bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neuron-specific partial reprogramming in the dentate gyrus impacts mouse behavior and ameliorates age-related decline in memory and learning
Authors: Vílchez-Acosta Alba , del Carmen Maza María , Parras Alberto , Planells Alejandra , Picó Sara , Desdín-Micó Gabriela , Mrabti Calida , Branchina Clémence , Maroun Céline Yacoub , Deigin Yuri , Ocampo Alejandro 
Published: July 2024

AbstractAge-associated neurodegenerative disorders represent significant challenges due to progressive neuronal decline and limited treatments. In aged mice, partial reprogramming, characterized by pulsed expression of reprogramming factors, has shown promise in improving function in various tissues, but its impact on the aging brain remains poorly understood. Here we investigated the impact ofin vivopartial reprogramming on mature neurons in the dentate gyrus of young and aged mice. Using two different approaches – a neuron-specific transgenic reprogrammable mouse model and neuron-specific targeted lentiviral delivery of OSKM reprogramming factors – we demonstrated thatin vivopartial reprogramming of mature neurons in the dentate gyrus, a neurogenic niche in the adult mouse brain, can influence animal behavior, and ameliorate age-related decline in memory and learning. These findings underscore the potential ofin vivopartial reprogramming as an important therapeutic intervention to rejuvenate the neurogenic niche and ameliorate cognitive decline associated with aging or neurodegeneration.
Experimental bleaching of photosymbiotic amoeba revealed strain-dependent differences in algal symbiosis ability
Authors: Yamagishi Daisuke , Onuma Ryo , Matsunaga Sachihiro , Miyagishima Shin-ya , Maruyama Shinichiro 
Published: July 2024

AbstractPhotosymbioses, the symbiotic relationships between photosynthetic algal symbionts and non-photosynthetic eukaryotic hosts, are sporadically found in a lot of eukaryotic lineages, but only a few taxa, such as cnidarians and ciliates hosting algal endosymbionts, have been actively studied for a long time. That has hindered understanding the universal mechanisms of the photosymbiosis establishment. Especially in Amoebozoa, only two species,Mayorella viridisandParachaos zoochlorella, are reported as photosymbiotic in nature, and their mechanisms of establishing symbiotic relationships are still unclear. To investigate the extent to which and how photosymbiotic amoebae depend on the symbiotic relationships,M. viridiswere treated with reagents that are known to induce the collapsing of photosymbiotic relationships, or bleaching, in other photosymbiotic species. As a result, we succeeded in artificially removing algal symbionts from hostM. viridiscells with an herbicide, 2-amino-3-chloro-1,4-naphthoquinone. The apo-symbiotic state amoeba cells were able to survive and grow to the same extent as the symbiotic state cells when they fed microbial prey, indicating that the algal symbionts are not essential for the host growth under certain conditions. Furthermore, to see whether the photosymbiotic state is reversible, we fed two strains of algal symbionts to the apo-symbiotic amoeba host. The result showed that the apo-symbiotic hosts were able to ingest symbiont cells and re-establish the symbiotic state. The efficiencies of ingesting algal cells were significantly different depending on algal symbiont strains, indicating that different algal strains possess discrete symbiotic abilities toM. viridis. To our knowledge, we provide first insights on the establishment and collapse of photosymbiosis in Amoebozoa, which pave the way to understand the universal mechanism of photosymbiosis utilizingM. viridisas a model system.
Overlapping Cortical Substrate of Biomechanical Control and Subjective Agency
Authors: Veillette John P. , Chao Alfred F. , Nith Romain , Lopes Pedro , Nusbaum Howard C. 
Published: July 2024

