Robustness versus productivity during evolutionary community assembly: short-term synergies and long-term trade-offs.

The realization that evolutionary feedbacks need to be considered to fully grasp ecological dynamics has sparked interest in the effect of evolution on community properties like coexistence and productivity. However, little is known about the evolution of community robustness and productivity along diversification processes in species-rich systems. We leverage the recent structural approach to coexistence together with adaptive dynamics to study such properties and their relationships in a general trait-based model of competition on a niche axis. We show that the effects of coevolution on coexistence are two-fold and contrasting depending on the time scale considered. In the short term, evolution of niche differentiation strengthens coexistence, while long-term diversification leads to niche packing and decreased robustness. Moreover, we find that coevolved communities tend to be on average more robust and more productive than non-evolutionary assemblages. We illustrate how our theoretical predictions echo in observed empirical patterns and the implications of our results for empiricists and applied ecologists. We suggest that some of our results such as the improved robustness of Evolutionarily Stable Communities could be tested experimentally in suitable model systems.

Dopamine in the nucleus accumbens shell controls systemic glucose metabolism via the lateral hypothalamus and hepatic vagal innervation in rodents.

BACKGROUND: Growing evidence demonstrates the role of the striatal dopamine system in the regulation of glucose metabolism. Treatment with dopamine antagonists is associated with insulin resistance and hyperglycemia, while dopamine agonists are used in treatment of type 2 diabetes. The mechanism underlying striatal dopamine effects in glucose metabolism, however is not fully understood. Here, we provide mechanistic insights into the role of nucleus accumbens shell (sNAc) dopaminergic signaling in systemic glucose metabolism. METHODS: Endogenous glucose production (EGP), blood glucose and mRNA expression in the lateral hypothalamic area (LHA) in male Wistar rats were measured following infusion of vanoxerine (VNX, dopamine reuptake inhibitor) in the sNAc. Thereafter, we analyzed projections from sNAc Drd1-expressing neurons to LHA using D1-Cre male Long-Evans rats, Cre-dependent viral tracers and fluorescence immunohistochemistry. Brain slice electrophysiology in adult mice was used to study spontaneous excitatory postsynaptic currents of sNAc Drd1-expressing neurons following VNX application. Finally, we assessed whether GABAergic LHA activity and hepatic vagal innervation were required for the effect of sNAc-VNX on glucose metabolism by combining infusion of sNAc-VNX with LHA-bicuculline, performing vagal recordings and combining infusion of sNAc-VNX with hepatic vagal denervation. RESULTS: VNX infusion in the sNAc strongly decreased endogenous glucose production, prevented glucose increases over time, reduced Slc17A6 and Hcrt mRNA in LHA, and increased vagal activity. Furthermore, sNAc Drd1-expressing neurons increased spontaneous firing following VNX application, and viral tracing of sNAc Drd1-expressing neurons revealed direct projections to LHA with on average 67 % of orexin cells directly targeted by sNAc Drd1-expressing neurons. Importantly, the sNAc-VNX-induced effect on glucose metabolism was dependent on GABAergic signaling in the LHA and on intact hepatic vagal innervation. CONCLUSIONS: We show that sNAc dopaminergic signaling modulates hepatic glucose metabolism through GABAergic inputs to glutamatergic LHA cells and hepatic vagal innervation. This demonstrates that striatal control of glucose metabolism involves a dopaminergic sNAc-LHA-liver axis and provides a potential explanation for the effects of dopamine agonists and antagonists on glucose metabolism.

The Impact of SIV-Induced Immunodeficiency on Clinical Manifestation, Immune Response, and Viral Dynamics in SARS-CoV-2 Coinfection.

