HIV envelope-CXCR4 signaling activates cofilin to overcome cortical actin restriction in resting CD4 T cells.

Binding of the HIV envelope to the chemokine coreceptors triggers membrane fusion and signal transduction. The fusion process has been well characterized, yet the role of coreceptor signaling remains elusive. Here, we describe a critical function of the chemokine coreceptor signaling in facilitating HIV infection of resting CD4 T cells. We find that static cortical actin in resting T cells represents a restriction and that HIV utilizes the Galphai-dependent signaling from the chemokine coreceptor CXCR4 to activate a cellular actin-depolymerizing factor, cofilin, to overcome this restriction. HIV envelope-mediated cofilin activation and actin dynamics are important for a postentry process that leads to viral nuclear localization. Inhibition of HIV-mediated actin rearrangement markedly diminishes viral latent infection of resting T cells. Conversely, induction of active cofilin greatly facilitates it. These findings shed light on viral exploitation of cellular machinery in resting T cells, where chemokine receptor signaling becomes obligatory.

Peptide receptor radionuclide therapy induced carcinoid crisis: A case report.

Peptide receptor radionuclide therapy (PRRT) is a therapeutic option in inoperable or metastatic neuroendocrine tumours (NETs). PRRT proved to be promising in prolonging survival and delaying disease progression in patients with advanced bronchopulmonary carcinoid. However, it may lead to worsening of carcinoid symptoms or even precipitate carcinoid crises. The incidence of PRRT induced carcinoid crisis would be between 1-10%. This usually takes place during the first PRRT cycle, either during the tracer infusion or 12-48 hours' post-administration. We report a 62-year-old man with underlying metastatic lung carcinoid tumour who developed carcinoid crisis at 10 hours after receiving PRRT. The carcinoid crisis was successfully treated with intravenous octreotide infusion, corticosteroid, a selective 5-HT3 receptor antagonist, parenteral ranitidine and chlorpheniramine for H1 and H2 antagonism respectively.

Ubiquitin ligase Nedd4-2 modulates Kv1.3 current amplitude and ion channel protein targeting.

Voltage-dependent potassium channels (Kv) go beyond the stabilization of the resting potential and regulate biochemical pathways, regulate intracellular signaling, and detect energy homeostasis. Because targeted deletion and pharmacological block of the Kv1.3 channel protein produce marked changes in metabolism, resistance to diet-induced obesity, and changes in olfactory structure and function, this investigation explored Nedd4-2-mediated ubiquitination and degradation to regulate Kv1.3 channel density. Heterologous coexpression of Nedd4-2 ligase and Kv1.3 in HEK 293 cells reduced Kv1.3 current density without modulation of kinetic properties as measured by patch-clamp electrophysiology. Modulation of current density was dependent on ligase activity and was lost through point mutation of cysteine 938 in the catalytic site of the ligase (Nedd4-2CS). Incorporation of adaptor protein Grb10 relieved Nedd4-2-induced current suppression as did application of the proteasome inhibitor Mg-132. SDS-PAGE and immunoprecipitation strategies demonstrated a channel/adaptor/ligase signalplex. Pixel immunodensity was reduced for Kv1.3 in the presence of Nedd4-2, which was eliminated upon additional incorporation of Grb10. We confirmed Nedd4-2/Grb10 coimmunoprecipitation and observed an increased immunodensity for Nedd4-2 in the presence of Kv1.3 plus Grb10, regardless of whether the catalytic site was active. Kv1.3/Nedd4-2 were reciprocally coimmunoprecipated, whereby mutation of the COOH-terminal, SH3-recognition (493-498), or ubiquitination sites on Kv1.3 (lysines 467, 476, 498) retained coimmunoprecipitation, while the latter prevented the reduction in channel density. A model is presented for which an atypical interaction outside the canonical PY motif may permit channel/ligase interaction to lead to protein degradation and reduced current density, which can involve Nedd4-2/Grb10 interactions to disrupt Kv1.3 loss of current density.

Prevalence of diabetes and prediabetes (impaired fasting glucose and/or impaired glucose tolerance) in urban and rural India: phase I results of the Indian Council of Medical Research-INdia DIABetes (ICMR-INDIAB) study.

