bluuebunny/crossref_metadata_2025_split huggingface dataset:
De novovariants inPLCG1are associated with hearing impairment, ocular pathology, and cardiac defects
Authors: Ma Mengqi , Zheng Yiming , Lu Shenzhao , Pan Xueyang , Worley Kim C. , Burrage Lindsay C. , Blieden Lauren S. , Allworth Aimee , Chen Wei-Liang , Merla Giuseppe , Mandriani Barbara , Rosenfeld Jill A. , Li-Kroeger David , Dutta Debdeep , Yamamoto Shinya , Wangler Michael F. ,   Undiagnosed Diseases Network, Glass Ian A. , Strohbehn Sam , Blue Elizabeth , Prontera Paolo , Lalani Seema R. , Bellen Hugo J. 
Published: January 2024

AbstractPhospholipase C isozymes (PLCs) hydrolyze phosphatidylinositol 4,5-bisphosphate into inositol 1,4,5-trisphosphate and diacylglycerol, important signaling molecules involved in many cellular processes.PLCG1encodes the PLCγ1 isozyme that is broadly expressed. Hyperactive somatic mutations ofPLCG1are observed in multiple cancers, but only one germline variant has been reported. Here we describe three unrelated individuals withde novoheterozygous missense variants inPLCG1(p.Asp1019Gly, p.His380Arg, and p.Asp1165Gly) who exhibit variable phenotypes including hearing loss, ocular pathology and cardiac septal defects. To model these variantsin vivo, we generated the analogous variants in theDrosophilaortholog,small wing(sl). We created a null alleleslT2Aand assessed the expression pattern.slis broadly expressed, including in wing discs, eye discs, and a subset of neurons and glia. Loss ofslcauses wing size reductions, ectopic wing veins and supernumerary photoreceptors. We document that mutant flies exhibit a reduced lifespan and age-dependent locomotor defects. Expressing wild-typeslinslT2Amutant rescues the loss-of-function phenotypes whereas expressing the variants causes lethality. Ubiquitous overexpression of the variants also reduces viability, suggesting that the variants are toxic. Ectopic expression of an established hyperactivePLCG1variant (p.Asp1165His) in the wing pouch causes severe wing phenotypes, resembling those observed with overexpression of the p.Asp1019Gly or p.Asp1165Gly variants, further arguing that these two are gain-of-function variants. However, the wing phenotypes associated with p.His380Arg overexpression are mild. Our data suggest that thePLCG1 de novoheterozygous missense variants are pathogenic and contribute to the features observed in the probands.
Insulin-like Growth Factor 1 Receptor Expression Correlates with Programmed Death Ligand 1 Expression and Poor Survival in Non-small Cell Lung Cancer
Authors: Nagamine Hiroaki , Yashiro Masakazu , Mizutani Megumi , Sugimoto Akira , Matsumoto Yoshiya , Tani Yoko , Sawa Kenji , Kaneda Hiroyasu , Yamada Kazuhiro , Watanabe Tetsuya , Asai Kazuhisa , Suzuki Satoshi , Kawaguchi Tomoya 
Published: January 2024

AbstractThe insulin-like growth factor 1 receptor (IGF1R) has been associated with growth and metastasis in various cancers. However, its role in postoperative recurrence and prognosis in lung cancer lacks clear consensus. Therefore, this study aimed to investigate the potential relationship between IGF1R and postoperative recurrence as well as long-term survival in a large cohort. Additionally, we assessed the relationship between IGF1R and programmed death ligand 1 (PD-L1) expression. Our study encompassed 782 patients with non-small cell lung cancer (NSCLC). Immunostaining of surgical specimens was performed to evaluate IGF1R and PD-L1 expression. Among the patients, 279 (35.8%) showed positive IGF1R expression, with significantly worse relapse-free survival (RFS) and overall survival (OS). Notably, no significant differences in RFS and OS were observed between IGF1R-positive and -negative groups in stages 2 and 3. However, in the early stages (0-1), the positive group displayed significantly worse RFS and OS. In addition, PD-L1 expression was detected in 100 (12.8%) patients, with a significant predominance in the IGF1R-positive. IGF1R may serve as a prognostic indicator and a guide for perioperative treatment strategies in early-stage lung cancer. In conclusion, our findings underscore an association between IGF1R expression and poor survival and PD-L1 expression in NSCLC.
Demographic characteristics and prevalence of asymptomaticLeishmania donovaniinfection in migrant workers working in an endemic area in Northwest Ethiopia
Authors: Yimer Mulat , Takele Yegnasew , Yizengaw Endalew , Nibret Endalkachew , Sumova Petra , Volf Petr , Yismaw Gizachew , Alehegn Michael , Rowan Aileen , Müller Ingrid , Cotton James A. , Chapman Lloyd A. C. , Kropf Pascale 
Published: January 2024

