IL-1R1 signaling in TBI: assessing chronic impacts and neuroinflammatory dynamics in a mouse model of mild closed-head injury.

Neuroinflammation contributes to secondary injury cascades following traumatic brain injury (TBI), with alternating waves of inflammation and resolution. Interleukin-1 (IL-1), a critical neuroinflammatory mediator originating from brain endothelial cells, microglia, astrocytes, and peripheral immune cells, is acutely overexpressed after TBI, propagating secondary injury and tissue damage. IL-1 affects blood-brain barrier permeability, immune cell activation, and neural plasticity. Despite the complexity of cytokine signaling post-TBI, we hypothesize that IL-1 signaling specifically regulates neuroinflammatory response components. Using a closed-head injury (CHI) TBI model, we investigated IL-1's role in the neuroinflammatory cascade with a new global knock-out (gKO) mouse model of the IL-1 receptor (IL-1R1), which efficiently eliminates all IL-1 signaling. We found that IL-1R1 gKO attenuated behavioral impairments 14 weeks post-injury and reduced reactive microglia and astrocyte staining in the neocortex, corpus callosum, and hippocampus. We then examined whether IL-1R1 loss altered acute neuroinflammatory dynamics, measuring gene expression changes in the neocortex at 3, 9, 24, and 72 h post-CHI using the NanoString Neuroinflammatory panel. Of 757 analyzed genes, IL-1R1 signaling showed temporal specificity in neuroinflammatory gene regulation, with major effects at 9 h post-CHI. IL-1R1 signaling specifically affected astrocyte-related genes, selectively upregulating chemokines like Ccl2, Ccl3, and Ccl4, while having limited impact on cytokine regulation, such as Tnfα. This study provides further insight into IL-1R1 function in amplifying the neuroinflammatory cascade following CHI in mice and demonstrates that suppression of IL-1R1 signaling offers long-term protective effects on brain health.

Factors that influence inpatient satisfaction after shoulder arthroplasty.

BACKGROUND: It is important to distinguish satisfaction regarding the outcome of care and satisfaction with the delivery of care. The Consumer Assessment of Healthcare Providers and Systems (CAHPS) surveys are modern assessments of hospitals and providers of delivery of care. The purpose of this study was to report inpatient satisfaction according to Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) and Clinician and Group Consumer Assessment of Healthcare Providers and Systems (CG-CAHPS) scores after shoulder arthroplasty and to determine factors that influence them, as well as their correlation with surgical expectations, pain perception, quality of life, surgical setting, and functional outcomes. METHODS: All patients scheduled for a shoulder arthroplasty were prospectively asked to complete a demographic and initial shoulder assessment form, a shoulder surgery expectations survey, a pain catastrophizing scale, the SF-12 (12-item Short Form) survey, and a resiliency form (Resilience Scale 11). Patient satisfaction was measured with the CG-CAHPS and HCAHPS surveys. Legacy forms, patient-specific factors, type of surgery performed, location of surgery, length of hospital stay, and discharge disposition were evaluated on their ability to predict these survey scores. Linear regression was used to calculate correlations and predictions of continuous variables, and logistic regression was used to compared the satisfied vs. unsatisfied cohorts. RESULTS: The average HCAHPS and CG-CAHPS satisfaction scores for the population were 74.7 ± 20.7 and 82.1 ± 19.4, respectively. Nonsmokers had a mean HCAHPS score of 77.7 ± 22.0, whereas current smokers reported a mean of 59.6 ± 5.2 (P = .03). Patients who were discharged home had a mean HCAHPS score of 77.3 ± 21.9, whereas those discharged to a skilled nursing facility reported a mean of 59.3 ± 6.6 (P = .05). These same groups also had significantly higher odds of being satisfied with the hospital. No significant differences or higher odds were seen for comparisons between overall CG-CAHPS satisfaction and any of the patient-specific factors tested. There was no significant correlation between age, length of stay, pain (pain catastrophizing scale), resiliency (Resilience Scale 11), expectations (shoulder surgery expectations survey), or function (SF-12) and both the HCAHPS and CG-CAHPS satisfaction scores. CONCLUSION: Overall, 37 patients (74%) had CG-CAHPS scores that indicated satisfaction and 34 patients (68%) had HCAHPS scores that indicated satisfaction. Nonsmokers and patients discharged home after surgery report higher levels of inpatient hospital (HCAHPS) satisfaction after shoulder arthroplasty. Patients with high preoperative surgical expectations, pain perception, and resiliency are not generally more satisfied with the hospital or clinician. Preoperative diagnosis, location of surgery, and length of stay do not reliably impact satisfaction with the hospital or clinician. Inpatient HCAHPS and CG-CAHPS satisfaction does not correlate with legacy functional outcome measures and, therefore, may not be predictive of long-term functional outcomes.

