Neuronal Nsun2 deficiency produces tRNA epitranscriptomic alterations and proteomic shifts impacting synaptic signaling and behavior.

Epitranscriptomic mechanisms linking tRNA function and the brain proteome to cognition and complex behaviors are not well described. Here, we report bi-directional changes in depression-related behaviors after genetic disruption of neuronal tRNA cytosine methylation, including conditional ablation and transgene-derived overexpression of Nsun2 in the mouse prefrontal cortex (PFC). Neuronal Nsun2-deficiency was associated with a decrease in tRNA m5C levels, resulting in deficits in expression of 70% of tRNAGly isodecoders. Altogether, 1488/5820 proteins changed upon neuronal Nsun2-deficiency, in conjunction with glycine codon-specific defects in translational efficiencies. Loss of Gly-rich proteins critical for glutamatergic neurotransmission was associated with impaired synaptic signaling at PFC pyramidal neurons and defective contextual fear memory. Changes in the neuronal translatome were also associated with a 146% increase in glycine biosynthesis. These findings highlight the methylation sensitivity of glycinergic tRNAs in the adult PFC. Furthermore, they link synaptic plasticity and complex behaviors to epitranscriptomic modifications of cognate tRNAs and the proteomic homeostasis associated with specific amino acids.

Through the years with on-a-chip gas chromatography: a review.

In recent years, the need for measurement and detection of samples in situ or with very small volume and low concentration (low and sub-parts per billion) is a cause for miniaturizing systems via microelectromechanical system (MEMS) technology. Gas chromatography (GC) is a common technique that is widely used for separating and measuring semi-volatile and volatile compounds. Conventional GCs are bulky and cannot be used for in situ analysis, hence in the past decades many studies have been reported with the aim of designing and developing chip-based GC. The focus of this review is to follow and investigate the development and the achievements in the field of chip-based GC and its components from the beginning up to the present.

Age-related sperm DNA methylation changes are transmitted to offspring and associated with abnormal behavior and dysregulated gene expression.

Advanced paternal age (APA) has been shown to be a significant risk factor in the offspring for neurodevelopmental psychiatric disorders, such as schizophrenia and autism spectrum disorders. During aging, de novo mutations accumulate in the male germline and are frequently transmitted to the offspring with deleterious effects. In addition, DNA methylation during spermatogenesis is an active process, which is susceptible to errors that can be propagated to subsequent generations. Here we test the hypothesis that the integrity of germline DNA methylation is compromised during the aging process. A genome-wide DNA methylation screen comparing sperm from young and old mice revealed a significant loss of methylation in the older mice in regions associated with transcriptional regulation. The offspring of older fathers had reduced exploratory and startle behaviors and exhibited similar brain DNA methylation abnormalities as observed in the paternal sperm. Offspring from old fathers also had transcriptional dysregulation of developmental genes implicated in autism and schizophrenia. Our findings demonstrate that DNA methylation abnormalities arising in the sperm of old fathers are a plausible mechanism to explain some of the risks that APA poses to resulting offspring.

25-hydroxyvitamin D3 concentration in serum and cerebrospinal fluid of patients with remitting-relapse multiple sclerosis.

There is epidemiological, geographical and immunological evidence suggesting that low environmental supplies of vitamin D3 may act as a risk factor for developing multiple sclerosis (MS), possibly due to dysfunction in the immunomodulatory properties of 25-hydroxyvitamin D3 (25-OH-D3) in the brain. The objective of this study is to measure the serum and cerebrospinal fluid (CSF) concentrations of 25-OH-D3 in MS patients during their relapsing phase. 52 patients with remitting-relapse and 58 patients with other non-inflammatory diseases of central and peripheral nervous system were entered into the study. Patients in both groups were admitted for the first time to do diagnostic procedures and they were not on any other treatment for neurological disorders. The means and medians for serum levels of 25-OH-D3 in MS patients and control group were 10.64 ± 9.2 ng/ml (median: 9.6 ng/ml) and 13.23 ± 17.56 ng/ml (median: 11.90 ng/ml), respectively (p=0.328). CSF concentrations for the same values were 2.02 ± 1.94 ng/ml (median: 0.23 ng/ml) and 3.28 ± 2.96 (median: 0.29 ng/ml), respectively (p=0.242). The differences between calculated numbers of serum/CSF ratios were not statistically significant too. The serum and CSF concentrations of 25-OH-D3 in MS group were lower than the control counterpart without any statistical difference and the authors did not find any influence of serum 25-OH-D3 concentration on the CSF concentration based on the non-significant statistical difference between the serum/CSF ratios in two study groups of MS patients and control cases.

