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The dietary specialist fruit fly Drosophila sechellia has evolved to specialize on the toxic fruit of its host plant Morinda citrifolia. Toxicity of Morinda fruit is primarily due to high levels of octanoic acid (OA). Using RNA interference (RNAi), prior work found that knockdown of Osiris family genes Osiris 6 (Osi6), Osi7, and Osi8 led to increased susceptibility to OA in adult D. melanogaster flies, likely representing genes underlying a Quantitative Trait Locus (QTL) for OA resistance in D. sechellia. While genes in this major effect locus are beginning to be revealed, prior work has shown at least five regions of the genome contribute to OA resistance. Here, we identify new candidate OA resistance genes by performing differential gene expression analysis using RNA-sequencing (RNA-seq) on control and OA-exposed D. sechellia flies. We found 104 significantly differentially expressed genes with annotated orthologs in D. melanogaster, including six Osiris gene family members, consistent with previous functional studies and gene expression analyses. Gene ontology (GO) term enrichment showed significant enrichment for cuticle development in upregulated genes and significant enrichment of immune and defense responses in downregulated genes, suggesting important aspects of the physiology of D. sechellia that may play a role in OA resistance. In addition, we identified five candidate OA resistance genes that potentially underlie QTL peaks outside of the major effect region, representing promising new candidate genes for future functional studies.

Background: Since the early 1980s, the Bahamas has experienced sequential epidemics of freebase/crack cocaine use, genital ulcer-inguinal adenopathy disease (GUD), and heterosexual HIV infection. Goal: To prospectively define the etiology of GUD in patients at the Princess Margaret Hospital during outbreaks of crack cocaine use, GUD, and HIV infection in the Bahamas. Study Design: In Nassau, 47 consecutive patients with GUD underwent serologic testing for syphilis and for infections with HIV, herpes simplex virus type 2 (HSV-2), and Chlamydia trachomatis. Genital ulcer specimens were tested by culture and/or polymerase chain reaction (PCR) assay for Haemophilus ducreyi; by PCR and/or antigen assay for HSV; and by PCR for C trachomatis. Lymph node aspirates were tested by PCR for C trachomatis and H ducreyi. Results: Twenty patients (43%) had HIV infection; eight had lymphogranuloma venereum (LGV), confirmed by PCR detection of C trachomatis sequences consistent with the L2 serovar; and nine others had possible LGV, on the basis of serum microimmunofluorescent C trachomatis antibody titers ≥256. Inguinal lymphadenopathy or bubo was present in 15 of 17 patients, who thus met the laboratory criteria for definite or possible LGV, and in 7 of 30 who did not meet such laboratory criteria (P < 0.001). Thirteen patients had confirmed genital herpes, seven had confirmed chancroid, and four had probable or possible primary syphilis. Conclusions: The epidemics in the Bahamas of crack use, heterosexual HIV infection, and GUD apparently included epidemic transmission of LGV.

Background Mental disorders are common in childhood, but many young people do not receive adequate professional support. Help-seeking interventions may bridge this treatment gap, however, there is limited research on interventions for primary-school children. This study aims to evaluate the effectiveness of an emotion literacy program at increasing literacy, reducing stigma, and promoting help-seeking in children aged 8–10 years. Methods and analysis A two-arm pragmatic cluster-controlled trial will compare Thriving Minds, an emotion literacy program for middle primary school children, to a wait-list control condition. Children aged 8–10 years will be recruited from approximately 12 schools (6 intervention schools/6 wait-list control) to participate in Thriving Minds via direct invitation by the program delivery service. Allocation to the intervention condition will be pragmatically, by school. Children will receive the intervention over two 50-minute sessions, across two weeks. Using story books and interactive discussion, the program aims to develop children’s knowledge of their own and other’s emotional experiences and emotion regulation strategies (self-care and help-seeking). The primary outcome is help-seeking intentions. Secondary outcomes include help-seeking knowledge, attitudes, and behaviours, emotion knowledge and attitudes, and stigma. Children will complete surveys at pre-intervention, post-intervention (one week after the program) and 12-week follow-up. Additional satisfaction data will be collected from teachers in intervention schools via surveys (post-intervention and 3-month follow-up) and semi-structured interviews (after follow-up), and selected children via focus groups (12-week follow-up). Analyses will compare changes in help-seeking intentions relative to the waitlist control condition using mixed-model repeated-measures analyses to account for clustering within schools. Discussion With demonstrated effectiveness, this universal emotion literacy program for promoting help-seeking for mental health could be more widely delivered in Australian primary schools, providing a valuable new resource, contributing to the mental health of young people by improving help-seeking for early mental health difficulties. Trial registration Australian New Zealand Clinical Trials Registry, ACTRN12623000910606 Registered on 24 August 2023.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection of vaccinated individuals is increasingly common but rarely results in severe disease, likely due to the enhanced potency and accelerated kinetics of memory immune responses. However, there have been few opportunities to rigorously study early recall responses during human viral infection. To better understand human immune memory and identify potential mediators of lasting vaccine efficacy, we used high-dimensional flow cytometry and SARS-CoV-2 antigen probes to examine immune responses in longitudinal samples from vaccinated individuals infected during the Omicron wave. These studies revealed heightened spike-specific responses during infection of vaccinated compared to unvaccinated individuals. Spike-specific cluster of differentiation (CD)4 T cells and plasmablasts expanded and CD8 T cells were robustly activated during the first week. In contrast, memory B cell activation, neutralizing antibody production and primary responses to nonspike antigens occurred during the second week. Collectively, these data demonstrate the functionality of vaccine-primed immune memory and highlight memory T cells as rapid responders during SARS-CoV-2 infection. Wherry and colleagues define the kinetics of vaccine-primed recall immune responses during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) breakthrough infection, highlighting rapid activation of memory T cells and broadly enhanced immune responses in previously vaccinated individuals.

