The non-receptor Abl tyrosine kinase regulates actin- dependent cellular processes. It stimulates F-actin microspikes and dorsal ruffles in response to adhesion and growth factor signals, respectively. Paradoxically, Abl inhibits cell migration, which also requires actin polymerization. In the present study, we show that Abl tyrosine kinase inhibits cell spreading on fibronectin. Induced dimerization of an Abl-FKBP fusion protein, which activated Abl-FKBP kinase activity, interfered with cell spreading. The Abl kinase inhibitor, imatinib, stimulated cell spreading and its effect was reversed by an imatinib- resistant AblT315I mutant. Re-introduction of Abl, but not its kinase-defective mutant, into Abl/Arg double knockout cells also inhibited cell spreading. Interestingly, Abl inhibits lamellipodia extension without affecting the overall levels of Rac-GTP. Furthermore, Abl kinase inhibited spreading of cells that expressed the constitutively active RacV12. Abl kinase caused the preferential localization of RacV12 to dorsal membrane protrusions, correlating with Abl kinase-dependent prolongation of dorsal ruffling during cell spreading. These results suggest that Abl tyrosine kinase may regulate the partitioning of actin polymerization machinery to favor dorsal ruffles at the expense of lamellipodia extension during cell spreading. This localized actin polymerization through Abl kinase may account for its positive role in dorsal ruffling and negative role in cell migration. But the Abl substrate(s) that is involved in dorsal ruffle formation remains unknown. To identify Abl kinase substrates we generated a 293 cell line that inducibly expresses constitutively active Abl kinase, Abl PP. With this cell line, a mass spectrometry-based method was used to screen for Abl kinase substrates. We followed tyrosine phosphorylation changes of cellular proteins in the 293 cells with Abl PP induction in the presence or absence of Abl kinase inhibitor, imatinib. From two independent experiments, we found eighteen proteins have increased tyrosine phosphorylation with Abl PP induction in the absence of imatinib. Among the eighteen proteins, eight proteins were identified in both experiments. Six out of the eighteen proteins are established Abl substrates; the remaining twelve are novel Abl substrates. Interestingly, among the eighteen proteins identified, eight of them are known Src substrates

Dynamic modulation of cell adhesion is integral to a wide range of biological processes. The small guanosine triphosphatase (GTPase) Rap1 is an important regulator of cell-cell and cell-matrix adhesions. We show here that induced expression of activated Abl tyrosine kinase reduces Rap1-GTP levels through phosphorylation of Tyr221 of CrkII, which disrupts interaction of CrkII with C3G, a guanine nucleotide exchange factor for Rap1. Abl-dependent down-regulation of Rap1-GTP causes cell rounding and detachment only when the Rho-ROCK1 pathway is also activated, for example, by lysophosphatidic acid (LPA). During ephrin-A1-induced retraction of PC3 prostate cancer cells, we show that endogenous Abl is activated and disrupts the CrkII-C3G complex to reduce Rap1-GTP. Interestingly, ephrin-A1-induced PC3 cell retraction also requires LPA, which stimulates Rho to a much higher level than that is activated by ephrin-A1. Our results establish Rap1 as another downstream target of the Abl-CrkII signaling module and show that Abl-CrkII collaborates with Rho-ROCK1 to stimulate cell retraction.

Post-Traumatic Stress Disorder (PTSD) is not solely a psychiatric disorder; it also includes significant medical morbidity. Although there is evidence of increased risk of metabolic syndrome (MetS) in PTSD, the interpretation of previous studies is confounded by inclusion of people on antipsychotic medications, which independently cause increased MetS. In this study we investigated whether Veterans with PTSD not treated with antipsychotic medications (n=115) demonstrate increased MetS compared to an age-comparable group of people from the U.S. National Health and Nutrition Examination Survey (NHNES; n=1005). Using standardized criteria (abnormal values in 3 out of the 5 domains of obesity, hypertension, high density lipoprotein, triglyceride and fasting glucose concentrations) we compared the prevalence of MetS across groups. Relative to the NHNES group, a significantly higher proportion of the Veteran PTSD group met criteria for MetS (26.9% vs. 41.7%) with a higher proportion of abnormal values in four out of five MetS domains (excepting glucose). Our results suggest that the elevation of MetS associated with PTSD cannot be fully explained by iatrogenic effects of antipsychotic medication. We suggest that extra attention be devoted to the clinical management of metabolic risk factors for morbidity in patients with PTSD.

Background

Persons with schizophrenia and schizoaffective disorder (PwS) have high rates of cardiometabolic pathology that contributes to premature mortality. Adiponectin is a metabolic hormone affecting insulin sensitivity and inflammation, and is active in the brain. High-molecular weight (HMW) adiponectin is considered a more sensitive marker of metabolic dysfunction than total adiponectin, but has been poorly studied in schizophrenia.

