Substitution load revisited: a high proportion of deaths can be selective.

Haldane's Dilemma refers to the concern that the need for many "selective deaths" to complete a substitution (i.e. selective sweep) creates a speed limit to adaptation.

'It is scary to pause treatment': perspectives on HIV cure-related research and analytical treatment interruptions from women diagnosed during acute HIV in Durban, South Africa.

Background: HIV remains a major challenge in KwaZulu-Natal, South Africa, particularly for young women who face disproportionate risks and barriers to prevention and treatment. Most HIV cure trials, however, occur in high-income countries.

Objective: To examine the perspectives of young women diagnosed with acute HIV in a longitudinal study, focusing on their perceptions on ATI-inclusive HIV cure trials and the barriers and facilitators to participation.

2024 White Paper on Recent Issues in Bioanalysis: Three Way-Cross Validation; Urine Clinical Analysis; Automated Methods; Regulatory Queries on Plasma Protein Binding; Automated Biospecimen Management; ELN Migration; Ultra-Sensitivity Mass Spectrometry ( - Recommendations on Advanced Strategies for Mass Spectrometry Assays, Chromatography, Sample Preparation and BMV/Regulated Bioanalysis - Regulatory Agencies' Inputs on Regulated Bioanalysis/BMV).

The 18 Workshop on Recent Issues in Bioanalysis (18 WRIB) took place in San Antonio, TX, USA on May 6-10, 2024. Over 1100 professionals representing pharma/biotech companies, CROs, and multiple regulatory agencies convened to actively discuss the most current topics of interest in bioanalysis. The 18 WRIB included 3 Main Workshops and 7 Specialized Workshops that together spanned 1 week to allow an exhaustive and thorough coverage of all major issues in bioanalysis of biomarkers, immunogenicity, gene therapy, cell therapy and vaccines.

2024 White Paper on Recent Issues in Bioanalysis: Evolution of Immunogenicity Assessment beyond ADA/NAb; Regulated Genomic/NGS Assays; Hypersensitivity Reactions; Minimum Noise Reduction; False Positive Range; Modernized Vaccine Approaches; NAb/TAb Correlation - Recommendations on Advanced Strategies for Molecular Assays and Immunogenicity of Gene Therapy, Cell Therapy, Vaccine; Biotherapeutics Immunogenicity Assessment & Clinical Relevance - Regulatory Agencies' Input on Immunogenicity/Technologies of Biotherapeutics, Gene, Cell & Vaccine Therapies).

The 18 Workshop on Recent Issues in Bioanalysis (18 WRIB) took place in San Antonio, TX, USA on May 6-10, 2024. Over 1100 professionals representing pharma/biotech companies, CROs, and multiple regulatory agencies convened to actively discuss the most current topics of interest in bioanalysis. The 18 WRIB included 3 Main Workshops and 7 Specialized Workshops that together spanned 1 week to allow an exhaustive and thorough coverage of all major issues in bioanalysis of biomarkers, immunogenicity, gene therapy, cell therapy and vaccines.

2024 White paper on recent issues in bioanalysis: Impact of LDT in US and IVDR in EU; AI/ML for High Parameter Flow Cytometry; The rise of Olink Technology; CDx for AAV Gene Therapies; Integrative Bioanalysis by Multiple Platforms; Super Sensitive ADA/NAb LBA ( - Recommendations on Advanced Strategies for Biomarkers, IVD/CDx Assays (BAV), Cell Based Assays (CBA), and Ligand-Binding Assays (LBA) - Regulatory Agencies' Input on Biomarkers, IVD/CDx, and Biomarker Assay Validation).

The 18th Workshop on Recent Issues in Bioanalysis (18th WRIB) took place in San Antonio, TX, USA on May 6-10, 2024. Over 1100 professionals representing pharma/biotech companies, CROs, and multiple regulatory agencies convened to actively discuss the most current topics of interest in bioanalysis. The 18th WRIB included 3 Main Workshops and 7 Specialized Workshops that together spanned 1 week to allow an exhaustive and thorough coverage of all major issues in bioanalysis of biomarkers, immunogenicity, gene therapy, cell therapy and vaccines.

The Impact of Optical Undersampling on the Ca Signal Resolution in Ca Imaging of Spontaneous Neuronal Activity.

Background: In neuroscience, Ca imaging is a prevalent technique used to infer neuronal electrical activity, often relying on optical signals recorded at low sampling rates (3 to 30 Hz) across multiple neurons simultaneously. This study investigated whether increasing the sampling rate preserves critical information that may be missed at slower acquisition speeds.

Methods: Primary neuronal cultures were prepared from the cortex of newborn pups.

Additive Effects of Glutathione in Improving Antibiotic Efficacy in HIV- Co-Infection in the Central Nervous System: A Systematic Review.