Differential chemokine receptor expression and usage by pre-cDC1 and pre-cDC2.

Conventional dendritic cells (cDCs) are continuously replenished by bone marrow-derived precursors called pre-DCs, which traffic through the blood to peripheral tissues. Pre-DCs are a heterogeneous population that includes cDC subset-committed progenitors, namely pre-cDC1 and pre-cDC2, which give rise to mature cDC1 and cDC2, respectively. Regulation of pre-DC subset trafficking is thought to aid the host response to immune challenge. However, the molecular cues regulating pre-cDC1 versus pre-cDC2 trafficking toward peripheral sites during homeostasis and disease remain elusive. Here, we report that pre-cDC1 but not pre-cDC2 express the T helper type 1-associated chemokine receptor CXCR3. Moreover, we identify a cell-intrinsic role for CXCR3 in the trafficking of pre-cDC1 to melanoma tumors but not to non-inflamed organs. We also show that tumor cDC1 numbers can be increased pharmacologically by targeting dipeptidyl peptidase-4 (CD26), a negative regulator of CXCR3 ligands. Our findings demonstrate that pre-cDC1 trafficking is regulated distinctly from pre-cDC2, which is relevant for our understanding of the DC lineage in the context of cancer and inflammation.

WIsH: who is the host? Predicting prokaryotic hosts from metagenomic phage contigs.

SUMMARY: WIsH predicts prokaryotic hosts of phages from their genomic sequences. It achieves 63% mean accuracy when predicting the host genus among 20 genera for 3 kbp-long phage contigs. Over the best current tool, WisH shows much improved accuracy on phage sequences of a few kbp length and runs hundreds of times faster, making it suited for metagenomics studies. AVAILABILITY AND IMPLEMENTATION: OpenMP-parallelized GPL-licensed C ++ code available at https://github.com/soedinglab/wish. CONTACT: clovis.galiez@mpibpc.mpg.de or soeding@mpibpc.mpg.de. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Transient isomers in the photodissociation of bromoiodomethane.

The photochemistry of halomethanes is fascinating for the complex cascade reactions toward either the parent or newly synthesized molecules. Here, we address the structural rearrangement of photodissociated CH2IBr in methanol and cyclohexane, probed by time-resolved X-ray scattering in liquid solution. Upon selective laser cleavage of the C-I bond, we follow the reaction cascade of the two geminate geometrical isomers, CH2I-Br and CH2Br-I. Both meta-stable isomers decay on different time scales, mediated by solvent interaction, toward the original parent molecule. We observe the internal rearrangement of CH2Br-I to CH2I-Br in cyclohexane by extending the time window up to 3 µs. We track the photoproduct kinetics of CH2Br-I in methanol solution where only one isomer is observed. The effect of the polarity of solvent on the geminate recombination pathways is discussed.

Transcriptional and metabolic alternations rebalance wheat grain storage protein accumulation under variable nitrogen and sulfur supply.

Wheat (Triticum aestivum L.) grain storage proteins (GSPs) are major determinants of flour end-use value. Biological and molecular mechanisms underlying the developmental and nutritional determination of GSP accumulation in cereals are as yet poorly understood. Here we timed the accumulation of GSPs during wheat grain maturation relative to changes in metabolite and transcript pools in different conditions of nitrogen (N) and sulfur (S) availability. We found that the N/S supply ratio modulated the duration of accumulation of S-rich GSPs and the rate of accumulation of S-poor GSPs. These changes are likely to be the result of distinct relationships between N and S allocation, depending on the S content of the GSP. Most developmental and nutritional modifications in GSP synthesis correlated with the abundance of structural gene transcripts. Changes in the expression of transport and metabolism genes altered the concentrations of several free amino acids under variable conditions of N and S supply, and these amino acids seem to be essential in determining GSP expression. The comprehensive data set generated and analyzed here provides insights that will be useful in adapting fertilizer use to variable N and S supply, or for breeding new cultivars with balanced and robust GSP composition.

Uncovering employment outcomes for autistic university graduates in the United Kingdom: An analysis of population data.