The evaluation of Candida albicans biofilms formation on silicone catheter, PVC and glass coated with titanium dioxide nanoparticles by XTT method and ATPase assay.

Lots of Candida albicans infections involve in biofilm formation on medical devices. This kind of biofilm can impede antifungal therapy and complicates the treatment of infectious diseases particularly in field of chronic diseases associated with implanted devices. This study has investigated the influence of treating silicone catheter, PVC and glass coated with Titanium dioxide (TiO2) nanoparticles on attachment of C. albicans. In this study TiO2 nanoparticles were synthesized from precursor TiCl4 and characterized by scanning electron microscopy (SEM) and X-ray diffraction (XRD) which showed TiO2 nanoparticles are 70-100 nm in size. In the simplest model of biofilms formation, C. albicans isolates (ATCC10231) and (ATCC 76615) were grown on the surface of small disks of catheter, PVC and glass in a flat-bottomed 12-well plates and evaluated biofilm formation using ATP bioluminescence and tetrazolium salt (XTT) reduction assays. In addition, morphology of C. albicans biofilms after 48 h incubation was observed by SEM. Results indicated that there is a statistical difference between mean of coated samples especially catheter and glass before and after TiO2 nanoparticles coating (p<0.05). In SEM analysis, C. albicans biofilm was more aggregated on the surface of glass and catheter than PVC and control groups and after treatment by these nanoparticles, catheter and glass both showed most significant decrease of C. albicans attachment in comparison to the control groups (Fig. 4, Ref. 23).

Comparative screening of Chlamydia trachomatis infection in women population in tehran, iran.

BACKGROUND: There are more than 30 different sexually transmissible agents while the most common one is Chlamydia trachomatis. In this prospective study, we decided to compare the prevalence of infection in symptomatic and asymptomatic females. METHODS: Two hundred sixty urine samples of women in two groups (symptomatic and asymptomatic) were collected from patients attending Mehrad Hospital in Tehran, Iran and tested by polymerase chain reaction. RESULTS: Thirty nine women in both groups were infected (14.99%), while 27/130 subjects were in symptomatic group (20.76%), compared with 12/130 person in asymptomatic group (9.23%). No statistically significant difference was found between two groups. Data analysis showed infection with C. trachomatis in symptomatic women to be significantly associated with history of sexually transmitted infections, white blood cells in urine and epithelial cells in urine. CONCLUSION: The present study recommends that targeted screening programs in high risk sexually active women (like as individuals who had a history of STIs) are needed as part of case-finding strategies and treatment.

Epigenetic regulation of serotonin transporter expression and behavior in infant rhesus macaques.

Epigenetic mechanisms may moderate genetic and environmental risk (GxE) for mood disorders. We used an experimental rhesus macaque model of early life stress to test whether epigenetic regulation of serotonin transporter (5-HTT) may contribute to GxE interactions that influence behavior and emotion. We hypothesized that peripheral blood mononuclear cell (PBMC) DNA methylation within an 800 bp cytosine-phosphate-guanosine (CpG) island that overlaps with the 5-HTT transcription initiation start site, a hypothesized model of the same genomic region in brain tissue, would mediate or moderate the effects of early life stress and a functional 5-HTT promoter polymorphism (rh5-HTTLPR) on two outcomes: PBMC 5-HTT expression and behavioral stress reactivity. Eighty-seven infant rhesus macaques (3-4 months of age) were either mother reared in large social groups (n = 70) or nursery reared (n = 17). During a maternal/social separation, infants' blood was sampled and behavioral stress reactivity recorded. PBMC DNA and RNA samples were used to determine rh5-HTTLPR genotype, 5-HTT mRNA expression using quantitative reverse transcription polymerase chain reaction (qRT-PCR) and 5-HTT CpG methylation status using sodium bisulfite pyrosequencing. Consistent with human data, carriers of the low-expressing rh5-HTTLPR alleles exhibited higher mean 5-HTT CpG methylation, which was associated with lower PBMC 5-HTT expression. Higher 5-HTT CpG methylation, but not rh5-HTTLPR genotype, exacerbated the effects of early life stress on behavioral stress reactivity in infants. 5-HTT CpG methylation may be an important regulator of 5-HTT expression early in development and may contribute to the risk for mood disorders observed in 'high-risk'5-HTTLPR carriers.

