bluuebunny/crossref_metadata_2025 huggingface dataset:
Widespread adaptive evolution in the photosystems of angiosperms provides new insight into the evolution of photosystem II repair
Authors: Robbins Elizabeth HJ , Kelly Steven
Published: May 2024

Oxygenic photosynthesis generates the initial energy source which fuels nearly all life on earth. At the heart of the process are the photosystems, pigment binding multi-protein complexes that catalyse the first step of photochemical conversion of light energy into chemical energy. Here, we investigate the molecular evolution at single residue resolution of the plastid-encoded subunits of the photosystems across 773 angiosperm species. We show that despite an extremely high level of conservation, 7% of residues in the photosystems, spanning all photosystem subunits, exhibit hallmarks of adaptive evolution. Throughin silicomodelling of these adaptive substitutions we uncover the impact of these changes on the properties of the photosystems, focussing on their effects on co-factor binding and the formation of inter-subunit interfaces. We further reveal that evolution has repeatedly destabilised the interaction photosystem II and its D1 subunit, thereby reducing the energetic barrier for D1 turn-over and photosystem repair. Together, these results provide new insight into the trajectory of photosystem evolution during the radiation of the angiosperms.
A Paradigm For Calling Sequence In Families: The Long Life Family Study
Authors: Daw E. Warwick , Anema Jason A. , Schwander Karen , Lin Shiow Jiuan , Wang Lihua , Wojczynski Mary , Thyagarajan Bharat , Stitziel Nathan , Province Michael A.
Published: May 2024

Over Several years, we have developed a system for assuring the quality of whole genome sequence (WGS) data in the LLFS families. We have focused on providing data to identify germline genetic variants with the aim of releasing as many variants on as many individuals as possible. We aim to assure the quality of the individual calls. The availability of family data has enabled us to use and validate some filters not commonly used in population-based studies. We developed slightly different procedures for the autosomal, X, Y, and Mitochondrial (MT) chromosomes. Some of these filters are specific to family data, but some can be used with any WGS data set. We also describe the procedure we use to construct linkage markers from the SNP sequence data and how we compute IBD values for use in linkage analysis.
Clonal evolution of hematopoietic stem cells after cancer chemotherapy
Authors: Uryu Hidetaka , Saeki Koichi , Haeno Hiroshi , Kapadia Chiraag Deepak , Furudate Ken , Nangalia Jyoti , Chapman Michael Spencer , Zhao Li , Hsu Joanne I. , Zhao Chong , Chen Shujuan , Tanaka Tomoyuki , Li Zongrui , Yang Hui , DiNardo Courtney , Daver Naval , Pemmaraju Naveen , Jain Nitin , Ravandi Farhad , Zhang Jianhua , Song Xingzhi , Thompson Erika , Tang Hongli , Little Latasha , Gumbs Curtis , Orlowski Robert Z. , Qazilbash Muzaffar , Bhalla Kapil , Colla Simona , Kantarjian Hagop , Shamanna Rashmi Kanagal , Ramos Carlos Bueso- , Nakada Daisuke , Futreal P. Andrew , Shpall Elizabeth , Goodell Margaret , Garcia-Manero Guillermo , Takahashi Koichi
Published: May 2024

Normal hematopoietic stem and progenitor cells (HSPCs) inherently accumulate somatic mutations and lose clonal diversity with age, processes implicated in the development of myeloid malignancies1. The impact of exogenous stressors, such as cancer chemotherapies, on the genomic integrity and clonal dynamics of normal HSPCs is not well defined. We conducted whole-genome sequencing on 1,032 single-cell-derived HSPC colonies from 10 patients with multiple myeloma (MM), who had undergone various chemotherapy regimens. Our findings reveal that melphalan treatment distinctly increases mutational burden with a unique mutation signature, whereas other MM chemotherapies do not significantly affect the normal mutation rate of HSPCs. Among these therapy-induced mutations were several oncogenic drivers such asTET2andPPM1D. Phylogenetic analysis showed a clonal architecture in post-treatment HSPCs characterized by extensive convergent evolution of mutations in genes such asTP53andPPM1D. Consequently, the clonal diversity and structure of post-treatment HSPCs mirror those observed in normal elderly individuals, suggesting an accelerated clonal aging due to chemotherapy. Furthermore, analysis of matched therapy-related myeloid neoplasm (t-MN) samples, which occurred 1-8 years later, enabled us to trace the clonal origin of t-MNs to a single HSPC clone among a group of clones with competing malignant potential, indicating the critical role of secondary mutations in dictating clonal dominance and malignant transformation. Our findings suggest that cancer chemotherapy promotes an oligoclonal architecture with multiple HSPC clones possessing competing leukemic potentials, setting the stage for the selective emergence of a singular clone that evolves into t-MNs after acquiring secondary mutations. These results underscore the importance of further systematic research to elucidate the long-term hematological consequences of cancer chemotherapy.
Mechanism of structure-specific DNA binding by the FANCM branchpoint translocase
Authors: Abbouche Lara , Murphy Vincent J , Gao Jixuan , van Twest Sylvie , Sobinoff Alexander P , Auweiler Karen M , Pickett Hilda A , Bythell-Douglas Rohan , Deans Andrew J
Published: May 2024

