Sirt3 Regulates Response to Oxidative Stress by Interacting with BER Proteins in Colorectal Cancer.

The oxidative damages are well-recognized factors in the pathogenesis of colorectal cancer (CRC). Increased levels of reactive oxygen species (ROS) can lead to oxidative DNA damage, which, if unrepaired, can be an underlying cause of cancerogenic transformation. To defend against these threats, cells have developed a range of defense mechanisms. One of the most important protection mechanisms is DNA repair systems, both nuclear and mitochondrial. Sirt3 is a mitochondrial protein involved in regulating NEIL1, NEIL2, MUTYH, APE1, and LIG3 proteins, which are involved in DNA repair, including mitochondrial repair through mtBER (mitochondrial Base Excision Repair). In this work, we show that NEIL1, NEIL2, MUTYH, APE1, and LIG3 are regulated by Sirt3 through deacetylation, and moreover, Sirt3 is directly involved in physical interaction with MUTYH, NEIL1, and APE1, which indicates the controlling role of Sirt3 over the mtBER mechanism. Also, if the cells deprived of Sirt3 are exposed to oxidative stress, altered levels of those proteins can be observed, which supports the theory of the regulatory role of Sirt3. Finally, to fully confirm the role of Sirt3 in DNA repair, we examined its role in apoptosis and found the impact of this protein on cell survival rate. Using the knowledge obtained in the course of conducted experiments, we postulate consideration of Sirt3 as a target in the rising vulnerability of cancer cells during therapy and therefore increasing the effectiveness of cancer treatment.

Roadmap on biology in time varying environments.

Biological organisms experience constantly changing environments, from sudden changes in physiology brought about by feeding, to the regular rising and setting of the Sun, to ecological changes over evolutionary timescales. Living organisms have evolved to thrive in this changing world but the general principles by which organisms shape and are shaped by time varying environments remain elusive. Our understanding is particularly poor in the intermediate regime with no separation of timescales, where the environment changes on the same timescale as the physiological or evolutionary response. Experiments to systematically characterize the response to dynamic environments are challenging since such environments are inherently high dimensional. This roadmap deals with the unique role played by time varying environments in biological phenomena across scales, from physiology to evolution, seeking to emphasize the commonalities and the challenges faced in this emerging area of research.

Photoswitchable transition metal complexes with azobenzene-functionalized imine-based ligands: structural and kinetic analysis.

We report on the characterization of two imine type ligands containing photoresponsive azobenzene units as side groups and their transition metal ions complexes. The ligands, both free and in their complexes undergo trans- > cis photoisomerization after irradiation with UV light, but binding of metal ions reduces both the photoisomerisation reaction rates and cis isomer concentrations in the photostationary states. The greatest diminution in the photoisomerisation rate was observed for the complex containing Cd(ii), the heaviest among the various transition metal ions tested in this study.

A de novo loss-of-function DYNC1H1 mutation in a patient with parkinsonian features and a favourable response to levodopa.

Graphical summary of 'A de novo loss-of-function DYNC1H1 mutation in a patient with parkinsonian features and a favourable response to levodopa' by Szczaluba et al..

Levels of unmet needs and distress amongst adolescents and young adults (AYAs) impacted by familial cancer.

OBJECTIVE: To describe levels of, and relationships between, distress and psychosocial unmet needs in adolescents and young adults (AYAs) with a family member with cancer. METHODS: Adolescents and young adults (12-24 years old) with a living sibling or parent with cancer participated. Participants completed demographics, the Kessler 10 (K10) distress scale and the Sibling or Offspring Cancer Needs Instruments. Descriptive statistics were obtained for all measures, item-level frequencies were examined to identify common unmet needs, and relationships between distress and unmet needs were explored. RESULTS: Average sibling (N = 106) and offspring (N = 256) distress levels were in the high range (K10total = 22-30), with 29.6% and 31.6% in the very high range (K10total = 31-50), respectively. Siblings had mean = 19.7 unmet needs (range 0-45), 66% had ≥10 unmet needs, and 44% of the 45 needs were unmet on average. Offspring had mean = 22.4 unmet needs (range 0-47), 77% had ≥10 unmet needs, and 48% of the 47 needs were unmet on average. Strong positive correlations were found between K10 distress and the number of sibling/offspring unmet needs (r = 0.599 and r = 0.522, respectively, P = .00). CONCLUSIONS: Australian AYA siblings and offspring impacted by familial cancer experience high levels and numbers of unmet needs and substantial distress. Strong associations were found between increased distress and more unmet needs. Distress levels were comparable to AYAs seeking treatment for mental health issues. Insights into the type and number of needs experienced by AYA siblings and offspring will facilitate development and delivery of targeted, age-appropriate interventions, and resources for these vulnerable and underserved young people.

