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Epidemics Jun 2024In the context of infectious diseases, the dynamic interplay between ever-changing host populations and viral biology demands a more flexible modeling approach than...
Unveiling ecological/evolutionary insights in HIV viral load dynamics: Allowing random slopes to observe correlational changes to CpG-contents and other molecular and clinical predictors.
In the context of infectious diseases, the dynamic interplay between ever-changing host populations and viral biology demands a more flexible modeling approach than common fixed correlations. Embracing random-effects regression models allows for a nuanced understanding of the intricate ecological and evolutionary dynamics underlying complex phenomena, offering valuable insights into disease progression and transmission patterns. In this article, we employed a random-effects regression to model an observed decreasing median plasma viral load (pVL) among individuals with HIV in Mexico City during 2019-2021. We identified how these functional slope changes (i.e. random slopes by year) improved predictions of the observed pVL median changes between 2019 and 2021, leading us to hypothesize underlying ecological and evolutionary factors. Our analysis involved a dataset of pVL values from 7325 ART-naïve individuals living with HIV, accompanied by their associated clinical and viral molecular predictors. A conventional fixed-effects linear model revealed significant correlations between pVL and predictors that evolved over time. However, this fixed-effects model could not fully explain the reduction in median pVL; thus, prompting us to adopt random-effects models. After applying a random effects regression model-with random slopes and intercepts by year-, we observed potential "functional changes" within the local HIV viral population, highlighting the importance of ecological and evolutionary considerations in HIV dynamics: A notably stronger negative correlation emerged between HIV pVL and the CpG content in the pol gene, suggesting a changing immune landscape influenced by CpG-induced innate immune responses that could impact viral load dynamics. Our study underscores the significance of random effects models in capturing dynamic correlations and the crucial role of molecular characteristics like CpG content. By enriching our understanding of changing host-virus interactions and HIV progression, our findings contribute to the broader relevance of such models in infectious disease research. They shed light on the changing interplay between host and pathogen, driving us closer to more effective strategies for managing infectious diseases. SIGNIFICANCE OF THE STUDY: This study highlights a decreasing trend in median plasma viral loads among ART-naïve individuals living with HIV in Mexico City between 2019 and 2021. It uncovers various predictors significantly correlated with pVL, shedding light on the complex interplay between host-virus interactions and disease progression. By employing a random-slopes model, the researchers move beyond traditional fixed-effects models to better capture dynamic correlations and evolutionary changes in HIV dynamics. The discovery of a stronger negative correlation between pVL and CpG content in HIV-pol sequences suggests potential changes in the immune landscape and innate immune responses, opening avenues for further research into adaptive changes and responses to environmental shifts in the context of HIV infection. The study's emphasis on molecular characteristics as predictors of pVL adds valuable insights to epidemiological and evolutionary studies of viruses, providing new avenues for understanding and managing HIV infection at the population level.
Topics: Viral Load; Humans; HIV Infections; Mexico; Female; Male; HIV-1; Adult; CpG Islands
PubMed: 38761432
DOI: 10.1016/j.epidem.2024.100770 -
FASEB Journal : Official Publication of... May 2024Pol II pause release is a rate-limiting step in gene transcription, influencing various cell fate alterations. Numerous proteins orchestrate Pol II pause release,... (Review)
Review
Pol II pause release is a rate-limiting step in gene transcription, influencing various cell fate alterations. Numerous proteins orchestrate Pol II pause release, thereby playing pivotal roles in the intricate process of cellular fate modulation. Super elongation complex (SEC), a large assembly comprising diverse protein components, has garnered attention due to its emerging significance in orchestrating physiological and pathological cellular identity changes by regulating the transcription of crucial genes. Consequently, SEC emerges as a noteworthy functional complex capable of modulating cell fate alterations. Therefore, a comprehensive review is warranted to systematically summarize the core roles of SEC in different types of cell fate alterations. This review focuses on elucidating the current understanding of the structural and functional basis of SEC. Additionally, we discuss the intricate regulatory mechanisms governing SEC in various models of cell fate alteration, encompassing both physiological and pathological contexts. Furthermore, leveraging the existing knowledge of SEC, we propose some insightful directions for future research, aiming to enhance our mechanistic and functional comprehension of SEC within the diverse landscape of cell fate alterations.
Topics: Humans; Animals; Cell Differentiation; Transcription, Genetic
PubMed: 38758186
DOI: 10.1096/fj.202400514R -
Communications Medicine May 2024High ovarian cancer mortality rates motivate the development of effective and patient-friendly diagnostics. Here, we explored the potential of molecular testing in...
