SARS-CoV-2 ferritin nanoparticle vaccines produce hyperimmune equine sera with broad sarbecovirus activity.

The rapid emergence of SARS-CoV-2 variants of concern (VoC) and the threat of future zoonotic sarbecovirus spillover emphasizes the need for broadly protective next-generation vaccines and therapeutics. We utilized SARS-CoV-2 spike ferritin nanoparticle (SpFN), and SARS-CoV-2 receptor binding domain ferritin nanoparticle (RFN) immunogens, in an equine model to elicit hyperimmune sera and evaluated its sarbecovirus neutralization and protection capacity. Immunized animals rapidly elicited sera with the potent neutralization of SARS-CoV-2 VoC, and SARS-CoV-1 pseudoviruses, and potent binding against receptor binding domains from sarbecovirus clades 1b, 1a, 2, 3, and 4. Purified equine polyclonal IgG provided protection against Omicron XBB.1.5 virus in the K18-hACE2 transgenic mouse model. These results suggest that SARS-CoV-2-based nanoparticle vaccines can rapidly produce a broad and protective sarbecovirus response in the equine model and that equine serum has therapeutic potential against emerging SARS-CoV-2 VoC and diverse sarbecoviruses, presenting a possible alternative or supplement to monoclonal antibody immunotherapies.

HIV incidence and its associated factors among young adults with multiple sexual partners in Maputo, Mozambique: a vaccine preparedness study.

INTRODUCTION: Sub-Saharan Africa has a high burden of HIV, particularly among female sex workers (FSW) and men who have sex with men (MSM). Future clinical trials to evaluate vaccines and other interventions to prevent HIV will need to enroll populations with high HIV incidence. We conducted an observational study of HIV incidence among men and women with multiple sexual partners-including MSM and FSW-in Maputo, Mozambique, in order to prepare the country to conduct future efficacy trials of candidate HIV vaccines and other HIV prevention products. METHODS: We conducted a prospective observational HIV incidence study in Maputo, Mozambique, that enrolled adults aged 18-35 years, without HIV, who had two or more sexual partners in the preceding three months. Recruitment strategies prioritized participation of MSM and FSW. Participants were followed for 24 months with HIV-1 testing every 3 months and staff-administered behavioral questionnaires every 6 months. Cox proportional hazard modeling was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for factors potentially associated with HIV acquisition. RESULTS: From January 2014 to October 2017, 505 adults without HIV were enrolled with median age of 21 years (interquartile range:19-24); 41% were female and 82% were single. There were 19 HIV seroconversions (10 female and 9 male) during 943 person-years (PY) of observation (overall HIV incidence 2.02/100PY; 95%CI 1.21-3.15). The highest HIV incidence was observed among sex workers (2.08/100PY; 95%CI 0.25-7.52) and MSM (19.18/100PY; 95%CI 3.96-56.06). Increased hazard of incident HIV was observed among participants who were MSM (HR = 27.95, 95%CI 4.39-117.94), p = 0.0004), reported three or more sexual partners at enrollment (HR = 7.39, 95%CI 1.64-33.25, p = 0.009), and indicated ever having a sexual partner living with HIV (HR = 9.64, 95%CI 2.23-41.71, p = 0.002). CONCLUSION: Our findings may inform inclusion criteria for upcoming clinical trials of HIV prevention interventions, including vaccine candidates, which may prioritize enrollment of MSM, people with more than three sexual partners, and people with sexual partners who are living with HIV. These same populations are in need of further intervention to reduce HIV incidence.

Investigating properties of sweet cherry (Prunus avium) flower buds that help promote freezing avoidance by supercooling.

