Unveiling the nexus: Long non-coding RNAs and the PI3K/Akt pathway in oral squamous cell carcinoma.

The PI3K/Akt pathway plays a critical role in the progression and treatment of oral squamous cell carcinoma (OSCC). Recent research has uncovered the involvement of long non-coding RNAs (lncRNAs) in regulating this pathway, influencing OSCC cell proliferation, survival, and metastasis. This review explores the latest findings on how certain lncRNAs act as either cancer promoters or cancer inhibitors within the PI3K/Akt signaling pathway. Certain lncRNAs act as oncogenic or tumor-suppressive agents, making them potential diagnostic and prognostic markers. Targeting these lncRNAs may lead to novel therapeutic strategies. The evolving fields of precision medicine and artificial intelligence promise advancements in OSCC diagnosis and treatment, enabling more personalized and effective patient care.

Mechanism research of non-coding RNA in immune checkpoint inhibitors therapy.

Immune checkpoint inhibitor (ICI) therapies for tumors of different systems have attained significant achievements and have changed the current situation of tumor treatment due to their therapeutic characteristics of high specificity and low side effects. The immune checkpoint Programmed death 1/Programmed cell death-Ligand 1 (PD-1/PD-L1) axis exerts a vital role in the immune escape of tumor cells. As a result, it has become a key target for tumor immunotherapy. Therefore, to perfect research into potential regulatory factors for the PD-1/PD-L1 axis, in order to understand and illustrate tumor ICI therapy mechanisms, is a significant goal. Moreover, ncRNA has been verified to regulate the PD-1/PD-L1 axis in the tumor immune microenvironment to regulate tumor genesis and development. ncRNAs can improve or decrease the efficacy of ICI therapy by modulating PD-L1 expression. This review aimed to investigate the mechanisms of action of ncRNA in regulating the PD-1/PD-L1 axis in ICI therapy, to provide more efficient immunotherapy for tumors of different systems.

Non-coding RNAs in Parkinson's disease: Regulating SNCA and alpha-synuclein aggregation.

Parkinson's disease is one of the vital neurodegenerative ailments attributed to a rise in Alpha-synuclein proteins leading to the advancement of motor and cognitive deterioration. Interestingly, in PD lncRNAs, miRNAs and siRNAs are also key regulators of SNCA and alpha-synuclein aggregation. This review will focus on the roles of these three types of small RNAs in trebling the development of PD through regulating SNCA expression or alpha-synuclein protein mediating the RNA from acting. Parkinson's disease is defined by the build-up of alpha-synuclein protein resulting predominantly from the elevated expression level of the SNCA gene. Non-coding RNAs have gained broad appeal as fundamental modulators of gene expression and protein aggregation dynamics, with significant implications on the aetiology of PD. LncRNAs modulate SNCA transcription and edit epigenetic modifications, while miRNA target mRNA is involved in the stability and translation of count alpha-synuclein. Considering all these data, siRNAs can achieve the precise gene silencing effect that directly induces the downregulation of SNCA mRNA. This review also summarizes some recent reports about the interaction between these ncRNAs with the SNCA gene and alpha-synuclein protein, each through its independent in addition to synergistic mechanisms. This review highlights the possibility of therapeutic interventions to perturb SNCA expression to prevent alpha-synuclein aggregation via targeting ncRNAs that might be spun off novel drug development for PD.

The evolving genetic landscape of telomere biology disorder dyskeratosis congenita.

Dyskeratosis congenita (DC) is a rare inherited bone marrow failure syndrome, caused by genetic mutations that principally affect telomere biology. Approximately 35% of cases remain uncharacterised at the genetic level. To explore the genetic landscape, we conducted genetic studies on a large collection of clinically diagnosed cases of DC as well as cases exhibiting features resembling DC, referred to as 'DC-like' (DCL). This led us to identify several novel pathogenic variants within known genetic loci and in the novel X-linked gene, POLA1. In addition, we have also identified several novel variants in POT1 and ZCCHC8 in multiple cases from different families expanding the allelic series of DC and DCL phenotypes. Functional characterisation of novel POLA1 and POT1 variants, revealed pathogenic effects on protein-protein interactions with primase, CTC1-STN1-TEN1 (CST) and shelterin subunit complexes, that are critical for telomere maintenance. ZCCHC8 variants demonstrated ZCCHC8 deficiency and signs of pervasive transcription, triggering inflammation in patients' blood. In conclusion, our studies expand the current genetic architecture and broaden our understanding of disease mechanisms underlying DC and DCL disorders.

