Protein phosphorylation mediated by serine-threonine kinases in the hippocampus is crucial to the synaptic modifications believed to underlie memory formation. The role of phosphatases has been the focus of comparatively little study.

A comprehensive literature search was conducted to identify all case-control studies investigating the association between GRIN1 G1001C polymorphism and schizophrenia susceptibility (MIM: 138249; dbSNP: rs 11146020). A total of 6 eligible studies (including 1639 schizophrenia cases and 1489 controls) were identified for the meta-analysis. Including all studies, there was significant heterogeneity between studies. In overall the GC (OR=1.00, 95 % CI: 0.0.85-1.19) and CC (OR=1.09, 95 % CI: 0.67-1.79) genotypes were not associated with schizophrenia risk compared with the GG genotype. In one study patients were diagnosed using DSM-IIIR criteria and in another study the genotypic frequencies of control subjects showed significant deviation from the expected frequencies according to the Hardy-Weinberg equilibrium. After excluding these studies from the meta-analysis, the heterogeneity between studies dramatically decreased. Statistical analysis showed that the GC genotype compared with the GG genotype significantly increased the risk of schizophrenia (OR=1.85, 95 % CI: 1.43-2.42, P<0.0001). The CC versus GG genotype significantly increased the schizophrenia risk (OR=2.46, 95% CI: 1.17-6.84, P=0.017). There was significant linear trend for presence of 0, 1, and 2 of the C allele and risk of schizophrenia (χ2=25.45, P<0.0001). In conclusion, the C variant allele may be associated with an increased risk for developing schizophrenia.

Epigallocatechin-3-gallate (EGCG) is a major ingredient of green tea (GT) and silibinin (SB), the active component of Silymarin presumably hold a potential to prevent pathogenomics. Prostate cancer exacerbation is triggered by fusion transcripts formed because of genomic instability induced by juxtapositioning of two genes. This chimeric transcript is implicated in androgen dependent and independent prostate cancer. Tremendous work is done on the characterization of the mediators involved in the disease refractoriness, yet no study has addressed clinical management of these prostate fusion transcripts impressively.

Macrophage migration inhibitory factor (MIF) is causally related to the pathogenesis of chronic liver disease but its hepatocellular mechanisms of action are largely unknown. Scattered reports in the literature hint at functional connections between the expression of MIF and major histocompatibility complex (MHC) Class II molecules. Not surprisingly, these relationships have not yet been explored in hepatocytes because MIF and MHC Class II cell surface receptors are commonly expressed by other cell types including various antigen presenting cells of the immune system. On the other hand, mounting evidence suggests that heteromeric MIF receptors share a common molecule with intracellular MHC Class II complexes, viz., CD74, which also serves as the MHC Class II chaperone; and, while it is unclear what cancer-related role(s) MHC Class II receptors might play, increasing evidence suggests that MIF and CD74 are also implicated in the biology of hepatocellular carcinoma. These reports are provocative for two reasons: firstly, IkkβΔhep mice carrying hepatocyte-targeted deletions of Ikkβ, an IκB kinase complex subunit required for the activation of the transcription factor NF-κB (nuclear factor-κB), have been shown to display heightened susceptibilities to hepatotoxins and chemical hepatocarcinogens; secondly, microarray profiling observations indicate that IkkβΔhep hepatocytes constitutively and "ectopically" overexpress genes, particularly CD74, CD44 (a MIF-receptor subunit) and MHC Class II I-A/E β and I-A α chains, and gene families that regulate host immune process and immune defense responses. These findings together suggest that IkkβΔhep mice might express functional MIF and MHC Class II receptors, leading to increased hepatocellular sensitivity to MIF signaling as well as to the unusual property of antigen presentation; both functions might contribute to the heightened liver disease phenotypes of IkkβΔhep mice. The findings raise questions about the potential existence of cohorts of human patients with genetic abnormalities of Ikkβ that might confer heightened susceptibility to liver disease including hepatocellular carcinoma.

