bluuebunny/crossref_metadata_2025_split huggingface dataset:
A behavioral roadmap for the development of agency in the rodent
Authors: Mitelut C , Diez Castro M , Peterson RE , Gonçalves M , Li J , Gamer MM , Nilsson SRO , Pereira TD , Sanes DH 
Published: November 2023

ABSTRACTBehavioral interactions within the nuclear family play a pivotal role in the emergence of agency: the capacity to regulate physiological, psychological and social needs. While behaviors may develop over days or weeks in line with nervous system maturation, individual behaviors can occur on sub-second time scales making it challenging to track development in lab studies with brief observation periods, or in field studies with limited temporal precision and animal identification. Here we study development in families of gerbils, a highly social rodent, collecting tens of millions of behavior time points and implementing machine learning methods to track individual subjects. We provided maturing gerbils with a large, undisturbed environment between postnatal day 15 and the age at which they would typically disperse from the family unit (day 30). We identified complex and distinct developmental trajectories for food and water acquisition, solitary exploration, and social behaviors, some of which displayed sex differences and diurnal patterns. Our work supports the emergence of well-delineated autonomous and social behavior phenotypes that correlate with specific periods and loci of neural maturation.
Genetic discovery and risk prediction for type 1 diabetes in individuals without high-risk HLA-DR3/DR4 haplotypes
Authors: McGrail Carolyn , Chiou Joshua , Elgamal Ruth , Luckett Amber M , Oram Richard A , Benaglio Paola , Gaulton Kyle J 
Published: November 2023

ABSTRACTOver 10% of type 1 diabetes (T1D) cases do not have high-risk HLA-DR3 or DR4 haplotypes with distinct clinical features such as later onset and reduced insulin dependence. To identify genetic drivers of T1D in the absence of DR3/DR4, we performed association and fine-mapping analyses in 12,316 non-DR3/DR4 samples. Risk variants at the MHC and other loci genome-wide had heterogeneity in effects on T1D dependent on DR3/DR4, and non-DR3/DR4 T1D had evidence for a greater polygenic burden. T1D-assocated variants in non-DR3/DR4 were more enriched for loci, regulatory elements, and pathways for antigen presentation, innate immunity, and beta cells, and depleted in T cells, compared to DR3/DR4. Non-DR3/DR4 T1D cases were poorly classified based on an existing genetic risk score GRS2, and we created a new GRS which highly discriminated non-DR3/DR4 T1D from both non-diabetes and T2D. In total we identified heterogeneity in T1D genetic risk and disease mechanisms dependent on high-risk HLA haplotype and which enabled accurate classification of T1D across HLA background.
Closed-loop Cortical Network Stimulation as treatment for refractory epilepsy originating from the primary motor cortex
Authors: van Blooijs D. , Blok S. , Aarnoutse E.J. , van Klink N.E.C. , Huiskamp G.J.M. , Bourez-Swart M.D. , Gebbink T.A. , van Eijsden P. , van der Salm S.M.A. , Ramsey N.F. , Leijten F.S.S. 
Published: November 2023

AbstractBackgroundIn epilepsy patients, cortical electrical stimulation is therapeutically applied in the seizure onset zone (SOZ) to reduce seizures. However, in patients with epilepsy arising from the primary motor cortex (M1), stimulation can result in undesired muscle contractions or loss of motor control. We postulate that seizure frequency reduction can also be obtained by cortical network stimulation in a site outside M1 with a connection to the SOZ in M1.MethodsPatients with electroclinical seizures suspected to arise from M1 were selected. SOZ was delineated during chronic intracranial EEG monitoring. Using Single Pulse Electrical Stimulation, the underlying effective corticocortical network was determined and a site for stimulation was selected that was connected to the SOZ. One subdural strip was implanted on top of the SOZ, and one on the stimulus location. A subcutaneous neurostimulator (Activa®PC+S, Medtronic), capable of recording and closed-loop stimulation, was connected to both strips. Seizure data was collected for three to five months and used to optimize a seizure detection algorithm. After this, closed-loop cortical network stimulation was applied during seven to nine months.ResultsIn five subjects (two females, mean age 34 years, range: 21-51 years), a neurostimulation system was implanted. One subject was seizure free for 17 months post- implantation without applying any electrical stimulation. Two subjects were responders with a mean seizure frequency reduction of 73%. In two subjects, seizure frequency was reduced by on average 35%.DiscussionIn this clinical trial with five subjects suffering from refractory epilepsy arising in M1, seizure frequency was reduced with electrical stimulation in all subjects. This is a proof of concept showing that closed-loop cortical network stimulation can reduce seizure frequency as equal to direct SOZ stimulation in non-primary motor epilepsy.
Age is Associated with Dampened Circadian Patterns of Rest and Activity: The Study of Muscle, Mobility and Aging (SOMMA)
Authors: Erickson Melissa L. , Blackwell Terri L. , Mau Theresa , Cawthon Peggy M. , Glynn Nancy W. , Qiao Yujia (Susanna) , Cummings Steven R. , Coen Paul M. , Lane Nancy E. , Kritchevsky Stephen B. , Newman Anne B. , Farsijani Samaneh , Esser Karyn A. 
Published: November 2023

