AbstractHuman-induced rapid environmental change is intensifying globally. Urbanization, a major form of human-induced rapid environmental change, alters ecosystems and exposes wildlife to environment...

AbstractHuman self-beliefs hinge on social feedback, but their formation and revision are not solely based on new information. Biases during learning, such as confirming initial expectations, can lead to inaccurate beliefs. This study uses computational modeling to explore how initial expectations about one’s own and others’ abilities and confidence in these beliefs affect processes of belief formation and belief revision in novel behavioral domains. In the first session, participants formed performance beliefs through trial-by-trial feedback. In the second session, feedback contingencies were reversed to promote a revision of beliefs. Results showed that people form and revise beliefs in a confirmatory manner, with lower initial expectations being linked to more negatively biased belief formation and revision, while growing confidence strengthened these beliefs over time. Once formed, these beliefs proved resistant to change even when faced with contradictory feedback. The findings suggest that newly formed beliefs become entrenched and resistant to new, contradictory information in a short period of time. Understanding how self-beliefs are formed, the role that confidence plays in this process, and why established beliefs are difficult to revise can inform the development of interventions aimed at promoting more adaptive learning in educational, clinical, and social contexts.

AbstractHuman activities alter connectivity via resource flows, ecosystem (patch) size, and disturbance regimes. While resource flows can interact with ecosystem size to affect ecosystem function, we ...

AbstractHuman rabies has a very high fatality rate and there have only been about 33 well-documented survivors, defined as survival at six months after onset of clinical rabies. Many have had serious neurological sequelae. After a young patient survived rabies in Milwaukee in 2004, the approach dubbed the “Milwaukee protocol” has been aggressively promoted as an effective therapy. The protocol has included therapeutic (induced) coma, ketamine, ribavirin, and amantadine and details of the protocol have changed over time. Over the last two decades no subsequent detailed reports have documented evidence of efficacy. There have been at least 64 cases with failure of the protocol. Likely critical care, which has been used for over 50 years, is an important component of an aggressive approach. The time has now come to abandon the failed Milwaukee protocol for the therapy of rabies and consider new approaches based our current knowledge of rabies pathogenesis.

AbstractHuman annotation of data, including texts and images, is a bedrock of political science research. Yet, we often fail to consider how the identities of our labelers may systematically affect th...

AbstractHuman immunodeficiency virus (HIV) viral suppression was evaluated after receipt of crushed or dissolved bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) administered via enteral tube during hospitalization. Eighty-nine percent of patients (17/19) were virally suppressed (<200 copies/mL) within 1 year of receiving B/F/TAF via tube, suggesting that administration via tube is a reasonable alternative to changing antiretroviral regimens.

AbstractHuman rabies has a very high fatality rate and there have only been about 34 well-documented survivors, defined as survival at 6 months after onset of clinical rabies. Many have had serious neurological sequelae. After a young patient survived rabies in Milwaukee in 2004, the approach dubbed the “Milwaukee protocol” has been aggressively promoted as an effective therapy. The protocol has included therapeutic (induced) coma, ketamine, ribavirin, and amantadine and details of the protocol have changed over time. Over the past 2 decades, no subsequent detailed reports have documented evidence of efficacy. There have been at least 64 cases with failure of the protocol. Likely critical care, which has been used for more than 50 years, is an important component of an aggressive approach. The time has now come to abandon the failed Milwaukee protocol for the therapy of rabies and consider new approaches based our current knowledge of rabies pathogenesis.