Persistent and uncontrolled SARS-CoV-2 replication in immunocompromised individuals has been observed and may be a contributing source of novel viral variants that continue to drive the pandemic. Importantly, the effects of immunodeficiency associated with chronic HIV infection on COVID-19 disease and viral persistence have not been directly addressed in a controlled setting. Here we conducted a pilot study wherein two pigtail macaques (PTM) chronically infected with SIVmac239 were exposed to SARS-CoV-2 and monitored for six weeks for clinical disease, viral replication, and viral evolution, and compared to our previously published cohort of SIV-naïve PTM infected with SARS-CoV-2. At the time of SARS-CoV-2 infection, one PTM had minimal to no detectable CD4+ T cells in gut, blood, or bronchoalveolar lavage (BAL), while the other PTM harbored a small population of CD4+ T cells in all compartments. Clinical signs were not observed in either PTM; however, the more immunocompromised PTM exhibited a progressive increase in pulmonary infiltrating monocytes throughout SARS-CoV-2 infection. Single-cell RNA sequencing (scRNAseq) of the infiltrating monocytes revealed a less activated/inert phenotype. Neither SIV-infected PTM mounted detectable anti-SARS-CoV-2 T cell responses in blood or BAL, nor anti-SARS-CoV-2 neutralizing antibodies. Interestingly, despite the diminished cellular and humoral immune responses, SARS-CoV-2 viral kinetics and evolution were indistinguishable from SIV-naïve PTM in all sampled mucosal sites (nasal, oral, and rectal), with clearance of virus by 3-4 weeks post infection. SIV-induced immunodeficiency significantly impacted immune responses to SARS-CoV-2 but did not alter disease progression, viral kinetics or evolution in the PTM model. SIV-induced immunodeficiency alone may not be sufficient to drive the emergence of novel viral variants.

Outcomes of Omniflow® II prosthesis used for revascularization in the femoral tract both in infected and non-infected setting.

BACKGROUND: Evidence regarding the outcomes of Omniflow® II prosthesis in peripheral arterial revascularization at different anatomical sites and for different indications is scarce. Therefore, the aim of this study was to evaluate the outcomes of the Omniflow® II used at various positions within the femoral tract both in infected and non-infected setting. METHODS: Patients who underwent reconstructive lower leg vascular surgery with implantation of an Omniflow® II from 2014 until 2021 at five medical centers were retrospectively included (N.=142). Patients were subdivided into the following categories: femoro-femoral crossover (N.=19), femoral interposition (N.=18), femoro-popliteal (above-the-knee [N.=25; AK] or below-the-knee [N.=47; BK]), and femoro-crural bypass grafts (N.=33). Primary outcome was primary patency and secondary outcomes included primary assisted patency, secondary patency, major amputation, vascular graft infection, and mortality. Outcomes were compared according to different subgroups and the surgical setting (infected versus non-infected). RESULTS: The median follow-up was 35.0 (17.5-54.3) months. Three years primary patency of 58% was observed for femoro-femoral crossover bypass, 75% for femoral interposition graft, 44% for femoro-popliteal above-the-knee bypass, 42% for femoro-popliteal below-the-knee bypass, and 27% in the femoro-crural position (P=0.006). Freedom from major amputation at three years were 84% for femoro-femoral crossover bypass, 88% for femoral interposition bypass, 90% for femoro-popliteal AK bypass, 83% for femoro-popliteal BK bypass, and 50% for femoro-crural bypass (P<0.001). CONCLUSIONS: This study demonstrates the safety and feasibility of the use of Omniflow® II for femoro-femoral crossover-, femoral interposition-, and femoro-popliteal (AK and BK) bypass. Omniflow® II seems to be less suitable for femoro-crural bypass with a significantly lower patency compared to other positions.

Use of Omniflow® II Biosynthetic Graft for the Treatment of Vascular Graft and Endograft Infections.

