bluuebunny/crossref_metadata_2025_split huggingface dataset:
Correlates of functional physical capacity in physically active older adults: a conceptual-framework-based cross-sectional analysis of social determinants of health and clinical parameters
Authors: Pfeifer Lucinéia Orsolin , Helal Lucas , Oliveira Nórton Luís , Umpierre Daniel 
Published: February 2022

AbstractThis study aimed to explore social determinants of health and health/clinical determinants on two outcomes of functional physical capacity. Therefore, a population-based sample of 327 older adults (69±7 years; 83.5% women) underwent demographical and clinical questionnaires, risk factors assessments, six-minute walk testing (walking capacity), and handgrip strength testing. Based on multivariable linear regression models, age (−4.05m; - 5.3 to −2.8), being men (71.40m; 50.5 to 92.3), body mass index (−3.88m; −5.6 to −2.1), and quality of life (18.48m; 6.3 to 30.6) remained as predictive variables for walking capacity (R2=30.8%). In the final model for handgrip strength, age (−0.6% kgf; 0.89 to 0.2) and male sex (65.2% kgf; 55.3 to 75.8) remained as predictive variables. Despite exploratory analyses including contextual factors as potential predictors of walking capacity and handgrip strength, only outcomes at the individual levels were associated, either positively or negatively, with the variations presented by this studied sample of older adults.
Enhanced excitability of the hippocampal CA2 region and its contribution to seizure generation in a mouse model of temporal lobe epilepsy
Authors: Whitebirch Alexander C. , LaFrancois John J. , Jain Swati , Leary Paige , Santoro Bina , Siegelbaum Steven A. , Scharfman Helen E. 
Published: February 2022

ABSTRACTThe hippocampal CA2 region, an area important for social memory, has been suspected to play a role in temporal lobe epilepsy (TLE) because of its resistance to the degeneration observed in neighboring CA1 and CA3 regions in both human and rodent models of TLE. However, little is known about whether alterations in CA2 properties serve to promote seizure generation or propagation. Here we have used the pilocarpine-induced status epilepticus (PILO-SE) model of TLE to explore the role of CA2. Ex vivo electrophysiological recordings from acute hippocampal slices revealed a set of coordinated changes that enhance CA2 intrinsic excitability, reduce CA2 local inhibitory input, and increase CA2 excitatory output to its major CA1 synaptic target. Moreover, selective silencing of CA2 pyramidal cells using a chemogenetic approach caused a significant decrease in the frequency of spontaneous seizures. These findings provide the first evidence that CA2 actively contributes to TLE seizure activity and may thus be a promising therapeutic target.
Genomic prediction with whole-genome sequence data in intensely selected pig lines
Authors: Ros-Freixedes Roger , Johnsson Martin , Whalen Andrew , Chen Ching-Yi , Valente Bruno D , Herring William O , Gorjanc Gregor , Hickey John M 
Published: February 2022

AbstractBackgroundEarly simulations indicated that whole-genome sequence data (WGS) could improve genomic prediction accuracy and its persistence across generations and breeds. However, empirical results have been ambiguous so far. Large data sets that capture most of the genome diversity in a population must be assembled so that allele substitution effects are estimated with high accuracy. The objectives of this study were to use a large pig dataset to assess the benefits of using WGS for genomic prediction compared to using commercial marker arrays, to identify scenarios in which WGS provides the largest advantage, and to identify potential pitfalls for its effective implementation.MethodsWe sequenced 6,931 individuals from seven commercial pig lines with different numerical size. Genotypes of 32.8 million variants were imputed for 396,100 individuals (17,224 to 104,661 per line). We used BayesR to perform genomic prediction for eight complex traits. Genomic predictions were performed using either data from a marker array or variants preselected from WGS based on association tests.ResultsThe prediction accuracy with each set of preselected WGS variants was not robust across traits and lines and the improvements in prediction accuracy that we achieved so far with WGS compared to marker arrays were generally small. The most favourable results for WGS were obtained when the largest training sets were available and used to preselect variants with statistically significant associations to the trait for augmenting the established marker array. With this method and training sets of around 80k individuals, average improvements of genomic prediction accuracy of 0.025 were observed in within-line scenarios.ConclusionsOur results showed that WGS has a small potential to improve genomic prediction accuracy compared to marker arrays in intensely selected pig lines in some settings. Thus, although we expect that more robust improvements could be attained with a combination of larger training sets and optimised pipelines, the use of WGS in the current implementations of genomic prediction should be carefully evaluated on a case-by-case basis against the cost of generating WGS at a large scale.
Identification of cell types in multiplexed in situ images by combining protein expression and spatial information using CELESTA reveals novel spatial biology
Authors: Zhang Weiruo , Li Irene , Reticker-Flynn Nathan E. , Good Zinaida , Chang Serena , Samusik Nikolay , Saumyaa Saumyaa , Li Yuanyuan , Zhou Xin , Liang Rachel , Kong Christina S. , Le Quynh-Thu , Gentles Andrew J. , Sunwoo John B. , Nolan Garry P. , Engleman Edgar G. , Plevritis Sylvia K. 
Published: February 2022

