bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dual-site tACS over the primary motor cortices increases interhemispheric inhibition and improves bimanual dexterity: A triple-blind, randomised, sham-controlled study
Authors: Lebihan Brooke , Mobers Lauren , Daley Shannae , Battle Ruth , Leclercq Natasia , Misic Katherine , Wansbrough Kym , Vallence Ann-Maree , Tang Alexander D. , Nitsche Michael A. , Fujiyama Hakuei 
Published: October 2024

AbstractConcurrent application of transcranial alternating current stimulation (tACS) over distant cortical regions has been shown to modulate functional connectivity between stimulated regions; however, the precise mechanisms remain unclear. Here, we investigated how dual-site tACS (ds-tACS) applied over the bilateral primary motor cortices (M1s) modulates connectivity between M1s. Using a cross-over sham-controlled triple-blind within- subject design, 37 (27 female, age 18-37yrs) healthy participants received tACS (1.0mA, 20Hz) over the bilateral M1s for 20 min. Before and after tACS, functional connectivity between M1s was assessed using imaginary coherence (ImCoh) measured via resting-state electroencephalography (EEG) and interhemispheric inhibition (IHI) via dual-site transcranial magnetic stimulation (TMS) protocol. Additionally, manual dexterity was assessed using the Purdue pegboard task. While ImCoh remained unchanged after simulation, spectral power analysis showed a significant decrease in beta (20 Hz) power during the tACS session. ds-tACS but not sham strengthened IHI between the M1s and improved bimanual assembly performance. These results suggest that improvement in bimanual performance may be explained by modulation in M1-M1 IHI, rather than by coupling in the oscillatory activity. As functional connectivity underlies many clinical symptoms in neurological and psychiatric disorders, these findings are invaluable in developing non-invasive therapeutic interventions that target neural networks to alleviate symptoms.
Structured Codes and Free-Text Notes: Measuring Information Complementarity in Electronic Health Records
Authors: Seinen Tom M , Kors Jan A , van Mulligen Erik M , Rijnbeek Peter R 
Published: October 2024

ABSTRACTBackgroundElectronic health records (EHRs) consist of both structured data (e.g., diagnostic codes) and unstructured data (e.g., clinical notes). It’s commonly believed that unstructured clinical narratives provide more comprehensive information. However, this assumption often lacks large-scale validation and direct validation methods.ObjectiveThis study aims to quantitatively compare the information in structured and unstructured EHR data and directly validate whether unstructured data offers more extensive information across a patient population.MethodsWe analyzed both structured and unstructured data from patient records and visits in a large Dutch primary care EHR database between January 2021 and January 2024. Clinical concepts were identified from free-text notes using an extraction framework tailored for Dutch and compared with concepts from structured data. Concept embeddings were generated to measure semantic similarity between structured and extracted concepts through cosine similarity. A similarity threshold was systematically determined via annotated matches and minimized weighted Gini impurity. We then quantified the concept overlap between structured and unstructured data across various concept domains and patient populations.ResultsIn a population of 1.8 million patients, 42% of structured concepts in patient records and 25% in individual visits had similar matches in unstructured data. Conversely, only 13% of extracted concepts from records and 7% from visits had similar structured counterparts. Condition concepts had the highest overlap, followed by measurements and drug concepts. Subpopulation visits, such as those with chronic conditions or psychological disorders, showed different proportions of data overlap, indicating varied reliance on structured versus unstructured data across clinical contexts.ConclusionsOur study demonstrates the feasibility of quantifying the information difference between structured and unstructured data, showing that the unstructured data provides important additional information in the studied database and populations. Despite some limitations, our proposed methodology proves versatile, and its application can lead to more robust and insightful observational clinical research.
Characterization of a novel neurodevelopmental rare disease caused by a mutation within the autophagy geneATG9B
Authors: Kılıç Seval , Esmen Kerem , Oto A. Miray , Kose T. Bilge , Sever-Bahçekapılı Melike , Eren-Koçak Emine , Demir Şeyda , Hız A. Semra , Karakülah Gökhan , Bağrıyanık H. Alper , Öztürk Mehmet , Diril M. Kasım 
Published: October 2024

