bluuebunny/crossref_metadata_2025_split huggingface dataset:
The incidence and prevalence of Dupuytren’s disease in primary care: Results from a text mining approach on registration data
Authors: van Straalen Roel J. M. , de Boer Michiel R. , Vos Francine , Werker Paul M. N. , Broekstra Dieuwke C. 
Published: July 2024

AbstractBackgroundThe focus of research and management of Dupuytren’s disease (DD) is shifting from relieving symptoms in the later stages of disease towards the prevention of contractures. Treatment services might likewise shift towards primary care. Studying characteristics of DD patients who seek medical care for the first time, may identify a symptomatic target group for early DD treatments. We present the first study that estimates the incidence and prevalence of DD in primary care by applying a text-mining algorithm to registration data.MethodsThis is a population-based cohort study using electronic health records from Dutch general practices involved in a regional research network. Descriptive statistics were used to describe sex, age, comorbidities and lifestyle factors, the latter two were identified via International Classification of Primary Care (ICPC) codes. Incidence rate was calculated as number of patients with a first contact for DD/1000 person years for the years 2017 to 2021, point prevalence as the percentage of patients with a contact for DD in 2021. DD contacts were identified using a text-mining algorithm.ResultsThe incidence ranged between 1.41 to 1.72/1000 person years and the overall prevalence was 1.99%. Incidence and prevalence are higher among males and increase with age, peaking between 61 to 80 years.ConclusionsOur results of prevalence and incidence of DD in primary care give an insight into the relevant population of patients with symptomatic DD that might be the future target group for potential disease controlling treatments.
Analysis of HER2-low breast cancer in Aotearoa New Zealand: a nationwide retrospective cohort study
Authors: Lasham Annette , Ramsaroop Reenadevi , Wrigley Abbey , Knowlton Nicholas 
Published: July 2024

AbstractAimTo perform the first national analysis of demographic and clinicopathological features associated with the HER2 positive, HER2-low and HER2-zero invasive breast cancers in New Zealand. The study will inform the proportion of women who benefit from new HER2-targeted antibody drug conjugate (ADC) therapies.MethodsUtilising data from Te Rēhita Mate Ūtaetae (Breast Cancer Foundation NZ National Register), the study analysed data from women diagnosed with invasive breast cancer over a 21-year period. The HER2 status of tumours was classified into three categories – HER2-zero, -low, - positive.ResultsFrom 2009-2021, 94% of women underwent HER2 testing, with 14% diagnosed with HER2-positive breast cancer. For advanced-stage disease, 38% formerly classified as HER2-negative were reclassified as HER2-low. Including HER2-positive breast cancers, this indicates 60% of women with advanced breast cancer would be eligible for the new HER2-directed ADCs (approximately 120 women per year). In future, these therapies may provide a targeted option for 40% of women with early-stage triple negative breast cancer now classified as HER2-low.ConclusionThe findings suggest a significant proportion of women with invasive breast cancer in New Zealand could benefit from new HER2-targeted treatments. There is a need to standardise HER2 testing to enhance personalised treatment and improve outcomes.
Nocturnal systolic blood pressure dipping among people living with HIV and people without HIV: a cross-sectional study in Rural Uganda
Authors: Sekitoleko Isaac , Kansiime Sheila , Mugamba Viola , Kawooya Ismael , Ntabadde Kauthra , Nakyeyune Rena , Bannink Femke , Nyirenda Moffat , Niwaha Anxious J , Byrd James Brian 
Published: July 2024

