that IAV infection impacts lipid-lipid interactions by decreasing membrane fluidity and increasing lipid packing. Because of such alterations, diffusive dynamics of membrane-associated proteins are hindered. Taken to-gether, our results indicate that the infection of avian and human cell lines with IAV strains of different origins had similar effects on the biophysical properties of the PM.
Dynamic Changes in Lymphocyte Populations Establish Zebrafish as a Thymic Involution Model
Authors: Hasan Ameera , Macias Jose J. , Wood Brashé , Malone-Perez Megan , Park Gilseung , Foster Clay A. , Frazer J. Kimble
Published: July 2023

The thymus is the site of T lymphocyte development and T cell education to recognize foreign, but not self, antigens. B cells also reside and develop in the thymus, although their functions are less clear. During ‘thymic involution,’ a process of lymphoid atrophy and adipose replacement linked to sexual maturation, thymocytes decline. However, thymic B cells decrease far less than T cells, such that B cells comprise ∼1% of human neonatal thymocytes, but up to ∼10% in adults. All jawed vertebrates possess a thymus, and we and others have shown zebrafish (Danio rerio) also have thymic B cells. Here, we investigated the precise identities of zebrafish thymic T and B cells and how they change with involution. We assessed the timing and specific details of zebrafish thymic involution using multiple lymphocyte-specific, fluorophore-labeled transgenic lines, quantifying the changes in thymic T- and B-lymphocytes pre- vs. post-involution. Our results prove that, as in humans, zebrafish thymic B cells increase relative to T cells post-involution. We also performed RNA sequencing (RNA-seq) onD. reriothymic and marrow lymphocytes of four novel double-transgenic lines, identifying distinct populations of immature T and B cells. Collectively, this is the first comprehensive analysis of zebrafish thymic involution, demonstrating its similarity to human involution, and establishing the highly genetically- manipulatable zebrafish model as a template for involution studies.
Calcineurin contributes to RNAi-mediated transgene silencing and small interfering RNA production in the human fungal pathogenCryptococcus neoformans
Authors: Yadav Vikas , Mohan Riya , Sun Sheng , Heitman Joseph
Published: July 2023

Adaptation to external environmental challenges at the cellular level requires rapid responses and involves relay of information to the nucleus to drive key gene expression changes through downstream transcription factors. Here, we describe an alternative route of adaptation through a direct role for cellular signaling components in governing gene expression via RNA interference-mediated small RNA production. Calcium-calcineurin signaling is a highly conserved signaling cascade that plays central roles in stress adaptation and virulence of eukaryotic pathogens, including the human fungal pathogenCryptococcus neoformans. Upon activation inC. neoformans, calcineurin localizes to P-bodies, membrane-less organelles that are also the site for RNA processing. Here, we studied the role of calcineurin and its substrates in RNAi-mediated transgene silencing. Our results reveal that calcineurin regulates both the onset and the reversion of transgene silencing. We found that some calcineurin substrates that localize to P-bodies also regulate transgene silencing but in opposing directions. Small RNA sequencing in mutants lacking calcineurin or its targets revealed a role for calcineurin in small RNA production. Interestingly, the impact of calcineurin and its substrates was found to be different in genome-wide analysis, suggesting that calcineurin may regulate small RNA production inC. neoformansthrough additional pathways. Overall, these findings define a mechanism by which signaling machinery induced by external stimuli can directly alter gene expression to accelerate adaptative responses and contribute to genome defense.