AbstractAutophagy is a highly conserved eukaryotic cellular process whose dysfunction results in human pathologies including cancer and neurodegenerative disease. First identified in yeast, ATG genes are central players in autophagy. Although their roles in cancer and neurodegenerative disease are well known, Mendelian diseases associated with ATG genes are rare. Mutations in core autophagy genesATG5andATG7have been previously reported to cause rare genetic disorders with autosomal recessive inheritance pattern.Here we report, for the first time, a rare genetic disorder that results from a deletion/frameshift mutation in human ATG9B, the placenta specific homologue of yeast ATG9 in humans. The 11-nucleotide deletion causes a frameshift and addition of a premature stop codon, truncating the C-terminal cytosolic domain of the ATG9B protein. The pediatric patients carrying the mutant allele homozygous were children of a consanguineous marriage and displayed neurodevelopmental anomalies including mental retardation. We hypothesized that this phenotype originates during placental development.To characterize the effects of the mutation and gain insight on the specific functions of ATG9B in a physiological setting, we used mammalian cells and generated a knock-in mouse model. Truncated ATG9B was not stable when expressed in cells. It was localized to perinuclear vesicles like the WT protein, but not to peripheral vesicles. Homozygous knock-in mice were viable, fertile and displayed no gross phenotypical abnormalities. Histomorphometry analysis of the placenta layers did not reveal a significant difference between mutant and control embryos. The assessments of neurobehavioral tests were similar in wild-type and homozygous knock-in mice. However, knock-in mice had a reduced fear memory trend, which is an amygdala-involved response.
Orchid losers and winners after fire in West Australian urban bushland: A response continuum deeply integrated with other traits
Authors: Brundrett Mark C. 
Published: October 2024

AbstractContextThe Southwest Australia Floristic Region (SWAFR) is a global hotspot for plant taxonomic and functional diversity. This region has many orchids with highly specialised associations with pollinators and mycorrhizal fungi that also face increasing threats from habitat loss, grazing, weeds, fire and climate change.AimsTo compare the fire ecology of 17 orchids with diverse ecological strategies and functional traits from an isolated urban banksia and eucalypt woodland, and develop fire response monitoring methods and management criteria.MethodsA 72-year fire record was intersected with ∼1000 orchid locations and 4.5 km of transects to measure fire effects on orchid abundance and diversity. Key traits such as plant size, flowering, pollination, tuber depth, clonality and population dynamics were also compared using 7-11 years of baseline data.Key resultsFire history was very complex with 58 large overlapping major fires over 5 decades, averaging 8.7% of the 63-ha area annually. Correlating fire history with orchids revealed 5 species usually lost to fire and 6 with substantial fire impacts, while 6 others benefited from fire, including 3 with strongly enhanced flowering, but even the latter could be killed by unseasonal fire. Pollination varied from moderate decreases to substantial increases, but three orchids produced seed primarily after fire. Overall, impacts of fire greatly out way benefits, as most orchids preferred long-unburnt areas, and five species were confined to them. Paradoxically,Pyrorchis nigricansrequires fire to flower, but was most productive in long-unburnt areas and primarily reproduced clonally.ConclusionsFire history maps revealed a spectrum of outcomes from catastrophic to beneficial for orchid species summarised by fire response indexes (FRI) and fire age safe thresholds (FAST) lasting decades. This response continuum was highly correlated with trait such as tuber depth, seed vs clonal reproduction, dispersion and lifespan. Fire was deeply integrated into the biology and ecology of SWAFR orchids which are adapted for long inter-fire intervals which maximise their diversity and abundance.ImplicationsResearch in an urban nature reserve provided essential tools for sustainable management of orchids that are also relevant to rare species. These tools include fire history maps, FRI and FAST. Many SWAFR orchids were most productive in long unburnt areas or intolerant to fire, and even fire tolerant orchids can be harmed by autumn fires. Thus, fire must be carefully managed in their habitats, since may orchids are most productive two or more decades after fire.
Structural insights into maturation and translation of a plant mitoribosome
Authors: Skaltsogiannis Vasileios , Nguyen Tan-Trung , Corre Nicolas , Pflieger David , Blevins Todd , Hashem Yaser , Giegé Philippe , Waltz Florent 
Published: October 2024

