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PubMed1991

M1 and M3 muscarinic receptor subtypes in rat forebrain.

At least three pharmacologically different muscarinic receptor subtypes (M1, M2 and M3) have been identified in rat brain. While M1 and M2 subtypes can be directly labelled by selective ligands (3H-pirenzepine and 3H-AF-DX 116, respectively), there are no truly selective ligands for the M3 subtype. In the present study, we have investigated a possible method of studying the pharmacological M3 subtype in rat forebrain using the non-selective labelled antagonist 3H-N-methyl-scopolamine (3H-NMS) in the presence of unlabelled pirenzepine to protect the M1 subtype. The results obtained in kinetic experiments using 3H-NMS in presence of 30.10(-9) M unlabelled pirenzepine (Kon 1.2.10(-8) M-1 m-1, Koff 4.7.10(-2) m-1 and Kd 0.4.10(-9) M) are compatible with the studies carried out in rat pancreatic islets and submaxillary gland which contain predominantly the M3 subtype. We have also performed inhibition experiments with the selective antagonist AF-DX 116. Due to the small proportion of M2 receptors present in rat forebrain, this drug is able to discriminate between M1 and non M1 non M2 receptor subtypes in competition experiments with 3H-NMS versus AF-DX 116 (Ki values 0.28.10(-6) M and 4.3.10(-6) M, respectively). When the competition experiments were performed using 3H-NMS in presence of 30.10(-9) M unlabelled pirenzepine, the Ki value obtained was 3.8.10(-6) M, very close to the value obtained for the non M1 non M2 receptor in competition experiments with 3H-NMS versus AF-DX 116 and in excellent agreement with the affinity of this drug for the glandular M3 subtype. All these data suggest that the approach using the non-selective antagonist 3H-N-methyl-scopolamine in presence of unlabelled pirenzepine allows the study of the pharmacological M3 subtype in rat forebrain.

Animals↗

PubMed1978

Clustering of different subtypes of hepatitis B surface antigen in families of patients with chronic liver diseases.

Clustering of hepatitis B surface antigen (HBsAg) with both subtypes adr and adw in three families of patients with chronic liver diseases or hepatocellular carcinoma was demonstrated in Taiwan where adw is the main subtype. The subtype in the children was similar to that in their mothers, suggesting maternal transmission. In all the family units clustered with different subtypes, the same pattern occurred, invariably with fathers carrying HBsAg/adr and the children carrying HBsAg/adw. The subtype difference clearly rules out the transmission of hepatitis B virus (HBV) from father. Horizontal infection with the locally dominant adw-subtyped HBV in the children of fathers carrying HBsAg/adr explains the discrepancy of the subtypes in these families. Clustering of two HBsAg-positive brothers with hepatocellular carcinoma in one of the families was found. That both adr-subtyped and adw-subtyped HBV are capable of inducing chronic active hepatitis in another family suggests that host factors are probably more important in determining the clinical course of HBV infection.

Adult↗

PubMed1987

Synthesis and degradation of H1 histone subtypes in mouse lymphoma L5178Y cells.

H1 histone of mouse lymphoma L5178Y was fractionated into five subtypes, I-V, by Bio-Rex 70 column chromatography. The rates of synthesis of subtypes III and V were higher than those of I, II, and IV, as determined by the measurement of [3H]lysine incorporation. The degradation of the subtype was estimated assuming first order kinetics; subtypes III and V had half-lives of 18 h and 25 h, respectively, and the three other subtypes all had half-lives of 63 h. The syntheses of these subtypes during the cell cycle were examined using synchronized cultures. The syntheses of subtypes I, II, and IV started at the beginning of S phase, whereas those of III and V started in mid-S phase. The syntheses of III and V were at least 1.5-2 times more rapid than those of I, II, and IV, and their active synthesis was accompanied by their rapid degradation. The five subtypes of H1 were further characterized in relation to phosphorylation. Each showed characteristic differences in its synthetic pattern or phosphorylation, and we concluded that each H1 subtype has its own specific function at least in the process of replication of chromatin.