ABSTRACTAdvances in multiplexed in situ imaging are revealing important insights in spatial biology. However, cell type identification remains a major challenge in imaging analysis, with most existing methods involving substantial manual assessment and subjective decisions for thousands of cells. We propose a novel machine learning algorithm, CELESTA, which uses both cell’s protein expression and spatial information to identify cell type of individual cells. We demonstrate the performance of CELESTA on multiplexed immunofluorescence in situ images of colorectal cancer and head and neck cancer. Using the cell types identified by CELESTA, we identify tissue architecture associated with lymph node metastasis in HNSCC, which we validate in an independent cohort. By coupling our in situ spatial analysis with single-cell RNA-sequencing data on proximal sections of the same tissue specimens, we identify and validate cell-cell crosstalk associated with lymph node metastasis, demonstrating the power of spatial biology to reveal clinically-relevant cellular interactions.
Curvelet Transform-based Sparsity Promoting Algorithm for Fast Ultrasound Localization Microscopy
Authors: You Qi , Trzasko Joshua D. , Lowerison Matthew R. , Chen Xi , Dong Zhijie , Chandra Sekaran Nathiya Vaithiyalingam , Llano Daniel A. , Chen Shigao , Song Pengfei 
Published: February 2022

AbstractUltrasound localization microscopy (ULM) based on microbubble (MB) localization was recently introduced to overcome the resolution limit of conventional ultrasound. However, ULM is currently challenged by the requirement for long data acquisition times to accumulate adequate MB events to fully reconstruct vasculature. In this study, we present a curvelet transform-based sparsity promoting (CTSP) algorithm that improves ULM imaging speed by recovering missing MB localization signal from data with very short acquisition times. CTSP was first validated in a simulated microvessel model, followed by the chicken embryo chorioallantoic membrane (CAM), and finally, in the mouse brain. In the simulated microvessel study, CTSP robustly recovered the vessel model to achieve an 86.94% vessel filling percentage from a corrupted image with only 4.78% of the true vessel pixels. In the chicken embryo CAM study, CTSP effectively recovered the missing MB signal within the vasculature, leading to marked improvement in ULM imaging quality with a very short data acquisition. Taking the optical image as reference, the vessel filling percentage increased from 2.7% to 42.2% using 50ms of data acquisition after applying CTSP. CTSP used 80% less time to achieve the same 90% maximum saturation level as compared with conventional MB localization. We also applied CTSP on the microvessel flow speed maps and found that CTSP was able to use only 1.6s of microbubble data to recover flow speed images that have similar qualities as those constructed using 33.6s of data. In the mouse brain study, CTSP was able to reconstruct the majority of the cerebral vasculature using 1-2s of data acquisition. Additionally, CTSP only needed 3.2s of microbubble data to generate flow velocity maps that are comparable to those using 129.6s of data. These results suggest that CTSP can facilitate fast and robust ULM imaging especially under the circumstances of inadequate microbubble localizations.
Multiple mechanisms mediate the suppression of motion vision during escape maneuvers in flying Drosophila
Authors: Fischer Philippe J. , Schnell Bettina 
Published: February 2022