Mechanisms involved in the supercooling of plant tissues as a means of low temperature survival are still not fully understood. We investigated properties that may promote supercooling in overwintering sweet cherry (Prunus avium) flower buds. We conducted experiments on sweet cherry flower buds using differential thermal analysis (DTA) and observed locations of ice formation in the bud structure. We also used anatomical development and water-soluble dye uptake throughout the overwintering period to identify changes that correlate with gain and loss of supercooling capacity. Our results revealed barriers to ice propagation are likely unique to each primordium, as inferred from exotherms produced from buds subjected to DTA, although multiple primordia may freeze simultaneously. Ice is accommodated between the bud scales and within the bud axis; however, full expression of supercooling was not dependent on the presence of scales. Anatomical and DTA studies revealed a correlation between vascular differentiation in primordia and loss of supercooling in the spring; these observations were at a higher temporal resolution than previously described for Prunus. Furthermore, disturbing tissues subtending the primordia interfered with typical patterns of supercooling, indicated more erratic and numerous exotherms produced during DTA. In summary, sweet cherry flower buds undergo extra-organ freezing. In winter, a barrier to ice propagation in the region directly subtending primordia protects the flower from freezing damage, but in the spring xylem differentiation in primordia provides a conduit for ice propagation that compromises supercooling.

Prediction of differential Gag versus Env responses to a mosaic HIV-1 vaccine regimen by HLA class I alleles.

HLA class I variation has the strongest effect genome-wide on outcome after HIV infection, and as such, an understanding of the impact of HLA polymorphism on response to HIV vaccination may inform vaccine design. We sought HLA associations with HIV-directed immunogenicity in the phase 1/2a APPROACH vaccine trial, which tested vaccine regimens containing mosaic inserts in Ad26 and MVA vectors, with or without a trimeric gp140 protein. While there were no HLA allelic associations with the overall cellular immune response to the vaccine assessed by ELISpot (Gag, Pol, and Env combined), significant associations with differential response to Gag compared to Env antigens were observed. Notably, HLA class I alleles known to associate with disease susceptibility in HIV natural history cohorts are associated with stronger Env-directed responses, whereas protective alleles are associated with stronger Gag-directed responses. Mean viral loads determined for each HLA allele in untreated individuals correlated negatively with the strength of the Gag response minus the Env response in Black vaccinees based on both ELISpot and CD8+ T cell ICS responses. As the association of T cell responses to conserved Gag epitopes with lower viral load in untreated individuals is well established, our data raise the possibility that the Ad26.Mos.HIV vaccine may induce more effective cellular responses in those with HLA alleles that confer improved virologic control in untreated HIV infection.IMPORTANCENo vaccine tested to date has shown sufficient efficacy against HIV infection. A vaccine that induces robust responses in one individual may fail to do so in another individual due to variation in HLA class I genes, loci central to the immune response. Extensive data have shown the strong effect of HLA variation on outcome after HIV infection, but very little is known about the effect of such variation on HIV vaccine success. Here, we identify a link between the effect of HLA variation on HIV disease outcome and immune responses to an HIV vaccine. HLA variants associated with better HIV control after infection also induce stronger responses against the HIV Gag protein relative to the Env protein after vaccination. Given the virologic control conferred by responses to Gag in natural history of HIV infection, these data suggest that HLA alleles conferring protection after HIV infection may also support a more effective cellular response to HIV vaccination.

High-risk percutaneous coronary intervention with or without mechanical circulatory support: Will Impella show superiority in the PROTECT IV randomized trial?

BACKGROUND: PROTECT IV is a current enrolling randomized controlled trial evaluating high-risk percutaneous coronary intervention (HR-PCI) with prophylactic Impella versus no Impella to reduce the composite primary endpoint of all-cause death, stroke, myocardial infarction (MI), or cardiovascular hospitalization. In a PROTECT IV-like cohort of patients who underwent HR-PCI without Impella, we aimed to report the rate of major adverse events to determine whether the trial is adequately powered. METHODS AND RESULTS: A total of 700 patients meeting similar inclusion/exclusion criteria of PROTECT IV who underwent HR-PCI without Impella at a single tertiary center from 2008 to 2022 were included in the analysis. The composite rates of all-cause death, MI, target lesion revascularization, and target vessel revascularization at 1, 2, and 3 years were estimated using the Kaplan-Meier method, and the results were used to calculate the sample size under the constant hazard ratio assumption and expected number of events to be observed used in planning PROTECT IV. The primary endpoint occurred in 30.8 % of patients at 2 years. PROTECT IV assumes a hazard ratio of 0.75 using a multivariate Cox regression, which, under a 5 % level and 90 % power, yields 516 events. This implies a 2-year primary outcome rate of 50 % for the non-Impella arm. CONCLUSION: Therefore, PROTECT IV estimates that a sample size of 1252 patients is required for Impella to be declared superior to the non-Impella group. Using our observed 2-year outcome of 30.8 %, we estimate that PROTECT IV requires 1966 patients, demonstrating that PROTECT IV is probably underpowered.