Ramifications of m6A Modification on ncRNAs in Cancer.

N6-methyladenosine (m6A) is an RNA modification wherein the N6-position of adenosine is methylated. It is one of the most prevalent internal modifications of RNA and regulates various aspects of RNA metabolism. M6A is deposited by m6A methyltransferases, removed by m6A demethylases, and recognized by reader proteins, which modulate splicing, export, translation, and stability of the modified mRNA. Recent evidence suggests that various classes of non- coding RNAs (ncRNAs), including microRNAs (miRNAs), circular RNAs (circRNAs), and long con-coding RNAs (lncRNAs), are also targeted by this modification. Depending on the ncRNA species, m6A may affect the processing, stability, or localization of these molecules. The m6A- modified ncRNAs are implicated in a number of diseases, including cancer. In this review, the author summarizes the role of m6A modification in the regulation and functions of ncRNAs in tumor development. Moreover, the potential applications in cancer prognosis and therapeutics are discussed.

Interaction of ncRNAs and the PI3K/AKT/mTOR pathway: Implications for osteosarcoma.

Osteosarcoma (OS) is the most common primary malignant bone tumor in children and adolescents, and is characterized by high heterogeneity, high malignancy, easy metastasis, and poor prognosis. Recurrence, metastasis, and multidrug resistance are the main problems that limit the therapeutic effect and prognosis of OS. PI3K/AKT/mTOR signaling pathway is often abnormally activated in OS tissues and cells, which promotes the rapid development, metastasis, and drug sensitivity of OS. Emerging evidence has revealed new insights into tumorigenesis through the interaction between the PI3K/AKT/mTOR pathway and non-coding RNAs (ncRNAs). Therefore, we reviewed the interactions between the PI3K/AKT/mTOR pathway and ncRNAs and their implication in OS. These interactions have the potential to serve as cancer biomarkers and therapeutic targets in clinical applications.

Non-coding RNAs in BRAF-mutant melanoma: targets, indicators, and therapeutic potential.

Melanoma, a highly aggressive skin cancer, is often driven by BRAF mutations, such as the V600E mutation, which promotes cancer growth through the MAPK pathway and contributes to treatment resistance. Understanding the role of non-coding RNAs (ncRNAs) in these processes is crucial for developing new therapeutic strategies. This review aims to elucidate the relationship between ncRNAs and BRAF mutations in melanoma, focusing on their regulatory roles and impact on treatment resistance. We comprehensively reviewed current literature to synthesize evidence on ncRNA-mediated regulation of BRAF-mutant melanoma and their influence on therapeutic responses. Key ncRNAs, including microRNAs and long ncRNAs, were identified as significant regulators of melanoma development and therapy resistance. MicroRNAs such as miR-15/16 and miR-200 families modulate critical pathways like Wnt signaling and melanogenesis. Long ncRNAs like ANRIL and SAMMSON play roles in cell growth, invasion, and drug susceptibility. Specific ncRNAs, such as BANCR and RMEL3, intersect with the MAPK pathway, highlighting their potential as therapeutic targets or biomarkers in BRAF-mutant melanoma. Additionally, ncRNAs involved in drug resistance, such as miR-579-3p and miR-1246, target processes like autophagy and immune checkpoint regulation. This review highlights the pivotal roles of ncRNAs in regulating BRAF-mutant melanoma and their contribution to drug resistance. These findings underscore the potential of ncRNAs as biomarkers and therapeutic targets, paving the way for innovative treatments to improve outcomes for melanoma patients.

Involvement of selected circulating ncRNAs in the regulation of cognitive dysfunction induced by anesthesia.

