The Association of HDL2b with Metabolic Syndrome Among Normal HDL-C Populations in Southern China.

Background: The annual prevalence of metabolic syndrome (MetS) is increasing. Therefore, early screening and recognition of MetS are critical. This study aimed to evaluate the association between high-density lipoprotein (HDL) subclasses and MetS and to examine whether they could serve as early indicators in a Chinese community-based population with normal high-density lipoprotein cholesterol (HDL-C) levels. Methods: We used microfluidic chip technology to measure HDL subclasses in 463 people with normal HDL levels in 2018. We assessed how HDL subclasses correlated with and predicted insulin resistance (IR) and metabolic syndrome (MetS), evaluated by homeostatic model insulin resistance index (HOMA-IR) and the 2009 International Diabetes Federation (IDF), the American Heart Association (AHA), and the National Heart, Lung, and Blood Institute (NHLBI) criteria, respectively. We used correlation tests and ROC curves for the analysis. Results: The results indicate that there was a negative association between HDL2b% and the risk of IR and MetS in both sexes. Subjects in the highest quartile of HDL2b% had a significantly lower prevalence of IR and MetS than those in the lowest quartile (P<0.01). Correlation analysis between HDL2b% and metabolic risk factors showed that HDL2b% had a stronger association with these factors than HDL-C did in both sexes. ROC curve analysis also showed that HDL2b% had significant diagnostic value for IR and MetS compared to other lipid indicators. Conclusion: This study showed that MetS alters the distribution of HDL subclasses even when HDL-C levels are within the normal range. HDL-2b% has better diagnostic value for IR and MetS than HDL-C alone and may be a useful marker for early screening.

The association between activation of the ERK1/2-NF-κB signaling pathway by TIMP2 expression and chronic renal allograft dysfunction in the CRAD rat model.

PURPOSE: The tissue inhibitor of metalloproteinase 2 (TIMP2), a natural inhibitor of matrix metalloproteinase (MMP), regulates inflammation, fibrosis, and cell proliferation. Chronic renal allograft dysfunction (CRAD) is a primary factor affecting the long-term survival of renal allografts. We assessed whether up-regulation of TIMP2 expression may affect the ERK1/2-NF-κB signaling pathway and CRAD development. METHODS: Lewis rats received orthotopic F344 kidney allografts to establish the classical CRAD model. The treatment group was injected with a lentivirus encoding a TIMP2-targeting small hairpin (sh)RNA (LTS) at 5 × 108 TU/ml monthly after kidney transplantation. A second CRAD group was injected with a lentivirus TIMP2-control vector (LTC). After 12 weeks, blood, urine, and kidney tissue were harvested to evaluate renal function and pathological examinations. Hematoxylin and eosin staining, Masson staining, and Periodic acid-Schiff staining were performed for renal histopathological evaluation according to the Banff criteria. TIMP2, phospho (p)-ERK1/2, p-p65 (NF-κB) expression levels were measured via immunohistochemical and Western blot analyses. RESULTS: Compared to the F344 and Lewis control groups, the expression of TIMP2, p-ERK1/2, and p-p65 were significantly higher in the CRAD and CRAD+LTC renal tissues (p < 0.05). There were also increased levels of serum creatinine, nitrogen, and 24 h urinary protein in these two groups (p < 0.05). Typical histopathological changes of CRAD were observed in the CRAD and CRAD+LTC groups. Administration of LTS effectively decreased the expression of TIMP2, p-ERK1/2, and p-P65, and reduced interstitial fibrosis and macrophage infiltration in the treatment group (p < 0.05). Additionally, MCP1 and ICAM-1, which are downstream cytokines of the NF-κB pathway, were also inhibited in the renal rat kidney from the LTS group (p < 0.05). Furthermore, renal function was well preserved in the LTS group compared to the CRAD group and CRAD+LTC group. CONCLUSION: A decrease of TIMP2 can alleviate the progression of inflammation in CRAD via inhibition of the ERK1/2-NF-κB signaling pathway.

