2024年 · 第04卷第02期

Background: Human immunodeficiency virus type 1 (HIV-1) remains a persistent global health challenge. Therefore, a continuous exploration of novel therapeutic strategies is essential. A comprehensive understanding of how HIV-1 utilizes the cellular metabolism machinery for replication can provide insights into new therapeutic approaches. Methods: In this study, we performed a flux balance analysis using a genome-scale metabolic model (GEM) integrated with an HIV-1 viral biomass objective function to identify potential targets for anti-HIV-1 interventions. We generated a GEM by integrating an HIV-1 production reaction into CD4+ T cells and optimized for both host and virus optimal states as objective functions to depict metabolic profiles of cells in the status for optimal host biomass maintenance or for optimal HIV-1 virion production. Differential analysis was used to predict biochemical reactions altered optimal for HIV-1 production. In addition, we conducted in silico simulations involving gene and reaction knock-outs to identify potential anti-HIV-1 targets, which were subsequently validated by human phytohemagglutinin (PHA) blasts infected with HIV-1. Results: Differential analysis identified several altered biochemical reactions, including increased lysine uptake and oxidative phosphorylation (OXPHOS) activities in the virus optima compared with the host optima. In silico gene and reaction knock-out simulations revealed de novo pyrimidine synthesis, and OXPHOS could serve as potential anti-HIV-1 metabolic targets. In vitro assay confirmed that targeting OXPHOS using metformin could suppress the replication of HIV-1 by 56.6% (385.4 ± 67.5 pg/mL in the metformin-treated group vs. 888.4 ± 32.3 pg/mL in the control group, P < 0.001). Conclusion: Our integrated host-virus genome-scale metabolic study provides insights on potential targets (OXPHOS) for anti-HIV therapies.

Background: Malaria remains a significant public health concern in Ghana, with varying risk levels across different geographical areas. Malaria affects millions of people each year and imposes a substantial burden on the health care system and population. Accurate risk estimation and mapping are crucial for effectively allocating resources and implementing targeted interventions to identify regions with disease hotspots. This study aimed to identify regions exhibiting elevated malaria risk so that public health interventions can be implemented, and to identify malaria risk predictors that can be controlled as part of public health interventions for malaria control. Methods: The data on laboratory-confirmed malaria cases from 2015 to 2021 were obtained from the Ghana Health Service and Ghana Statistical Service. We studied the spatial and spatiotemporal patterns of the relative risk of malaria using Bayesian spatial and spatiotemporal models. The malaria risk for each region was mapped to visually identify regions with malaria hotspots. Clustering and heterogeneity of disease risks were established using correlated and uncorrelated structures via the conditional autoregressive and Gaussian models, respectively. Parameter estimates from the marginal posterior distribution were estimated within the Integrated Nested Laplace Approximation using the R software. Results: The spatial model indicated an increased risk of malaria in the North East, Bono East, Ahafo, Central, Upper West, Brong Ahafo, Ashanti, and Eastern regions. The spatiotemporal model results highlighted an elevated malaria risk in the North East, Upper West, Upper East, Savannah, Bono East, Central, Bono, and Ahafo regions. Both spatial and spatiotemporal models identified the North East, Upper West, Bono East, Central, and Ahafo Regions as hotspots for malaria risk. Substantial variations in risk were evident across regions (H = 104.9, P < 0.001). Although climatic and economic factors influenced malaria infection, statistical significance was not established. Conclusions: Malaria risk was clustered and varied among regions in Ghana. There are many regions in Ghana that are hotspots for malaria risk, and climate and economic factors have no significant influence on malaria risk. This study could provide information on malaria transmission patterns in Ghana, and contribute to enhance the effectiveness of malaria control strategies.

Antimicrobial resistance is a global concern that has led to millions of deaths worldwide. Genetic changes occur naturally in pathogens such as viruses, bacteria, parasites, and fungi. To overcome these concerns, there is a need to develop a new generation of antimicrobials. In an effort to encourage innovation, both the United States (US) and the European Union have introduced exclusivity programs. The US offered 5 years of additional nonpatent exclusivity for Qualified Infectious Disease Products under the Generating Antibiotic Incentives Now Act. In parallel, the European Commission offers a patent extension of 12 months across Europe (EU) countries or the option to sell the vouchers to other pharmaceutical companies through transferable exclusivity extension vouchers. This review focuses on the most important innovative strategies of antibiotic development the drug approvals, their mode of action, spectra of activity, and targeting of microorganisms, in past 5 years were mentioned, and discusses how to overcome the challenges of drug approval under antibiotic exclusivity in the US and EU, which will benefit the companies to develop novel drugs in several nations.

The dynamics of COVID-19 and mucormycosis reveal a complex interplay of genetic factors that influence the susceptibility, severity, and immune responses. COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), exhibits an increased incidence of mucormycosis, particularly in individuals with comorbidities or corticosteroid therapy. Mucormycosis is a fungal infection that affects the sinuses, orbits, and lungs and demands timely intervention with antifungal medications and surgery because of its life-threatening nature. Research on the genetic underpinnings of this intersection has unveiled key insights into the pathogenicity of Mucorales. Breakthroughs in genetic tools have exposed virulence factors, such as the CotH protein family and high-affinity iron-uptake mechanisms. Genetic susceptibility is a pivotal element in identifying individuals at risk of developing COVID-19, facilitating early detection, and allowing for personalized treatment strategies. DPP9, MIF, and TYK2 are among the genes implicated in COVID-19 severity, emphasizing the intricate relationship between genetic makeup and viral response. The genetic landscape extends to viral entry mechanisms, thereby affecting infection efficiency. Specific polymorphisms in genes such as IFNAR2, OAS3, and TYK2 are associated with COVID-19 severity, indicating shared genetic bases between severe and hospitalized cases. Mucormycosis is genetically predisposed, particularly in immunocompromised individuals. The challenge lies in understanding the genetic factors influencing susceptibility and offering insights into pathogenesis and potential therapeutic avenues. Organ transplantation adds another layer, increasing susceptibility to infections such as COVID-19 and mucormycosis. The impact of immunosuppression on COVID-19 severity remains elusive, necessitating ongoing research on the immunological mechanisms. Despite the challenges posed by emerging SARS-CoV-2 variants, the intricate connection between genetic factors and the interplay of COVID-19 and mucormycosis presents an opportunity for personalized treatment, targeted interventions, and refined public health strategies.

Emphysematous gastritis (EG) is a rare form of gastritis characterized by gastric wall pneumatosis. It is associated with a high mortality rate. Our case report describes a patient with a history of atrial fibrillation treated with apixaban, prior stroke, and schizoaffective disorder who showed epigastric tenderness on examination. However, no peritonitis signs were recorded, and laboratory values revealed high lactate levels and the presence of adenovirus F40/41. Abdominal computed tomography scan showed extensive portal venous gas in the left hepatic lobe of the liver, as well as pneumatosis involving the entire stomach, indicating EG. The diagnosis was histologically confirmed and initially managed medically, which proved inefficacious, necessitating surgical intervention in the form of a laparotomy and esophagojejunostomy with Roux-en-Y reconstruction. This case report suggests a potential association between EG and adenovirus F40/41-induced gastroenteritis, thereby emphasizing the challenging nature of EG. It underscores the need for comprehensive research to enhance our understanding of its underlying causes and effective treatment strategies.