Differences in neutralizing antibody sensitivities and envelope characteristics indicate distinct antigenic properties of Nigerian HIV-1 subtype G and CRF02_AG.

The magnitude of the HIV-1 epidemic in Nigeria is second only to the subtype C epidemic in South Africa, yet the subtypes prevalent in Nigeria require further characterization. A panel of 50 subtype G and 18 CRF02_AG Nigerian HIV-1 pseudoviruses (PSV) was developed and envelope coreceptor usage, neutralization sensitivity and cross-clade reactivity were characterized. These PSV were neutralized by some antibodies targeting major neutralizing determinants, but potentially important differences were observed in specific sensitivities (eg. to sCD4, MPER and V2/V3 monoclonal antibodies), as well as in properties such as variable loop lengths, number of potential N-linked glycans and charge, demonstrating distinct antigenic characteristics of CRF02_AG and subtype G. There was preferential neutralization of the matched CRF/subtype when PSV from subtype G or CRF02_AG were tested using pooled plasma. These novel Nigerian PSV will be useful to study HIV-1 CRF- or subtype-specific humoral immune responses for subtype G and CRF02_AG.

Intravascular Lithotripsy for Treatment of Severely Calcified Common Femoral Artery Disease: Results From the Disrupt PAD III Observational Study.

BACKGROUND: Surgical endarterectomy is currently considered the front-line therapy for the treatment of calcified lesions in the common femoral artery (CFA). Endovascular interventions have evolved, and their use is increasing in frequency. Intravascular lithotripsy (IVL) has shown promising safety and effectiveness in calcified CFA lesions in a small pilot study, but "real-world" evidence from a larger cohort is lacking. METHODS: The Disrupt PAD III Observational Study (NCT02923193) was a prospective, multicenter registry designed to assess the acute safety and effectiveness of IVL treatment for calcified peripheral arterial disease. Any concomitant treatment with other calcium-modifying technologies as well as definitive treatment strategies was at the discretion of the operators. Patients with CFA lesions were evaluated for acute angiographic safety and effectiveness outcomes following IVL treatment as determined by an independent angiographic core lab. RESULTS: Common femoral artery treatment was indicated in 177 patients (n=163 could be analyzed based on core-laboratory data) enrolled at 23 sites. Characteristics for 164 treated lesions included moderate-severe calcification 95.1%, diameter stenosis 74.8±17.7%, and lesion length 53.6±53.1 mm. Concomitant calcium-modifying therapy was used in 32.3% of lesions. Final therapy included drug-coated balloons in 68.9% and stenting in 16.5% of lesions. Post-IVL and final residual stenoses were 29.2±16.5%and 23.6±11.5%, respectively. No vascular complications (flow-limiting dissections, perforations, embolization, slow or no reflow, or abrupt closure) were present at the end of the procedure by core-laboratory assessment, with 1 (0.8%) flow-limiting dissection initially occurring immediately following IVL treatment. CONCLUSION: This study represents the largest real-world experience of IVL treatment in heavily calcified CFA lesions. Intravascular lithotripsy treatment showed significant stenosis reduction and favorable periprocedural safety in this challenging patient population. CLINICAL IMPACT: In this study we show that calcified common femoral artery disease can be safely and effectively treated with shockwave balloon angioplasty with high procedural success and low complication rates and in clinical practice can now be offered as an alternative to surgical treatment in those patients reluctant to or high risk for vascular surgery. This opens another option for clinicians to treat calcified common femoral artery disease without the risk of dissection, perforation or distal embolization that are associated with atherectomy. This study shows that shockwave lithoplasty offers an innovative plaque modification technology to tackle calcified disease in the common femoral artery.

Impella Versus Non-Impella for Nonemergent High-Risk Percutaneous Coronary Intervention.