A DFT study of sulforaphane adsorption on the group III nitrides (B12N12, Al12N12 and Ga12N12) nanocages.

In this paper, the adsorption behavior of group III nitrides (B12N12, Al12N12, and Ga12N12) nanocages to sulforaphane (SF) anticancer medicine were studied by density functional theory (DFT). The adsorption energy, solvation energy, desorption time and related quantum molecular descriptors were calculated in neutral and acidic solutions. When the drugs were adsorbed to nanocages, the structure of nanocages and drugs changed after adsorption, indicating that the process was effective adsorption. The adsorption energy and solvation energy of the complexes created after adsorption were negative values, which indicated that the structure of complexes formed by adsorption were stable. According to charge decomposition analysis (CDA) and natural bonding orbitals (NBO), drugs act as charge donors and nanocages act as charge acceptors, so that the charge flows from drugs to nanocages. Thermodynamic calculations demonstrate that drugs adsorption on nanocages is a spontaneous exothermic process. The calculation of quantum molecular descriptors confirmed that drugs adsorption on nanocages increased the chemical reactivity and solubility of drugs, which facilitated its transfer in biological fluids. Both interaction region index (IRI) and topological analysis of atom in molecule (AIM) revealed Van Der Waals interaction between drugs and nanocages. Protonation studies demonstrated that acidic circumstances could improve the polarity of complexes, increase the solvation effect, and boost drugs release in target cancer cells. The results of this work indicate that X12N12(X = B, Al, Ga) nanocages can be used as the delivery vehicle of SF drug.Communicated by Ramaswamy H. Sarma.

Metabolism Score for Visceral Fat (METS-VF): A New Predictive Surrogate for CKD Risk.

Purpose: Metabolic disorders are closely related to the occurrence and development of chronic kidney disease (CKD). We explored the prospective association between the Metabolic Score for Visceral Fat (METS-VF) and CKD in a 5-year follow-up study. Patients and Methods: In this cohort study, 631 adults not suffering from CKD from Wanzhai Town, in China in 2012 were included at baseline and followed up in 2017 and 2018. Multivariable logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between METS-VF and CKD risk. Area under the receiver operating characteristic curve (AUC) analyses were used to evaluate the ability of METS-VF, waist-to-height ratio (WhtR), visceral adiposity index (VAI), homeostatic model assessment of insulin resistance (HOMA-IR), body mass index (BMI) to predict CKD risk. Results: We identified 103 CKD cases during follow-up. After adjustment for confounding factors, comparing the lowest quartile of METS-VF, the OR (95% CI) of CKD risk in the highest quartile was 3.04 (1.39-6.64). The per Standard deviation (SD) increase in METS-VF was positively correlated with CKD risk. The AUC of METS-VF for predicting CKD risk was, in general, higher than that for WhtR, VAI, HOMA-IR, and BMI. Conclusion: METS-VF may be an indicator for predicting CKD risk.

Durable ibrutinib responses in relapsed/refractory marginal zone lymphoma: long-term follow-up and biomarker analysis.