FANCM is a DNA repair protein that recognizes stalled replication forks, and recruits downstream repair factors. FANCM activity is also essential for the survival of cancer cells that utilize the Alternative Lengthening of Telomeres (ALT) mechanism. FANCM efficiently recognizes stalled replication forks in the genome or at telomeres through its strong affinity for branched DNA structures. In this study, we demonstrate that the N-terminal translocase domain drives this specific branched DNA recognition. The Hel2i subdomain within the translocase is crucial for effective substrate engagement and couples DNA binding to catalytic ATP-dependent branch migration. Removal of Hel2i or mutation of key DNA-binding residues within this domain diminished FANCM’s affinity for junction DNA and abolished branch migration activity. Importantly, these mutant FANCM variants failed to rescue the cell cycle arrest, telomere-associated replication stress, or lethality of ALT-positive cancer cells depleted of endogenous FANCM. Our results reveal the Hel2i domain is key for FANCM to properly engage DNA substrates, and therefore plays an essential role in its tumour-suppressive functions by restraining the hyperactivation of the ALT pathway.
A reference-free algorithm discovers regulation in the plant transcriptome
Authors: Meyer Elisabeth , Saldivar Evan V. , Kokot Marek , Xue Bo , Deorowicz Sebastian , Rhee Seung Y. , Salzman Julia
Published: May 2024

Most plant genomes and their regulation remain unknown. We used SPLASH - a new, reference-genome free sequence variation detection algorithm - to analyze transcriptional and post-transcriptional regulation from RNA-seq data. We discovered differential homolog expression during maize pollen development, and imbibition-dependent cryptic splicing in Arabidopsis seeds. SPLASH enables discovery of novel regulatory mechanisms, including differential regulation of genes from hybrid parental haplotypes, without the use of alignment to a reference genome.
Exploring the Architectural Biases of the Canonical Cortical Microcircuit
Authors: Balwani Aishwarya , Cho Suhee , Choi Hannah
Published: May 2024

The cortex plays a crucial role in various perceptual and cognitive functions, driven by its basic unit, thecanonical cortical microcircuit. Yet, we remain short of a framework that definitively explains the structure-function relationships of this fundamental neuroanatomical motif. To better understand how physical substrates of cortical circuitry facilitate their neuronal dynamics, we employ a computational approach using recurrent neural networks and representational analyses. We examine the differences manifested by the inclusion and exclusion of biologically-motivated inter-areal laminar connections on the computational roles of different neuronal populations in the microcircuit of two hierarchically-related areas, throughout learning. Our findings show that the presence of feedback connections correlates with the functional modularization of cortical populations in different layers, and provides the microcircuit with a natural inductive bias to differentiate expected and unexpected inputs at initialization. Furthermore, when testing the effects of training the microcircuit and its variants with a predictive-coding inspired strategy, we find that doing so helps better encode noisy stimuli in areas of the cortex that receive feedback, all of which combine to suggest evidence for a predictive-coding mechanism serving as an intrinsic operative logic in the cortex.
The unique and enigmatic spirochete symbiont of latrunculid sponges
Authors: Waterworth Samantha Che , Solomons Gabriella M , Kalinski Jarmo-Charles J , Madonsela Luthando S , Parker-Nance Shirley , Dorrington Rosemary Ann
Published: May 2024

Bacterial symbionts are critical members of many marine sponge holobionts. Some sponge-associated bacterial lineages, such as Poribacteria, SAUL, and Tethybacterales appear to have broad host ranges and associate with a diversity of sponge species, while others are more species-specific, having adapted to the niche environment of their host. Host-associated spirochete symbionts that are numerically dominant have been documented in several invertebrates including termites, starfish, and corals. However, dominant spirochete populations are rare in marine sponges, thus far only observed in Clathrina clathrus and various species within the Latrunculiidae family, where they are co-dominant alongside Tethybacterales symbionts. This study aimed to characterize these spirochetes and their potential role in the host sponge. Analysis of metagenome-assembled genomes from eight latrunculid sponges revealed that these unusual spirochetes are relatively recent symbionts and are phylogenetically distinct from other sponge-associated spirochetes. Functional comparative analysis suggests that the host sponge may have selected for these spirochetes due to their ability to produce terpenoids and/or possible structural contributions.
Energy contribution from ultra-processed foods in Peruvian children: Frequency, Bimodality and Determinants
Authors: Miranda Marianella Yolanda , Campos-Sanchez Miguel , Cediel Gustavo , da Costa Louzada Maria Laura , Marron-Ponce Joaquin Alejandro
Published: May 2024

Objective: To assess the energy contribution of ultra-processed foods (UPF) and its association to sociodemographic and anthropometric factors in 6-35 months old children in the databases of national surveys carried out in 2008-2010, 2015-2016 and 2019. Methods: All surveys were stratified multi-stage random samples. Sub-samples had 24-hr food recall on a random day for each child, using a modified multiple step method with visual aids and scales. UPF were defined based on the Nova 4 classification system. Factors were evaluated with two generalized linear models (binomial for the percentage of UPF consumers and normal for the mean UPF energy contribution among UPF consumers only). Estimations and models were adjusted by the sampling design. Results: 2887 children were included. UPF contributed 29% [CI95 27 to 31] of the total energy intake. UPF contributed 31% [30 to 33%] of energy intake among UPF consumers, decreasing with age, increasing with height-for-age and showing seasonal variation. UPF were consumed by 86% [84 to 89%] of children, increasing with age and height-for-age, slightly increasing over the years and decreasing with poverty. UPF energy contribution comes mainly from milk and derivatives 19% [17 to 20] and cereals 5% [4 to 6]. Conclusions: The mean UPF energy contribution and the percentage of UPF consumers vary with age, height, poverty and survey year in 6-35 months old children in Peru. Keywords: Peru; Children; Food Intake; Energy Intake; Ultra-processed Foods.
Incidence of prostate cancer in Medicaid beneficiaries with and without HIV in 2001-2015 in 14 states
Authors: Pirsl Filip , Calkins Keri , Rudolph Jacqueline E. , Wentz Eryka , Xu Xiaoqiang , Lau Bryan , Joshu Corinne E.
Published: May 2024