The Lack of Association between FCN2 Gene Promoter Region Polymorphisms and Dental Caries in Polish Children.

The aim of this study was to examine the association of single-nucleotide polymorphisms (SNPs) in the gene encoding ficolin-2 protein (FCN2 gene) at positions -986 (rs17514136), -602 (rs3124953), and -4 (rs3124952) with dental caries in Polish children. Two hundred and sixty Polish Caucasian children aged 15 years were enrolled in this study: 82 with "higher" caries experience (DMFT >5) and 178 with "lower" caries experience (DMFT ≤5). In addition, subjects with caries experience (DMFT ≥1) and caries-free subjects (DMFT = 0) were compared. FCN2 SNPs were genotyped with PCR-RFLP methods. There were no significant differences in the genotype, allele, or haplotype distributions in 3 analyzed SNPs of the FCN2 gene between children with "higher" and those with "lower" caries experience as well as between children with caries experience and caries-free children. In conclusion, we did not find any association of FCN2 promoter polymorphisms at positions -986, -602, and -4 with dental caries in Polish children.

Spondyloepimetaphyseal dysplasia with neurodegeneration associated with AIFM1 mutation - a novel phenotype of the mitochondrial disease.

In 1999, based on a single family, spondyloepimetaphyseal dysplasia (SEMD) with mental retardation (MR) was described as a novel syndrome with probably X-linked recessive inheritance and unknown molecular defect (MIM 300232). Our purpose was to search for the causative defect in the originally described family and in an independently ascertained second family. All patients had slowly progressive neurodegeneration with central and peripheral involvement and identical skeletal dysplasia. Whole exome sequencing performed in two subjects showed a single plausible candidate - the p.Asp237Gly variant in AIFM1 (chr. Xq26.1). The p.Asp237Gly segregated with disease as indicated by linkage analysis [maximum logarithm of odds score (LOD) score at theta 0 for the two families was 3.359]. This variant had not been previously reported and it was predicted to be pathogenic by Polyphen2, SIFT, MutationTaster and Mutation Assessor. AIFM1 encodes mitochondria associated apoptosis-inducing factor. The AIFM1 gene has been linked with COXPD6 encephalomyopathy (MIM 300816), Cowchock syndrome (MIM 310490) and X-linked deafness with neuropathy (DFNX5, MIM 300614), none of which are similar to SEMD-MR. Our results place SEMD as the third instance of a skeletal phenotype associated with a mitochondrial disease (the others being EVEN-PLUS syndrome caused by mutations of HSPA9 and CODAS syndrome due to LONP1 mutations).

KIF5A de novo mutation associated with myoclonic seizures and neonatal onset progressive leukoencephalopathy.

The KIF5A gene (OMIM 602821) encodes a neuron-specific kinesin heavy chain involved in intracellular transport of mitochondria and other cargoes. KIF5A protein comprises the N terminal motor domain, the stalk domain and the C-terminal cargo binding domain. The binding between KIF5A and its cargoes is mediated by kinesin adaptor proteins such as TRAK1 and TRAK2. Numerous missense KIF5A mutations in the motor and stalk domains cause spastic paraplegia type 10 (SPG10, OMIM 604187). Conversely, the role of loss-of-function mutations, especially those affecting the cargo binding domain, is unclear. We describe a novel de novo KIF5A p.Ser974fs/c.2921delC mutation found by whole exome sequencing in a patient with a congenital severe disease characterized by myoclonic seizures and progressive leukoencephalopathy. Since this phenotype differs considerably from the KIF5A/SPG10 disease spectrum we propose that the KIF5A p.Ser974fs and possibly other mutations which lead to truncation of the C-terminal tail of the protein cause a novel disorder. We speculate that the unique effect of the C-terminal truncating KIF5A mutations may result from the previously described complex role of this protein domain in binding of the TRAK2 and possibly other kinesin adaptor protein(s).

