Phylodynamic Insights into Global Emergence and Diversification of the Tomato Pathogen Xanthomonas hortorum pv. gardneri.

The emergence of plant pathogens is often associated with waves of unique evolutionary and epidemiological events. Xanthomonas hortorum pv. gardneri is one of the major pathogens causing bacterial spot disease of tomatoes. After its first report in the 1950s, there were no formal reports on this pathogen until the 1990s, despite active global research on the pathogens that cause tomato and pepper bacterial spot disease. Given the recently documented global distribution of X. hortorum pv. gardneri, our objective was to examine genomic diversification associated with its emergence. We sequenced the genomes of X. hortorum pv. gardneri strains collected in eight countries to examine global population structure and pathways of emergence using phylodynamic analysis. We found that strains isolated post-1990 group by region of collection and show minimal impact of recombination on genetic variation. A period of rapid geographic expansion in X. hortorum pv. gardneri is associated with acquisition of a large plasmid conferring copper tolerance by horizontal transfer and coincides with the burgeoning hybrid tomato seed industry through the 1980s. The ancestry of X. hortorum pv. gardneri is consistent with introduction to hybrid tomato seed production and dissemination during the rapid increase in trade of hybrid seeds.

Outcome of early detection approach in control of breast, cervical, and oral cancer: Experience from a rural cancer center in India.

In low- and middle-income countries most of the cancer patients attend the hospital at a late stage and treatment completion of these cases is challenging. The early detection program (EDP), in rural areas of Punjab state, India was initiated to identify breast, cervical, and oral cancer at an early stage by raising awareness and providing easy access to diagnosis and treatment. A total of 361 health education programs and 99 early detection clinics were organized. The symptomatic and self-interested (non-symptomatic individuals who opted for screening) cases visited the detection clinic. They were screened for breast, cervical, and/or oral cancer. Further diagnosis and treatment of screen-positive cases were carried out at Homi Bhabha Cancer Hospital (HBCH), Sangrur. Community leaders and healthcare workers were involved in all the activities. The EDP, Sangrur removed barriers between cancer diagnosis and treatment with the help of project staff. From 2019 to 2023, a total of 221,317 populations were covered. Symptomatic and self-interested individuals attended the breast (1627), cervical (1601), and oral (1111) examinations. 46 breast (in situ-4.3%; localized-52.2%), 9 cervical (localized-77.8%), and 12 oral (localized-66.7%) cancer cases were detected, and treatment completion was 82.6%, 77.8%, and 50.0%, respectively. We compared cancer staging and treatment completion of cases detected through EDP with the cases attended HBCH from Sangrur district in 2018; the difference between two groups is statistically significant. Due to the early detection approach, there is disease down-staging and improvement in treatment completion. This approach is feasible and can be implemented to control these cancers in low- and middle-income countries.

ThermoBRET: A Ligand-Engagement Nanoscale Thermostability Assay Applied to GPCRs.

Measurements of membrane protein thermostability reflect ligand binding. Current thermostability assays often require protein purification or rely on pre-existing radiolabelled or fluorescent ligands, limiting their application to established targets. Alternative methods, such as fluorescence-detection size exclusion chromatography thermal shift, detect protein aggregation but are not amenable to high-throughput screening. Here, we present a ThermoBRET method to quantify the relative thermostability of G protein coupled receptors (GPCRs), using cannabinoid receptors (CB1 and CB2 ) and the ß2 -adrenoceptor (ß2 AR) as model systems. ThermoBRET reports receptor unfolding, does not need labelled ligands and can be used with non-purified proteins. It uses Bioluminescence Resonance Energy Transfer (BRET) between Nanoluciferase (Nluc) and a thiol-reactive fluorescent dye that binds cysteines exposed by unfolding. We demonstrate that the melting point (Tm ) of Nluc-fused GPCRs can be determined in non-purified detergent solubilised membrane preparations or solubilised whole cells, revealing differences in thermostability for different solubilising conditions and in the presence of stabilising ligands. We extended the range of the assay by developing the thermostable tsNLuc by incorporating mutations from the fragments of split-Nluc (Tm of 87 °C versus 59 °C). ThermoBRET allows the determination of GPCR thermostability, which is useful for protein purification optimisation and drug discovery screening.