Background

Prostate cancer is projected to be the most common cancer among people living with HIV; however, incidence of prostate cancer has been reported to be lower in men with HIV compared to men without HIV with little evidence to explain this difference. We describe prostate cancer incidence by HIV status in Medicaid beneficiaries, allowing for comparison of men with and without HIV who are similar with respect to socioeconomic characteristics and access to healthcare.

Methods

Medicaid beneficiaries (N=15,167,636) aged 18-64 with ≥7 months of continuous enrollment during 2001-2015 in 14 US states were retained for analysis. Diagnoses of HIV and prostate cancer were identified using inpatient and other non-drug claims. We estimated cause-specific (csHR) and sub-distribution hazard ratios comparing incidence of prostate cancer by HIV status, adjusted for age, race-ethnicity, state of residence, year of enrollment, and comorbid conditions. Models were additionally stratified by age and race-ethnicity.

Results

There were 366 cases of prostate cancer observed over 299,976 person-years among beneficiaries with HIV and 17,224 cases over 22,298,914 person-years in beneficiaries without HIV. The hazard of prostate cancer was lower in men with HIV than men without HIV (csHR=0.89; 95% CI: 0.80, 0.99), but varied by race-ethnicity, with similar observations among non-Hispanic Black (csHR=0.79; 95% CI: 0.69, 0.91) and Hispanic (csHR=0.85; 95% CI: 0.67, 1.09), but not non-Hispanic white men (csHR=1.17; 95% CI: 0.91, 1.50). Results were similar in models restricted to ages 50-64 and 40-49, except for a higher hazard of prostate cancer in Hispanic men with HIV in their 40s, while the hazard of prostate cancer was higher in men with HIV across all models for men aged 18-39.

Conclusion

Reported deficits in prostate cancer incidence by HIV status may be restricted to specific groups defined by age and race-ethnicity.
Fine-scale spatial and social patterns of SARS-CoV-2 transmission from identical pathogen sequences
Authors: Tran-Kiem Cécile , Paredes Miguel I. , Perofsky Amanda C. , Frisbie Lauren A. , Xie Hong , Kong Kevin , Weixler Amelia , Greninger Alexander L. , Roychoudhury Pavitra , Peterson JohnAric M. , Delgado Andrew , Halstead Holly , MacKellar Drew , Dykema Philip , Gamboa Luis , Frazar Chris D. , Ryke Erica , Stone Jeremy , Reinhart David , Starita Lea , Thibodeau Allison , Yun Cory , Aragona Frank , Black Allison , Viboud Cécile , Bedford Trevor
Published: May 2024

Pathogen genomics can provide insights into underlying infectious disease transmission patterns, but new methods are needed to handle modern large-scale pathogen genome datasets and realize this full potential. In particular, genetically proximal viruses should be highly informative about transmission events as genetic proximity indicates epidemiological linkage. Here, we leverage pairs of identical sequences to characterise fine-scale transmission patterns using 114,298 SARS-CoV-2 genomes collected through Washington State (USA) genomic sentinel surveillance with associated age and residence location information between March 2021 and December 2022. This corresponds to 59,660 sequences with another identical sequence in the dataset. We find that the location of pairs of identical sequences is highly consistent with expectations from mobility and social contact data. Outliers in the relationship between genetic and mobility data can be explained by SARS-CoV-2 transmission between postal codes with male prisons, consistent with transmission between prison facilities. We find that transmission patterns between age groups vary across spatial scales. Finally, we use the timing of sequence collection to understand the age groups driving transmission. Overall, this work improves our ability to leverage large pathogen genome datasets to understand the determinants of infectious disease spread.
Mobile Phone Dependence Syndrome and its influencing factors among middle school students in Guangzhou, China: a cross-sectional study
Authors: Wang Chang , Zhu Haiyuan , Lin Rong , Liu Hui , Li Jinrong , Sun Minying , Lin Weiquan , Zhou Qin , Huang Bing , Zhao Jierong , Yang Yingyu , Li Ying , Zhang Runquan , Wu Qiqi , Dong Xiaomei
Published: May 2024

Background

Mobile Phone Dependence Syndrome (MPDS), a kind of addiction caused by extra phone use, is characterized by impairment of physical, mental, and social functioning. This study aimed to assess the prevalence of MPDS, injury due to overfocusing on phone, and explore MPDS’s associated factors among middle school students in Guangzhou, China.

Methods

1928 questionnaires were collected from April 2023 to May 2023 in Liwan and Nansha districts of Guangzhou through multi-stage cluster sampling. We used the Mobile Phone Dependence Scale for Middle School Students (MPDS Scale) and analyzed its reliability and validity. Frequency distribution, Chi-square test, fisher exact test and binary logistic regression were performed in data analysis.