BACKGROUND: Vascular graft/endograft infection is a rare but life-threatening complication of cardiovascular surgery and remains a surgical challenge. Several different graft materials are available for the treatment of vascular graft/endograft infection, each having its own advantages and disadvantages. Biosynthetic vascular grafts have shown low reinfection rates and could be a potential second best after autologous veins in the treatment of vascular graft/endograft infection. Therefore, the aim of our study was to evaluate the efficacy and morbidity of Omniflow® II for the treatment of vascular graft/endograft infection. METHODS: A multicenter retrospective cohort study was performed to evaluate the use of Omniflow® II in the abdominal and peripheral region to treat vascular graft/endograft infection between January 2014 and December 2021. Primary outcome was recurrent vascular graft infection. Secondary outcomes included primary patency, primary assisted patency, secondary patency, all-cause mortality, and major amputation. RESULTS: Fifty-two patients were included with a median follow-up duration of 26.5 (10.8-54.8) months. Nine (17%) grafts were implanted in intracavitary position and 43 (83%) in peripheral position. Most grafts were used as femoral interposition (n = 12, 23%), femoro-femoral crossover (n = 10, 19%), femoro-popliteal (n = 8, 15%), and aorto-bifemoral (n = 8, 15%) graft. Fifteen (29%) grafts were implanted extra-anatomically and 37 (71%) in situ. Eight patients (15%) presented with reinfection during follow-up, most of these patients received an aorto-bifemoral graft (n = 3, 38%). Intracavitary vascular grafting had a 33% (n = 3) reinfection rate and peripheral grafting 12% (n = 5; P = 0.025). The estimated primary patencies at 1, 2, and 3 years were 75%, 72%, and 72% for peripherally located grafts and 58% (at all timepoints) for intracavitary grafts (P = 0.815). Secondary patencies at 1, 2, and 3 years were 77% (at all timepoints) for peripherally located prostheses and 75% (at all timepoints) for intracavitary prostheses (P = 0.731). A significantly higher mortality during follow-up was observed in patients who received an intracavitary graft compared to patients with a peripheral graft (P = 0.003). CONCLUSIONS: This study highlights the efficacy and safety of the Omniflow® II biosynthetic prosthesis for the treatment of vascular graft/endograft infection, in absence of suitable venous material, with acceptable reinfection, patency, and freedom of amputation prevalences, especially in replacing peripheral vascular graft/endograft infection. However, a control group with either venous reconstruction or another alternative graft is needed to make firmer conclusions.

NHP BurkPx: A multiplex serodiagnostic bead assay to monitor Burkholderia pseudomallei exposures in non-human primates.

BACKGROUND: Melioidosis is a disease caused by the bacterium Burkholderia pseudomallei, infecting humans and non-human primates (NHP) through contaminated soil or water. World-wide there are an estimated 165,000 human melioidosis cases each year, but recordings of NHP cases are sporadic. Clinical detection of melioidosis in humans is primarily by culturing B. pseudomallei, and there are no standardized detection protocols for NHP. NHP are an important animal model for melioidosis research including clinical trials and development of biodefense countermeasures. METHODOLOGY/PRINCIPLE FINDINGS: We evaluated the diagnostic potential of the multiple antigen serological assay, BurkPx, in NHP using two sera sets: (i) 115 B. pseudomallei-challenged serum samples from 80 NHP collected each week post-exposure (n = 52) and at euthanasia (n = 47), and (ii) 126 B. pseudomallei-naïve/negative serum samples. We observed early IgM antibody responses to carbohydrate antigens followed by IgG antibody recognition to multiple B. pseudomallei protein antigens during the second week of infection. B. pseudomallei negative serum samples had low to intermediate antibody cross reactivity to the antigens in this assay. Infection time was predicted as the determining factor in the variation of antibody responses, with 77.67% of variation explained by the first component of the principal component analysis. A multiple antigen model generated a binary prediction metric ([Formula: see text]), which when applied to all data resulted in 100% specificity and 63.48% sensitivity. Removal of week 1 B. pseudomallei challenged serum samples increased the sensitivity of the model to 95%. CONCLUSION/SIGNIFICANCE: We employed a previously standardized assay for humans, the BurkPx assay, and assessed its diagnostic potential for detection of B. pseudomallei exposure in NHP. The assay is expected to be useful for surveillance in NHP colonies, in investigations of suspected accidental releases or exposures, and for identifying vaccine correlates of protection.