The benefit of mechanical circulatory support with Impella (Abiomed, Inc., Danvers, Massachusetts) for high-risk percutaneous coronary intervention (HR-PCI) is uncertain. PROTECT III registry data showed improved outcomes with Impella compared with historical data (PROTECT II) but lack a direct comparison with the HR-PCI cohort without Impella support. We retrospectively identified patients meeting the PROTECT III inclusion criteria for HR-PCI and compared this group (non-Impella cohort [NonIMP]) with the outcomes data from the PROTECT III registry (Impella cohort). Baseline differences were balanced using inverse propensity weighting. The coprimary outcome was major adverse cardiac events (MACE) in-hospital and at 90 days. A total of 283 patients at great risk did not receive Impella support; 200 patients had 90-day event ascertainment and were included in the inverse propensity weighting analysis and compared with 504 patients in the Impella cohort group. After calibration, few residual differences remained between groups. The primary outcome was not different in-hospital (3.0% vs 4.8%, p = 0.403) but less in NonIMP at 90 days (7.5% vs 13.8%, p = 0.033). Periprocedural vascular complications, bleeding, and transfusion rate did not differ between groups; however, acute kidney injury occurred more frequently in the NonIMP group (10.5% vs 5.4%, p = 0.023). In conclusion, under identical HR-PCI inclusion criteria for Impella use in PROTECT III, an institutional non-Impella-supported HR-PCI cohort showed similar MACE in-hospital but fewer MACE at 90 days, whereas there was no signal for periprocedural harm with Impella use. These results do not support routine usage of Impella for patients with HR-PCI.

Percutaneous intervention of a giant native coronary artery aneurysm using self-expanding stents.

In the absence of standardized management guidelines, coronary artery aneurysms (CAAs) present therapeutic challenges. Percutaneous coronary intervention (PCI) is rarely explored, especially in giant aneurysms with persistent angina, where surgery might be presumed as a preferred option. We describe the technical aspects and feasibility of PCI using Gore Viabahn expanded polytetrafluoroethylene (ePTFE)-covered nitinol self-expanding stents in a 66-year-old woman with a complex medical history and an enlarging, symptomatic right coronary artery aneurysm. The case was complicated by endoleak after the first stent, but intravascular ultrasound guidance enabled the precise deployment of additional stents, resulting in the successful exclusion of the aneurysm. This case demonstrates steps to successful CAA PCI with Gore Viabahn ePTFE-covered nitinol self-expanding stents and emphasizes that in unsuitable surgical candidates, PCI might be a potential alternative for symptomatic CAAs.

Immunogenicity of 2 therapeutic mosaic HIV-1 vaccine strategies in individuals with HIV-1 on antiretroviral therapy.

Mosaic HIV-1 vaccines have been shown to elicit robust humoral and cellular immune responses in people living with HIV-1 (PLWH), that had started antiretroviral therapy (ART) during acute infection. We evaluated the safety and immunogenicity of 2 mosaic vaccine regimens in virologically suppressed individuals that had initiated ART during the chronic phase of infection, exemplifying the majority of PLWH. In this double-blind, placebo-controlled phase 1 trial (IPCAVD013/HTX1002) 25 ART-suppressed PLWH were randomized to receive Ad26.Mos4.HIV/MVA-Mosaic (Ad26/MVA) (n = 10) or Ad26.Mos4.HIV/Ad26.Mos4.HIV plus adjuvanted gp140 protein (Ad26/Ad26+gp140) (n = 9) or placebo (n = 6). Primary endpoints included safety and tolerability and secondary endpoints included HIV-specific binding and neutralizing antibody titers and HIV-specific T cell responses. Both vaccine regimens were well tolerated with pain/tenderness at the injection site and fatigue, myalgia/chills and headache as the most commonly reported solicited local and grade 3 systemic adverse events, respectively. In the Ad26/Ad26+gp140 group, Env-specific IFN-γ T cell responses showed a median 12-fold increase while responses to Gag and Pol increased 1.8 and 2.4-fold, respectively. The breadth of T cell responses to individual peptide subpools increased from 11.0 pre-vaccination to 26.0 in the Ad26/Ad26+gp140 group and from 10.0 to 14.5 in the Ad26/MVA group. Ad26/Ad26+gp140 vaccination increased binding antibody titers against vaccine-matched clade C Env 5.5-fold as well as augmented neutralizing antibody titers against Clade C pseudovirus by 7.2-fold. Both vaccine regimens were immunogenic, while the addition of the protein boost resulted in additional T cell and augmented binding and neutralizing antibody titers. These data suggest that the Ad26/Ad26+gp140 regimen should be tested further.

