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PubMed2001

Construction and analysis of an infectious human Immunodeficiency virus type 1 subtype C molecular clone.

Human immunodeficiency virus type 1 (HIV-1) subtype C is now the predominant subtype in the global epidemic. This subtype is encountered in southern Africa and parts of Asia, where the epidemic is rapidly spreading. One possible explanation for these epidemiological observations is that this subtype has genetic characteristics that may contribute to its spread and/or pathogenic potential. In this report, we describe the construction of MJ4, an infectious chimeric molecular clone of HIV-1 subtype C that replicates in donor peripheral blood mononuclear cells and macrophages. We also tested this clone for its ability to use the chemokine receptors CCR1, CCR2b, CCR3, CXCR4, and CCR5 and found that the clone utilizes only CCR5 as the coreceptor for cell entry. The MJ4 clone will be useful in further biological and virological characterization of HIV-1 subtype C and will be an important tool in the continuing efforts to understand what may constitute protective immunity in HIV-1. The clone may also be used in experimental design of vaccine candidates that may be directed against HIV-1 subtype C.

Africa↗

PubMed2002

Identification of binding sites of prazosin, tamsulosin and KMD-3213 with alpha(1)-adrenergic receptor subtypes by molecular modeling.

This investigation was performed to assess the importance of interaction in the bindings of selective and nonselective alpha(1)-antagonists to alpha(1)-adrenergic receptor (alpha(1)-AR) subtypes using molecular modeling. The alpha(1)-antagonists used in this study were prazosin, tamsulosin and KMD-3213. Molecular modeling was performed on Octane 2 workstation (Silicon Graphics) using Discover/Insight II software (Molecular Simulations Inc.). Through molecular modeling, possible binding sites for these drugs were suggested to lie between transmembrane domains (TM) 3, 4, 5 and 6 of the alpha(1)-AR subtypes. In prazosin, the 4-amino group, 1-nitrogen atom and two methoxy groups of quinazoline ring possibly interact with the amino acids in TM3, TM5 and TM6 of alpha(1)-ARs. In tamsulosin, amine group of ethanyl amine chain, methoxy group of benzene ring and sulfonamide nitrogen of benzene ring interacts in TM3, TM4 and TM5 of alpha(1)-ARs. In KMD-3213, amine of ethyl amine chain and indoline nitrogen of this compound possibly interact within TM3 and TM5 of alpha(1)-ARs. Amide nitrogen of KMD-3213 also interacts within TM4 of alpha(1A)-AR. The results of the present study suggested that prazosin has similar binding sites in all the alpha(1)-AR subtypes while tamsulosin interacts at higher number of sites with alpha(1D)-subtype than other alpha(1)-AR subtypes. KMD-3213 being an alpha(1A)-AR selective ligand, binds to higher number of sites of alpha(1A) subtype than to other subtypes. All these amino acids are located near the extracellular loop. These findings are consistent with the previous studies that antagonists bind higher in the pocket closer to the extracellular surface unlike agonist binding.

Adrenergic alpha-Antagonists↗

PubMed2002

Two distinct signaling pathways upregulate NMDA receptor responses via two distinct metabotropic glutamate receptor subtypes.

Molecular processes regulating the gain of NMDA receptors modulate diverse physiological and pathological responses in the CNS. Group I metabotropic glutamate receptors (mGluRs), which neighbor NMDA receptors and which can be coactivated by synaptically released glutamate, couple to several different second messenger pathways, each of which could target NMDA receptors. In CA3 pyramidal cells we show that the activation of mGluR1 potentiates NMDA current via a G-protein-independent mechanism involving Src kinase activation. In contrast, mGluR5-mediated enhancement of NMDA current requires G-protein activation, triggering a signaling cascade including protein kinase C and Src. These results indicate that one neurotransmitter, glutamate, can activate two distinct and independent signaling systems to target the same effector. These two pathways are likely to contribute significantly to the highly differentiated control of NMDA receptor function.

Animals↗

PubMed2025

The protective role of γδ T cells in endometrial cancer.