Sodium bicarbonate for kidney transplant recipients with metabolic acidosis in Switzerland: a multicentre, randomised, single-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Metabolic acidosis is common in kidney transplant recipients and is associated with declining graft function. Sodium bicarbonate treatment effectively corrects metabolic acidosis, but no prospective studies have examined its effect on graft function. Therefore, we aimed to test whether sodium bicarbonate treatment would preserve graft function and slow the progression of estimated glomerular filtration rate (GFR) decline in kidney transplant recipients. METHODS: The Preserve-Transplant Study was a multicentre, randomised, single-blind, placebo-controlled, phase 3 trial at three University Hospitals in Switzerland (Zurich, Bern, and Geneva), which recruited adult (aged ≥18 years) male and female long-term kidney transplant recipients if they had undergone transplantation more than 1 year ago. Key inclusion criteria were an estimated GFR between 15 mL/min per 1·73 m2 and 89 mL/min per 1·73 m2, stable allograft function in the last 6 months before study inclusion (<15% change in serum creatinine), and a serum bicarbonate of 22 mmol/L or less. We randomly assigned patients (1:1) to either oral sodium bicarbonate 1·5-4·5 g per day or matching placebo using web-based data management software. Randomisation was stratified by study centre and gender using a permuted block design to guarantee balanced allocation. We did multi-block randomisation with variable block sizes of two and four. Treatment duration was 2 years. Acid-resistant soft gelatine capsules of 500 mg sodium bicarbonate or matching 500 mg placebo capsules were given at an initial dose of 500 mg (if bodyweight was <70 kg) or 1000 mg (if bodyweight was ≥70 kg) three times daily. The primary endpoint was the estimated GFR slope over the 24-month treatment phase. The primary efficacy analyses were applied to a modified intention-to-treat population that comprised all randomly assigned participants who had a baseline visit. The safety population comprised all participants who received at least one dose of study drug. The trial is registered with ClinicalTrials.gov, NCT03102996. FINDINGS: Between June 12, 2017, and July 10, 2019, 1114 kidney transplant recipients with metabolic acidosis were assessed for trial eligibility. 872 patients were excluded and 242 were randomly assigned to the study groups (122 [50%] to the placebo group and 120 [50%] to the sodium bicarbonate group). After secondary exclusion of two patients, 240 patients were included in the intention-to-treat analysis. The calculated yearly estimated GFR slopes over the 2-year treatment period were a median -0·722 mL/min per 1·73 m2 (IQR -4·081 to 1·440) and mean -1·862 mL/min per 1·73 m2 (SD 6·344) per year in the placebo group versus median -1·413 mL/min per 1·73 m2 (IQR -4·503 to 1·139) and mean -1·830 mL/min per 1·73 m2 (SD 6·233) per year in the sodium bicarbonate group (Wilcoxon rank sum test p=0·51; Welch t-test p=0·97). The mean difference was 0·032 mL/min per 1·73 m2 per year (95% CI -1·644 to 1·707). There were no significant differences in estimated GFR slopes in a subgroup analysis and a sensitivity analysis confirmed the primary analysis. Although the estimated GFR slope did not show a significant difference between the treatment groups, treatment with sodium bicarbonate effectively corrected metabolic acidosis by increasing serum bicarbonate from 21·3 mmol/L (SD 2·6) to 23·0 mmol/L (2·7) and blood pH from 7·37 (SD 0·06) to 7·39 (0·04) over the 2-year treatment period. Adverse events and serious adverse events were similar in both groups. Three study participants died. In the placebo group, one (1%) patient died from acute respiratory distress syndrome due to SARS-CoV-2 and one (1%) from cardiac arrest after severe dehydration following diarrhoea with hypotension, acute kidney injury, and metabolic acidosis. In the sodium bicarbonate group, one (1%) patient had sudden cardiac death. INTERPRETATION: In adult kidney transplant recipients, correction of metabolic acidosis by treatment with sodium bicarbonate over 2 years did not affect the decline in estimated GFR. Thus, treatment with sodium bicarbonate should not be generally recommended to preserve estimated GFR (a surrogate marker for graft function) in kidney transplant recipients with chronic kidney disease who have metabolic acidosis. FUNDING: Swiss National Science Foundation.