Parks and protected areas (PPAs) are facing complex, transboundary, social, and ecological pressures, including those related to visitor use. Effective visitor use management (VUM) in PPAs requires interdisciplinary thinking across multiple spatial and temporal scales. Yet, the majority of this VUM research is short-term and occurs at relatively discrete spatial scales. A few existing frameworks and conceptual models used in VUM encourage thinking across scales. No single, interdisciplinary conceptual model exists, however, despite longstanding recognition of the need for one. This need was highlighted as a research priority by PPA and VUM subject area experts from across the U.S. at a workshop at Clemson University in 2018. This manuscript draws from the discussions at that workshop and addresses this recognized need. We propose and describe a single multi-scalar conceptual model that integrates topical areas in PPA VUM. Thoughtful, multi-scalar research that transcends disciplines is essential to address contemporary issues across VUM topics. The proposed model and the subsequent discussion are meant to serve as a catalyst for VUM researchers to begin considering both spatial and temporal scales in their PPA-based inquiries.

Purpose of ReviewPeriprosthetic joint infection (PJI) is a devastating complication that can occur following total joint arthroplasty (TJA), causing significant morbidity and often requiring revision surgery. This goal of this manuscript is to review the current evidence for the prevention and diagnosis of PJI in patients with inflammatory arthritis.Recent FindingsPatients with inflammatory arthritis have a higher risk of PJI after TJA; however, there are several preventive, diagnostic, and therapeutic measures that can be optimized to lower the burden of PJI in this population. This manuscript will review the current evidence and clinical practice recommendations that support specific features of preoperative evaluation, perioperative medication management, and surgical planning in inflammatory arthritis patients undergoing TJA. Evidence and recommendations for the diagnosis of PJI in this patient population will also be reviewed.SummaryDespite increased research efforts directed towards PJI, specific approaches directed at the inflammatory arthritis patient population remain surprisingly limited. Optimization strategies such as adequately managing disease-modifying medications, treating preoperative anemia, encouraging smoking cessation, and improving weight management are strongly encouraged before entering the perioperative period. If PJI does occur in the inflammatory arthritis patient, establishing the diagnosis is challenging, since guidelines were created from investigations of PJI in primarily patients without inflammatory arthritis. Future prospective research is required to better guide clinicians in preventing and diagnosing PJI in inflammatory arthritis patients undergoing TJA.

Conditional expression of short hairpin RNAs with binary genetic systems is an indispensable tool for studying gene function. Addressing mechanisms underlying cell–cell communication in vivo benefits from simultaneous use of 2 independent gene expression systems. To complement the abundance of existing Gal4/UAS-based resources in Drosophila, we and others have developed LexA/LexAop-based genetic tools. Here, we describe experimental and pedagogical advances that promote the efficient conversion of Drosophila Gal4 lines to LexA lines, and the generation of LexAop-short hairpin RNA lines to suppress gene function. We developed a CRISPR/Cas9-based knock-in system to replace Gal4 coding sequences with LexA, and a LexAop-based short hairpin RNA expression vector to achieve short hairpin RNA-mediated gene silencing. We demonstrate the use of these approaches to achieve targeted genetic loss-of-function in multiple tissues. We also detail our development of secondary school curricula that enable students to create transgenic flies, thereby magnifying the production of well-characterized LexA/LexAop lines for the scientific community. The genetic tools and teaching methods presented here provide LexA/LexAop resources that complement existing resources to study intercellular communication coordinating metazoan physiology and development.