Genetic architecture of the human tryptophan hydroxylase 2 Gene: existence of neural isoforms and relevance for major depression.

Impaired brain serotonin neurotransmission is a potential component of the diathesis of major depression. Tryptophan hydroxylase-2 (TPH2), is the rate limiting biosynthetic isoenzyme for serotonin that is preferentially expressed in the brain and a cause of impaired serotonin transmission. Here, we identify a novel TPH2 short isoform with truncated catalytic domain expressed in human brainstem, prefrontal cortex, hippocampus and amygdala. An exploratory study of 166 Caucasian subjects revealed association with major depression or suicide of a novel single nucleotide polymorphism (SNP) g.22879A>G located in exon 6 of this short isoform. This SNP and additional SNPs were discovered through a systematic characterization of the genetic architecture of the TPH2 gene for further genetic and functional investigations of its relationship to major depression and other psychopathology.

Managing nutritional programmes in developing countries.

Improving community nutrition in developing countries requires a detailed epidemiological picture of the prevalent nutritional problems in different regions and age groups. This makes it possible to identify priorities, sensitize policy-makers, establish political commitment and design appropriate community programmes for income generation and education for the best use of food resources. Experiences acquired from community-based nutritional programmes show that ownership of a programme by the community and using a tailor-made approach are essential factors in the successful implementation of programmes. A multifaceted approach is needed, involving a range of sectors-agriculture, commerce, education and health--and commitment at all levels from government to communities and individuals.

Managing nutritional programmes in developing countries

Improving community nutrition in developing countries requires a detailed epidemiological picture of the prevalent nutritional problems in different regions and age groups. This makes it possible to identify priorities, sensitize policy-makers, establish political commitment and design appropriate community programmes for income generation and education for the best use of food resources. Experiences acquired from community-based nutritional programmes show that ownership of a programme by the community and using a tailor-made approach are essential factors in the successful implementation of programmes. A multifaceted approach is needed, involving a range of sectors-agriculture, commerce, education and health-- and commitment at all levels from government to communities and individuals

Sympathetic skin response (SSR) in erythromelalgia.

BACKGROUND: Erythromelalgia (EM) is characterized by severe pain associated with local redness and hotness in the extremities. When the extremity is lowered, or heat is applied, the pain is intensified and when coldness is applied, or the extremity is elevated the pain is decreased. OBJECTIVE: To evaluate if there is any sympathetic nervous system involvement in erythromelalgia, sympathetic skin response (SSR) test was done. SETTING: This study was conducted during the years 1998-2000 in the Department of Physical medicine and Rehabilitation, Shiraz University of Medical Sciences. METHODS: SSR study was done on 22 patients with erythromelalgia and 22 normal subjects were matched for age and sex for comparison. RESULTS: There is a significant difference between the patients and controls especially in the lower extremity findings (P = 0.000). More than 72.7% of the patients had abnormal SSR. CONCLUSION: It is concluded that sympathetic peripheral fibers (C fibers) are involved in erythromelalgia and it is probably the pathogenesis of the disease.

Stoppage: an issue for segregation analysis.

