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Viruses Jun 2024The human immunodeficiency virus type-1 epidemic in Pakistan has significantly increased over the last two decades. In Karachi, Pakistan, there is a lack of updated...
The human immunodeficiency virus type-1 epidemic in Pakistan has significantly increased over the last two decades. In Karachi, Pakistan, there is a lack of updated information on the complexity of HIV-1 genetic diversity and the burden of drug resistance mutations (DRMs) that can contribute to ART failure and poor treatment outcomes. This study aimed to determine HIV-1 genetic diversity and identify drug-resistance mutations among people living with HIV in Karachi. A total of 364 HIV-positive individuals, with a median age of 36 years, were enrolled in the study. The HIV-1 partial gene was successfully sequenced from 268 individuals. The sequences were used to generate phylogenetic trees to determine clade diversity and also to assess the burden of DRMs. Based on the partial sequences, 13 distinct HIV-1 subtypes and recombinant forms were identified. Subtype A1 was the most common clade (40%), followed by CRF02_AG (33.2%). Acquired DRMs were found in 30.6% of the ART-experienced patients, of whom 70.7%, 20.7%, and 8.5% were associated with resistance to NNRTIs, NRTIs, and PIs, respectively. Transmitted DRMs were found in 5.6% of the ART-naïve patients, of whom 93% were associated with resistance against NNRTIs and 7% to PIs. The high prevalence of DRMs in ART-experienced patients poses significant challenges to the long-term benefits and sustainability of the ART program. This study emphasizes the importance of continuous HIV molecular epidemiology and drug resistance surveillance to support evidence-based HIV prevention, precise ART, and targeted AIDS care.
Topics: Humans; HIV-1; Pakistan; HIV Infections; Drug Resistance, Viral; Adult; Male; Female; Genetic Variation; Mutation; Phylogeny; Anti-HIV Agents; Middle Aged; Young Adult; Genotype; Adolescent
PubMed: 38932254
DOI: 10.3390/v16060962 -
Veterinary Sciences Jun 2024In recent years, the clinical cases of ENTV-2 infection have increased and become prevalent in several provinces of China. In this study, we reported the occurrence of...
In recent years, the clinical cases of ENTV-2 infection have increased and become prevalent in several provinces of China. In this study, we reported the occurrence of ENTV-2 in one goat farm in Chongqing, southwest China. The complete genome of an emerged ENTV-2 isolate (designated as CQ2) was sequenced with 7468 bp in length. Phylogenetic analysis revealed that ENTV-2 consisted of two main lineages. Lineage 1 was composed of Chinese strains and could be subdivided into five sublineages. CQ2 and the other six recent isolates from China were clustered in sublineage 1.5; however, CQ2 was significantly different from the other six isolates. Furthermore, recombination analysis suggested that CQ2 might be a recombinant variant derived from sublineage 1.5 and sublineage 1.2 strains, with the recombination region in areas of and genes. In conclusion, we sequenced and analyzed the complete genome of a potential ENTV-2 recombinant, which may contribute to our understanding of the genetic variation and evolution of ENTV-2 in China.
PubMed: 38921995
DOI: 10.3390/vetsci11060248 -
ELife Jun 2024While often undetected and untreated, persistent seasonal asymptomatic malaria infections remain a global public health problem. Despite the presence of parasites in the...
While often undetected and untreated, persistent seasonal asymptomatic malaria infections remain a global public health problem. Despite the presence of parasites in the peripheral blood, no symptoms develop. Disease severity is correlated with the levels of infected red blood cells (iRBCs) adhering within blood vessels. Changes in iRBC adhesion capacity have been linked to seasonal asymptomatic malaria infections, however how this is occurring is still unknown. Here, we present evidence that RNA polymerase III (RNA Pol III) transcription in is downregulated in field isolates obtained from asymptomatic individuals during the dry season. Through experiments with in vitro cultured parasites, we have uncovered an RNA Pol III-dependent mechanism that controls pathogen proliferation and expression of a major virulence factor in response to external stimuli. Our findings establish a connection between cytoadhesion and a non-coding RNA family transcribed by Pol III. Additionally, we have identified Maf1 as a pivotal regulator of Pol III transcription, both for maintaining cellular homeostasis and for responding adaptively to external signals. These results introduce a novel perspective that contributes to our understanding of virulence. Furthermore, they establish a connection between this regulatory process and the occurrence of seasonal asymptomatic malaria infections.