Γδ T cells are non-conventional T cells that are not MHC restricted and have T cell receptors (TCRs) that are stimulated by phosphoantigens, stress-induced proteins, lipids, and other antigens. These cells are prognostic across cancer types in The Cancer Genome Atlas (TCGA) but have not been well studied in endometrial cancer, which has a rising incidence and mortality rate. Endometrial cancer patients have variable responses to checkpoint inhibitors which are related to the molecular subtype of their cancer. As such, there is a pressing need to understand the immune microenvironment in endometrial cancer. This study addresses this gap in knowledge by investigating γδ T cell repertoires and transcriptomes in this disease site. γδ T cell repertoires were obtained for 543 endometrial cancer patients within the TCGA and from 5 endometrial cancer patients in the single cell dataset SRP349751 using TRUST4. GLIPH2 was used to identify TCRs predicted to bind the same antigen. Transcriptomes were investigated in the single cell dataset. DNA Polymerase Epsilon Exonuclease (POLE) and Microsatellite Instability High (MSI-H) endometrial cancer subtypes had the most γδ T cell infiltration. Vδ1 and Vδ3 γδ T cell infiltration was prognostic independent of stage and molecular subtype. GLIPH2 analysis revealed TCRδ motifs for TDK, YTD, and GEL were public across all four molecular subtypes and were present in the single cell data set. Vδ1 γδ T cell transcriptomes were associated with cytotoxicity and recent TCR stimulation. These data support further investigation of immunotherapies targeting γδ T cells in endometrial cancer.

Humans↗

PubMed2003

Identification of the binding sites and selectivity of sarpogrelate, a novel 5-HT2 antagonist, to human 5-HT2A, 5-HT2B and 5-HT2C receptor subtypes by molecular modeling.

The aim of the present study was to investigate the binding sites interactions and the selectivity of sarpogrelate to human 5-HT(2) receptor family (5-HT(2A), 5-HT(2B) and 5-HT(2C) receptor subtypes) using molecular modeling. Rhodopsin (RH) crystal structures were used as template to build structural models of the human serotonin-2A and -2C receptors (5-HT(2A)R, 5-HT(2C)R), whereas for 5-HT(2B)R, we used our previously published three-dimensional (3D) models based on bacteriorhodopsin (BR). Sarpogrelate, a novel 5-HT(2)R antagonist, was docked to the receptors. Molecular dynamics (MD) simulations produced the strongest interaction for 5-HT(2A)R/sarpogrelate complex. Upon binding, sarpogrelate constraints aromatic residues network (Trp(3.28), Phe(5.47), Trp(6.48), Phe(6.51), Phe(6.52) in 5-HT(2A)R; Phe(3.35), Phe(6.51), Trp(7.40) in 5-HT(2B)R; Trp(3.28), Phe(3.35), Phe(5.47), Trp(6.48), Phe(6.51), Phe(6.52) in 5-HT(2C)R) in a stacked configuration, preventing activation of the receptor. The models suggest that the structural origin of the selectivity of sarpogrelate to 5-HT(2A)R vs both 5-HT(2B)R and 5-HT(2C)R comes from the following results: (1) The tight interaction between the antagonist and the transmembrane domain (TMD) 3. Asp(3.32) neutralizes the cationic head and interacts simultaneously with carboxylic group hydrogen of the antagonist molecule. (2) Due to steric hindrance, Ser(5.46) (vs Ala(5.46) in 5HT(2B) and 5HT(2C)) prevents sarpogrelate to enter deeply inside the hydrophobic core of the helix bundle and to interact with Pro(5.50). (3) The side chain of Ile(4.56) (vs Ile(4.56) in 5HT(2B)R and Val(4.56) in 5HT(2C)R) constraints sarpogrelate to adjust its position by translating toward the strongly attractive Asp(3.32). These results are in good agreement with binding affinities (pKi) of sarpogrelate for 5-HT(2) receptor family expressed in transfected cell.

Amino Acid Sequence↗

PubMed2001

In vitro clonal analysis of rat cerebral cortical neurons expressing latexin, a subtype-specific molecular marker of glutamatergic neurons.

Latexin is expressed in a subset of glutamatergic projection neurons located in the lateral but not the dorsomedial neocortex in rat. In the present study, we performed clonal analysis of embryonic cortical neurons in vitro using latexin as a subtype-specific molecular marker of glutamatergic neurons to address whether certain precursors in early cortical anlage are already committed to a single molecular phenotype. Dissociated cells from lateral cortex at embryonic day 12 were labelled with a replication-deficient retroviral vector containing the bacterial lacZ gene, and cultured in a monolayer for 3 weeks. Double-immunofluorescence staining was used to simultaneously visualize latexin- and beta-galactosidase-immunopositive neurons. Out of 572 beta-galactosidase-immunopositive clones examined, 27 clones contained latexin-expressing neuron(s). Of these 27 clones, 25 clones that contained three or more neurons were mixed clones containing both latexin-immunopositive and -immunonegative neurons. These results suggest that committed precursors to producing solely latexin-expressing neurons are not exist in the early cerebral cortical anlage.