AbstractBackgroundAging is associated with declines in circadian functions. The effects of aging on circadian patterns of behavior are insufficiently described. We characterized age-specific features of rest-activity rhythms (RAR) in community dwelling older adults, both overall, and in relation, to sociodemographic characteristics.MethodsWe analyzed baseline assessments of older adults with wrist-worn free-living wrist-worn actigraphy data (N=820, Age=76.4 yrs, 58.2% women) participating in the Study of Muscle, Mobility and Aging (SOMMA). We applied an extension to the traditional cosine curve to map RAR to activity data, calculating the parameters: rhythmic strength (amplitude); robustness (pseudo-F statistic); and timing of peak activity (acrophase). We also used function principal component analysis to determine 4 components describing underlying patterns of activity accounting for RAR variance. Linear models were used to examine associations between RAR and sociodemographic variables.ResultsAge was associated with several metrics of dampened RAR; women had stronger and more robust RAR metrics vs. men (allP< 0.05). Total activity (56%) and time of activity (20%) accounted for most the RAR variance. Compared to the latest decile of acrophase, those in the earliest decile had higher average amplitude (P<0.001). Compared to the latest decile of acroaphase, those is the earliest and midrange categories had more total activity (P=0.02). RAR was associated with some sociodemographic variables.ConclusionsOlder age was associated with dampened circadian behavior; and behaviors were sexually dimorphic. We identified a behavioral phenotype characterized by early time-of-day of peak activity, high rhythmic amplitude, and more total activity.
Application of the Fluctuation Test to the data of Morbidity and Mortality by COVID-19 in China 2020-2023
Authors: López-Ramírez Anyi Yannire , Fernández-Ramírez María Alejandra , Grassi Hilda Cristina , de Jesús Andrades Efrén , Andrades-Grassi Jesús Enrique 
Published: November 2023

AbstractIn this work the Luria and Delbruck Fluctuation Test was applied to the data of Morbidity and Mortality by COVID-19 in China from January 2020 to August 2023. Three types of data were used:es.statista.com,datosmacro.expansion.comand larepublica.co without modification, but trying to avoid and justify the anomalies and inconsistencies observed. The methods originally used to establish the interactions of two populations were evaluated: the viral population with that of its host and the drift of both organisms. Only the fluctuations of the weekly Variance of daily increase of Cases (Morbidity) and of the weekly Variance of daily increase of Deaths (Mortality) were studied. The results showed that the Fluctuation Test is applicable to the selected data from China and other data from India, Japan and South Korea, used as controls. The study was separated into two periods: a first initial period from January 2020 to September 2021 and a second final period from October 2021 to August 2023. Results were obtained for Morbidity and Mortality that relate the fluctuations of the first with the fluctuations of the second. However, it was possible to detect some anomalies and uncertainties that were possibly derived from inconsistencies in the original data. A repeated fluctuation was observed in the boreal winter in January, February and March of each one of the year studied. A clear decrease in fluctuation was detected in that period in 2021 that could be attributed to the strict confinement during the quarantine in China between 2020 and 2021. Massive, extensive and intensive vaccinations failed to completely eliminate the most important fluctuations. In this work we tried to correlate the appearance of some virus variants with the fluctuations. The most relevant results of said correlation are presented. With the results of this work, the animal origin cannot be confirmed nor can the human or laboratory origin of the SARS CoV-2 virus that caused the initial emerging infection, be ruled out. However, it was concluded that this method could be used to search for clues about its origin. One of these keys is the comparison of the result of the first important fluctuation in the boreal winter of 2020 in each of the countries studied as controls: India, Japan and South Korea. The comparison of this result with the first fluctuation of China for that same period could give clues about the origin of the virus.
The Parkinson’s drug entacapone disrupts gut microbiome homeostasis via iron sequestration
Authors: Pereira Fátima C. , Ge Xiaowei , Kristensen Jannie Munk , Kirkegaard Rasmus H. , Maritsch Klara , Zhu Yifan , Decorte Marie , Hausmann Bela , Berry David , Wasmund Kenneth , Schintlmeister Arno , Boettcher Thomas , Cheng Ji-Xin , Wagner Michael 
Published: November 2023