Quantum tailoring of electronic properties in covalently functionalized graphene: application to ammonia gas detection.

Functionalized graphene offers great potential in the field of rapid detection of gases at room temperature. We performed first-principles calculations to study the suitability of 4-sulfobenzenediazonium salts (4SBD) as bandgap modifier in graphene. The signature of unpaired spins is evidenced near the Fermi level owing to the symmetry breaking of graphene sublattices. 4SBD-chemisorbed on graphene is found to be electronically sensitive to the presence of ammonia NH3 with increasing gas concentration.

Entering the Third Decade After Kidney Transplantation: Excellent Graft Function Refers to Superior Graft but Not Patient Survival.

Kidney transplant recipients (KTRs) with ultralong-term survival represent a growing, yet insufficiently studied patient cohort. In this single-center retrospective study, we analyzed 248 ultralong-term survivors (≥20 years). KTRs were classified into those with superior graft function (defined as eGFR ≥45 ml/min + proteinuria ≤300 mg/day + eGFR-slope ≤ 2 ml/min/1.73 m2/year) and inferior graft function regarding the risk of CKD progression. 20 years post-transplant, median eGFR was 54 ml/min (11-114), proteinuria 200 mg/24 h (0-7,620), eGFR decline 0.45 ml/min/1.73 m2/year (11.7 6.5) and DSA had been detected in 19.7% of KTRs. We identified 96 KTRs (38.7%) with superior (group 1) and 152 KTRs (61.3%) with inferior graft function (group 2). Donation after cardiac death, female sex, glomerulonephritis as primary disease, and early TCMR were independently associated with inferior graft function. Graft survival was significantly better in group 1 compared to group 2 (LogRank, p < 0.001). Besides group affiliation (HR 20.515, p = 0.003), multivariable analysis identified DSA development (HR 3.081, p = 0.023) and donor age (HR 1.032, p = 0.024) as independent factors. Interestingly, there was no significant difference in patient survival (LogRank, p = 0.350). In ultralong-term survivors, excellent graft function refers to superior graft survival but does not extend ultimate patient survival. DSA-formation should be taken seriously even in the ultralong-term.

Early treatment regimens achieve sustained virologic remission in infant macaques infected with SIV at birth.

Early antiretroviral therapy (ART) in HIV-infected infants generally fails to achieve a sustained state of ART-free virologic remission, even after years of treatment. Our studies show that viral reservoir seeding is different in neonatal macaques intravenously exposed to SIV at birth, in contrast to adults. Furthermore, one month of ART including an integrase inhibitor, initiated at day 3, but not day 4 or 5 post infection, efficiently and rapidly suppresses viremia to undetectable levels. Intervention initiated at day 3 post infection and continued for 9 months achieves a sustained virologic remission in 4 of 5 infants. Collectively, an early intervention strategy within a key timeframe and regimen may result in viral remission or successful post-exposure prophylaxis for neonatal SIV infection, which may be clinically relevant for optimizing treatment strategies for HIV-infected or exposed infants.

Durable protection against the SARS-CoV-2 Omicron variant is induced by an adjuvanted subunit vaccine.