Article summary

Signaling cascades primarily drive responses to external stimuli through gene expression changes via transcription factors that localize to the nucleus and bind to DNA. Our study identifies an alternative mechanism whereby calcineurin, a key and direct downstream effector of calcium signaling, is involved in post-transcriptional regulation of gene expression through RNAi-mediated small RNA production. We propose that such signaling allows cells to bypass the requirement for communication to the nucleus and rapidly drive stress responses in a reversible fashion.
YAP and TAZ differentially regulate postnatal cortical progenitor proliferation and astrocyte differentiation
Authors: Chen Jessie , Tsai Yung-Hsu , Linden Anne , Kessler John A , Peng Chian-Yu
Published: July 2023

WW domain-containing transcription regulator 1 (TAZ) and Yes-associated protein (YAP) are transcriptional co-activators traditionally studied together as a part of the Hippo pathway and best known for their roles in stem cell proliferation and differentiation. Despite their similarities, TAZ and YAP can exert divergent cellular effects by differentially interacting with other signaling pathways that regulate stem cell maintenance or differentiation. In the developing central nervous system, In this study, we show that TAZ regulates astrocytic differentiation and maturation of postnatal neural stem and progenitor cells (NPCs), and that TAZ mediates some but not all of the effects of bone morphogenetic protein (BMP) signaling on astrocytic development. By contrast, TAZ and YAP both mediate effects on NPC fate of β1-integrin and integrin-linked kinase (ILK) signaling, and these effects are dependent on extracellular matrix (ECM) cues. These findings demonstrate that TAZ and YAP perform divergent functions in the regulation of astrocyte differentiation, where YAP regulates cell cycle states of astrocytic progenitors and TAZ regulates differentiation and maturation from astrocytic progenitors into astrocytes.

Summary Statement

Astrocytes are accounts for nearly half of the cells in the central nervous system, where they perform a diverse array of physiological functions. During development, astrocytes are primarily generated after neuronal differentiation in a stepwise manner from multiple glial committed progenitor subtypes. How gliogenic progenitors maintain proliferative properties versus differentiate into astrocytes is not fully understood. This work aims to elucidate how environmental signals utilizes molecularly similar intracellular components to achieve distinct developmental outcomes. In addition, many of the cell types that are involved in glial development are also present in brain tumors including glioblastoma. Knowledge on mechanisms regulating proliferation and differentiation of glial progenitors will provide insights into differences and similarities between normal and malignant cells.
Experimental infection of elk (Cervus canadensis) and mule deer (Odocoileus hemionus) with SARS-CoV-2
Authors: Porter Stephanie M. , Hartwig Airn E. , Bielefeldt-Ohmann Helle , Root J. Jeffrey , Bosco-Lauth Angela M.
Published: July 2023

Elk (Cervus canadensis) and mule deer (Odocoileus hemionus) were experimentally evaluated for susceptibility to SARS-CoV-2. Elk did not shed infectious virus but produced low-level serological responses. Mule deer shed and transmitted virus in addition to mounting pronounced serological responses; they could therefore play a role in the epidemiology of SARS-CoV-2.

Article Summary Line

Experimental infection of elk (Cervus canadensis) and mule deer (Odocoileus hemionus) with SARS-CoV-2 revealed that while elk are minimally susceptible to infection, mule deer become infected, shed infectious virus, and can infect naïve contacts.
Mechanical control of cell proliferation patterns in growing tissues
Authors: Carpenter Logan C. , Pérez-Verdugo Fernanda , Banerjee Shiladitya
Published: July 2023

Cell proliferation plays a crucial role in regulating tissue homeostasis and development. However, our understanding of how cell proliferation is controlled in densely packed tissues is limited. Here we develop a computational framework to predict the patterns of cell proliferation in growing tissues, connecting single-cell behaviors and cell-cell interactions to tissue-level growth. Our model incorporates probabilistic rules governing cell growth, division, and elimination, while also taking into account their feedback with tissue mechanics. In particular, cell growth is suppressed and apoptosis is enhanced in regions of high cell density. With these rules and model parameters calibrated using experimental data, we predict how tissue confinement influences cell size and proliferation dynamics, and how single-cell physical properties influence the spatiotemporal patterns of tissue growth. Our findings indicate that mechanical feedback between tissue confinement and cell growth leads to enhanced cell proliferation at tissue boundaries, whereas cell growth in the bulk is arrested. By tuning cellular elasticity and contact inhibition of proliferation we can regulate the emergent patterns of cell proliferation, ranging from uniform growth at low contact inhibition to localized growth at higher contact inhibition. Furthermore, mechanical state of the tissue governs the dynamics of tissue growth, with cellular parameters affecting tissue pressure playing a significant role in determining the overall growth rate. Our computational study thus underscores the impact of cell mechanical properties on the spatiotemporal patterns of cell proliferation in growing tissues.
A comparison of convolutional neural networks and few-shot learning in classifying long-tailed distributed tropical bird songs
Authors: Zhong Ming , LeBien Jack , Campos-Cerqueira Marconi , Aide T. Mitchell , Dodhia Rahul , Lavista Ferres Juan
Published: July 2023