Improving access to cancer clinical research in Brazil: recent advances and new opportunities. Expert opinions from the 4th CURA meeting, São Paulo, 2023.

Clinical research is the cornerstone of improvements in cancer care. However, it has been conducted predominantly in high-income countries with few clinical trials available in Brazil and other low-and-middle-income countries (LMIC). Of note, less than one-third of registered clinical trials addressing some of the most commonly diagnosed cancers (breast, lung and cervical) recruited patients from LMIC in the last years. The Institute Project CURA promoted the fourth CURA meeting, discussing barriers to cancer clinical research and proposing potential solutions. A meeting was held in São Paulo, Brazil, in June 2023 with representatives from different sectors: Brazilian Health Regulatory Agency (Anvisa), National Commission of Ethics in Research (CONEP), non-governmental organisations, such as the Latin American Cooperative Oncology Group, the Brazilian Society of Clinical Oncology (SBOC), Contract Research Organisations, pharmaceutical companies and investigators. A total of 16 experts pointed out achievements as shortening the time of regulatory processes involving Anvisa and CONEP, development of staff training programs, maintenance of the National Program of Oncological Attention (PRONON), and the foundation of qualified centres in North and Northeast Brazilian regions. Participants also highlighted the need to be more competitive in the field, which requires optimising ongoing policies and implementing new strategies as decentralisation of clinical research centres, public awareness campaigns, community-centered approaches, collaborations and partnerships, expansion of physicians-directed policies, exploring the role of the steering committee. Active and consistent reporting of the initiatives might help to propagate ongoing advances, increasing Brazilian participation in clinical cancer research. Engagement of all players is crucial to maintain continuous progress with further improvements in critical points including regulatory timelines and increments in qualified human resources which aligned with new educational initiatives focused on physicians and the general population will expand access to cancer clinical trials in Brazil.

SARS-CoV-2 recombinant spike ferritin nanoparticle vaccine adjuvanted with Army Liposome Formulation containing monophosphoryl lipid A and QS-21: a phase 1, randomised, double-blind, placebo-controlled, first-in-human clinical trial.

BACKGROUND: A self-assembling SARS-CoV-2 WA-1 recombinant spike ferritin nanoparticle (SpFN) vaccine co-formulated with Army Liposomal Formulation (ALFQ) adjuvant containing monophosphoryl lipid A and QS-21 (SpFN/ALFQ) has shown protective efficacy in animal challenge models. This trial aims to assess the safety and immunogenicity of SpFN/ALFQ in a first-in-human clinical trial. METHODS: In this phase 1, randomised, double-blind, placebo-controlled, first-in-human clinical trial, adults were randomly assigned (5:5:2) to receive 25 µg or 50 µg of SpFN/ALFQ or saline placebo intramuscularly at day 1 and day 29, with an optional open-label third vaccination at day 181. Enrolment and randomisation occurred sequentially by group; randomisation was done by an interactive web-based randomisation system and only designated unmasked study personnel had access to the randomisation code. Adults were required to be seronegative and unvaccinated for inclusion. Local and systemic reactogenicity, adverse events, binding and neutralising antibodies, and antigen-specific T-cell responses were quantified. For safety analyses, exact 95% Clopper-Pearson CIs for the probability of any incidence of an unsolicited adverse event was computed for each group. For immunogenicity results, CIs for binary variables were computed using the exact Clopper-Pearson methodology, while CIs for geometric mean titres were based on 10 000 empirical bootstrap samples. Post-hoc, paired one-sample t tests were used to assess the increase in mean log-10 neutralising antibody titres between day 29 and day 43 (after the second vaccination) for the primary SARS-CoV-2 targets of interest. This trial is registered at ClinicalTrials.gov, NCT04784767, and is closed to new participants. FINDINGS: Between April 7, and June 29, 2021, 29 participants were enrolled in the study. 20 individuals were assigned to receive 25 µg SpFN/ALFQ, four to 50 µg SpFN/ALFQ, and five to placebo. Neutralising antibody responses peaked at day 43, 2 weeks after the second dose. Neutralisation activity against multiple omicron subvariants decayed more slowly than against the D614G or beta variants until 5 months after second vaccination for both dose groups. CD4+ T-cell responses were elicited 4 weeks after the first dose and were boosted after a second dose of SpFN/ALFQ for both dose groups. Neutralising antibody titres against early omicron subvariants and clade 1 sarbecoviruses were detectable after two immunisations and peaked after the third immunisation for both dose groups. Neutralising antibody titres against XBB.1.5 were detected after three vaccinations. Passive IgG transfer from vaccinated volunteers into Syrian golden hamsters controlled replication of SARS-CoV-1 after challenge. INTERPRETATION: SpFN/ALFQ was well tolerated and elicited robust and durable binding antibody and neutralising antibody titres against a broad panel of SARS-CoV-2 variants and other sarbecoviruses. FUNDING: US Department of Defense, Defense Health Agency.

