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• 3. Good health close

There is an ongoing debate on the importance of genetic factors in cancer development, where gene-centered cancer predisposition seems to show that only 5 to 10% of the cancer cases are inheritable. By conducting a systematic analysis of germline genomes of 9712 cancer patients representing 22 common cancer types along with 16,670 noncancer individuals, we identified seven cancer-associated germline genomic patterns (CGGPs), which summarized trinucleotide mutational spectra of germline genomes. A few CGGPs were consistently enriched in the germline genomes of patients whose tumors had smoking signatures or correlated with oncogenesis- and genome instability–related mutations. Furthermore, subgroups defined by the CGGPs were significantly associated with distinct oncogenic pathways, tumor histological subtypes, and prognosis in 13 common cancer types, suggesting that germline genomic patterns enable to inform treatment and clinical outcomes. These results provided evidence that cancer risk and clinical outcomes could be encoded in germline genomes. Germline variants when organized as genomic patterns are associated with cancer risk, oncogenic pathways, and clinical outcomes.

Abstract The objective of this study was to investigate the effect of docosahexaenoic acid (DHA) supplementation on blood and intestinal DHA levels and lung function in mild/moderately affected adult CF patients with the ΔF508 genotype. Background Cystic Fibrosis (CF) patients often present with plasma fatty acid levels indicating low levels of linoleic (18:2 n −6) and docosahexaenoic (22:6 n −3) acids and an increased level of arachidonic acid (20:4 n −6). Improved dietary fat intake or reducing fat malabsorption with pancreatic enzymes has failed to normalize this biochemical deficiency of DHA. Methods Five CF patients, aged 18–43, received 70 mg of DHA/kg body weight/d for six weeks. At baseline and at six weeks a physical exam, lung function, 3-day dietary intake, duodenal mucosal biopsy and blood sample were assessed. The blood was analyzed for plasma vitamin A, D and E levels, liver function tests, clinical chemistry (CBC, differential and electrolytes). Plasma and red blood cell fatty acid levels were also analyzed. At three weeks, assessment included a physical exam, lung function test and fasting blood sample (vitamin levels, liver function and clinical chemistry only). Results Pre- and post-measurements were compared for the four subjects who completed the study. An increase in DHA content (% w/w) was observed in all phospholipid fractions of plasma, red blood cell and mucosal samples. No significant differences in vitamin levels, liver function or lung function were observed. Conclusions The study proves the concept that an increase in tissue DHA levels in CF patients can be achieved by supplementing for six weeks with 70 mg/kg/d DHA.

Phosphoribosyl pyrophosphate synthetase (PRPS) is a rate-limiting enzyme whose function is important for the biosynthesis of purines, pyrimidines, and pyridines. Importantly, while missense mutations of PRPS1 have been identified in neurological disorders such as Arts syndrome, how they contribute to neuropathogenesis is still unclear. We identified the Drosophila ortholog of PRPS (dPRPS) as a direct target of RB/E2F in Drosophila, a vital cell cycle regulator, and engineered dPRPS alleles carrying patient-derived mutations. Interestingly, while they are able to develop normally, dPRPS mutant flies have a shortened lifespan and locomotive defects, common phenotypes associated with neurodegeneration. Careful analysis of the fat body revealed that patient-derived PRPS mutations result in profound defects in lipolysis, macroautophagy, and lysosome function. Significantly, we show evidence that the nervous system of dPRPS mutant flies is affected by these defects. Overall, we uncovered an unexpected link between nucleotide metabolism and autophagy/lysosome function, providing a possible mechanism by which PRPS-dysfunction contributes to neurological disorders. Author summary Phosphoribosyl pyrophosphate synthetase (PRPS) is an important enzyme in nucleotide synthesis: the building blocks of DNA and RNA and other important metabolites. Importantly, while PRPS is mutated in neurological disorders such as Arts syndrome, Charcot-Marie-Tooth disease, and nonsyndromic sensorineural deafness, it is currently unclear why PRPS dysfunction leads to neurological disorders. In this study, we engineered a Drosophila model of ARTS syndrome and discovered that PRPS mutations result in defects in lysosome-mediated and autophagy processes, which are known to be important for neuronal homeostasis. Our study provides crucial insights into the way that PRPS mutations contribute to neurological disorders.

In this study, we consider the pretreatment phase for cancer patients. This is defined as the period between the referral to a cancer center and the confirmation of the treatment plan. Physicians have been identified as bottlenecks in this process, and the goal is to determine a weekly cyclic schedule that improves the patient flow and shortens the pretreatment duration. High uncertainty is associated with the arrival day, profile and type of cancer of each patient. We also include physician satisfaction in the objective function. We present a MIP model for the problem and develop a tabu search algorithm, considering both deterministic and stochastic cases. Experiments show that our method compares very well to CPLEX under deterministic conditions. We describe the stochastic approach in detail and present a real application.

Abstract The ligands RN(CH2-2-C5H4N)2, L1, R = CH2C6H4-2-OH; L2, R = CH2C6H3-4-Me-2-OH; L3, R = CH2C6H3-5-Cl-2-OH; L4, R = CH2C6H3-5-NO2-2-OH; give dimethylplatinum(II) complexes that activate dioxygen in the absence of a protic solvent. The initial reaction with [Pt2Me4(SMe2)2] gives [PtMe2(κ2-N,N’-L)], and these react with oxygen to give [Pt(OH)Me2(κ3-N,N’,N”-L-H)], which exist as a mixture of isomers. The factors influencing reactivity and mechanism in these reactions are elucidated, and the presence of both a free pyridyl donor (push group) and a free hydroxyl (pull group) is suggested to give a synergy for dioxygen activation. Some platinum(II) complexes and trimethylplatinum(IV) complexes with these ligands are also reported.