Animals↗

PubMed1995

Heterogeneity of HLA-B35. Oligotyping and direct sequencing for B35 subtypes reveals a high mismatching rate in B35 serologically compatible kidney and bone marrow donor/recipient pairs.

We used a simple HLA-B35 PCR/SSO-oligotyping procedure, combined with exon 3 direct sequencing for the analysis of B35 subtype frequencies in our population, and for the evaluation of the degree of B35-subtype compatibility in serologically matched unrelated bone marrow and kidney transplant pairs. B*3501 was the most frequent allele (0.6), followed by B*3503 (0.19), B*3502 (0.13), B*3508 (0.07), and B*3505 (< 0.01). HLA-B35-subtype matching of donors and recipients was strongly dependent on the stringency of ABDRB1 matching. Among 10 kidney donor/recipient pairs, only 30% were B35-subtype-matched. Due to the lack of ABDRB1 haplotype matching, this low degree of matching was not better than what would be expected on the basis of the subtype frequency distribution in the population. In contrast, HLA-B35 subtype compatibility was higher in unrelated bone marrow donor/recipient pairs that were serologically ABDR-matched: 30 of the 62 (48.4%) B35-positive combinations tested were B35-subtype-compatible. When all patient/donor plus donor/donor combinations (n = 160) were taken into account, 46% of the ABDR-matched pairs were B35-subtype-compatible. When only pairs that were DRB1/DRB3/DRB5-subtype-matched by oligotyping (n = 62) were considered, 71% were B35-subtype-compatible. The fact that a significant percent of patient/donor pairs matched by conventional HLA-typing are found incompatible, as shown here for B35, explains the difficulties in assessing the beneficial effect of HLA matching in transplantation.

Base Sequence↗

PubMed1995

Expression of muscarinic receptor subtype mRNA in the human ciliary muscle.

PURPOSE: To investigate the expression of the muscarinic receptor (mAChR) subtypes (m1, m2, m3, m4, and m5) in the human ciliary muscle. METHODS: cDNA probes specific for the m1 to m5 subtypes were used to characterize the expression of subtype-specific mRNAs by in situ hybridization and Northern blot analysis on a cell line derived from human ciliary muscle tissue (H7CM), sectioned tissue from four donors, and fresh human ciliary muscle tissue from three donors. RESULTS: Messenger RNA for m2, m3, and m5 was detected in situ hybridization and Northern blot analysis in the H7CM cell line and in human ciliary muscle tissue from the donors. In human ciliary muscle tissues, the expression of mRNA of the m2 and m3 subtypes was more prominent in the circular portion than in the longitudinal portion. In contrast, mRNA for the m5 subtype was greater in the longitudinal portion than in the circular portion. Additionally, Northern blot analysis showed that m1 and m4 were expressed in ciliary muscle tissue. CONCLUSION: These studies show that the human ciliary muscle definitely expresses the mRNA of subtypes m2, m3, and m5, and may also express the mRNA of m1 and m4. Although the expression of mRNA for the m2, m3, and m5 subtypes differed between the circular and longitudinal portions of the ciliary muscle, the strong expression of all three subtypes of muscarinic receptors by both portions demonstrates that the differential distribution of muscarinic subtypes probably is not responsible for the dissociation between outflow facility and accommodation that can occur under certain conditions.

Adult↗

PubMed1995

Subtype selectivity of the positive allosteric action of alcuronium at cloned M1-M5 muscarinic acetylcholine receptors.