Animals↗

PubMed2006

Intrinsic molecular signature of breast cancer in a population-based cohort of 412 patients.

BACKGROUND: Molecular markers and the rich biological information they contain have great potential for cancer diagnosis, prognostication and therapy prediction. So far, however, they have not superseded routine histopathology and staging criteria, partly because the few studies performed on molecular subtyping have had little validation and limited clinical characterization. METHODS: We obtained gene expression and clinical data for 412 breast cancers obtained from population-based cohorts of patients from Stockholm and Uppsala, Sweden. Using the intrinsic set of approximately 500 genes derived in the Norway/Stanford breast cancer data, we validated the existence of five molecular subtypes--basal-like, ERBB2, luminal A/B and normal-like--and characterized these subtypes extensively with the use of conventional clinical variables. RESULTS: We found an overall 77.5% concordance between the centroid prediction of the Swedish cohort by using the Norway/Stanford signature and the k-means clustering performed internally within the Swedish cohort. The highest rate of discordant assignments occurred between the luminal A and luminal B subtypes and between the luminal B and ERBB2 subtypes. The subtypes varied significantly in terms of grade (p < 0.001), p53 mutation (p < 0.001) and genomic instability (p = 0.01), but surprisingly there was little difference in lymph-node metastasis (p = 0.31). Furthermore, current users of hormone-replacement therapy were strikingly over-represented in the normal-like subgroup (p < 0.001). Separate analyses of the patients who received endocrine therapy and those who did not receive any adjuvant therapy supported the previous hypothesis that the basal-like subtype responded to adjuvant treatment, whereas the ERBB2 and luminal B subtypes were poor responders. CONCLUSION: We found that the intrinsic molecular subtypes of breast cancer are broadly present in a diverse collection of patients from a population-based cohort in Sweden. The intrinsic gene set, originally selected to reveal stable tumor characteristics, was shown to have a strong correlation with progression-related properties such as grade, p53 mutation and genomic instability.

Breast Neoplasms↗

PubMed1999

Methods for subtyping and molecular comparison of human viral genomes.

The development over the past two decades of molecular methods for manipulation of RNA and DNA has afforded molecular virologists the ability to study viral genomes in detail that has heretofore not been possible. There are many molecular techniques now available for typing and subtyping of viruses. The available methods include restriction fragment length polymorphism analysis, Southern blot analysis, oligonucleotide fingerprint analysis, reverse hybridization, DNA enzyme immunoassay, RNase protection analysis, single-strand conformation polymorphism analysis, heteroduplex mobility assay, nucleotide sequencing, and genome segment length polymorphism analysis. The methods have certain advantages and disadvantages which should be considered in their application to specific viruses or for specific purposes. These techniques are likely to become more widely used in the future for epidemiologic studies and for investigations into the pathophysiology of virus infections.

Blotting, Southern↗

PubMed2004

Outbreak of Pseudomonas aeruginosa infections caused by commercial piercing of upper ear cartilage.

CONTEXT: Sporadic infections following ear piercing are well documented, but common-source outbreaks are rarely recognized. OBJECTIVE: To investigate reports of auricular chondritis subsequent to commercial ear piercing. DESIGN, SETTING, AND SUBJECTS: Outbreak investigation by Oregon public health agencies, including cohort study of persons pierced at a jewelry kiosk in August-September 2000, environmental sampling, and molecular subtyping of isolates. Confirmed cases had Pseudomonas aeruginosa cultured from ear wounds. Suspected cases had signs and symptoms of external ear infection, including drainage of pus or blood for at least 14 days. MAIN OUTCOME MEASURES: Risk factors for infection and comparison of bacterial isolates by molecular subtyping. RESULTS: From 186 piercings in 118 individuals, we identified 7 confirmed P aeruginosa infections and 18 suspected infections. Confirmed cases were 10 to 19 years old. Most were initially treated with antibiotics ineffective against Pseudomonas. Four were hospitalized, 4 underwent incision and drainage surgeries (1 as an outpatient), and several were cosmetically deformed. Upper ear cartilage piercing was more likely to result in either confirmed or suspected infection than was lobe piercing (confirmed: RR undefined, P<.001; suspected: RR, 3.6; 95% confidence interval, 1.5-8.5). All persons with confirmed infections had their ear cartilage pierced with an open, spring-loaded piercing gun. Patient isolates were indistinguishable by molecular subtyping, and matching isolates were recovered from a disinfectant bottle and nearby sink. At least 1 worker admitted sometimes spraying the disinfectant on the ear studs before piercing. CONCLUSIONS: Ear cartilage piercing is inherently more risky than lobe piercing. Clinicians should respond aggressively to potential auricular chondritis and consider Pseudomonas a possible cause pending culture results.