AbstractIncreasing evidence shows that many human-targeted drugs alter the gut microbiome, leading to implications for host health. However, much less is known about the mechanisms by which drugs target the microbiome and how drugs affect microbial function. Here we combined quantitative microbiome profiling, long-read metagenomics, stable isotope probing and single cell chemical imaging to investigate the impact of two widely prescribed nervous system targeted drugs on the gut microbiome.Ex vivosupplementation of physiologically relevant concentrations of entacapone or loxapine succinate to faecal samples significantly impacted the abundance of up to one third of the microbial species present. Importantly, we demonstrate that the impact of these drugs on microbial metabolism is much more pronounced than their impact on abundances, with low concentrations of drugs reducing the activity, but not the abundance of key microbiome members likeBacteroides, RuminococcusorClostridiumspecies. We further demonstrate that entacapone impacts the microbiome due to its ability to complex and deplete available iron, and that microbial growth can be rescued by replenishing levels of microbiota-accessible iron. Remarkably, entacapone-induced iron starvation selected for iron-scavenging organisms carrying antimicrobial resistance and virulence genes. Collectively, our study unveils the impact of two under-investigated drugs on whole microbiomes and identifies metal sequestration as a mechanism of drug-induced microbiome disturbance.
OprF functions as a latch to direct Outer Membrane Vesicle release inPseudomonas aeruginosa
Authors: Mathur Shrestha , Erickson Susan K. , Goldberg Leah R. , Hills Sonia , Radin Abigail G.B. , Schertzer Jeffrey W. 
Published: November 2023

AbstractBacterial Outer Membrane Vesicles (OMVs) contribute to virulence, competition, immune avoidance and communication. This has led to great interest in how they are formed. To date, investigation has focused almost exclusively on what controls the initiation of OMV biogenesis. Regardless of the mechanism of initiation, all species face a similar challenge before an OMV can be released: How does the OM detach from the underlying peptidoglycan (PG) in regions that will ultimately bulge and then vesiculate? The OmpA family of OM proteins (OprF inP. aeruginosa) is widely conserved and unusually abundant in OMVs across species considering their major role in PG attachment. OmpA homologs also have the interesting ability to adopt both PG-bound (two-domain) and PG-released (one-domain) conformations. Using targeted deletion of the PG-binding domain we showed that loss of cell wall association, and not general membrane destabilization, is responsible for hypervesiculation in OprF-modified strains. We therefore propose that OprF functions as a ‘latch’, capable of releasing PG in regions destined to become OMVs. To test this hypothesis, we developed a protocol to assess OprF conformation in live cells and purified OMVs. While >90% of OprF proteins exist in the two-domain conformation in the OM of cells, we show that the majority of OprF in OMVs is present in the one-domain conformation. With this work, we take some of the first steps in characterizing late-stage OMV biogenesis and identify a family of proteins whose critical role can be explained by their unique ability to fold into two distinct conformations.SignificanceVesicular transport is now recognized to operate in all domains of life. However, the study of OMV biogenesis has been challenging because genetic screens failed to identify proteins analogous to those involved in eukaryotic vesicular transport. With this work we identify the first protein whose direct action can both define the location and govern the mechanism of OMV release. Our latch model is consistent with previous observations linking OmpA family proteins to OMV biogenesis, but further describes a physical mechanism that has broad implications for vesicle production and function across species. The work presented here advances our understanding of a fundamental virulence-associated process in bacteria, while underscoring stark differences in how transport vesicles are formed in prokaryotesversuseukaryotes.
Carboxydovores from the Pseudomonadota colonise volcanic soils during succession
Authors: Dawson Robin A. , Aguila Patricia , King Gary M. , Hernández Marcela 
Published: November 2023