AbstractHuman immunodeficiency virus (HIV) and tuberculosis (TB) co-infection in Nigeria are medical conditions of public health importance because they double the country’s and its citizens’ burden. Several management measures, including artificial intelligence (AI), are crucial for properly diagnosing and preventing these diseases. This study explores the role of AI in managing HIV and TB co-infection in Nigeria. A comprehensive literature search strategy was developed using the keywords “HIV,” “TB,” “co-infection,” “artificial intelligence,” and “Nigeria” across six electronic databases: PubMed, Google Scholar, Cochrane Library, Web of Science, ResearchGate, and African Journals Online. The review focused on articles published between January 2014 and December 2022 to capture recent advancements and trends in AI applications in managing HIV and TB co-infection. Approximately 23%–26% of people with HIV in Nigeria are infected with both TB and HIV. People living with HIV in Nigeria are 26 times more likely to develop TB due to their weakened immune systems. The Early Warning Outbreak Recognition Systems is an AI system used for TB detection that is in practice in Nigeria. However, findings showed that AI models, including deep learning, machine learning, Computer-aided detection, Fuzzy cognitive maps, and Logistic regressions, the Twin model could be helpful in the accurate management of HIV/TB co-infection in Nigeria compared to traditional models, for example, inaccurate classification of radiographs and detection of HIV drug resistance. Despite the importance of AI toward managing these diseases, Nigeria faces challenges, including the unavailability of skilled personnel and AI experts, and the poor quality of the IT infrastructure, which are barriers to integrating AI into healthcare in the country. Strategic collaboration between the Nigerian government, digital health agencies, and healthcare organizations is crucial to implementing AI effectively for the treatment of HIV and TB co-infection in Nigeria. By embracing AI, Nigeria can revolutionize its healthcare system, improve patient outcomes, and address public health challenges such as HIV and TB co-infection.

AbstractHuman Papillomavirus variants are classified into lineages and sublineages based upon their genome sequence, but the impact of variation on the function of encoded proteins is unclear. We used a global panel of natural infection sera and relational antigenic maps to assess HPV33 and HPV45 neutralizing antibody specificity. HPV33 A2, A3, B and C variants were spatially resolved ∼5-fold distant from the A1 reference while HPV45 variants were resolved within ∼2-fold with differences mapped to residues on the capsid surface. These data inform the degree of lineage and sublineage specificity within the natural infection humoral immune response to oncogenic HPV.

ABSTRACTHuman cytomegalovirus (HCMV) remains the leading viral cause of congenital birth defects and a significant pathogen in transplant recipients. The most commonly used drugs inhibit the viral DNA polymerase, but result in severe side effects and the emergence of drug resistance. The terminase inhibitor (letermovir) and viral UL97 kinase inhibitor (maribavir) have improved the CMV armamentarium; however, both select for resistance, and have limited therapeutic indications. We recently identified MLS8091, a highly selective HCMV inhibitor. While its maximal time of HCMV inhibition overlaps with ganciclovir (GCV), it remains active against GCV-resistant strains, suggesting a distinct mechanism involving the CMV replisome. Using resistance selection protocols and next-generation sequencing of mutant viruses that escaped MLS8091 inhibition, we identified point mutations in the HCMV primase (UL70 D486H, D487Y) and the primase-associated factor (UL102 P165S, F275L) of the helicase-primase (H/P) complex. Marker transfer experiments confirmed that UL70 D486H, UL70 D487Y, and UL102 F275L each conferred resistance to MLS8091. UL102 P165S was identified together with UL70 D487Y; however, its independent contribution to resistance was not determined. Sequencing of 17 wild-type and GCV-resistant clinical isolates identified a UL102 polymorphism, A294G, that did not confer reduced susceptibility to MLS8091 upon marker transfer. Among the herpesviruses tested, only guinea pig CMV (GPCMV) was moderately inhibited by MLS8091. Sequence alignment revealed some similarity between GPCMV and HCMV UL70 486–487. In summary, we identified an inhibitor of HCMV replication that acts through a novel mechanism involving the H/P complex, opening new avenues in the development of HCMV-specific drugs.

ABSTRACTHuman immunodeficiency virus (HIV) is largely incurable, due to the presence of a viral reservoir, which primarily consists of resting ... View article...