BACKGROUND
High ovarian cancer mortality rates motivate the development of effective and patient-friendly diagnostics. Here, we explored the potential of molecular testing in patient-friendly samples for ovarian cancer detection.
METHODS
Home-collected urine, cervicovaginal self-samples, and clinician-taken cervical scrapes were prospectively collected from 54 patients diagnosed with a highly suspicious ovarian mass (benign n = 25, malignant n = 29). All samples were tested for nine methylation markers, using quantitative methylation-specific PCRs that were verified on ovarian tissue samples, and compared to non-paired patient-friendly samples of 110 age-matched healthy controls. Copy number analysis was performed on a subset of urine samples of ovarian cancer patients by shallow whole-genome sequencing.
RESULTS
Three methylation markers are significantly elevated in full void urine of ovarian cancer patients as compared to healthy controls (C2CD4D, P = 0.008; CDO1, P = 0.022; MAL, P = 0.008), of which two are also discriminatory in cervical scrapes (C2CD4D, P = 0.001; CDO1, P = 0.004). When comparing benign and malignant ovarian masses, GHSR shows significantly elevated methylation levels in the urine sediment of ovarian cancer patients (P = 0.024). Other methylation markers demonstrate comparably high methylation levels in benign and malignant ovarian masses. Cervicovaginal self-samples show no elevated methylation levels in patients with ovarian masses as compared to healthy controls. Copy number changes are identified in 4 out of 23 urine samples of ovarian cancer patients.
CONCLUSIONS
Our study reveals increased methylation levels of ovarian cancer-associated genes and copy number aberrations in the urine of ovarian cancer patients. Our findings support continued research into urine biomarkers for ovarian cancer detection and highlight the importance of including benign ovarian masses in future studies to develop a clinically useful test.
PubMed: 38755429
DOI: 10.1038/s43856-024-00517-8 -
Proceedings of the National Academy of... May 2024The RNA polymerase II (Pol II) elongation rate influences poly(A) site selection, with slow and fast Pol II derivatives causing upstream and downstream shifts,...
The RNA polymerase II (Pol II) elongation rate influences poly(A) site selection, with slow and fast Pol II derivatives causing upstream and downstream shifts, respectively, in poly(A) site utilization. In yeast, depletion of either of the histone chaperones FACT or Spt6 causes an upstream shift of poly(A) site use that strongly resembles the poly(A) profiles of slow Pol II mutant strains. Like slow Pol II mutant strains, FACT- and Spt6-depleted cells exhibit Pol II processivity defects, indicating that both Spt6 and FACT stimulate the Pol II elongation rate. Poly(A) profiles of some genes show atypical downstream shifts; this subset of genes overlaps well for FACT- or Spt6-depleted strains but is different from the atypical genes in Pol II speed mutant strains. In contrast, depletion of histone H3 or H4 causes a downstream shift of poly(A) sites for most genes, indicating that nucleosomes inhibit the Pol II elongation rate in vivo. Thus, chromatin-based control of the Pol II elongation rate is a potential mechanism, distinct from direct effects on the cleavage/polyadenylation machinery, to regulate alternative polyadenylation in response to genetic or environmental changes.
Topics: RNA Polymerase II; Polyadenylation; Chromatin; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Histones; Transcriptional Elongation Factors; Nucleosomes; Transcription Elongation, Genetic; DNA-Binding Proteins; Histone Chaperones; Poly A
PubMed: 38748572
DOI: 10.1073/pnas.2405827121 -
Plant Physiology and Biochemistry : PPB Jun 2024The COMPASS-like complex, responsible for depositing H3K4 methylation, exhibits a conserved composition across yeast, plants, and animals, with functional analysis...
The COMPASS-like complex, responsible for depositing H3K4 methylation, exhibits a conserved composition across yeast, plants, and animals, with functional analysis highlighting its crucial roles in plant development and stress response. In this study, we identified nine genes encoding four subunits of the COMPASS-like complex through homologous search. Phylogenetic analysis revealed the presence of two additional ASH2 genes in the sorghum genome, specifically expressed in endosperms, suggesting the formation of a unique COMPASS-like complex in sorghum endosperms. Y2H and BiFC protein-protein interaction tests demonstrated the interaction between SbRbBP5 and SbASH2A/B/C, while the association between other subunits appeared weak, possibly due to sequence variations in SbWDR5 or synergistic interactions among COMPASS-like complex subunits. The interaction between ATX1 and the C-Terminal Domain (CTD) of Pol II, reported in Arabidopsis, was not detected in sorghum. However, we made the novel discovery of transcriptional activation activity in RbBP5, which is conserved in sorghum, rice, and Arabidopsis, providing valuable insights into the mechanism by which the COMPASS-like complex regulates gene expression in plants.