Results

The reliability and validity of the MPDS Scale were good. The prevalence of MPDS was 10.0% and injury rate because of overfocusing on phone is 11.9%. Binary logistic regression demonstrated that gender, grade, personality, father’s parenting style, time of mobile phone use on rest days, and the most important motivation for using phone might influence occurrence of MPDS among middle school students (P<0.05).

Conclusion

Prevalence of MPDS among middle school students in Guangzhou was at a low level relatively. Students with MPDS had higher injury proportion than students with no MPDS. Female gender, grade of senior high school, introverted character, fathers with authoritarian parenting styles, spending 6 hours above on phone on rest days, and motivation of entertainment for using phone were associated with occurrence of MPDS. These findings can help develop measures to reduce occurrence of MPDS.
The characteristics and risk factors of burnout for public servants in North China
Authors: Jia Zhiyi , Chen Jinping , Dang Yalong
Published: May 2024

Objective

Burnout significantly affected the working efficiency of public servants. This study aimed to identify the characteristics and risk factors of burnout among public servants in North China.

Methods

A cross-sectional online and anonymous survey was conducted between March 2024 and April 2024. The inclusion criteria included active public servants aged between 18 and 60 years with fluency in Chinese. Participants with mental disorders were excluded. The study utilized the Maslach Burnout Inventory-General Survey with Chinese adaptation to measure burnout across three dimensions: exhaustion, cynicism, and professional efficacy. The survey consisted of 16 seven-point Likert scale questions, with response options ranging from “never” to “daily,” and scored from 1 to 7. Participants with burnout had to meet at least one of the following criteria: 1) scoring in the upper third for exhaustion, 2) scoring in the upper third for cynicism, or 3) scoring in the lower third for professional efficacy. Severe burnout was defined as meeting all three criteria, moderate burnout was defined as meeting two criteria, and mild burnout was defined as meeting one criterion.

Results

The study included 1064 participants from seventeen provinces in North China. The breakdown of burnout levels among the participants was as follows: 34.3% (365/1064) experienced no burnout, 29.5% (314/1064) had mild burnout, 35.6% (379/1064) had moderate burnout, and 0.6% (6/1064) experienced severe burnout. The study revealed no significant differences in burnout risk based on gender, age, academic degrees, occupation types, and length of service. However, significant variations were observed in burnout risk based on job position, salary, income satisfaction, job security, work stress, and interpersonal ability.

Conclusion

In North China, two-thirds of public servants experienced occupational burnout. Job position, salary, income satisfaction, job security, work stress, and interpersonal ability were identified as the risk factors.
Tolerability of Long-acting Diquafosol Ophthalmic Solution as per Tear Film and Meibomian Glands Findings
Authors: Arita Reiko , Fukuoka Shima , Kaido Minako
Published: May 2024

Long-acting diquafosol (DQS) ophthalmic solution (DQS-LX) has significant advantages regarding patient adherence owing to the reduced frequency of required eye drops; however, some patients prefer conventional DQS over DQS-LX. Herein, to clarify the characteristics of patients according to their preference for ophthalmic solutions, dry eye (DE) and meibomian gland (MG) findings were retrospectively investigated. This study enrolled 341 patients with DE (mean age, 62.1 ± 11.7 years) treated at the Itoh Clinic between November 8, 2022, and July 31, 2023, who switched from DQS to DQS-LX. Patients were divided into two groups: those who continued DQS-LX administration (DQS-LX group) and those who wished to revert to conventional DQS (DQS group). Data regarding subjective symptoms assessed using the Standard Patient Evaluation of Eye Dryness (SPEED) questionnaire, tear film breakup time (BUT), tear meniscus height (TMH), corneal and conjunctival fluorescein staining (CFS), conjunctival hyperemia/papilla, meiboscore, plugging, vascularity, meibum grade, and Schirmer’s score at the time of DQS-LX switch were evaluated. Of the 341 patients, 31 (9.1%) wished to revert to conventional DQS. In total, 32 eyes of 16 patients in the DQS group and 64 eyes of 32 patients in the DQS-LX group—for whom complete data were available—were included in the analysis. Compared with the DQS group, the DQS-LX group had significantly higher SPEED scores, shorter BUTs, lower TMHs, greater CFS findings, larger meibum grades (allP< 0.001), lower Schirmer scores (P= 0.008), and more pluggings (P= 0.001) than the DQS group. More allergic conjunctivitis-related complications were observed in the DQS group (P= 0.034). In conclusion, patients with low tear film volume and DE complicated by moderate or severe MG dysfunction preferred DQS-LX, while those with allergic findings preferred conventional DQS.
Comparison of actionable alterations in cancers with kinase fusion, mutation, and amplification
Authors: Suzuki Shinsuke , Akahane Toshiaki , Tanimoto Akihide , Higashi Michiyo , Kitazono Ikumi , Kirishima Mari , Nishigaki Masakazu , Ikeda Toshiro , Kanemitsu Shuichi , Nakazawa Junichi , Akahane Erina , Nishihara Hiroshi , Uozumi Kimiharu , Yoshimitsu Makoto , Ishitsuka Kenji , Ueno Shin-ichi
Published: May 2024

