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Ischemic stroke is a major disease causing death and disability in the elderly and is one of the major diseases that seriously threaten human health and cause a great economic burden. In the early stage of ischemic stroke, neuronal structure is destroyed, resulting in death or damage, and the release of a variety of damage-associated pattern molecules induces an increase in neuroglial activation, peripheral immune response, and secretion of inflammatory mediators, which further exacerbates the damage to the blood–brain barrier, exacerbates cerebral edema, and microcirculatory impairment, triggering secondary brain injuries. After the acute phase of stroke, various immune cells initiate a protective effect, which is released step by step and contributes to the repair of neuronal cells through phenotypic changes. In addition, ischemic stroke induces Central Nervous System (CNS) immunosuppression, and the interaction between the two influences the outcome of stroke. Therefore, modulating the immune response of the CNS to reduce the inflammatory response and immune damage during stroke is important for the protection of brain function and long-term recovery after stroke, and modulating the immune function of the CNS is expected to be a novel therapeutic strategy. However, there are fewer studies on B-cells in brain function protection, which may play a dual role in the stroke process, and the understanding of this cell is still incomplete. We review the existing studies on the mechanisms of the role of B-cells, inflammatory response, and immune response in the development of ischemic stroke and provide a reference for the development of adjuvant therapeutic drugs for ischemic stroke targeting inflammatory injury.

Over the past decade, there has been an uptick in the number of studies conducting research on the role of microRNA (miRNA) molecules in stroke. Among these molecules, miR-34a has emerged as a significant player, as its levels have been observed to exhibit a substantial rise following ischemic events. Elevated levels of miR-34a have been found to have multiple effects, including the modulation of inflammatory molecules involved in the post-stroke recovery process, as well as negative effects on the blood–brain barrier (BBB) permeability. Interestingly, the increase of miR-34a appears to increase BBB permeability post stroke, through the negative effect on mitochondrial function. The strength of mitochondrial function is crucial for limiting para-cellular permeability and maintaining the structural integrity of the BBB. Furthermore, the activation of ischemic repair mechanisms and the reduction of ischemic event damage depend on healthy mitochondrial activity. This review aims to emphasize the involvement of miR-34a in ischemic stroke, specifically its interaction with mitochondrial genes in cerebrovascular endothelial cells, the effect on mitochondrial function, and lastly its regulatory role in BBB permeability. A comprehensive understanding of the role of miR-34a in maintaining BBB integrity and its contribution to the pathogenesis of stroke holds significant value in establishing a foundation for the development of future therapeutics and diagnostic markers.

Although species interactions are often proposed to be stronger at lower latitudes and elevations, few studies have evaluated the mechanisms driving such patterns. In this study, we assessed whether, and by which mechanisms, abiotic changes associated with elevation altered the outcome of an ant–aphid protection mutualism. To do so, we characterized the multi-trophic interactions among the ant Formica podzolica, the aphid Aphis varians, and aphid natural enemies occurring on the plant Chamerion angustifolium within replicate high and low elevation valleys. Low (versus high) elevation sites had longer summers (snowmelt 13 days earlier) and were on average 1.1°C warmer and 41% drier throughout the year. At low elevations, individual ant colonies consumed approximately double the volume of carbohydrate baits, likely due to a higher foraging tempo, and possibly due to a greater demand for sugar- versus protein-rich resources (as indicated by stable isotope analysis). Wild aphid colonies at low elevations were visited by 1.4-fold more natural enemies (controlling for variation in aphid abundance), while experimental aphid colonies on potted plants were tended 52% more frequently by ants. As a result, ants increased aphid colony survival by 66% at low elevations but had no detectable effect at high elevations; at low (versus high) elevations aphid colonies without ants had lower survival, demonstrating stronger predator effects, while aphid colonies with ants had higher survival, demonstrating even stronger ant benefits. Analyses for the effects of mean summer temperature yielded qualitatively identical results to those based on elevation. Collectively, these findings support predictions for a greater sensitivity of higher trophic levels to warming and demonstrate how species interactions can vary across environmental gradients due to simultaneous changes in species traits and abundances across multiple trophic levels.

This article draws on findings from the first cross-national study of school exclusion in the four jurisdictions of the UK. It casts new light on the crucial aspects of children's education that lead to school exclusion. It investigates the reasons for the UK disparities, as well as the policy and practice in place. The focus of this article is on a detailed analysis of the policy context in Scotland, where official permanent exclusion reduced to an all-time low of just five cases in 2014/15. This is much lower than in Northern Ireland and Wales and in stark contrast to England, where exclusions have increased substantially since 2012. Our analysis seeks to understand Scotland's success in reducing exclusion and offers new insight into the ways in which national policies and local factors more generally shape schools and their practices and the consequent impacts for children and young people more broadly in the UK.