LAY ABSTRACT: International research suggests that more autistic people are entering higher education. Currently, very little is known about this group in the United Kingdom, for example, we have little information about how many autistic people enrol at UK-based higher education institutions, their backgrounds, the academic programmes they study and what they do once they have graduated. Our study tries to explore these issues by comparing outcomes between autistic students, other disabled students and non-disabled students. We use population data collected by the Higher Education Statistical Agency in the United Kingdom, which included 1,326,416 graduates across the years 2012-2018. Our findings indicate that the degree subjects studied at university by autistic students are more diverse than often people think. We also found that graduates go on to work in a range of employment sectors following graduation but often experience worse outcomes in terms of access to full-time work and worse pay. We argue that universities and colleges must focus greater attention on developing better employment transition support for autistic students and graduates.

Does learning you are autistic at a younger age lead to better adult outcomes? A participatory exploration of the perspectives of autistic university students.

LAY ABSTRACT: People learn they are autistic at different ages. We wanted to know if telling kids they are autistic earlier helps them feel better about their lives when they grow up. We are a team of autistic and non-autistic students and professors. Seventy-eight autistic university students did our online survey. They shared how they found out they were autistic and how they felt about being autistic. They also shared how they feel about their lives now. Around the same number of students learned they were autistic from doctors and parents. Students who learned they were autistic when they were younger felt happier about their lives than people who learned they were autistic when they were older. Students who learned they were autistic when they were older felt happier about being autistic when they first found out than people who did not have to wait as long. Our study shows that it is probably best to tell people they are autistic as soon as possible. The students who did our study did not think it was a good idea to wait until children are adults to tell them they are autistic. They said that parents should tell their children they are autistic in ways that help them understand and feel good about who they are.

ODAS: Open embeddeD Audition System.

Artificial audition aims at providing hearing capabilities to machines, computers and robots. Existing frameworks in robot audition offer interesting sound source localization, tracking and separation performance, although involve a significant amount of computations that limit their use on robots with embedded computing capabilities. This paper presents ODAS, the Open embeddeD Audition System framework, which includes strategies to reduce the computational load and perform robot audition tasks on low-cost embedded computing systems. It presents key features of ODAS, along with cases illustrating its uses in different robots and artificial audition applications.

Exploring the Career Motivations, Strengths, and Challenges of Autistic and Non-autistic University Students: Insights From a Participatory Study.

Supports for the growing number of autistic university students often focus on helping them succeed in university. However, even educated autistic people experience discrimination and other challenges which can make it very difficult for them to obtain meaningful jobs. Little remains known about how universities can better support their autistic students and alumni in overcoming barriers to meaningful employment. In this participatory study, a team of autistic and non-autistic researchers asked autistic (n = 92) and non-autistic (n = 774) university students about their career aspirations, strengths they believe will help them succeed in their "dream jobs," and obstacles they expect to encounter. Autistic participants' top goal in attending college was to improve their career prospects. However, relatively few autistic students reported learning career-specific skills at university. Autistic students were more likely to seek an academic job and less likely to seek a career in healthcare than non-autistic students. Autistic students highlighted writing skills and detail orientation as strengths that could help them succeed in their dream jobs more often than non-autistic students. However, they were also more likely to expect discrimination, social, and psychological difficulties to stand in the way of their dream jobs. These findings suggest that universities should prioritize experiential learning opportunities to help autistic (and non-autistic) students develop employment-related skills while providing mental health supports. Universities should demonstrate their commitment to supporting diverse learners by seeking out and hiring autistic professionals and by teaching their own staff and employers how to appreciate and support autistic colleagues.

A proposed time-resolved X-ray scattering approach to track local and global conformational changes in membrane transport proteins.

Time-resolved X-ray scattering has emerged as a powerful technique for studying the rapid structural dynamics of small molecules in solution. Membrane-protein-catalyzed transport processes frequently couple large-scale conformational changes of the transporter with local structural changes perturbing the uptake and release of the transported substrate. Using light-driven halide ion transport catalyzed by halorhodopsin as a model system, we combine molecular dynamics simulations with X-ray scattering calculations to demonstrate how small-molecule time-resolved X-ray scattering can be extended to the study of membrane transport processes. In particular, by introducing strongly scattering atoms to label specific positions within the protein and substrate, the technique of time-resolved wide-angle X-ray scattering can reveal both local and global conformational changes. This approach simultaneously enables the direct visualization of global rearrangements and substrate movement, crucial concepts that underpin the alternating access paradigm for membrane transport proteins.