ABSTRACTCarbon monoxide (CO) degrading microorganisms are present in volcanic deposits throughout succession, with vegetation and soil influencing the communities present. The carboxydovores are a subset of CO degraders that use CO only as an energy source, raising the question of how the physiological and metabolic features of the carboxydovores can make these bacteria more competitive in harsh volcanic ecosystems. An enrichment strategy was modified, which enabled the isolation of two carboxydovore representatives from genera that were abundant in the native soils,Cupriavidussp. CV2T(92.3% ANI vs.Cupriavidus basilensisDSM 11853) and a putative strain ofParaburkholderia terrae(Pb. terraeCOX) (96.42% ANI vs.Pb. terraeKU-64T). These isolates oxidise CO across a very broad range of concentrations, and genome sequence analysis indicated that they use form-I carbon monoxide dehydrogenase (CODH) to do so.Cupriavidussp. CV2TandPb. terraeCOX each oxidised CO specifically at stationary phase, but the conditions for induction of CODH expression were distinct.Cupriavidussp. CV2Texpressed CODH only in the presence of CO, whilePb. terraeCOX expressed CODH regardless of the presence of CO. Based on metabolic and phylogenetic analyses,Cupriavidussp. CV2Tis recommended as a novel species within the genusCupriavidus. Therefore, we propose the nameCupriavidus ulmosensissp. nov. for the type strain CV2T(= NCIMB 15506T, = CECT 30956T). This study provides valuable insights into the physiology and metabolism of carboxydovores, which colonise volcanic ecosystems during succession.ImportanceVolcanic ecosystems harbour many bacteria that contribute to the environmentally important process of carbon monoxide (CO) oxidation. We demonstrate a modified method for isolating bacteria, which consume CO at very low concentrations as a supplementary energy source (carboxydovory), leading to the isolation of two novel strains (Cupriavidussp. CV2TandParaburkholderia terraeCOX) from volcanic strata that formed in 1917 and 2015, respectively. The conditions under which CO consumption occurs were investigated; each strain consumed CO during stationary phase, butPb. terraeCOX consumed CO regardless of the prior growth conditions whileCupriavidussp. CV2 was more controlled.Cupriavidussp. CV2 is a type strain of a new species,Cupriavidus ulmosensisstr. CV2, which demonstrates relatively high tolerance for CO. These strains provide the basis for further study of the physiology, metabolism, and genetics of CO oxidation by carboxydovores, and will help us to understand how bacteria colonise harsh volcanic ecosystems.
Cerebellar α1D-adrenergic receptors mediate stress-induced dystonia in totteringtg/tgmice
Authors: Bohne Pauline , Josten Mareike , Rambuschek Lina , Zhu Xinran , Rybarski Max O. , Mark Melanie D. 
Published: November 2023

AbstractEpisodic ataxia type 2 (EA2) is an inherited neurological disorder, where patients suffer from chronic ataxia and severe episodes of motor dysfunction exhibited as dystonia. Despite other factors, physical and emotional stress triggers those episodes reliably in both human and mice. We used the well-established EA2 mouse model tottering to explore the cerebellar adrenergic receptor (AR) involvement in stress-induced dystonic attacks. We found that α1-ARs, but not α2-ARs, on cerebellar Purkinje cells (PCs) are activated by norepinephrine (NE) from the locus coeruleus (LC), differentially expressed and required for initiation of dystonia. Moreover, pharmacological blockade and shRNA-induced knock down of cerebellar α1D-ARs was sufficient to effectively prevent stress-induced dystonia in homozygous totteringtg/tgmice but had no impact on ataxia amelioration.In vivorecordings and live calcium (Ca2+) imaging of PCs demonstrated that α1D-AR blockade successfully protects PCs from NE-mediated erratic firing patterns through decreased release of calcium from intracellular stores, thus preventing stress-induced dystonia. Furthermore, chemogenetic inhibition of the LC-NE pathway alleviated the frequency and symptoms of stress-induced dystonia. Together, our data show the modulatory effects of NE on dystonia severity and suggest a predominant role of cerebellar α1D-ARs in the formation of stress-induced dystonia in totteringtg/tgmice and, thereby providing a potential new therapeutic target to treat stress-induced dystonia in EA2.
Ancestry diversity in the genetic determinants of the human plasma proteome and associated new drug targets
Authors: Said Saredo , Pozarickij Alfred , Lin Kuang , Morris Sam , Kartsonaki Christiana , Wright Neil , Fry Hannah , Chen Yiping , Du Huaidong , Bennett Derrick , Avery Daniel , Schmidt Dan Valle , Li Liming , Lv Jun , Yu Canqing , Sun Dianjianyi , Pei Pei , Chen Junshi , Hill Michael , Peto Richard , Collins Rory , Clarke Robert , Millwood Iona Y , Chen Zhengming , Walters Robin G 
Published: November 2023

