bluuebunny/crossref_metadata_2025_split huggingface dataset:
Elucidating the clinical and molecular spectrum ofSMARCC2-associated NDD in a cohort of 65 affected individuals
Authors: Bosch Elisabeth , Popp Bernt , Güse Esther , Skinner Cindy , van der Sluijs Pleuntje J. , Maystadt Isabelle , Pinto Anna Maria , Renieri Alessandra , Bruno Lucia Pia , Granata Stefania , Marcelis Carlo , Baysal Özlem , Hartwich Dewi , Holthöfer Laura , Isidor Bertrand , Cogne Benjamin , Wieczorek Dagmar , Capra Valeria , Scala Marcello , De Marco Patrizia , Ognibene Marzia , Jamra Rami Abou , Platzer Konrad , Carter Lauren B. , Kuismin Outi , van Haeringen Arie , Maroofian Reza , Valenzuela Irene , Cuscò Ivon , Martinez-Agosto Julian A. , Rabani Ahna M. , Mefford Heather C. , Pereira Elaine M. , Close Charlotte , Anyane-Yeboa Kwame , Wagner Mallory , Hannibal Mark C. , Zacher Pia , Thiffault Isabelle , Beunders Gea , Umair Muhammad , Bhola Priya T. , McGinnis Erin , Millichap John , van de Kamp Jiddeke M , Prijoles Eloise J. , Dobson Amy , Shillington Amelle , Graham Brett H. , Garcia Evan-Jacob , Galindo Maureen Kelly , Ropers Fabienne G. , Nibbeling Esther AR , Hubbard Gail , Karimov Catherine , Goj Guido , Bend Renee , Rath Julie , Morrow Michelle M , Millan Francisca , Salpietro Vincenzo , Torella Annalaura , Nigro Vincenzo , Kurki Mitja , Stevenson Roger E , Santen Gijs W.E. , Zweier Markus , Campeau Philippe M. , Severino Mariasavina , Reis André , Accogli Andrea , Vasileiou Georgia 
Published: April 2023

ABSTRACTPURPOSECoffin-Siris and Nicolaides-Baraitser syndromes, are recognisable neurodevelopmental disorders caused by germline variants in BAF complex subunits. TheSMARCC2BAFopathy was recently reported. Herein, we present clinical and molecular data on a large cohort.METHODSClinical symptoms for 41 novel and 24 previously published cases were analyzed using the Human Phenotype Ontology. For genotype-phenotype correlation, molecular data were standardized and grouped into non-truncating and likely gene-disrupting variants (LGD). Missense variant protein expression and BAF subunit interactions were examined using 3D protein modeling, co-immunoprecipitation, and proximity-ligation assays.RESULTSNeurodevelopmental delay with intellectual disability, muscular hypotonia and behavioral disorders were the major manifestations. Clinical hallmarks of BAFopathies were rare. Clinical presentation differed significantly, with LGD variants being predominantly inherited and associated with mildly reduced or normal cognitive development, while non-truncating variants were mostlyde novoand presented with severe developmental delay. These distinct manifestations and non-truncating variant clustering in functional domains suggest different pathomechanisms.In vitrotesting showed decreased protein expression for N-terminal missense variants similar to LGD.CONCLUSIONThis study improvedSMARCC2variant classification and identified discernibleSMARCC2-associated phenotypes for LGD and non-truncating variants, which were distinct from other BAFopathies. The pathomechanism of most non-truncating variants has yet to be investigated.
Prescribing differences among older adults with differing health cover and socioeconomic status: a cohort study
Authors: Prendergast Ciaran , Flood Michelle , Murry Logan T. , Clyne Barbara , Fahey Tom , Moriarty Frank 
Published: April 2023