Biodiversity monitoring depends on reliable species identification, but it can often be difficult due to detectability or survey constraints, especially for rare and endangered species. Advances in bioacoustic monitoring and AI-assisted classification are improving our ability to carry out long-term studies, of a large proportion of the fauna, even in challenging environments, such as remote tropical rainforests. AI classifiers need training data, and this can be a challenge when working with tropical animal communities, which are characterized by high species richness but only a few common species and a long tail of rare species. Here we compare species identification results using two approaches: convolutional neural networks (CNN) and Siamese Neural Networks (SNN), a few-shot learning approach. The goal is to develop methodology that accurately identifies both common and rare species. To do this we collected more than 600 hours of audio recordings from Barro Colorado Island (BCI), Panama and we manually annotated calls from 101 bird species to create the training data set. More than 40% of the species had less than 100 annotated calls and some species had less than 10. The results showed that Siamese Networks outperformed the more widely used convolutional neural networks (CNN), especially when the number of annotated calls is low.
14-3-3 protein augments the protein stability of phosphorylated spastin and promotes the recovery of spinal cord injury through its agonist intervention
Authors: Liu Qiuling , Yang Hua , Luo Jianxian , Peng Cheng , Wang Ke , Zhang Guowei , Ji Zhisheng , Lin Hongsheng
Published: July 2023

Axon regeneration is abortive in the central nervous system following injury. Orchestrating microtubule dynamics has emerged as a promising approach to improve axonal regeneration. The microtubule severing enzyme spastin is essential for axonal development and regeneration through remodeling of microtubule arrangement. To date, however, little is known regarding the mechanisms underlying spastin action in neural regeneration after spinal cord injury. Here, we use glutathione transferase pulldown and immunoprecipitation assays to demonstrate that 14-3-3 interacts with spastin, bothin vivoandin vitro,via spastin Ser233 phosphorylation. Moreover, we show that 14-3-3 protects spastin from degradation by inhibiting the ubiquitination pathway and upregulates the spastin-dependent severing ability. Furthermore, the 14-3-3 agonist Fusicoccin (FC-A) promotes neurite outgrowth and regenerationin vitrowhich needs spastin activation. Western blot and immunofluorescence results revealed that 14-3-3 protein is upregulated in the neuronal compartment after spinal cord injuryin vivo. In addition, administration of FC-A not only promotes locomotor recovery, but also nerve regeneration following spinal cord injury in both contusion and lateral hemisection models; however, application of spastin inhibitor spastazoline successfully reverses these phenomena. Taken together, these results indicate that 14-3-3 is a molecular switch that regulates spastin protein levels, and the small molecule 14-3-3 agonist FC-A effectively mediates the recovery of spinal cord injury in mice which requires spastin participation.

Highlights

The formation of the 14-3-3 and spastin protein complex requires phosphorylation of spastin at the S233 site.

14-3-3 is involved in the phosphorylation-ubiquitination crosstalk of spastin, thus impacting the protein stability.

14-3-3 agonists Fusicoccin-A can facilitate the repair of spinal cord injury in mice.

Activation of spastin function is a prerequisite for nerve regeneration and recovery of spinal cord injury in mice.

Graphical Abstract