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Background Leber congenital amaurosis (LCA) is a severe visual impairment responsible for infantile blindness, representing ~5% of all inherited retinal dystrophies. LCA encompasses a group of heterogeneous disorders, with 24 genes currently implicated in pathogenesis. Such clinical and genetic heterogeneity poses great challenges for treatment, with personalized therapies anticipated to be the best treatment candidates. Unraveling the individual genetic etiology of disease is a prerequisite for personalized therapies, and could identify potential treatment candidates, inform patient management, and discriminate syndromic forms of disease. Methods We have genetically analyzed 45 affected and 82 unaffected individuals from 34 unrelated LCA pedigrees using predominantly next‐generation sequencing and Array CGH technology. Results We present the molecular findings for an Australian LCA cohort, sourced from the Australian Inherited Retinal Disease Registry & DNA Bank. CEP290 and GUCY2D mutations, each represent 19% of unrelated LCA cases, followed by NMNAT1 (12%). Genetic subtypes were consistent with other reports, and were resolved in 90% of this cohort. Conclusion The high resolution rate achieved, equivalent to recent findings using whole exome/genome sequencing, reflects the progression from hypothesis (LCA Panel) to non‐hypothesis (RD Panel) testing and, coupled with Array CGH analysis, is a highly effective first‐tier test for LCA. Leber congenital amaurosis (LCA) is a severe visual impairment responsible for infantile blindness, representing ~5% of all inherited retinal dystrophies. We present the molecular findings for an Australian LCA cohort, sourced from the Australian Inherited Retinal Disease Registry & DNA Bank, which utilized next‐generation sequencing and Array CGH to resolve 90% of this cohort. The high resolution rate achieved, equivalent to recent findings using whole exome/genome sequencing, reflects the progression from hypothesis (LCA Panel) to non‐hypothesis (RD Panel) testing and, coupled with Array CGH analysis, is a highly effective first‐tier test for LCA.

Honeybees (Apis mellifera) and bumblebees (Bombus spp.) often undergo exploitative competition for shared floral resources, which can alter their foraging behaviour and flower choice, even causing competitive exclusion. This may be strongest in summer, when foraging conditions are most challenging for bees, compared to other times of the year. However, the seasonal dynamics of competition between these major pollinator groups are not well understood. Here, we investigate whether the strength of exploitative competition for nectar between honeybees and bumblebees varies seasonally, and whether competitive pressure is greatest in summer months. We carried out experimental bee exclusion trials from May to late September, using experimental patches of lavender, variety Grosso, in full bloom. In each trial, we compared the numbers of honeybees (HB) foraging on patches from which bumblebees had been manually excluded (bumblebee excluded, BBE) versus control (CON) patches, HB(BBE-CON). This measure of exploitative competition varied significantly with season. As expected, mean HB(BBE-CON) was significantly greater in summer trials than in spring or autumn trials. This was despite high nectar standing crop volumes in BBE patch flowers in spring and autumn trials. Mean HB(BBE-CON) was not different between spring and autumn trials. Our results show that nectar competition between honeybees and bumblebees varies seasonally and is stronger in summer than spring or autumn, adding to current understanding of the seasonality of resource demand and competition between bee species. This information may also help to inform conservation programs aiming to increase floral resources for bees by showing when these resources are most needed.

Following acute retinal damage, zebrafish possess the ability to regenerate all neuronal subtypes through Müller glia (MG) reprogramming and asymmetric cell division that produces a multipotent Müller glia-derived neuronal progenitor cell (MGPC). This raises three key questions. First, do MG reprogram to a developmental retinal progenitor cell (RPC) state? Second, to what extent does regeneration recapitulate retinal development? And finally, does loss of different retinal cell subtypes induce unique MG regeneration responses? We examined these questions by performing single-nuclear and single-cell RNA-Seq and ATAC-Seq in both developing and regenerating retinas. Here we show that injury induces MG to reprogram to a state similar to late-stage RPCs. However, there are major transcriptional differences between MGPCs and RPCs, as well as major transcriptional differences between activated MG and MGPCs when different retinal cell subtypes are damaged. Validation of candidate genes confirmed that loss of different subtypes induces differences in transcription factor gene expression and regeneration outcomes. The molecular mechanisms controlling injury-dependent neuronal regeneration are largely unknown. Here, the authors use integrated multiomic analysis to characterize gene regulatory networks controlling injury-induced neurogenesis in zebrafish retina