AIMS/HYPOTHESIS: This study reports the results of the first phase of a national study to determine the prevalence of diabetes and prediabetes (impaired fasting glucose and/or impaired glucose tolerance) in India. METHODS: A total of 363 primary sampling units (188 urban, 175 rural), in three states (Tamilnadu, Maharashtra and Jharkhand) and one union territory (Chandigarh) of India were sampled using a stratified multistage sampling design to survey individuals aged ≥ 20 years. The prevalence rates of diabetes and prediabetes were assessed by measurement of fasting and 2 h post glucose load capillary blood glucose. RESULTS: Of the 16,607 individuals selected for the study, 14,277 (86%) participated, of whom 13,055 gave blood samples. The weighted prevalence of diabetes (both known and newly diagnosed) was 10.4% in Tamilnadu, 8.4% in Maharashtra, 5.3% in Jharkhand, and 13.6% in Chandigarh. The prevalences of prediabetes (impaired fasting glucose and/or impaired glucose tolerance) were 8.3%, 12.8%, 8.1% and 14.6% respectively. Multiple logistic regression analysis showed that age, male sex, family history of diabetes, urban residence, abdominal obesity, generalised obesity, hypertension and income status were significantly associated with diabetes. Significant risk factors for prediabetes were age, family history of diabetes, abdominal obesity, hypertension and income status. CONCLUSIONS/INTERPRETATIONS: We estimate that, in 2011, Maharashtra will have 6 million individuals with diabetes and 9.2 million with prediabetes, Tamilnadu will have 4.8 million with diabetes and 3.9 million with prediabetes, Jharkhand will have 0.96 million with diabetes and 1.5 million with prediabetes, and Chandigarh will have 0.12 million with diabetes and 0.13 million with prediabetes. Projections for the whole of India would be 62.4 million people with diabetes and 77.2 million people with prediabetes.

Prevalence of diabetes, obesity, and metabolic syndrome in subjects with and without schizophrenia (CURES-104).

BACKGROUND: There are some reports that diabetes and metabolic syndrome (MS) are more prevalent among schizophrenia patients. However, there are very few studies in India which have estimated the prevalence of diabetes and MS in schizophrenia patients. AIMS: The aim of this study was to determine the prevalence of diabetes, obesity, and MS in subjects with and without schizophrenia. SETTINGS AND DESIGN: This case control study comprised of "cases" i.e. subjects with schizophrenia recruited from a schizophrenia centre at Chennai and "controls" i.e. healthy age- and gender-matched subjects without psychiatric illness selected from an ongoing epidemiological study in Chennai in a 1:4 ratio of cases: Controls. MATERIALS AND METHODS: Fasting plasma glucose and serum lipids were estimated for all subjects. Anthropometric measures including height, weight, and waist circumference were assessed. Diabetes and impaired fasting glucose (IFG) were defined using American Diabetes Association criteria. STATISTICAL ANALYSIS: One-way ANOVA or student's "t" test was used to compare continuous variables and Chi-square test to compare proportion between two groups. RESULTS: The study group comprised of 655 subjects, 131 with schizophrenia and a control group of 524 subjects without schizophrenia. The prevalence of the diabetes, IFG, abdominal obesity and MS were significantly higher among subjects with schizophrenia compared to those without schizophrenia-diabetes (15.3% vs. 7.3%, P=0.003), IFG (31.3% vs. 8.6%, P<0.001), abdominal obesity (59.2% vs. 44.7%, P<0.001), and MS (34.4% vs. 24%, P=0.014). CONCLUSION: In subjects with schizophrenia, the prevalence of diabetes, IFG, abdominal obesity, and MS is significantly higher than in those without schizophrenia.

Measurement of human immunodeficiency virus type 1 preintegration transcription by using Rev-dependent Rev-CEM cells reveals a sizable transcribing DNA population comparable to that from proviral templates.

Preintegration transcription is an early process in human immunodeficiency virus type 1 infection and has been suggested to occur at a low level. The templates have also been suggested to represent a small population of nonintegrated viral DNA, particularly the two-long-terminal-repeat (2-LTR) circles. However, these determinations were made by either using PCR amplification of viral transcripts in bulk cell populations or utilizing the LTR-driving reporter cells that measure the synthesis of Tat. The intrinsic leakiness of LTR often makes the measurement of low-level viral transcription inaccurate. Since preintegration transcription also generates Rev, to eliminate the nonspecificity associated with the use of LTR alone we have developed a novel Rev-dependent indicator cell, Rev-CEM, to measure preintegration transcription based on the amount of Rev generated. In this report, using Rev-CEM cells, we demonstrate that preintegration transcription occurs on a much larger scale than expected. The transcribing population derived from nonintegrated viral DNA was comparable (at approximately 70%) to that derived from provirus in a productive viral replication cycle. Nevertheless, each nonintegrated viral DNA template exhibited a significant reduction in the level of transcriptional activity in the absence of integration. We also performed flow cytometry sorting of infected cells to identify viral templates. Surprisingly, our results suggest that the majority of 2-LTR circles are not active in directing transcription. It is likely that the nonintegrated templates are from the predominant DNA species, such as the full-length, linear DNA. Our results also suggest that a nonintegrating lentiviral vector can be as effective as an integrating vector in directing gene expression in nondividing cells, with the proper choice of an internal promoter.

2,4-Dichloro-7,8-dimethyl-quinoline.

There are two independent mol-ecules in the asymmetric unit of the title compound, C(11)H(9)Cl(2)N, both of which are essentially planar [maximum deviations of 0.072 (5) and 0.072 (7) Å]. In the crystal structure, weak π-π stacking inter-actions [centroid-centroid distances = 3.791 (3) Šand 3.855 (3) Å] link pairs of mol-ecules.