Stories of childhood sexual abuse (CSA) among older adults living with HIV (OALH) in South Carolina: a qualitative study.

Childhood sexual abuse (CSA) devastatingly impacts an individual's behavioral, psychological, and social health. Childhood, a developmental stage directly influenced by the home or school environment, leaves a life-long imprint. Compared with the general population, CSA prevalence is doubled among people living with HIV. Thus, the study aimed to explore CSA circumstances among older adults living with HIV (OALH) in South Carolina (SC). We included 24 OALH aged 50 and above who reported CSA. The data were collected at an immunology center in SC. In-depth semi-structured interviews were conducted, audio-recorded, transcribed, and analyzed using a thematic analysis approach. The iterative analytic process included a discussion of initial thoughts and key concepts, identification, and reconciliation of codes, and naming of emergent themes. Six themes emerged: known perpetrators, re-victimization, "nobody believed me", "cannot live like others", lack of CSA disclosure, and interconnections with other adverse childhood experiences (ACEs). CSA experiences and non-disclosure were found to be linked with shame, embarrassment, fear, and trust issues. Hence, trauma-focused interventions are required to resolve these issues and improve the quality of life of OALH with past trauma. Counseling or therapy programs should incorporate psychological and behavioral theoretical models to best target OALH who are CSA survivors.

Childhood sexual abuse and antiretroviral therapy adherence among older adults living with HIV: a mixed methods study.

Findings on the association between childhood sexual abuse (CSA) and antiretroviral therapy (ART) adherence have been varied, with some studies showing a relationship, or a lack thereof. However, to our knowledge, no study has examined this association among older adults living with HIV (OALH). Therefore, the purpose of this study was to examine the association between CSA and ART adherence among OALH using a mixed methods approach. This study, which involved a concurrent design, had two phases. The first phase comprised in-depth, semi-structured interviews of 24 adults aged 50 and older living with HIV in South Carolina. The second phase included data from 91 OALH. Thematic analysis and multivariable regression models, adjusting for age, gender, race, and income, were used to determine the association between CSA and ART adherence. The main theme emerging from the qualitative data was that CSA was not linked with ART adherence. However, contrastingly, quantitative analyses revealed a negative statistically significant association between CSA and ART adherence (adjusted ß: -3.35; 95% CI: -5.37, -1.34). This difference in findings could be due to the hidden impact of trauma and/or the use of different study populations. Future research should assess mediating pathways between CSA and ART adherence.

Health disparities in mortality among individuals with HIV-associated dementia in South Carolina.

HIV disproportionately affects the South compared to other regions of the US. Some people living with HIV (PLWH) may acquire HIV-associated neurocognitive disorders (HAND), of which HIV-associated dementia (HAD) is the most severe form. This study aimed to examine the disparities in mortality among individuals with HAD. Data were obtained from the South Carolina Alzheimer's Disease and Related Dementias Registry from 2010 to 2016 (HAD: n = 505; N = 164,982). Logistic regression and Cox proportional hazards models were used to determine mortality related to HIV-associated dementia and potential sociodemographic differences. Adjusted models controlled for age, gender, race, rurality, and place of diagnosis. Individuals diagnosed in a nursing facility were three times more likely to die with HAD compared to those diagnosed in the community (OR: 3.25; 95% CI: 2.08-5.08). Black populations were more likely to die with HAD compared to White populations (OR: 1.52; 95% CI: 0.953-2.42). Disparities in mortality among patients with HAD were found in place of diagnosis and by race. Future research should determine if mortality among individuals with HAD were as a result of HAD or non-HIV related decline.