SUMMARYDuring voluntary behaviors, animals need to disable any reflexes that could interfere with the intended movements. With the optomotor response, for example, flies stabilize a straight flight path by correcting for unintended deviations sensed as panoramic motion of the surround. HS cells of the fly are thought to mediate optomotor responses to horizontal motion. During spontaneous flight turns, an efference copy acts on HS cells with the right sign to counteract the visual input elicited by the fly’s own behavior. Here, we investigated HS cell activity during looming-elicited turns in flying Drosophila. We show that looming stimuli themselves can influence the processing of panoramic motion stimuli in HS cells and that in addition, an inhibitory efference copy suppresses excitatory motion responses during turns, but only in a subset of HS cells. In conclusion, our findings support the notion that processing of sensory information is finely tuned to behavioral context.
Evolutionary responses of energy metabolism, development, and reproduction to artificial selection for increasing heat tolerance inDrosophila subobscura
Authors: Mesas Andrés , Castañeda Luis E. 
Published: February 2022

AbstractAdaptations to warming conditions exhibited by ectotherms include increasing heat tolerance but also metabolic changes to reduce maintenance costs (metabolic depression), which can allow them to redistribute the energy surplus to biological functions close to fitness. Currently, there is evidence that energy metabolism evolves in response to warming conditions but we know little about how the rate of temperature change during heat stress determines the evolutionary response of metabolism and the consequences on life-history traits. Here, we evaluated the evolutionary response of energy metabolism (metabolic rate and activity of enzymes of the glucose-6-phosphate branchpoint) and life-history traits to artificial selection for increasing heat tolerance inDrosophila subobscura, using two different thermal selection protocols for heat tolerance: slow and fast ramping protocols. We found that the increase in heat thermal tolerance was associated with a reduction of the hexokinase activity in the slow-ramping selected lines, and a slight reduction of the glucose-6-phosphate dehydrogenase activity in the fast-ramping selected lines. We also found that the evolution of increased heat tolerance increased the early fecundity in selected lines and increased the egg-to-adult viability only in the slow-ramping selected lines. However, heat tolerance evolution was not associated with changes in the metabolic rate in selected populations. This work shows heat tolerance can evolve under different thermal scenarios but with different evolutionary outcomes on associated traits depending on the intensity of thermal stress. Therefore, spatial and temporal variability of thermal stress intensity should be taken into account to understand and predict the adaptive response to ongoing and future climatic conditions.
Interaction of an α-synuclein epitope with HLA-DRB1*15:01 triggers enteric features in mice reminiscent of prodromal Parkinson’s disease
Authors: Garretti Francesca , Monahan Connor , Sloan Nicholas , Bergen Jamie , Shahriar Sanjid , Kim Seon Woo , Sette Alessandro , Cutforth Tyler , Kanter Ellen , Agalliu Dritan , Sulzer David 
Published: February 2022