Abstract Background T cells in people with human immunodeficiency virus (HIV) demonstrate an exhausted phenotype, and HIV-specific CD4+ T cells expressing programmed cell death 1 (PD-1) are enriched for latent HIV, making antibody to PD-1 a potential strategy to target the latent reservoir. Methods This was a phase 1/2, randomized (4:1), double-blind, placebo-controlled study in adults with suppressed HIV on antiretroviral therapy with CD4+ counts ≥350 cells/μL who received 2 infusions of cemiplimab versus placebo. The primary outcome was safety, defined as any grade 3 or higher adverse event (AE) or any immune-related AE (irAE). Changes in HIV-1–specific polyfunctional CD4+ and CD8+ T-cell responses were evaluated. Results Five men were enrolled (median CD4+ count, 911 cells/μL; median age, 51 years); 2 received 1 dose of cemiplimab, 2 received 2 doses, and 1 received placebo. One participant had a probable irAE (thyroiditis, grade 2); another had a possible irAE (hepatitis, grade 3), both after a single low-dose (0.3 mg/kg) infusion. The Safety Monitoring Committee recommended no further enrollment or infusions. All 4 cemiplimab recipients were followed for 48 weeks. No other cemiplimab-related serious AEs, irAEs, or grade 3 or higher AEs occurred. One 2-dose recipient of cemiplimab had a 6.2-fold increase in polyfunctional, Gag-specific CD8+ T-cell frequency with supportive increases in plasma HIV RNA and decreases in total HIV DNA. Conclusions One of 4 participants exhibited increased HIV-1-specific T-cell responses and transiently increased HIV-1 expression following 2 cemiplimab infusions. The occurrence of irAEs after a single, low dose may limit translating the promising therapeutic results of cemiplimab for cancer to immunotherapeutic and latency reversal strategies for HIV. Clinical Trials Registration. NCT03787095. One of 4 participants administered anti-PD-1 antibody exhibited increased HIV-1–specific T-cell responses and transiently increased HIV-1 expression. Significant immune-related adverse events after a single, low dose of anti-PD-1 antibody may limit translating the benefits of anti-PD-1 therapies from cancer to HIV.

Palmer et al discuss the importance of studying the ecology of Earth, which will be overpopulated for the foreseeable future. Thus, a research perspective that incorporates human activities as integral components of Earth's ecosystems is needed, as is a focus on a future in which Earth's life support systems are maintained while human needs are met. They also recommend a research agenda centered on ecosystem services and the science of ecological restoration and design.

Background Obesity and pubertal insulin resistance worsen cardiovascular (CV) risk factors in youth. It is unclear how the relationships of obesity and insulin resistance with CV risk compare to adults. Subjects and Methods We evaluated 66 pubertal youth (mean ± SD: age 14.2 ± 2.0 years, body mass index [BMI] 36.6 ± 6.0 kg/m2, hemoglobin A1c [HbA1c] 38.5 ± 6.1 mmol/mol) and 355 adults with comparable BMI (age 52.7 ± 9.4 years, BMI 35.1 ± 5.1 kg/m2, HbA1c 39.8 ± 4.2 mmol/mol) participating in a multicenter study. Insulin sensitivity was quantified using hyperglycemic clamps. Assessment of CV risk factors was standardized across sites. Regression analyses compared the impact of insulin sensitivity and CV risk factors between youth and adults. Results Obese pubertal youth were more insulin resistant than comparably obese adults (P < .001), but with similar slopes for the inverse relationship between insulin sensitivity and obesity. The impact of obesity on CV risk factors was explained by insulin sensitivity (P = NS after adjustment for sensitivity). The two age groups did not differ in relationships between insulin sensitivity and diastolic blood pressure, total cholesterol, and low‐density lipoprotein (LDL) cholesterol, after adjusting for obesity. However, while systolic blood pressure (SBP) and high‐density lipoprotein (HDL) cholesterol exhibited the expected direct and inverse relationships, respectively with insulin sensitivity in adults, these slopes were flat in youth across the range of insulin sensitivity (P ≤ .05 for group differences). Conclusions Effects of obesity on CV risk factors were attributable to insulin sensitivity in both groups. The relationships between insulin sensitivity and CV risk factors were similar in obese youth and adult groups except for SBP and HDL cholesterol. Clinical Trial Registration: The RISE consortium studies are registered through Clinicaltrials.gov as NCT01779362 (Adult Medication Study); NCT01763346 (Adult Surgery Study); and NCT01779375 (Pediatric Medication Study). Clinical trial registration numbers: NCT01779362, NCT01779375 and NCT01763346 at clinicaltrials.gov