Topics: Sorghum; Plant Proteins; Phylogeny; Gene Expression Regulation, Plant
PubMed: 38744082
DOI: 10.1016/j.plaphy.2024.108709 -
Polish Journal of Pathology : Official... 2024Breast cancer is the most common cancer and a leading cause of death in women in Saudi Arabia. P16 is a tumour suppressor gene that plays a crucial role in...
Breast cancer is the most common cancer and a leading cause of death in women in Saudi Arabia. P16 is a tumour suppressor gene that plays a crucial role in regulating cell cycle. Several studies have investigated the significance of p16 expression in various cancer types. However, the significance of p16 in breast cancer remains controversial and insufficiently studied. The present study aims to examine the association between p16 expression and clinicopathological factors in breast cancer using immunohistochemistry staining. The study utilised 475 prospectively collected tissue samples from 475 women with breast cancer in Saudi Arabia. Nuclear and cytoplasmic immunohistochemical staining of p16 was observed in 338 (71%) of the cases and showed significant direct associations with adverse tumour features, including high tumour grade (p < 0.0001), negative oestrogen receptor/progesterone receptor status (p < 0.001), and lymph node metastasis (p = 0.02). Our study revealed a significant association between p16 protein expression and the established negative prognostic parameters in breast carcinoma including tumour grade, lymph node metastasis, and oestrogen receptor and progesterone receptor status.
Topics: Humans; Female; Breast Neoplasms; Cyclin-Dependent Kinase Inhibitor p16; Middle Aged; Biomarkers, Tumor; Adult; Aged; Immunohistochemistry; Receptors, Progesterone; Aged, 80 and over; Lymphatic Metastasis; Receptors, Estrogen; Prognosis
PubMed: 38741426
DOI: 10.5114/pjp.2024.136028 -
Polish Journal of Pathology : Official... 2024Although BRCA genes are well-known breast cancer genes, the clinicopathological features of breast cancer patients carrying BRCA1/2 pathogenic variants have not been...
Although BRCA genes are well-known breast cancer genes, the clinicopathological features of breast cancer patients carrying BRCA1/2 pathogenic variants have not been adequately defined. The goals of this study were to determine the distribution of BRCA1/2 variants in the Turkish population and its correlation with clinicopathological features. Clinical data of 151 women who underwent BRCA1/2 gene testing at Mersin University Medical Faculty Hospital between 2016 and 2019 were retrospectively analyzed. BRCA1/2 variants were detected as pathogenic (n = 11), variants of uncertain significance (n = 5), likely benign (n = 3), and benign (n = 81) in breast cancer cases. The BRCA1/2 pathogenic variant carriers had a higher histological grade, rate of triple- negative type, Ki-67 proliferation index, and rate of no special type carcinoma than the group without mutation (p = 0.03, 0.01, 0.04, and 0.02 respectively). We analyzed the distribution of variants we detected in women living in our region and found that pathogenic variants in patients with breast cancer were associated with high histological grade, triple-negative type, high Ki-67 proliferation index, and histological type. Studies in diverse populations are needed to establish a clinicopathological relationship with variants more easily.
Topics: Humans; Female; Middle Aged; BRCA1 Protein; BRCA2 Protein; Breast Neoplasms; Adult; Retrospective Studies; Genetic Predisposition to Disease; Aged; Turkey; Mutation; Biomarkers, Tumor
PubMed: 38741424
DOI: 10.5114/pjp.2024.135703 -
BMC Veterinary Research May 2024Small ruminant lentiviruses (SRLVs) are widespread and infect goats and sheep. Several reports also suggest that SRLVs can infect wild ruminants. The presence of...
Small ruminant lentiviruses (SRLVs) are widespread and infect goats and sheep. Several reports also suggest that SRLVs can infect wild ruminants. The presence of specific antibodies against SRLVs has been identified in wild ruminants from Poland, but no studies have been conducted to detect proviral DNA of SRLVs in these animals. Therefore, the purpose of this study was to examine samples from Polish wild ruminants to determine whether these animals can serve as reservoirs of SRLVs under natural conditions. A total of 314 samples were tested from red deer (n = 255), roe deer (n = 52) and fallow deer (n = 7) using nested real-time PCR. DNA from positive real-time PCR samples was subsequently used to amplify a CA fragment (625 bp) of the gag gene, a 1.2 kb fragment of the pol gene and an LTR-gag fragment. Three samples (0.95%) were positive according to nested real-time PCR using primers and probe specific for CAEV (SRLV group B). All the samples were negative for the primers and probe specific for MVV (SRLV A group). Only SRLV LTR-gag sequences were obtained from two red deer. Phylogenetic analysis revealed that these sequences were more closely related to CAEV than to MVV. Our results revealed that deer can carry SRLV proviral sequences and therefore may play a role in the epidemiology of SRLVs. To our knowledge, this is the first study describing SRLV sequences from red deer.