ABSTRACTBackgroundIn this study, we investigated sleep quality, depression and stress symptoms as hypothesized factors affecting the association between HIV status and nocturnal blood pressure dipping status in rural Uganda.MethodsIndividuals living with HIV (PLHIV) and people without HIV (PwoHIV) underwent 24-hour ambulatory blood pressure monitoring (ABPM) and classified as extreme dippers, dippers and non-dippers based on a percentage nocturnal drop in mean systolic and diastolic blood pressure. Ordinal logistic regression models were used to assess the effect of different exposure variables (HIV status, sleep quality and other covariates) on the outcome (dipping status).ResultsThe median age was 45 years (IQR: 35-54) and 80% of the participants were female. 24% of PwoHIV and 16% of PLHIV were overweight, 10% of HIV negative and 3% of the HIV positive individuals were obese. Depression was prevalent in both PLHIV and PwoHIV. Additionally, poor sleep quality was more prevalent in PLHIV compared to PwoHIV (70% versus 58%, P= 0.046). The study found that 53% of participants had normal dipping, while 35.1% were non-dippers, with non-dipping being more prevalent in PwoHIV individuals (34.9% vs 29.7%, P<0.001). PLHIV had 3.6 times the odds of being extreme dippers compared to PwoHIV (OR 3.64, 95% CI: 1.40 – 9.44).ConclusionThis study identified high proportions of non-dipping BP profiles among both PLHIV and PwoHIV. However, the odds of being extreme dippers were higher among PLHIV compared to PwoHIV. Further research is needed to understand the underlying mechanisms contributing to extreme dipping patterns in PLHIV.
Modulating immune cell fate and inflammation through CRISPR-mediated DNA methylation editing
Authors: Valcárcel Gemma , López-Rubio Anna V. , Lazarenkov Aleksey , Berenguer Clara , Calafell Josep , Rodríguez-Ubreva Javier , Ballestar Esteban , Sardina José Luis 
Published: July 2024

ABSTRACTDNA methylation is traditionally associated with gene silencing, but its causal relationship and role in shaping cell fate decisions still need to be fully elucidated. Here, we conducted a genome-wide analysis to investigate the relationship between DNA methylation and geneexpressionat gene regulatory regions in human immune cells. By utilizing CRISPR-dCas9 DNA methylation editing tools, we successfully established a cause-and-effect relationship between the methylation levels of the promoter of the Interleukin1-receptor antagonist (IL1RN) gene and its expression. Notably, we observed that modifying the DNA methylation status of theIL1RNpromoter is sufficient to alter the acquisition of the human myeloid cell fate and change the cellular response to inflammatory stimuli, resulting in abnormal cytokine release and distinctive capacity to support cancer growth.
Transient Naive Treatment (TNT) iPS cells do not feature Sendai virus expression: Response to Sendai virus persistence questions the transient naive reprogramming method for iPSC generation
Authors: Buckberry Sam , Liu Xiaodong , Poppe Daniel , Tan Jia Ping , Faulkner Geoffrey J. , Polo Jose M , Lister Ryan 
Published: July 2024

SummaryThe Transient Naive Treatment (TNT) reprogramming method involves a brief period of culturing in naive media early in the reprogramming process. Through conducting extensive molecular, epigenetic, and functional analyses on numerous induced pluripotent stem cell lines, we have demonstrated that TNT reprogramming facilitates epigenetic memory erasure and produces induced pluripotent stem (iPS) cells more similar to embryonic stem (ES) cells than conventional reprogramming methods1. In 2024, De Los Angeleset al. posted a ‘contradictory results’ preprint onbioRxivtitled ‘Sendai virus persistence questions the transient naive reprogramming method for iPSC generation’2. Their claims include: 1) that Sendai virus expression in naive cultured cells questions the TNT reprogramming method, 2) the possible selection of cells (clonal expansion) with Sendai virus expression during TNT reprogramming, 3) Sendai virus genes being expressed in control samples implying a potential sample mix-up. Here, we demonstrate these claims are not directly supported by the data, and emphasize that we assessed the possibility of cell sub-population selection experimentally in Buckberryet al. (2023). Moreover, our re-analyses of the data in the context of Sendai virus expression during reprogramming actually highlight the advantages of TNT reprogramming concerning the timing of the naive media treatment and the absence of detectable Sendai virus gene expression.
TDP-43 mutations-induced defects in miRNA biogenesis and cytotoxicity by differentially obstructing Dicer activity inDrosophilaand in vitro
Authors: Long Xiang , Jiang Mengni , Miao Yongzhen , Du Huanhuan , Zhang Ting , Ma Zhuoya , Li Jiao , Liu Chunfeng , Meng Hongrui 
Published: July 2024