Topics: Plasmodium falciparum; Virulence; RNA Polymerase III; Humans; Malaria, Falciparum; Erythrocytes; Protozoan Proteins; Virulence Factors; Cell Adhesion; Gene Expression Regulation
PubMed: 38921824
DOI: 10.7554/eLife.95879 -
MicroPublication Biology 2024Partial hepatectomy is a model of acute liver injury that is known to induce a strong reprogrammation of gene expression. Transcriptional induction of Immediate Early...
Partial hepatectomy is a model of acute liver injury that is known to induce a strong reprogrammation of gene expression. Transcriptional induction of Immediate Early Genes is extremely fast and this would be due to the release of RNA Polymerase II poised for elongation at 'paused' genes. Using bioinformatic analysis, we identified 23 genes sharing features of paused genes before hepatectomy, and with predicted quick and strong expression induction after. This transcriptional dynamic, confirmed by RT-qPCR for , , is very precocious. RNA Pol II CTD Ser2 hyperphosphorylation indicates a switch to productive elongation and release from transcriptional pause.
PubMed: 38919542
DOI: 10.17912/micropub.biology.001160 -
Nature Communications Jun 2024Although our understanding of the involvement of heterochromatin architectural factors in shaping nuclear organization is improving, there is still ongoing debate...
Although our understanding of the involvement of heterochromatin architectural factors in shaping nuclear organization is improving, there is still ongoing debate regarding the role of active genes in this process. In this study, we utilize publicly-available Micro-C data from mouse embryonic stem cells to investigate the relationship between gene transcription and 3D gene folding. Our analysis uncovers a nonmonotonic - globally positive - correlation between intragenic contact density and Pol II occupancy, independent of cohesin-based loop extrusion. Through the development of a biophysical model integrating the role of transcription dynamics within a polymer model of chromosome organization, we demonstrate that Pol II-mediated attractive interactions with limited valency between transcribed regions yield quantitative predictions consistent with chromosome-conformation-capture and live-imaging experiments. Our work provides compelling evidence that transcriptional activity shapes the 4D genome through Pol II-mediated micro-compartmentalization.
Topics: Animals; Mice; Mouse Embryonic Stem Cells; Transcription, Genetic; RNA Polymerase II; Chromosomal Proteins, Non-Histone; Cohesins; Heterochromatin; Chromosomes; Chromatin; Cell Cycle Proteins; Gene Expression Regulation
PubMed: 38918438
DOI: 10.1038/s41467-024-49727-7 -
BioRxiv : the Preprint Server For... Jun 2024Notch proteins undergo ligand-induced proteolysis to release a nuclear effector that influences a wide range of cellular processes by regulating transcription. Despite...
Notch proteins undergo ligand-induced proteolysis to release a nuclear effector that influences a wide range of cellular processes by regulating transcription. Despite years of study, however, how Notch induces the transcription of its target genes remains unclear. Here, we comprehensively examined the response to human Notch1 across a time course of activation using genomic assays of nascent RNA and chromatin accessibility. These data revealed that Notch induces target gene transcription primarily by releasing paused RNA polymerase II (RNAPII), in contrast to prevailing models suggesting that Notch acts by promoting chromatin accessibility. Indeed, we found that open chromatin is established at Notch-responsive regulatory elements prior to Notch signaling, through SWI/SNF-mediated remodeling. Notch activation, however, elicited no further chromatin opening at these loci. Together, these studies reveal that the nuclear response to Notch signaling is dictated by the pre-existing chromatin state and RNAPII distribution at time of signal activation.
