Too much alcohol, different gene surface? Alcohol abuse could be associated with monoamine oxidase A gene methylation

Monoamine oxidase A (MAO-A) is an enzyme that metabolizes neurotransmitters involved in alcohol dependency. To investigate if MAO-A is associated with alcohol abuse, I compared MAOA gene methylation in males with or without alcohol use disorders (N = 24 and N = 55, respectively). Methylation of MAOA gene in white blood cells was used as an index of MAO-A activity in the brain. Average methylation was higher in males with alcohol use disorders (AUD), but only in the nonsmokers’ subsample (Wilcoxon p = 0.01, proportion of better responses = 0.86). Methylation at gene site CpG10 was also higher in nonsmokers with AUD (p = 0.05, proportion = 0.80). Interaction between smoking and methylation is a novel finding. Because the sample of nonsmokers is small (N = 5 + 19), these results should be considered only as initial.http://www.ester.ee/record=b4453848*es

Similar neural networks respond to coherence during comprehension and production of discourse

When comprehending discourse, listeners engage default-mode regions associated with integrative semantic processing to construct a situation model of its content. We investigated how similar networks are engaged when we produce, as well as comprehend, discourse. During functional magnetic resonance imaging, participants spoke about a series of specific topics and listened to discourse on other topics. We tested how activation was predicted by natural fluctuations in the global coherence of the discourse, that is, the degree to which utterances conformed to the expected topic. The neural correlates of coherence were similar across speaking and listening, particularly in default-mode regions. This network showed greater activation when less coherent speech was heard or produced, reflecting updating of mental representations when discourse did not conform to the expected topic. In contrast, regions that exert control over semantic activation showed task-specific effects, correlating negatively with coherence during listening but not during production. Participants who showed greater activation in left inferior prefrontal cortex also produced more coherent discourse, suggesting a specific role for this region in goal-directed regulation of speech content. Results suggest strong correspondence of discourse representations during speaking and listening. However, they indicate that the semantic control network plays different roles in comprehension and production

Whole exome sequencing of benign pulmonary metastasizing leiomyoma reveals mutation in the BMP8B gene

Background: Benign metastasizing leiomyoma (BML) is an orphan neoplasm commonly characterized by pulmonary metastases consisting of smooth muscle cells. Patients with BML have usually a current or previous uterine leiomyoma, which is therefore suggested to be the most probable source of this tumour. The purpose of this case report was to determine the possible genetic grounds for pulmonary BML. Case presentation: We present a case report in an asymptomatic 44-year-old female patient, who has developed uterine leiomyoma with subsequent pulmonary BML. Whole exome sequencing (WES) was used to detect somatic mutations in BML lesion. Somatic single nucleotide mutations were identified by comparing the WES data between the pulmonary metastasis and blood sample of the same BML patient. One heterozygous somatic mutation was selected for validation by Sanger sequencing. Clonality of the pulmonary metastasis and uterine leiomyoma was assessed by X-chromosome inactivation assay. Conclusions: We describe a potentially deleterious somatic heterozygous mutation in bone morphogenetic protein 8B (BMP8B) gene (c.1139A > G, Tyr380Cys) that was identified in the pulmonary metastasis and was absent from blood and uterine leiomyoma, and may play a facilitating role in the metastasizing of BML. The clonality assay confirmed a skewed pattern of X-chromosome inactivation, suggesting monoclonal origin of the pulmonary metastases.Peer reviewe

Programmi RITA tegevuse 1 projekti „Varustuskindluse tagamine toidu, esmatarbekaupade, isikukaitsevahendite ja vee tarneahelas Eestis“ lõpparuanne