Large cryptic internal sequence repeats in protein structures from Homo sapiens.

Amino acid sequences are known to constantly mutate and diverge unless there is a limiting condition that makes such a change deleterious. However, closer examination of the sequence and structure reveals that a few large, cryptic repeats are nevertheless sequentially conserved. This leads to the question of why only certain repeats are conserved at the sequence level. It would be interesting to find out if these sequences maintain their conservation at the three-dimensional structure level. They can play an active role in protein and nucleotide stability, thus not only ensuring proper functioning but also potentiating malfunction and disease. Therefore,insights into any aspect of the repeats - be it structure, function or evolution - would prove to be of some importance. This study aims to address the relationship between protein sequence and its three-dimensional structure, by examining if large cryptic sequence repeats have the same structure.

2-Chloro-6-methyl-quinoline-3-carbaldehyde.

The quinolinyl fused-ring of the title compound, C(11)H(8)ClNO, is almost planar (r.m.s. deviation = 0.013 Å); the formyl group is slightly bent out of the plane of the fused ring system [C-C-C-O torsion angle = 13.5 (4)°].

2-Chloro-7,8-dimethyl-quinoline-3-carbaldehyde.

All the non-H atoms of the title compound, C(12)H(10)ClNO, lie on a crystallographic mirror plane orientated perpendicular to the crystallographic b axis.

2-Chloro-quinoline-3-carbaldehyde.

The quinolinyl fused ring system of the title compound, C(10)H(6)ClNO, is planar (r.m.s. deviation = 0.018 Å); the formyl group is slightly bent out of the plane of the fused ring system [C-C-C-O torsion angle = 8.2 (3)°].

2-Chloro-benzo[h]quinoline-3-carbaldehyde.

The benzo[h]quinolinyl fused-ring of the title compound, C(14)H(8)ClNO, is planar (r.m.s. deviation = 0.016 Å); the formyl group is slightly bent out of the plane [the C-C-C-O torsion angle is 10.7 (4)°].

2-Chloro-8-methoxy-quinoline-3-carbaldehyde.

In the title compound, C(11)H(8)ClNO(2), the quinoline fused-ring system is almost planar (r.m.s. deviation = 0.020 Å). The formyl group is slightly bent out of the quinoline plane [deviation of the O atom = 0.371 (2) Å].

2-Chloro-7-methyl-quinoline-3-carbaldehyde.

The quinoline fused-ring system of the title compound, C(11)H(8)ClNO, is planar (r.m.s. deviation = 0.007 Å); the formyl group is bent slightly out of the plane [C-C-C-O torsion angles = -9.6 (5) and 170.4 (3)°].

2-Chloro-8-methyl-quinoline-3-carbaldehyde.

The quinoline fused-ring system of the title compound, C(11)H(8)ClNO, is planar (r.m.s. deviation = 0.005 Å); the formyl group is slightly bent out of the plane [C-C-C-O1 torsion angles = 8.8 (7) and -172.8 (4)°].

2-Chloro-6-methoxy-quinoline-3-carbaldehyde.

The quinoline fused-ring system of the title compound, C(11)H(8)ClNO(2), is planar (r.m.s. deviation = 0.0095 Å); the formyl group is slightly bent out of this plane [C-C-C-O torsion angles = -2.4 (3) and 175.9 (2)°].

Ethyl 6-chloro-2-methyl-4-phenyl-quinoline-3-carboxyl-ate.

In the title compound, C(19)H(16)ClNO(2), the quinoline ring system is planar (r.m.s. deviation = 0.008 Å). The phenyl group and the -CO(2) fragment of the ester unit form dihedral angles of 60.0 (1) and 60.5 (1)°, respectively, with the quinoline ring system.

1-(4-Chloro-phen-yl)-2-[(3-phenyl-isoquinolin-1-yl)sulfan-yl]ethanone.

The title compound, C(23)H(16)ClNOS, exhibits dihedral angles of 11.73 (1) and 66.07 (1)°, respectively, between the mean plane of the isoquinoline system and the attached phenyl ring, and between the isoquinoline system and the chloro-phenyl ring. The dihedral angle between the phenyl and chlorophenyl rings is 54.66 (1)°.

3-Phenyl-isoquinolin-1(2H)-one.

The title compound, C(15)H(11)NO, consists of a planar isoquinolinone group to which a phenyl ring is attached in a twisted fashion [dihedral angle = 39.44 (4)°]. The crystal packing is dominated by inter-molecular N-H⋯O and C-H⋯O hydrogen bonds which define centrosymmetric dimeric entitities.

2,4-Dichloro-6-methoxy-quinoline.

The title compound, C(10)H(7)Cl(2)NO, features a planar mol-ecule, excluding the methyl H atoms [maximum deviation = 0.0385 (1) Å]. The crystal packing is stabilized by π-π stacking inter-actions across inversion centres [centroid-to-centroid distance = 3.736 (3) Å].