SUMMARYEnteric symptoms, including constipation, are hallmarks of prodromal Parkinson’s disease (PD) that can appear decades before the onset of motor symptoms and diagnosis. PD patients possess circulating T cells that recognize specific α-synuclein-(α-syn)-derived epitopes. One epitope, α-syn32-46, binds with strong affinity to the HLA-DRB1*15:01 allele implicated in autoimmune diseases. We report that α-syn32-46immunization in a mouse expressing HLA-DRB1*15:01 triggers intestinal inflammation leading to loss of enteric neurons, damage of enteric dopaminergic neurons, constipation and weight loss. α-Syn32-46immunization activates innate and adaptive immune gene signatures in the gut and induces changes in CD4+TH1/ TH17 transcriptome that resemble tissue resident memory cells found in mucosal barriers during inflammation. Depletion of CD4+, but not CD8+, T cells partially rescues enteric neurodegeneration. Therefore, interaction of α-syn32-46and HLA-DRB1*15:0 is critical for gut inflammation and CD4+T cell-mediated loss of enteric neurons in humanized mice, suggesting potential mechanisms of prodromal enteric PD.HIGHLIGHTS AND eTOC Blurbα-syn32-46immunization of an HLA-DRB1*15:01 mouse triggers weight loss and constipation.α-syn32-46immunizations induce gut inflammation, loss of enteric neurons and damage to dopaminergic neurons.α-syn32-46immunization induces innate and adaptive immune responses in the gut.Depletion of CD4+, but not CD8+, T cells partially rescues enteric neural loss.An interaction between α-syn32-46and HLA-DRB1*15:01 is critical for this model of prodromal PD.Parkinson’s disease (PD) patients exhibit elevated number of circulating T cells that recognize α-synuclein-(α-syn)- epitopes, particularly during early disease stages. One epitope, α-syn32-46, interacts with the HLA-DRB1*15:01; however, its role in PD pathogenesis remains unknown. Garrettiet al. show that α-syn32-46immunization of a mouse expressing HLA-DRB1*15:01 triggers intestinal inflammation, a loss of enteric neurons, constipation and weight loss, suggesting a critical role for α-syn autoimmunity in HLA-DRB1*15:01 carriers in prodromal PD.
The Ca2+-gated Cl- channel TMEM16A amplifies capillary pericyte contraction reducing cerebral blood flow after ischemia
Authors: Korte Nils , Ilkan Zeki , Pearson Claire , Pfeiffer Thomas , Singhal Prabhav , Rock Jason , Sethi Huma , Gill Dipender , Attwell David , Tammaro Paolo 
Published: February 2022

ABSTRACTPericyte-mediated capillary constriction decreases cerebral blood flow in stroke after an occluded artery is unblocked. The determinants of pericyte tone are poorly understood. We show that a small rise in cytoplasmic Ca2+ concentration ([Ca2+]i) in pericytes activates chloride efflux through the Ca2+-gated anion channel TMEM16A, thus depolarizing the cell and opening voltage-gated calcium channels. This mechanism strongly amplifies the pericyte [Ca2+]i rise and capillary constriction evoked by contractile agonists and ischemia. In a rodent stroke model, TMEM16A inhibition slows the ischemia-evoked pericyte [Ca2+]i rise, capillary constriction and pericyte death, reduces neutrophil stalling and improves cerebrovascular reperfusion. Genetic analysis implicates altered TMEM16A expression in poor patient recovery from ischemic stroke. Thus, pericyte TMEM16A is a crucial regulator of cerebral capillary function, and a potential therapeutic target for stroke and possibly other disorders of impaired microvascular flow, such as Alzheimer’s disease and vascular dementia.
Evidence for evolutionary adaptation of mixotrophic nanoflagellates to warmer temperatures
Authors: Lepori-Bui Michelle , Paight Christopher , Eberhard Ean , Mertz Conner M. , Moeller Holly V. 
Published: February 2022

AbstractMixotrophs, organisms that combine photosynthesis and heterotrophy to gain energy, play an important role in global biogeochemical cycles. Metabolic theory predicts that mixotrophs will become more heterotrophic with rising temperatures, potentially creating a positive feedback loop that accelerates carbon dioxide accumulation in the atmosphere. Studies testing this theory have focused on phenotypically plastic (short-term) thermal responses of mixotrophs. However, as small organisms with short generation times and large population sizes, mixotrophs may rapidly evolve in response to climate change. Here we present data from a 3-year experiment quantifying the evolutionary response of two mixotrophic nanoflagellates to temperature. We found evidence for adaptive evolution through increasing growth rates in the obligately mixotrophic strain, but not in the facultative mixotroph. All lineages showed trends of increased carbon use efficiency, flattening of thermal reaction norms, and a return to homeostatic gene expression. Generally, mixotrophs evolved reduced photosynthesis and higher grazing with increased temperatures, suggesting that evolution may act to exacerbate mixotrophs’ effects on global carbon cycling.
Insights in the complex DegU, DegS, Spo0A regulation system of Paenibacillus polymyxa by CRISPR-Cas9-based targeted point mutations
Authors: Meliawati Meliawati , May Tobias , Eckerlin Jeanette , Heinrich Daniel , Herold Andrea , Schmid Jochen 
Published: February 2022