Abscess↗

PubMed2002

Novel evolutionary analyses of full-length HIV type 1 subtype C molecular clones from Cape Town, South Africa.

Understanding the origin, distribution, and evolving dominance of HIV-1 subtype C strains is an important component in the design and evaluation of a globally effective AIDS vaccine. To better understand subtype C viruses, we constructed complete molecular clones of primary, CCR-5-using isolates from South Africa and analyzed the molecular phylogenies of these clones using best fitting evolutionary substitution models. Analyses were performed on three full-length sequences, and on the individual genes. All clones were nonrecombinant, and although two of three had open reading frames and intact splice sites, they were not infectious. At the genomic level, the models demonstrated the increasing variability of subtype C in South Africa. At the subgenomic level, they revealed marked differences in the evolutionary patterns of individual genes, a finding that suggests that the genes are under different selective pressures and constraints. These data underscore the dynamic nature of the subtype C epidemic and emphasize the need for continuous monitoring of local strains.

Acquired Immunodeficiency Syndrome↗

PubMed2005

New insights into beta-adrenoceptors in smooth muscle: distribution of receptor subtypes and molecular mechanisms triggering muscle relaxation.

1. The beta-adrenoceptor is currently classified into beta(1), beta(2) and beta(3) subtypes and all three subtypes are expressed in smooth muscle. Each beta-adrenoceptor subtype exhibits tissue-specific distribution patterns, which may be a determinant controlling the mechanical functions of corresponding smooth muscle. Airway and uterine smooth muscles abundantly express the beta(2)-adrenoceptor, the physiological significance of which is established as a fundamental regulator of the mechanical activities of these muscles. Recent pharmacomechanical and molecular approaches have revealed roles for the beta(3)-adrenoceptor in the gastrointestinal tract and urinary bladder smooth muscle. 2. The beta-adrenoceptor is a G(s)-protein-coupled receptor and its activation elevates smooth muscle cAMP. A substantial role for a cAMP-dependent mechanism(s) is generally believed to be the key trigger for eliciting beta-adrenoceptor-mediated relaxation of smooth muscle. Downstream effectors activated via a cAMP-dependent mechanism(s) include plasma membrane K(+) channels, such as the large-conductance, Ca(2+)-activated K(+) (MaxiK) channel. 3. Beta-Adrenoceptor-mediated relaxant mechanisms also include cAMP-independent signalling pathways. This view is supported by numerous pharmacological and electrophysiological lines of evidence. In airway smooth muscle, direct activation of the MaxiK channel by G(s)alpha is a mechanism by which stimulation of beta(2)-adrenoceptors elicits muscle relaxation independently of the elevation of cAMP. 4. The cAMP-independent mechanism(s) is also substantial in beta(3)-adrenoceptor-mediated relaxation of gastrointestinal tract smooth muscle. However, in the case of the beta(3)-adrenoceptor, a delayed rectified K(+) channel rather than the MaxiK channel seems to mediate, in part, cAMP-independent relaxant mechanisms. 5. In the present article, we review the distribution of beta-adrenoceptor subtypes in smooth muscle tissues and discuss the molecular mechanisms by which each subtype elicits muscle relaxation, focusing on the roles of cAMP and plasma membrane K(+) channels.

Adrenergic Agonists↗

PubMed2026

Transcriptomic profiling across stages of non-muscle-invasive bladder cancer identifies fibroblast activation protein-alpha as a stromal biomarker associated with progression.