Despite the remarkable efficacy of COVID-19 vaccines, waning immunity and the emergence of SARS-CoV-2 variants such as Omicron represents a global health challenge. Here, we present data from a study in nonhuman primates demonstrating durable protection against the Omicron BA.1 variant induced by a subunit SARS-CoV-2 vaccine comprising the receptor binding domain of the ancestral strain (RBD-Wu) on the I53-50 nanoparticle adjuvanted with AS03, which was recently authorized for use in individuals 18 years or older. Vaccination induced neutralizing antibody (nAb) titers that were maintained at high concentrations for at least 1 year after two doses, with a pseudovirus nAb geometric mean titer (GMT) of 1978 and a live virus nAb GMT of 1331 against the ancestral strain but not against the Omicron BA.1 variant. However, a booster dose at 6 to 12 months with RBD-Wu or RBD-ß (RBD from the Beta variant) displayed on I53-50 elicited high neutralizing titers against the ancestral and Omicron variants. In addition, we observed persistent neutralization titers against a panel of sarbecoviruses, including SARS-CoV. Furthermore, there were substantial and persistent memory T and B cell responses reactive to Beta and Omicron variants. Vaccination resulted in protection against Omicron infection in the lung and suppression of viral burden in the nares at 6 weeks after the final booster immunization. Even at 6 months after vaccination, we observed protection in the lung and rapid control of virus in the nares. These results highlight the durable and cross-protective immunity elicited by the AS03-adjuvanted RBD-I53-50 nanoparticle vaccine.

Cancer among kidney transplant recipients >20 years after transplantation: post-transplant lymphoproliferative disorder remains the most common cancer type in the ultra long-term.

Background: Cancer risk is increased by 2- to 4-fold in kidney transplant recipients (KTRs) compared with the general population. Little attention, however, has been given to KTRs with ultra long-term survival >20 years. Methods: We studied 293 of 1241 KTRs (23.6%), transplanted between 1981 and 1999, who showed kidney allograft survival >20 years. These long-term survivors were analysed for cancer development, cancer type, cancer-associated risk factors and patient and allograft outcomes. Results: By 10, 20 and 30 years post-transplantation, these long-term KTRs showed a cancer rate of 4.4%, 14.6% and 33.2%, and a non-melanoma skin cancer (NMSC) rate of 10.3%, 33.5% and 76.8%, respectively. By recipients' ages of 40, 60 and 80 years, KTRs showed a cancer rate of 3.4%, 14.5% 55.2%, and a NMSC rate of 1.7%, 31.6% and 85.2%, respectively. By 30 years post-transplantation, post-transplant lymphoproliferative disorder (PTLD) showed the highest incidence of 8.5%, followed by renal cell carcinoma (RCC) with 5.1%. Risk factors associated with the development of cancer were only recipient age (P = 0.016). Smoking history was associated with the risk of lung cancer (P = 0.018). Risk factors related to the development of NMSC included recipient age (P = 0.001) and thiazide diuretics (P = 0.001). Cancer increased the risk of death by 2.4-fold (P = 0.002), and PTLD increased the risk of kidney allograft loss by 6.5-fold (P = 0.001). No differences were observed concerning the development of donor-specific antibodies (P > 0.05). Conclusions: In long-term KTRs, cancer is a leading cause of death. PTLD remains the most common cancer type followed by RCC. These results emphasize the need for focused long-term cancer surveillance protocols.

Towards a system-level causative knowledge of pollinator communities.

Pollination plays a central role in both crop production and maintaining biodiversity. However, habitat loss, pesticides, invasive species and larger environmental fluctuations are contributing to a dramatic decline of pollinators worldwide. Different management solutions require knowledge of how ecological communities will respond following interventions. Yet, anticipating the response of these systems to interventions remains extremely challenging due to the unpredictable nature of ecological communities, whose nonlinear behaviour depends on the specific details of species interactions and the various unknown or unmeasured confounding factors. Here, we propose that this knowledge can be derived by following a probabilistic systems analysis rooted on non-parametric causal inference. The main outcome of this analysis is to estimate the extent to which a hypothesized cause can increase or decrease the probability that a given effect happens without making assumptions about the form of the cause-effect relationship. We discuss a road map for how this analysis can be accomplished with the aim of increasing our system-level causative knowledge of natural communities. This article is part of the theme issue 'Natural processes influencing pollinator health: from chemistry to landscapes'.