ABSTRACTVisceral leishmaniasis (VL), a neglected tropical disease that causes substantial morbidity and mortality, is a serious health problem in Ethiopia. Infections are caused byLeishmania(L.)donovaniparasites. Most individuals remain asymptomatic, but some develop VL, which is fatal if not treated.We identified the area of Metema-Humera in Northwest Ethiopia as a setting in which we could follow migrant workers when they arrived in an endemic area. The demographic characteristics of this population and factors associated with their risk of asymptomatic infection are poorly characterised. We divided our cohort into individuals who visited this area for the first time (first comers, FC) and those who had already been in this area (repeat comers, RC). We followed them from the beginning (Time 1, T1) to the end of the agricultural season (Time 2, T2), performing tests for sand fly bite exposure (anti-sand fly saliva antibody ELISA) and serology forLeishmaniainfection (rK39 rapid diagnostic test and the direct agglutination test) at each time point and collecting information on risk factors for infection.Our results show that most migrant workers come from non-endemic areas, are male, young (median age of 20 years) and are farmers or students.At T1, >80% of them had been already exposed to sand fly bites, as shown by the presence of anti-saliva antibodies. However, due to seasonality of sand flies there was no difference in exposure between FC and RC, or between T1 and T2. The serology data showed that at T1, but not at T2, a significantly higher proportion of RC were asymptomatic. Furthermore, 28.6% of FC became asymptomatic between T1 and T2. Over the duration of this study, one FC and one RC developed VL.In multivariable logistic regression of asymptomatic infection at T1, only age and the number of visits to Metema/Humera were significantly associated with asymptomatic infection.A better understanding of the dynamics of parasite transmission and the risk factors associated with the development of asymptomatic infections and potentially VL will be essential for the development of new strategies to prevent leishmaniasis.
Remote and unsupervised digital memory assessments can reliably detect cognitive impairment in Alzheimer’s disease
Authors: Berron David , Olsson Emil , Andersson Felix , Janelidze Shorena , Tideman Pontus , Düzel Emrah , Palmqvist Sebastian , Stomrud Erik , Hansson Oskar 
Published: January 2024

AbstractINTRODUCTIONRemote unsupervised cognitive assessments have the potential to complement and facilitate cognitive assessment in clinical and research settings.METHODSHere we evaluate the usability, validity and reliability of unsupervised remote memory assessments via mobile devices in individuals without dementia from the Swedish BioFINDER-2 study and explore their prognostic utility regarding future cognitive decline.RESULTSUsability was rated positively; remote memory assessments showed good construct validity with traditional neuropsychological assessments and were significantly associated with tau-PET and downstream MRI measures. Memory performance at baseline was associated with future cognitive decline and prediction of future cognitive decline was further improved by combining remote digital memory assessments with plasma p-tau217. Finally, retest reliability was moderate for a single assessment and good for an aggregate of two sessions.DISCUSSIONOur results demonstrate that unsupervised digital memory assessments might be used for diagnosis and prognosis in Alzheimer’s disease, potentially in combination with plasma biomarkers.
Pontine Infarction: A Prospective Cohort Study on Its Clinical Features, Prognosis, and Association with Branch Atheromatous Disease
Authors: Motoie Ryota , Ono Kotaro , Oketani Hiroshi , Kawano Yosuke , Nagaoka Shintaro , Maeda Kazushi , Suyama Yoshio , Gi Hidefuku , Kanemoto Yukihide 
Published: January 2024