AbstractMutations in the DNA/RNA-binding protein 43 (TDP-43) can cause amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD). As an RNA-binding protein, TDP-43 plays a diverse physiological role in RNA processing and is potentially involved in the pathological progression caused by disease mutations. However, the precise mechanisms linking RNA dysregulation and TDP-43 mutations, which propel disease progression, are not yet fully understood. Here, we demonstrate that TDP-43 and itsDrosophilahomolog, TBPH, whose mutations crucially perturb Dicer presentation, result in dysregulated miRNA profiles. Genetically modulating the expression or pharmacologically activating Dicer implies unique interactions of TDP-43 A315T and M337V with the Dicer protein, suggesting a specific mechanism of C-terminal disease mutations contributes to the pathological process. Unlike TDP-43 A315T, the M337V mutation causes the assembly of aggregates and reorganizes but functionally preserves the Dicer activity in miRNA processing. Mutations in TDP-43 disrupt miRNA biogenesis by hindering its interaction with Dicer, leading to cytotoxicity and providing mechanistic insight into the pathogenic mutations associated with ALS-FTD.
GlyT2-positive interneurons regulate timing and variability of information transfer in a cerebellar-behavioural loop
Authors: Palacios Ensor Rafael , Houghton Conor , Chadderton Paul 
Published: July 2024

ABSTRACTGlyT2-positive interneurons, Golgi and Lugaro cells, reside in the input layer of the cerebellar cortex in a key position to influence information processing. Here, we examine the contribution of GlyT2-positive interneurons to network dynamics in Crus 1 of mouse lateral cerebellar cortex during free whisking. We recorded neuronal population activity using NeuroPixels probes before and after chemogenetic downregulation of GlyT2-positive interneurons. Under resting conditions, cerebellar population activity reliably encoded whisker movements. Reductions in the activity of GlyT2-positive cells produced mild increases in neural activity which did not significantly impair these sensorimotor representations. However, reduced Golgi and Lugaro cell inhibition did increase the temporal alignment of local population network activity at the initiation of movement. These network alterations had variable impacts on behaviour, producing both increases and decreases in whisking velocity. Our results suggest that inhibition mediated by GlyT2-positive interneurons primarily governs the temporal patterning of population activity, which in turn is required to support downstream cerebellar dynamics and behavioural coordination.SIGNIFICANCE STATEMENTThe cerebellum has a simple and conserved structure which has tantalised neurobiologists wishing to understand its function. Here we look at the role of granule cell layer inhibitory interneurons, Golgi and Lugaro cells, in the cerebellar cortex. We selectively turned down the activity of these cells in the awake cerebellum to characterise their influence on network activity and behaviour. We show that downregulation of Golgi and Lugaro cells has very little influence on sensorimotor representations in the cerebellum (i.e.,whatis represented), but instead modulates the timing of cortical population activity (i.e.,wheninformation is represented). Our results indicate that inhibitory interneurons in the granule cell layer are necessary to appropriately pace changes in cerebellar activity to match ongoing behaviour.
Mobius Assembly for Plant Systems highlights promoter-coding sequences-terminator interaction in gene regulation
Authors: Kocaoglan Elif Gediz , Andreou Andreas , Nirkko Jessica , Ochoa-Villarreal Marisol , Loake Gary , Nakayama Naomi 
Published: July 2024

ABSTRACTPlants are the primary biological platforms for producing food, energy, and materials in agriculture; however, they remain a minor player in the recent synthetic biology-driven transformation in bioproduction. Molecular tools and technologies for complex, multigene engineering in plants are as yet limited, with the challenge to enhance their stability and predictivity. Here, we present a new standardized and streamlined toolkit for plant synthetic biology, Mobius Assembly for Plant Systems (MAPS). It is based on small plant binary vectors pMAPs, which contain a fusion origin of replication that enhances plasmid yield in bothEscherichia coliandRhizobium radiobacter. MAPS includes a new library of promoters and terminators with different activity levels; part sizes were minimized to improve construct stability and transformation efficiency. These promoters and terminators were characterized using a high-throughput protoplast expression assay. We observed a significant influence of terminators on gene expression, as the strength of a single promoter can change more than seven-folds in combination with different terminators. Changing the coding sequence changed the relative strength of promoter and terminator pairs, thus uncovering combinatorial gene regulation among all parts of a transcriptional unit. We further gained insights into the mechanisms of such interactions by analyzing RNA folding, with which we suggest a design principle for more predictive and context-independent genetic parts in synthetic biology of plant systems and beyond.
Maternal obesity and offspring neurodevelopment are associated with hypoxic gene expression in term human placenta
Authors: Gunter-Rahman Fatima , Mallett Shayna , White Frédérique , Jacques Pierre-Étienne , Raju Ravikiran M. , Hivert Marie-France , Lee Eunjung Alice 
Published: July 2024

