Search Results (394)

Background: Valproic acid (VPA) is a medication used to treat epilepsy, bipolar disorder, and migraine. If taken during pregnancy, it can cause neural tube defects (NTDs) and leads to offspring ASD behavioral phenotype. It has recently been found that early postnatal VPA exposure can also induce the ASD phenotype, but the details of model production and intervention still need further investigation. Dimethylmalonic acid (DMM), a competitive inhibitor of succinate dehydrogenase, blocks the key element succinate of OXPHOS, decreasing the secretion of anti-inflammatory cytokines and ROS production. However, it is still unclear whether DMM is involved in the repair of developmental brain injuries. Objectives: The aim of this study was to evaluate the intervention effect and optimal dosage of DMM on behavioral phenotypes using a neonatal mouse VPA autism model. Methods: This experiment consists of two parts. The first part observed the effects of different concentrations of VPA on the development and neurobehavioral phenotype of mice. The second part determined the intervention effect of DMM on a developmental VPA autism model and determined the optimal therapeutic dose. Results: We found that the 40 mg/mL concentration had a greater impact on the neural reflex damage in mice. Moreover, DMM treatment can partially improve the neurobehavioral damage in the VPA model, and 20 mg/kg has the best intervention effect. Conclusions: This study provides valuable model construction data for further exploring the mechanism of DMM treatment for an ASD phenotype induced by VPA exposure in neonates. Full article

Energetic complexes with multi-component architectures represent a frontier in contemporary energetic materials research. In this work, we report a novel high-energy complex—bis(5-nitro-3-(dinitromethyl)-1,2,4-triazole)-hexaamminecobalt(III) [[Co(NH₃)₆](HNTD)(NTD)·H₂O]—that is synthesized using the oxygen-rich energetic compound 5-nitro-3-(trinitromethyl)-1,2,4-triazole (HNTF) as a precursor. Compared with metallic H₂NTD salts, [Co(NH₃)₆](HNTD)(NTD)·H₂O exhibits a higher density (ρ = 1.886 g cm⁻³) and unrivaled energy properties (V_d = 8030 m s⁻¹ and P = 29.2 GPa). The formation of a dense hydrogen-bonding network—mediated by ammonium groups in the [Co(NH₃)₆]³⁺ core and nitro groups of HNTD⁻ and NTD²⁻—significantly dampens the mechanical sensitivity (IS = 10 J and FS = 140 N). These combined attributes establish [Co(NH₃)₆](HNTD)(NTD)·H₂O as a promising high-energy-density material (HEDM), offering critical insights for the design of next-generation energetic complexes. Full article

The burden of mental health among individuals affected by skin-neglected tropical diseases (skin-NTDs) has increased significantly, prompting systemic measures to improve their mental health and well-being. Healthcare professionals have instrumental roles to play in this area in terms of integrating mental health into the existing primary and community healthcare services for skin-NTDs. The current study investigates the readiness of healthcare professionals for integrated healthcare, barriers to mental health service delivery and the professional development needs for mental health service delivery. A total of 252 healthcare professionals recruited from Nkwanta North and South Districts in the Oti Region of Ghana participated in the study by completing a set of questionnaires measuring the above variables, in addition to demographic factors. Descriptive statistics were used to summarize the study variables while Pearson Moment Product Correlation was used to investigate the relationship between continuous study variables. Confirmatory factor analysis (CFA) was conducted to elucidate the factorial validity of the study measures. Structural Equation Modeling (SEM) was used to examine the association between the variables and the mediating effects of professional development needs. The results showed that over 50% of the participants encountered several barriers in their attempt to provide mental health services to patients, and over 80% of them requested training and capacity building in mental health. CFA supports a two-factor structure of the readiness scale and one-factor structure of mental health barrier and professional development needs scales. SEM revealed a significant relationship between readiness for integrated healthcare, mental health barriers and professional development needs (p < 0.05). Further SEM analysis revealed that professional development needs significantly mediated the relationship between readiness for integrated healthcare and mental health barriers (p < 0.05). Addressing mental health professional development needs of healthcare professionals will help ensure their readiness for integrated healthcare for people with skin-NTDs. Full article