AbstractDespite being unicellular organisms, bacteria undergo complex regulation mechanisms which coordinate different physiological traits. Among others, DegU, DegS, and Spo0A are the pleiotropic proteins which govern various cellular responses and behaviors. However, the functions and regulatory networks between these three proteins are rarely described in the highly interesting bacterium Paenibacillus polymyxa. In this study, we investigate the roles of DegU, DegS, and Spo0A by introduction of targeted point mutations facilitated by a CRISPR-Cas9-based system. In total, five different mutant strains were generated: the single mutants DegU Q218*, DegS L99F, Spo0A A257V, the double mutant DegU Q218* DegS L99F, and the triple mutant DegU Q218* DegS L99F Spo0A A257V. Characterization of the wild type and the engineered strains revealed differences in swarming behavior, genetic competence, sporulation, and viscosity formation of the culture broth. In particular, the double mutant DegU Q218* DegS L99F showed significant increase in regard to the genetic competence as well as a stable exopolysaccharides formation. Furthermore, we highlight similarities and differences of the roles of DegU, DegS, and Spo0A between P. polymyxa and related species. Finally, this study provides novel insights in the complex regulatory system of P. polymyxa DSM 365.ImportanceTo date, only limited knowledge is available on how complex cellular behaviors are regulated in P. polymyxa. In this study, we investigate three regulatory proteins which play a role in governing different physiological traits. Precise targeted point mutations are introduced to their respective genes by employing a highly efficient CRISPR-Cas9-based system. Characterization of the strains revealed some similarities, but also differences, with the model bacterium Bacillus subtilis in regard to the regulation of cellular behaviors. Furthermore, we identified several strains which have superior performance in comparison to the wild type strain. Overall, our study provides novel insights which will be of importance in understanding how multiple cellular processes are regulated in Paenibacillus species.
The urothelial transcriptomic response to interferon gamma predicts T1 recurrence-free and basal/squamous muscle-invasive bladder cancer survival and better targeted strategies for immune checkpoint blocking
Authors: Baker Simon C. , Mason Andrew S. , Slip Raphael G. , Eriksson Pontus , Sjödahl Gottfrid , Trejdosiewicz Ludwik K , Southgate Jennifer 
Published: February 2022

AbstractIntravesical Bacillus Calmette-Guérin vaccine (BCG) is an established immunotherapeutic in bladder cancer (BlCa), provoking inflammation leading to tumour-specific immunity. Immune checkpoint blockers such as anti-PD-L1 have potential for enhancing tumour-specific lymphocyte-mediated cytotoxicity in BCG-refractive or advanced disease. In both cases, Interferon-gamma (IFNγ) plays a central role. We investigated the transcriptomic response of normal human urothelium to IFNγ to disentangle mechanisms of BCG and anti-PD-L1 therapy failure.Exposure of differentiated human urothelium to IFNγ resulted in upregulated MHC class I and class II and de novo expression of CXCL9-11 chemokine genes. Normal urothelium expressed only immuno-inhibitory B7 family members: PD-L1 expression was induced by IFNγ, whereas VISTA was expressed constitutively.A urothelial IFNγ response gene set was derived and used for unsupervised clustering of tumours, which predicted longer recurrence-free survival in non-muscle invasive bladder cancer (NMIBC). In muscle invasive bladder cancer (MIBC), the IFNγ-signature split the basal/squamous consensus subtype, with significantly worse overall survival when weak/absent.Normal urothelium has few resident lymphocytes. Tumour cell killing requires recruitment and activation of IFNγ-secreting pro-inflammatory/cytotoxic lymphocytes while surmounting both innate (VISTA) and upregulated (PD-L1) inhibitory mechanisms. This study offers supportive evidence for strategies to enhance immunotherapy via the IFNγ and VISTA/PD-L1 nexus.Patient SummaryImmunotherapy brings promise of harnessing a patient’s own immune system to seek and destroy malignant cells, but it has yet to deliver widespread clinical benefit. We exposed human urothelium to interferon gamma, a key messenger of the immune system and identified a novel signature of 33 genes that predicted cancers with better outcomes. Our study revealed alternative strategies for targeting checkpoint proteins to improve immunotherapy in the future.