Solvent dependent structural perturbations of chemical reaction intermediates visualized by time-resolved x-ray diffraction.

Ultrafast time-resolved wide angle x-ray scattering from chemical reactions in solution has recently emerged as a powerful technique for determining the structural dynamics of transient photochemical species. Here we examine the structural evolution of photoexcited CH(2)I(2) in the nonpolar solvent cyclohexane and draw comparisons with a similar study in the polar solvent methanol. As with earlier spectroscopic studies, our data confirm a common initial reaction pathway in both solvents. After photoexcitation, CH(2)I(2) dissociates to form CH(2)I* + I*. Iodine radicals remaining within the solvent cage recombine with a nascent CH(2)I* radical to form the transient isomer CH(2)I-I, whereas those which escape the solvent cage ultimately combine to form I(2) in cyclohexane. Moreover, the transient isomer has a lifetime approximately 30 times longer in the nonpolar solvent. Of greater chemical significance is the property of time-resolved wide angle x-ray diffraction to accurately determine the structure of the of CH(2)I-I reaction intermediate. Thus we observe that the transient iodine-iodine bond is 0.07 A+/-0.04 A shorter in cyclohexane than in methanol. A longer iodine-iodine bond length for the intermediate arises in methanol due to favorable H-bond interaction with the polar solvent. These findings establish that time-resolved x-ray diffraction has sufficient sensitivity to enable solvent dependent structural perturbations of transient chemical species to be accurately resolved.

It's the fear of the unknown: Transition from higher education for young autistic adults.

More young people with a diagnosis of autism are enrolling and successfully completing higher education courses than ever before and this is set to increase; however, while there is a burgeoning body of literature surrounding the transition into this stage of education, there is a paucity of research that investigates the transition as this population exit higher education. This exploratory qualitative study is one of the first to identify the specific experiences of young autistic adults making this transition, drawing on semi-structured interviews with 21 students and recent graduates. Findings indicate that transition out of higher education is challenging on both practical and psychological levels, manifested by feelings of anxiety and loss. However, there is also evidence that the same phenomenon can also be understood as a positive departure with important implications for identity development. Findings are discussed in relation to future research and implications for practice in higher education institutions.

Hepatic venous pressure gradient correlates with advanced hepatic fibrosis: a retrospective review.

PURPOSE: To determine if hepatic venous pressure gradient (HVPG) correlates with advanced hepatic fibrosis, as a complement to transjugular (transvenous) core needle liver biopsy. MATERIALS AND METHODS: After institutional review board approval, a retrospective review was conducted on 340 patients who underwent transjugular (transvenous) core needle liver biopsy with concurrent pressure measurements between 6/1/2007 and 6/1/2013. Spearman correlation and linear regression were performed. A receiver operating characteristic (ROC) curve was created and sensitivity, specificity, predictive values and likelihood ratios were calculated. RESULTS: Indications included hepatitis C, abnormal liver function tests, non-alcoholic steatohepatitis, autoimmune hepatitis, and cirrhosis, among others. Biopsies showed stage 1 or 2 fibrosis in 15.6% each, stage 3 fibrosis in 21.6%, stage 4 fibrosis in 40.7%, and no fibrosis in 6.5%. Mean HVPG was 6.5 mm Hg (SD 5.0) with a range of 0-26 mm Hg. Spearman correlation coefficient for association between HVPG and fibrosis stage was 0.561 (p < 0.001). R2 on linear regression was 0.247 (p < 0.001). ROC curve for the prediction of stage 4 fibrosis had an area under the curve of 0.79 (95% CI 0.73-0.85). HVPG of ≥6 mm Hg had a sensitivity of 71.3%, specificity of 79.6%, positive predictive value of 70.5%, negative predictive value of 80.2%, positive likelihood ratio of 3.49 (95% CI 2.45-4.97) and negative likelihood ratio of 0.36 (95% CI 0.26-0.50) for diagnosis of stage 4 fibrosis. CONCLUSIONS: HVPG correlates with stage 4 (advanced) hepatic fibrosis.

RulNet: A Web-Oriented Platform for Regulatory Network Inference, Application to Wheat -Omics Data.