Uuring valmis Majandus- ja Kommunikatsiooniministeeriumi, Rahandusministeeriumi, Sotsiaalministeeriumi, Siseministeeriumi, Kaitseministeeriumi, Maaeluministeeriumi ja Riigikantselei eesmärkide elluviimiseks.Lõpparanne täieneb aja jooksul. Käesolev versioon on seisuga 30.03.2022.Käesolev aruanne võtab kokku uuringu „Varustuskindluse tagamine toidu, esmatarbekaupade, isikukaitsevahendite ja vee tarneahelas Eestis (VARUST)“ olulisemad järeldused. Uuringut rahastati Eesti Teadusagentuuri Euroopa Regionaalarengu Fondi programmi „Valdkondliku teadus- ja arendustegevuse tugevdamine“ (RITA) tegevusest 1 „Strateegilise TA tegevuse toetamine“ (leping nr 7.2-2/20/24). Uuring valmis Majandus- ja Kommunikatsiooniministeeriumi, Rahandusministeeriumi, Sotsiaalministeeriumi, Siseministeeriumi, Kaitseministeeriumi, Maaeluministeeriumi ja Riigikantselei eesmärkide elluviimiseks. Uuringu viis läbi kolmest organisatsioonist koosnev konsortsium, kuhu kuulusid Eesti Maaülikool (3 töögruppi), Eesti Konjunktuuriinstituut ja Eesti Taimekasvatuse Instituut. Uuringu lähteülesande kohaselt oli uuringu eesmärgiks luua ettevõtetele toimepidevuse hindamiseks universaalne lähenemine (edaspidi mudel), pakkuda välja varustuskindluse mõõdikud ja sihttasemed ning pakkuda välja soovitused, kuidas korraldada varustuskindluse lahendamine Eesti oludele sobivaimal ja riigieelarvet ning ettevõtjaid vähem koormaval viisil.Uuringu tellis ja uuringut rahastas Eesti Teadusagentuur Euroopa Regionaalarengu Fondist toetatava programmi „Valdkondliku teadus- ja arendustegevuse tugevdamine“ (RITA) tegevuse 1 „Strateegilise TA tegevuse toetamine“ kaudu

Mutations in the nuclear localization signal of nsP2 influencing RNA synthesis, protein expression and cytotoxicity of Semliki Forest virus

The cytotoxicity of Semliki Forest virus (SFV) infection is caused partly by the non-structural protein nsP2, an essential component of the SFV replicase complex. Due to the presence of a nuclear localization signal (NLS), nsP2 also localizes in the nucleus of infected cells. The present study analysed recombinant SFV replicons and genomes with various deletions or substitutions in the NLS, or with a proline-to-glycine mutation at position 718 of nsP2 (P718G). Deletion of one or two arginine residues from the NLS or substitution of two of the arginines with aspartic acid resulted in a virus with a temperature-sensitive phenotype, and substitution of all three arginines was lethal. Thus, most of the introduced mutations severely affected nsP2 functioning in viral replication; in addition, they inhibited the ability of SFV to induce translational shut-off and kill infected cells. SFV replicons with a P718G mutation or replacement of the NLS residues 648RRR650 with RDD were found to be the least cytotoxic. Corresponding replicons expressed non-structural proteins at normal levels, but had severely reduced genomic RNA synthesis and were virtually unable to replicate and transcribe co-electroporated helper RNA. The non-cytotoxic phenotype was maintained in SFV full-length genomes harbouring the corresponding mutations; however, during a single cycle of cell culture, these were converted to a cytotoxic phenotype, probably due to the accumulation of compensatory mutations

Properties of non-structural protein 1 of Semliki Forest virus and its interference with virus replication

Semliki Forest virus (SFV) non-structural protein 1 (nsP1) is a major component of the virus replicase complex. It has previously been studied in cells infected with virus or using transient or stable expression systems. To extend these studies, tetracycline-inducible stable cell lines expressing SFV nsP1 or its palmitoylation-negative mutant (nsP16D) were constructed. The levels of protein expression and the subcellular localization of nsP1 in induced cells were similar to those in virus-infected cells. The nsP1 expressed by stable, inducible cell lines or by SFV-infected HEK293 T-REx cells was a stable protein with a half-life of approximately 5 h. In contrast to SFV infection, induction of nsP1 expression had no detectable effect on cellular transcription, translation or viability. Induction of expression of nsP1 or nsP16D interfered with multiplication of SFV, typically resulting in a 5–10-fold reduction in virus yields. This reduction was not due to a decrease in the number of infected cells, indicating that nsP1 expression does not block virus entry or initiation of replication. Expression of nsP1 interfered with virus genomic RNA synthesis and delayed accumulation of viral subgenomic RNA translation products. Expression of nsP1 with a mutation in the palmitoylation site reduced synthesis of genomic and subgenomic RNAs and their products of translation, and this effect did not resolve with time. These results are in agreement with data published previously, suggesting a role for nsP1 in genomic RNA synthesis