Post-operative cognitive dysfunction (POCD) refers to the functional impairment of the nervous system caused by prolonged exposure to anesthetics. It is known that prolonged exposure to anesthetics may increase the risk for the development of several cognitive impairments. The drugs used to induce general anesthesia are generally safe, owing to the CNS's direct and/or indirect self-protective activity against drug-induced damages. Non-coding RNAs have recently started to gain attention to better understand the mechanism of gene regulation correlated to cellular physiology and pathology. In order to provide new insights for the neuroprotective function of highly expressed ncRNAs in the central nervous system, we investigated their expression profile in the circulating exosomes of patients exposed to anesthesia vs healthy controls. The experimental design envisaged the recruitment of 30 adult patients undergoing general anesthesia and healthy controls. The effects of anesthetics have been evaluated on miR-34a and miR-124, on the lncRNAs MALAT-1, HOTAIR, GAS5, BLACAT1, HULC, PANDA, and on YRNAs. NcRNAs miR-34a, miR-124, MALAT-1, HOTAIR, GAS5, BLACAT1, and YRNA1 are significantly overexpressed following anesthesia, while YRNA5 is significantly down regulated. Some of them have neuroprotective function, while other correlate with neurological dysfunctions. Our data suggests that, during anesthesia, the toxic action of some non-coding RNAs could be compensated by other non-coding RNAs, both synthesized by the CNS or also transported into neurons from other tissues. It is reasonable to suppose a mutual action of these molecules likely to secure the CNS from anesthetics, that drive a convoluted cascade of ncRNA-dependent biological counter-responses. Our findings are novel in the field of brain dysfunction, indicating that some of the analyzed ncRNAs, although several of their functions still need to be addressed, could be suggested as potential biomarkers and therapeutic targets in post-operative cognitive dysfunction-related processes.

Participation of TLRs in cancer immunopathogenesis and drug resistance via interacting with immunological and/or non-immunological signaling pathways as well as lncRNAs.

Toll-like receptors (TLRs) have a convoluted role in cancer even though they are crucial to the immune system. By bridging the innate immune system and cancer, TLRs have a very complex impact on the formation of tumors and the effectiveness of anti-cancer treatments. TLR signaling links the innate and adaptive immune systems and initiates direct pathogen eradication. In cancer immunopathogenesis and treatment resistance, long non-coding RNAs (lncRNAs) modify TLR signaling linkages with immunological and non-immunological pathways. We identified lncRNAs that positively and negatively control TLR signaling, impacting immunological response and drug sensitivity. These results highlight the complex interactions between long non-coding RNAs and TLRs that influence the start of cancer and its response to treatment. Targeting specific lncRNAs is a practical way to control TLR signaling and perhaps enhance anti-tumor immunity while overcoming medication resistance. We provide a framework for developing novel immunotherapeutic regimens and customized medicine approaches for cancer treatment. The exact mechanisms by which lncRNAs regulate TLR signaling pathways should be defined by further research, and these findings should be validated in clinical situations. This finding makes future research of lncRNA-based drugs in combination with existing cancer treatments feasible.

Emerging Roles of ncRNAs Regulating PKM2 in Cancer Progression.

Cancer is one of the main reasons for death, and it threatens human life and health. Both the environment and genes can lead to cancers. It dates back more than a million years; more importantly, tumor cells can not be detected until they grow to a large number. Currently, cancers are treated with surgical excision or non-surgical procedures. By studying the interaction between ncRNAs and PKM2, we aim to provide new targets for diagnosis, treatment, and prognosis for cancers. Read relevant articles and made a summary and classification. Non-coding RNAs (ncRNAs) are RNAs that do not code for proteins. They perform a function in transcription and translation and can be used as targets for cancer therapy. Pyruvate kinase M2 (PKM2) is a form of PKM, and it catalyzes the glycolysis of the final cellular processes to promote tumorigenesis. Not only that, but it also plays non-metabolic functions, including the expression of the gene, cell proliferation, cell migration, and tumor angiogenesis in cancer cells. The existing studies have found that microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) can promote or inhibit the aerobic glycolysis of cancer cells by affecting PKM2, which increases or decrease the risk of cancers and affect the progression of cancers. This review focuses on the mechanism of ncRNAs regulating PKM2 in cancers and summarizes the roles of some ncRNAs.

Exosomes: compositions, biogenesis, and mechanisms in diabetic wound healing.