The neuromuscular blocking drug alcuronium was found earlier to increase the affinity of muscarinic receptors for methyl-N-scopolamine (NMS). This effect could be observed in some but not in other tissues. Subtype selectivity of the positive allosteric action of alcuronium was now investigated in radioligand binding experiments in Chinese hamster ovary (CHO) cells stably transfected with the genes encoding the M1-M5 subtypes of muscarinic receptors. Alcuronium had a particularly high affinity for the M2 receptor subtype (Kd = 0.6 microM) and its affinity for muscarinic receptor subtypes diminished in the order M2 > M4 = M3 > M1 > M5. Alcuronium allosterically increased the binding of (3H)NMS to membranes containing receptors of the M2 (cooperativity factor alpha = 0.38) and M4 subtypes (alpha = 0.72) and inhibited the binding of (3H)NMS to membranes containing receptors of the M1, M3 and M5 subtypes (alpha = 3.35-4.35). The positive effects of alcuronium could also be observed in experiments with (3H)NMS binding to intact whole cells, indicating that the positive allosteric action of alcuronium occurs by alcuronium binding to receptor domains that are accessible from the extracellular space. Alcuronium diminished the affinity for (3H)quinuclidinyl benzilate [(3H)QNB] at all five subtypes of muscarinic receptors and slowed down the dissociation of both (3H)NMS and (3H)QNB; its decelerating effect on radioligand dissociation was most pronounced at the M2 receptor subtype. Differences between the effects of alcuronium on individual muscarinic receptor subtypes are apparently responsible for differences between the allosteric effects of alcuronium on muscarinic receptors in various tissues that had been described previously.

Alcuronium↗

PubMed1995

Differential distribution of alpha 2-adrenoceptor subtypes and messenger RNA expression between renal cortex of salt-sensitive and salt-resistant Sabra rats.

OBJECTIVE: To assess whether alterations of alpha 2-adrenoceptor subtypes in distribution and gene expression in the renal cortex could explain the predisposition to salt-sensitivity or salt-resistance in Sabra rats. DESIGN: Studies were performed using plasma membranes and RNA preparations from renal cortex of 8- to 10-week-old Sabra salt-sensitive (SBH) and salt-resistant (SBN) rats on a normal-sodium diet. METHODS: The alpha 2-adrenoceptor subtypes were determined by competition experiments with [3H]-yohimbine or [3H]-RX821002. Their gene expression was studied by RNA-directed complementary DNA synthesis followed by Taq DNA polymerase amplification. RESULTS: Binding studies showed that alpha 2B- and alpha 2A-adrenoceptor subtypes represented in SBN 72 and 28% of the maximal binding capacities of the two radioligands, respectively. In contrast, only the alpha 2B subtype was detected in the SBH rat. However, the use of guanoxabenz disclosed alpha 2B-adrenoceptors in alpha 2B1 and alpha 2B2 subtypes. The densities of those alpha 2B subtypes appeared to be higher in the SBH rat than in the SBN rat. Messenger RNA corresponding to alpha 2A and alpha 2B subtypes were found both in SBH rats and in SBN rats. The expression of the alpha 2B subtype was permanently higher in the SBH rats than in the SBN rats. The expression of the alpha 2A gene in the SBH rats suggests a specific SBH post-transcriptional regulation resulting in the absence of alpha 2A-adrenoceptor. CONCLUSIONS: Differences exist in the renal cortex concerning expression and distribution of alpha 2-adrenoceptor subtypes between SBH and SBN rats. From these differences there might result different alpha 2-adrenoceptor-mediated renal functions in SBH and in SBN rats, which could lead to a predisposition to sensitivity or resistance to a high sodium intake.

Animals↗

PubMed1994

[Effect of alpha 1-adrenoceptor subtypes on beta-adrenoceptor mediated positive inotropic response in rat left atria].

