ATXN3 controls DNA replication and transcription by regulating chromatin structure.

The deubiquitinating enzyme Ataxin-3 (ATXN3) contains a polyglutamine (PolyQ) region, the expansion of which causes spinocerebellar ataxia type-3 (SCA3). ATXN3 has multiple functions, such as regulating transcription or controlling genomic stability after DNA damage. Here we report the role of ATXN3 in chromatin organization during unperturbed conditions, in a catalytic-independent manner. The lack of ATXN3 leads to abnormalities in nuclear and nucleolar morphology, alters DNA replication timing and increases transcription. Additionally, indicators of more open chromatin, such as increased mobility of histone H1, changes in epigenetic marks and higher sensitivity to micrococcal nuclease digestion were detected in the absence of ATXN3. Interestingly, the effects observed in cells lacking ATXN3 are epistatic to the inhibition or lack of the histone deacetylase 3 (HDAC3), an interaction partner of ATXN3. The absence of ATXN3 decreases the recruitment of endogenous HDAC3 to the chromatin, as well as the HDAC3 nuclear/cytoplasm ratio after HDAC3 overexpression, suggesting that ATXN3 controls the subcellular localization of HDAC3. Importantly, the overexpression of a PolyQ-expanded version of ATXN3 behaves as a null mutant, altering DNA replication parameters, epigenetic marks and the subcellular distribution of HDAC3, giving new insights into the molecular basis of the disease.

The p97-Ataxin 3 complex regulates homeostasis of the DNA damage response E3 ubiquitin ligase RNF8.

The E3 ubiquitin ligase RNF8 (RING finger protein 8) is a pivotal enzyme for DNA repair. However, RNF8 hyper-accumulation is tumour-promoting and positively correlates with genome instability, cancer cell invasion, metastasis and poor patient prognosis. Very little is known about the mechanisms regulating RNF8 homeostasis to preserve genome stability. Here, we identify the cellular machinery, composed of the p97/VCP ubiquitin-dependent unfoldase/segregase and the Ataxin 3 (ATX3) deubiquitinase, which together form a physical and functional complex with RNF8 to regulate its proteasome-dependent homeostasis under physiological conditions. Under genotoxic stress, when RNF8 is rapidly recruited to sites of DNA lesions, the p97-ATX3 machinery stimulates the extraction of RNF8 from chromatin to balance DNA repair pathway choice and promote cell survival after ionising radiation (IR). Inactivation of the p97-ATX3 complex affects the non-homologous end joining DNA repair pathway and hypersensitises human cancer cells to IR. We propose that the p97-ATX3 complex is the essential machinery for regulation of RNF8 homeostasis under both physiological and genotoxic conditions and that targeting ATX3 may be a promising strategy to radio-sensitise BRCA-deficient cancers.

The ACTN3 R577X polymorphism is associated with metabolic alterations in a sex-dependent manner in subjects from western Mexico.

BACKGROUND: The ACTN3 gene is primarily expressed in fast skeletal muscle fibres. A common nonsense polymorphism in this gene is ACTN3 R577X (rs1815739), which causes an absolute deficiency of α-actinin-3 protein and alterations in muscle metabolism. Considering metabolic alterations are influenced by nutrition and genetic factors, as well as lifestyle factors, we hypothesise a possible association of the ACTN3 R577X polymorphism with metabolic alterations. METHODS: In this cross-sectional study, 397 adults met the inclusion criteria. Body composition was measured by electrical bioimpedance. Dietary data were analysed using Nutritionist Pro™ software. Biochemical variables were determined by dry chemistry. Genomic DNA was extracted from peripheral leukocytes and genotyping of the ACTN3 R577X polymorphism was determined by allelic discrimination using TaqMan probes. The statistical analyses were performed using SPSS statistical software. p < 0.05 was considered statistically significant. RESULTS: The ACTN3 577XX genotype was associated with high glucose, triglyceride and very low density lipoprotein-cholesterol levels and a higher frequency of hypertriglyceridaemia and insulin resistance in women. In males, the genetic variant showed a trend towards significance for insulin resistance. CONCLUSIONS: The ACTN3 R577X polymorphism was associated with metabolic alterations in women and a tendency was observed in men variant carriers. Thus, this common genetic variant could be implicated in the development of chronic metabolic diseases.

