bluuebunny/crossref_metadata_2025_split huggingface dataset:
Deciphering autoantibody landscape of systemic sclerosis through systems-based approach: insights from a B-cell depletion clinical trial
Authors: Matsuda Kazuki M , Ebata Satoshi , Iwadoh Kazuhiro , Kotani Hirohito , Hisamoto Teruyoshi , Kuzumi Ai , Fukasawa Takemichi , Yoshizaki-Ogawa Asako , Sato Shinichi , Yoshizaki Ayumi 
Published: July 2024

AbstractSystemic sclerosis (SSc) is a progressive fibrotic disorder with a high mortality rate, characterized by extensive autoantibody production. Despite recent advancements, effective treatments remain limited. Rituximab (RTX), a B-cell depleting agent, has shown promise in clinical trials. The DESIRES trial highlighted the reduction in modified Rodnan Skin Score (mRSS) and the association between serum immunoglobulin levels and RTX responsiveness. We employed proteome-wide autoantibody screening (PWAS) using wet protein arrays (WPAs) that display 13,455 human autoantigens to analyze serum samples from SSc patients in the DESIRES trial and age- and sex-matched healthy controls (HCs). As a result, the sum of autoantibody levels (SAL) was significantly higher in SSc patients compared to HCs. High responders (HRs) to RTX showed a greater initial SAL and significant reductions post-treatment, unlike low responders (LRs). Machine learning identified specific autoantibodies linked to disease status, and 58 autoantibodies were identified as clinically relevant. Some of those autoantibodies targeted membrane proteins including G protein-coupled receptors, associated with better differentiation between HRs and LRs. Our findings underscore the significance of autoantibodies in SSc pathogenesis and their potential role in predicting RTX responsiveness. This comprehensive autoantibody profiling could enhance diagnostic and therapeutic strategies, and moreover, better understanding of the pathophysiology of SSc.
Diversification ofPseudomonas aeruginosabiofilm populations under repeated phage exposures decreases the efficacy of the treatment
Authors: Martinet Mark Grevsen , Lohde Mara , Higazy Doaa , Brandt Christian , Pletz Mathias W. , Middelboe Mathias , Makarewicz Oliwia , Ciofu Oana 
Published: July 2024

AbstractPhage therapy has been proposed as a therapeutic alternative to antibiotics for treatment of chronic, biofilm-relatedP. aeruginosainfections. To get a deeper insight into the complex biofilm-phage interactions, we investigated in the present study the effect of three successive exposures to lytic phages of biofilms formed by the reference strains PAO1 and PA14 as well as of two sequential clinicalP. aeruginosaisolates from the sputum of a patient with cystic fibrosis (CF). The Calgary device was employed as biofilm model and the efficacy of phage treatment was evaluated by measurements of the biomass stained with crystal violet (CV) and of the cell density of the biofilm bacterial population (CFU/ml) after each of the three phage exposures. The genetic alterations ofP. aeruginosaisolates from biofilms exposed to phages were investigated by whole genome sequencing.We show here that the anti-biofilm efficacy of the phage treatment decreased rapidly with repeated applications of lytic phages onP. aeruginosastrains with different genetic background. Although we observed the maintenance of a small subpopulation of sensitive cells after repeated phage treatments, a fast recruitment of mechanisms involved in the persistence of biofilms to the phage attack occurred, mainly by mutations causing alterations of the phage receptors. However, mutations causing phage tolerant phenotypes such as alginate-hyperproducing mutants were also observed.In conclusion, a decreased anti-biofilm effect occurred after repeated exposure to lytic phages ofP. aeruginosabiofilms due to recruitment of different resistance and tolerance mechanisms.
Ciliary biology intersects autism and congenital heart disease
Authors: Teerikorpi Nia , Lasser Micaela C. , Wang Sheng , Kostyanovskaya Elina , Bader Ethel , Sun Nawei , Dea Jeanselle , Nowakowski Tomasz J. , Willsey A. Jeremy , Willsey Helen Rankin 
Published: July 2024