AbstractEvery movement requires the nervous system to solve a complex biomechanical control problem, but this process is mostly veiled from one’s conscious awareness. Simultaneously, we also have conscious experience of controlling our movements—our sense of agency (SoA). Whether SoA corresponds to those neural representations that implement actual neuromuscular control is an open question with ethical, medical, and legal implications. If SoA is the conscious experience of control, this predicts that SoA can be decoded from the same brain structures that implement the so-called “inverse dynamics” computations for planning movement. We correlated human (male and female) fMRI measurements during hand movements with the internal representations of a deep neural network (DNN) performing the same hand control task in a biomechanical simulation– revealing detailed cortical encodings of sensorimotor states, idiosyncratic to each subject. We then manipulated SoA by usurping control of participants’ muscles via electrical stimulation, and found that the same voxels which were best explained by modeled inverse dynamics representations— which, strikingly, were located in canonically visual areas—also predicted SoA. Importantly, model-brain correspondences and robust SoA decoding could both be achieved within single subjects, enabling relationships between motor representations and awareness to be studied at the level of the individual.Significance StatementThe inherent complexity of biomechanical control problems is belied by the seeming simplicity of directing movements in our subjective experience. This aspect of our experience suggests we have limited conscious access to the neural and mental representations involved in controlling the body – but of which of the many possible representations are we, in fact, aware? Understanding which motor control representations percolate into awareness has taken on increasing importance as emerging neural interface technologies push the boundaries of human autonomy. In our study, we leverage machine learning models that have learned to control simulated bodies to localize biomechanical control representations in the brain. Then, we show that these brain regions predict perceived agency over the musculature during functional electrical stimulation.
Sox10 is required for systemic initiation of bone mineralization
Authors: Gjorcheska Stefani , Paudel Sandhya , McLeod Sarah , Snape Louisa , Sosa Karen Camargo , Duan Cunming , Kelsh Robert , Barske Lindsey 
Published: July 2024

AbstractHeterozygous variants in the gene encoding the SOX10 transcription factor cause congenital syndromes affecting pigmentation, digestion, hearing, and neural function. Most of these symptoms are attributable to failed differentiation and loss of neural crest cells. Extensive research on mouse and zebrafish models has confirmed that Sox10 is essential for most non-skeletal crest derivatives, but seemingly dispensable for skeletal development. We challenge that concept here by revealing a novel requirement for Sox10 in skeletal mineralization. Neither neural crest- nor mesoderm-derived bones initiate mineralization on time in zebrafishsox10mutants, despite normal osteoblast differentiation and matrix production. We show that mutants are deficient in the ionocyte subpopulation tasked with taking up calcium from the environment through the Trpv6 epithelial calcium channel, leading to a severe calcium deficit that explains the lack of mineralization. As these ionocytes do not derive from asox10+ lineage, we hypothesized that the primary defect instead resides in a separate organ that regulates ionocyte numbers or calcium uptake at a systemic level. Screening of the endocrine hormones known to regulate calcium homeostasis in adult vertebrates revealed significantly elevated levels of stanniocalcin (Stc1a), an anti-hypercalcemic hormone, in larvalsox10mutants. Previous studies demonstrated that Stc1a inhibits calcium uptake in fish by repressingtrpv6expression and blocking proliferation of Trpv6+ ionocytes. Our epistasis assays indicate that excess Stc1a is the proximate cause of the calcium deficit insox10mutants. Lineage tracing shows that the pronephros-derived glands that synthesize Stc1a interact withsox10+ neural crest-derived cells, and that the latter are missing in mutants. We conclude that a subpopulation of Sox10+ neural crest non-cell-autonomously limit Stc1a production to allow the inaugural wave of calcium uptake necessary for the initiation of bone mineralization.
Going around the bend to understand the role of leg coalescence in metachronal swimming
Authors: Tack Nils B. , Santos Sara O. , Wilhelmus Monica M. 
Published: July 2024