LTR retrotransposons are widespread genomic elements that significantly impact genome structure and function. In Arabidopsis thaliana, the EVD LTR retrotransposon encodes a GAG protein essential for retrotransposon particle assembly. Here, we present a comprehensive analysis of the structural features, intracellular localization, and transcriptomic effects of the EVD GAG (evdGAG) protein. Using AlphaFold3, we identified canonical capsid (CA-NTD and CA-CTD) and nucleocapsid (NC) domains, with predicted disordered regions likely facilitating oligomerization. Transient expression of GFP-tagged evdGAG in protoplasts of A. thaliana and distant plant species (Nicotiana benthamiana and Helianthus annuus) revealed the formation of multiple large cytoplasmic aggregates resembling retrosomes, often localized near the nucleus. Stable overexpression of evdGAG in wild-type and ddm1 mutant backgrounds induced significant transcriptomic changes, including up-regulation of stress response and defense-related genes and downregulation of photosynthesis and chloroplast-associated pathways. Importantly, genes linked to stress granule formation were also up-regulated, suggesting a role for evdGAG in modulating cellular stress responses. Our findings provide novel insights into the cellular and molecular properties of plant retrotransposon GAG proteins and their influence on host gene expression. Full article

Background/Objectives: Folic acid (FA) supplementation can effectively reduce the occurrence of neural tube defects (NTDs). Vitamin B12 is involved in folate metabolism; however, studies have not reached a definitive conclusion on the association between vitamin B12 and NTDs independent of folate levels. A systematic review and meta-analysis were performed to summarize existing research and investigate the effect of vitamin B12 on NTDs. Methods: Studies were systematically searched in PubMed, Web of Science, Embase, and Cochrane, published before 1 March 2024. Standardized mean difference (SMD) with 95% confidence interval (CI) was employed to assess the association between maternal vitamin B12 in blood and NTDs. Results: A total of 38 studies were included, with a total of 2316 NTDs and 4298 controls, covering 14 countries worldwide. Compared with the non-NTD group, the NTD group exhibited a lower vitamin B12 level [SMD = −0.23, 95% CI (−0.32, −0.14), p < 0.001, I² = 58.3%] with a statistically significant difference. Additionally, there was a significant association between maternal vitamin B12 concentration and NTDs when there was no significant difference in folate between the NTD and control groups [SMD: −0.19, 95% CI (−0.28, −0.10)]. Conclusions: Vitamin B12 supplement is also essential for the prevention of NTDs besides folic acid. Monitoring vitamin B12 concentration among pregnant women and considering appropriate supplementation with a combination of vitamin B12 and folic acid could be explored. Full article

Background: Group A Streptococcus (GAS) is a major human pathogen associated with serious diseases. Evaluating immune responses against GAS vaccines—immunogenicity, quality, and efficacy—is complicated by interference from co-infections, like Staphylococcus aureus (S. aureus). We aimed to evaluate peptide-based GAS vaccines in mice for antisera efficacy against standard and mutant GAS strains and to assess immunological methods under co-infection conditions. Methods: Female C57BL/6 mice were infected with S. aureus and immunized with various M-protein-derived peptide antigens: J8, J8i, J8i-J8i, and the native p145 sequence. Two novel, conserved M-protein-derived antigens (NTD and CTD2) were also evaluated. Enzyme-linked immunosorbent assays (ELISAs) were used to assess immunogenicity and GAS-specific antibody responses. Peptide antigens were either conjugated to or physically mixed with the PADRE T-helper epitope and tested for enhanced antisera immunogenicity and opsonic efficacy. Result: ELISA against the immunizing peptides as coating antigens reflected the immunogenicity, while p145-based ELISA correlated with GAS-specific antibody titres without S. aureus interference for J8-based vaccines. Immunogenicity ranked J8 > J8i ≈ J8i-J8i > p145. NTD and CTD2 antisera demonstrated opsonic activity, indicating protective potential. PADRE–J8 conjugates significantly enhanced antibody magnitude and quality, producing strong opsonic bactericidal responses against both standard and p145-mutant GAS strains. PADRE–J8i was effective only against standard strains. This is the first report to suggest at least two B-cell epitopes within the J8i peptide. Conclusion: These findings support the diagnostic utility of p145, NTD, and CTD2 under co-infection settings, and the vaccine potential of J8, NTD, and CTD2, particularly when conjugated to a T helper for enhanced antigen presentation. Full article