AbstractIntroductionAs health reforms move Ireland from a mixed public-private system toward universal healthcare, it is important to understand variations in prescribing practice for patients with differing health cover and socioeconomic status. This study aims to determine how prescribing patterns for patients aged ≥65 years in primary care in Ireland differ between patients with public and private health cover.MethodsThis was an observational study using anonymised data collected as part of a larger study from 44 general practices in Ireland (2011-2018). Data were extracted from electronic records relating to demographics and prescribing for patients aged ≥65 years. The cohort was divided between those with public health cover (via the General Medical Services (GMS) scheme) and those without. Standardised rates of prescribing were calculated for pre-specified drug classes. We also analysed the number of medications, polypharmacy, and trends over time between groups, using multilevel linear regression adjusting for age and sex.ResultsOverall, 42,456 individuals were included (56% female). Most were covered by the GMS scheme (62%, n=26,490). The rate of prescribing in all medication classes was higher for GMS patients compared to non-GMS patients, with the greatest difference in benzodiazepine anxiolytics. The mean number of unique medications prescribed to GMS patients was 10.9 (SD 5.9), and 8.1 (SD 5.8) for non-GMS patients. The number of unique medications prescribed to both GMS and non-GMS cohorts increased over time. The increase was steeper in the GMS group where the mean number of medications prescribed increased by 0.67 medications/year. The rate of increase was 0.13 (95%CI 0.13, 0.14) medications/year lower for non-GMS patients, a statistically significant difference.ConclusionOur study found a significantly larger number of medicines were prescribed to patients with public health cover, compared to those without. Increasing medication burden and polypharmacy among older adults may be accelerated for those of lower socioeconomic status. These findings may inform planning for moves towards universal health care, and this would provide an opportunity to evaluate the effect of expanding entitlement on prescribing and medicines use.
PREVELANCE OF ISCHEMIC AND HEMORRAGHIC STROKE AMONG GERAITIC PATIENTS ADMITTED IN THE PUBLIC TERTIARY CARE HOSPITALS OF PESHAWAR
Authors: Haider Zeeshan , Hussain Sayed Sajid 
Published: April 2023

ABSTRACTBackgroundStroke is a life-threatening medical condition that can result in lifelong brain impairment, complications, and demise. Stroke is the world’s second biggest cause of mortality and could soon overtake as the biggest cause of death globally. It has 2 major pathological types’ i.e. ischemic stroke and hemorrhagic stroke. Hypertension, diabetes mellitus, cardiac diseases, smoking, physical inactivity and age are the risk factors that contribute in the occurrence of a stroke.ObjectiveTo find out the epidemiological status of stroke types among patients admitted in the public tertiary care hospitals of Peshawar.MethodologyA descriptive cross-sectional study was carried out to determine the prevalence of stroke types in tertiary care hospitals of Peshawar. The sample size calculated for the research study was 109. Convenience sampling technique was used in this study.ResultsThis study was performed among 109 research participants. The most affected were males as 51.13% and females were 45.87%.And the rate of ischemic stroke were 71% while that of hemorrhagic stroke were 28%.Conclusionthe current research study concluded that majority of the patients had ischemic stroke as compared to the hemorrhagic stroke.
Uncovering the history of recombination and population structure in western Canadian stripe rust populations through mating-type alleles
Authors: Holden Samuel , Bakkeren Guus , Hubensky John , Bamrah Ramandeep , Abbasi Mehrdad , Qutob Dinah , de Graaf Mei-Lan , Kim Sang Hu , Kutcher Hadley R. , McCallum Brent D. , Randhawa Harpinder S. , Iqbal Muhammad , Uloth Keith , Burlakoti Rishi , Brar Gurcharn S. 
Published: April 2023

AbstractThe population structure of crop pathogens such asPuccinia striiformisf. sp.tritici(Pst); the cause of wheat stripe rust, is of interest to researchers looking to understand these pathogens on a molecular level, as well as those with an applied focus such as disease epidemiology. Cereal rusts can reproduce sexually or asexually, and the introduction of novel genetic lineages has the potential to cause serious epidemics such as the one caused by ‘Warrior’ lineage in Europe. In a global context,Pstlineages in Canada were not well-characterized and origin of foreign incursions was not known. We used a whole-genome/transcriptome sequencing approach for the CanadianPstpopulation to identify lineages in a global context, origin, and evidence for foreign incursion. More importantly, for the first time ever, we identified nine alleles of the homeodomain mating-type locus in the worldwidePstpopulation and show that previously identified lineages generally exhibit a single pair of these alleles. In addition, we find only two pheromone receptor alleles. We show that the recent population shift from the ‘PstS1’lineage to the ‘PstS1-related’lineage is also associated with the introduction of a novel mating-type allele (b-3) to the Canadian population. We also show evidence for high levels of mating-type diversity in samples associated with the Himalayan center of diversity forPst, including a single Canadian race previously identified as ‘PstPr’(probable recombinant) which we identify as a foreign incursion from China circa. 2010. These data provide comprehensive details on the population biology of CanadianPstdiversity and mating-type alleles in the globalPstpopulation which can be utilized in testing several research questions and hypotheses around sexuality and parasexuality in rust fungi.
A Trisomy 21 Lung Cell Atlas
Authors: Bhattacharya Soumyaroop , Cherry Caroline , Deutsch Gail ,   Birth Defects Research Laboratory (BDRL), Glass Ian A. , Mariani Thomas J. , Alam Denise Al , Danopoulos Soula 
Published: April 2023