Diabetic wounds are characterized by incomplete healing and delayed healing, resulting in a considerable global health care burden. Exosomes are lipid bilayer structures secreted by nearly all cells and express characteristic conserved proteins and parent cell-associated proteins. Exosomes harbor a diverse range of biologically active macromolecules and small molecules that can act as messengers between different cells, triggering functional changes in recipient cells and thus endowing the ability to cure various diseases, including diabetic wounds. Exosomes accelerate diabetic wound healing by regulating cellular function, inhibiting oxidative stress damage, suppressing the inflammatory response, promoting vascular regeneration, accelerating epithelial regeneration, facilitating collagen remodeling, and reducing scarring. Exosomes from different tissues or cells potentially possess functions of varying levels and can promote wound healing. For example, mesenchymal stem cell-derived exosomes (MSC-exos) have favorable potential in the field of healing due to their superior stability, permeability, biocompatibility, and immunomodulatory properties. Exosomes, which are derived from skin cellular components, can modulate inflammation and promote the regeneration of key skin cells, which in turn promotes skin healing. Therefore, this review mainly emphasizes the roles and mechanisms of exosomes from different sources, represented by MSCs and skin sources, in improving diabetic wound healing. A deeper understanding of therapeutic exosomes will yield promising candidates and perspectives for diabetic wound healing management.

Non-coding RNA: A key regulator in the Glutathione-GPX4 pathway of ferroptosis.

Ferroptosis, a form of regulated cell death, has emerged as a crucial process in diverse pathophysiological states, encompassing cancer, neurodegenerative ailments, and ischemia-reperfusion injury. The glutathione (GSH)-dependent lipid peroxidation pathway, chiefly governed by glutathione peroxidase 4 (GPX4), assumes an essential part in driving ferroptosis. GPX4, as the principal orchestrator of ferroptosis, has garnered significant attention across cancer, cardiovascular, and neuroscience domains over the past decade. Noteworthy investigations have elucidated the indispensable functions of ferroptosis in numerous diseases, including tumorigenesis, wherein robust ferroptosis within cells can impede tumor advancement. Recent research has underscored the complex regulatory role of non-coding RNAs (ncRNAs) in regulating the GSH-GPX4 network, thus influencing cellular susceptibility to ferroptosis. This exhaustive review endeavors to probe into the multifaceted processes by which ncRNAs control the GSH-GPX4 network in ferroptosis. Specifically, we delve into the functions of miRNAs, lncRNAs, and circRNAs in regulating GPX4 expression and impacting cellular susceptibility to ferroptosis. Moreover, we discuss the clinical implications of dysregulated interactions between ncRNAs and GPX4 in several conditions, underscoring their capacity as viable targets for therapeutic intervention. Additionally, the review explores emerging strategies aimed at targeting ncRNAs to modulate the GSH-GPX4 pathway and manipulate ferroptosis for therapeutic advantage. A comprehensive understanding of these intricate regulatory networks furnishes insights into innovative therapeutic avenues for diseases associated with perturbed ferroptosis, thereby laying the groundwork for therapeutic interventions targeting ncRNAs in ferroptosis-related pathological conditions.

Insights into the role of non-coding RNAs in the development of insecticide resistance in insects.

Pest control heavily relies on chemical pesticides has been going on for decades. However, the indiscriminate use of chemical pesticides often results in the development of resistance in pests. Almost all pests have developed some degree of resistance to pesticides. Research showed that the mechanisms of insecticide resistance in insects encompass metabolic resistance, behavioral resistance, penetration resistance and target-site resistance. Research on the these mechanisms has been mainly focused on the cis-regulatory or trans-regulatory for the insecticide resistance-related genes, with less attention paid to non-coding RNAs (ncRNAs), such as microRNA (miRNA), long non-coding RNA (lncRNA), and circular RNA (circRNA). There has been increased studies focus on understanding how these ncRNAs are involved in post-transcriptional regulation of insecticide resistance-related genes. Besides, the formatted endogenous RNA (ceRNA) regulatory networks (lncRNA/circRNA-miRNA-mRNA) has been identified as a key player in governing insect resistance formation. This review delves into the functions and underlying mechanisms of miRNA, lncRNA, and circRNA in regulating insect resistance. ncRNAs orchestrate insect resistance by modulating the expression of detoxification enzyme genes, insecticide target genes, as well as receptor genes, effectively regulating both target-site, metabolic and penetration resistance in insects. It also explores the regulatory mechanisms of ceRNA networks in the development of resistance. By enhancing our understanding of the mechanisms of ncRNAs in insecticide resistance, it will not only provide valuable insights into the new mechanisms of insecticide resistance but also help to enrich new directions in ncRNAs gene regulation research.