AbstractHuman papillomavirus (HPV) vaccination of US individuals aged 27–45 years is recommended through shared clinical decision-making. To enable shared decision-making, we used a microsimulation-based state-transition model to develop and validate a risk-prediction model to identify heterosexual men aged 27–45 years at high-risk of acquiring oral HPV-16 infections. A risk model for incident oral HPV-16 infections had good discrimination (AUC = 0.73) and calibration (ratio of expected to the observed number of incident oral HPV-16 infections through age 45 years [E/O] = 1.01) in internal cross-validation. Compared to vaccinating all men aged 27–45, vaccinating 44% of men with highest model-predicted risk would prevent 80% of incident oral HPV-16 infections through age 45 years and reduce the number needed to be vaccinated to prevent 1 infection by 45% (184 vs 100).

ABSTRACTHuman adenovirus (HAdV) is one of the most infectious pathogens that can cause diseases affecting multiple organ systems, posing a significant threat to public health. Currently, there are no specific antiviral therapies available for HAdV infection. In this study, three folate antagonists aminopterin (AMT), pralatrexate (PDX), and methotrexate (MTX) with potent antiviral activity against HAdV infection have been identified through a drug repurposing screening strategy. The three drugs showed broad and potent antiviral efficiency against multiple clinically prevalent HAdV serotypes, including HAdV-B3, HAdV-B7, HAdV-B55, HAdV-C2, and HAdV-C5 with half-maximal effective concentration (EC50) values ranging from 0.31 to 79.74 nM, and PDX further showed similar antiviral efficiency against HAdV-B55 in a 3D lung organoid model (EC50 = 0.51 nM). Mechanistic studies revealed that PDX achieved its antiviral activity through suppression of dihydrofolate reductase (DHFR). These findings support the potential of folate antagonists as repurposed therapeutic agents against HAdV infection and provide a rationale for the development of host-directed antiviral strategies.

ABSTRACTHuman babesiosis is an emerging tick-borne disease caused by Babesia parasites, most notably Babesia microti and Babesia duncani in North America and Babesia divergens in Europe. Infections can be severe or persistent or relapse despite treatment, and current therapeutic options remain limited, underscoring the urgent need for new and effective treatment options. Acridone derivatives originally developed as potent antimalarial agents against multiple life cycle stages of the malaria parasites were evaluated for their antibabesial activity using continuous in vitro culture systems of B. duncani and B. divergens. Lead candidates were assessed for selectivity against human cell lines to establish preliminary safety profiles, and select compounds were further advanced into preliminary in vivo efficacy studies using murine models of B. duncani and B. microti babesiosis to assess their therapeutic potential. A set of prioritized acridone derivatives demonstrated potent in vitro activity against both B. duncani and B. divergens and displayed favorable selectivity indices relative to human cell lines. However, in vivo evaluation of representative compounds did not achieve parasite clearance in murine models. Structure-activity relationship (SAR) analyses highlight key structural features that are critical for maintaining antibabesial potency and offer guidance for further lead optimization. Acridone derivatives show strong in vitro antibabesial activity and represent promising lead chemotypes for therapeutic development. To advance these candidates, future studies focused on optimizing their pharmacokinetic properties and evaluating synergistic combination regimens will be essential for progressing toward effective treatments for human babesiosis.

ABSTRACTHuman norovirus (HNoV) is a major cause of gastroenteritis worldwide, for which no antiviral therapies exist to date. Previously, our lab has demonstrated that both HNoV and murine norovirus (MNV1) are highly dependent on the expression of the Ras-GTPase-activating protein-binding protein 1 (G3BP1), a cellular protein mostly involved in the assembly of stress granules. We, therefore, hypothesize that targeting G3BP1 could be a promising antiviral strategy against noroviruses. Here, we designed a proof-of-concept study to test targeted protein degradation as a mechanism to induce the specific proteolysis of G3BP1 via the proteasome. To do so, we generated a cellular platform for the overexpression of G3BP1 fused to the bacterial protein Halotag (HaloG3BP1). First, we showed that MNV1 replication is restored in G3BP1-knockout (ΔG3BP1) cells complemented with HaloG3BP1. We then used a PROteolysis TArgeting Chimera (PROTAC) directed toward the Halotag (HaloPROTAC) to induce the specific degradation of HaloG3BP1. We further demonstrate that proteolysis of G3BP1 reduces MNV1 replication, leading to a lower infectious virus yield and preventing virus-induced cell death. We also confirmed that the mechanism of HaloPROTAC3 is mediated via the recruitment of Cullin2-VHL E3-ubiquitin ligase. Our findings add to the body of evidence supporting that targeting of the cellular protein G3BP1 can be used as an antiviral approach and validates the use of PROTACs for the efficient and specific degradation of cellular factors as a feasible methodology to combat viral diseases.