Kinase-related gene fusion and point mutations play pivotal roles as drivers in cancer, necessitating optimized targeted therapy against these alterations. The efficacy of molecularly targeted therapeutics varies depending on the specific alteration, with great success reported for such therapeutics in the treatment of cancer with kinase fusion proteins. However, the involvement of actionable alterations in solid tumors, especially in relation to kinase fusions, remains incompletely understood. This study aimed to compare the number of actionable alterations in patients with tyrosine or serine/threonine kinase domain fusions, mutations, and amplifications. We analyzed 613 patients with 40 solid cancer types who visited our division between June 2020 and April 2024. To detect alterations involving multiple-fusion calling, we performed comprehensive genomic sequencing using FoundationOne®companion diagnostic (F1CDx) and FoundationOne®Liquid companion diagnostic (F1LCDx). Patient characteristics and genomic profiles were analyzed to assess the frequency and distribution of actionable alterations across different cancer types. Of the 613 patients, 44 had fusions involving kinases, transcriptional regulators, or tumor suppressors. F1CDx and F1LCDx detected 13 with kinase-domain fusions. We identified 117 patients with kinase-domain mutations and 58 with kinase-domain amplifications. The number of actionable alterations in patients with kinase-domain fusion, mutation, or amplification (median [interquartile range; IQR]) was 2 (1–3), 5 (3–7), and 6 (4–8), respectively. Patients with kinase fusion had significantly fewer actionable alterations than those with kinase-domain mutations and amplifications. However, those cancers with fusion involving tumor suppressors tended to have more actionable alterations (median [IQR]; 4 [2–9]). Cancers with kinase fusions tended to exhibit fewer actionable alterations than those with kinase mutations and amplifications. These findings underscore the importance of detecting kinase alterations and indicate the pivotal role of kinase fusions are strong drivers of cancer development, highlighting their potential as prime targets for molecular therapeutics.
Health and economic impact of caregiving on informal caregivers of people with chronic diseases in Sub-Saharan Africa: A systematic review
Authors: Kisangala Ephraim , Mbivnjo Etheldreda Leinyuy , Webb Edward JD , Barrett Barbara , Rukundo Godfrey Zari , Namisango Eve , Heslin Margaret
Published: May 2024

Background

With a disproportionate burden of chronic diseases and severe shortage of health workers in sub-Saharan Africa (SSA), the region implicitly relies on informal caregivers (ICGs) to support the patients both within and outside the health facilities. The aim of this review is to explore the health and economic impact of caregiving on ICGs of patients with chronic diseases in SSA.

Methods

Medline (Ovid), CINAHL (EBSCOhost), PsycINFO (Ovid), Embase (Ovid), Global Health and Web of Science databases were systematically searched to identify original articles that considered the economic and/or health impacts of caregiving in SSA. The results from the included studies were synthesised narratively.

Results

After screening 4,372 articles, 47 were included for synthesis. The articles were from all sub-regions of SSA with more than half (25/47) of the articles focussing on caregivers for patients with cancer. Although the primary motivation for becoming caregivers was love and responsibility, the caring responsibilities described in twenty articles, had profound effects on the caregiver’s lives. Healthwise, ICGs experienced changes in their physical and mental health like developing musculoskeletal problems and depression. Economically, caregiving was expensive, and financially draining. The opportunity cost of caregiving included loss of jobs, loss of income, foregoing planned important activities and missed education opportunities.

Conclusion

ICGs reported a range of mainly negative health and economic effects of the work they do. Health care systems should consider how to better support ICGs in terms of their own physical and mental wellbeing and governments should consider how to better financially support ICGs.
Shared genetics linking sociability with the brain's default mode network.
Authors: Fanelli Giuseppe , Robinson Jamie , Fabbri Chiara , Bralten Janita , Mota Nina Roth , Arenella Martina , Sprooten Emma , Franke Barbara , Kas Martien , Andlauer Till FM , Serretti Alessandro
Published: May 2024

The brain's default mode network (DMN) plays a role in social cognition, with altered DMN function being associated with social impairments across various neuropsychiatric disorders. In the present study, we examined the genetic relationship between sociability and DMN-related resting-state functional magnetic resonance imaging (rs-fMRI) traits. To this end, we used genome-wide association summary statistics for sociability and 31 activity and 64 connectivity DMN-related rs-fMRI traits (N=34,691-342,461). First, we examined global and local genetic correlations between sociability and the rs-fMRI traits. Second, to assess putatively causal relationships between the traits, we conducted bi-directional Mendelian randomisation (MR) analyses. Finally, we prioritised genes influencing both sociability and rs-fMRI traits by combining three methods: gene-expression eQTL MR analyses, the CELLECT framework using single-nucleus RNA-seq data, and network propagation in the context of a protein-protein interaction network. Significant local genetic correlations were found between sociability and two rs-fMRI traits, one representing spontaneous activity within the temporal cortex, the other representing connectivity between the frontal/cingulate and angular/temporal cortices. Sociability affected 12 rs-fMRI traits when allowing for weakly correlated genetic instruments. Combing all three methods for gene prioritisation, we defined 17 highly prioritised genes, withDRD2andLINGO1showing the most robust evidence across all analyses. By integrating genetic and transcriptomics data, our gene prioritisation strategy may serve as a blueprint for future studies. The prioritised genes could be explored as potential biomarkers for social dysfunction in the context of neuropsychiatric disorders and as drug target genes.
Engaging dystonia networks with subthalamic stimulation
Authors: Butenko Konstantin , Neudorfer Clemens , Dembek Till A. , Hollunder Barbara , Meyer Garance M. , Li Ningfei , Oxenford Simón , Bahners Bahne H. , Al-Fatly Bassam , Lofredi Roxanne , Gordon Evan M. , Dosenbach Nico U.F. , Ganos Christos , Hallett Mark , Starr Philip A. , Ostrem Jill L. , Wu Yiwen , Zhang ChenCheng , Fox Michael D. , Horn Andreas
Published: May 2024