BACKGROUND: T1 non-muscle-invasive bladder cancer (NMIBC) represents a biologically aggressive subgroup with substantial heterogeneity in recurrence and progression risk. Current clinicopathological risk stratification tools lack sufficient precision to identify patients at the highest risk of progression to muscle-invasive bladder cancer (MIBC). OBJECTIVE: To characterize transcriptomic differences between T1 and < T1 (Ta/Tis) NMIBC and to explore the association of fibroblast activation protein-α (FAP) gene expression with disease progression. METHODS: Transcriptomic profiling was performed on formalin-fixed paraffin-embedded (FFPE) tumor tissue from 66 patients with primary, treatment-naïve NMIBC and 5 patients with T2 disease (included for exploratory comparisons). Analyses included differential gene expression, gene set enrichment analysis (GSEA), molecular subtyping, immune cell deconvolution, and evaluation of FAP expression in relation to recurrence and progression. External validation of FAP was conducted in three independent NMIBC cohorts. RESULTS: T1 tumors demonstrated a distinct transcriptomic profile compared with < T1 tumors, characterized by enrichment of cell cycle-related and metabolic pathways and a higher prevalence of aggressive molecular subtypes. Despite these molecular differences, no statistically significant differences in recurrence-free, progression-free, cancer-specific, and overall survival were observed, likely reflecting limited event numbers. Among recurrent tumors, early recurrences (≤ 24 months) were associated with epithelial-mesenchymal transition signatures. FAP expression increased with tumor stage (p = 0.0005) and was associated with progression (p = 0.002) and mortality (p = 0.01). Patients with tumors in the highest quartile of FAP expression had worse progression-free survival. This association was consistently observed in three external NMIBC cohorts. CONCLUSIONS: T1 NMIBC exhibits distinct transcriptomic features suggestive of increased biological aggressiveness. Elevated FAP expression is reproducibly associated with progression risk across multiple cohorts, supporting its potential role as a biomarker of aggressive disease. Given the limited number of progression events, these findings should be considered hypothesis-generating and warrant prospective validation before clinical implementation.

Humans↗

PubMed2026

Stage-Independent Real-Time Subtype Classification and Comprehensive Biopsy Profiling of Urothelial Carcinomas by the Lund Taxonomy System.

Bladder cancer is a heterogeneous malignancy with diverse clinical outcomes, and conventional pathological assessment alone is insufficient to capture its underlying biology. Gene expression profiling can stratify tumors into molecular subtypes with prognostic and predictive potential, but the reliability of transcriptomic classification and its clinical utility remains to be established. The translational/observational UROSCANSEQ study (ISRCTN15459149) prospectively evaluates RNA-based Lund Taxonomy (LundTax) molecular subtype classification in a clinical setting. Among 784 consecutive biopsies collected between 2018 and 2022, RNA sequencing was successful for 90% of all biopsies, encompassing 662 bladder cancer patients with a stage distribution of 48% Ta, 27% T1, 24% ≥T2, and 1% CIS. We demonstrate that the LundTax subtype classification algorithm, applied to individual samples, accurately identifies cancer cell phenotypes with characteristic gene and protein expression patterns in a manner robust to RNA quality, data preprocessing strategies, and batch effects, supporting its clinical feasibility across both non-muscle-invasive and muscle-invasive disease. We further extend the LundTax framework by incorporating single-sample molecular risk scores reflecting tumor grade, proliferation, and progression risk, as well as tumor microenvironment signatures. Both risk scores and overall immune and stromal content in biopsies were significantly associated with an increased risk of clinical progression in noninvasive disease. In a separate analysis of the relative cellular composition of the tumor microenvironment, however, only the fraction of natural killer cells remained significant. Together, the expanded LundTax system provides a comprehensive molecular portrait of individual tumor biopsies. By explicitly separating cancer cell-intrinsic phenotypes, prognostic indexes, and microenvironmental signals, the framework minimizes biological confounding and establishes a strong foundation for future studies evaluating clinical outcomes and treatment responses.

Humans↗

PubMed2026

Plasma cell-CD8+ T cell co-enrichment distinguishes immunotherapy-responsive hepatocellular carcinoma subtypes.