Topics: Animals; Deer; Poland; Proviruses; Lentivirus Infections; DNA, Viral; Lentivirus; Phylogeny; Real-Time Polymerase Chain Reaction
PubMed: 38741095
DOI: 10.1186/s12917-024-04059-y -
Scientific Reports May 2024The Scutellaris Group of Aedes comprises 47 mosquito species, including Aedes albopictus. While Ae. albopictus is widely distributed, the other species are mostly found...
The Scutellaris Group of Aedes comprises 47 mosquito species, including Aedes albopictus. While Ae. albopictus is widely distributed, the other species are mostly found in the Asia-Pacific region. Evolutionary history researches of Aedes species within the Scutellaris Group have mainly focused on Ae. albopictus, a species that raises significant public health concerns, neglecting the other species. In this study, we aimed to assess genetic diversity and estimate speciation times of several species within the Scutellaris Group. Mosquitoes were therefore collected from various Asia-Pacific countries. Their mitochondrial cytochrome c oxidase subunit 1 (cox1) and subunit 3 (cox3) sequences were analyzed alongside those of other Scutellaris Group species available in the GenBank database. To estimate the divergence time, we analyzed 1849 cox1 gene sequences from 21 species, using three species (Aedes aegypti, Aedes notoscriptus and Aedes vigilax) as outgroups. We found that most of the speciation dates occurred during the Paleogene and the Neogene periods. A separation between the Scutellaris Subgroup and the Albopictus Subgroup occurred approximately 64-61 million years ago (MYA). We also identified a split between species found in Asia/Micronesia and those collected in Melanesia/Polynesia approximately 36-35 MYA. Our findings suggest that the speciation of Aedes species within the Scutellaris Group may be driven by diversity in mammalian hosts, climate and environmental changes, and geological dynamics rather than human migration.
Topics: Animals; Aedes; Genetic Speciation; Phylogeny; Electron Transport Complex IV; Mitochondria; Genetic Variation; DNA, Mitochondrial; Evolution, Molecular; Asia
PubMed: 38740928
DOI: 10.1038/s41598-024-61573-7 -
Scientific Reports May 2024The selection pressure imposed by the host immune system impacts on hepatitis B virus (HBV) variability. This study evaluates HBV genetic diversity, nucleos(t)ide...
The selection pressure imposed by the host immune system impacts on hepatitis B virus (HBV) variability. This study evaluates HBV genetic diversity, nucleos(t)ide analogs resistance and HBsAg escape mutations in HBV patients under distinct selective pressures. One hundred and thirteen individuals in different phases of HBV infection were included: 13 HBeAg-positive chronic infection, 9 HBeAg-positive chronic hepatitis, 47 HBeAg-negative chronic infection (ENI), 29 HBeAg-negative chronic hepatitis (ENH) and 15 acute infected individuals. Samples were PCR amplified, sequenced and genetically analyzed for the overlapping POL/S genes. Most HBV carriers presented genotype A (84/113; 74.3%), subgenotype A1 (67/84; 79.7%), irrespective of group, followed by genotypes D (20/113; 17.7%), F (8/113; 7.1%) and E (1/113; 0.9%). Clinically relevant mutations in polymerase (tL180M/M204V) and in the Major Hydrophilic Region of HBsAg (sY100C, T118A/M, sM133T, sD144A and sG145R) were observed. Our findings, however, indicated that most polymorphic sites were located in the cytosolic loops (CYL1-2) and transmembrane domain 4 (TMD4) of HBsAg. Lower viral loads and higher HBV genetic diversity were observed in ENI and ENH groups (p < 0.001), suggesting that these groups are subjected to a higher selective pressure. Our results provide information on the molecular characteristics of HBV in a diverse clinical setting, and may guide future studies on the balance of HBV quasispecies at different stages of infection.
Topics: Humans; Hepatitis B virus; Hepatitis B, Chronic; Brazil; Male; Genetic Variation; Adult; Female; Middle Aged; Hepatitis B Surface Antigens; Genotype; Mutation; Drug Resistance, Viral; DNA, Viral; Young Adult; Phylogeny; Hepatitis B e Antigens
PubMed: 38730249
DOI: 10.1038/s41598-024-60900-2