Advanced marginal zone lymphoma (MZL) is an incurable B-cell malignancy dependent on B-cell receptor signaling. The phase 2 PCYC-1121 study demonstrated the safety and efficacy of single-agent ibrutinib 560 mg/d in 63 patients with relapsed/refractory MZL treated with prior rituximab (RTX) or rituximab-based chemoimmunotherapy (RTX-CIT). We report the final analysis of PCYC-1121 with median follow-up of 33.1 months (range: 1.4-44.6). Overall response rate (ORR) was 58%; median duration of response (DOR) was 27.6 months (95% confidence interval [CI]: 12.1 to not estimable [NE]); median progression-free survival (PFS) was 15.7 months (95% CI: 12.2-30.4); and median overall survival (OS) was not reached (95% CI: NE to NE). Patients with prior RTX treatment had better outcomes (ORR: 81%; median DOR: not reached [95% CI: 12.2 to NE]; median PFS: 30.4 months [95% CI: 22.1 to NE]; median OS: not reached [95% CI: 30.3 to NE]) vs those with prior RTX-CIT treatment (ORR: 51%; DOR: 12.4 months [95% CI: 2.8 to NE]; PFS: 13.8 months [95% CI: 8.3-22.5]; OS: not reached [95% CI: NE to NE]). ORRs were 63%, 47%, and 62% for extranodal, nodal, and splenic subtypes, respectively. With up to 45 months of ibrutinib treatment, the safety profile remained consistent with prior reports. The most common grade ≥3 event was anemia (16%). Exploratory biomarker analysis showed NF-κB pathway gene mutations correlated with outcomes. Final analysis of PCYC-1121 demonstrated long-term safety and efficacy of ibrutinib in patients with relapsed/refractory MZL, regardless of prior treatment or MZL subtype. This trial was registered at www.clinicaltrials.gov as #NCT01980628.

Cytokines Elevated in HIV Elite Controllers Reduce HIV Replication In Vitro and Modulate HIV Restriction Factor Expression.

A subset of HIV-infected individuals termed elite controllers (ECs) maintain CD4+ T cell counts and control viral replication in the absence of antiretroviral therapy (ART). Systemic cytokine responses may differentiate ECs from subjects with uncontrolled viral replication or from those who require ART to suppress viral replication. We measured 87 cytokines in four groups of women: 73 ECs, 42 with pharmacologically suppressed viremia (ART), 42 with uncontrolled viral replication (noncontrollers [NCs]), and 48 HIV-uninfected (NEG) subjects. Four cytokines were elevated in ECs but not NCs or ART subjects: CCL14, CCL21, CCL27, and XCL1. In addition, median stromal cell-derived factor-1 (SDF-1) levels were 43% higher in ECs than in NCs. The combination of the five cytokines suppressed R5 and X4 virus replication in resting CD4+ T cells, and individually SDF-1ß, CCL14, and CCL27 suppressed R5 virus replication, while SDF-1ß, CCL21, and CCL14 suppressed X4 virus replication. Functional studies revealed that the combination of the five cytokines upregulated CD69 and CCR5 and downregulated CXCR4 and CCR7 on CD4+ T cells. The CD69 and CXCR4 effects were driven by SDF-1, while CCL21 downregulated CCR7. The combination of the EC-associated cytokines induced expression of the anti-HIV host restriction factors IFITM1 and IFITM2 and suppressed expression of RNase L and SAMHD1. These results identify a set of cytokines that are elevated in ECs and define their effects on cellular activation, HIV coreceptor expression, and innate restriction factor expression. This cytokine pattern may be a signature characteristic of HIV-1 elite control, potentially important for HIV therapeutic and curative strategies.IMPORTANCE Approximately 1% of people infected with HIV control virus replication without taking antiviral medications. These subjects, termed elite controllers (ECs), are known to have stronger immune responses targeting HIV than the typical HIV-infected subject, but the exact mechanisms of how their immune responses control infection are not known. In this study, we identified five soluble immune signaling molecules (cytokines) in the blood that were higher in ECs than in subjects with typical chronic HIV infection. We demonstrated that these cytokines can activate CD4+ T cells, the target cells for HIV infection. Furthermore, these five EC-associated cytokines could change expression levels of intrinsic resistance factors, or molecules inside the target cell that fight HIV infection. This study is significant in that it identified cytokines elevated in subjects with a good immune response against HIV and defined potential mechanisms as to how these cytokines could induce resistance to the virus in target cells.

The role of PIM1 in the ibrutinib-resistant ABC subtype of diffuse large B-cell lymphoma.