Clinical, molecular, and drug resistance epidemiology of HIV in Jordan, 2019-2021: A national study.

BACKGROUND: Limited epidemiologic studies have been conducted in Jordan describing the HIV epidemic. This study aimed to address this gap to inform HIV prevention and control. METHODS: A nationally-representative cross-sectional study was conducted among adults living with HIV in Jordan. Laboratory testing included HIV viral load and next-generation-sequencing-based clinical genotype. Log-binomial regression estimated risk ratios (RRs) and 95% confidence intervals (CIs). RESULTS: Among 231 (70%) participants, most were male (184/80%), and from Jordan (217/94%). Among 188 treatment-experienced-participants (>6 months), 165 (88%) were virally suppressed. High-level resistance was most frequent against nucleoside reverse transcriptase inhibitor (13/81%), and integrase-strand transfer inhibitor (INSTI) (10/62%) drugs among viremic (≥1000 HIV copies/mL) treatment-experienced participants with drug-resistant mutations (DRMs, n = 16). Common HIV subtypes (n = 43) were B (6/14%), A1 (5/12%), and CRF01_AE (5/12%); additionally, novel recombinant forms were detected. In multivariate analysis, independently higher risk for late diagnosis (n = 49) was observed with diagnosis through blood donation (vs check-up: RR 2.20, 95%CI 1.16-4.17) and earlier time-period of diagnosis (1986-2014 vs 2015-2021: RR 2.87, 95%CI 1.46-5.62). CONCLUSIONS: Late diagnosis and INSTI resistance endanger national HIV prevention and treatment in Jordan-high-level resistance to INSTI suggests therapeutic drug monitoring is needed for treatment efficacy and conservation of treatment options.

A novel approach to saline/contrast delivery in excimer laser coronary atherectomy (ELCA) to enhance efficacy: MAXCon ELCA technique.

The advent of excimer laser coronary atherectomy (ELCA) nearly four decades ago heralded a novel way to treat complex lesions, both coronary and peripheral, which were previously untraversable and thus untreatable. These complex lesions include heavily calcified lesions, ostial lesions, bifurcation lesions, chronic total occlusions, in-stent restenosis (including stent underexpansion), and degenerative saphenous vein grafts. We discuss the technology of ELCA, its indications, applications, and complications, and suggest the "MAXCon ELCA" technique for better outcomes without increased risk. Lastly, we present a case of MAXCon ELCA effectively treating a complex lesion.

Comparative transcriptome analysis of false codling moth, Thaumatotibia leucotreta in response to high and low-temperature treatments.