Development of stapled NONO-associated peptides reveals unexpected cell permeability and nuclear localisation.

The non-POU domain-containing octamer-binding protein (NONO) is a nucleic acid-binding protein with diverse functions that has been identified as a potential cancer target in cell biology studies. Little is known about structural motifs that mediate binding to NONO apart from its ability to form homodimers, as well as heterodimers and oligomers with related homologues. We report a stapling approach to macrocyclise helical peptides derived from the insulin-like growth factor binding protein (IGFBP-3) that NONO interacts with, and also from the dimerisation domain of NONO itself. Using a range of chemistries including Pd-catalysed cross-coupling, cysteine arylation and cysteine alkylation, we successfully improved the helicity and observed modest peptide binding to the NONO dimer, although binding could not be saturated at micromolar concentrations. Unexpectedly, we observed cell permeability and preferential nuclear localisation of various dye-labelled peptides in live confocal microscopy, indicating the potential for developing peptide-based tools to study NONO in a cellular context.

Synthesis and studies of new purines/pyrimidine derivatives as multi-targeted agents involving various receptor sites in the immune system.

Pro-inflammation, which is developed due to the increased production of cytokines, mainly interleukin-6 (IL-6), during the working of immune system pathways, becomes a major concern these days for many researchers. So, it is desired to design, screen, and synthesize new molecules with multi-parametric features showing their efficacy for Toll-like receptors (TLRs) and inhibiting the disease-causing receptor sites like viral infections, cancers, etc. along with controlling inflammation, fever, and other side effects during such pathways. Further, looking at the literature, curcumin a multi-targeted agent is showing its efficiency toward various receptor sites involved in many diseases as mentioned above. This fascinated us to build up new molecules which behave like curcumin with minimum side effects. In silico studies, involving ADMET studies, toxicological data, and docking analyses, of newly synthesized compounds (3-5) along with tautomers of curcumin i.e., (1-2), and some reported compounds like 9 and 10 have been studied in detail. Great emphasis has been made on analyzing binding energies, protein-ligand structural interactions, stabilization of newly synthesized molecules against various selected receptor sites using such computational tools. Compound 3 is the most efficient multifunctional agent, which has shown its potential toward most of the receptor sites in docking analysis. It has also responded well in Molecular dynamics (MD) simulation toward 5ZLN, 4RJ3, 4YO9, 4YOJ, and 1I1R sites. Finally, studies were extended to understand in vitro anti-inflammatory activity for particularly compound 3 in comparison to diclofenac and curcumin, which signifies the efficiency of compound 3.

Xanthomonas as a model system for studying pathogen emergence and evolution.

In this review, we highlight studies where whole genome sequencing, comparative genomics and population genomics have provided unprecedented insights into past and ongoing pathogen evolution. These include new understanding of adaptive evolution of secretion systems and their effectors. We focus on Xanthomonas pathosystems that have seen intensive study and improved our understanding of pathogen emergence and evolution, particularly in the context of host specialization: citrus canker, bacterial blight of rice, and bacterial spot of tomato and pepper. Across pathosystems, pathogens appear to follow a pattern of bursts of evolution and diversification that impact host adaptation. There remains a need for studies on the mechanisms of host range evolution and genetic exchange among closely related but differentially host-specialized species, and to start moving beyond the study of specific strain and host cultivar pairwise interactions to thinking about these pathosystems in a community context.

A Review and Comparative Analysis of Relevant Approaches of Zero Trust Network Model.

The Zero Trust safety architecture emerged as an intriguing approach for overcoming the shortcomings of standard network security solutions. This extensive survey study provides a meticulous explanation of the underlying principles of Zero Trust, as well as an assessment of the many strategies and possibilities for effective implementation. The survey begins by examining the role of authentication and access control within Zero Trust Architectures, and subsequently investigates innovative authentication, as well as access control solutions across different scenarios. It more deeply explores traditional techniques for encryption, micro-segmentation, and security automation, emphasizing their importance in achieving a secure Zero Trust environment. Zero Trust Architecture is explained in brief, along with the Taxonomy of Zero Trust Network Features. This review article provides useful insights into the Zero Trust paradigm, its approaches, problems, and future research objectives for scholars, practitioners, and policymakers. This survey contributes to the growth and implementation of secure network architectures in critical infrastructures by developing a deeper knowledge of Zero Trust.