Gerard J Criner,1 Therese Cole,2 Kristen A Hahn,3 Kari Kastango,3 James Eudicone,4 Ileen Gilbert4 1Department of Thoracic Medicine and Surgery, Lewis Katz School of Medicine at Temple University Hospital, Philadelphia, PA, USA; 2IQVIA, Rockville, MD, USA; 3IQVIA, Cambridge, MA, USA; 4AstraZeneca, Wilmington, DE, USACorrespondence: Gerard J CrinerDepartment of Thoracic Medicine and Surgery, Lewis Katz School of Medicine at Temple University Hospital, Philadelphia, PA, 19140, USATel +1 215 707 8113Email gerard.criner@tuhs.temple.eduPurpose: Among patients with chronic obstructive pulmonary disease (COPD), adherence to inhaled medication leads to fewer exacerbations and improved health status. The goal of the present study was to evaluate the effects of medication reminders via the BreatheMate device on adherence in patients with COPD.Patients and Methods: A 6-month, phase 4, randomized, multicenter, open-label US study (NCT02864342) enrolled 138 patients aged ≥ 40 years with moderate to very severe COPD and ≥ 10 pack-year smoking history. Patients in the intervention (n = 68) and control (n = 70) groups received the BreatheMate device, smartphone application, and vouchers to redeem pressurized metered-dose inhalers (pMDIs) for the prescribed 2 puffs of budesonide/formoterol 160/4.5 μg twice daily. The intervention group also received twice-daily electronic reminders to take budesonide/formoterol. The primary endpoint was the mean number of sets of adherent puffs/day (4 puffs: 2 puffs within 60 minutes, twice daily) over 6 months. Secondary endpoints included adherence by three 60-day intervals, usage days, prescription refills, and Clinical COPD Questionnaire (CCQ) score. Study enrollment terminated early due to issues with inconsistent syncing.Results: A higher mean proportion of adherent days (77.6% vs 60.2%; P < 0.001) and sets of adherent puffs/day (1.61 vs 1.33; P < 0.001) were recorded for the intervention group versus the control group. Intervention group adherence was higher than that of the control group for each 60-day interval (P < 0.001); the intervention group was 3.07 (95% confidence interval: 1.49– 6.52) times more likely than the control group to be adherent for ≥ 80% of study days. Overuse (> 2 sets of 2 puffs/day), underuse (< 2 sets of 2 puffs/day), and no use days were lower in the intervention group versus control (P < 0.05). Patients aged ≥ 65 years had higher adherence (P < 0.001).Conclusion: Medication reminders through the BreatheMate device and application produced greater adherence to inhaled therapy in patients with COPD.Keywords: chronic obstructive pulmonary disease, telemedicine, adherence, pressurized metered-dose inhaler

This article draws on findings from the first cross-national study of school exclusions in the four jurisdictions of the UK. It sketches factors associated with the past research with reductions in exclusions. It then reports interview data gathered in England in 2018 from five specialist officers working in two Local Authorities and a senior officer working for a national voluntary organisation. The officers describe good practice but also national, local and school level developments contributing to a deteriorating situation. These developments include unhelpful government guidance and regulations; school accountability frameworks affecting curriculum and leading to the neglect of Special Educational Needs; loss of Local Authority powers and funding resulting in reductions in support services. Data gathered for this study in other UK jurisdictions suggests that in Scotland and Northern Ireland, and to a lesser extent in Wales, a practice that avoids school exclusions has persisted more than in England.

We have successfully designed and constructed a RAEV vector system with regulated-delayed attenuation in vivo attributes that synthesizes Ichthyophthirius multifiliis (Ich) protective antigen IAG52B to enable vaccination of fish susceptible to edwardsiellosis and white spot disease. The first feature of this vaccine delivery system is an Edwardsiella piscicida strain carrying genomic deletions of asdA. AsdA is an enzyme necessary for the synthesis of diaminopimelic acid (DAP), which is an essential component of the peptidoglycan layer of the cell wall of Gram-negative bacteria. asdA mutant strains have obligate growth requirements for DAP in the medium or a plasmid vector with the wild-type asdA gene enabling synthesis of DAP. This balanced-lethal plasmid vector-host system in E. piscicida enables as a second feature the synthesis of recombinant antigens to induce protective immunity against fish pathogens. Recombinant protective antigen IAG52B from the fish pathogen I. multifiliis was synthesized by RAEV strains harboring the AsdA+ plasmid pG8R8029. The third feature of this vaccine strain is a regulated-delayed attenuation in vivo phenotype that is based on the replacement of an arabinose-regulated araC ParaBAD cassette for the promoters of the fur and crp genes of E. piscicida such that the expression of these genes is dependent on arabinose provided during growth. Thus, following colonization, the Fur and Crp proteins stop being synthesized due to the lack of arabinose and attenuation is progressively achieved in vivo to prevent generation of diseases symptoms. Our vaccine strain χ16022 with the genotype ΔasdA10 ΔPfur170::TT araC ParaBADfur ΔPcrp68::TT araC ParaBADcrp contains the AsdA+ plasmid, pG8R8029, which encodes the IAG52B antigen. Vaccine strain χ16022(pG8R8029) is attenuated and induces systemic and mucosal IgM titer against E. piscicida and Ich in zebrafish. In addition, transcript levels of tnf-α, il-1β, il-6 and il-8 were significantly increased in different tissues of vaccinated zebrafish compared to unimmunized fish. Zebrafish vaccinated with χ16022(pG8R8029) showed 60% survival upon intracoelomic (i.c.) challenge with a lethal dose of virulent E. piscicida strain J118. Our RAEV system could be used as a generalized vaccine-vector system to protect teleost fish against multiple bacterial, viral and parasitic infectious diseases.

Introduction: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. Methods: We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. Results: We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. Conclusions: This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.