AbstractTrisomy 21 (T21), resulting in Down Syndrome (DS), is the most prevalent chromosomal abnormality worldwide. While pulmonary disease is a major cause of morbidity and mortality in DS, the ontogeny of pulmonary complications remains poorly understood. We recently demonstrated that T21 lung anomalies, including airway branching and vascular lymphatic abnormalities, are initiated in utero. Here, we aimed to describe molecular changes at the single cell level in prenatal T21 lungs. Our results demonstrate differences in the proportion of cell populations and detail changes in gene expression at the time of initiation of histopathological abnormalities. Notably, we identify shifts in the distribution of alveolar epithelial progenitors, widespread induction of key extracellular matrix molecules in mesenchymal cells and hyper-activation of IFN signaling in endothelial cells. This single cell atlas of T21 lungs greatly expands our understanding of antecedents to pulmonary complications and should facilitate efforts to mitigate respiratory disease in DS.
Evolution of the Telencephalon Anterior-Posterior Patterning by Core Endogenous Network Bifurcation
Authors: Sun Chen , Yao Mengchao , Xiong Ruiqi , Su Yang , Zhu Binglin , Ao Ping 
Published: April 2023

AbstractHow did the complex structure of telencephalon evolve? Existing explanations are based on phenomena and lack the first principle. The Darwinian dynamics and the endogenous network theory established a few years ago provide a mathematical and theoretical framework of a dynamical structure, and a general constitutive structure for theory-experiment coupling, respectively, for answering this question from the first principle perspective. By revisiting a gene network that explains the anterior-posterior patterning of the vertebrate telencephalon, we found that with the increase of the cooperative effect in this network, the fixed points gradually evolve, accompanied by the occurrence of two bifurcations. The dynamic behavior of this network consists with the knowledge obtained from experiments on telencephalon evolution. Furtherly, our work drew an answer quantitatively of how the telencephalon anterior-posterior patterning evolved from the pre-vertebrate chordate to the vertebrate and gave a series of verifiable predictions in a first principle manner.Figure Abstract
QCT-based computational bone strength assessment updated with MRI-derived ‘hidden’ microporosity
Authors: McPhee Samuel , Kershaw Lucy E , Daniel Carola R , Fernández Marta Peña , Cillán-García Eugenio , Taylor Sarah E , Wolfram Uwe 
Published: April 2023

AbstractMicrodamage accumulated through sustained periods of cyclic loading or single over-loading events contributes to bone fragility through a reduction in stiffness and strength. Monitoring microdamagein vivoremains unattainable by clinical imaging modalities. As such, there are no established computational methods for clinical fracture risk assessment that account for microdamage that existsin vivoat any specific timepoint. We propose a method that combines multiple clinical imaging modalities to identify an indicative surro-gate, which we term ’hidden porosity’, that incorporates pre-existing bone microdamagein vivo. To do so, we use the third metacarpal bone of the equine athlete as an exemplary model for fatigue induced microdamage, which coalesces in the subchondral bone. N=10 metacarpals were scanned by clinical quantitative computed tomography (QCT) and mag-netic resonance imaging (MRI). We used a patch-based similarity method to quantify the signal intensity of a fluid sensitive MRI sequence in bone regions where microdamage coa-lesces. The method generated MRI-derived pseudoCT images which were then used to de-termine a pre-existing damage (Dpex) variable to quantify the proposed surrogate and which we incorporate into a nonlinear constitutive model for bone tissue. The minimum, median, and maximum detectedDpexof 0.059, 0.209, and 0.353 reduced material stiffness by 5.9%, 20.9%, and 35.3% as well as yield stress by 5.9%, 20.3%, and 35.3%. Limb-specific voxel-based finite element meshes were equipped with the updated material model. Lateral and medial condyles of each metacarpal were loaded to simulate physiological joint loading dur-ing gallop. The degree of detectedDpexcorrelated with a relative reduction in both condylar stiffness (p= 0.001, R2> 0.74) and strength (p< 0.001, R2> 0.80). Our results illustrate the complementary value of looking beyond clinical CT, which neglects the inclusion of micro-damage due to partial volume effects. As we use clinically available imaging techniques, our results may aid research beyond the equine model on fracture risk assessment in human diseases such as osteoarthritis, bone cancer, or osteoporosis.
Immunoproteasome deficiency results in accelerated brain aging and epilepsy
Authors: Leister Hanna , Krause Felix F. , Gil Beatriz , Prus Ruslan , Prus Inna , Hellhund-Zingel Anne , Mitra Meghma , Rosa Gerbatin Rogerio Da , Delanty Norman , Beausang Alan , Brett Francesca M. , Farrell Michael A. , Cryen Jane , O’Brien Donncha F. , Henshall David , Helmprobst Frederik , Pagenstecher Axel , Steinhoff Ulrich , Visekruna Alexander , Engel Tobias 
Published: April 2023