Background: HIV and tuberculosis (TB) co-infection poses a significant health challenge, particularly when involving the central nervous system (CNS), where it leads to severe morbidity and mortality. Current treatments face challenges such as drug resistance, immune reconstitution inflammatory syndrome (IRIS), and persistent inflammation. Glutathione (GSH) has the therapeutic potential to enhance treatment outcomes by improving antibiotic efficacy, reducing inflammation, and mitigating immune dysfunction.

Flunarizine as a Candidate for Drug Repurposing Against Human Pathogenic Mammarenaviruses.

Lassa fever (LF), a viral hemorrhagic fever disease with a case fatality rate that can be over 20% among hospitalized LF patients, is endemic to many West African countries. Currently, no vaccines or therapies are specifically licensed to prevent or treat LF, hence the significance of developing therapeutics against the mammarenavirus Lassa virus (LASV), the causative agent of LF. We used in silico docking approaches to investigate the binding affinities of 2015 existing drugs to LASV proteins known to play critical roles in the formation and activity of the virus ribonucleoprotein complex (vRNP) responsible for directing replication and transcription of the viral genome.

Repurposing Drugs for Synergistic Combination Therapies to Counteract Monkeypox Virus Tecovirimat Resistance.

The ongoing monkeypox (mpox) disease outbreak has spread to multiple countries in Central Africa and evidence indicates it is driven by a more virulent clade I monkeypox virus (MPXV) strain than the clade II strain associated with the 2022 global mpox outbreak, which led the WHO to declare this mpox outbreak a public health emergency of international concern. The FDA-approved small molecule antiviral tecovirimat (TPOXX) is recommended to treat mpox cases with severe symptoms, but the limited efficacy of TPOXX and the emergence of TPOXX resistant MPXV variants has challenged this medical practice of care and highlighted the urgent need for alternative therapeutic strategies. In this study we have used vaccinia virus (VACV) as a surrogate of MPXV to assess the antiviral efficacy of combination therapy of TPOXX together with mycophenolate mofetil (MMF), an FDA-approved immunosuppressive agent that we have shown to inhibit VACV and MPXV, or the N-myristoyltransferase (NMT) inhibitor IMP-1088.

Perspective on the 65-Year Anniversary of the Discovery of Cytomegalovirus.

This volume presents research and reviews bringing forward new insights into cytomegalovirus (CMV) pathogenesis and biology; CMV is a herpesvirus that has long been recognized as being medically significant [...

Impact of Combined Antiretroviral Treatment (cART) on Latent Cytomegalovirus Infection.

Cytomegalovirus infections and reactivations are more frequent in people living with HIV (PLWH) and have been associated with increased risk of HIV progression and immunosenescence. We explored the impact of combination antiretroviral therapy (cART) on latent CMV infection in 225 young adults parenterally infected with HIV during childhood. Anti-CMV IgG antibodies were present in 93.

eEF-2K Deficiency Boosts the Virus-Specific Effector CD8 T Cell Responses During Viral Infection.

In this study, we revealed a critical role of eukaryotic elongation factor-2 kinase (eEF-2K), a negative regulator of protein synthesis, in regulating T cells during vaccinia virus (VACV) infection. We found that eEF-2K-deficient (eEF-2K⁻/⁻) mice exhibited a significantly higher proportion of VACV-specific effector CD8 T cells without compromising the development of VACV-specific memory CD8 T cells. RNA sequencing demonstrated that eEF-2K⁻/⁻ VACV-specific effector CD8 T cells had enhanced functionality, which improves their capacity to combat viral infection during the effector phase.

Employing the Oncolytic Vesicular Stomatitis Virus in Cancer Virotherapy: Resistance and Clinical Considerations.

Vesicular Stomatitis Virus (VSV) has emerged as a promising candidate for various clinical applications, including vaccine development, virus pseudotyping, and gene delivery. Its broad host range, ease of propagation, and lack of pre-existing immunity in humans make it ideal for therapeutic use. VSV's potential as an oncolytic virus has garnered attention; however, resistance to VSV-mediated oncolysis has been observed in some cell lines and tumor types, limiting its effectiveness.

Effect of Fusion to the LTB Carrier Protein on Coronavirus Spike Protein Vaccine Candidates Produced in Maize.

Coronaviruses continue to disrupt health and economic productivity worldwide. Porcine epidemic diarrhea virus (PEDV) is a devastating swine disease and SARS-CoV-2 is the latest coronavirus to infect the human population. Both viruses display a similar spike protein on the surface that is a target of vaccine development.

Identifying Allosteric Small-Molecule Binding Sites of Inactive NS2B-NS3 Proteases of Pathogenic .