AbstractIntroductionThis study aimed to analyse disease characteristics and prognostic factors among a cohort of 407 patients with pontine infarction, focusing on the effect of branch atheromatous disease (BAD).Patients and MethodsA retrospective analysis of patients diagnosed with brainstem stroke at Baba Memorial Hospital from 2012 to 2022 was conducted. The study included patients with pontine stroke, excluding those with missing data, chronic or multiple cerebral infarctions, non-brainstem stroke, or without timely MRI. Patient analysis involved age, sex, Japan Coma Scale (JCS) score, medical history, symptoms at admission, and MRI findings. Prognostic groups were classified based on the modified Rankin Scale (mRS) and Functional Independence Measure (FIM) scores at admission and discharge.ResultsOf the 407 patients, 66.1% belonged to the good prognosis group (mRS 0–2) and 33.9% to the poor prognosis group (mRS 35). Younger patients tended to have a better prognosis. JCS scores correlated with prognosis severity. Significant differences in dysarthria, paralysis, and admission FIM scores were observed between patients with and without BAD. Logistic regression analysis identified the FIM score at admission as an independent predictor of prognosis.DiscussionBAD was not directly related to prognosis. The absence of differences in discharge FIM scores and similar prognoses to other stroke types suggested effective rehabilitation. However, due to the lack of pre-stroke FIM measurements and specific treatment details, further research is needed.ConclusionAge and JCS scores were significant prognostic factors, with BAD not directly affecting prognosis. There is need for investigation into treatment methods and detailed prognostic factors.
Triterpene RDF: Developing a database of plant enzymes and transcription factors involved in triterpene biosynthesis using the Resource Description Framework
Authors: Tamura Keita , Chiba Hirokazu , Bono Hidemasa 
Published: January 2024

AbstractPlants produce structurally diverse triterpenes (triterpenoids and steroids). Their biosynthesis occurs from a common precursor, namely 2,3-oxidosqualene, followed by cyclization catalyzed by oxidosqualene cyclases (OSCs) to yield various triterpene skeletons. Steroids, which are biosynthesized from cycloartenol or lanosterol, are essential primary metabolites in most plant species, along with lineage-specific steroids, such as steroidal glycoalkaloids found in theSolanumspecies. Other diverse triterpene skeletons are converted into triterpenoids, often classified as specialized compounds that are biosynthesized only in a limited number of plant species with tissue-or cell-type-specific accumulation in plants. Recent studies have identified various tailoring enzymes involved in the structural diversification of triterpenes as well as transcription factors that regulate the expression of these enzymes. However, the coverage of these proteins is scarce in publicly available databases for curated proteins or enzymes, which complicates the functional annotation of newly assembled genomes or transcriptome sequences. Here, we created the Triterpene RDF, a manually curated database of enzymes and transcription factors involved in plant triterpene biosynthesis. The database (https://github.com/ktamura2021/triterpene_rdf/) contains 526 proteins, with links to the UniProt Knowledgebase or NCBI protein database, and it enables direct download of a set of protein sequences filtered by protein type or taxonomy. Triterpene RDF will enhance the functional annotation of enzymes and regulatory elements for triterpene biosynthesis, in a current expansion of availability of genomic information on various plant species.
Deep rhizospheres extend the nitrogen cycle meters below the base of soil into weathered bedrock
Authors: Crutchfield-Peters Kelsey , Rempe Daniella M. , Tune Alison K. , Dawson Todd E. 
Published: January 2024