Soil-transmitted helminths (STHs) are parasitic nematodes that infect humans, particularly in tropical and subtropical regions, where they contribute substantially to neglected tropical diseases (NTDs). Among them, hookworms (Ancylostoma duodenale, Necator americanus and Ancylostoma ceylanicum) cause substantial morbidity, leading to anaemia, malnutrition, and developmental impairment. Despite the global impact of hookworm disease, genomic research on A. duodenale has lagged behind that of other hookworms, limiting comparative and molecular biological investigations. Here, we report the first chromosome-level reference genome of A. duodenale, assembled from a single adult specimen archived in ethanol at −20 °C for more than 27 years. Using third-generation sequencing (PacBio Revio, Menlo Park, CA, USA, Oxford Nanopore, Oxford, UK), Hi-C scaffolding, and advanced computational tools, we produced a high-quality 319 Mb genome, filling a critical gap in hookworm genomics. Comparative analyses with N. americanus and the related, free-living nematode Caenorhabditis elegans provided new insights into genome organisation, synteny, and specific adaptations. While A. duodenale exhibited strong chromosomal synteny with N. americanus, its limited synteny with C. elegans highlights its distinct parasitic adaptations. We identified 20,015 protein-coding genes, including conserved single-copy orthologues (SCOs) linked to host–pathogen interactions, immune evasion and essential biological processes. The first comprehensive secretome analysis of A. duodenale revealed a diverse repertoire of excretory/secretory (ES) proteins, including immunomodulatory candidates predicted to interact with host structural and immune-related proteins. This study advances hookworm genomics, establishes a basis for the sequencing of archival specimens, and provides fundamental insights into the molecular biology of A. duodenale. The genomic resource for this hookworm species creates new opportunities for diagnostic, therapeutic, and vaccine development within a One Health framework. It complements recent epidemiological work and aligns with the WHO NTD roadmap (2021–2030) and Sustainable Development Goal 3.3. Full article

Background/Objectives: Identification and characterization of broadly neutralizing monoclonal antibodies from individuals exposed to SARS-CoV-2, either by infection or vaccination, can inform the development of next-generation vaccines and antibody therapeutics with pan-SARS-CoV-2 protection. Methods: Through single B cell sorting and RT-PCR, monoclonal antibodies (mAbs) were isolated from a donor who experienced a BA.5 or BF.7 breakthrough infection after three doses of inactivated vaccines. Their binding and neutralizing capacities were measured with ELISA and a pseudovirus-based neutralization assay, respectively. Their epitopes were mapped by competition ELISA and site-directed mutation. Results: Among a total of 67 spike-specific mAbs cloned from the donor, four mAbs (KXD643, KXD652, KXD681, and KXD686) can neutralize all tested SARS-CoV-2 variants from wild-type to KP.3. Moreover, KXD643, KXD652, and KXD681 belong to a clonotype encoded by IGHV5-51 and IGKV1-13 and recognize the cryptic and conserved RBD-8 epitope on the receptor-binding domain (RBD). In contrast, KXD686 is encoded by IGHV1-69 and IGKV3-20 and targets a conserved epitope (NTD Site iv) outside the antigenic supersite (NTD Site i) of the N-terminal domain (NTD). Notably, antibody cocktails containing these two groups of mAbs can neutralize SARS-CoV-2 more potently due to synergistic effects. In addition, bispecific antibodies derived from KXD643 and KXD686 demonstrate further improved neutralizing potency compared to antibody cocktails. Conclusions: These four mAbs can be developed as candidates of pan-SARS-CoV-2 antibody therapeutics through further antibody engineering. On the other hand, vaccines designed to simultaneously elicit neutralizing antibodies towards RBD-8 and NTD Site iv have the potential to provide pan-SARS-CoV-2 protection. Full article