Dengue, West Nile, Zika, Yellow fever, and Japanese encephalitis viruses persist as significant global health threats. The development of new therapeutic strategies based on inhibiting essential viral enzymes or viral-host protein interactions is problematic due to the fast mutation rate and rapid emergence of drug resistance. This study focuses on the NS2B-NS3 protease as a promising target for antiviral drug development.

Correction: Razzaq et al. Development of Cephradine-Loaded Gelatin/Polyvinyl Alcohol Electrospun Nanofibers for Effective Diabetic Wound Healing: In-Vitro and In-Vivo Assessments. 2021, , 349.

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Development of Spray-Dried Micelles, Liposomes, and Solid Lipid Nanoparticles for Enhanced Stability.

Micelles, liposomes, and solid lipid nanoparticles (SLNs) are promising drug delivery vehicles; however, poor aqueous stability requires post-processing drying methods for maintaining long-term stability. The objective of this study was to compare the potential of lipid-based micelles, liposomes, and SLNs for producing stable re-dispersible spray-dried powders with trehalose or a combination of trehalose and L-leucine. This study provides novel insights into the implementation of spray drying as a technique to enhance long-term stability for these lipid-based nanocarriers.

Investigations of Long-Acting Formulations in Children, Adolescents, and Pregnant Women: A Systematic Review.

Long-acting and extended-release drug delivery strategies have greatly improved treatment for a variety of medical conditions. Special populations, specifically infants, children, young people, and pregnant and postpartum women, could greatly benefit from access to these strategies but are often excluded from clinical trials. We conducted a systematic review of all clinical studies involving the use of a long-acting intramuscular injection or implant in infants, children, young people, and pregnant and postpartum people.

Single Exposure to Low-Intensity Focused Ultrasound Causes Biphasic Opening of the Blood-Brain Barrier Through Secondary Mechanisms.

The blood-brain barrier (BBB) is selectively permeable, but it also poses significant challenges for treating CNS diseases. Low-intensity focused ultrasound (LiFUS), paired with microbubbles is a promising, non-invasive technique for transiently opening the BBB, allowing enhanced drug delivery to the central nervous system (CNS). However, the downstream physiological effects following BBB opening, particularly secondary responses, are not well understood.

Infection in Lemon Influences Host Preference of the Citrus Whitefly by Affecting the Host Metabolite Composition.

Plant viruses have been known to alter host metabolites that influence the attraction of insect vectors. Our study investigated whether (CYVCV) infection influences vector attractiveness, focusing on the citrus whitefly, (Ashmead). Free choice assays showed that citrus whiteflies exhibited a preference for settling on CYVCV-infected lemon plants versus healthy control plants.

Central Asia Cold Case: Siberian Pine Fingers New Suspects in Growth Decline CA 1700 CE.

Tree-ring width chronologies of Du Tour from near the upper treeline in the Western Sayan, Southern Siberia are found to have an exceptional (below mean-3SD) multi-year drop near 1700 CE, highlighted by the seven narrowest-ring years in a 1524-2022 regional chronology occurring in the short span of one decade. Tree rings are sometimes applied to reconstruct seasonal air temperatures; therefore, it is important to identify other factors that may have contributed to the growth suppression. The spatiotemporal scope of the "nosedive" in tree growth is investigated with a large network of (14 sites) and Ledeb.

Evolutionary Trajectories of Shoots vs. Roots: Plant Volatile Metabolomes Are Richer but Less Structurally Diverse Belowground in the Tropical Tree Genus .

The breadth and depth of plant leaf metabolomes have been implicated in key interactions with plant enemies aboveground. In particular, divergence in plant species chemical composition-amongst neighbors, relatives, or both-is often suggested as a means of escape from insect herbivore enemies. Plants also experience strong pressure from enemies such as belowground pathogens; however, little work has been carried out to examine the evolutionary trajectories of species' specialized chemistries in both roots and leaves.

Adherence and Body Weight with Daily Avocado Consumption Among Latina Women of the Habitual Diet and Avocado Trial (HAT).

The aim of this study was to examine the adherence, changes in weight, and, waist circumference associated with the daily consumption of a culturally preferred food, namely an avocado, among Hispanic/Latina females in the Habitual Diet and Avocado Trial (HAT). HAT was a multisite, randomized controlled trial conducted between 2018 and 2020. Participants in the Avocado-Supplemented Diet Group were provided with and instructed to consume one avocado/day (~2.

A Pilot Study Exploring the Relationship Between Milk Composition and Microbial Capacity in Breastfed Infants.

Background: Maternal obesity may contribute to childhood obesity in a myriad of ways, including through alterations of the infant gut microbiome. For example, maternal obesity may contribute both directly by introducing a dysbiotic microbiome to the infant and indirectly through the altered composition of human milk that fuels the infant gut microbiome. In particular, indigestible human milk oligosaccharides (HMOs) are known to shape the composition of the infant gut microbiome.