PubMed: 38915655
DOI: 10.1101/2024.06.13.598853 -
Veterinary World May 2024Feline coronavirus (FCoV), feline panleukopenia virus (FPV), and feline leukemia virus (FeLV) are prevalent throughout China and significantly threaten cat health. These...
One-step triplex TaqMan quantitative reverse transcription polymerase chain reaction for the detection of feline coronavirus, feline panleukopenia virus, and feline leukemia virus.
BACKGROUND AND AIM
Feline coronavirus (FCoV), feline panleukopenia virus (FPV), and feline leukemia virus (FeLV) are prevalent throughout China and significantly threaten cat health. These viruses cause similar manifestations and pathological damage. Rapid and accurate diagnosis depends on detection in the laboratory. This study aimed to establish a reliable and rapid method for accurate detection of FCoV, FPV, and FeLV so that a definite diagnosis can be made and effective measures can be taken to prevent and control viral infection.
MATERIALS AND METHODS
We designed three pairs of specific primers and probes for the detection of FCoV 5' untranslated region, FPV viral protein 2, and FeLV pol genes. Recombinant plasmid constructs were generated for use as standard plasmid constructs. Optimal reaction conditions, including primer and probe concentrations, reaction cycles, and annealing temperatures, were obtained on the basis of optimization tests. One-step triplex real-time reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was successfully established to simultaneously detect FCoV, FPV, and FeLV. The specificity, sensitivity, and repeatability of the assay were analyzed, and its applicability was validated by testing 1175 clinical samples.
RESULTS
One-step triplex RT-qPCR had a high degree of specificity only for the detection of FCoV, FPV, and FeLV; it had high sensitivity with limits of detection of 139.904, 143.099, and 152.079 copies/reaction for p-FCoV, p-FPV, and p-FeLV standard plasmid constructs, respectively, and it had reliable repeatability with 0.06%-0.87% intra-assay coefficients of variations. A total of 1175 clinical samples were examined for FCoV, FPV, and FeLV using triplex RT-qPCR, and the FCoV, FPV, and FeLV positivity rates were 18.47%, 19.91%, and 47.57%, respectively. The clinical sensitivity and specificity of one-step triplex RT-qPCR were 93.07% and 97.99%, respectively.
CONCLUSION
We developed a rapid and reliable one-step triplex RT-qPCR method for the detection of FCoV, FPV, and FeLV, which could be used as a diagnostic tool for clinical monitoring and diagnosis.
PubMed: 38911097
DOI: 10.14202/vetworld.2024.946-955 -
PloS One 2024Uric acid induces radical oxygen species formation, endothelial inflammation, and endothelial dysfunction which contributes to the progression of atherosclerosis....
Uric acid induces radical oxygen species formation, endothelial inflammation, and endothelial dysfunction which contributes to the progression of atherosclerosis. Febuxostat inhibits BCRP- and allopurinol stimulates MRP4-mediated uric acid efflux in human embryonic kidney cells. We hypothesized that endothelial cells express uric acid transporters that regulate intracellular uric acid concentration and that modulation of these transporters by febuxostat and allopurinol contributes to their different impact on cardiovascular mortality. The aim of this study was to explore a potential difference between the effect of febuxostat and allopurinol on uric acid uptake by human umbilical vein endothelial cells. Febuxostat increased intracellular uric acid concentrations compared with control. In contrast, allopurinol did not affect intracellular uric acid concentration. In line with this observation, febuxostat increased mRNA expression of GLUT9 and reduced MRP4 expression, while allopurinol did not affect mRNA expression of these uric acid transporters. These findings provide a possible pathophysiological pathway which could explain the higher cardiovascular mortality for febuxostat compared to allopurinol but should be explored further.
Topics: Humans; Allopurinol; Febuxostat; Uric Acid; Multidrug Resistance-Associated Proteins; Human Umbilical Vein Endothelial Cells; Glucose Transport Proteins, Facilitative; Biological Transport; RNA, Messenger; Gene Expression Regulation
PubMed: 38905201
DOI: 10.1371/journal.pone.0305906 -
Frontiers in Public Health 2024To comprehensively investigate the molecular transmission patterns of HIV-1 genotypes among men who have sex with men (MSM) in Chongqing, we employed 392 pol sequences...