ABSTRACTMany of the most abundant aquatic invertebrates display metachronal swimming by sequentially beating closely spaced flexible appendages. Common biophysical mechanisms like appendage spatial asymmetry and phase drive the success and performance of this locomotor mode, which is generally explained by the need to maximize thrust production. However, the potential role of these mechanisms in drag reduction, another important contributor to the overall swimming performance, has yet to be evaluated. We present a comprehensive overview of the morphological, functional, and physical mechanisms promoting drag reduction during metachronal swimming by exploring appendage differential bending and leg grouping (coalescence). We performed μ-CT andin-vivovelocimetry measurements of shrimp (Palaemonetes vulgaris) to design a five-legged robotic metachronal analog. This test platform enabled simultaneous flow and force measurements to quantify the thrust and drag forces produced by flexible and stiff pleopods (legs) beating independently or coalescing. We tested the hypothesis that coalescence and bending effectively reduce drag during the recovery stroke (RS). The curved cross-section of the pleopods enables passive asymmetrical bending during the RS to reduce their coefficient of drag by up to 75.8% relative to stiff pleopods. Bending promotes physical interactions facilitating the coalescence of three pleopods at any time during the RS to reduce drag such that the mean net thrust produced during coalescence is increased by 30.2%. These improvements are explained by the production of a weaker wake compared with stiff and non-coalescing pleopods. Our results describe fundamental biological and physical components of metachronal propulsion that may aid the development of novel bio-inspired underwater vehicles.Summary statementShrimp swimming legs bend nearly horizontally and cluster together during metachronal propulsion to reduce drag and improve the overall swimming performance.
Scalable assessment of genome editing off-targets associated with genetic variants
Authors: Lin Jiecong , Nguyen My Anh , Lin Linda Y. , Zeng Jing , Verma Archana , Neri Nola R. , da Silva Lucas Ferreira , Mucci Adele , Wolfe Scot , Shaw Kit L , Clement Kendell , Brendel Christian , Pinello Luca , Pellin Danilo , Bauer Daniel E. 
Published: July 2024

ABSTRACTGenome editing with RNA-guided DNA binding factors carries risk of off-target editing at homologous sequences. Genetic variants may introduce sequence changes that increase homology to a genome editing target, thereby increasing risk of off-target editing. Conventional methods to verify candidate off-targets rely on access to cells with genomic DNA carrying these sequences. However, for candidate off-targets associated with genetic variants, appropriate cells for experimental verification may not be available. Here we develop a method, Assessment By Stand-in Off-target LentiViral Ensemble with sequencing (ABSOLVE-seq), to integrate a set of candidate off-target sequences along with unique molecular identifiers (UMIs) in genomes of primary cells followed by clinically relevant gene editor delivery. Gene editing of dozens of candidate off-target sequences may be evaluated in a single experiment with high sensitivity, precision, and power. We provide an open-source pipeline to analyze sequencing data. This approach enables experimental assessment of the influence of human genetic diversity on specificity evaluation during gene editing therapy development.
Mitfover-expression leads to microphthalmia and coloboma inMitf-cremice
Authors: Longakit Anne Nathalie , Bourget Hannah , Van Raamsdonk Catherine D. 
Published: July 2024

ABSTRACTThe Microphthalmia associated transcription factor (Mitf) is a critical regulator of the melanocyte lineage and also plays an important role in eye development. Mitf activity in different cell types is controlled in part by ten alternative promoters and their resulting isoforms. A useful tool for melanocyte-based research, theMitf-cretransgene was designed to express Cre recombinase from the Mitf-M promoter, which is melanocyte specific. However,Mitf-cremice are also microphthalmic, perhaps because of insertional mutagenesis or disrupted gene expression. Here, we investigated these possibilities. We determined that the eye phenotype arises early, withMitf-creembryos at E13.5 exhibiting variable ocular sizes and abnormalities, but all with coloboma. Targeted locus amplification and next generation sequencing indicated that multiple copies of the transgene integrated into an intergenic region on chromosome 2, in betweenSpred1andMeis2. The BAC transgene used to makeMitf-crewas larger than expected, carrying three upstream alternative promoters, Mitf-H, Mitf-D, and Mitf-B, which could express their isoforms intact off the transgene. RT-qPCR using eye tissue demonstrated a 5-fold increase inMitftranscripts containing exon 1B1b, which is shared by Mitf-H, Mitf-D, and Mitf-B, whileSpred1andMeis2did not differ in their expression. These findings clarify and support the usage ofMitf-crein conditional mutagenesis in melanocytes. The specific over-expression of the Mitf-H and Mitf-D isoforms, which are preferentially expressed in the RPE, presents a unique resource for those interested in eye development and coloboma.
Peripheral blood DNA methylation signatures predict response to vedolizumab and ustekinumab in adult patients with Crohn’s disease: The EPIC-CD study
Authors: Joustra Vincent W. , Li Yim Andrew Y.F. , Henneman Peter , Hageman Ishtu , de Waard Tristan , Levin Evgeni , Noble Alexandra J. , Chapman Thomas P. , Mol Femke , van Zon Sarah , Lee Donghyeok , McGregor Colleen G.C. , Adams Alex T. , Satsangi Jack J. , de Jonge Wouter J. , D’Haens Geert R. ,   EPIC-CD Consortium
Published: July 2024