Molecular Characterization of BK Polyomavirus Replication in Allogeneic Hematopoietic Cell Transplantation Patients.

BACKGROUND: High-level BK polyomavirus (BKPyV) replication in allogeneic hematopoietic cell transplantation (HCT) predicts failing immune control and BKPyV-associated hemorrhagic cystitis. METHODS: To identify molecular markers of BKPyV replication and disease, we scrutinized BKPyV DNA-loads in longitudinal urine and plasma pairs from 20 HCT patients using quantitative nucleic acid testing (QNAT), DNase-I treatment prior to QNAT, next-generation sequencing (NGS), and tested cell-mediated immunity. RESULTS: We found that larger QNAT amplicons led to under-quantification and false-negatives results (P < .001). DNase-I reduced urine and plasma BKPyV-loads by >90% (P < .001), indicating non-encapsidated BKPyV genomes. DNase-resistant urine BKPyV-loads remained infectious in cell culture. BKPyV genome fragmentation of ≤250 bp impaired NGS coverage of genetic variation using 1000-bp and 5000-bp amplicons. Conversely, 250-bp amplicons captured viral minority variants. We identified genotype-specific and genotype-independent changes in capsid Vp1 or T-antigen predicted to escape from antibody neutralization or cytotoxic CD8 T-cells, respectively. Genotype-specific changes in immunodominant 9mers were associated with reduced or absent CD8 T-cell responses. Thus, failure to control BKPyV replication in HCT Patients may involve insufficient genotype-specific cytotoxic CD8 T-cell responses, potentially predictable by low neutralizing antibodies as well as genotype-independent immune escape. CONCLUSIONS: Our results provide new insights for patient evaluation and for designing immune protection through neutralizing antibodies, adoptive T-cell therapy, or vaccines.

STAT5B mutations in myeloid neoplasms differ by disease subtypes but characterize a subset of chronic myeloid neoplasms with eosinophilia and/or basophilia.

STAT5B has been reported as a recurrent mutation in myeloid neoplasms (MNs) with eosinophilia, but the overall frequency and importance across a spectrum of MNs are largely unknown. We conducted a multicenter study on a series of 82 MNs with STAT5B mutations detected by next-generation sequencing. The estimated frequency of STAT5B mutation in MNs was low.

Social Support, Internalized HIV Stigma, Resilience and Depression Among People Living with HIV: A Moderated Mediation Analysis.

Internalized HIV stigma has been associated with depression among people living with HIV (PLWH). However, it is still unclear whether resilience would mediate the association between internalized HIV stigma and depression and how this indirect effect would be moderated by social support. Data were collected from 402 PLWH in South Carolina using a cross-sectional survey. Data were fitted using a path model that specified the extent to which internalized HIV stigma and depression were related through resilience and how this effect was moderated by social support. Sociodemographic characteristics were included in the model as covariates. The indirect effect of internalized HIV stigma on depression through resilience was statistically significant for high social support but not for low social support. To mitigate negative impacts of internalized HIV stigma on mental health of PLWH, intervention efforts should integrate multilevel components for promoting both resilience and social support.

Psychosocial Protective and Risk Factors of Quality of Life Outcomes Among Older Adults Living With HIV.