The distribution of the alpha 1-adrenoceptor (alpha 1-AR) subtypes and the effects of activation of alpha 1-AR subtypes on the beta-adrenoceptor (beta-AR) mediated positive inotropic response were investigated. The radioligand binding assays indicated that the Bmax and Kd values were 11.7 +/- 18 fmol/mg.protein and 86.0 +/- 9.6 pmol/L respectively. Pretreatment of the preparations with 20 mumol/L chloroethylclonidine (CEC) which inactivated alpha 1B subtype, decreased the Bmax to 45.7 +/- 5.2 fmol/mg.protein (P < 0.01). The inhibition curves of 5-methyl-urapidil were best fitted to two site model and indicated that alpha 1A subtype took 28.5% of total 125IBE specific binding sites. In the functional experiments, norepinephrine (NE) induced a positive inotropic response in a concentration dependent manner by activation of both beta- and alpha 1-AR. The concentration-response curves (CRC) for NE were shifted rightward after the pretreatment of the preparations with 20 mumol/L CEC, but leftward in the presence of 1 nmol/L WB4101. In the presence of 10 mumol/L phentolamine which inactivated both alpha 1-AR subtypes, the CRC for NE were shifted leftward. When alpha 1-AR was activated by phenylephrine the CRC for isoproterenol (selective beta-AR agonist) were shifted rightward. The results suggested that the alpha 1B subtype enhanced while the alpha 1A subtype inhibited the beta-AR mediated positive inotropic response. When both alpha 1A and alpha 1B subtypes were activated simultaneously the alpha 1A subtype showed a dominate role.

Animals↗

PubMed1993

Characterization of alpha 2-adrenergic receptor subtype-specific antibodies.

Subtypes of alpha 2-adrenergic receptors have been defined pharmacologically in a variety of mammalian tissues. The alpha 2A, alpha 2B, alpha 2C, and most recently alpha 2D subtypes have been characterized by their affinities for selective receptor antagonists and agonists. The genes that may encode the alpha 2A, alpha 2B, and alpha 2C subtypes have been identified in human and rat. In human these genes are termed alpha 2-C10, alpha 2-C2, and alpha 2-C4, respectively, based on their chromosomal localization, whereas three genes, designated RG20 alpha 2, RNG alpha 2, and RG10 alpha 2, are thought to be the corresponding rat homologues. These assignments were based on the pharmacology of the cloned receptor genes expressed in transfected cells and on the detection of homologous mRNAs by Northern blot analyses in cell lines or tissues with pharmacologically defined alpha 2-adrenergic receptors. However, the subtype assignment of cloned genes has not been fully resolved by these means. To help clarify the subtype assignment, we have raised antibodies against sequences from the divergent third intracellular loop of the human and rat alpha 2-adrenergic receptors. These antibodies were found to be subtype specific in immunoprecipitating either the cloned receptors expressed by DNA transfection or the pharmacologically defined receptors prepared from various tissues. Our immunological data corroborate the assignments of alpha 2-C2/RNG alpha 2 as encoding the alpha 2B subtype in NG108-15 cells and rat neonatal lung and of alpha 2-C4/RG10 alpha 2 as encoding the alpha 2C subtype in opossum kidney cells. Furthermore, antibodies against alpha 2-C10 and RG20 alpha 2 but not alpha 2-C2/RNG alpha 2 or alpha 2-C4/RG10 alpha 2 were both found to recognize alpha 2-adrenergic receptors expressed in rat submaxillary glands and in bovine pineal gland, two tissues with alpha 2D pharmacology. Because three genes were identified in the rat and human genome, these data suggest that the pharmacologically defined "alpha 2D receptor" is genetically of the alpha 2A subtype.

Adrenergic alpha-Agonists↗

PubMed1975

Further data on HBs subtypes: geographical distribution.