Deep brain stimulation is a viable and efficacious treatment option for dystonia. While the internal pallidum serves as the primary target, more recently, stimulation of the subthalamic nucleus (STN) has been investigated. However, optimal targeting within this structure and its complex surroundings have not been studied in depth. Indeed, multiple historical targets that have been used for surgical treatment of dystonia are directly adjacent to the STN. Further, multiple types of dystonia exist, and outcomes are variable, suggesting that not all types would profit maximally from the exact same target. Therefore, a thorough investigation of the neural substrates underlying effects on dystonia symptoms is warranted.

Here, we analyze a multi-center cohort of isolated dystonia patients with subthalamic implantations (N= 58) and relate their stimulation sites to improvement of appendicular and cervical symptoms as well as blepharospasm. Stimulation of the ventral oral posterior nucleus of thalamus and surrounding regions was associated with improvement in cervical dystonia, while stimulation of the dorsolateral STN was associated with improvement in limb dystonia and blepharospasm. This dissociation was also evident for structural connectivity, where the cerebellothalamic, corticospinal and pallidosubthalamic tracts were associated with improvement of cervical dystonia, while hyperdirect and subthalamopallidal pathways were associated with alleviation of limb dystonia and blepharospasm. Importantly, a single well-placed electrode may reach the three optimal target sites. On the level of functional networks, improvement of limb dystonia was correlated with connectivity to the corresponding somatotopic regions in primary motor cortex, while alleviation of cervical dystonia was correlated with connectivity to the recently described ‘action-mode’ network that involves supplementary motor and premotor cortex. Our findings suggest that different types of dystonia symptoms are modulated via distinct networks. Namely, appendicular dystonia and blepharospasm are improved with modulation of the basal ganglia, and, in particular, the subthalamic circuitry, including projections from the primary motor cortex. In contrast, cervical dystonia was more responsive when engaging the cerebello-thalamo-cortical circuit, including direct stimulation of ventral thalamic nuclei.

These findings may inform DBS targeting and image-based programming strategies for patient-specific treatment of dystonia.
UnitedMet harnesses RNA-metabolite covariation to impute metabolite levels in clinical samples
Authors: Xie Amy X. , Tansey Wesley , Reznik Ed
Published: May 2024

Comprehensively studying metabolism requires the measurement of metabolite levels. However, in contrast to the broad availability of gene expression data, metabolites are rarely measured in large molecularly-defined cohorts of tissue samples. To address this basic barrier to metabolic discovery, we propose a Bayesian framework (“UnitedMet”) which leverages the empirical strength of RNA-metabolite covariation to impute otherwise unmeasured metabolite levels from widely available transcriptomic data. We demonstrate that UnitedMet is equally capable of imputing whole pool sizes as well as the outcomes of isotope tracing experiments. We apply UnitedMet to investigate the metabolic impact of driver mutations in kidney cancer, identifying a novel association betweenBAP1and a highly oxidative tumor phenotype. We similarly apply UnitedMet to determine that advanced kidney cancers upregulate oxidative phosphorylation relative to early-stage disease, that oxidative metabolism in kidney cancer is associated with inferior outcomes to combination therapy, and that kidney cancer metastases themselves demonstrate elevated oxidative phosphorylation relative to primary tumors. UnitedMet therefore enables the assessment of metabolic phenotypes in contexts where metabolite measurements were not taken or are otherwise infeasible, opening new avenues for the generation and evaluation of metabolite-centered hypotheses. UnitedMet is open source and publicly available (https://github.com/reznik-lab/UnitedMet).
Comparative analysis of tardigrade locomotion across life stage, species, and pharmacological treatment
Authors: Anderson Emma M. , Houck Sierra G. , Conklin Claire L. , Tucci Katrina L. , Rodas Joseph D. , Mori Kate E. , Armstrong Loriann J. , Illingworth Virginia B. , Lo Te-Wen , Woods Ian G.
Published: May 2024

Animal locomotion requires coordination between the central and peripheral nervous systems, between sensory inputs and motor outputs, and between nerves and muscles. Analysis of locomotion thus provides a comprehensive and sensitive readout of nervous system function and dysfunction. Tardigrades, the smallest known walking animals, coordinate movement of their eight legs with a relatively simple nervous system, and are a promising model for neuronal control of limb-driven locomotion. Here, we developed open-source tools for automated tracking of tardigrade locomotion in an unconstrained two-dimensional environment, for measuring multiple parameters of individual leg movements, and for quantifying interleg coordination. We used these tools to analyze >13,000 complete strides in >100 tardigrades, and identified preferred walking speeds and distinct step coordination patterns associated with those speeds. In addition, the rear legs of tardigrades, although they have distinct anatomy and step kinematics, were nonetheless incorporated into overall patterns of interleg coordination. Finally, comparisons of tardigrade locomotion across lifespan, between species, and between pharmacological treatments suggested that neuronal regulation of high-level aspects of walking (e.g. speed, turns, walking bout initiation) operate independently from circuits controlling individual leg movements and interleg coordination.
Perceptual tri-stability, measured and fitted as emergent from a model for bistable alternations
Authors: Sun Jiaqiu Vince , Jing Zeyu , Rankin James , Rinzel John
Published: May 2024