SummaryThe proteome is fundamental to human biology and disease but little is known about ancestral diversity of its genetic determinants. In GWAS of plasma levels of 1,451 proteins in 3,974 Chinese adults, we identified pQTLs for 1,082 proteins, including 743 with at least onecis-pQTL. Fine-mapping defined credible sets for 3,336 independent pQTLs, of which 31% did not overlap with corresponding analyses in European adults. We assessed 777 sentinelcis-pQTLs in phenome-wide MR analyses using GWAS Catalog and identified Bonferroni-significant associations for 22 protein-disease pairs. Among 10 protein-disease pairs identified from East Asian-specific GWAS, four had evidence of colocalisation. Evaluation of current drug development confirmed indications for one protein target, identified potential repurposing for seven, and discovered nine potential novel targets, including GP2 for Type-2-diabetes. The findings demonstrate the importance of extending genome-wide plasma proteomic analyses to non-European ancestry populations to identify potential novel drug targets for major diseases.
Mapping the Interplay of Atrial Fibrillation, Brain Structure and Cognitive Dysfunction
Authors: Petersen Marvin , Chevalier Céleste , Naegele Felix L. , Ingwersen Thies , Omidvarnia Amir , Hoffstaedter Felix , Patil Kaustubh , Eickhoff Simon B. , Schnabel Renate B. , Kirchhof Paulus , Schlemm Eckhard , Cheng Bastian , Thomalla Götz , Jensen Märit 
Published: November 2023

AbstractAtrial fibrillation (AF) is associated with an elevated risk of cognitive impairment and dementia. The investigation of the cognitive sequelae and alterations of brain structure linked to AF is crucial to help address ensuing health care needs. In this study, we conducted a comprehensive neuropsychological and neuroimaging analysis of 1335 stroke-free individuals with AF (30% women, average age 69.1 years) and compared them with 2683 demographically and cardiovascular risk-matched controls (31% women, average age 69.1 years). Primary study outcomes were neuropsychological test scores and advanced magnetic resonance imaging (MRI) measures of gray matter morphology, gray and white matter microstructure, and white matter hyperintensity (WMH) load. Our analysis identified deficits in attention/executive function, information processing speed and reasoning in individuals with AF. These cognitive impairments were accompanied by a complex imaging profile suggestive of small vessel pathology: (1) reduced cortical thickness and gray matter volume in areas including primary motor, somatosensory and visual cortices as well as the orbitofrontal, lateral prefrontal, posterior insular, and temporal cortices; (2) increased extracellular free-water content in the anterior cingulate, insula, medial prefrontal cortex, medial temporal lobe, and precuneus; (3) widespread microstructural anomalies in the cerebral white matter, marked by lower fractional anisotropy (FA), higher mean diffusivity (MD) and extracellular free-water, and a higher burden of markers of small vessel disease (WMH load and peak width of skeletonized mean diffusivity). Crucially, brain structural differences statistically mediated the link between AF and cognitive performance. By integrating a multimodal analysis approach with extensive clinical and MRI data, our study highlights small vessel pathology as a possible unifying link between AF, cognitive decline and abnormal brain structure. These insights can inform diagnostic approaches and motivate the ongoing implementation of effective therapeutic strategies.