1123 HBs antigens from silent carriers of different parts of Europe, Africa and Asia were subtyped and classed in the eight categories previously described: a1y(w1), a2yl(w2), a2(3)y(w3), a3y(w4), ayr, a2ld(w2), a3d(w4) and adr: We have showed that w can be subdivided into the system of a subdeterminants, but for the present time, we do not know if r is a fifth subdeterminant of a. Subtyping was performed by CIEP and by ID using antisera from guinea pigs and goats immunized with selected HBs antigens. With these 8 categories it is possible to greatly increase our knowledge about the geographical distribution of HBs antigen: in Africa six areas can be distinguished: North Africa with a predominance of a2ly(w2) (75%) and with none a3y(w4); areas between North and West Africa where a2ly(w2) and a3y(4) represent respectively 62.8% and 25.7%; West Africa with a great predominance of a3y(w4) (84.5%); Central Africa with less a3y(w4) (53.4%), appearance of a2ld(w2) (8.7%) and presence of a2ly(w2) (37%); East Africa appears to be especially a2ld(w) (only 3 sera from Burundi); South Africa with a great predominance of a2ld(w2) (86%) and with ay subtype represented by a2(3)y(w3), very exceptional in the other parts of Africa. In France, The Netherlands, Hungary, a2ld(w) subtype is predominant, respectively 73.3%, 74% and 63%, a2(3)y(w3) is the main ay subtype in France and the only one in The Netherlands whereas in Hungary the same amount of a2ly(w) and a2(3)(w) is encountered. In Rumania, Italy and Greece, a great predominance of ay subtype is found (80%): a2ly(w2) is predominant in Rumania (66%) and Italy (as in North Africa) whereas a weak predominance of a2(3)y(w3) over a2ly(w2) is found in Greece. In the Antilles, 75% of a2ld(w2) are encountered. In the Far East, a great predominance of adr is found in Laos, Japan and Thailand (100% and 84% respectively) but no adr is encountered in Vietnam where 8 a1y(w1) and 1 ayr are found of of 11 HBs sera. This a1y(w1) subtype has also been found, although infrequently, in some countries of Africa. Among French people who have lived in Africa, many examples are found which show that the HBs subtype is related to the country and does not seen to depend on the host. Among the French who have been contaminated in Indochina all are carriers of adr HBsAg and none exhibits an a1y(w1) subtype.

Africa↗

PubMed1994

The alpha 1-adrenergic receptor that mediates smooth muscle contraction in human prostate has the pharmacological properties of the cloned human alpha 1c subtype.

Molecular cloning studies have revealed the existence of three subtypes of alpha 1-adrenergic receptors. However, the link between any individual subtype and its functional role in the body has remained elusive. In an effort to bridge the gap between molecular biology and pathophysiology, we have chosen a model smooth muscle system, the human prostate, and investigated the role of alpha 1 subtypes in this tissue. To determine which alpha 1-adrenergic receptor subtype mediates the contractile response of the human prostate, we first studied the pharmacological properties of three cloned human alpha 1 subtypes (alpha 1a/d, alpha 1b, and alpha 1c). Prazosin, terazosin, doxazosin, alfuzosin, and abanoquil showed no selectivity for the human alpha 1 subtypes. WB-4101 and 5-methylurapidil showed a rank order of potency of alpha 1c > alpha 1a/d >> alpha 1b. Indoramin and (+)-niguldipine were selective for the alpha 1c-adrenergic receptor, with at least 10-fold lower affinity at either alpha 1a/d or alpha 1b subtypes. SK&F104856 was found to be 6-fold more potent at the alpha 1a/d receptor subtype than at alpha 1b- or alpha 1c-adrenergic receptors. We next determined the potency of these antagonists to inhibit the phenylephrine-induced contraction of human prostatic tissue in vitro. The potencies of indoramin, 5-methylurapidil, and SK&F104856 to inhibit the contractile response and to displace [3H]prazosin from the cloned human alpha 1c subtype were similar. Our data suggest that the alpha 1 receptor that mediates the contraction of human prostate smooth muscle has the pharmacological properties of the cloned human alpha 1c-adrenergic receptor. The findings of the present study suggest that selective alpha 1c-adrenergic receptor antagonists may be clinically more efficacious and better tolerated agents for the treatment of symptomatic benign prostatic hyperplasia.

Animals↗

PubMed1993

Comparison of alpha 1-adrenergic receptor subtypes and signal transduction in SK-N-MC and NB41A3 neuronal cell lines.