AbstractRibosomes are key molecular machines that translate mRNA into proteins. Mitoribosomes are specific ribosomes found in mitochondria, which have been shown to be remarkably diverse across eukaryotic lineages. In plants, they possess unique features, including additional rRNA domains stabilized by numerous pentatricopeptide repeat proteins. However, the molecular mechanisms of translation by plant mitoribosomes remain largely unknown. Here, we use cryo-electron microscopy to provide a high-resolution structural characterization of the flowering plant mitoribosome, in translating and maturation states. The structure reveals the mitoribosome bound to tRNA in the peptidyl site, along with a segment of mRNA and a nascent polypeptide. Moreover, we identify an extensive set of ribosomal RNA modifications that we confirmed by nanopore sequencing. Additionally, we observe a late assembly intermediate of the small ribosomal subunit, in complex with the RsgA assembly factor. This reveals how a plant-specific extension of RsgA blocks the mRNA channel to prevent premature mRNA association before complete small subunit maturation. Our findings elucidate key aspects of translation in flowering plant mitochondria, revealing its distinct features compared to other eukaryotic lineages.
Intraspecific microbiome dynamics across the life cycle of the milkweed bugOncopeltus fasciatus
Authors: Larner Will , Thölke da Silva Grego Nádia , Panfilio Kristen A. 
Published: October 2024

AbstractThe microbiome is an important part of the complete nutritional and genomic profile of insects. The species-rich insect order Hemiptera (aphids, cicadas, true bugs) is highly diverse for mode of microbiome acquisition, with the conundrum that species in the seed-feeding subfamily Lygaeinae have lost obvious anatomy for housing bacteria, either in bacteriocytes or midgut crypts. Here we characterize the microbiome of the milkweed bugOncopeltus fasciatusas a tractable lygaeinid, using16S rRNAsequencing. We assess how bacterial taxa vary between the sexes and across life history stages in a controlled environment, focusing on maternal-to-embryo transmission and distinguishing egg-stage constituents that are superficial or internal (transovarially transmitted). Among a core microbiome of 28 genera, the egg stage shows the greatest diversity, with a particular expansion of the family Comamonadaceae. We also analyze inter-individual variability in nymphs and adults and validate structured, stage-specific detection of seed material. Comparative analysis identifies Rhizobium as a notable microbiome constituent in seed-feeding Hemiptera, which we had previously shown to lack nitrogen metabolism components in the genome. Overall, we provide a nuanced assessment of bacterial abundance dynamics between individuals and across the life cycle and discuss the implications for acquisition and potential relevance as nutritional endosymbionts. This will underpin comparative investigations in seed-feeding bugs and future work inO. fasciatuson tissue-specific and diet-specific microbiome profiles, including in natural populations.
Imagery priming of binocular rivalry is not a reliable metric of individual differences in the subjective vividness of visualisations
Authors: Bouyer Loren N. , Schwarzkopf Dietrich S. , Saurels Blake W. , Arnold Derek H. 
Published: October 2024

AbstractMost people can imagine images that they experience within their mind’s eye. However, there are marked individual differences, with some people reporting that they are unable to construct mental images at all (aphantasics), and others who report having imagined experiences that are as realistic as seeing (hyper-phantasics). The vividness of imagined images is most often measured via subjective self-report. Chang and Pearson (2018), however, have suggested that a binocular rivalry (BR) protocol can be used as anobjectivemeasure. They found that pre-imagining a moving input could enhance performance on anobjectiveprobe detection task when probes were embedded in imagery consistent inputs, as opposed to imagery inconsistent inputs. To date, nobody has assessed if this type ofobjectiveimagery priming can be used to predict the vividness of different people’s visualisations. Here, we report that imagery priming ofobjectivesensitivity to probes within static BR inputsdoes notcorrelate with the typical ratings people use to describe the vividness of their visualisations (a between participants effect). However,objectivepriming of sensitivity to probes embedded in BR inputs was greater on trials when participants reported that their pre-imagined experience had been relatively vivid (a within participants effect). Overall, our data suggest that while imagery can prime objective sensitivity to probes during BR, there is currently no strong evidence that this effect can be used as an objective method of predicting the subjective vividness of different people’s visualisations.Highlights➢There are marked individual differences in the subjective intensity of visual imagery➢Most measures of the subjective intensity of visual imagery are subjective➢A binocular rivalry probe-detection protocol has been suggested as an objective measure➢The authors find that there is only a very small predictive relationship between outcomes in a binocular rivalry task and participant’s reported imagery strength➢We still lack an objective measure that reliably predicts the subjective intensity of visual imagery
Rare diseases load through the study of a regional population
Authors: Michel Élisa , Moreau Claudia , Gagnon Laurence , Leblanc Josianne , Tardif Jessica , Girard Lysanne , Mathieu Jean , Gagnon Cynthia , Desmeules Mathieu , Brisson Jean-Denis , Bouchard Luigi , Girard Simon L. 
Published: October 2024