Diffuse large B cell lymphoma (DLBCL) is a heterogeneous lymphoma and the most common subtype of non-Hodgkin lymphoma, accounting for roughly 30% of newly diagnosed cases in the United States. DLBCL can be separated into the activated B cell-like (ABC) and germinal center B cell-like (GCB) subtypes, with distinct gene expression profiles, oncogenic aberrations, and clinical outcomes. ABC-DLBCL is characterized by chronically active B-cell receptor (BCR) signaling that can be modulated by Bruton's tyrosine kinase (BTK) activity. Thus, BTK serves as an attractive therapeutic target in this type of B-cell malignancy. Ibrutinib, a first-in-class, orally available covalent BTK inhibitor, has demonstrated clinical activity in several B-cell leukemias and lymphomas. A phase 1/2 clinical trial of single-agent ibrutinib in relapsed and refractory DLBCL patients revealed an overall response rate of 37% in ABC-DLBCL patients. However, responses to kinase-directed therapies are often limited by emerging resistance mechanisms that bypass the therapeutic target. Here we report the discovery of point mutations within the kinase PIM1 that reduce sensitivity to ibrutinib in ABC-DLBCL. These mutations stabilize PIM1 and affect upstream regulators and downstream targets of NF-κB signaling. The introduction of mutant PIM1 into an ABC-DLBCL cell line, TMD8, increased colony formation and decreased sensitivity to ibrutinib. In addition, ibrutinib-resistant cell lines generated by prolonged ibrutinib exposure in vitro upregulated PIM1 expression, consistent with a role for PIM1 in antagonizing ibrutinib activity. The combination of a pan-PIM inhibitor with ibrutinib synergistically inhibited proliferation in vitro and tumor growth in vivo. Together, these data provide a rationale for combining BTK and PIM1 inhibition in the treatment of ABC-DLBCL.

Magnitude and Quality of Cytokine and Chemokine Storm during Acute Infection Distinguish Nonprogressive and Progressive Simian Immunodeficiency Virus Infections of Nonhuman Primates.

Acute human immunodeficiency virus (HIV) infection represents a period of intense immune perturbation and activation of the host immune system. Study of the eclipse and viral expansion phases of infection is difficult in humans, but studies in nonprogressive and progressive nonhuman primate (NHP) infection models can provide significant insight into critical events occurring during this time. Cytokines, chemokines, and other soluble immune factors were measured in longitudinal samples from rhesus macaques infected with either SIVmac251 (progressive infection) or SIVmac239Δnef (attenuated/nonprogressive infection) and from African green monkeys infected with SIVsab9315BR (nonpathogenic infection). Levels of acute-phase peak viral replication were highest in SIVmac251 infection but correlated positively with viremia at 3 months postinfection in all three infection models. SIVmac251 infection was associated with stronger corresponding acute-phase cytokine/chemokine responses than the nonprogressive infections. The production of interleukin 15 (IL-15), IL-18, gamma interferon (IFN-γ), granulocyte colony-stimulating factor (G-CSF), monocyte chemoattractant protein 1 (MCP-1), macrophage inflammatory protein 1ß (MIP-1ß), and serum amyloid A protein (SAA) during acute SIVmac251 infection, but not during SIVmac239Δnef or SIVsab9315BR infection, correlated positively with chronic viremia at 3 months postinfection. Acute-phase production of MCP-1 correlated with viremia at 3 months postinfection in both nonprogressive infections. Finally, a positive correlation between the acute-phase area under the curve (AUC) for IL-6 and soluble CD40 ligand (sCD40L) and chronic viremia was observed only for the nonprogressive infection models. While we observed dynamic acute inflammatory immune responses in both progressive and nonprogressive SIV infections, the responses in the nonprogressive infections were not only lower in magnitude but also qualitatively different biomarkers of disease progression. IMPORTANCE: NHP models of HIV infection constitute a powerful tool with which to study viral pathogenesis in order to gain critical information for a better understanding of HIV infection in humans. Here we studied progressive and nonprogressive simian immunodeficiency virus (SIV) infection models in both natural and nonnatural host NHP species. Regardless of the pathogenicity of the virus infection and regardless of the NHP species studied, the magnitude of viremia, as measured by area under the curve, during the first 4 weeks of infection correlated positively with viremia in chronic infection. The magnitude of cytokine and chemokine responses during primary infection also correlated positively with both acute-phase and chronic viremia. However, the pattern and levels of specific cytokines and chemokines produced differed between nonprogressive and progressive SIV infection models. The qualitative differences in the early immune response in pathogenic and nonpathogenic infections identified here may be important determinants of the subsequent disease course.