We compared the alpha 1-adrenergic receptor subtypes in two neuronal cell lines, SK-N-MC (human neuroepithelioma) and NB41A3 (murine neuroblastoma). 125I-BE 2254 labeled alpha 1-adrenergic receptor binding sites in membranes from both cell lines. Pretreatment with the alpha 1B-selective alkylating agent chloroethylclonidine (CEC) completely eliminated these binding sites in NB41A3 cells but caused only a 50% loss in SK-N-MC cells. Displacement with subtype-selective antagonists suggested that NB41A3 cells express only the alpha 1B subtype, whereas SK-N-MC cells express a pharmacologically heterogeneous receptor population, including both alpha 1A and alpha 1B subtypes. Norepinephrine increased [3H] inositol phosphate formation in both cell lines, but with different sensitivities to pertussis toxin and the presence of extracellular Ca2+. CEC pretreatment eliminated this response in NB41A3 cells but caused a maximal 42% reduction in SK-N-MC cells. Use of subtype-selective antagonists showed that the [3H]inositol phosphate response involved only the alpha 1B subtype in NB41A3 cells but a combination of subtypes in SK-N-MC cells. Norepinephrine induced both transient and sustained increases in intracellular Ca2+ concentrations in both cell lines, as measured with fura-2. CEC pretreatment abolished the Ca2+ response in NB41A3 cells but had little effect in SK-N-MC cells. In SK-N-MC cells the Ca2+ response was potently blocked by alpha 1A-selective antagonists. Chelation of extracellular Ca2+ eliminated the sustained component of the Ca2+ signal in both cell lines. Poly(A)+ RNA from NB41A3, DDT1MF-2, BC3H1, and MDCK-D1 cell lines showed one or more prominent transcripts (2.2-4.2 kilobases) that strongly hybridized to the hamster alpha 1B cDNA probe but not to the bovine alpha 1C or rat alpha 1D cDNA probes. Poly(A)+ RNA from SK-N-MC cells showed multiple transcripts (1.3-5.6 kilobases) that hybridized to both hamster alpha 1B and rat alpha 1D but not bovine alpha 1C cDNA probes. We conclude that NB41A3 cells contain exclusively alpha 1B-adrenergic receptors linked to inositol phosphate formation and mobilization of intracellular Ca2+, whereas at least two alpha 1-adrenergic receptor forms, which resemble the alpha 1A and alpha 1B subtypes, coexist in SK-N-MC cells. The CEC-insensitive alpha 1A-like subtype in SK-N-MC cells is capable of increasing inositol phosphate formation and mobilizing intracellular Ca2+.

Animals↗

PubMed1996

Binding and presentation of peptides derived from melanoma antigens MART-1 and glycoprotein-100 by HLA-A2 subtypes. Implications for peptide-based immunotherapy.

Cellular immune responses to melanoma-associated Ags are the focus of ongoing studies aimed at developing immunotherapies for treatment of malignant melanoma. Melanoma predominantly affects Caucasians, a population in whom expression of HLA-A2 is prevalent. Among HLA-A2 subtypes, HLA-A*0201 is widely expressed, and HLA-A*0201-restricted, tumor-reactive CTL responses are well studied. We have observed in a group of melanoma patients an unexpectedly high frequency (approximately 20%) of non-HLA-A*0201 subtypes (*0202, *0204, and *0205), and little is known regarding antimelanoma response profiles in patients expressing such subtypes. We analyzed non-HLA-A*0201 peptide response profiles using HLA-A*0201-restricted epitopes from melanoma Ags MART-1/Melan A and glycoprotein 100. Most of these peptides bound to the majority of subtypes tested with 50% inhibitory concentrations less than 500 nM. Recognition of cells pulsed with different peptides (MART-1(27-35), G9(154), and G9(280) Flu M1(58-66)) and expressing different subtype molecules by HLA-A*0201-restricted CTL was limited to only a subset of non-HLA-A*0201 molecules, and the peptide/subtype complexes recognized varied among the effector populations tested. CTL responses elicited from PBL of patients and healthy donors expressing subtypes HLA-A*0202 and HLA-A*0205 suggested significant differences among HLA-A2 subtype function in the context of melanoma Ag presentation. These observations imply the necessity of subtyping patients considered for peptide-based protocols and highlight the need for further study of melanoma-directed cellular responses among patients expressing non-HLA-A*0201 subtypes.

Alleles↗

PubMed1997

Shedding of HIV-1 subtype E in semen and cervico-vaginal fluid.