The Nucleocapsid protein triggers the main humoral immune response in COVID-19 patients.

In order to control the COVID-19 pandemic caused by SARS-CoV-2 infection, serious progress has been made to identify infected patients and to detect patients with a positive immune response against the virus. Currently, attempts to generate a vaccine against the coronavirus are ongoing. To understand SARS-CoV-2 immunoreactivity, we compared the IgG antibody response against SARS-CoV-2 in infected versus control patients by dot blot using recombinant viral particle proteins: N (Nucleocapsid), M (Membrane) and S (Spike). In addition, we used different protein fragments of the N and S protein to map immune epitopes. Most of the COVID-19 patients presented a specific immune response against the full length and fragments of the N protein and, to lesser extent, against a fragment containing amino acids 300-685 of the S protein. In contrast, immunoreactivity against other S protein fragments or the M protein was low. This response is specific for COVID-19 patients as very few of the control patients displayed immunoreactivity, likely reflecting an immune response against other coronaviruses. Altogether, our results may help develop method(s) for measuring COVID-19 antibody response, selectivity of methods detecting such SARS-CoV-2 antibodies and vaccine development.

Role of interleukin-6 in inhibiting hepatic autophagy markers in exercised mice.

BACKGROUND: Based on the crosstalk of inflammation with apoptosis, autophagy, and endoplasmic reticulum (ER) stress, the main objective of this study was to explore the role of interleukin-6 (IL-6) on genes and proteins related to these phenomena in the livers of mice submitted to acute exhaustive exercise. METHODS: Reverse transcription-quantitative polymerase chain reaction and immunoblotting technique were used to evaluate the livers of wild-type (WT) and IL-6 knockout (KO) mice at baseline (BL) and 3 h after the acute exhaustive physical exercise (EE). RESULTS: Compared to the WT at baseline, the IL-6 KO had lower exhaustion velocity, mRNA levels of Mtor, Ulk1, Map1lc3b, and Mapk14, and protein contents of ATG5 and p-p70S6K/p70S6K. For the WT group, the EE decreased glycemia, mRNA levels of Casp3, Mtor, Ulk1, Foxo1a, Mapk14, and Ppargc1a, and protein contents of ATG5 and p-p70S6K/p70S6K, but increased mRNA levels of Sqstm1. For the IL-6 KO group, the EE decreased glycemia, mRNA levels of Casp3 and Foxo1a, and protein contents of pAkt/Akt and Mature/Pro IL-1beta, but increased mRNA levels of Sqstm1, and protein contents of p-AMPK/AMPK. CONCLUSION: The inhibition of the hepatic autophagy markers induced by the acute EE was attenuated in IL-6 KO mice, highlighting a new function of this cytokine.

Growth of foetal bones and metabolic profile during gestation in primiparous ewes and multiparous ewes.

Primiparous ewes and multiparous ewes show physiological differences during pregnancy, which can have an impact on the development of their offspring. The objective of this study was to compare the changes in the metabolic profile and in the size of some foetal bones throughout gestation between primiparous and multiparous ewes. Twelve primiparous (PM) ewes and 14 multiparous (MT) ewes were used. According to the dates of lambing, two groups of ewes were formed: Group 1 (G1, n = 6 PM and n = 7 MT) and Group 2 (G2, n = 6 PM and n = 7 MT). The body weight, body condition score, metabolic and foetal morphometric parameters were determined from before conception until the end of gestation. After lambing, the body weight and survival rate during the first 72 hr of life of lambs, as well as the maternal behaviour score were recorded. The PM ewes were lighter (p < .01) and had a greater mobilization of body reserves during gestation, mainly evidenced by a greater serum concentration of NEFAs and lower serum concentration of total proteins (p < .05) compared with the MT ewes. The parity did not affect the foetal morphometric variables. The lambs of MT ewes were heavier at parturition (p = .002) and tended to have a greater survival rate than those lambs of PM ewes (p = .09). In conclusion, PM ewes and MT ewes differ in their metabolic profile throughout the gestation. However, in the present study, we did not find parity differences in the dimensions of foetal bones during growth in gestation.