High-temperature inhibition of biosynthesis and transportation of anthocyanins results in the poor red coloration in red-fleshed Actinidia chinensis.

In plants, the role of anthocyanins trafficking in response to high temperature has been rarely studied, and therefore poorly understood. Red-fleshed kiwifruit has stimulated the world kiwifruit industry owing to its appealing color. However, fruit in warmer climates have been found to have poor flesh coloration, and the factors responsible for this response remain elusive. Partial correlation and regression analysis confirmed that accumulative temperatures above 25 °C (T25) was one of the dominant factors inhibiting anthocyanin accumulation in red-fleshed Actinidia chinensis, 'Hongyang'. Expression of structural genes, AcMRP and AcMYB1 in inner pericarp sampled from the two high altitudes (low temperature area), was notably higher than the low altitude (high temperature area) during fruit coloration. AcMYB1 and structural genes coordinate expression supported the MYB-bHLH (basic helix-loop-helix)-WD40 regulatory complex mediated downregulation of anthocyanin biosynthesis induced by high temperatures in kiwifruit. Moreover, cytological observations using the light and transmission electronic microscopy showed that there were a series of anthocyanic vacuolar inclusion (AVI)-like structures involved in their vacuolization process and dissolution of the pigmented bodies inside cells of fruit inner pericarp. Anthocyanin transport was inhibited by high temperature via retardation of vacuolization or reduction in AIV-like structure formation. Our findings strongly suggested that complex multimechanisms influenced the effects of high temperature on red-fleshed kiwifruit coloration.

Low-coverage single-cell mRNA sequencing reveals cellular heterogeneity and activated signaling pathways in developing cerebral cortex.

Large-scale surveys of single-cell gene expression have the potential to reveal rare cell populations and lineage relationships but require efficient methods for cell capture and mRNA sequencing. Although cellular barcoding strategies allow parallel sequencing of single cells at ultra-low depths, the limitations of shallow sequencing have not been investigated directly. By capturing 301 single cells from 11 populations using microfluidics and analyzing single-cell transcriptomes across downsampled sequencing depths, we demonstrate that shallow single-cell mRNA sequencing (~50,000 reads per cell) is sufficient for unbiased cell-type classification and biomarker identification. In the developing cortex, we identify diverse cell types, including multiple progenitor and neuronal subtypes, and we identify EGR1 and FOS as previously unreported candidate targets of Notch signaling in human but not mouse radial glia. Our strategy establishes an efficient method for unbiased analysis and comparison of cell populations from heterogeneous tissue by microfluidic single-cell capture and low-coverage sequencing of many cells.

Increased frequency of Tim-3 expressing T cells is associated with symptomatic West Nile virus infection.

More than a decade after West Nile virus (WNV) entered North America, and despite a significant increase in reported cases during the 2012 and 2013 seasons, no treatment or vaccine for humans is available. Although antiviral T cells contribute to the control of WNV, little is known about their regulation during acute infection. We analyzed the expression of Tim-3 and PD-1, two recently identified T cell negative immune checkpoint receptors, over the course of WNV infection. Symptomatic WNV+ donors exhibited higher frequencies of Tim-3+ cells than asymptomatic subjects within naïve/early differentiated CD28+/-CD57-CD4+ and differentiated CD28-CD57-CD8+ T cells. Our study links Tim-3-expression on T cells during acute WNV infection with the development of symptomatic disease, suggesting Tim-3 and its ligands could be targeted therapeutically to alter anti-WNV immunity and improve disease outcome.

