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GIGANTEA ( GI ) was originally identified by a late-flowering mutant in Arabidopsis , but subsequently has been shown to act in circadian period determination, light inhibition of hypocotyl elongation, and responses to multiple abiotic stresses, including tolerance to high salt and cold (freezing) temperature. Genetic mapping and analysis of families of heterogeneous inbred lines showed that natural variation in GI is responsible for a major quantitative trait locus in circadian period in Brassica rapa. We confirmed this conclusion by transgenic rescue of an Arabidopsis gi-201 loss of function mutant. The two B. rapa GI alleles each fully rescued the delayed flowering of Arabidopsis gi-201 but showed differential rescue of perturbations in red light inhibition of hypocotyl elongation and altered cold and salt tolerance. The B. rapa R500 GI allele, which failed to rescue the hypocotyl and abiotic stress phenotypes, disrupted circadian period determination in Arabidopsis . Analysis of chimeric B. rapa GI alleles identified the causal nucleotide polymorphism, which results in an amino acid substitution (S264A) between the two GI proteins. This polymorphism underlies variation in circadian period, cold and salt tolerance, and red light inhibition of hypocotyl elongation. Loss-of-function mutations of B. rapa GI confer delayed flowering, perturbed circadian rhythms in leaf movement, and increased freezing and increased salt tolerance, consistent with effects of similar mutations in Arabidopsis . Collectively, these data suggest that allelic variation of GI —and possibly of clock genes in general—offers an attractive target for molecular breeding for enhanced stress tolerance and potentially for improved crop yield. Significance The plant circadian clock affects many aspects of growth and development and influences both fitness in natural settings and performance in cultivated conditions. We show that GIGANTEA ( GI ) underlies a major quantitative trait locus for circadian period in Brassica rapa by fine-mapping, analysis of heterogeneous inbred lines, and transgenic rescue of an Arabidopsis gi-201 loss-of-function mutant. Analysis of chimeric and mutated B. rapa GI alleles identified the causal nucleotide polymorphism responsible for the allelic variation in circadian period, cold and salt tolerance, and red light inhibition of hypocotyl elongation. Allelic variation of GI and of clock genes in general offers targets for marker-assisted (molecular) breeding for enhanced stress tolerance and potentially for improved crop yield.

The treatment of frostbite injuries has undergone a radical change over the past decade with a shift from supportive therapy and observation towards early and aggressive medical intervention with thrombolytics and vasodilators. Institutions that have implemented evidence-based protocols have significantly decreased their amputation rates (Bruen et al., 2007; Lindford et al., 2017a; Twomey et al., 2005). We present the case of a middle-aged male treated for frostbite of multiple fingers on both hands. Because there was no treatment protocol at our institution, there were multiple delays in the patient's care including imaging and initiation of intravenous (IV) prostanoids. This case illustrates the deleterious effects of delays in treatment and strongly suggests that all facilities located in areas of cold exposure should have protocols in place for such an occurrence.

Pulmonary arterial hypertension (PAH) involves progressive cellular and molecular change within the pulmonary vasculature, leading to increased vascular resistance. Current therapies targeting nitric oxide (NO), endothelin, and prostacyclin pathways yield variable treatment responses. Patients with systemic sclerosis-associated PAH (SSc-PAH) often experience worse outcomes than those with idiopathic PAH (IPAH). Lung tissue samples from four SSc-PAH, four IPAH, and four failed donor specimens were obtained from the Pulmonary Hypertension Breakthrough Initiative (PHBI) lung tissue bank. Single-cell RNA sequencing (scRNAseq) was performed using the 10X Genomics Chromium Flex platform. Data normalization, clustering, and differential expression analysis were conducted using Seurat. Additional analyses included gene set enrichment analysis (GSEA), transcription factor activity analysis, and ligand-receptor signaling. Pharmacotranscriptomic screening was performed using the Connectivity Map. SSc-PAH samples showed a higher proportion of fibroblasts and dendritic cells/macrophages compared to IPAH and donor samples. GSEA revealed enriched pathways related to epithelial-to-mesenchymal transition (EMT), apoptosis, and vascular remodeling in SSc-PAH samples. There was pronounced differential gene expression across diverse pulmonary vascular cell types and in various epithelial cell types in both IPAH and SSc-PAH, with epithelial to endothelial cell signaling observed. Macrophage to endothelial cell signaling was particularly pronounced in SSc-PAH. Pharmacotranscriptomic screening identified TIE2, GSK-3, and PKC inhibitors, among other compounds, as potential drug candidates for reversing SSc-PAH gene expression signatures. Overlapping and distinct gene expression patterns exist in SSc-PAH versus IPAH, with significant molecular differences suggesting unique pathogenic mechanisms in SSc-PAH. These findings highlight the potential for precision-targeted therapies to improve SSc-PAH patient outcomes. Future studies should validate these targets clinically and explore their therapeutic efficacy.