AbstractThe immunoproteasome is a central protease complex required for optimal antigen presentation. Immunoproteasome activity is also associated with facilitating degradation of misfolded and oxidized proteins, which prevents cellular stress. While extensively studied during diseases with increasing evidence suggesting a role for the immunoproteasome during pathological conditions including neurodegenerative diseases, this enzyme complex is believed to be mainly inactive in the healthy brain. Here, we show an age-dependent increase in polyubiquitination in the brain of wild-type mice, accompanied with induction of immunoproteasomes, which was most prominent in neurons and microglia. In contrast, mice completely lacking immunoproteasomes (triple-knockout (TKO) mice deficient for LMP2, LMP7 and MECL-1), displayed a strong increase in polyubiquitinated proteins already in the young brain and developed spontaneous epileptic seizures, beginning at the age of 6 months. Injections of kainic acid led to high epilepsy-related mortality of aged TKO mice, confirming increased pathological hyperexcitability states. Notably, the expression of the immunoproteasome was reduced in the brains of patients suffering from epilepsy. In addition, aged TKO mice showed increased anxiety, tau hyperphosphorylation and degeneration of Purkinje cell population with the resulting ataxic symptoms and locomotion alterations. Collectively, our study suggests a critical role for the immunoproteasome in the maintenance of a healthy brain during aging.
PRMT1 is a critical dependency in clear cell renal cell carcinoma through its role in post-transcriptional regulation of DNA damage response genes
Authors: Walton Joseph , Ng Angel SN , Arevalo Karen , Apostoli Anthony , Meens Jalna , Karamboulas Christina , St-Germain Jonathan , Prinos Panagiotis , Dmytryshyn Julia , Chen Eric , Arrowsmith Cheryl H. , Raught Brian , Ailles Laurie 
Published: April 2023

AbstractBiallelic inactivation of the Von Hippel-Lindau (VHL) tumor suppressor gene occurs in almost all cases of clear cell renal cell carcinoma (ccRCC) and leads to disrupted oxygen sensing and the upregulation of hypoxia-related genetic programs. Although the loss of VHL appears to be a necessary oncogenic driver event in the majority of ccRCC instances, it is not always a sufficient one. Large genomics studies have revealed that co-deletions ofVHLwith genes involved in chromatin regulation are common and important co-drivers of tumorigenesis. Several conserved evolutionary subtypes have been described clinically and the majority implicate disruptions in epigenetic regulators. It is now clear that impairments in cellular epigenetic mechanisms are important co-drivers of disease and signal a potential vulnerability in the epigenetic network of ccRCC cells relative to their normal counterparts. Using a clinically relevant panel of ccRCC models, we herein sought to exploit this potential vulnerability by screening a library of small molecule inhibitors that target a spectrum of epigenetic regulators. We identified MS023, an inhibitor of type I protein arginine methyltransferases (PRMTs) as an agent with antitumor activity. Using orthogonal genetic technologies, we further validated PRMT1 as the specific critical dependency for cancer growth. Mechanistically, our transcriptomic and functional analyses suggest that MS023 treatment results in substantial impairments to cell cycle and DNA damage repair (DDR) pathways, while spawning an accumulation of DNA damage over time. Our PRMT1 specific proteomics analysis revealed an interactome rich in RNA binding proteins including the specific regulator of DDR mRNA metabolism: the BCLAF1/THRAP3 complex. Further investigation suggests that MS023 treatment may result in impairments to DDR specific mRNA activities including nucleocytoplasmic transport and RNA splicing. Together, our data supports PRMT1 as a compelling target in ccRCC and informs a potential mechanism-based strategy for translational development.
RNAi-mediated knockdown of two orphan G-protein coupled receptors reduces fecundity in the yellow fever mosquitoAedes aegypti
Authors: Keyes-Scott Nia I. , Swade Kyle R. , Allen Lena R. , Vogel Kevin J. 
Published: April 2023