AbstractRare genetic diseases impact many people worldwide and are challenging to diagnose. In this study, we introduce a novel regional population cohort approach to identify pathogenic variants that occur more frequently within specific populations and are of clinical interest. We utilized a cohort from Quebec, including the Saguenay–Lac-Saint-Jean region, which is known for its founder effect and higher frequency of certain pathogenic variants. By analyzing both the frequency of these variants and their origin through shared identical-by-descent segments, we validated 38 variants previously reported as being more common due to the founder effect. Additionally, we identified 42 unreported founder variants in Quebec or the Saguenay–Lac-Saint-Jean, some with carrier rates estimates as high as 1/22. We also observed a greater deleterious mutational load for the studied variants in individuals from the Saguenay–Lac-Saint-Jean compared to other urban Quebec regions. These findings were brought to the clinic where 12 pathogenic variants were detected in patients, including 3 that are responsible for very severe diseases and could be considered for inclusion in a carrier test for the Saguenay–Lac-Saint-Jean population. This study highlights the potential underestimation of rare disease prevalence and presents a population-based approach that could aid clinicians in their diagnostic efforts and patients’ management.
Impact of a Clinical Orientation Programme as perceived by new entrant international medical graduate resident doctors partaking in the programme: Results from an NHS district hospital survey
Authors: Quadery Syed Rehan , John Thomas , Winn Simon 
Published: October 2024

ABSTRACTBackgroundInternational Medical Graduates (IMGs) constitute 40% of the NHS resident doctor workforce. However, there is no documented clinical orientation programme (COP) facilitating their transition into the workplace. We developed and implemented a structured COP to support new entrant IMGs.MethodSurvey data was collected from new entrant IMGs in medicine who completed the COP between December 2017 and December 2019. In addition, formal feedback was collected from supervising registrars during the COP period. Data was analysed, and a framework was developed to assess impact using realist evaluation.Results97% (31of 32) of IMGs completed the survey. Results revealed 84% were satisfied with the programme, 81% felt confident they were prepared to begin clinical posts at completion of the programme, and 90% would recommend this programme. In addition, the overall comments from the IMGs were positive and supportive of the COP. Moreover, feedback from supervising registrars was complementary. It was seen that 87% of IMGs remained Trust employees with a mean tenure of 13 months. Of those eligible, 90% completed their annual appraisal.ConclusionThis report confirms that Trust in this COP results in a high degree of satisfaction, workforce retention and performance of new entrant IMGs. Larger scale implementation is recommended.
Molecular dynamics of the matrisome across sea anemone life history
Authors: Bergheim B. Gideon , Cole Alison G. , Rettel Mandy , Stein Frank , Redl Stefan , Hess Michael W. , Ikmi Aissam , Özbek Suat 
Published: October 2024