AbstractNitrogen is the most limiting nutrient to forest productivity worldwide. Recently, it has been established that diverse ecosystems source a substantial fraction of their water from weathered bedrock, leading to questions about whether root-driven nitrogen cycling extends into weathered bedrock as well. In this study, we specifically examined nitrogen dynamics using specialized instrumentation distributed across a 16 m weathered bedrock vadose zone (WBVZ) underlying an old growth forest in northern California where the rhizosphere—composed of plant roots and their associated microbiome—extends meters into rock. We documented total dissolved nitrogen (TDN), dissolved organic carbon (DOC), inorganic N (ammonium and nitrate) and CO2and O2gasses every 1.5 m to 16 m depth for two years. We found that biologically available nitrogen in the weathered bedrock rhizosphere was comparable in concentration to temperate forest soils and primarily organic. TDN concentrations in the WBVZ exhibited distinct patterns with depth and were correlated with periods of increased whole-ecosystem metabolic activity as well as stream discharge, suggesting competing rhizosphere and leaching processes in the fate of TDN in the WBVZ. Carbon isotope composition of the DOC suggests that dissolved organic matter in the WBVZ is primarily derived from fresh plant sources. We conclude that N cycling in the WBVZ is driven by an active rhizosphere meters below the base of soil and represents an important and overlooked component of deeply rooted ecosystems that must be incorporated into future models and theory of ecosystem function.
Hippocampal trauma memory processing conveying susceptibility to traumatic stress
Authors: Dirven Bart C.J. , Melis Lennart van , Daneva Teya , Dillen Lieke , Homberg Judith R. , Kozicz Tamas , Henckens Marloes J.A.G. 
Published: January 2024

AbstractWhile the majority of the population is ever exposed to a traumatic event during their lifetime, only a fraction develops posttraumatic stress disorder (PTSD). Disrupted trauma memory processing has been proposed as a core factor underlying PTSD symptomatology. We used transgenic Targeted- Recombination-in-Active-Populations (TRAP) mice to investigate potential alterations in trauma- related hippocampal memory engrams associated with the development of PTSD-like symptomatology. Mice were exposed to a stress-enhanced fear learning paradigm, in which prior exposure to a stressor affects the learning of a subsequent fearful event (contextual fear conditioning using foot shocks), during which neuronal activity was labeled. One week later, mice were behaviorally phenotyped to identify mice resilient and susceptible to developing PTSD-like symptomatology. Three weeks post-learning, mice were re-exposed to the conditioning context to induce remote fear memory recall, and associated hippocampal neuronal activity was assessed. While no differences in the size of the hippocampal neuronal ensemble activated during fear learning were observed between groups, susceptible mice displayed a smaller ensemble activated upon remote fear memory recall in the ventral CA1, higher regional hippocampal PV+neuronal density and a relatively lower activity of PV+interneurons upon recall. Investigation of potential epigenetic regulators of the engram revealed rather generic (rather than engram-specific) differences between groups, with susceptible mice displaying lower hippocampal histone deacetylase 2 expression, and higher methylation and hydroxymethylation levels. These finding implicate variation in epigenetic regulation within the hippocampus, as well as reduced regional hippocampal activity during remote fear memory recall in interindividual differences in susceptibility to traumatic stress.
Unraveling the seasonal dynamics of ixodid ticks: A flexible matrix population model with delayed life history effects
Authors: Vindenes Yngvild , Mysterud Atle 
Published: January 2024

AbstractMany vector-borne diseases are sensitive to changes in land use and climate, making it crucial to understand the factors that govern the vector populations. Ixodid ticks, which serve as vectors for multiple diseases, have a slow life cycle compared to many of their hosts. The duration of each active life stage (larvae, nymph, adult) varies greatly and depends on factors such as timing of questing and development, host availability throughout the seasons, and photoperiod-related behavioral and developmental diapause. Importantly, the observable questing population only represents a fraction of the total tick population and may include overlapping generations in each stage. Mathematical models are therefore essential to understand how complex life cycle transitions and host interactions impact the dynamics of the tick population. In this study, we present a flexible seasonal matrix model for ixodid ticks that feed on small and large hosts varying in seasonal availability. This model incorporates the delayed life history effects of overwintering and seasonal timing of feeding, density regulation through limited host capacity, and scramble competition among larvae and nymphs for small hosts. We extract the equilibrium seasonal numbers of questing, feeding, and emerging ticks for each life stage, as well as the seasonal patterns of host use. We also calculate key life history characteristics including the mean generation time, stable stage structure, and reproductive values. The baseline model represents a northern life history of the sheep tick (Ixodes ricinus) feeding on a seasonal small host and constant large host, which is compared to a scenario without host seasonality and a scenario representing a southern ecosystem. Our findings support the importance of small hosts in regulating tick populations, and highlight that feeding of larvae is a critical transition. Our analyses shed light on the complex mechanisms underlying the seasonal composition of the questing population, with its important implications for disease risk. The model can be applied to other ixodid tick species and provides a framework for future investigations into population dynamics under various tick and host scenarios.
Absolute quantitative and base-resolution sequencing reveals comprehensive landscape of pseudouridine across the human transcriptome
Authors: Xu Haiqi , Kong Linzhen , Cheng Jingfei , Moussawi Khatoun Al , Chen Xiufei , Iqbal Aleema , Wing Peter A. C. , Harris James M. , Tsukuda Senko , Embarc-Buh Azman , Wei Guifeng , Castello Alfredo , Kriaucionis Skirmantas , McKeating Jane A. , Lu Xin , Song Chun-Xiao 
Published: January 2024