BACKGROUND: Hepatocellular carcinoma (HCC) is characterised by significant racial disparities in incidence and outcomes, yet whether these reflect distinct tumour biology or differential distribution of molecular subtypes among immunotherapy patients remains unclear. METHODS: We characterised molecular heterogeneity among 46 patients with HCC of differing background population from the NCI-CLARITY cohort receiving immune checkpoint inhibitor therapy, using transcriptomic and genomic profiling, with validation across multiple independent cohorts. RESULTS: Differential expression analysis comparing African American versus non-African American patients identified 126 genes, of which 55 demonstrated tumour-specific expression across independent validation cohorts with paired tumour-normal samples. Consensus clustering revealed two molecular subtypes with no significant race association, indicating these clusters capture tumour-intrinsic biology rather than ancestry. The genomic landscape showed minimal differences between subtypes. A prognostic signature derived from these expression profiles demonstrated significant risk stratification in the NCI-CLARITY cohort and TCGA-LIHC, but not in Asian cohorts, suggesting population-specific applicability. Immune deconvolution revealed that the two subtypes represent distinct immune microenvironments: one subtype exhibited markedly elevated plasma cell infiltration with strong plasma cell-CD8+T cell correlation suggesting coordinated adaptive immunity, along with elevated tertiary lymphoid structure signatures. The other subtype showed regulatory T cell-macrophage correlation and enrichment for immune-excluded phenotypes. The immune-enriched subtype trended towards higher immunotherapy response rates. CONCLUSIONS: Molecular heterogeneity in HCC reveals distinct tumour-immune ecosystems that transcend racial classification. Tumour immune heterogeneity in HCC reflects distinct molecular patterns, with immune hot tumours characterised by elevated tertiary lymphoid structure signatures and enriched plasma cell and CD8+T cells. These patterns may serve as prognostic biomarkers for immunotherapy patient stratification and demonstrate the value of diverse cohort representation in identifying clinically relevant therapeutic targets.

Gastrointestinal Cancer↗

PubMed2026

Dietary Polyphenol Acteoside-Related Molecular Signatures in Clear Cell Renal Cell Carcinoma: Multi-Omics Profiling and Functional Validation of IMPDH1.

Clear cell renal cell carcinoma (ccRCC) is characterized by substantial metabolic and molecular heterogeneity, but the disease-relevant programs associated with acteoside, a dietary polyphenol, remain poorly understood. We integrated predicted acteoside targets with bulk, single-cell, and spatial transcriptomic data from ccRCC and combined molecular subtyping with cross-cohort machine-learning analysis. Acteoside-related signatures were preferentially enriched in malignant compartments and increased with tumor grade and stage. Consensus clustering identified two molecular subtypes with distinct biological and clinical features. C1 was associated with immune activation, metabolic activity, and more favorable survival, whereas C2 showed greater genomic instability, reduced renal epithelial differentiation, and poorer outcomes. We further benchmarked multiple machine-learning strategies and established a 10-gene prognostic model that retained predictive performance across independent cohorts, with IMPDH1 emerging as the strongest risk-associated feature. Functional experiments confirmed the biological relevance of IMPDH1: its knockdown suppressed ccRCC cell proliferation, DNA synthesis, colony formation, and migration, whereas overexpression produced the opposite effects. Together, these findings indicate that acteoside-related molecular signatures capture clinically relevant heterogeneity in ccRCC and provide a framework for linking dietary-polyphenol-related molecular space with tumor biology. The identification and functional validation of IMPDH1 further highlight its potential importance in ccRCC progression.

IMPDH1↗

PubMed2002

Human immunodeficiency virus type 1 subtype C molecular phylogeny: consensus sequence for an AIDS vaccine design?

An evolving dominance of human immunodeficiency virus type 1 subtype C (HIV-1C) in the AIDS epidemic has been associated with a high prevalence of HIV-1C infection in the southern African countries and with an expanding epidemic in India and China. Understanding the molecular phylogeny and genetic diversity of HIV-1C viruses may be important for the design and evaluation of an HIV vaccine for ultimate use in the developing world. In this study we analyzed the phylogenetic relationships (i) between 73 non-recombinant HIV-1C near-full-length genome sequences, including 51 isolates from Botswana; (ii) between HIV-1C consensus sequences that represent different geographic subsets; and (iii) between specific isolates and consensus sequences. Based on the phylogenetic analyses of 73 near-full-length genomes, 16 "lineages" (a term that is used hereafter for discussion purposes and does not imply taxonomic standing) were identified within HIV-1C. The lineages were supported by high bootstrap values in maximum-parsimony and neighbor-joining analyses and were confirmed by the maximum-likelihood method. The nucleotide diversity between the 73 HIV-1C isolates (mean value of 8.93%; range, 2.9 to 11.7%) was significantly higher than the diversity of the samples to the consensus sequence (mean value of 4.86%; range, 3.3 to 7.2%, P < 0.0001). The translated amino acid distances to the consensus sequence were significantly lower than distances between samples within all HIV-1C proteins. The consensus sequences of HIV-1C proteins accompanied by amino acid frequencies were presented (that of Gag is presented in this work; those of Pol, Vif, Vpr, Tat, Rev, Vpu, Env, and Nef are presented elsewhere [http://www.aids.harvard.edu/lab_research/concensus_sequence.htm]). Additionally, in the promoter region three NF-kappa B sites (GGGRNNYYCC) were identified within the consensus sequences of the entire set or any subset of HIV-1C isolates. This study suggests that the consensus sequence approach could overcome the high genetic diversity of HIV-1C and facilitate an AIDS vaccine design, particularly if the assumption that an HIV-1C antigen with a more extensive match to the circulating viruses is likely to be more efficacious is proven in efficacy trials.