Genes targeted by the estrogen and progesterone receptors in the human endometrial cell lines HEC1A and RL95-2

<p>Abstract</p> <p>Background</p> <p>When the steroid hormones estrogen and progesterone bind to nuclear receptors, they have transcriptional impact on target genes in the human endometrium. These transcriptional changes have a critical function in preparing the endometrium for embryo implantation.</p> <p>Methods</p> <p>382 genes were selected, differentially expressed in the receptive endometrium, to study their responsiveness of estrogen and progesterone. The endometrial cell lines HEC1A and RL95-2 were used as experimental models for the non-receptive and receptive endometrium, respectively. Putative targets for activated steroid hormone receptors were investigated by chromatin immunoprecipitation (ChIP) using receptor-specific antibodies. Promoter occupancy of the selected genes by steroid receptors was detected in ChIP-purified DNA by quantitative PCR (qPCR). Expression analysis by reverse transcriptase (RT)-PCR was used to further investigate hormone dependent mRNA expression regulation of a subset of genes.</p> <p>Results</p> <p>ChIP-qPCR analysis demonstrated that each steroid hormone receptor had distinct group of target genes in the endometrial cell lines. After estradiol treatment, expression of estrogen receptor target genes predominated in HEC1A cells (n = 137) compared to RL95-2 cells (n = 35). In contrast, expression of progesterone receptor target genes was higher in RL95-2 cells (n = 83) than in HEC1A cells (n = 7) after progesterone treatment. RT-PCR analysis of 20 genes demonstrated transcriptional changes after estradiol or progesterone treatment of the cell lines.</p> <p>Conclusions</p> <p>Combined results from ChIP-qPCR and RT-PCR analysis showed different patterns of steroid hormone receptor occupancy at target genes, corresponding to activation or suppression of gene expression after hormone treatment of HEC1A and RL95-2 cell lines.</p

A clinical pathway for community-acquired pneumonia: an observational cohort study

<p>Abstract</p> <p>Background</p> <p>Six hospitals instituted a voluntary, system-wide, pathway for community acquired pneumonia (CAP). We proposed this study to determine the impact of pathway antibiotics on patient survival, hospital length of stay (LOS), and total hospital cost.</p> <p>Methods</p> <p>Data were collected for adults from six U.S. hospitals with a principal CAP discharge diagnosis code, a chest infiltrate, and medical notes indicative of CAP from 2005-2007. Pathway and non-pathway cohorts were assigned according to antibiotics received within 48 hours of admission. Pathway antibiotics included levofloxacin 750 mg monotherapy or ceftriaxone 1000 mg plus azithromycin 500 mg daily. Multivariable regression models assessed 90-day mortality, hospital LOS, total hospital cost, and total pharmacy cost.</p> <p>Results</p> <p>Overall, 792 patients met study criteria. Of these, 505 (64%) received pathway antibiotics and 287 (36%) received non-pathway antibiotics. Adjusted means and p-values were derived from Least Squares regression models that included Pneumonia Severity Index risk class, patient age, heart failure, chronic obstructive pulmonary disease, and admitting hospital as covariates. After adjustment, patients who received pathway antibiotics experienced lower adjusted 90-day mortality (<it>p </it>= 0.02), shorter mean hospital LOS (3.9 vs. 5.0 days, <it>p </it>< 0.01), lower mean hospital costs ($2,485 vs.$3,281, <it>p </it>= 0.02), and similar mean pharmacy costs ($356 vs.$442, <it>p </it>= 0.11).</p> <p>Conclusions</p> <p>Pathway antibiotics were associated with improved patient survival, hospital LOS, and total hospital cost for patients admitted to the hospital with CAP.</p