Segregation analysis assumes that the observed family-size distribution (FSD), i.e., distribution of number of offspring among nuclear families, is independent of the segregation ratio p. However, for certain serious diseases with early onset and diagnosis (e.g., autism), parents may change their original desired family size, based on having one or more affected children, thus violating that assumption. Here we investigate "stoppage," the situation in which such parents have fewer children than originally planned. Following Brookfield et al. [J Med Genet 25:181-185, 1988], we define a stoppage probability d that after the birth of an affected child, parents will stop having children and thus not reach their original desired family size. We first derive the full correct likelihood for a simple segregation analysis as a function of p, d, and the ascertainment probability pi. We show that p can be estimated from this likelihood if the FSD is known. Then, we show that under "random" ascertainment, the presence of stoppage does not bias estimates of p. However, for other ascertainment schemes, we show that is not the case. We use a simulation study to assess the magnitude of bias, and we demonstrate that ignoring the effect of stoppage can seriously bias the estimates of p when the FSD is ignored. In conclusion, stoppage, a realistic scenario for some complex diseases, can represent a serious and potentially intractable problem for segregation analysis.

Investigation of dopamine receptor (DRD4) and dopamine transporter (DAT) polymorphisms for genetic linkage or association to panic disorder.

Clinical and animal studies suggest a role for the neurotransmitter dopamine in anxiety states. In humans, one such condition is panic disorder, which is typified by recurrent panic attacks accompanied by anticipatory anxiety. Family, segregation, and twin studies imply a genetic component to the pathophysiology of panic disorder. In this study, we examined the genes for the D4 dopamine receptor (DRD4) and the dopamine transporter (DAT) using three common sequence polymorphisms. Two of these polymorphisms were in DRD4, a 12 base-pair insertion/deletion in exon 1 and a 48 base-pair repeat in exon 3, and the third was a 40 base-pair repeat in the 3' untranslated region of DAT. We employed a family-based design, using 622 individuals in 70 families, as well as 82 haplotype relative risk "trios". Subjects were genotyped at the polymorphic loci, and the data were analyzed for genetic association and linkage. There were no significant differences in allele frequencies or occurrence of genotypes within the triads for any of the three polymorphisms. No significant linkage between the DRD4 or DAT polymorphisms and panic disorder was observed in the multiplex families, using a variety of simulations for dominant and recessive models of inheritance. However, LOD scores of approximately 1.1 and 1.05 were observed for the DAT and DRD4 exon 1 loci, respectively. The results reported here provide little support for the role of these polymorphisms in panic disorder.

Fine mapping of PPH1, a gene for familial primary pulmonary hypertension, to a 3-cM region on chromosome 2q33.

Familial primary pulmonary hypertension (PPH) is a rare autosomal dominant disease characterized by distinctive changes in pulmonary arterioles that lead to increased pulmonary artery pressures, right ventricular failure, and death. Our previous studies had mapped the disease locus, PPH1, to a 27-cM region on chromosome 2q31-q33, with a maximum multipoint logarithm of the odds favoring genetic linkage score of 3.87 with markers D2S350 and D2S364. To narrow the minimal genetic region for PPH, we physically mapped 33 highly polymorphic microsatellite markers and used them to genotype 44 affected individuals and 133 unaffected individuals from 17 families with PPH. We observed recombination events that substantially reduced the interval for PPH1 to the approximately 3-cM region that separates D2S311 and D2S1384. This entire region lies within chromosome 2q33. A maximum two-point lod score of 7.23 at a recombination fraction of zero was obtained for marker D2S307. A maximum multipoint lod score of 7.41 was observed close to marker D2S1367. The current minimal genetic region contains multiple candidate genes for PPH, including a locus thought to play a role in lung cancer.

Potential panic disorder syndrome: clinical and genetic linkage evidence.