Transformation of galena to pyromorphite produces bioavailable sulfur for neutrophilic chemoautotrophy.

The aqueous concentration of lead [Pb(II)] in geochemical environments is controlled by the solubility of Pb-bearing minerals and their weathering products. In contaminated soils, a common method for in situ stabilization of Pb(II) is the addition of phosphate to convert more redox sensitive sulfide minerals into sparingly soluble pyromorphite [Pb5 (PO4 )3 X]. In this study, we conducted experimental studies to investigate the fate of reduced sulfur during the conversion of galena [PbS] to chloropyromorphite [Pb5 (PO4 )3 Cl]. Powder X-ray diffraction analysis indicated that the reaction of phosphate with galena under oxic conditions resulted in the oxidation of sulfide and formation of elemental sulfur [S8 ]. Under oxic abiotic conditions, the S8 was retained in the solid phase, and negligible concentrations of sulfur as sulfide and thiosulfate were detected in the aqueous phase and only a small amount of sulfate. When PbS reacted in the presence of the chemoautotrophic organism Bosea sp. WAO, the S8 in the secondary mineral was oxidized to sulfate. Strain WAO produced significantly more sulfate from the secondary S8 than from the primary galena. Microscopic analysis of mineral-microbe aggregates on mineral-embedded slide cultures showed that the organism was colocalized and increased in biomass over time on the secondary mineral surface supporting a microbial role. The results of this study indicate that stimulation of sulfur-oxidizing activity may be a direct consequence of phosphate amendments to Pb(II)-contaminated soils.

Acute phase proteins disturbances indicate uncompensated obesity declining physical fitness.

OBJECTIVE: The correlation between physical fitness and health indicators still requires a research aimed at improving the knowledge about physical fitness and the impact of obesity on the health status in children and adolescents. The aim of this study is an analysis of the results of the EUROFIT battery tests in relation to routine laboratory parameters and the inflammation markers. PATIENTS AND METHODS: In the group of 123 Polish adolescents the routine parameters of lipid metabolism and acute phase proteins were investigated, and compared with EUROFIT motor fitness tests results, expressed as percentiles of the results achieved by healthy Polish population. RESULTS: Most of the EUROFIT tests battery were performed by overweight adolescent girls on an insufficient level. Children who were described by parameters indicating more advanced obesity performed the EUROFIT tests worse. There was showed a negative correlation between the concentration of HDL cholesterol and the long jump (rho=-0.304) as well as with the speed of limb movement (rho=-0.277). There was a positive correlation between the speed of limb movement and the concentration of triglycerides (rho=0.335), LDL cholesterol (rho=0.305) and the percentage of the A4 (rho=0.239). CONCLUSIONS: Disturbed lipid parameters, as well as altered glycosylation profiles of acute phase proteins, were observed in all overweight children, and the intensity of alterations correlated with worse fitness.

Time-dependent information transmission in a model regulatory circuit.

Many biological regulatory systems respond with a physiological delay when processing signals. A simple model of regulation which respects these features shows how the ability of a delayed output to transmit information is limited: at short times by the time scale of the dynamic input, at long times by that of the dynamic output. We find that topologies of maximally informative networks correspond to commonly occurring biological circuits linked to stress response and that circuits functioning out of steady state may exploit absorbing states to transmit information optimally.

Patients with multiple sclerosis resisted to glucocorticoid therapy: abnormal expression of heat-shock protein 90 in glucocorticoid receptor complex.