Cytokine and chemokine responses in the acute phase of hepatitis B virus replication in naive and previously vaccinated blood and plasma donors.

BACKGROUND: Blood and plasma donor screening for hepatitis B virus (HBV) DNA, HBV surface antigen (HBsAg), and antibodies to surface (anti-HBs) and core (anti-HBc) antigens allows identification of individuals who acquired HBV despite previous HBV vaccination. METHODS: Of 14 HBV acute infection donor panels (HBV-DNA-positive/anti-HBc-negative), 6 donors were previously vaccinated (anti-HBs+). We investigated the differences in viral kinetics and immune responses in vaccinated and nonvaccinated individuals. Serial specimens were characterized for HBV DNA and serological markers and 39 cytokines. RESULTS: The rate of viral load increase was blunted, and virus was cleared more rapidly in vaccinated individuals (P = .004). In unvaccinated individuals, induced protein 10 (IP-10), interleukin 10 (IL-10), macrophage inflammatory protein 1ß (MIP-1ß), and soluble interleukin 2Rα (sIL-2Rα) levels were commonly elevated at the time of peak viremia. In contrast, vaccinated individuals had earlier peaks in IL-10 and IP-10 responses that occurred at much lower viral loads and coincided with anamnestic anti-hepatitis B surface (HBs) responses and clearance of viremia. CONCLUSION: There is earlier engagement of innate and adaptive immunity in infected subjects with previous vaccination, possibly explaining suppressed viremia in vaccine breakthrough infections. Although breakthrough infections occur in partially protected vaccine recipients, vaccination likely contributes to early control of replication, limiting immune activation and preventing development of clinically significant acute and chronic HBV infection.

Exosomes from red blood cell units bind to monocytes and induce proinflammatory cytokines, boosting T-cell responses in vitro.

Extracellular vesicles (EVs) are small, double membrane vesicles derived from leukocytes, platelets, and cells of other tissues under physiological or pathological conditions. Generation of EVs in stored blood is thought to be associated with adverse effects and potentially immunosuppression in blood transfusion recipients. We measured the quantity and cells of origin for EVs isolated from stored red blood cell (RBC) units and tested whether they had any effects on T-cell-mediated immune responses. Mixing peripheral blood mononuclear cells (PBMCs) with EVs resulted in secretion of proinflammatory cytokines and chemokines and increased survival of unstimulated PBMCs. EVs augmented mitogen-induced CD4(+) and CD8(+) T-cell proliferation in an antigen-presenting cell (APC)-dependent manner. We demonstrated that EVs interacted primarily with monocytes and induced proinflammatory cytokine secretion. We also showed that the exosome fraction of EVs and not larger microvesicles was responsible for induction of TNF-α production by monocytes. Furthermore, blockade of CD40 or CD40L accessory molecules largely neutralized the EV augmentation of T-cell responses, implying a role for cell-cell interaction between T cells and EV-activated monocytes. Contrary to our hypothesis, the data demonstrate that EVs isolated from RBC units increase the potency of APCs and boost mitogen-driven T-cell proliferative responses.

Genomic characterization of a three-dimensional skin model following exposure to ionizing radiation.