The primary aim of this work was to analyze feasibility of combined treatment of retroperitoneal sarcomas (RS): surgery (S) and intraoperative brachytherapy (IOBRT). The secondary aim was to analyze results and complications after this treatment.

Mechanical properties of thermoplastic polyurethane elastomers based on either polyether or polycarbonate (PC)-glycols, 4,4'-dipheylmethane diisocyanate (1,1'-methylenebis(4-isocyanatobenzene)), 1,4-butanediol, were controlled by restriction of crystallization of polymer glycols. For the polyether glycol based-polyurethane elastomers (PUEs), poly(oxytetramethylene) glycol (PTMG), and PTMG incorporating dimethyl groups (PTG-X) and methyl side groups (PTG-L) were employed as a polymer glycol. For the PC-glycol, the randomly copolymerized PC-glycols with hexamethylene (C₆) and tetramethylene (C₄) units between carbonate groups with various composition ratios (C₄/C₆ = 0/100, 50/50, 70/30 and 90/10) were employed. The degree of microphase separation and mechanical properties of both the PUEs were investigated using differential scanning calorimetry, dynamic viscoelastic property measurements and tensile testing. Mechanical properties could be controlled by changing the molar ratio of two different monomer components.

Genetic variants in the brain-derived neurotrophic factor (BDNF) gene, predominantly the functional Val66Met polymorphism, have been associated with risk of bipolar disorder and other psychiatric disorders. However, not all studies support these findings, and overall the evidence for the association of BDNF with disease risk is weak. As differences in population genetic structure between patient samples could cause discrepant or spurious association results, we investigated this possibility by carrying out population genetic analyses of the BDNF genomic region. Substantial variation was detected in BDNF coding region single-nucleotide polymorphism (SNP) allele and haplotype frequencies between 58 global populations, with the derived Met allele of Val66Met ranging in frequency from 0 to 72% across populations. F(ST) analyses to assess diversity in the HapMap populations determined that the Val66Met F(ST) value was at the 99.8th percentile among all SNPs in the genome. As the BDNF population genetic differences may be due to local selection, we performed the long-range haplotype test for selection using 68 SNPs spanning the BDNF genomic region in 12 European-derived pedigrees. Evidence for positive selection was found for a high-frequency Val-carrying haplotype, with a relative extended haplotype homozygosity value above the 99 th percentile compared with HapMap data (P=4.6 x 10(-4)). In conclusion, we observed considerable BDNF allele and haplotype diversity among global populations and evidence for positive selection at the BDNF locus. These phenomena can have a profound impact on the detection of disease susceptibility genes and must be considered in gene association studies of BDNF.

Liver regeneration is still not fully understood. Partial liver transplantation (LT) can provide the opportunity to investigate the mechanisms of liver regeneration, including the contribution of extrahepatic cells to liver regeneration.

Assessment of disordered eating has uncertain validity across culturally diverse populations. This study evaluated Eating Disorder Examination Questionnaire (EDE-Q) performance in an ethnic Fijian study population.

Huntington's disease (HD) is a neurodegenerative disease caused by mutant huntingtin protein containing an expanded polyglutamine tract, which may cause abnormal protein-protein interactions such as increased association with calmodulin (CaM). We previously demonstrated in HEK293 cells that a peptide containing amino acids 76-121 of CaM (CaM-peptide) interrupted the interaction between CaM and mutant huntingtin, reduced mutant huntingtin-induced cytotoxicity and reduced transglutaminase (TG)-modified mutant huntingtin. We now report that adeno-associated virus (AAV)-mediated expression of CaM-peptide in differentiated neuroblastoma SH-SY5Y cells, stably expressing an N-terminal fragment of huntingtin containing 148 glutamine repeats, significantly decreases the amount of TG-modified huntingtin and attenuates cytotoxicity. Importantly, the effect of the CaM-peptide shows selectivity, such that total TG activity is not significantly altered by expression of CaM-peptide nor is the activity of another CaM-dependent enzyme, CaM kinase II. In vitro, recombinant exon 1 of huntingtin with 44 glutamines (htt-exon1-44Q) binds to CaM-agarose; the addition of 10 microM of CaM-peptide significantly decreases the interaction of htt-exon1-44Q and CaM but not the binding between CaM and calcineurin, another CaM-binding protein. These data support the hypothesis that CaM regulates TG-catalyzed modifications of mutant huntingtin and that specific and selective disruption of the CaM-huntingtin interaction is potentially a new target for therapeutic intervention in HD.