This paper reports evidence for a possible "chromosome 13 syndrome," which includes panic disorder, kidney or bladder problems, serious headaches, thyroid problems (usually hypothyroid), and/or mitral valve prolapse (MVP). In the course of a genetic linkage study of panic disorder, we noted these medical conditions in individual family members. (We were blind to family relationships and marker data.) We hypothesized that there may exist a subgroup of panic families with these medical conditions, which for simplicity we called it the "syndrome." Subsequently we reclassified the families as with or without the "syndrome" and extended the phenotype for analysis to include the above medical conditions. All these classifications were also done before the analysis and blind to marker data. We then examined our linkage results, looking for significant differences between families with and without the "syndrome" (using several definitions of the "syndrome")-i.e., testing for genetic heterogeneity. When the families with and without bladder/kidney problems were separated from each other, one marker-D13S779 (ATA26D07)-yielded a lod score of over 3 in the families with bladder/kidney problems. This lod score went up to 4.2 in these families when we diagnosed any individual with any one of the "syndrome" conditions as affected. These results were statistically significant even after applying an extremely overconservative Bonferroni correction for multiple tests. We present these results in order to alert other investigators working on panic disorder, for replication. If replicated, one may hypothesize that a candidate gene for the syndrome should be expressed in CNS, kidney, gut, thyroid, etc. We also noted that two independent studies report recent linkage findings between schizophrenia and the same region on chromosome 13. No connection between schizophrenia and panic disorder has ever been reported. Finally, we suggest that genetic studies of psychiatric disorders might prove more fruitful if phenotypes were expanded to include possible manifestations of the disorder in medical (non-mental) symptoms. Am. J. Med. Genet.(Neuropsychiatr. Genet.) 96:24-35, 2000.

Design of artificial neural network and its applications to the analysis of alcoholism data.

Artificial neural networks were applied to the alcoholism data to reveal nonlinear relationships between intermediate phenotypes, marker identity-by-descent sharing, and the affection status. A variable number of hidden units were considered to achieve a balance between the minimal mean-squared error and over-fitting of the data. The predictability of the affection status based on intermediate phenotype information (event-related potential 300, monoamine oxidase, and gender) was 65% to 75%, and sensitivity/specificity ranged around 50% to 80%. The IBD approach succeeded in identifying the same marker as previous studies, but also found additional peaks.

Lack of genetic linkage or association between a functional serotonin transporter polymorphism and panic disorder.

Given the efficacy of medications that interact with the serotonin transporter (5-HTT) in the treatment of panic disorder, we have used a family-based design to test for genetic association and linkage between panic disorder and a functional polymorphism in the promoter of the gene for 5-HTT. In this study, 340 individuals in 45 families, as well as 74 haplotype relative risk 'trios' were genotyped at the polymorphic locus, which consists of a 44 base pair deletion/insertion. There were no significant differences in allele frequencies or occurrence of genotypes within the triads. No linkage between the 5-HTT polymorphism and panic disorder was observed in the multiplex families, using a variety of simulations for dominant and recessive models of inheritance. Recent reports suggest an association between the 5-HTT polymorphism and anxiety-related traits, as measured with personality assessment. The results reported here provide evidence that the genetic basis of panic disorder may be distinct from anxiety-related traits assessed by personality inventories in normal populations.

Parent-of-origin effect in panic disorder.

Parent-of-origin effect was examined in a series of 64 pedigrees with panic disorder (PD) under both the narrow and broad diagnostic models. The narrow diagnostic model defined the affected phenotype to include only the "definite" and "probable" forms of PD, whereas the broad diagnostic model included the entire PD symptomatology. The pattern of maternal vs. paternal transmission of disease was analyzed through a number of comparisons. These comparisons were performed first on all pedigrees and then on a subset of "pure" pedigrees including only strictly maternal transmission or strictly paternal transmission of PD. There were no significant differences in the proportion of offspring born to transmitting mothers vs. transmitting fathers under either diagnostic model or pedigree set. When the difference in the sex ratio among affected offspring from both transmission types was considered, only the "pure" pedigree sample under the broad diagnostic model yielded nominally (i.e., not corrected for multiple tests) significant results (P < .05). Also, the comparisons of cumulative lifetime risk for PD between offspring of transmitting mothers and fathers gave some nominally significant results; when affected and unaffected offspring were considered, significant results were observed under the narrow and broad diagnostic models, P < .0005 and P < .05, respectively. These findings must be considered provisional until confirmed by further study.