ABSTRACTAutism spectrum disorder (ASD) commonly co-occurs with congenital heart disease (CHD), but the molecular mechanisms underlying this comorbidity remain unknown. Given that children with CHD come to clinical attention by the newborn period, understanding which CHD variants carry ASD risk could provide an opportunity to identify and treat individuals at high risk for developing ASD far before the typical age of diagnosis. Therefore, it is critical to delineate the subset of CHD genes most likely to increase the risk of ASD. However, to date there is relatively limited overlap between high confidence ASD and CHD genes, suggesting that alternative strategies for prioritizing CHD genes are necessary. Recent studies have shown that ASD gene perturbations commonly dysregulate neural progenitor cell (NPC) biology. Thus, we hypothesized that CHD genes that disrupt neurogenesis are more likely to carry risk for ASD. Hence, we performed anin vitropooled CRISPR interference (CRISPRi) screen to identify CHD genes that disrupt NPC biology similarly to ASD genes. Overall, we identified 45 CHD genes that strongly impact proliferation and/or survival of NPCs. Moreover, we observed that a cluster of physically interacting ASD and CHD genes are enriched for ciliary biology. Studying seven of these genes with evidence of shared risk (CEP290, CHD4, KMT2E, NSD1, OFD1, RFX3, TAOK1), we observe that perturbation significantly impacts primary cilia formationin vitro. Whilein vivoinvestigation ofTAOK1reveals a previously unappreciated role for the gene in motile cilia formation and heart development, supporting its prediction as a CHD risk gene. Together, our findings highlight a set of CHD risk genes that may carry risk for ASD and underscore the role of cilia in shared ASD and CHD biology.
Myeloid-Specific Thrombospondin-1 Deficiency Exacerbates Aortic Rupture via Broad Suppression of Extracellular Matrix Proteins
Authors: Zhou Ting , Yang Huan , Assa Carmel , DeRoo Elise , Bontekoe Jack , Burkel Brian , Ponik Suzanne , Lu Hong S. , Daugherty Alan , Liu Bo 
Published: July 2024

AbstractRationaleRupture of abdominal aortic aneurysms (AAA) is associated with high mortality. However, the precise molecular and cellular drivers of AAA rupture remain elusive. Our prior study showed that global and myeloid-specific deletion of matricellular protein thrombospondin-1 (TSP1) protects mice from aneurysm formation primarily by inhibiting vascular inflammation.ObjectiveTo investigate the cellular and molecular mechanisms that drive AAA rupture by testing how TSP1 deficiency in different cell populations affects the rupture event.Methods and ResultsWe deleted TSP1 in endothelial cells and macrophages --- the major TSP1-expressing cells in aneurysmal tissues ---- by crossbreedingThbs1flox/floxmice withVE-cadherin CreandLyz2-cremice, respectively. Aortic aneurysm and rupture were induced by angiotensin II in mice with hypercholesterolemia. Myeloid-specificThbs1knockout, but not endothelial-specific knockout, increased the rate of lethal aortic rupture by more than 2 folds. Combined analyses of single-cell RNA sequencing and histology showed a unique cellular and molecular signature of the rupture-prone aorta that was characterized by a broad suppression in inflammation and extracellular matrix production. Visium spatial transcriptomic analysis on human AAA tissues showed a correlation between low TSP1 expression and aortic dissection.ConclusionsTSP1 expression by myeloid cells negatively regulates aneurysm rupture, likely through promoting the matrix repair phenotypes of vascular smooth muscle cells thereby increasing the strength of the vascular wall.
Enhanced detection for antibiotic resistance genes in wastewater samples using a CRISPR-enriched metagenomic method
Authors: Mao Yuqing , Shisler Joanna L. , Nguyen Thanh H. 
Published: July 2024