Schistosomiasis, a neglected tropical disease caused by parasitic worms of the genus Schistosoma and transmitted through freshwater snails, affects over 200 million people worldwide. Climate change, through rising temperatures, altered rainfall patterns, and extreme weather events, is influencing the distribution and transmission dynamics of schistosomiasis. This scoping review examines the impact of climate change on schistosomiasis transmission and its implications for disease control. This review aims to synthesize current knowledge on the influence of climate variables (temperature, rainfall, water bodies) on snail populations, transmission dynamics, and the shifting geographic range of schistosomiasis. It also explores the potential effects of climate adaptation policies on disease control. The review follows the Arksey and O’Malley framework and PRISMA-ScR guidelines, including studies published from 2000 to 2024. Eligible studies were selected based on empirical data on climate change, schistosomiasis transmission, and snail dynamics. A two-stage study selection process was followed: title/abstract screening and full-text review. Data were extracted on environmental factors, snail population dynamics, transmission patterns, and climate adaptation strategies. Climate change is expected to increase schistosomiasis transmission in endemic regions like Sub-Saharan Africa, Southeast Asia, and South America, while some areas, such as parts of West Africa, may see reduced risk. Emerging hotspots were identified in regions not currently endemic. Climate adaptation policies, such as improved water management and early warning systems, were found effective in reducing transmission. Integrating climate adaptation strategies into schistosomiasis control programs is critical to mitigating the disease’s spread, particularly in emerging hotspots and shifting endemic areas. Full article

Scabies and tungiasis are skin-related neglected tropical diseases (NTDs) associated with poverty and poor living conditions. We performed an ecological study covering a state in northeast Brazil to identify socio-economic and environmental factors associated with the occurrence of severe scabies and severe tungiasis, respectively. Data on disease occurrence on the municipality level were derived from a previous study based on online questionnaires. A total of 47 (26.0%) of the 181 state’s municipalities reported severe tungiasis, and 113 (62.4%) severe scabies. Municipalities with occurrence of severe tungiasis were characterized by higher annual rainfalls (median = 883 mm vs. 741 mm; p = 0.037), higher minimum temperatures (median = 23.4 °C vs. 22.7 °C; p = 0.002), higher aridity indices indicating more humid climates (median = 45.1 vs. 50.6; p = 0.019), lower altitudes (median = 88.8 m vs. 201 m; p < 0.001), higher mean air humidity (66.5% vs. 63%; p = 0.018), and better socioeconomic indices (Municipal Human Development Index [MHDI]—median = 0.616 vs. 0.611; p = 0.048/MHDI Longevity—mean = 0.769 vs. 0.759; p = 0.007/Municipal Development Index [MDI]—median = 27.5 vs. 21.8; p < 0.001). Municipalities with predominant luvisol soil characteristics had a lower risk for severe tungiasis (RR = 0.46; 95% CI = 0.27–0.79; p = 0.003), whereas municipalities with predominant gleysols had a significantly higher risk (RR = 2.44; 95% CI = 1.43–4.15; p = 0.010). Municipalities with occurrence of severe scabies were characterized by significantly higher annual rainfalls (median = 804 mm vs. 708 mm; p = 0.001), higher minimum temperatures (23.1 °C vs. 22.3 °C; p < 0.001), higher aridity index (median = 48.2 vs. 41.9; p = 0.014), higher air humidity (65.9% vs. 61%; p = 0.001), lower altitudes (median = 153 m vs. 246 m; p = 0.003), and better socio-economic indicators (MHDI—median = 0.616 vs. 608; p= 0.012/MHDI Education—mean = 0.559 vs. 0.541; p = 0.014/MDI—median = 24.3 vs. 21.1; p = 0.005). In multivariate regression analysis, MDI remained significantly associated with the presence of severe tungiasis in the final model (RR = 1.04; 95% CI: 1.02–1.05; p < 0.001) and the presence of severe scabies with minimum temperature (RR = 1.13; 95% CI: 1.04–1.24; p = 0.003) and aridity index (RR = 1.01; 95% CI: 1.00–1.01; p = 0.004). Our study underscores the importance of environmental and socioeconomic factors for the occurrence of severe scabies and tungiasis in a semi-arid climatic context, offering a perspective for identification of high-risk areas, and providing evidence for the control of skin NTDs withina One Health approach. Full article