The human auditory system in attempting to decipher ambiguous sounds appears to resort to perceptual exploration as evidenced by multi-stable perceptual alternations. This phenomenon has been widely investigated via the auditory streaming paradigm, employing ABA_ triplet sequences with much research focused on perceptual bi-stability with the alternate percepts as either a single integrated stream or as two simultaneous distinct streams. We extend this inquiry with experiments and modeling to include tri-stable perception. Here, the segregated percepts may involve a foreground/background distinction. We collected empirical data from participants engaged in a tri-stable auditory task, utilizing this dataset to refine a neural mechanistic model that had successfully reproduced multiple features of auditory bi-stability. Remarkably, the model successfully emulated basic statistical characteristics of tri-stability without substantial modification. This model also allows us to demonstrate a parsimonious approach to account for individual variability by adjusting the parameter of either the noise level or the neural adaptation strength.
Noise Reduction in Resource-Coupled Multi-Module Gene Circuits through Antithetic Feedback Control
Authors: Chakravarty Suchana , Zhang Rong , Tian Xiao-Jun
Published: May 2024

Gene circuits within the same host cell often experience coupling, stemming from the competition for limited resources during transcriptional and translational processes. This resource competition introduces an additional layer of noise to gene expression. Here we present three multi-module antithetic control strategies: negatively competitive regulation (NCR) controller, alongside local and global controllers, aimed at reducing the gene expression noise within the context of resource competition. Through stochastic simulations and fluctuation-dissipation theorem (FDT) analysis, our findings highlight the superior performance of the NCR antithetic controller in reducing noise levels. Our research provides an effective control strategy for attenuating resource-driven noise and offers insight into the development of robust gene circuits.
N-Methyl-D-aspartate receptor hypofunction causes recurrent and transient failures of perceptual inference
Authors: Weilnhammer Veith , Rothkirch Marcus , Yilmaz Deniz , Fritsch Merve , Ptasczynski Lena Esther , Reichenbach Katrin , Roediger Lukas , Corlett Philip , Sterzer Philipp
Published: May 2024

Perception alternates between an external mode, driven by sensory inputs, and an internal mode, shaped by prior knowledge. We found that the external mode is more prevalent during pharmacologically induced N-Methyl-D-aspartate receptor (NMDAR) hypofunction and in schizophrenia. This NMDAR-dependent increase in external mode suggests that psychotic experiences are caused by recurring dissociations of perception from prior knowledge about the world.
Delayed developmental maturation of frontal cortical circuits impacts decision-making
Authors: Mastro Kevin , Lee Wen-Chun , Wang Wengang , Stevens Beth , Sabatini Bernardo L.
Published: May 2024

In humans, frontal cortical circuits mature in parallel with the development of higher cognitive functions over the course of 15-20 years. In mice, behavior and brain structure change rapidly until reaching sexual maturity (∼8 weeks of age). In contrast, the degree to which frontal cortices and the behaviors they support continue to develop in mice after this period is unclear. Here, we uncover age-related changes in the acquisition and execution of a probabilistic reward reinforcement task. Both young and old mice complete a similar number of trials per session, but 16-30-week-old mice obtain higher reward rates than younger mice. The older mice adjust their behavior more readily after failing to receive a reward, suggesting that age-dependent changes to circuits relevant to forming action-outcome associations, such as those in frontal associative cortices (FACs). Indeed, we identified cell-type and input-specific refinements of FAC circuits over the first 24 weeks of age, including protracted reductions in excitatory drive and increases in inhibition onto pyramidal cells. Dampening inhibitory activity in FAC alters behavior in a manner that counteracts the age-related differences. Together, these reveal an extended period of synaptic maturation in FAC that directly impacts age-related changes in decision-making.
A modular strategy for extracellular vesicle-mediated CRISPR-Cas9 delivery through aptamer-based loading and UV-activated cargo release
Authors: Elsharkasy Omnia M. , Hegeman Charlotte V. , Lansweers Ivana , Cotugno Olaf L. , de Groot Ingmar Y. , de Wit Zoë E.M.N.J. , Liang Xiuming , Garcia-Guerra Antonio , Moorman Niels J.A. , Lefferts Juliet , de Voogt Willemijn S. , Gitz-Francois Jerney J. , van Wesel Annet C.W. , El Andaloussi Samir , Schiffelers Raymond M. , Kooijmans Sander A.A. , Mastrobattista Enrico , Vader Pieter , de Jong Olivier G.
Published: May 2024