OBJECTIVE: The majority of patients with multiple sclerosis (MS) respond favorably to glucocorticoids (GS) for their relapse treatment (steroid-sensitive multiple sclerosis). Unfortunately, a small subset of patients with multiple-sclerosis fails to adequately respond even to high dose of GS (steroid-resistant multiple sclerosis). Mechanism of GS therapeutic unresponsiveness is not resolved. METHODS: Transcripts for glucocorticoid receptor (GR) was assessed in peripheral blood mononuclear cells by real-time polymerase chain reaction in patients with steroid-sensitive and steroid-resistant multiple sclerosis. GR expression was assessed by Western blotting. The amount of heat-shock protein 90 (hsp90) in GR cytoplasmic complex was assessed by immunoprecipitation. Hsp90 was shown to stabilize the GR complex, to prevent its translocation to nucleus, and to inhibit GR transcription. RESULTS: Peripheral blood mononuclear cells of steroid-resistant multiple sclerosis transcripts for all three isoforms of GR, alpha, beta, and gamma, were reduced by about two-folds compared with patients with steroid-sensitive multiple sclerosis. We have not found an increase in the beta and gamma transcripts of GR, which might serve as a dominant negative mutants, over GR alpha in steroid-resistant multiple sclerosis. The amount of hsp90 in the GR complex in cytoplasm was significantly higher in steroid-resistant multiple sclerosis compared with steroid-sensitive multiple sclerosis. CONCLUSIONS: Molecular mechanism of GS unresponsiveness in some patients with multiple sclerosis might be related to increased presence of hsp90 in the GR cytoplasmic complex, leading to the inhibition of GR translocation to nucleus and reduction in its transcription.

Self-regulating gene: an exact solution.

An exact steady-state solution of the stochastic equations governing the behavior of a gene regulated by a self-generated proteomic atmosphere is presented. The solutions depend on an adiabaticity parameter measuring the relative rate of DNA-protein unbinding and protein degradation. The steady-state solution reveals deviations from the commonly used Ackers et al approximation based on the equilibrium law of mass action, allowing anticooperative behavior in the "nonadiabatic" limit of slow binding and unbinding rates. Noise from binding and unbinding events dominates the shot noise of protein synthesis and degradation up to quite high values of the adiabaticity parameter.

Nutrition habits of patients operated because of coronary heart disease: income structure linkage.

PURPOSE: The purpose of the above work is description and assessment of nutritional habits of the patient group operated because of CHD in relation to their income sources. MATERIAL AND METHODS: Among 100 patients hospitalized in The Cardiosurgery Clinic of Pomeranian Medical University in Szczecin, (72 M and 28 F) there were collected data concerning nutritional habits and income sources. To estimate the way of nutrition there was used the method of a direct interview, led individually according to the questions of an anonymous questionnaire. Quantitative biomedical data connected with body mass index (BMI), systolic (RRs) and diastolic (RRd) blood pressure and total cholesterol (CHL) came from the hospital files. RESULTS: The diet of all investigated people was not consistent with the requirements of rational nutrition in respect of quality (sort of meat, brown bread, fruit and vegetables) and daily quantity of meals. This incorrectness was particularly showed in not working group of people (pensioners, people on unemployment benefits). Almost all measured parameters (BMI, CHL, RRs), except RRd, are higher than commonly admitted referenced values. CONCLUSIONS: Our investigated category of patients proves how important is adapting to the requirements of rational nutrition, especially in lower socio-economic status societies.

Prevalence of visual acuity anomalies among pupils in age 7 and 8 years in Westpomeranian Region (Poland).

PURPOSE: Evaluation of visual acuity anomalies among 7 and 8 year olds pupils in Westpomeranian Region in the aspect of school nurses health services quality in that matter. MATERIAL AND METHODS: Representative sample (n=141) from the whole population of 7 and 8 years old pupils of Westpomeranian schools were screened for visual acuity with the use of Snellen standard boards. Classical methods for statistical analysis of results were used. RESULTS: 141 children were examined, among them 59 (42%) from urban areas and 82 (58%) from rural areas. The prevalence of abnormal visual acuity in general population of children in the age of 7 and 8 years in the region was estimated on the base of results from studied sample on the level of 17.7% +/- 5.0% for confidence interval 95% and was in the range 12.3-24.9%. CONCLUSIONS: High prevalence of visual acuity anomalies in general population of pupils (17.7 +/- 5.0%) indicates that more intensive preventive care is needed, also serving by school nurses. Precision in defining methodical approach in nursing care and procedure standards with respect to the affected pupils will result in improved preventive strategies.