AbstractThe spread of antibiotic resistance genes (ARGs) in the environment is a global public health concern. To date, over 5,000 genes have been identified to express resistance to antibiotics. ARGs are usually low in abundance for wastewater samples, making them difficult to detect. Metagenomic sequencing and quantitative polymerase chain reaction (qPCR), two conventional ARG detection methods, have low sensitivity and low throughput limitations, respectively. We developed a CRISPR-Cas9-modified next-generation sequencing (NGS) method to enrich the targeted ARGs during library preparation. The false negative and false positive of this method were determined based on a mixture of bacterial isolates with known whole-genome sequences. Low values of both false negative (2/1,208) and false positive (1/1,208) proved the method’s reliability. We compared the results obtained by this CRISPR-NGS and the conventional NGS method for six untreated wastewater samples. As compared to the ARGs detected in the same samples using the regular NGS method, the CRISPR-NGS method found up to 1,189 more ARGs and up to 61 more ARG families in low abundances, including the clinically important KPC beta-lactamase genes in the six wastewater samples collected from different sources. Compared to the regular NGS method, the CRISPR-NGS method lowered the detection limit of ARGs from the magnitude of 10−4to 10−5as quantified by qPCR relative abundance. The CRISPR-NGS method is promising for ARG detection in wastewater. A similar workflow can also be applied to detect other targets that are in low abundance but of high diversity.
Unique longitudinal contributions of sulcal interruptions to reading acquisition in children
Authors: Bouhali Florence , Dubois Jessica , Hoeft Fumiko , Weiner Kevin S. 
Published: July 2024

AbstractA growing body of literature indicates strong associations between indentations of the cerebral cortex (i.e., sulci) and individual differences in cognitive performance. Interruptions, or gaps, of sulci (historically known aspli de passage) are particularly intriguing as previous work suggests that these interruptions have a causal effect on cognitive development. Here, we tested how the presence and morphology of sulcal interruptions in the left posterior occipitotemporal sulcus (pOTS) longitudinally impact the development of a culturally-acquired skill: reading. Forty-three children were successfully followed from age 5 in kindergarten, at the onset of literacy instruction, to ages 7 and 8 with assessments of cognitive, pre-literacy, and literacy skills, as well as MRI anatomical scans at ages 5 and 8. Crucially, we demonstrate that the presence of a left pOTS gap at 5 years is a specific and robust longitudinal predictor of better future reading skills in children, with large observed benefits on reading behavior ranging from letter knowledge to reading comprehension. The effect of left pOTS interruptions on reading acquisition accumulated through time, and was larger than the impact of benchmark cognitive and familial predictors of reading ability and disability. Finally, we show that increased local U-fiber white matter connectivity associated with such sulcal interruptions possibly underlie these behavioral benefits, by providing a computational advantage. To our knowledge, this is the first quantitative evidence supporting a potential integrative gray-white matter mechanism underlying the cognitive benefits of macro-anatomical differences in sulcal morphology related to longitudinal improvements in a culturally-acquired skill.
Multiplicity of Type 6 Secretion System toxins limits the evolution of resistance
Authors: Smith William P. J. , Armstrong-Bond Ewan , Coyte Katharine Z. , Knight Christopher G. , Basler Marek , Brockhurst Michael A. 
Published: July 2024

AbstractThe bacterial Type 6 Secretion System (T6SS) is a toxin-injecting nanoweapon that mediates competition in plant- and animal-associated microbial communities. Bacteria can evolvede novoresistance against T6SS attacks, but resistance is far from universal in natural communities, suggesting key features of T6SS weaponry may act to limit its evolution. Here, we combine eco-evolutionary modelling and experimental evolution to examine how toxin type and multiplicity inAcinetobacter baylyiattackers shape resistance evolution in susceptibleEscherichia colicompetitors. In both our models and experiments, we find that combinations of multiple distinct toxins limit resistance evolution by creating genetic bottlenecks, driving resistant lineages extinct before they can reach high frequency. We also show that, paradoxically, single-toxin attackers often drive the evolution of cross-resistance, protecting bacteria against unfamiliar toxin combinations, even though such evolutionary pathways were inaccessible against multi-toxin attackers. Our findings indicate that, comparable to antimicrobial and anticancer combination therapies, multi-toxin T6SS arsenals function to limit resistance evolution in competing microbes. This helps us to understand why T6SSs remain widespread and effective weapons in microbial communities, and why many bacteria T6SS-armed encode functionally diverse anti-competitor toxins.SignificanceToxin secretion systems, such as T6SSs, are widely used by bacteria to inhibit competing microorganisms. Here, we show that the secretion of multiple toxins in combination can suppress the evolution of resistance to the T6SS, rationalising its continued widespread use across diverse communities. Our work shows that principles of combination therapy—well known in the context of antimicrobial, antiviral and anticancer therapies—also apply in the context of microbial warfare, helping to explain why many bacteria maintain diverse T6SS toxin arsenals. Resistance suppression is also a technologically useful property of T6SS toxin cocktails, which could be harnessed as part of future biocontrol or biotherapeutic applications, using live T6SS-armed bacteria to limit the growth of problem microorganisms.
Assessing the effects of warming and carbonate chemistry parameters on marine microbes in the Gulf of Mexico through basin-scale DNA metabarcoding
Authors: Anderson Sean R. , Silliman Katherine , Barbero Leticia , Gomez Fabian A. , Stauffer Beth A. , Schnetzer Astrid , Kelble Christopher R. , Thompson Luke R. 
Published: July 2024