Thiamine (vitamin B1) is an essential molecule for all life forms because thiamine diphosphate (ThDP) is an indispensable cofactor for oxidative energy metabolism. The less abundant thiamine monophosphate (ThMP), thiamine triphosphate (ThTP) and adenosine thiamine triphosphate (AThTP), present in many organisms, may have still unidentified physiological functions. Diseases linked to thiamine deficiency (polyneuritis, Wernicke-Korsakoff syndrome) remain frequent among alcohol abusers and other risk populations. This is the first comprehensive study on the distribution of thiamine derivatives in human biopsies, body fluids and cell lines.

Profilin-1 is an ubiquitous actin binding protein. Under pathological conditions such as diabetes, profilin-1 levels are increased in the vascular endothelium. We recently demonstrated that profilin-1 overexpression triggers indicators of endothelial dysfunction downstream of LDL signaling, and that attenuated expression of profilin-1 confers protection from atherosclerosis in vivo.

Current diagnostic screening strategies based on karyotyping or fluorescent in situ hybridization (FISH) for detection of chromosomal abnormalities in chronic lymphocytic leukemia (CLL) are laborious, time-consuming, costly, and have limitations in resolution. Multiplex ligation-dependent probe amplification (MLPA) can simultaneously detect copy number changes of multiple loci in one simple PCR reaction, making it an attractive alternative to FISH. To enhance the clinical robustness and further harness MLPA technology for routine laboratory operations, we have developed and validated a protocol for comprehensive, automatic data analysis and interpretation. A training set of 50 normal samples was used to establish reference ranges for each individual probe, for the calling of statistically significant copy number changes. The maximum normal ranges of 2 and 3 standard deviations (SD) are distributed between 0.82 and 1.18 (Mean ± 2SD, 95% CI, P = 0.05), and between 0.73 and 1.27 (Mean ± 3SD, 99% CI, P = 0.01), respectively. We found an excellent correlation between MLPA and FISH with 93.6% concordance (P<0.0001) from a testing cohort of 100 clinically suspected CLL cases. MLPA analyses done on 94/100 patients showed sensitivity and specificity of 94.2% and 92.9%, respectively. MLPA detected additional copy number gains on 18q21.1 and chromosome 19, and novel micro-deletions at 19q13.43 and 19p13.2 loci in six samples. Three FISH-failed samples were tested positive by MLPA, while three 13q- cases with a low percentage of leukemia cells (7%, 12% and 19%) were not detected by MLPA. The improved CLL MLPA represents a high-throughput, accurate, cost-effective and user-friendly platform that can be used as a first-line screening test in a clinical laboratory.

Snakebite is a significant cause of death and disability in subsistent farming populations of sub-Saharan Africa. Antivenom is the most effective treatment of envenoming and is manufactured from IgG of venom-immunised horses/sheep but, because of complex fiscal reasons, there is a paucity of antivenom in sub-Saharan Africa. To address the plight of thousands of snakebite victims in savannah Nigeria, the EchiTAb Study Group organised the production, testing and delivery of antivenoms designed to treat envenoming by the most medically-important snakes in the region. The Echis saw-scaled vipers have a wide African distribution and medical importance. In an effort to maximise the clinical utility of scarce antivenom resources in Africa, we aimed to ascertain, at the pre-clinical level, to what extent the E. ocellatus-specific EchiTAbG antivenom, which was designed specifically for Nigeria, neutralised the lethal activity of venom from two other African species, E. pyramidum leakeyi and E. coloratus.