AbstractBiological therapeutics are now widely used in Crohn’s disease (CD), with evidence of efficacy from randomized trials and real-world experience. Primary non-response is a common, poorly understood problem. We assessed blood methylation as a predictor of response to vedolizumab (VDZ, anti-a4b7 integrin) or ustekinumab (USTE, anti-IL-12/23p40). We report a two-center, prospective cohort study in which we profiled the peripheral blood DNA methylome of 184 adult male and female CD patients prior to and during treatment with VDZ or USTE in a discovery (n=126) and an external validation cohort (n=58). We defined epigenetic biomarkers that were stable over time and associated with combined clinical and endoscopic response to VDZ or USTE with an area under curve (AUC) of 0.87 and 0.89, respectively. We validated these models in an external cohort yielding an AUC of 0.75 for both VDZ and USTE. These data will now be prospectively tested in a multicenter randomized clinical trial.Graphical abstract
Adherence to the 2016 PAHO Clinical Practice Guideline on Dengue in a Hospital in Northern Peru, 2022-2023
Authors: León Jiménez Franco E. , Mendoza-Farro Nataly BF. , Montoya Reategui Adriana , Inga-Chero Joel Emmanuel , Dioses Diaz Karim , Barranzuela-Herrera Moisés , Cavalcanti Ramírez Sophia , Moyano Luz M. ,   de Neuroepidemiology and Science of life working group
Published: July 2024

ABSTRACTBackgroundEffective dengue management enhances the chances of survival. The level of adherence to the suggestions in northern Peru is uncertain. The primary aim of the study was to assess adherence to the 2016 PAHO guideline on dengue in a hospital located in northern Peru during the period from 2022 to 2023.Methodology/principal findingsThe study performed a cross-sectional design and exploratory analysis, reviewing 141 medical records. Fifty-four percent were from 2023; 65.9% were from women; 46.1% came from another healthcare center; 76.6% had diagnosis of dengue with warning signs; 20.7% had severe dengue; and 18.44% died. We found at least one error in the classification of severity and/or treatment in non-hospital healthcare facilities (91.5%), triage (88.5%), and uviclin/observation (52.6%). Errors in classification and inadequate hydration in the non-hospital healthcare centers, triage, and uviclin/observation were: 35.8%/53.7%, 30.6%/76.6%, and 10.1%/45.6%, respectively. Persistent errors were inadequate hydration in triage (76.86%) and urinary flow in the center (73.13%). In a bivariate analysis, mortality was associated with older age (p = 0.035), having a case from 2023 (p = 0.0073), having a case from the study hospital (p = 0.083), and having severe dengue (p<0.001). In the multivariate analysis, only severe dengue (OR 318.4, 95% IC [33.8-2996], p<0.001) was associated with mortality.Conclusions/significanceWe found a high frequency of misclassification and management errors in these three scenarios, but they were not associated with higher mortality.Author summaryAccording to the PAHO 2016 Dengue Guidelines, this descriptive study found deficiencies in the diagnosis of severity and treatment in a public hospital of the Ministry of Health of Peru, located in the region with the highest dengue incidence rate in 2023. We identified these deficiencies in the pre-hospital phase, as well as in the emergency, observation, and dengue management units, which had a high mortality rate of 18%. While it is true that management errors were not associated with higher mortality in the exploratory analysis, study biases may explain this result. We must take these findings into account when investigating the effectiveness of the health worker training that took place between 2023 and 2024, employing a master-class methodology and awaiting a before and after analysis to gauge its impact on knowledge. The need for improvements in health data management highlights the need to digitize information and electronic health records.
Time-trends in life expectancy of people with severe mental illness in Scotland, 2000-2019: a population-based study
Authors: Fleetwood Kelly , Alotaibi Raied , Scheuer Stine H , Smith Daniel J , Wild Sarah H , Jackson Caroline A 
Published: July 2024