Molecular components of nitrate and nitrite efflux in yeast.

Some eukaryotes, such as plant and fungi, are capable of utilizing nitrate as the sole nitrogen source. Once transported into the cell, nitrate is reduced to ammonium by the consecutive action of nitrate and nitrite reductase. How nitrate assimilation is balanced with nitrate and nitrite efflux is unknown, as are the proteins involved. The nitrate assimilatory yeast Hansenula polymorpha was used as a model to dissect these efflux systems. We identified the sulfite transporters Ssu1 and Ssu2 as effective nitrate exporters, Ssu2 being quantitatively more important, and we characterize the Nar1 protein as a nitrate/nitrite exporter. The use of strains lacking either SSU2 or NAR1 along with the nitrate reductase gene YNR1 showed that nitrate reductase activity is not required for net nitrate uptake. Growth test experiments indicated that Ssu2 and Nar1 exporters allow yeast to cope with nitrite toxicity. We also have shown that the well-known Saccharomyces cerevisiae sulfite efflux permease Ssu1 is also able to excrete nitrite and nitrate. These results characterize for the first time essential components of the nitrate/nitrite efflux system and their impact on net nitrate uptake and its regulation.

The Role of Diet and Physical Activity in Shaping COVID-19 Severity: Design, Validation, and Application of a Retrospective Questionnaire.

After the global challenges posed by COVID-19, researchers strived to identify risk factors for severe cases, which lead to various complications-including death. Lifestyle modifications, such as implementing a healthy diet and recommended physical activity, have been shown to be protective against severe COVID-19 cases. Despite an association of a plant-based diet with reduced COVID-19 severity, specific dietary characteristics have not been identified. Also, the methodology for measuring physical activity is variable, with studies overlooking the intensity or the habit components of physical activity. To bridge this gap, our study designed, validated, and applied a retrospective questionnaire with aims of exploring the relationship between lifestyle factors, specifically diet and physical activity, and severe COVID-19. We considered the intensity and years of physical activity habit, which is a limitation of other questionnaires. Results reveal associations of age and BMI with severe COVID-19. An excessive sugar diet was found to be associated with severe COVID-19 and increased symptom duration. We also observed an inverse relationship pattern of moderate- and vigorous-intensity physical activity across case severity, which is absent in walking physical activity. This study lays a foundation for research aiming to identify lifestyle factors that prevent severe COVID-19 cases.

Physical Activity Protocols in Non-Alcoholic Fatty Liver Disease Management: A Systematic Review of Randomized Clinical Trials and Animal Models.

Non-alcoholic fatty liver disease (NAFLD) is closely associated with other metabolic disease and cardiovascular disease. Regular exercise reduces hepatic fat content and could be the first-line treatment in the management of NAFLD. This review aims to summarize the current evidence of the beneficial effects of exercise training and identify the molecular pathways involved in the response to exercise to define their role in the resolution of NAFLD both in animal and human studies. According to the inclusion criteria, 43 animal studies and 14 RCTs were included in this systematic review. Several exercise modalities were demonstrated to have a positive effect on liver function. Physical activity showed a strong association with improvement in inflammation, and reduction in steatohepatitis and fibrosis in experimental models. Furthermore, both aerobic and resistance exercise in human studies were demonstrated to reduce liver fat, and to improve insulin resistance and blood lipids, regardless of weight loss, although aerobic exercises may be more effective. Resistance exercise is more feasible for patients with NAFLD with poor cardiorespiratory fitness. More effort and awareness should be dedicated to encouraging NAFLD patients to adopt an active lifestyle and benefit from it its effects in order to reduce this growing public health problem.