Accumulated literature suggests that the acidic nuclear phosphoprotein 32 kilodalton (Anp32) proteins control multiple cellular activities through different molecular mechanisms. Like other Anp32 family members, Anp32e (a.k.a. Cpd1, PhapIII) has been conserved throughout vertebrate evolution, suggesting that it has an important function in organismal survival.

A role for endocannabinoid signaling in neuronal morphogenesis as the brain develops has recently been suggested. Here we used the developing somatosensory circuit as a model system to examine the role of endocannabinoid signaling in neural circuit formation. We first show that a deficiency in cannabinoid receptor type 1 (CB(1)R), but not G-protein-coupled receptor 55 (GPR55), leads to aberrant fasciculation and pathfinding in both corticothalamic and thalamocortical axons despite normal target recognition. Next, we localized CB(1)R expression to developing corticothalamic projections and found little if any expression in thalamocortical axons, using a newly established reporter mouse expressing GFP in thalamocortical projections. A similar thalamocortical projection phenotype was observed following removal of CB(1)R from cortical principal neurons, clearly demonstrating that CB(1)R in corticothalamic axons was required to instruct their complimentary connections, thalamocortical axons. When reciprocal thalamic and cortical connections meet, CB(1)R-containing corticothalamic axons are intimately associated with elongating thalamocortical projections containing DGLβ, a 2-arachidonoyl glycerol (2-AG) synthesizing enzyme. Thus, 2-AG produced in thalamocortical axons and acting at CB(1)Rs on corticothalamic axons is likely to modulate axonal patterning. The presence of monoglyceride lipase, a 2-AG degrading enzyme, in both thalamocortical and corticothalamic tracts probably serves to restrict 2-AG availability. In summary, our study provides strong evidence that endocannabinoids are a modulator for the proposed 'handshake' interactions between corticothalamic and thalamocortical axons, especially for fasciculation. These findings are important in understanding the long-term consequences of alterations in CB(1)R activity during development, a potential etiology for the mental health disorders linked to prenatal cannabis use.

Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) is a global healthcare problem. The purpose of this study was to characterize CA-MRSA clones and their distribution in Kuwait hospitals.

Carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1) is a transmembrane protein with multiple functions in different cell types. CEACAM1 expression is frequently mis-regulated in cancer, with down-regulation reported in several tumors of epithelial origin and de novo expression of CEACAM1 in lung cancer and malignant melanoma. In this report we analyzed the regulation of CEACAM1 expression in three breast cancer cell lines that varied in CEACAM1 expression from none (MCF7) to moderate (MDA-MB-468) to high (MCF10A, comparable to normal breast).

The molecular mechanisms of genome reprogramming during transcriptional responses to stress are associated with specific chromatin modifications. Available data, however, describe histone modifications only at individual plant genes induced by stress. We have no knowledge of chromatin modifications taking place at genes whose transcription has been down-regulated or on the genome-wide chromatin modification patterns that occur during the plant's response to dehydration stress.

Natural sex selection methods have been applied for several decades, but their use and effectiveness are still a matter of debate. Therefore, this study assessed the efficacy of a maternal diet low in sodium and high in calcium, in combination with timing of intercourse well before ovulation as a method to improve the chances of conceiving a girl. A total of 172 couples wanting a girl participated in the study. For the 150 couples that actually started, compliance with diet was assessed through mineral analyses of blood and timing of intercourse relative to ovulation was determined by ovulation tests. Based on mineral blood values and timing of intercourse of 28 participants, a prediction rule for conceiving a girl was constructed and was tested prospectively for validity on a subsequent group of 50 women. In this group, 21 women satisfied the criteria of the prediction rule and 16 gave birth to a daughter. It is concluded that the combination of maternal diet with timing of intercourse is capable of increasing the probability of conceiving a girl (P=0.005). The observed percentage of female babies for all 32 women satisfying the prediction rule was 81% (95% confidence interval 68-95%).