Durable protection against SARS-CoV-2 Omicron induced by an adjuvanted subunit vaccine

Despite the remarkable efficacy of COVID-19 vaccines, waning immunity, and the emergence of SARS-CoV-2 variants such as Omicron represents a major global health challenge. Here we present data from a study in non-human primates demonstrating durable protection against the Omicron BA.1 variant induced by a subunit SARS-CoV-2 vaccine, consisting of RBD (receptor binding domain) on the I53-50 nanoparticle, adjuvanted with AS03, currently in Phase 3 clinical trial (NCT05007951). Vaccination induced robust neutralizing antibody (nAb) titers that were maintained at high levels for at least one year after two doses (Pseudovirus nAb GMT: 2207, Live-virus nAb GMT: 1964) against the ancestral strain, but not against Omicron. However, a booster dose at 6-12 months with RBD-Wu or RBD-{beta} (RBD from the Beta variant) displayed on I53-50 elicited equivalent and remarkably high neutralizing titers against the ancestral as well as the Omicron variant. Furthermore, there were substantial and persistent memory T and B cell responses reactive to Beta and Omicron variants. Importantly, vaccination resulted in protection against Omicron infection in the lung (no detectable virus in any animal) and profound suppression of viral burden in the nares (median peak viral load of 7567 as opposed to 1.3x107 copies in unvaccinated animals) at 6 weeks post final booster. Even at 6 months post vaccination, there was significant protection in the lung (with 7 out of 11 animals showing no viral load, 3 out of 11 animals showing ~20-fold lower viral load than unvaccinated controls) and rapid control of virus in the nares. These results highlight the durable cross-protective immunity elicited by the AS03-adjuvanted RBD-I53-50 nanoparticle vaccine platform.

Single-dose Diazepam Administration Improves Pairing Success of Unfamiliar Adult Male Rhesus Macaques (Macaca mulatta).

Social housing is one of the best forms of environmental enhancement for nonhuman primates, and current research into pair compatibility and introduction techniques focuses on improving safety and outcome. The gradual steps method (GS), which is widely used for introducing indoor-housed macaques, involves an initial phase of limited physical contact to allow animals to acclimate to one another prior to full contact. A safer, more efficacious introduction method is needed. The administration of diazepam, a sedating anxiolytic medication, is known to increase affiliative behavior in familiar, socially housed rhesus macaques. We hypothesized that administration of a single dose of diazepam prior to full contact introduction without a protected contact phase would improve the success rate of isosexual introductions of unfamiliar macaques as compared with the success rate of GS. We administered 3.2 mg/kg oral diazepam to 34 adult male rhesus macaques (Macaca mulatta) 30-45 min prior to introduction into full contact. Pairs were deemed successful after 14 consecutive days of compatible full-contact housing. Behavioral data collected during these introductions was compared with data collected on 58 adult males during social introductions using GS. Sixteen of 17 introductions (94%) employing diazepam were successful. This success rate was significantly higher than the 45% success rate of introductions using GS. We also found that a longer duration of single housing and increased age were predictive of pair failure in animals introduced using GS. Our results suggest that diazepam administration prior to full contact introductions increases the success rate of male social introductions.

Safety, immunogenicity, and protection provided by unadjuvanted and adjuvanted formulations of a recombinant plant-derived virus-like particle vaccine candidate for COVID-19 in nonhuman primates.