With the increasing amount of -omics data available, a particular effort has to be made to provide suitable analysis tools. A major challenge is that of unraveling the molecular regulatory networks from massive and heterogeneous datasets. Here we describe RulNet, a web-oriented platform dedicated to the inference and analysis of regulatory networks from qualitative and quantitative -omics data by means of rule discovery. Queries for rule discovery can be written in an extended form of the RQL query language, which has a syntax similar to SQL. RulNet also offers users interactive features that progressively adjust and refine the inferred networks. In this paper, we present a functional characterization of RulNet and compare inferred networks with correlation-based approaches. The performance of RulNet has been evaluated using the three benchmark datasets used for the transcriptional network inference challenge DREAM5. Overall, RulNet performed as well as the best methods that participated in this challenge and it was shown to behave more consistently when compared across the three datasets. Finally, we assessed the suitability of RulNet to analyze experimental -omics data and to infer regulatory networks involved in the response to nitrogen and sulfur supply in wheat (Triticum aestivum L.) grains. The results highlight putative actors governing the response to nitrogen and sulfur supply in wheat grains. We evaluate the main characteristics and features of RulNet as an all-in-one solution for RN inference, visualization and editing. Using simple yet powerful RulNet queries allowed RNs involved in the adaptation of wheat grain to N and S supply to be discovered. We demonstrate the effectiveness and suitability of RulNet as a platform for the analysis of RNs involving different types of -omics data. The results are promising since they are consistent with what was previously established by the scientific community.

Conserved cis-regulatory modules in promoters of genes encoding wheat high-molecular-weight glutenin subunits.

The concentration and composition of the gliadin and glutenin seed storage proteins (SSPs) in wheat flour are the most important determinants of its end-use value. In cereals, the synthesis of SSPs is predominantly regulated at the transcriptional level by a complex network involving at least five cis-elements in gene promoters. The high-molecular-weight glutenin subunits (HMW-GS) are encoded by two tightly linked genes located on the long arms of group 1 chromosomes. Here, we sequenced and annotated the HMW-GS gene promoters of 22 electrophoretic wheat alleles to identify putative cis-regulatory motifs. We focused on 24 motifs known to be involved in SSP gene regulation. Most of them were identified in at least one HMW-GS gene promoter sequence. A common regulatory framework was observed in all the HMW-GS gene promoters, as they shared conserved cis-regulatory modules (CCRMs) including all the five motifs known to regulate the transcription of SSP genes. This common regulatory framework comprises a composite box made of the GATA motifs and GCN4-like Motifs (GLMs) and was shown to be functional as the GLMs are able to bind a bZIP transcriptional factor SPA (Storage Protein Activator). In addition to this regulatory framework, each HMW-GS gene promoter had additional motifs organized differently. The promoters of most highly expressed x-type HMW-GS genes contain an additional box predicted to bind R2R3-MYB transcriptional factors. However, the differences in annotation between promoter alleles could not be related to their level of expression. In summary, we identified a common modular organization of HMW-GS gene promoters but the lack of correlation between the cis-motifs of each HMW-GS gene promoter and their level of expression suggests that other cis-elements or other mechanisms regulate HMW-GS gene expression.

dbWFA: a web-based database for functional annotation of Triticum aestivum transcripts.

The functional annotation of genes based on sequence homology with genes from model species genomes is time-consuming because it is necessary to mine several unrelated databases. The aim of the present work was to develop a functional annotation database for common wheat Triticum aestivum (L.). The database, named dbWFA, is based on the reference NCBI UniGene set, an expressed gene catalogue built by expressed sequence tag clustering, and on full-length coding sequences retrieved from the TriFLDB database. Information from good-quality heterogeneous sources, including annotations for model plant species Arabidopsis thaliana (L.) Heynh. and Oryza sativa L., was gathered and linked to T. aestivum sequences through BLAST-based homology searches. Even though the complexity of the transcriptome cannot yet be fully appreciated, we developed a tool to easily and promptly obtain information from multiple functional annotation systems (Gene Ontology, MapMan bin codes, MIPS Functional Categories, PlantCyc pathway reactions and TAIR gene families). The use of dbWFA is illustrated here with several query examples. We were able to assign a putative function to 45% of the UniGenes and 81% of the full-length coding sequences from TriFLDB. Moreover, comparison of the annotation of the whole T. aestivum UniGene set along with curated annotations of the two model species assessed the accuracy of the annotation provided by dbWFA. To further illustrate the use of dbWFA, genes specifically expressed during the early cell division or late storage polymer accumulation phases of T. aestivum grain development were identified using a clustering analysis and then annotated using dbWFA. The annotation of these two sets of genes was consistent with previous analyses of T. aestivum grain transcriptomes and proteomes. Database URL: urgi.versailles.inra.fr/dbWFA/