In the past 5 years, the COVID-19 pandemic has experienced frequently changing variants contextualizing immune evasion. The emergence of Omicron with >30–50 mutations on the spike gene has shown a sharp divergence from its relative VOCs, such as WT, Alpha, Beta, Gamma, and Delta. The requisition of prime boosting was essential within 3–6 months to improve the Nab response that had been not lasted for longer. Omicron subvariant BA.1.1 was less transmissible, but with an extra nine mutations in next variant BA.2 made it more transmissible. This remarkable heterogeneity was reported in ORF1ab or TRS sites, ORF7a, and 10 regions in the genomic sequences of Omicron BA.2 and its evolving subvariants BA.4.6, BF.7, BQ.2, BF. 7, BA.2.75.2, and BA.5 (BQ.1 and BQ.1.1). The mutational stability of subvariants XBB, XBB 1, XBB 1.5, and XBB 1.6 conferred a similar affinity towards ACE-2. This phenomenon has been reported in breakthrough infections and after booster vaccinations producing hybrid immunity. The reduced pathogenic nature of Omicron has implicated its adaptation either through immunocompromised individuals or other animal hosts. The binding capacity of RBD and ACE-2, including the proteolytic priming via TMPRSS2, reveals its (in-vitro) transmissibility behavior. RBD mutations signify transmissibility, S1/S2 enhances virulence, while S2 infers the effective immunogenic response. Initial mutations D614G, E484A, N501Y, Q493K, K417N, S477N, Y505H, and G496S were found to increase the Ab escape. Some mutations such as, R346K, L452R, and F486Vwere seen delivering immune pressure. HR2 region (S2) displayed mutations R436S, K444T, F486S, and D1199N with altered spike positions. Later on, the booster dose or breakthrough infections contributed to elevating the immune profile. Several other mutations in BA.1.1-N460K, R346T, K444T, and BA.2.75.2-F486S have also conferred the neutralization resistance. The least studied T-cell response in SARS-CoV-2 affects HLA- TCR interactions, thus, it plays a role in limiting the virus clearance. Antigenic cartographic analysis has also shown Omicron’s drift from its predecessor variants. The rapidly evolving SARS-CoV-2 variants and subvariants have driven the population-based immunity escape in fully immunized individuals within short period. This could be an indication that Omicron is heading towards endemicity and may evolve in future with subvariants could lead to outbreaks, which requires regular surveillance. Full article

Porcine epidemic diarrhea virus (PEDV) is a major pathogen responsible for viral diarrhea in pigs, causing particularly high mortality in neonatal piglets. In recent years, genetic variations in PEDV have resulted in alterations in both its virulence and antigenicity, leading to a reduced efficacy of existing vaccines. In this study, diarrheal samples were collected from four commercial pig farms in the Hubei, Guangxi, and Jiangxi provinces, China, which experienced vaccine failure. RT-qPCR confirmed PEDV infection, and three PEDV strains, 2021-HBMC, 2024-JXYX, and 2024-JXNC, were successfully isolated. Sequence analysis and phylogenetic tree construction classified these strains into the G2c genotype, the predominant subtype in China. The neutralization assays revealed a significant reduction in the neutralizing titers of these strains against the immune serum compared with the AJ1102 reference strain. Further amino acid sequence analysis of the spike (S) protein identified several mutations in key neutralizing epitopes compared with the AJ1102 strain, including S27L, E57A, N139D, M214T, and P229L in the S-NTD epitope; A520S, F539L, K566N, D569E, G612V, P634S, E636V/K in the COE epitope; and Y1376H in the 2C10 epitope, along with several deletions at N-glycosylation sites (347NSSD and 510NITV). Additionally, whole-genome sequencing and recombination analysis indicated that the 2021-HBMC strain may have resulted from a recombination event. The findings of this study underscore the challenge posed by the continuous genetic evolution of PEDV to vaccine efficacy and provide valuable insights for future vaccine development and control strategies. Full article