GIGANTEA(GI) was originally identified by a late-flowering mutant inArabidopsis,but subsequently has been shown to act in circadian period determination, light inhibition of hypocotyl elongation, and responses to multiple abiotic stresses, including tolerance to high salt and cold (freezing) temperature. Genetic mapping and analysis of families of heterogeneous inbred lines showed that natural variation inGIis responsible for a major quantitative trait locus in circadian period inBrassica rapa.We confirmed this conclusion by transgenic rescue of anArabidopsis gi-201loss of function mutant. The twoB. rapa GIalleles each fully rescued the delayed flowering ofArabidopsis gi-201but showed differential rescue of perturbations in red light inhibition of hypocotyl elongation and altered cold and salt tolerance. TheB. rapaR500GIallele, which failed to rescue the hypocotyl and abiotic stress phenotypes, disrupted circadian period determination inArabidopsis.Analysis of chimericB. rapa GIalleles identified the causal nucleotide polymorphism, which results in an amino acid substitution (S264A) between the two GI proteins. This polymorphism underlies variation in circadian period, cold and salt tolerance, and red light inhibition of hypocotyl elongation. Loss-of-function mutations ofB. rapa GIconfer delayed flowering, perturbed circadian rhythms in leaf movement, and increased freezing and increased salt tolerance, consistent with effects of similar mutations inArabidopsis.Collectively, these data suggest that allelic variation ofGI—and possibly of clock genes in general—offers an attractive target for molecular breeding for enhanced stress tolerance and potentially for improved crop yield.

Israel says its strikes are aimed at militants involved in daily rocket fire from Gaza against Israeli towns. However, targeting rocket launchers in crowded Gaza is a problem in the summer, when thousands of children play in the streets. Two five-year-olds and a 16year-old were killed in an air strike on Tuesday. Falestin alSharif, mother of one of the five-year-olds killed in the air strike, said her daughter Samia was fetching a sandwich for her disabled aunt when she was killed. Al Sharif said she would like to become a suicide bomber to avenge the death.

With highly active anti-retroviral therapy (HAART), higher incidence of airway abnormalities is common in the HIV population consistent with the concept of accelerated lung “aging”. Our previous findings demonstrated that HIV induces human airway basal cells (BC) into destructive and inflammatory phenotypes. Since BC function as stem/progenitor cells of the small airway epithelium (SAE), responsible for self-renewal and differentiation of SAE, we hypothesized that BC from people living with HIV (PLWH) may have altered differentiation capacity that contribute to premature aging. The data demonstrates that BC from PLWH have impaired capacity to differentiate in vitro and senescent phenotypes including shortened telomeres, increased expression of β-galactosidase and cell cycle inhibitors, and mitochondrial dysfunction. In vitro studies demonstrated that BC senescence is partly due to adverse effects of HAART on BC. These findings provide an explanation for higher incidence of airway dysfunction and accelerated lung aging observed in PLWH.

Despite the introduction of anti-retroviral therapy, chronic HIV infection is associated with an increased incidence of other comorbidities such as COPD. Based on the knowledge that binding of HIV to human airway basal stem/progenitor cells (BC) induces a destructive phenotype by increased MMP-9 expression through MAPK signaling pathways, we hypothesized that HIV induces the BC to express inflammatory mediators that contribute to the pathogenesis of emphysema. Our data demonstrate that airway BC isolated from HAART-treated HIV + nonsmokers spontaneously release inflammatory mediators IL-8, IL-1β, ICAM-1 and GM-CSF. Similarly, exposure of normal BC to HIV in vitro up-regulates expression of the same inflammatory mediators. These HIV-BC derived mediators induce migration of alveolar macrophages (AM) and neutrophils and stimulate AM proliferation. This HIV-induced inflammatory phenotype likely contributes to lung inflammation in HIV + individuals and provides explanation for the increased incidence of COPD in HIV + individuals.