Methods

This was a cross-sectional study of 100 PwS, age range 26-68 years (46 women), and 93 age- and sex-comparable non-psychiatric comparison (NC) subjects. Assessments included measures of psychopathology, physical health, cognitive function, and circulating biomarkers of metabolic dysfunction (HMW adiponectin, lipids, insulin resistance) and inflammation (high-sensitivity C-reactive protein or hs-CRP, Tumor Necrosis Factor-α, Interleukin-6, and Interleukin-10).

Results

HMW adiponectin levels were lower in PwS compared to NCs. Lower HMW adiponectin levels were associated with higher body mass index (BMI), higher Framingham risk for coronary heart disease, higher number of metabolic syndrome criteria, greater insulin resistance, lower HDL cholesterol, and higher hs-CRP in both groups. Only in PwS, lower HMW adiponectin correlated with younger age. In the best-fit regression models of HMW adiponectin, lower levels were associated with lower HDL cholesterol and minority race/ethnicity in both groups; but with younger age, non-smoking, higher insulin resistance, and a diagnosis of schizoaffective disorder only among PwS, and with male sex, better cognitive functioning, and higher hs-CRP levels in NCs only.

Discussion

HMW adiponectin may be a promising biomarker of cardiometabolic health, especially among PwS. Adiponectin is a potential target for lifestyle and pharmacological interventions. Research on the possible role of HMW adiponectin in modifying cardiometabolic pathology in schizophrenia is needed.

Factors associated with HIV-associated neurocognitive disorders (HAND) include CD4(+) nadir and count, HIV RNA level, and HIV-1 subtype. Here, we investigated demographical and clinical markers with respect to HAND in a homogenous Chinese population. Individuals with HAND (global deficit score ≥0.5) had lower nadir (p < 0.01) and CD4(+) counts (p = 0.03). HAND was also associated with AIDS (p < 0.01), but subtype was not (p = 0.198). Furthermore, worse impairment correlated with higher viral diversity (r = 0.16, p < 0.01), lower nadir (r = -0.17, p < 0.01), and CD4(+) counts (r = -0.11, p = 0.01). These remained significant even when correcting for subtype. Our findings suggest that subtype does not have a major impact on HAND.

Transcription factors positively and/or negatively impact gene expression by recruiting coregulatory factors, which interact through protein-protein binding. Here we demonstrate that mouse pancreas size and islet β-cell function are controlled by the ATP-dependent Swi/Snf chromatin remodeling coregulatory complex that physically associates with Pdx1, a diabetes-linked transcription factor essential to pancreatic morphogenesis and adult islet cell function and maintenance. Early embryonic deletion of just the Swi/Snf Brg1 ATPase subunit reduced multipotent pancreatic progenitor cell proliferation and resulted in pancreas hypoplasia. In contrast, removal of both Swi/Snf ATPase subunits, Brg1 and Brm, was necessary to compromise adult islet β-cell activity, which included whole-animal glucose intolerance, hyperglycemia, and impaired insulin secretion. Notably, lineage-tracing analysis revealed Swi/Snf-deficient β-cells lost the ability to produce the mRNAs for Ins and other key metabolic genes without effecting the expression of many essential islet-enriched transcription factors. Swi/Snf was necessary for Pdx1 to bind to the Ins gene enhancer, demonstrating the importance of this association in mediating chromatin accessibility. These results illustrate how fundamental the Pdx1:Swi/Snf coregulator complex is in the pancreas, and we discuss how disrupting their association could influence type 1 and type 2 diabetes susceptibility.

Higher prevalence of physical comorbidity and premature mortality in persons with schizophrenia (PwS) results primarily from heightened cardiovascular and metabolic risks. The literature suggests that insulin resistance precedes the development of obesity, smoking, and use of antipsychotic medications, although these likely play a compounding role later in the course of the disorder. It is thus important to discover the clinical characteristics of PwS with high insulin resistance, as these individuals may represent an etiopathologically distinct subgroup with a distinct course and treatment needs. We conducted a cross-sectional study and compared insulin resistance between 145 PwS and 140 nonpsychiatric comparison (NC) participants, similar in age, sex, and race distribution. In addition, we examined correlates of insulin resistance in PwS. As expected, PwS had higher levels of insulin resistance [Homeostatic Model Assessment of Insulin Resistance (HOMA-IR)] and body mass index (BMI) compared to the NC participants. HOMA-IR in the PwS was most associated with negative symptoms, BMI, and non-White race/ethnicity. The mechanistic relationships between insulin resistance and negative symptoms in schizophrenia patients warrant further investigation, and future studies should examine outcomes of PwS with this cluster of physical and mental symptoms and determine how management of insulin resistance might improve health of these individuals.

Background

The MATRICS consensus cognitive battery (MCCB) has been widely used to evaluate cognitive deficits in schizophrenia (SCZ), however, no study has formally examined the validity of the MCCB in Chinese SCZ. This study compared Chinese SCZ patients with healthy Chinese controls on the MCCB and some additional neurocognitive tests to determine if the Chinese MCCB is an optimal battery to assess the cognitive deficits in Chinese SCZ patients.