ABSTRACTObjectiveTo determine time-trends in life expectancy (LE) of people with a severe mental illness (SMI) compared with the general population.DesignObservational population-based study.SettingScotland, 2000-2019. Linked psychiatric hospital admission and death records.ParticipantsAdults with a psychiatric hospital admission record for schizophrenia (28,797), bipolar disorder (16,657) or major depression (72,504) compared with the Scottish population (4.3 million adults in 2011).Main outcome measuresTrends over time in life years lost for people with schizophrenia, bipolar disorder or major depression compared with the Scottish population, for all deaths, and natural and unnatural deaths, stratified by sex.ResultsAmong people with SMI, one third died during the study period. Between 2000 and 2019, LE increased in the general Scottish population and the LE gap widened for people with schizophrenia. For 2000-2002, men and women with schizophrenia lost an excess 9.4 (95% CI 8.5 to 10.3) and 8.2 (7.4 to 9.0) life years, respectively, compared to the general population. In 2017-2019, this excess life years lost increased to 11.8 (10.9 to 12.7) and 11.1 (10.0 to 12.1) for men and women, respectively. There was no evidence of a change over time in the LE gap of 5 to 8 years for people with bipolar disorder or major depression. Changes in LE for natural and unnatural causes of death varied by individual SMI and sex.ConclusionsThe LE gap in people with an SMI persisted or widened in Scotland from 2000-2019. These entrenched disparities reflect intersecting inequalities requiring coordinated solutions at multiple levels to improve LE in this and other marginalised and socially excluded groups.SUMMARY BOXWhat is already known on this topicPeople with a severe mental illness (SMI) such as schizophrenia, bipolar disorder or major depression have a lower life expectancy (LE) than people without these conditionsThis gap is largely due to natural causes, particularly cardiovascular diseaseLE has increased for the general population but it is unclear whether the gaps in life expectancy for people with SMI have changed over time within the UKWhat this study addsThe LE gap widened in people with schizophrenia and persisted for those with bipolar disorder and major depression in Scotland between 2000 and 2019These findings reflect entrenched disparities in the LE of people with SMIMulti-level and synergistic solutions are needed to address these disparities
TRAMP assembly alters the conformation and RNA binding of Mtr4 and Trf4-Air2
Authors: Denson Joshua M. , Zhang Naifu , Ball Darby , Thompson Kayla , Johnson Sean J. , D’Arcy Sheena 
Published: July 2024

AbstractThe TRAMP complex contains two enzymatic activities essential for RNA processing upstream of the nuclear exosome. Within TRAMP, RNA is 3’ polyadenylated by a sub-complex of Trf4/5 and Air1/2 and unwound 3’ to 5’ by Mtr4, a DExH helicase. The molecular mechanisms of TRAMP assembly and RNA shuffling between the two TRAMP catalytic sites are poorly understood. Here, we report solution hydrogen-deuterium exchange data with thermodynamic and functional assays to uncover these mechanisms for yeast TRAMP with Trf4 and Air2 homologs. We show that TRAMP assembly constrains RNA-recognition motifs that are peripheral to catalytic sites. These include the Mtr4 Arch and Air2 zinc knuckles 1, 2, and 3. While the Air2 Arch-interacting motif likely constrains the Mtr4 Arch via transient interactions, these do not fully account for the importance of the Mtr4 Arch in TRAMP assembly. We further show that tRNA binding by single active-site subunits, Mtr4 and Trf4-Air2, differs from the double active-site TRAMP. TRAMP has reduced tRNA binding on the Mtr4 Fist and RecA2 domains, offset by increased tRNA binding on Air2 zinc knuckles 2 and 3. Competition between these RNA-binding sites may drive tRNA transfer between TRAMP subunits. We identify dynamic changes upon TRAMP assembly and RNA-recognition motifs that transfer RNA between TRAMP catalytic sites.