HIV continues to be a public health issue for older adults. Previous studies have examined predictors of quality of life (QoL) among people living with HIV (PLWH), but the majority have been in international settings and have not focused on older adults living with HIV (OALH). The aim of this study was to examine the associations between psychosocial protective and risk factors (resilience, internalized HIV-related stigma, and depression), and overall and domains (physical, psychological, independence, social, environmental, and spiritual) of QoL among OALH. Data were obtained from 156 OALH living in South Carolina. Resilience was positively associated with all QoL domains except the spiritual domain. Internalized HIV-related stigma was associated with all QoL domains except the psychological and environmental domains. Depression was associated with the overall QoL measure and all domains. Interventions aimed at increasing resilience, attenuating internalized HIV-related stigma and depressive symptoms may be warranted for OALH, which may improve overall and varying domains of QoL.

Coping and ART adherence self-efficacy among people living with HIV in South Carolina.

In the US, more than 50% of new HIV infections are reported in southern states. Besides, the incidence rate of HIV in South Carolina is 17 per 100,000 population. Regardless of improved quality of life with the advent of ART, coping with stressors may influence ART adherence self-efficacy. This study assessed the association between coping strategies and ART adherence self-efficacy among people living with HIV (PLWH) in South Carolina. Cross-sectional data were obtained from 402 PLWH attending a large immunology center in South Carolina in 2018. Unadjusted and adjusted linear regression models were used to determine the association between coping strategies and ART adherence self-efficacy. Alcohol or drug use was negatively associated with ART adherence self-efficacy (b = -0.170, 95% CI [-0.255, -0.085], p = 0.0001). Religiosity was positively associated with ART adherence self-efficacy (b = 0.101, 95% CI [0.017, 0.185], p = 0.019). Overall coping and self-motivation were not significantly associated with ART adherence self-efficacy. Accentuating religiosity and attenuating alcohol or drug use as a means of coping may improve ART adherence self-efficacy among PLWH.

Association between sociodemographic characteristics and HIV disclosure among people living with HIV in South Carolina: a structural equation modeling approach.

HIV disclosure continues to be a key consideration among people living with HIV (PLWH). However, there is a lack of studies assessing factors associated with HIV disclosure among PLWH in the Southern U.S. Therefore, the aim of this study was to assess the association between sociodemographic risk factors and HIV disclosure using a structural equation modeling approach among PLWH in South Carolina. Exploratory factor analysis was used to operationalize HIV disclosure. Structural equation models were used to determine the associations between sociodemographic factors and HIV disclosure among PLWH. Two latent variables were obtained for HIV disclosure: partners (stable partners, spouses, casual partners), and family/friends (parents, grandparents, siblings, children, adult children, friends, and coworkers). After adjusting for confounders, Black populations were less likely to disclose their HIV status to both partners (ß = -0.250, p = 0.006) and family/friends (ß = -0.246, p < 0.001) compared to non-Black populations. As yearly income increased, the likelihood of HIV disclosure to family/friends decreased (ß = -0.300, p = <0.001). As time since diagnosis increased, the likelihood of HIV disclosure to family/friends increased (ß = 0.266, p = 0.001). Future research can assess the feasibility of implementing disclosure interventions that are geared towards Black, high income and newly diagnosed PLWH and the associations of psychosocial factors and HIV disclosure.

Gender and coping with HIV: a qualitative study of older childhood sexual abuse survivors living with HIV.

People living with HIV often have complex identities and histories. Understanding how these experiences influence adherence to treatment and quality of life are critical to the HIV care. The experiences of older adults living with HIV are uniquely embedded within biology and aging as well as gender. This study described the gendered strategies for coping with HIV among older adults who are childhood sexual abuse survivors. Audio-recorded semi-structured interviews were performed with 24 adults who are 50 years and older from a clinic in South Carolina. Thematic analysis approach was used to discuss key concepts, reconcile codes, and name emergent themes. Overall, the participants used a spectrum of coping strategies including spirituality, seclusion, social support, substance use, engagement in HIV care, information acquisition and sharing, and cognitive reframing. Our findings suggest the potential for growth and recovery is heightened if the interplay of HIV diagnosis, aging, coping, and mental health is considered. Healthcare providers should assess the ways in which individuals interpret their HIV diagnosis and other lived experiences to better understand their patients' mental health. Knowledge of gender-based coping strategies used in HIV-relevant outcomes can be translated into more effective treatment plans to improve the overall quality of life.