To comprehensively investigate the molecular transmission patterns of HIV-1 genotypes among men who have sex with men (MSM) in Chongqing, we employed 392 pol sequences of MSM to construct a phylogenetic tree and gene transmission network. Among the viral subtypes, CRF07_BC accounted for 73.2% (287/392) and CRF01_AE accounted for 20.7% (81/392), emerging as the predominant subtypes in this investigation. Additionally, we observed the presence of CRF55_01B, subtype B, CRF08_BC and other circulating recombinant forms. The HIV-1 molecular network was constructed with a gene distance threshold of 1.5%, resulting in an entry rate of 61.4% (241/392). Within the network, we identified a total of 23 molecular clusters, with the largest cluster being the CRF07_BC molecular cluster comprising 148 node values. Transmitted drug-resistance (TDR) mutations were found in 4.34% of the cases, with 1.79% associated with protease inhibitors (PIs), 0.51% with nucleoside reverse transcriptase inhibitors (NRTIs), and 2.55% with non-nucleoside reverse transcriptase inhibitors (NNRTIs). Statistical analysis indicated a higher enrollment rate in the HIV-1 molecular network among infected individuals with the CRF07_BC subtype, those identifying with same-sex sexual roles as "vers," and individuals with higher education levels. This suggests the need for strengthened investigation and intervention in this population to prevent the formation of larger transmission clusters. Furthermore, continuous monitoring of the HIV-1 molecular dynamics network is necessary to promptly and accurately track changes in molecular epidemic characteristics.
Topics: Humans; Male; China; Homosexuality, Male; HIV-1; Drug Resistance, Viral; Adult; Phylogeny; HIV Infections; Genotype; Acquired Immunodeficiency Syndrome; Middle Aged; Mutation
PubMed: 38903589
DOI: 10.3389/fpubh.2024.1308784 -
Frontiers in Neurology 2024-related disorders (-RD) encompass a diverse spectrum of neurodevelopmental and movement disorders arising from variants in the gene. Dyskinetic crises, marked by...
BACKGROUND
-related disorders (-RD) encompass a diverse spectrum of neurodevelopmental and movement disorders arising from variants in the gene. Dyskinetic crises, marked by sudden and intense exacerbations of abnormal involuntary movements, present a significant challenge in -RD.
OBJECTIVES
This study aimed to establish a standardized framework for understanding dyskinetic crises, addressing crucial aspects such as definition, triggers, diagnostic criteria, complications, and management strategies.
METHODS
A Delphi consensus process was conducted involving international experts in -RD. The panel of thirteen experts participated in three voting rounds, discussing 90 statements generated through a literature review and clinical expertise.
RESULTS
Consensus was achieved on 31 statements, defining dyskinetic crises as abrupt, paroxysmal episodes involving distinct abnormal movements in multiple body regions, triggered by emotional stress or infections. Dyskinetic crises may lead to functional impairment and complications, emphasizing the need for prompt recognition. While individualized pharmacological recommendations were not provided, benzodiazepines and clonidine were suggested for acute crisis management. Chronic treatment options included tetrabenazine, benzodiazepines, gabapentin, and clonidine. Deep brain stimulation should be considered early in the treatment of refractory or prolonged dyskinetic crisis.
CONCLUSION
This consensus provides a foundation for understanding and managing dyskinetic crises in -RD for clinicians, caregivers, and researchers. The study emphasizes the importance of targeted parental and caregiver education, which enables early recognition and intervention, thereby potentially minimizing both short- and long-term complications. Future research should concentrate on differentiating dyskinetic crises from other neurological events and investigating potential risk factors that influence their occurrence and nature. The proposed standardized framework improves clinical management, stakeholder communication, and future -RD research.
PubMed: 38903163
DOI: 10.3389/fneur.2024.1403815