Decoding high mobility group A2 protein expression regulation and implications in human cancers.

High Mobility Group A2 (HMGA2) oncofetal proteins are a distinct category of Transcription Factors (TFs) known as "architectural factors" due to their lack of direct transcriptional activity. Instead, they modulate the three-dimensional structure of chromatin by binding to AT-rich regions in the minor grooves of DNA through their AT-hooks. This binding allows HMGA2 to interact with other proteins and different regions of DNA, thereby regulating the expression of numerous genes involved in carcinogenesis. Consequently, multiple mechanisms exist to finely control HMGA2 protein expression at various transcriptional levels, ensuring precise concentration adjustments to maintain cellular homeostasis. During embryonic development, HMGA2 protein is highly expressed but becomes absent in adult tissues. However, recent studies have revealed its re-elevation in various cancer types. Extensive research has demonstrated the involvement of HMGA2 protein in carcinogenesis at multiple levels. It intervenes in crucial processes such as cell cycle regulation, apoptosis, angiogenesis, epithelial-to-mesenchymal transition, cancer cell stemness, and DNA damage repair mechanisms, ultimately promoting cancer cell survival. This comprehensive review provides insights into the HMGA2 protein, spanning from the genetic regulation to functional protein behavior. It highlights the significant mechanisms governing HMGA2 gene expression and elucidates the molecular roles of HMGA2 in the carcinogenesis process.

Regulatory role of exosome-derived miRNAs and other contents in adipogenesis.

Intramuscular fat (IMF) content significantly impacts meat quality. influenced by complex interactions between skeletal muscle cells and adipocytes. Adipogenesis plays a pivotal role in IMF formation. Exosomes, extracellular membranous nanovesicles, facilitate intercellular communication by transporting proteins, nucleic acids (DNA and RNA), and other biomolecules into target cells, thereby modulating cellular behaviors. Recent studies have linked exosome-derived microRNAs (miRNAs) and other cargo to adipogenic processes. Various cell types, including skeletal muscle cells, interact with adipocytes via exosome secretion and uptake. Exosomes entering adipocytes regulate adipogenesis by modulating key signaling pathways, thereby influencing the extent and distribution of IMF deposition. This review comprehensively explores the origin, formation, and mechanisms of exosome action, along with current research and their applications in adipogenesis. Emphasis is placed on exosome-mediated regulation of miRNAs, non-coding RNAs (ncRNAs), proteins, lipids, and other biomolecules during adipogenesis. Leveraging exosomal contents for genetic breeding and treating obesity-related disorders is discussed. Insights gathered contribute to advancing understanding and potential therapeutic applications of exosome-regulated adipogenesis mechanisms.

Whole transcriptome analysis revealed the regulatory network and related pathways of non-coding RNA regulating ovarian atrophy in broody hens.

Poultry broodiness can cause ovarian atresia, which has a detrimental impact on egg production. Non-coding RNAs (ncRNAs) have become one of the most talked-about topics in life sciences because of the increasing evidence of their novel biological roles in regulatory systems. However, the molecular mechanisms of ncRNAs functions and processes in chicken ovarian development remain largely unknown. Whole-transcriptome RNA sequencing of the ovaries of broodiness and laying chickens was thus performed to identify the ncRNA regulatory mechanisms associated with ovarian atresia in chickens. Subsequent analysis revealed that the ovaries of laying chickens and those with broodiness had 40 differentially expressed MicroRNA (miRNAs) (15 up-regulated and 25 down-regulated), 379 differentially expressed Long Noncoding RNA (lncRNAs) (213 up-regulated and 166 down-regulated), and 129 differentially expressed circular RNA (circRNAs) (63 up-regulated and 66 down-regulated). The competing endogenous RNAs (ceRNA) network analysis further revealed the involvement of ECM-receptor interaction, AGE-RAGE signaling pathway, focal adhesion, cytokine-cytokine receptor interaction, inflammatory mediator regulation of TRP channels, renin secretion, gap junction, insulin secretion, serotonergic synapse, and IL-17 signaling pathways in broodiness. Upon further analysis, it became evident that THBS1 and MYLK are significant candidate genes implicated in the regulation of broodiness. The expression of these genes is linked to miR-155-x, miR-211-z, miR-1682-z, gga-miR-155, and gga-miR-1682, as well as to the competitive binding of novel_circ_014674 and MSTRG.3306.4. The findings of this study reveal the existence of a regulatory link between non-coding RNAs and their competing mRNAs, which provide a better comprehension of the ncRNA function and processes in chicken ovarian development.