This study aimed at characterizing the genomic response to low versus moderate doses of ionizing radiation (LDIR versus MDIR) in a three-dimensional (3D) skin model, which exhibits a closer tissue complexity to human skin than monolayer cell cultures. EpiDermFT skin plugs were exposed to 0, 0.1 and 1 Gy doses of X-rays and harvested at 5 min, 3, 8 and 24 h post-irradiation (post-IR). RNA was interrogated for global gene expression alteration. Our results show that MDIR modulated a larger number of genes over the course of 24 h compared to LDIR. However, immediately and throughout the first 3h post-IR, LDIR modulated a larger number of genes than MDIR, mostly associated with cell-cell signaling and survival promotion. Significant modulation of pathways was detected only at 3 h post-IR in MDIR with induction of genes promoting apoptosis. Collectively, the data show different dynamics in the response to LDIR versus MDIR, especially in cell-cycle distribution. LDIR-exposed tissues showed signs of attempted cell-cycle re-entry as early as 3 h post-IR, but were arrested beyond 8 h at the G1/S checkpoint. At 24 h, cells appeared to accumulate at the G2/M checkpoint. MDIR-exposed tissues did not exhibit a prolonged G1/S arrest but rather a prolonged G2/M arrest, which was sustained at least up to 24 h. By 24 h cells exhibited signs of recovery in both LDIR- and MDIR-exposed tissues. In summary, the most pronounced difference in the initial cellular response to LDIR versus MDIR is the promotion of protection and survival in LDIR versus the promotion of apoptosis in MDIR.

Transcriptional response of ex vivo human skin to ionizing radiation: comparison between low- and high-dose effects.

Although human exposure to low-dose ionizing radiation can occur through a variety of sources, including natural, medical, occupational and accidental, the true risks of low-dose ionizing radiation are still poorly understood in humans. Here, the global transcriptional responses of human skin after ex vivo exposure to low (0.05 Gy) and high (5 Gy) doses of X rays and of time in culture (0 Gy) at 0, 2, 8 and 30 h postirradiation were analyzed and compared. Responses to low and high doses differed quantitatively and qualitatively. Differentially expressed genes fell into three groups: (1) unique genes defined as responsive to either 0.05 or 5 Gy but not both and also responsive to time in culture, (2) specific genes defined as responsive to either 0.05 or 5 Gy but not both and not responsive to time in culture, and (3) dose-independent responsive genes. Major differences observed in ex vivo irradiated skin between transcriptional responses to low or high doses were twofold. First, gene expression modulated by 0.05 Gy was transient, while in response to 5 Gy persistence of modified gene expression was observed for a limited number of genes. Second, neither TP53 nor TGFß target genes were modulated after exposure to an acute low dose, suggesting that the TP53-dependent DNA damage response either was not triggered or was triggered only briefly.

Association between HLA class I and class II alleles and the outcome of West Nile virus infection: an exploratory study.

BACKGROUND: West Nile virus (WNV) infection is asymptomatic in most individuals, with a minority developing symptoms ranging from WNV fever to serious neuroinvasive disease. This study investigated the impact of host HLA on the outcome of WNV disease. METHODS: A cohort of 210 non-Hispanic mostly white WNV(+) subjects from Canada and the U.S. were typed for HLA-A, B, C, DP, DQ, and DR. The study subjects were divided into three WNV infection outcome groups: asymptomatic (AS), symptomatic (S), and neuroinvasive disease (ND). Allele frequency distribution was compared pair-wise between the AS, S, and ND groups using χ2 and Fisher's exact tests and P values were corrected for multiple comparisons (Pc). Allele frequencies were compared between the groups and the North American population (NA) used as a control group. Logistic regression analysis was used to evaluate the potential synergistic effect of age and HLA allele phenotype on disease outcome. RESULTS: The alleles HLA-A*68, C*08 and DQB*05 were more frequently associated with severe outcomes (ND vs. AS, P(A*68) = 0.013/Pc = 0.26, P(C*08) = 0.0075/Pc = 0.064, and P(DQB1*05) = 0.029/Pc = 0.68), However the apparent DQB1*05 association was driven by age. The alleles HLA-B*40 and C*03 were more frequently associated with asymptomatic outcome (AS vs. S, P(B*40) = 0.021/Pc = 0.58 and AS vs. ND P(C*03) = 0.039/Pc = 0.64) and their frequencies were lower within WNV(+) subjects with neuroinvasive disease than within the North American population (NA vs. S, P(B*40) = 0.029 and NA vs. ND, P(C*03) = 0.032). CONCLUSIONS: Host HLA may be associated with the outcome of WNV disease; HLA-A*68 and C*08 might function as "susceptible" alleles, whereas HLA-B*40 and C*03 might function as "protective" alleles.