The false codling moth (FCM), Thaumatotibia leucotreta, is a major quarantine pest native to Africa. Physical postharvest phytosanitary measures such as cold and heat treatments are championed to control its spread to new regions. However, the molecular changes that T. leucotreta undergoes as it attempts to adjust to its surroundings during the treatments and withstand the extreme temperatures remain largely unknown. The current study employs RNA-seq using the next-generation Illumina HiSeq platform to produce transcriptome profiles for differential gene expression analysis of T. leucotreta larvae under thermal stress. The transcriptome assembly analysis revealed 226,067 transcripts, clustering into 127,018 unigenes. In comparison to the 25 °C treated group, 874, 91, 159, and 754 individual differentially expressed genes (DEGs) co-regulated at -10, 0, 40, and 50 °C, respectively were discovered. Annotation of the DEGs by gene ontology (GO) revealed several genes, previously implicated in low and high-temperature stresses, including heat shock proteins, cytochrome P450, cuticle proteins, odorant binding proteins, and immune system genes. Kyoto Encyclopedia of Genes and Genomics (KEGG) classification analysis revealed that substantive DEGs were those involved in metabolic pathways such as thiamine, purine, folate, and glycerolipid metabolism pathways. The RT-qPCR validation of several significantly up- and down-regulated DEGs showed congruence between RNA-seq and qPCR data. This baseline study lays a foundation for future research into the molecular mechanisms underlying T. leucotreta's cold/heat tolerance by providing a thorough differential gene expression analysis that has identified multiple genes that may be associated with the insect's ability to withstand cold and heat.

Operational data for the risk management of victim operated explosive devices in humanitarian mine action: A Practitioner's perspective.

Since Mine Action's inception at the end of the 1980s, operators have collected limited data on the Victim Operated Explosive Devices (VOEDs) they clear. This includes not only data on the explosive ordnance itself but data on how they were found, where they were found and how they were processed and ultimately destroyed. In a context where detection of mines, boobytraps and certain Victim Operated Improvised Explosive Devices (VOIEDs) is an ongoing humanitarian and military challenge, significantly expanded operational data collection provides an achievable way to facilitate enhanced operational risk management. Risk decisions inherent in the clearance of VOEDs are better if made on the basis of extensive operational data. In the absence of a technological solution to detect and positively discriminate VOEDs from false positive indications, the collection of operational data offers the best prospect for "managing" if not "solving" the problem.

Impact of HLA class I functional divergence on HIV control.

Heterozygosity of Human leukocyte antigen (HLA) class I genes is linked to beneficial outcomes after HIV infection, presumably through greater breadth of HIV epitope presentation and cytotoxic T cell response. Distinct allotype pairs, however, differ in the extent to which they bind shared sets of peptides. We developed a functional divergence metric that measures pairwise complementarity of allotype-associated peptide binding profiles. Greater functional divergence for pairs of HLA-A and/or HLA-B allotypes was associated with slower AIDS progression and independently with enhanced viral load control. The metric predicts immune breadth at the peptide level rather than gene level and redefines HLA heterozygosity as a continuum differentially affecting disease outcome. Functional divergence may affect response to additional infections, vaccination, immunotherapy, and other diseases where HLA heterozygote advantage occurs.

Diverse array of neutralizing antibodies elicited upon Spike Ferritin Nanoparticle vaccination in rhesus macaques.

The repeat emergence of SARS-CoV-2 variants of concern (VoC) with decreased susceptibility to vaccine-elicited antibodies highlights the need to develop next-generation vaccine candidates that confer broad protection. Here we describe the antibody response induced by the SARS-CoV-2 Spike Ferritin Nanoparticle (SpFN) vaccine candidate adjuvanted with the Army Liposomal Formulation including QS21 (ALFQ) in non-human primates. By isolating and characterizing several monoclonal antibodies directed against the Spike Receptor Binding Domain (RBD), N-Terminal Domain (NTD), or the S2 Domain, we define the molecular recognition of vaccine-elicited cross-reactive monoclonal antibodies (mAbs) elicited by SpFN. We identify six neutralizing antibodies with broad sarbecovirus cross-reactivity that recapitulate serum polyclonal antibody responses. In particular, RBD mAb WRAIR-5001 binds to the conserved cryptic region with high affinity to sarbecovirus clades 1 and 2, including Omicron variants, while mAb WRAIR-5021 offers complete protection from B.1.617.2 (Delta) in a murine challenge study. Our data further highlight the ability of SpFN vaccination to stimulate cross-reactive B cells targeting conserved regions of the Spike with activity against SARS CoV-1 and SARS-CoV-2 variants.