Research progress on the role of lncRNA, circular RNA, and microRNA networks in regulating ferroptosis in osteosarcoma.

Noncoding RNAs (ncRNAs) do not participate in protein-coding. Ferroptosis is a newly discovered form of cell death mediated by reactive oxygen species and lipid peroxidation. Recent studies have shown that ncRNAs such as microRNAs, long noncoding RNAs, circular RNAs, and ferroptosis are involved in the occurrence and development of osteosarcoma (OS). Studies have confirmed that ncRNAs participate in the development of OS by regulating the ferroptosis. However, systematic summary on this topic are still lacking. This review summarises the potential role of ncRNAs in the diagnosis, treatment, drug resistance, and prognosis of OS and the basis for diagnosing, preventing, and treating clinical OS and developing effective drugs. This review summarises the latest research progress on ncRNAs that regulate ferroptosis in OS, attempts to clarify the molecular mechanisms by which ncRNAs regulate ferroptosis in the pathogenesis of OS, and elaborates on the involvement of ferroptosis in OS from the perspective of ncRNAs.

Competing endogenous RNA networks were associated with fat accumulation in skeletal muscle of aged male mice.

Muscle aging contributed to morbidity and mortality in the elderly adults by leading to severe outcomes such as frailty, falls and fractures. Post-transcriptional regulation especially competing endogenous RNA (ceRNA) mechanism may modulate the process of skeletal muscle aging. RNA-seq was performed in quadriceps of 6-month-old (adult) and 22-month-old (aged) male mice to identify differentially expressed ncRNAs and mRNAs and further construct ceRNA networks. Decreased quadriceps-body weight ratio and muscle fiber cross-sectional area as well as histological characteristics of aging were observed in the aged mice. Besides, there were higher expressions of atrogin-1 and MuRF-1 and lower expression of Myog, Myf4 and Myod1 in the quadriceps of aged mice relative to that of adult mice. The expression of 85 lncRNAs, 52 circRNAs, 10 miRNAs and 277 mRNAs were significantly dysregulated in quadriceps between the two groups, among which two ceRNA networks lncRNA 2700081O15Rik/circRNA_0000820-miR-673-3p-Tmem120b were constructed. Level of triglycerides and expression of PPARγ, C/EBPα, FASN and leptin were elevated and the expression of adiponectin was reduced in quadriceps of aged mice compared with that of adult mice. LncRNA 2700081O15Rik/circRNA_0000820-miR-673-3p-Tmem120b were possibly associated with the adipogenesis and fat accumulation in skeletal muscle of age male mice.

Non-Coding RNAs in HIV Infection, NeuroHIV, and Related Comorbidities.

NeuroHIV affects approximately 30-60% of people living with HIV-1 (PLWH) and is characterized by varying degrees of cognitive impairments, presenting a multifaceted challenge, the underlying cause of which is chronic, low-level neuroinflammation. Such smoldering neuroinflammation is likely an outcome of lifelong reliance on antiretrovirals coupled with residual virus replication in the brains of PLWH. Despite advancements in antiretroviral therapeutics, our understanding of the molecular mechanism(s) driving inflammatory processes in the brain remains limited. Recent times have seen the emergence of non-coding RNAs (ncRNAs) as critical regulators of gene expression, underlying the neuroinflammatory processes in HIV infection, NeuroHIV, and their associated comorbidities. This review explores the role of various classes of ncRNAs and their regulatory functions implicated in HIV infection, neuropathogenesis, and related conditions. The dysregulated expression of ncRNAs is known to exacerbate the neuroinflammatory responses, thus contributing to neurocognitive impairments in PLWH. This review also discusses the diagnostic and therapeutic potential of ncRNAs in HIV infection and its comorbidities, suggesting their utility as non-invasive biomarkers and targets for modulating neuroinflammatory pathways. Understanding these regulatory roles could pave the way for novel diagnostic strategies and therapeutic interventions in the context of HIV and its comorbidities.