Antimicrobial resistance (AMR) is a high priority across countries as it increases morbidity, mortality and costs. Concerns with AMR have resulted in multiple initiatives internationally, nationally and regionally to enhance appropriate antibiotic utilization across sectors to reduce AMR, with the overuse of antibiotics exacerbated by the COVID-19 pandemic. Effectively tackling AMR is crucial for all countries. Principally a narrative review of ongoing activities across sectors was undertaken to improve antimicrobial use and address issues with vaccines including COVID-19. Point prevalence surveys have been successful in hospitals to identify areas for quality improvement programs, principally centering on antimicrobial stewardship programs. These include reducing prolonged antibiotic use to prevent surgical site infections. Multiple activities centering on education have been successful in reducing inappropriate prescribing and dispensing of antimicrobials in ambulatory care for essentially viral infections such as acute respiratory infections. It is imperative to develop new quality indicators for ambulatory care given current concerns, and instigate programs with clear public health messaging to reduce misinformation, essential for pandemics. Regular access to effective treatments is needed to reduce resistance to treatments for HIV, malaria and tuberculosis. Key stakeholder groups can instigate multiple initiatives to reduce AMR. These need to be followed up.

Immune checkpoint inhibitors are associated with immune-related adverse events (irAEs), including arthritis (arthritis-irAE). Management of arthritis-irAE is challenging because immunomodulatory therapy for arthritis should not impede antitumor immunity. Understanding of the mechanisms of arthritis-irAE is critical to overcome this challenge, but the pathophysiology remains unknown. Here, we comprehensively analyze peripheral blood and/or synovial fluid samples from 20 patients with arthritis-irAE, and unmask a prominent Th1-CD8 + T cell axis in both blood and inflamed joints. CX3CR1 hi CD8 + T cells in blood and CXCR3 hi CD8 + T cells in synovial fluid, the most clonally expanded T cells, significantly share TCR repertoires. The migration of blood CX3CR1 hi CD8 + T cells into joints is possibly mediated by CXCL9/10/11/16 expressed by myeloid cells. Furthermore, arthritis after combined CTLA-4 and PD-1 inhibitor therapy preferentially has enhanced Th17 and transient Th1/Th17 cell signatures. Our data provide insights into the mechanisms, predictive biomarkers, and therapeutic targets for arthritis-irAE. Arthritis is the most common rheumatic immune-related adverse event (irAE) occurring in cancer patients receiving immune checkpoint inhibitors. Here the authors study the immune landscape of blood and synovial fluid samples from patients with arthritis-irAE, reporting immunological differences and similarities with classic autoimmune arthritis.

Transgenic animals are invaluable for modeling cancer genomics, but often require complex crosses of multiple germline alleles to obtain the desired combinations. Zebrafish models have advantages in that transgenes can be rapidly tested by mosaic expression, but typically lack spatial and temporal control of tumor onset, which limits their utility for the study of tumor progression and metastasis. To overcome these limitations, we have developed a method referred to as Transgene Electroporation in Adult Zebrafish (TEAZ). TEAZ can deliver DNA constructs with promoter elements of interest to drive fluorophores, oncogenes or CRISPR-Cas9-based mutagenic cassettes in specific cell types. Using TEAZ, we created a highly aggressive melanoma model via Cas9-mediated inactivation of Rb1 in the context of BRAFV600E in spatially constrained melanocytes. Unlike prior models that take ∼4 months to develop, we found that TEAZ leads to tumor onset in ∼7 weeks, and these tumors develop in fully immunocompetent animals. As the resulting tumors initiated at highly defined locations, we could track their progression via fluorescence, and documented deep invasion into tissues and metastatic deposits. TEAZ can be deployed to other tissues and cell types, such as the heart, with the use of suitable transgenic promoters. The versatility of TEAZ makes it widely accessible for rapid modeling of somatic gene alterations and cancer progression at a scale not achievable in other in vivo systems.