AbstractOcean acidification and warming threaten marine life, yet the impact of these processes on microbes remains unclear. Here, we performed basin-scale DNA metabarcoding of prokaryotes (16S V4–V5) and protists (18S V9) in the Gulf of Mexico and applied generalized linear models to reveal group-specific environmental correlates of functionally diverse microbes. Models supported prior physiological trends for some groups, like positive temperature effects on SAR11 and SAR86, and a positive effect of pH onProchlorococcusthat implied a negative response to decreasing pH. New insights were revealed for protists, like Syndiniales and Sagenista (e.g., positive pH effects), which offset positive relationships with temperature and reinforced the importance of considering multiple stressors simultaneously. Indicator analysis revealed phytoplankton, likeOstreococcussp. andEmiliania huxleyi, that were associated with more acidic waters and may reflect candidate indicators of ocean change. Our findings highlight the need for sustained microbial sampling in marine systems, with implications for carbon export, nutrient cycling, and ecosystem health.
The big tau splice isoform resists Alzheimer’s-related pathological changes
Authors: Chung Dah-eun Chloe , Deng Xue , Yalamanchili Hari K. , Revelli Jean-Pierre , Han Alexander L. , Tadros Bakhos , Richman Ronald , Dias Michelle , Naini Fatemeh Alavi , Boeynaems Steven , Hyman Bradley T. , Zoghbi Huda Y. 
Published: July 2024

SUMMARYIn Alzheimer’s disease (AD), the microtubule-binding protein tau becomes abnormally hyperphosphorylated and aggregated in selective brain regions such as the cortex and hippocampus1–3. However, other brain regions like the cerebellum and brain stem remain largely intact despite the universal expression of tau throughout the brain. Here, we found that an understudied splice isoform of tau termed “big tau” is significantly more abundant in the brain regions less vulnerable to tau pathology compared to tau pathology-vulnerable regions. We used various cellular and animal models to demonstrate that big tau possesses multiple properties that can resist AD-related pathological changes. Importantly, human AD patients show a higher expression level of pathology-resisting big tau in the cerebellum, the brain region spared from tau pathology. Our study examines the unique properties of big tau, expanding our current understanding of tau pathophysiology. Altogether, our data suggest that alternative splicing to favor big tau is a viable strategy to modulate tau pathology.
Healthy aging delays and dedifferentiates high-level visual representations
Authors: Haupt Marleen , Garrett Douglas D. , Cichy Radoslaw M. 
Published: July 2024

1.AbstractHealthy aging impacts visual information processing with consequences for subsequent high-level cognition and everyday behavior, but the underlying neural changes in visual representations remain unknown. Here, we investigate the nature of representations underlying object recognition in older compared to younger adults by tracking them in time using EEG, across space using fMRI, and by probing their behavioral relevance using similarity judgements. Applying a multivariate analysis framework to combine experimental assessments, four key findings about how brain aging impacts object recognition emerge. First, aging selectively delays the formation of object representations, profoundly changing the chronometry of visual processing. Second, the delay in the formation of object representations emerges in high-level rather than low- and mid-level ventral visual cortex, supporting the theory that brain areas developing last deteriorate first. Third, aging reduces content selectivity in high-level ventral visual cortex, indicating age-related neural dedifferentiation as the mechanism of representational change. Finally, we demonstrate that the identified representations of the aging brain are behaviorally relevant, ascertaining ecological relevance. Together, our results reveal the impact of healthy aging on the visual brain.
patter: particle algorithms for animal tracking in R and Julia
Authors: Lavender Edward , Scheidegger Andreas , Albert Carlo , Biber Stanisław W. , Illian Janine , Thorburn James , Smout Sophie , Moor Helen 
Published: July 2024