AbstractPseudouridine (Ψ) is one of the most abundant modifications in cellular RNA. However, its function remains elusive, mainly due to the lack of highly sensitive and accurate detection methods. To address this challenge, we introduced 2-bromoacrylamide-assisted cyclization sequencing (BACS) for quantitative profiling of Ψ at single-base resolution. Based on novel bromoacrylamide cyclization chemistry, BACS enables a Ψ-to-C transition. Compared to previous methods, BACS allowed the precise identification of Ψ positions, especially in densely modified Ψ regions and consecutive uridine sequences. BACS successfully detected all known Ψ sites in human rRNA and spliceosomal snRNAs and generated the first quantitative Ψ map of human snoRNA and tRNA. Furthermore, BACS simultaneously detected adenosine-to-inosine (A-to-I) editing sites andN1-methyladenosine (m1A). Depletion of three key pseudouridine synthases (PUS) enabled us to elucidate the targets and sequence motifs of TRUB1, PUS7, and PUS1 in HeLa cells. We further applied BACS to Epstein-Barr virus (EBV)-encoded small RNAs (EBERs) and identified a highly abundant Ψ114site in EBER2. Surprisingly, applying BACS to a panel of RNA viruses demonstrated the absence of Ψ in their viral transcripts or genomes, shedding light on differences in pseudouridylation between virus families. We anticipate BACS to serve as a powerful tool to uncover the biological importance of Ψ in future studies.
The predictive outfielder: a critical test across gravities
Authors: Aguado Borja , López-Moliner Joan 
Published: January 2024

Intercepting moving targets, like fly balls, is a common challenge faced by several species. Historically, models attempting to explain this behavior in humans have relied on optical variables alone. Such models, while insightful, fall short in several respects, particularly in their lack of predictive capabilities. This absence of prediction limits the ability to plan movements or compensate for inherent sensorimotor delays. Moreover, these traditional models often imply that an outfielder must maintain a constant gaze on the target throughout to achieve successful interception. In this study, we present a new model that continuously updates its predictions, not just on the immediate trajectory of the ball, but also on its eventual landing position in the 3D scene and remaining flight time based on the outfielder’s real time movements. A distinct feature is the model’s adaptability to different gravitational scenarios, making its predictions inherently tailored to specific environmental conditions. By actively integrating gravity, our model produces trajectory predictions that can be validated against actual paths, providing a significant departure from previous models. To compare our model to the traditional ones, we conducted experiments within a virtual reality setting, strategically varying simulated gravity among other parameters. This gravity variation yielded qualitatively distinct predictions between error-nulling optical-based heuristics and our model. The trajectories, kinematic patterns and timing responses produced by participants were in good agreement with the predictions of our proposed model, suggesting a paradigm shift in our understanding of interceptive actions.Significance statementCatching a moving target, a challenge consistently faced across various species, exemplifies the complex interplay between perception, prediction, and motor action in dynamic environments. Prevailing models have been largely rooted in optical cues, often overlooking the predictive capacities essential for understanding real-world human behaviors and sidestepping crucial physical variables such as gravity. Our research introduces a novel model that emphasizes both the predictive component and the broader gravitational dynamics allowing for a more holistic understanding of interception tasks. This innovative approach not only holds implications for refining existing models of interception but also carries broader significance for training platforms, ensuring relevance across diverse settings, from Earth to altered gravity environments.