"Is it worth living?" psychosocial challenges of childhood sexual abuse survivors aging with HIV.

Older adults living with HIV (OALH) undergo challenges such as comorbidities, social isolation, and "double stigma" associated with their HIV and aging statuses. Simultaneously, research has shown that experiences of childhood sexual abuse (CSA) continue to impact the quality of life across the lifespan and may pose unique hardships for older adults. Despite the high prevalence of trauma among people living with HIV, research examining the psychosocial challenges of OALH with a CSA history is scant. To address this gap in the literature, this study aimed to explore psychosocial challenges among OALH who are CSA survivors using a qualitative approach. Twenty-four in-depth, semi-structured interviews were completed with OALH (age 50 years and older) who reported histories of CSA. Multiple coders and an inductive coding process were employed for data analysis. Four main themes regarding psychosocial challenges emerged from the analysis: (1) depression and suicidal ideation, (2) fear and anxiety, (3) social support issues, and (4) memory issues. The authors discuss the implications of these findings and the importance of trauma-informed treatment for these individuals.

Multi-omics assisted breeding for biotic stress resistance in soybean.

Biotic stress is a critical factor limiting soybean growth and development. Soybean responses to biotic stresses such as insects, nematodes, fungal, bacterial, and viral pathogens are governed by complex regulatory and defense mechanisms. Next-generation sequencing has availed research techniques and strategies in genomics and post-genomics. This review summarizes the available information on marker resources, quantitative trait loci, and marker-trait associations involved in regulating biotic stress responses in soybean. We discuss the differential expression of related genes and proteins reported in different transcriptomics and proteomics studies and the role of signaling pathways and metabolites reported in metabolomic studies. Recent advances in omics technologies offer opportunities to reshape and improve biotic stress resistance in soybean by altering gene regulation and/or other regulatory networks. We suggest using 'integrated omics' to precisely understand how soybean responds to different biotic stresses. We also discuss the potential challenges of integrating multi-omics for the functional analysis of genes and their regulatory networks and the development of biotic stress-resistant cultivars. This review will help direct soybean breeding programs to develop resistance against different biotic stresses.

Switching of newly synthesized linker-based derivatives of non-steroidal anti-inflammatory drugs toward anti-inflammatory and anticancer activity.

A new series of linker-based derivatives of non-steroidal anti-inflammatory drugs were designed and synthesized. All the compounds were well characterized with the help of various spectroscopic techniques such as FT-IR, 1H NMR, 13C NMR, and HRMS. The main emphasis of this paper is to understand the switching of the most promising compounds 8 and 10 towards anti-inflammatory and anticancer activity in terms of in-silico and in-vitro studies in detail. During the molecular docking study, compounds 8 and 10 demonstrated the importance of hetero atoms as well as the perfect alignment of a compound in the binding pocket of a target site, which may affect their bioactivity. Here, the presence of 1,3­dicarbonyl interactions with ASN 351 in compound 8 (not found in compound 10) may be responsible for its better inhibitory activity against the COX-2 target site. On the other hand, a slight increase in the potency of compound 10 towards anticancer activity may be due to the instantaneous participation of the OH group and carbonyl group to give conventional hydrogen bonds towards THR 149 amino acid residue, which was missing in compound 8. Molecular dynamics simulation was also performed for compounds 10 and 8 toward COX-2 and HER-2 protein sites. Further, compounds 8 and 10 were subjected to in-vitro COX-2 inhibition and cytotoxicity assay and the results obtained were in accordance with the in-silico study. Thus, compound 8 become more potent towards COX-2 inhibition with IC50 value of 48.51 µg/ml and compound 10 showed good bioactivity toward cytotoxic activity with IC50 value of 93.03 µg/ml.