AbstractOne third of women in the United States are affected by obesity during pregnancy. Maternal obesity (MO) is associated with an increased risk of neurodevelopmental and metabolic disorders in the offspring. The placenta, located at the maternal-fetal interface, is a key organ determining fetal development and likely contributes to programming of long-term offspring health. We profiled the term placental transcriptome in humans (pre-pregnancy BMI 35+ [MO condition] or 18.5-25 [lean condition]) using single-nucleus RNA-seq to compare expression profiles in MO versus lean conditions, and to reveal potential mechanisms underlying offspring disease risk. We recovered 62,864 nuclei of high quality from 10 samples each from the maternal-facing and fetal-facing sides of the placenta. On both sides in several cell types, MO was associated with upregulation of hypoxia response genes. On the maternal-facing side only, hypoxia gene expression was associated with offspring neurodevelopmental measures, in Gen3G, an independent pregnancy cohort with bulk placental tissue RNA-seq. We leveraged Gen3G to determine genes that correlated with impaired neurodevelopment and found these genes to be most highly expressed in extravillous trophoblasts (EVTs). EVTs further showed the strongest correlation between neurodevelopment impairment gene scores (NDIGSs) and the hypoxia gene score. We reanalyzed gene expression of cultured EVTs, and found increased NDIGSs associated with exposure to hypoxia. Among EVTs, accounting for the hypoxia gene score attenuated 44% of the association between BMI and NDIGSs. These data suggest that hypoxia in EVTs may be a key process in the neurodevelopmental programming of fetal exposure to MO.
Impacts of Antiretroviral Therapy on the Oral Microbiome and Periodontal Health of Feline Immunodeficiency Virus Positive Cats
Authors: Bashor Laura , Rawlinson Jennifer E. , Kozakiewicz Christopher P. , Behzadi Elisa , Miller Craig , Kim Jeffrey , Conry Megan , Nehring Mary , Carver Scott , Abdo Zaid , VandeWoude Sue 
Published: July 2024

ABSTRACTFeline immunodeficiency virus (FIV) is the domestic cat analogue of HIV infection in humans. Both viruses induce oral disease in untreated individuals, with clinical signs that include gingivitis and periodontal lesions. Oral disease manifestations in HIV patients are abated by highly effective combination antiretroviral therapy (cART), though certain oral manifestations persist despite therapy. Microorganisms associated with oral cavity opportunistic infections in patients with HIV cause similar pathologies in cats. To further develop this model, we evaluated characteristics of feline oral health and oral microbiome during experimental FIV infection over an 8-month period following cART. Using 16S metagenomics sequencing, we evaluated gingival bacterial communities at four timepoints in uninfected and FIV-infected cats treated with cART or placebo. Comprehensive oral examinations were also conducted by a veterinary dental specialist over the experimental period. Gingival inflammation was higher in FIV-infected cats treated with placebo compared to cART-treated cats and controls at study endpoint. Oral microbiome alpha diversity increased in all groups, while beta diversity differed among treatment groups, documenting a significant effect of cART therapy on microbiome community composition. This finding has not previously been reported and indicates cART ameliorates immunodeficiency virus-associated oral disease via preservation of oral mucosal microbiota. Further, this study illustrates the value of the FIV animal model for investigations of mechanistic associations and therapeutic interventions for HIV oral manifestations.IMPORTANCEFeline Immunodeficiency Virus (FIV) is the viral analogue to HIV in humans, and both infections are associated with oral disease. Our study explored how antiretroviral treatment affects the oral health and microbiome of domestic cats infected with FIV. Cats treated with antiretroviral therapy had less gum inflammation and a different community of oral bacteria compared to untreated FIV-positive cats. This suggests that antiretroviral therapy not only helps in controlling FIV infection but also benefits feline oral health. These findings advance our understanding of antiretroviral treatment for lentiviral-associated oral disease and highlight FIV as a valuable experimental model for the similar condition in humans.
Neuronal Hyperactivity in Neurons Derived from Individuals with Grey Matter Heterotopia
Authors: Di Matteo Francesco , Bonrath Rebecca , Schmidt Hanna , Ayo Martin Ane Cristina , Pravata Veronica , Di Giaimo Rossella , Menegaz Danusa , Riesenberg Stephan , de Vrij Femke M.S. , Maccarrone Giuseppina , Holzapfel Maria , Straub Tobias , Kushner Steven A. , Robertson Stephen P. , Eder Matthias , Cappello Silvia 
Published: July 2024