CRISPR-Cas9 gene editing technology offers the potential to permanently repair genes containing pathological mutations. However, efficient intracellular delivery of the Cas9 ribonucleoprotein complex remains one of the major hurdles in its therapeutic application. Extracellular vesicles (EVs) are biological nanosized membrane vesicles released by cells, that play an important role in intercellular communication. Due to their innate capability of intercellular transfer of proteins, RNA, and various other biological cargos, EVs have emerged as a novel promising strategy for the delivery of macromolecular biotherapeutics, including CRISPR-Cas9 ribonucleoproteins. Here, we present a versatile, modular strategy for the loading and delivery of Cas9. We leverage the high affinity binding of MS2 coat proteins (MCPs) fused to EV-enriched proteins to MS2 aptamers incorporated into single guide RNAs (sgRNAs), in combination with a UV-activated photocleavable linker domain, PhoCl. Combined with the Vesicular stomatitis virus G (VSV-G) protein this modular platform enables efficient loading and subsequent delivery of the Cas9 ribonucleoprotein complex, which shows critical dependence on the incorporation and activation of the photocleavable linker domain. As this approach does not require any direct fusion of Cas9 to EV-enriched proteins, we demonstrate that Cas9 can readily be exchanged for other variants, including transcriptional activator dCas9-VPR and adenine base editor ABE8e, as confirmed by various sensitive fluorescent reporter assays. Taken together, we describe a robust and modular strategy for successful Cas9 delivery, which can be applied for CRISPR-Cas9-based genetic engineering as well as transcriptional regulation, underlining the potential of EV-mediated strategies for the treatment of genetic diseases.
Sex-focused analyses of M83 A53T hemizygous mouse model with recombinant human alpha-synuclein preformed fibril injection identifies female resilience to disease progression: A combined magnetic resonance imaging and behavioural study
Authors: Tullo Stephanie , Park Janice , Gallino Daniel , Park Megan , Mar Kristie , Novikov Vladislav , Sandoval Contreras Rodrigo , Patel Raihaan , del Cid-Pellitero Esther , Fon Edward A. , Luo Wen , Shlaifer Irina , Durcan Thomas M. , Prado Marco A.M. , Prado Vania F. , Devenyi Gabriel A. , Chakravarty M. Mallar
Published: May 2024

Alpha-synuclein (aSyn) pathology has been extensively studied in mouse models harbouring human mutations. In spite of the known sex differences in age of onset, prevalence and disease presentation in human synucleinopathies, the impact of sex on aSyn propagation has received very little attention. To address this need, we examined sex differences in whole brain signatures of neurodegeneration due to aSyn toxicity in the M83 mouse model using longitudinal magnetic resonance imaging (MRI; T1-weighted; 100 μm3isotropic voxel; acquired −7, 30, 90 and 120 days post-injection [dpi]; n≥8 mice/group/sex/time point). To initiate aSyn spreading, M83 mice were inoculated with recombinant human aSyn preformed fibrils (Hu-PFF) or phosphate buffered saline (PBS) injected in the right dorsal striatum. We observed more aggressive neurodegenerative profiles over time for male M83 Hu-PFF-injected mice when examining voxel-wise trajectories. However, at 90 dpi, we observed widespread patterns of neurodegeneration in the female Hu-PFF-injected mice. These differences were not accompanied with any differences in motor symptom onset between the male and female Hu-PFF-injected mice. However, male Hu-PFF-injected mice reached their humane endpoint sooner. These findings suggest that post-motor symptom onset, even though more accelerated disease trajectories were observed for male Hu-PFF-injected mice, neurodegeneration may appear sooner in female Hu-PFF-injected mice (prior to motor symptomatology). These findings suggest that sex-specific synucleinopathy phenotypes urgently need to be considered to improve our understanding of neuroprotective and neurodegenerative mechanisms.
Structural comparison of protein-RNA homologous interfaces reveals widespread overall conservation contrasted with versatility in polar contacts
Authors: Mahmoudi Ikram , Quignot Chloé , Martins Carla , Andreani Jessica
Published: May 2024

Protein-RNA interactions play a critical role in many cellular processes and pathologies. However, experimental determination of protein-RNA structures is still challenging, therefore computational tools are needed for the prediction of protein-RNA interfaces. Although evolutionary pressures can be exploited for structural prediction of protein-protein interfaces, and recent deep learning methods using protein multiple sequence alignments have radically improved the performance of protein-protein interface structural prediction, protein-RNA structural prediction is lagging behind, due to the scarcity of structural data and the flexibility involved in these complexes. To study the evolution of protein-RNA interface structures, we first identified a large and diverse dataset of 2,022 pairs of structurally homologous interfaces (termed structural interologs). We leveraged this unique dataset to analyze the conservation of interface contacts among structural interologs based on the properties of involved amino acids and nucleotides. We uncovered that 73% of distance-based contacts and 68% of apolar contacts are conserved on average, and the strong conservation of these contacts occurs even in distant homologs with sequence identity below 20%. Distance-based contacts are also much more conserved compared to what we had found in a previous study of homologous protein-protein interfaces. In contrast, hydrogen bonds, salt bridges, and π-stacking interactions are very versatile in pairs of protein-RNA interologs, even for close homologs with high interface sequence identity. We found that almost half of the non-conserved distance-based contacts are due to a small proportion of interface residues that no longer belong to the interface in the interolog, a phenomenon we term “interface switching out”. We also examined possible recovery mechanisms for non-conserved hydrogen bonds and salt bridges, uncovering diverse scenarii of switching out, change in amino acid chemical nature, intermolecular and intramolecular compensations. Our findings provide insights for integrating evolutionary signals into predictive protein-RNA structural modeling methods.