AbstractThe evolutionary expansion of extracellular matrix (ECM) molecules has been crucial for the establishment of cell adhesion and the transition from unicellular to multicellular life. Members of the pre-bilaterian phylum cnidaria offer an exceptionally rich perspective into the metazoan core adhesome and its original function in developmental and morphogenetic processes. Here, we present the ensemble of ECM proteins and associated factors for the starlet sea anemoneNematostella vectensisbased onin silicoprediction and quantitative proteomic analysis of decellularized mesoglea from different life stages. The integration of the matrisome with single cell transcriptome atlases reveals thatNematostella’scomplex ECM is predominantly produced by gastrodermal cells, confirming the homology of the cnidarian inner cell layer with bilaterian mesoderm. The transition from larva to polyp is characterized by an upregulation of metalloproteases and basement membrane components including all members of an unusually diversified SVEP1/Polydom family, suggesting massive epithelial remodeling. The enrichment of Wnt/PCP pathway factors during this process further indicates directed cell rearrangements as a key contributor to the polyp’s morphogenesis. Mesoglea maturation in adult polyps involves wound response proteins suggesting similar molecular patterns in growth and regeneration. Our study identifies conserved matrisomal networks that coordinate transitions inNematostella’slife history.
Stratified analysis identifies HIF-2αas a therapeutic target for highly immune-infiltrated melanomas
Authors: Huang Amy Y. , Burke Kelly P. , Porter Ryan , Meiger Lynn , Fatouros Peter , Yang Jiekun , Robitschek Emily , Vokes Natalie , Ricker Cora , Rosado Valeria , Tarantino Giuseppe , Chen Jiajia , Aprati Tyler J. , Glettig Marc C. , He Yiwen , Wang Cassia , Fu Doris , Ho Li-Lun , Galani Kyriakitsa , Freeman Gordon J. , Buchbinder Elizabeth I. , Hodi F. Stephen , Kellis Manolis , Boland Genevieve M. , Sharpe Arlene H. , Liu David 
Published: October 2024

AbstractWhile immune-checkpoint blockade (ICB) has revolutionized treatment of metastatic melanoma over the last decade, the identification of broadly applicable robust biomarkers has been challenging, driven in large part by the heterogeneity of ICB regimens and patient and tumor characteristics. To disentangle these features, we performed a standardized meta-analysis of eight cohorts of patients treated with anti-PD-1 (n=290), anti-CTLA-4 (n=175), and combination anti-PD-1/anti-CTLA-4 (n=51) with RNA sequencing of pre-treatment tumor and clinical annotations. Stratifying by immune-high vs -low tumors, we found that surprisingly, high immune infiltrate was a biomarker for response to combination ICB, but not anti-PD-1 alone. Additionally, hypoxia-related signatures were associated with non-response to anti-PD-1, but only amongst immune infiltrate-high melanomas. In a cohort of scRNA-seq of patients with metastatic melanoma, hypoxia also correlated with immunosuppression and changes in tumor-stromal communication in the tumor microenvironment (TME). Clinically actionable targets of hypoxia signaling were also uniquely expressed across different cell types. We focused on one such target, HIF-2α, which was specifically upregulated in endothelial cells and fibroblasts but not in immune cells or tumor cells. HIF-2αinhibition, in combination with anti-PD-1, enhanced tumor growth control in pre-clinical models, but only in a more immune-infiltrated melanoma model. Our work demonstrates how careful stratification by clinical and molecular characteristics can be leveraged to derive meaningful biological insights and lead to the rational discovery of novel clinical targets for combination therapy.
Tethered exosomes containing MT1-MMP contribute to extracellular matrix degradation during breast cancer progression
Authors: Palmulli Roberta , Jackson Hannah K. , Edgar James R. 
Published: October 2024

AbstractFor cancer cells to escape from the primary tumor and metastasize, they must degrade and navigate through the extracellular matrix (ECM). The transmembrane protease MT1-MMP plays a key role in localized matrix degradation, and its overexpression promotes cancer invasion. In this study, we demonstrate that MT1- MMP is trafficked to the intraluminal vesicles of multivesicular endosomes, and subsequently released from cells on exosomes, a subtype of extracellular vesicle that can be retained to the surface of the originating cell by the anti-viral restriction factor, tetherin. While tetherin overexpression is linked to increased cell migration and invasion in various cancers, its role in these processes remains unclear. Our findings reveal that expression of tetherin by breast cancer cells promotes the retention of MT1-MMP-positive exosomes at their cell surface, while tetherin loss enhances exosome escape and impairs ECM degradation. Thus, tethered exosomes promote the retention of MT1-MMP at the surface of cells, aiding the degradation of the ECM and promoting cancer cell invasion.