AbstractPeriventricular heterotopia (PH), a common form of grey matter heterotopia associated with developmental delay and drug-resistant seizures, poses a challenge in understanding its neurophysiological basis. Human cerebral organoids (hCOs) derived from patients with causative mutations inFAT4orDCHS1mimic PH features. However, neuronal activity in these 3D models has not yet been invetigated. Here, silicon probe recordings revealed exaggerated spontaneous spike activity in FAT4 and DCHS1 hCOs, suggesting functional changes in neuronal networks. Transcriptome and proteome analyses identified changes in gene ontology terms associated with neuronal morphology and synaptic function. Furthermore, patch-clamp recordings revealed a decreased spike threshold specifically in DCHS1 neurons, likely due to increased somatic voltage-gated sodium channels. Morphological reconstructions and immunostainings revealed greater morphological complexity of PH neurons and synaptic alterations contributing to hyperactivity, with morphological rescue observed in DCHS1 neurons by wild-typeDCHS1expression. Overall, we provide new comprehensive insights into the cellular changes underlying symptoms of grey matter heterotopia.
Cardiomyocyte antisense transcription regulates exon usage in the elastic spring region of Titin to modulate sarcomere function
Authors: Celik Selvi , Hyrefelt Ludvig , Czuba Tomasz , Li Yuan , Assis Juliana , André Oscar , Sandstedt Joakim , Nordenfelt Pontus , Vukusic Kristina , Smith J. Gustav , Gidlöf Olof 
Published: July 2024

AbstractBackgroundThe spring-like sarcomere protein Titin (TTN) is a key determinant of cardiac passive stiffness and diastolic function. Alternative splicing of TTN I-band exons produce protein isoforms with variable size and elasticity, but the mechanisms regulating TTN exon skipping and isoform composition in the human heart are not well studied. Non-coding RNA transcripts from the antisense strand of protein-coding genes have been shown to regulate alternative splicing of the sense gene. TheTTNgene locus harbours >80 antisense transcripts with unknown function in the human heart. The aim of this study was to determine ifTTNantisense transcripts play a role in alternative splicing ofTTN.MethodsRNA-sequencing and RNA in situ hybridization (ISH) of cardiac tissue from unused organ donor hearts (n=7) and human induced pluripotent stem cell-derived cardiomyocytes (iPS-CMs) were used to determine the expression and localization of TTN antisense transcripts. The effect of siRNA-mediated knock down ofTTNantisense transcripts onTTNexon usage in iPS-CMs was determined using RNA-sequencing. Live cell imaging with sarcomere tracking was used to analyze the effect of antisense transcript knock down on sarcomere length, organization and contraction dynamics. RNA ISH, immunofluorescence and high content microscopy was performed in iPS-CMs to study the interaction between antisense transcripts, TTN mRNA and splice factor protein RBM20.ResultsIn mappingTTNantisense transcription, we found thatTTN-AS1-276was the predominant transcript in the human heart and that it was mainly localized in cardiomyocyte nuclear chromatin. Knock down ofTTN-AS1-276in human iPS-CMs resulted in decreased interaction between the splicing factor RBM20 andTTNpre-mRNA, decreasedTTNI-band exon skipping, and markedly lower expression of the less elastic TTN isoform N2B. The effect onTTNexon usage was independent of sense-antisense exon overlap and polymerase II elongation rate. Furthermore, knockdown resulted in longer sarcomeres with preserved alignment, improved fractional shortening and relaxation times.ConclusionsWe demonstrate a role for the cardiacTTNantisense transcriptTTN-AS1-276in facilitating alternative splicing ofTTNand regulating sarcomere properties. This transcript could constitute a target for improving cardiac passive stiffness and diastolic function in conditions such as heart failure with preserved ejection fraction.