The uneven expansion of HIV-1 subtypes in each transmitted group raises the possibility that some viruses have less/more potential by qualitative/quantitative for heterosexual transmission compared to others. In Thailand, HIV-1 subtype E is mainly spread via heterosexual route and accounts for about 95 per cent of the infected cases. To determine whether high sexual infectivity of HIV-1 subtype E is due to the presence of a virus in genital fluid, we conducted a study to characterize shedding of HIV-1 in seminal and cervico-vaginal fluids of 30 HIV-1 subtype E infected Thai couples by PCR and virus isolation methods. All subjects had no HIV-associated diseases and other sexually transmitted diseases. HIV-1 subtype E DNA was detected in 22/30 (77.33%) of cervico-vaginal and also 22/30 (77.33%) of seminal fluid samples. The isolation rate of HIV-1 from semen and cervico-vaginal secretion was 36.67 per cent and 16.67 per cent, respectively. Number of HIV-1 subtype E DNA copies in the blood is reversely correlated with the number of blood CD4+ T cells, while that in genital fluid was not related to CD4+ T cell count. An increase in shedding of HIV- DNA subtype E in female genital tract compared to other HIV subtypes reported by other investigators might be one reason to explain the rapid spread of subtype E by heterosexual transmission in Thailand.

Adolescent↗

PubMed2026

Molecular epidemiological characteristics of H9N2 subtype avian influenza virus in the external environment of western Zhejiang, China, 2014-2025.

OBJECTIVE: To elucidate the epidemiological distribution patterns of avian influenza virus (AIV) in the external environment of western Zhejiang from 2014 to 2025, analyze the molecular epidemiological characteristics of the H9N2 subtype, and assess its public health risks. METHODS: According to the Zhejiang Provincial Surveillance Program for Avian Influenza in Occupationally Exposed Populations and External Environments, real-time RT-PCR was used to detect AIV subtypes in environmental specimens. H9N2-positive samples with cycle threshold values <30 were inoculated into specific pathogen-free (SPF) embryonated chicken eggs for virus isolation, followed by whole-genome sequencing and bioinformatics analysis for phylogenetic and molecular characterization. RESULTS: A total of 7,762 specimens were tested from 2014 to 2025, with an overall positivity rate of 34.64% (2,689/7,762) for AIV. Significant differences in positivity rates were observed in seasons, regions, sampling sites, and specimen types (all p < 0.001). AIV activity peaked in winter and spring, with the highest rates detected in live poultry markets and chopping board swabs. The H9 was the predominant subtype, with co-circulation of multiple subtypes. All 48 H9N2 subtype isolates belonged to the G57 genotype, with the hemagglutinin (HA) and neuraminidase (NA) genes falling into the Y280-like branch, while the internal genes exhibited a mosaic pattern combining G1-like and F/98-like lineages. Molecular characterization analysis revealed multiple mammalian adaptive mutations, involving alterations in receptor-binding sites (T163N, H191N, T197D, T198V, Q234L, Q235M), antigenic epitopes (D280G, N285S), and glycosylation sites (218NRTF, 313NCSK). NA stalk deletion (62-64 aa), along with multiple mutations in the hemadsorption site (E/K368N, D369S/G, D401G/V, N402D, W403L/R, Q432H). Additionally, multiple key amino acid substitutions were also identified in the internal proteins. CONCLUSION: The external environment in western Zhejiang exhibits a high prevalence of AIVs with pronounced spatiotemporal clustering. H9 was the dominant subtype and co-circulated with multiple subtypes, with live poultry markets and slaughterhouses identified as high-risk settings. The H9N2 subtype AIV has accumulated multiple mammalian adaptive mutations, and exhibits genetic linkages across eastern Chinese provinces. These findings collectively underscore the need for an integrated One Health surveillance and early-warning system to reduce the risk of human infections with avian influenza.

Influenza in Birds↗

PubMed2026

Thrombus Metabolism-Based Molecular Subtyping for Prognostic Risk Stratification in Acute Ischemic Stroke: A Preliminary Study.