AIDS Vaccines↗

PubMed2026

Molecular Signature of Prediabetes With High-Risk of Diabetes Revealed by Deep Plasma Proteome.

AIMS: Prediabetes is biologically heterogeneous, but molecular subtypes linked to diabetes progression remain poorly defined. We aimed to identify plasma proteome-based subtypes of impaired fasting glucose (IFG), characterise their molecular features and assess their association with future diabetes risk. MATERIALS AND METHODS: We quantified 2584 plasma proteins using liquid chromatography-mass spectrometry in 538 IFG participants from a prospective discovery cohort (Nutrition and Health of Aging Population in China, NHAPC). Proteomic subtypes were defined by consensus clustering, linked to longitudinal changes in insulin sensitivity and incident type 2 diabetes mellitus (T2DM), which were further validated in an independent Shanghai Brain Aging Study (SBAS) cohort. RESULTS: Two reproducible IFG molecular subtypes based on plasma proteomics were identified. The high-risk subtype showed higher incident diabetes and a greater 6-year decline in insulin sensitivity and was characterised by enrichment of glycolysis/gluconeogenesis, insulin signalling and neutrophil degranulation, together with a dyslipidemic lipidomic profile indicating co-dysregulation of glucose and lipid homeostasis. The low-risk subtype demonstrated a higher complement cascade and high-density lipoprotein particle remodelling signature. In the high-risk subtype, key proteins and lipids showed stronger associations with longitudinal declines in insulin sensitivity, including PPBP, PGK1 and ALDOA, as well as PE-P 18:0/20:3 and PE-P 18:1/20:3. CONCLUSIONS: Proteome-based molecular subtyping stratifies IFG individuals with similar fasting glucose levels but distinct biology and future diabetes risk, supporting earlier and more targeted prevention.

Humans↗

PubMed2006

Constitutional UPD for chromosome 11p15 in individuals with isolated hemihyperplasia is associated with high tumor risk and occurs following assisted reproductive technologies.

Isolated hemihyperplasia (IH) refers to a distinct diagnosis involving asymmetric overgrowth of single or multiple organs or regions of the body and can result from various genomic changes including molecular alterations of 11p15; these are paternal uniparental disomy (UPD), and alterations of methylation at two imprinting centers at 11p15: IC1 (H19) and IC2 (KCNQ1OT1). As little information is available on the molecular basis of tumor development in IH, or on the frequency of tumors in children with different molecular subtypes of IH, molecular testing was undertaken on 51 patients with IH and revealed: 8 (16%) with UPD, 3 (6%) with hypomethylation at KCNQ1OT1, and 0 with hypermethylation at H19. Of the 8 patients with UPD, 4 had tumors (3 hepatoblastomas, 1 Wilms tumor); 0/3 patients with hypomethylation at KCNQ1OT1 had a tumor; of the remaining 40 with no molecular alterations, 6 had tumors (3 Wilms tumors, 2 neuroblastomas, 1 adrenocortical adenoma). The 50% tumor frequency in patients with IH and UPD was statistically significantly higher than the 15% tumor frequency in those with IH and no molecular alteration detected (Fisher's exact test P = 0.047, OR 5.67). This is the first demonstration that UPD at 11p15 in patients with IH confers a higher tumor risk than in patients with IH without this molecular change. Of note, two of the eight patients with UPD and IH were conceived using assisted reproductive technologies (ART), thus raising the question whether ART might impact the rate of somatic recombination during embryonic development.

Abnormalities, Multiple↗