Treatment of human cells with Type 1 interferons restricts HIV replication. Here we report that the tripartite motif protein TRIM22 is a key mediator. We used transcriptional profiling to identify cellular genes that were induced by interferon treatment and identified TRIM22 as one of the most strongly up-regulated genes. We confirmed, as in previous studies, that TRIM22 over-expression inhibited HIV replication. To assess the role of TRIM22 expressed under natural inducing conditions, we compared the effects of interferon in cells depleted for TRIM22 using RNAi and found that HIV particle release was significantly increased in the knockdown, implying that TRIM22 acts as a natural antiviral effector. Further studies showed that TRIM22 inhibited budding of virus-like particles containing Gag only, indicating that Gag was the target of TRIM22. TRIM22 did not block the release of MLV or EIAV Gag particles. Inhibition was associated with diffuse cytoplasmic staining of HIV Gag rather than accumulation at the plasma membrane, suggesting TRIM22 disrupts proper trafficking. Mutational analyses of TRIM22 showed that the catalytic amino acids Cys15 and Cys18 of the RING domain are required for TRIM22 antiviral activity. These data disclose a pathway by which Type 1 interferons obstruct HIV replication. Author Summary Interferons are produced by cells in response to challenge by foreign pathogens such as viruses. The molecular mechanisms by which Type I interferons (e.g., IFNβ) inhibit the replication of HIV-1 are not fully clarified. We identified a gene called TRIM22 that belongs to the tripartite motif (TRIM) family that was strongly induced by IFNβ. Using RNA interference to reduce the expression of TRIM22, we showed that TRIM22 is a key mediator of the IFNβ response when expressed at natural levels. We demonstrate that TRIM22 blocks the intracellular trafficking of the viral structural protein Gag to the surface of the cell, and that the antiviral activity of TRIM22 is dependent on two cysteine residues (Cys15 and Cys18) that are critical for the E3 ligase activity of RING-containing proteins. This report describes a mechanism by which Type I interferons block HIV-1 replication.

Additional file 5. Complete list of GO term treemaps for essential genes

Arsenicosis, a syndrome caused by ingestion of arsenic contaminated drinking water, currently affects millions of people in South-East Asia and elsewhere. Previous animal studies revealed that the toxicity of arsenite essentially can be abolished if selenium is co-administered as selenite. Although subsequent studies have provided some insight into the biomolecular basis of this striking antagonism, many details of the biochemical pathways that ultimately result in the detoxification and excretion of arsenic using selenium supplements have yet to be thoroughly studied. To this end and in conjunction with the recent Phase III clinical trial "Selenium in the Treatment of Arsenic Toxicity and Cancers", we have applied synchrotron X-ray techniques to elucidate the mechanisms of this arsenic-selenium antagonism at the tissue and organ levels using an animal model. X-ray fluorescence imaging (XFI) of cryo-dried whole-body sections of laboratory hamsters that had been injected with arsenite, selenite, or both chemical species, provided insight into the distribution of both metalloids 30 minutes after treatment. Co-treated animals showed strong co-localization of arsenic and selenium in the liver, gall bladder and small intestine. X-ray absorption spectroscopy (XAS) of freshly frozen organs of co-treated animals revealed the presence in liver tissues of the seleno bis-(S-glutathionyl) arsinium ion, which was rapidly excreted via bile into the intestinal tract. These results firmly support the previously postulated hepatobiliary excretion of the seleno bis-(S-glutathionyl) arsinium ion by providing the first data pertaining to organs of whole animals.

AbstractTreponema pallidum subsp. pallidum, the causative agent of syphilis, is a highly invasive spirochete pathogen that uses the vasculature to disseminate throughout the body. Identification of bacterial factors promoting dissemination is crucial for syphilis vaccine development. An important step in dissemination is bacterial adhesion to blood vessel surfaces, a process mediated by bacterial proteins that can withstand forces imposed on adhesive bonds by blood flow (vascular adhesins). The study of T. pallidum vascular adhesins is hindered by the uncultivable nature of this pathogen. We overcame these limitations by expressing T. pallidum adhesin Tp0751 (pallilysin) in an adhesion-attenuated strain of the cultivable spirochete Borrelia burgdorferi. Under fluid shear stress representative of conditions in postcapillary venules, Tp0751 restored bacterial-vascular interactions to levels similar to those observed for infectious B. burgdorferi and a gain-of-function strain expressing B. burgdorferi vascular adhesin BBK32. The strength and stability of Tp0751- and BBK32-dependent endothelial interactions under physiological shear stress were similar, although the mechanisms stabilizing these interactions were distinct. Tp0751 expression also permitted bacteria to interact with postcapillary venules in live mice as effectively as BBK32-expressing strains. These results demonstrate that Tp0751 can function as a vascular adhesin.

A new phase field crystal (PFC) type theory is presented, which accounts for the full spectrum of solid-liquid-vapor phase transitions within the framework of a single density order parameter. Its equilibrium properties show the most quantitative features to date in PFC modelling of pure substances, and full consistency with thermodynamics in pressure-volume-temperature space is demonstrated. A method to control either the volume or the pressure of the system is also introduced. Non-equilibrium simulations show that 2 and 3-phase growth of solid, vapor and liquid can be achieved, while our formalism also allows for a full range of pressure-induced transformations. This model opens up a new window for the study of pressure driven interactions of condensed phases with vapor, an experimentally relevant paradigm previously missing from phase field crystal theories. 5 pages, 4 figures, peer reviewed version