Method

The study enrolled and examined 230 patients met DSM-IV criteria for SCZ and 656 healthy controls matched for gender, age and education. Besides the MCCB, we also included some additional neurocognitive tests that have been widely used in patients with schizophrenia. We selected MCCB and non-MCCB tests with large effect size, to assemble a new "optimal battery" and compared its performance with that of the standard MCCB.

Results

Comparing the putative "optimal" battery with the original MCCB, more patients with SCZ were identified as cognitively impaired according to the criteria of GDS ≥ 0.50 for the optimal battery (166 vs 135, or 72.2% vs 58.7%). The rate of cognitive impairment according to MCCB GDS in patients with SCZ who were currently working, ever worked and never worked are 45.5%, 61.6% and 70.8% (p = 0.051), whereas the optimal battery GDS showed 56.4%, 74.8%, 91.7% (p = 0.003), respectively.

Conclusions

Our study needs validation with independent samples but suggests that the current "optimal" cognitive battery could be more sensitive than the widely used MCCB in detecting SCZ related cognitive impairment in China.

Sepsis is a major cause of neonatal mortality and morbidity worldwide. A recent report suggested that murine neonatal host defense against infection could be compromised by immunosuppressive CD71(+) erythroid splenocytes. We examined the impact of CD71(+) erythroid splenocytes on murine neonatal mortality to endotoxin challenge or polymicrobial sepsis and characterized circulating CD71(+) erythroid (CD235a(+)) cells in human neonates. Adoptive transfer or an Ab-mediated reduction in neonatal CD71(+) erythroid splenocytes did not alter murine neonatal survival to endotoxin challenge or polymicrobial sepsis challenge. Ex vivo immunosuppression of stimulated adult CD11b(+) cells was not limited to neonatal splenocytes; it also occurred with adult and neonatal bone marrow. Animals treated with anti-CD71 Ab showed reduced splenic bacterial load following bacterial challenge compared with isotype-treated mice. However, adoptive transfer of enriched CD71(+) erythroid splenocytes to CD71(+)-reduced animals did not reduce bacterial clearance. Human CD71(+)CD235a(+) cells were common among cord blood mononuclear cells and were shown to be reticulocytes. In summary, a lack of effect on murine survival to polymicrobial sepsis following adoptive transfer or diminution of CD71(+) erythroid splenocytes under these experimental conditions suggests that the impact of these cells on neonatal infection risk and progression may be limited. An unanticipated immune priming effect of anti-CD71 Ab treatment, rather than a reduction in immunosuppressive CD71(+) erythroid splenocytes, was likely responsible for the reported enhanced bacterial clearance. In humans, the well-described rapid decrease in circulating reticulocytes after birth suggests that they may have a limited role in reducing inflammation secondary to microbial colonization.

Abstract Background Dengue, a mosquito-borne febrile viral disease, is found in tropical and sub-tropical regions around the world. Since the first occurrence of dengue was confirmed in Guangdong, China in 1978, dengue outbreaks have been reported sequentially in different provinces in South China transmitted by.peridomestic Ae. albopictus mosquitoes, diplaying Ae. aegypti, a fully domestic vector that transmits dengue worldwide. Rapid and uncontrolled urbanization is a characteristic change in developing countries, which impacts greatly on vector habitat, human lifestyle and transmission dynamics on dengue epidemics. In September 2010, an outbreak of dengue was detected in Dongguan, a city in Guangdong province characterized by its fast urbanization. An investigation was initiated to identify the cause, to describe the epidemical characteristics of the outbreak, and to implement control measures to stop the outbreak. This is the first report of dengue outbreak in Dongguan, even though dengue cases were documented before in this city. Methods Epidemiological data were obtained from local Center of Disease Control and prevention (CDC). Laboratory tests such as real-time Reverse Transcription Polymerase Chain Reaction (RT-PCR), the virus cDNA sequencing, and Enzyme-Linked immunosorbent assay (ELISA) were employed to identify the virus infection and molecular phylogenetic analysis was performed with MEGA5. The febrile cases were reported every day by the fever surveillance system. Vector control measures including insecticidal fogging and elimination of habitats of Ae. albopictus were used to control the dengue outbreak. Results The epidemiological studies results showed that this dengue outbreak was initiated by an imported case from Southeast Asia. The outbreak was characterized by 31 cases reported with an attack rate of 50.63 out of a population of 100,000. Ae. albopictus was the only vector species responsible for the outbreak. The virus cDNA sequencing analysis showed that the virus responsible for the outbreak was Dengue Virus serotype-1 (DENV-1). Conclusions Several characterized points of urbanization contributed to this outbreak of dengue in Dongguan: the residents are highly concentrated; the residents' life habits helped to form the habitats of Ae. albopictus and contributed to the high Breteau Index; the self-constructed houses lacks of mosquito prevention facilities. This report has reaffirmed the importance of a surveillance system for infectious diseases control and aroused the awareness of an imported case causing the epidemic of an infectious disease in urbanized region.