AbstractHuman papillomavirus variants are classified into lineages based on their whole genome sequence, but the impact of lineage variation on the structure or function of encoded proteins is unclear. We used a global panel of lineage-specific natural infection sera to assess antibody-binding specificity for lineage-specific L1L2 antigens, and we used these data to create relational antigenic maps. Merging these data with neutralizing antibody data demonstrated similar spatial geometry and revealed dependency on a limited number of amino residues on the capsid surface. These data inform the degree of lineage specificity within the natural infection humoral immune response to oncogenic human papillomaviruses.

ABSTRACTHuman papillomavirus (HPV) is a prevalent sexually transmitted infection linked to genital warts and various cancers. While effective screening methods exist for women, detecting HPV in men remains challenging due to asymptomatic infections and the lack of standardized, non-invasive diagnostic tools. This study aimed to assess the correlation between HPV DNA detection in urine and semen samples from men attending a fertility clinic in Ecuador. This cross-sectional study included 106 sexually active male patients referred for semen analysis at the Fertility Unit of Hospital del Río, Cuenca, Ecuador, between June 2024 and March 2025. Each participant provided paired semen and urine samples, which were analyzed for HPV genotyping. Sociodemographic and behavioral data were also collected. HPV DNA was detected in 15% of semen samples and 9.4% of urine samples. Both low- and high-risk genotypes were identified in semen and urine. In semen samples, high-risk HPV was detected in 9.4% and low-risk HPV in 5.7%. In urine, high-risk HPV was detected in 8.5% and low-risk HPV in 0.9% of samples. Among high-risk genotypes, HPV 58 was the most frequent in urine (20%), while HPV 81 was the most frequent in semen (19%). Genotypes such as HPV 16, 18, 39, 52, and 66 were detected exclusively in semen. Compared with semen sampling, urine sampling showed a sensitivity of 37.5% and a specificity of 95%. Agreement between the two sample types was fair (kappa = 0.39). Although urine sampling offers a non-invasive option, its limited sensitivity restricts its utility as an HPV detection method in asymptomatic men. Semen analysis provides higher detection rates and may be more reliable for HPV screening in male fertility populations.IMPORTANCEThis study addresses a critical knowledge gap regarding human papillomavirus (HPV) detection in men, a topic insufficiently covered in current control and prevention strategies. While screening and vaccination efforts in women have advanced considerably, the absence of standardized, well-accepted, and non-invasive methods for HPV detection in men limits the recognition of their roles as reservoirs and transmitters in the HPV transmission pathway. Evaluating alternative solutions for HPV testing, such as urine and semen sampling, not only contributes valuable scientific knowledge to improve detection in this population but also establishes the foundation for public health policies on male HPV testing. Ultimately, this work supports the goal of reducing global HPV prevalence and its associated diseases.

AbstractHuman hookworm infection is caused by the nematodes Necator americanus, Ancylostoma duodenale, and Ancylostoma ceylanicum. Iron deficiency anemia is the hallmark of chronic, moderate-to-heavy-intensity infections, promoting a vicious poverty cycle. Overt severe and acute life-threatening lower gastrointestinal hemorrhage is an extremely rare manifestation of hookworm infection, as well as finding multiple nematodes attached to the colonic mucosae. This rare hookworm presentation with hematochezia from the colon in a patient living with human immunodeficiency virus highlights the importance of physicians’ awareness of this neglected tropical disease responsible for high morbidity and burden in healthcare systems of endemic regions.