AIMS: To preliminarily characterize metabolic molecular subtypes of cerebral thromboemboli and evaluate their clinical significance in anterior circulation acute ischemic stroke due to large vessel occlusion (AIS-LVO). METHODS: Untargeted metabolomics was performed on thromboemboli retrieved from 36 patients with anterior circulation AIS-LVO using ultra-performance coupled liquid chromatography with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS). Unsupervised hierarchical clustering was employed to identify distinct metabolic molecular subtypes, and their associations with stroke etiology, radiographic severity, and functional outcomes were analyzed. RESULTS: Two distinct thrombus metabolic molecular subtypes (C1 and C2) were identified based on 12 metabolites significantly associated with both short-term (7-day ∆NIHSS) and long-term (90-day mRS) functional outcomes. The C1 subtype, predominantly cardioembolic, exhibited enhanced lipid metabolism, whereas the C2 subtype, primarily atherothrombotic, demonstrated increased folate metabolism. Patients with C1 thromboemboli presented more severe admission ischemic lesions (as indicated by ASPECTS) and experienced poorer short-term and long-term outcomes. A six-metabolite signature derived from LASSO regression was identified for exploratory discrimination of thrombus metabolic subtypes, etiological subtypes, and 90-day outcomes. CONCLUSION: This preliminary exploratory study identifies two metabolically distinct thrombus molecular subtypes with clinical implications in anterior circulation AIS-LVO, providing a novel basis for risk stratification and personalized secondary prevention and warrants further investigation.

Humans↗

PubMed2026

Functional neuroimaging subtypes of obsessive-compulsive disorder: A systematic review and meta-analysis.

Obsessive-compulsive disorder (OCD) exhibits substantial clinical heterogeneity that may reflect underlying neurobiological diversity. Neuroimaging-based subtyping may advance precision psychiatry by identifying biologically distinct subgroups with differential treatment responses. This study systematically synthesized evidence from functional neuroimaging subtyping studies in OCD to identify reproducible neurobiological subtypes, characterize their clinical profiles, and establish a consensus-based classification framework. We reviewed 40 original studies employing machine learning, clustering, normative modeling, or classification approaches, encompassing approximately 8,150 patients. Consensus clustering identified three reproducible neurobiological subtypes. The Limbic-Hyperactive subtype, comprising approximately 40% of patients, exhibited amygdala and insula hyperconnectivity, elevated anxiety levels, predominant contamination and washing symptoms, and favorable response to cognitive-behavioral therapy. The Fronto-Striatal-Hypoconnected subtype, comprising approximately 35% of patients, demonstrated reduced orbitofrontal-striatal connectivity, cognitive inflexibility, predominant checking and ordering symptoms, and a favorable response to selective serotonin reuptake inhibitors. The Global-Disrupted subtype, comprising approximately 25% of patients, exhibited widespread connectivity disruption, greater symptom severity, and poor treatment response. Support vector machine classification achieved 81.5% accuracy for subtype assignment, though classification of OCD versus healthy controls showed limited generalizability in multisite settings (AUC 0.567-0.673). These findings support a neuroimaging-based framework for personalized treatment selection but require prospective validation.

Humans↗

PubMed2005

Maladaptive behaviors and risk factors among the genetic subtypes of Prader-Willi syndrome.

Maladaptive behaviors among 65 people with Prader-Willi syndrome were assessed using the Reiss Screen for maladaptive behaviors. Young adults in their twenties were more likely to display aggressive behavior than adolescents and older adults. Differences in maladaptive behaviors between the typical deletion and uniparental disomy (UPD) subtypes were evaluated. The typical deletion subtype had higher self-injury and stealing scores than the UPD subtype. Subject characteristics were differentially related to maladaptive behavior among the typical deletion and UPD subtypes. Differences in maladaptive behavior were also examined between the typical deletion type I and type II subtypes. The type I deletion subtype had greater physical depression scores than the type II deletion subtype. The Reiss Screen cut-off scores were used to determine whether differences occurred between the subtypes at a clinically significant level. These findings offer insight into the health care needs of people with PWS.

Adaptation, Psychological↗