Understanding dense matter hydrodynamics is critical for predicting plasma behavior in environments relevant to laser-driven inertial confinement fusion. Traditional diagnostic sources face limitations in brightness, spatiotemporal resolution, and in their ability to detect relevant electromagnetic fields. In this work, we present a dual-probe, multi-messenger laser wakefield accelerator platform combining ultrafast X-rays and relativistic electron beams at 1 Hz, to interrogate a free-flowing water target in vacuum, heated by an intense 200 ps laser pulse. This scheme enables high-repetition-rate tracking the evolution of the interaction using both particle types. Betatron X-rays reveal a cylindrically symmetric shock compression morphology assisted by low-density vapor, resembling foam-layer-assisted fusion targets. The synchronized electron beam detects time-evolving electromagnetic fields, uncovering charge separation and ion species differentiation during plasma expansion – phenomena not captured by photons or hydrodynamic simulations. We show that combining both probes provides complementary insights spanning kinetic to hydrodynamic regimes, highlighting the need for hybrid physics models to accurately predict fusion-relevant plasma behavior. The authors demonstrate dual-probe multi-messenger imaging of high-energy-density plasmas based on laser-wakefield-accelerated electrons. This enables spatiotemporally resolved simultaneous probing of plasma hydrodynamics and electromagnetic field evolution with both x-ray and electron beams.

Cancer genome alterations often lead to vulnerabilities that can be used to selectively target cancer cells. Various inhibitors of such synthetic lethal targets have been approved by the FDA or are in clinical trials, highlighting the potential of this approach 1 , 2 – 3 . Here we analysed large-scale CRISPR knockout screening data from the Cancer Dependency Map and identified a new synthetic lethal target, PELO , for two independent molecular subtypes of cancer: biallelic deletion of chromosomal region 9p21.3 or microsatellite instability-high (MSI-H). In 9p21.3-deleted cancers, PELO dependency emerges from biallelic deletion of the 9p21.3 gene FOCAD , a stabilizer of the superkiller complex (SKIc). In MSI-H cancers, PELO is required owing to MSI-H-associated mutations in TTC37  (also known as  SKIC3 ), a critical component of the SKIc. We show that both cancer subtypes converge to destabilize the SKIc, which extracts mRNA from stalled ribosomes. In SKIc-deficient cells, PELO depletion induces the unfolded protein response, a stress response to accumulation of misfolded or unfolded nascent polypeptides. Together, our findings indicate PELO as a promising therapeutic target for a large patient population with cancers characterized as MSI-H with deleterious TTC37 mutations or with biallelic 9p21.3 deletions involving FOCAD . Analysis of large-scale CRISPR screening data, combined with experiments in patient-derived tumour organoid models, identifies PELO as a potential therapeutic target in chromosomal 9p21.3-deleted cancers and microsatellite-unstable cancers harbouring specific mutations.

Numerous studies have demonstrated evidence of obesity bias in healthcare settings, however, little is known about obesity bias in the Emergency Department (ED). The objective of this study was to investigate obesity bias in an ED setting by assessing the association between body mass index (BMI) and door-to-room (DTR) or door-to-provider (DTP) times among ED patients. We conducted an observational cohort study of all adult patient (age ≥ 18 years of age) visits to 21 Mayo Clinic and Mayo Clinic Health System EDs between November 1, 2018 and March 31, 2020. We compared DTR and DTP times based on BMI category. We found that median DTR and DTP times for adults with class 3 obesity are significantly shorter than patients in the normal weight category. For men with class 3 obesity, median DTR and DTP times were 7.5% and 5.4% shorter than men in the normal weight category. Relative to women in the normal weight category, the median DTR and DTP times were 4.6% and 3.8% faster for women in obesity class 1, 4.9% and 5.1% faster for women in obesity class 2, and DTR was 4.4% faster for women in obesity class 3. These percentage differences translated to slightly shorter wait times of 0.4–1.2 min compared to median wait times for patients with normal BMI. We did not find evidence of longer wait times experienced by people with obesity. Rather, patients with obesity often experienced wait times that were shorter than patients of normal weight.