AbstractIn the field of movement ecology, state-space models have emerged as a powerful modelling framework that represents individual movements and the processes that connect movements to observations. However, fitting state-space models to animal tracking data is often difficult and computationally expensive.Here, we introducepatter, a package that provides particle filtering and smoothing algorithms that fit Bayesian state-space models to tracking data, with a focus on data from aquatic animals in autonomous receiver arrays.patteris written inR, with a high-performanceJuliabackend. Package functionality supports data simulation, preparation, filtering, smoothing and mapping.In two worked examples, we demonstrate how to implementpatterto reconstruct the movements of a tagged animal in an acoustic telemetry system from acoustic detections and ancillary observations. With perfect information, the particle filter reconstructs the true (unobserved) movement path (Example One). More generally, particle-based methods represent an individual’s possible location probabilistically as a weighted series of samples (‘particles’). In our illustration, we resolve an individual’s (unobserved) location every two minutes during one month in minutes and use particles to visualise movements, map space use and quantify residency (Example Two).patterfacilitates robust, flexible and efficient analyses of animal tracking data. The methods are widely applicable and enable refined analyses of home ranges, residency and habitat preferences.
The role of the synaptic vesicle protein SV2A in regulating mitochondrial morphology and autophagy
Authors: Jörg Marko , Reichert Jonas S. , Pauly Karin , Distler Ute , Tenzer Stephan , Bartholomé Odile , Rogister Bernard , Kern Andreas , Behl Christian , Gellérie Martón , Cremer Christoph , Ritz Sandra , Peslalz Philipp , Plietker Bernd , Friedland Kristina 
Published: July 2024

AbstractThe synaptic vesicle glycoprotein 2A (SV2A) is a transmembrane protein of synaptic vesicles. It is involved in key functions of neurons, focused on the regulation of neurotransmitter release. Here we report three novel findings suggesting a completely new role of SV2A. First, we demonstrate that SV2A is localized at the outer mitochondrial membrane (OMM) using confocal and super-resolution microscopy. Second, Inactivation of SV2A in our cell and animal models leads to fragmented mitochondria. In addition, SV2A also affects the basal autophagic flux as well as mitophagy. Third, using proteomics analysis we demonstrate that SV2A interacts with the fission factor DRP1 and the autophagy factor ATG9A. Using AlphaFold3 we provide a first glimpse of the molecular interaction between DRP1 and SV2A. Our findings demonstrate that SV2A is not only a vesicular protein but also a mitochondrial protein in the OMM with defined functions regulating mitochondrial morphology and autophagy.
Interaural level difference sensitivity in neonatally deafened rats fitted with bilateral cochlear implants
Authors: Buchholz Sarah , Schnupp Jan W. H. , Arndt Susan , Roßkothen-Kuhl Nicole 
Published: July 2024

AbstractBilateral cochlear implant (CI) patients exhibit significant limitations in spatial hearing. Their ability to process interaural time differences (ITDs) is often impaired, while their ability to process interaural level differences (ILDs) remains comparatively good. Clinical studies aiming to identify the causes of these limitations are often plagued by confounds and ethical limitations. Recent behavioral work suggests that rats may be a good animal model for studying binaural hearing under neuroprosthetic stimulation, as rats develop excellent ITD sensitivity when provided with suitable CI stimulation. However, their ability to use ILDs has not yet been characterized. Objective of this study is to address this knowledge gap. Neontally deafened rats were bilaterally fitted with CIs, and trained to lateralize binaural stimuli according to ILD. Their behavioral ILD thresholds were measured at pulse rates from 50 to 2400 pps. CI rats exhibited high sensitivity to ILDs with thresholds of a few dB at all tested pulse rates. We conclude that early deafened rats develop good sensitivity, not only to ITDs but also to ILDs, if provided with appropriate CI stimulation. Their generally good performance, in line with expectations from other mammalian species, validates rats as an excellent model for research on binaural auditory prostheses.