AbstractHuman Papillomavirus variants are classified into lineages based upon their whole genome sequence, but the impact of lineage variation on the structure or function of encoded proteins is unclear. We used a global panel of lineage-specific natural infection sera to assess antibody binding specificity for lineage-specific L1L2 antigens and used these data to create relational antigenic maps. Merging these data with neutralizing antibody data demonstrated similar spatial geometry and support dependency on a limited number of amino residues on the capsid surface. These data inform the degree of lineage specificity within the natural infection humoral immune response to oncogenic HPVs.

AbstractHuman immunodeficiency virus (HIV) and hepatitis B virus (HBV) coinfection is common due to similar routes of transmission. Even though antiretroviral therapy (ART) regimens containing tenofovir suppressed HIV and HBV effectively, slower CD4+ T-cell recovery was still reported in people with HIV/HBV coinfection. Here, a large and longitudinal treated HIV/AIDS cohort including HBV-coinfected individuals was enrolled, and people with HIV/HBV coinfection were categorized into groups with or without deletion mutants based on the PreS sequence of HBV in plasma at treatment baseline. Subsequent to >4 years of ART, longitudinal CD4+ T-cell counts and CD4/CD8 ratios were consistently lower and inflammatory cytokines such as IL-10, IL-18, IP-10, MCP-1, and IFN-γ were significantly higher in the group with PreS deletion mutants compared to the group without PreS deletion mutants; in addition, either HIV or HBV in plasma was consistently undetectable during ART. HBV PreS deletion mutants in blood at baseline could be an important predictor for delayed immune reconstitution in people with HIV/HBV coinfection, related to enhanced inflammatory response.

AbstractHuman metapneumovirus (hMPV) is a nonsegmented, single-stranded, negative-sense RNA virus belonging to the Pneumoviridae family. It was first identified in 2001 in the nasopharyngeal secretions of 28 Dutch children with bronchiolitis collected over a 20-year period. hMPV exhibited paramyxovirus-like morphology with many genetic similarities to respiratory syncytial virus. hMPV has 1 serotype with 2 major subgroups (A and B) and 5 sublineages (A1, A2a, A2b, B1, and B2). In the wake of its discovery, a wealth of observational research has demonstrated global circulation of hMPV causing a wide spectrum of clinical disease. It accounts for 2% to 7% of all symptomatic respiratory infections in children who are universally infected by age 5 years. However, long-lasting immunity to hMPV is incomplete, and reinfections occur throughout life. With increasing age, the impact of hMPV is greater. Adult patients with hMPV infection may develop pneumonia, resulting in hospitalization and severe outcomes, such as intensive care unit admission or mechanical ventilation. Risk factors for severe hMPV are still being defined but include profound immunosuppression (20%), congestive heart failure (25%), and severe chronic obstructive pulmonary disease (20%). In this supplement, several studies from diverse geographic and clinical locations explore the pathogenesis, epidemiology, and clinical profile of hMPV as compared with respiratory syncytial virus and/or influenza and examine the impact of risk factors for severe disease, including age and chronic comorbid conditions. These data are needed to provide the basis for understanding who might benefit from future hMPV vaccines.

AbstractHuman bocavirus 1 (HBoV1) causes mild to life-threatening respiratory tract infections in children but may persist in the airways for months. Currently used polymerase chain reaction may thus lead to false diagnoses and irrelevant codetections. Our aim was to differentiate acute infections from persistent shedding by pretreatment of airway or serum samples with an endonuclease, followed by polymerase chain reaction (ePCR). We show that HBoV1 DNA is protected by a capsid in the acute phase but not in persistent shedding, and we provide proof of concept of a novel test that may be applied in routine diagnosis of acute HBoV1 respiratory tract infection for more accurate results.