Although antivirals are important tools to control severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, effective vaccines are essential to control the current coronavirus disease 2019 (COVID-19) pandemic. Plant-derived virus-like particle (VLP) vaccine candidates have previously demonstrated immunogenicity and efficacy against influenza. Here, we report the immunogenicity and protection induced in rhesus macaques by intramuscular injections of a VLP bearing a SARS-CoV-2 spike protein (CoVLP) vaccine candidate formulated with or without Adjuvant System 03 (AS03) or cytidine-phospho-guanosine (CpG) 1018. Although a single dose of the unadjuvanted CoVLP vaccine candidate stimulated humoral and cell-mediated immune responses, booster immunization (at 28 days after priming) and adjuvant administration significantly improved both responses, with higher immunogenicity and protection provided by the AS03-adjuvanted CoVLP. Fifteen micrograms of CoVLP adjuvanted with AS03 induced a polyfunctional interleukin-2 (IL-2)-driven response and IL-4 expression in CD4 T cells. Animals were challenged by multiple routes (i.e., intratracheal, intranasal, and ocular) with a total viral dose of 106 plaque-forming units of SARS-CoV-2. Lower viral replication in nasal swabs and bronchoalveolar lavage fluid (BALF) as well as fewer SARS-CoV-2-infected cells and immune cell infiltrates in the lungs concomitant with reduced levels of proinflammatory cytokines and chemotactic factors in the BALF were observed in animals immunized with the CoVLP adjuvanted with AS03. No clinical, pathologic, or virologic evidence of vaccine-associated enhanced disease was observed in vaccinated animals. The CoVLP adjuvanted with AS03 was therefore selected for vaccine development and clinical trials.

Medical imaging of pulmonary disease in SARS-CoV-2-exposed non-human primates.

Chest X-ray (CXR), computed tomography (CT), and positron emission tomography-computed tomography (PET-CT) are noninvasive imaging techniques widely used in human and veterinary pulmonary research and medicine. These techniques have recently been applied in studies of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-exposed non-human primates (NHPs) to complement virological assessments with meaningful translational readouts of lung disease. Our review of the literature indicates that medical imaging of SARS-CoV-2-exposed NHPs enables high-resolution qualitative and quantitative characterization of disease otherwise clinically invisible and potentially provides user-independent and unbiased evaluation of medical countermeasures (MCMs). However, we also found high variability in image acquisition and analysis protocols among studies. These findings uncover an urgent need to improve standardization and ensure direct comparability across studies.

Circular RNA-based biomarkers in blood of patients with Fabry disease and related phenotypes.

BACKGROUND: Fabry disease is a rare X-linked lysosomal storage disease caused by mutations in the galactosidase α gene. Deficient activity of α-galactosidase A leads to glycosphingolipid accumulations in multiple organs. Circular RNAs represent strong regulators of gene expression. Their circular structure ensures high stability in blood. We hypothesised that blood-based circular RNA profiles improve phenotypic assignment and therapeutic monitoring of Fabry disease. METHODS: A genome-wide circular RNA expression analysis was performed in blood of genetically diagnosed patients with Fabry disease (n=58), age-matched and sex-matched healthy volunteers (n=14) and disease control patients with acute kidney injury (n=109). Most highly dysregulated circular RNAs were validated by quantitative real-time PCR. Circular RNA biomarker sensitivity, specificity, predictive values and area under the curve (AUC) were determined. Linear regression analyses were conducted for validated circular RNA biomarkers and clinical patient characteristics. RESULTS: A distinct circular RNA transcriptome signature identified patients with Fabry disease. Level of circular RNAs hsa_circ_0006853 (AUC=0.73), hsa_circ_0083766 (AUC=0.8) and hsa_circ_0002397 (AUC=0.8) distinguished patients with Fabry disease from both healthy controls and patients with acute kidney injury. Hsa_circ_0002397 was, furthermore, female-specifically expressed. Circular RNA level were significantly related to galactosidase α gene mutations, early symptoms, phenotypes, disease severities, specific therapies and long-term complications of Fabry disease. CONCLUSION: The discovery of circular RNA-based and Fabry disease-specific biomarkers may advance future diagnosis of Fabry disease and help to distinguish related phenotypes.