Naked DNA vaccination differentially modulates autoimmune responses in experimental autoimmune encephalomyelitis.

Vaccination with naked DNA represents a therapeutic strategy currently under consideration in multiple sclerosis (MS). In this study, we tested the potential therapeutic effect of vaccination with a naked DNA construct encoding proteolipid protein (pRc/CMV-PLP) upon the outcome of subsequent sensitization for experimental autoimmune encephalomyelitis (EAE) actively-induced in SJL mice with PLP139-151 peptide in adjuvant. Intramuscular vaccination with the naked DNA pRc/CMV-PLP construct led to PLP expression in local muscle tissue that persisted for about 8 weeks. Early sensitization for EAE (4 weeks after DNA vaccination) caused recipient mice to develop a severe, exacerbated form of disease (in comparison to control mice), while late sensitization (>10 weeks) resulted in a milder, ameliorated form. In the groups sensitized <10 weeks post-DNA vaccination with pRc/CMV-PLP induction of a Th1-type cytokine response was noted. In contrast, sensitization >10 weeks post-DNA vaccination led to peripheral tolerance as evidenced by a decrease in T cell proliferation and cytotoxic T cell response, no Th2 response, and no increase in apoptosis. These data are novel in that they demonstrate a differential effect of DNA vaccination and have important implications for its use as a mechanism to enhance or modulate immune reactivity.

Shedding of TNF receptors in multiple sclerosis patients.

OBJECTIVE: To evaluate the rate of shedding of tumor necrosis factor (TNF) receptors (TNFRs) in MS patients. BACKGROUND: It was previously suggested that TNF might play a significant role in the immunopathologic mechanism of MS. TNF mediates its biologic effects by interacting with two distinct receptors: TNFR-p55 and TNFR-p75. Both of these receptors exist in soluble and membrane-bound forms. Soluble receptors have been shown to influence TNF activity in vitro and in vivo and maintain balance between active, free TNF and inactive form of this cytokine bound to its soluble receptors. METHODS: In the current study, the authors measured shedding of TNFRs from cell surface of peripheral blood mononuclear cells, peripheral blood lymphocytes, and monocytes in three groups of MS patients: relapsing-remitting in relapse, relapsing-remitting in remission, and chronic progressive. RESULTS: The authors observed a significant distortion in generation of both soluble TNF receptors. Whereas the TNFR-p55 was shed at lower rate compared with healthy volunteers, the shedding of TNFR-p75 was significantly higher in MS patients. CONCLUSION: Disturbance in TNFR shedding might contribute to the distortion of a fine balance between circulating TNF and its natural inhibitors in MS.

Suppression of experimental autoimmune encephalomyelitis with a TNF binding protein (TNFbp) correlates with down-regulation of VCAM-1/VLA-4.

The effect of a novel TNF binding protein (TNFbp), a polyethylene glycol-linked form of the type I soluble receptor of TNF, on the expression of adhesion molecules has been investigated with a passive transfer model of experimental autoimmune encephalomyelitis (EAE) in SJL/J mice. The expression of L-selectin, VLA-4 and LFA-1 on spleen cells of EAE animals treated with TNFbp or saline was examined by FACS analysis. The expression of VCAM-1 and ICAM-1 was investigated by immunochemistry in spinal cord tissue of SJL/J mice with EAE. In animals sensitized for EAE and treated with TNFbp, the expression of VCAM-1 in the central nervous system as well as VLA-4 on spleen cells was clearly diminished. Reduction in VCAM-1 staining and VLA-4 expression corresponded to inhibition of inflammation in the spinal cord and to prevention of clinical signs of EAE. The results have also shown that myelin basic protein responses as well as non-antigen-specific responses were not diminished in animals treated with TNFbp. The findings suggest that TNFbp might prevent EAE development by modulating the expression of VCAM-1 and VLA-4.