The effect of HIV infection and HAART on inflammatory biomarkers in a population-based cohort of women.

OBJECTIVE: HIV causes inflammation that can be at least partially corrected by HAART. To determine the qualitative and quantitative nature of cytokine perturbation, we compared cytokine patterns in three HIV clinical groups, including HAART responders (HAART), untreated HIV noncontrollers, and HIV-uninfected (NEG). METHODS: Multiplex assays were used to measure 32 cytokines in a cross-sectional study of participants in the Women's Interagency HIV Study. Participants from three groups were included: HAART (n = 17), noncontrollers (n = 14), and HIV NEG (n = 17). RESULTS: Several cytokines and chemokines showed significant differences between noncontrollers and NEG participants, including elevated interferon gamma-induced 10 (IP-10) and tumor necrosis factor-α (TNF-α) and decreased interleukin-12(p40) [IL-12(p40)], IL-15, and fibroblast growth factor-2 (FGF-2) in noncontroller participants. Biomarker levels among HAART women more closely resembled the NEG, with the exception of TNF-α and FGF-2. Secondary analyses of the combined HAART and noncontroller groups revealed that IP-10 showed a strong, positive correlation with viral load and negative correlation with CD4(+) T-cell counts. The growth factors vascular endothelial growth factor, epidermal growth factor, and FGF-2 all showed a positive correlation with increased CD4(+) T-cell counts. CONCLUSION: Untreated, progressive HIV infection was associated with decreased serum levels of cytokines important in T-cell homeostasis (IL-15) and T-cell phenotype determination (IL-12), and increased levels of innate inflammatory mediators such as IP-10 and TNF-α. HAART was associated with cytokine profiles that more closely resembled those of HIV-uninfected women. The distinctive pattern of cytokine levels in the three study groups may provide insights into HIV pathogenesis, and responses to therapy.

Algorithms for multiple genome rearrangement by signed reversals.

We discuss a multiple genome rearrangement problem by signed reversals: Given a collection of genomes, we generate them in the minimum number of signed reversals. It is NP-hard and equivalent to finding an optimal Steiner tree to connect the genomes by reversal paths. We design two algorithms to find the optimal Steiner nodes of the problem: Neighbor-perturbing algorithm and branch-and-bound algorithm. The first one is a polynomial running time approximation algorithm. It searches for the optimal Steiner nodes by perturbing initial Steiner nodes nearby their neighborhoods and improving them better and better until convergence. The second one is an exact exponential running time algorithm for a median problem. It finds the optimal Steiner node by checking all candidates that satisfy the necessary conditions for optimal Steiner nodes. We implement the algorithms into two programs respectively and show by experimental examples that they are more efficient than other similar ones, such as GRAPPA, BPAnalysis, and MGR, etc.

Multiple genome rearrangement by reversals.

In this paper, we discuss a multiple genome rearrangement problem: Given a collection of genomes represented by permutations, we generate the collection from some fixed genome, e.g., the identity permutation, in a minimum number of signed reversals. It is NP-hard, so efficient heuristics is important for finding its optimal solution. We at first discuss how to generate two and three genomes from a fixed genome by polynomial algorithms for some special cases. Then based on the polynomial algorithms, we obtain some approximation algorithms for generating two and three genomes in general, respectively. Finally, we apply these approximation algorithms to design a new approximation algorithm for generating more genomes. We also show by some experimental examples that the algorithms are efficient.