The trematodes Fasciola hepatica and F. gigantica are transmitted by lymnaeid snails and cause fascioliasis in livestock and humans. Human infection is emerging in southern and southeastern Asia. In India, the number of case reports has increased since 1993. This multidisciplinary study analyzes the epidemiological scenario of human infection. The study reviews the total of 55 fascioliasis patients, their characteristics, and geographical distribution. Causes underlying this emergence are assessed by analyzing (i) the climate change suffered by India based on 40-year-data from meteorological stations, and (ii) the geographical fascioliasis hotspots according to archeological–historical records about thousands of years of pack animal movements. The review suggests frequent misdiagnosis of the wide lowland-distributed F. gigantica with F. hepatica and emphasizes the need to obtain anamnesic information about the locality of residence and the infection source. Prevalence appears to be higher in females and in the 30–40-year age group. The time elapsed between symptom onset and diagnosis varied from 10 days to 5 years (mean 9.2 months). Infection was diagnosed by egg finding (in 12 cases), adult finding (28), serology (3), and clinics and image techniques (12). Climate diagrams and the Wb-bs forecast index show higher temperatures favoring the warm condition-preferring main snail vector Radix luteola and a precipitation increase due to fewer rainy days but more days of extreme rainfall, leading to increasing surface water availability and favoring fascioliasis transmission. Climate trends indicate a risk of future increasing fascioliasis emergence, including a seasonal infection risk from June–July to October–November. Geographical zones of high human infection risk defined by archeological–historical analyses concern: (i) the Indo-Gangetic Plains and corridors used by the old Grand Trunk Road and Daksinapatha Road, (ii) northern mountainous areas by connections with the Silk Road and Tea-Horse Road, and (iii) the hinterlands of western and eastern seaport cities involved in the past Maritime Silk Road. Routes and nodes are illustrated, all transhumant–nomadic–pastoralist groups are detailed, and livestock prevalences per state are given. A baseline defining areas and seasons of high infection risk is established for the first time in India. This is henceforth expected to be helpful for physicians, prevention measures, control initiatives, and recommendations for health administration officers. Full article

This study aimed to evaluate the effects of no tail docking on the performance, health, and behavior of piglets raised under commercial conditions in Brazil. The study included 768 weaned piglets from the Pietrain synthetic line, randomly divided into two groups: DT = the final third part of the tail-docked (n = 384) and NTD = non-tail-docked (n = 384). Tail docking was performed on day two using an electrocautery clipper for piglets from the DT group, and both groups were subjected to standard environmental enrichment with branched chains. In cases of tail biting, a contingency plan was adopted to mitigate this problem by enriching the pen with a sisal rope. Behavioral measurements were performed using scan sampling. Tail biting, reactivity to humans, and health were assessed using a methodology adapted from the Welfare Quality Protocol^®. The piglets were weighed at 140 days of age and inspected according to the parameters established by the Pig Genealogical Registration Service to be used as reproduction animals. The off-test rate was calculated based on the total number of piglets approved for animal use relative to the total number evaluated. During the nursery stage, the NDT piglets showed a trend toward significance (p = 0.07) toward a higher occurrence of tail biting than the DT piglets and exhibited a higher incidence of severe lesions. They also engaged more frequently (p < 0.05) in exploratory behavior, interacting with branched chains and sisal rope, than the DT piglets. During the finishing phase, tail biting was observed only in the NDT piglets (p = 0.001). The NDT piglets that did not require the contingency plan exhibited lower fear responses (p = 0.02) during human interactions in the nursery phase than the DT piglets. Conversely, the NDT piglets that required a contingency plan showed higher fear levels (p < 0.001). Productivity performance was not affected (p > 0.05), and new cases of tail biting ceased after the contingency plan was implemented. The number of animals that died or were removed did not differ between the treatments (p > 0.05). In conclusion, managing piglets with intact tails on commercial farms presents a significant welfare challenge. By contrast, docking the final third of the tail, in accordance with regulations, was associated with fewer negative welfare outcomes, even when best management practices were applied. Full article