Tilapias (family Cichlidae) are of importance in aquaculture and fisheries. Hybridisation and introgression are common within tilapia genera but are difficult to analyse due to limited numbers of species-specific genetic markers. We tested the potential of double digested restriction-site associated DNA (ddRAD) sequencing for discovering single nucleotide polymorphism (SNP) markers to distinguish between 10 tilapia species. Analysis of ddRAD data revealed 1,371 shared SNPs in the de novo -based analysis and 1,204 SNPs in the reference-based analysis. Phylogenetic trees based on these two analyses were very similar. A total of 57 species-specific SNP markers were found among the samples analysed of the 10 tilapia species. Another set of 62 species-specific SNP markers was identified from a subset of four species which have often been involved in hybridisation in aquaculture: 13 for Oreochromis niloticus , 23 for O . aureus , 12 for O . mossambicus and 14 for O . u . hornorum . A panel of 24 SNPs was selected to distinguish among these four species and validated using 91 individuals. Larger numbers of SNP markers were found that could distinguish between the pairs of species within this subset. This technique offers potential for the investigation of hybridisation and introgression among tilapia species in aquaculture and in wild populations.

Background Renin-angiotensin system (RAS) signaling and angiotensin-converting enzyme 2 (ACE2) have been implicated in the pathogenesis of acute respiratory distress syndrome (ARDS). We postulated that repleting ACE2 using GSK2586881, a recombinant form of human angiotensin-converting enzyme 2 (rhACE2), could attenuate acute lung injury. Methods We conducted a two-part phase II trial comprising an open-label intrapatient dose escalation and a randomized, double-blind, placebo-controlled phase in ten intensive care units in North America. Patients were between the ages of 18 and 80 years, had an American-European Consensus Criteria consensus diagnosis of ARDS, and had been mechanically ventilated for less than 72 h. In part A, open-label GSK2586881 was administered at doses from 0.1 mg/kg to 0.8 mg/kg to assess safety, pharmacokinetics, and pharmacodynamics. Following review of data from part A, a randomized, double-blind, placebo-controlled investigation of twice-daily doses of GSK2586881 (0.4 mg/kg) for 3 days was conducted (part B). Biomarkers, physiological assessments, and clinical endpoints were collected over the dosing period and during follow-up. Results Dose escalation in part A was well-tolerated without clinically significant hemodynamic changes. Part B was terminated after 39 of the planned 60 patients following a planned futility analysis. Angiotensin II levels decreased rapidly following infusion of GSK2586881, whereas angiotensin-(1–7) and angiotensin-(1–5) levels increased and remained elevated for 48 h. Surfactant protein D concentrations were increased, whereas there was a trend for a decrease in interleukin-6 concentrations in rhACE2-treated subjects compared with placebo. No significant differences were noted in ratio of partial pressure of arterial oxygen to fraction of inspired oxygen, oxygenation index, or Sequential Organ Failure Assessment score. Conclusions GSK2586881 was well-tolerated in patients with ARDS, and the rapid modulation of RAS peptides suggests target engagement, although the study was not powered to detect changes in acute physiology or clinical outcomes. Trial registration ClinicalTrials.gov, NCT01597635 . Registered on 26 January 2012.

Background Young people often face significant challenges accessing effective mental health support as they navigate through complex healthcare systems, education pathways, and social pressures. Understanding the service-level barriers they encounter is critical to improving mental health system design and delivery. While previous studies have examined individual barriers to mental healthcare access, few have adopted a cross-sectorial, youth-informed approach which captures the interrelated structural, institutional, and socio-cultural factors influencing young people’s mental health experiences. Methods Seventeen participants aged 18–24 years with lived experience of depression and/or anxiety participated in nine in-person focus groups and interviews in Perth. Reflexive thematic analysis was used to identify systemic barriers and facilitators to mental healthcare, with a particular focus on access, care coordination, therapeutic engagement, and service responsiveness. Results Key themes included fragmented care pathways, inadequate provider follow-up, prolonged wait times, financial constraints, lack of youth-specific mental health training among clinicians, and limited therapeutic rapport. Participants also described inadequate mental health literacy within schools and persistent stigma in social and familial settings. These intersecting barriers hindered access, disrupted continuity of care, and undermined trust in the mental health system. Conclusions Findings highlight critical inefficiencies in mental health service delivery for young Australians. Policy responses should prioritise integrated care models, investment in multidisciplinary youth mental health hubs, improved school-based mental health literacy, and culturally inclusive anti-stigma initiatives to promote access, trust, and continuity of care.