AbstractG-protein coupled receptors (GPCRs) control numerous physiological processes in insects, including reproduction. While many GPCRs have known ligands, orphan GPCRs do not have identified ligands in which they bind. Advances in genomic sequencing and phylogenetics provide the ability to compare orphan receptor protein sequences to sequences of characterized GPCRs, and thus gain a better understanding of their potential function. Our study investigated two orphan GPCRs, AAEL003647 and AAEL019988, in the yellow fever mosquito,Aedes aegypti. From our phylogenetic analysis, we found that AAEL003647 is orthologous to the SIFamide-2/SMYamide receptor, while AAEL019988 is orthologous to the Trapped in endoderm (Tre1) receptor ofDrosophila melanogaster. Tissue-specific expression analysis revealed that both receptors had highest expression in the ovaries, suggesting they may be important for reproduction. We then used RNA interference (RNAi) to knock down both genes and found a significant reduction in the number of eggs laid per individual female mosquito, suggesting both receptors are important forAe. aegyptireproduction.
3D-Printed LEGO®-inspired Titanium Scaffolds for Patient-Specific Regenerative Medicine
Authors: Lee Seunghun S. , Du Xiaoyu , Smit Thijs , Bissacco Elisa G. , Seiler Daniel , de Wild Michael , Ferguson Stephen J. 
Published: April 2023

AbstractDespite the recent advances in 3D-printing, it is difficult to fabricate implants that optimally fit a defect size/shape. There are some approaches to resolve this issue, such as patient-specific implant based on CT images, however, it is labor-intensive and costly. Especially in developing countries, affordable treatments are required, while still not excluding these patient groups from manufacturing advances. Here, a SLM 3D-printing strategy was used to fabricate a hierarchical, Assemblable Titanium Scaffold(ATS), which can be manually assembled in any shape or size with ease. A surgeon can create a scaffold that would fit to the defect right before the implantation during the surgery. Additionally, the direct inclusion of micro- and macroporous structures via 3D-printing, as well as a double acid-etched surface treatment(ST) in the ATS, ensure improved nutrient flow and cellular activity. Different structures were designed, 3D-printed and then surface treated for the ST groups. Both individual and stacked ATS have sufficient mechanical properties to withstand physiological loading, and the porous groups resulted enhanced cell proliferation, mineralizaton and osteogenesis compared to non-porous group. Furthermore, successful cell attachment and migration between the assembled ATS were observed. Finally, we demonstrate possible medical applications that reveal the potential of the ATS through assembly.
FSHβ links photoperiodic signalling to seasonal reproduction in Japanese quail
Authors: Majumdar Gaurav , Liddle Timothy A , Stewart Calum , Marshall Christopher J , Bain Maureen , Stevenson Tyler J 
Published: April 2023

AbstractAnnual cycles in daylength provide an initial predictive environmental cue that plants and animals use to time seasonal biology. Seasonal changes in photoperiodic information acts to entrain endogenous programs in physiology to optimize an animal’s fitness. Attempts to identify the neural and molecular substrates of photoperiodic time measurement in birds have, to date, focussed on blunt changes in light exposure during a restricted period of photoinducibility. The objectives of these studies were first to characterise a molecular seasonal clock in Japanese quail and second, to identify the key transcripts involved in endogenously generated interval timing that underlies photosensitivity in birds. We hypothesized that the mediobasal hypothalamus (MBH) provides the neuroendocrine control of photoperiod-induced changes in reproductive physiology, and that the pars distalis of the pituitary gland contains an endogenous internal timer for the short photoperiod dependent development of reproductive photosensitivity. Here we report distinct seasonal waveforms of transcript expression in the MBH, and pituitary gland and discovered the patterns were not synchronized across tissues. Follicle-stimulating hormone-β (FSHβ) expression increased during the simulated spring equinox, prior to photoinduced increases in prolactin, thyrotropin-stimulating hormone-β and testicular growth. Diurnal analyses of transcript expression showed sustained elevated levels ofFSHβ under conditions of the spring equinox, compared to autumnal equinox, short (<12L) and long (>12L) photoperiods.FSHβ expression increased in quail held in non-stimulatory short photoperiod, indicative of the initiation of an endogenously programmed interval timer. These data identify that FSHβ establishes a state of photosensitivity for the external coincidence timing of seasonal physiology. The independent regulation of FSHβ expression provides an alternative pathway through which other supplementary environmental cues, such as temperature, can fine tune seasonal reproductive maturation and involution.