A Balanced Dietary Ratio of n-6:n-3 Polyunsaturated Fatty Acids Exerts an Effect on Total Fatty Acid Profile in RBCs and Inflammatory Markers in Subjects with Obesity.

The n-3 polyunsaturated fatty acids (PUFAs) can reduce inflammatory markers and may therefore be useful in obesity management. The aim of this study was to analyze the effect of supplementation with n-3 PUFAs on total fatty acid profile in red blood cells (RBCs), as well as biochemical and inflammatory markers, in subjects with obesity. The study consisted in a randomized placebo-controlled, double-blind clinical trial involving 41 subjects with obesity during a 4-month follow-up. Individuals were randomly assigned to two groups: n-3 PUFA supplementation (1.5 g fish oil) and placebo (1.5 g sunflower oil). Anthropometric, biochemical, dietetic, cytokine and total fatty acid profiles in RBCs were measured. Both groups increased their PUFA intake and DHA incorporation in RBCs. However, the placebo group showed a reduction in serum IL-8 and MCP-1 at the end of the study. A multiple linear regression model adjusted by body fat mass and sex showed that an increase in DHA in RBCs decreased the serum IL-8 levels in both study groups at the end of the study. Our results highlight the role of dietary DHA and n-3 supplementation usefulness in exerting beneficial anti-inflammatory effects.

Npr1 Ser/Thr protein kinase links nitrogen source quality and carbon availability with the yeast nitrate transporter (Ynt1) levels.

Ynt1, the single high affinity nitrate and nitrite transporter of the yeast Hansenula polymorpha, is regulated by the quality of nitrogen sources. Preferred nitrogen sources cause Ynt1 dephosphorylation, ubiquitinylation, endocytosis, and vacuolar degradation. In contrast, under nitrogen limitation Ynt1 is phosphorylated and sorted to the plasma membrane. We show here the involvement of the Ser/Thr kinase HpNpr1 in Ynt1 phosphorylation and regulation of Ynt1 levels in response to nitrogen source quality and the availability of carbon. In Δnpr1, Ynt1 phosphorylation does not take place, although Ynt1 ubiquitin conjugates increase. As a result, in this strain Ynt1 is sorted to the vacuole, from both plasma membrane and the later biosynthetic pathway in nitrogen-free conditions and nitrate. In contrast, overexpression of NPR1 blocks down-regulation of Ynt1, increasing Ynt1 phosphorylation at Ser-244 and -246 and reducing ubiquitinylation. Furthermore, Npr1 is phosphorylated in response to the preferred nitrogen sources, and indeed it is dephosphorylated in nitrogen-free medium. Under conditions where Npr1 is phosphorylated, Ynt1 is not and vice versa. We show for the first time that carbon starvation leads to Npr1 phosphorylation, whereas Ynt1 is dephosphorylated and degraded in the vacuole. Rapamycin prevents this, indicating a possible role of the target of rapamycin signaling pathway in this process. We concluded that Npr1 plays a key role in adapting Ynt1 levels to the nitrogen quality and availability of a source of carbon.

K(+) uptake systems in the yeast Hansenula polymorpha. Transcriptional and post-translational mechanisms involved in high-affinity K(+) transporter regulation.

We have identified the two main K(+) transporters in the yeast Hansenula polymorpha. So far this is the only yeast with these transporters amenable to molecular genetic analysis. Two ORF-encoding permeases with high similarity to Trk1 and Hak1 are present in the genome of this yeast. Deletion of either of these genes led to defective growth in low K(+). The K(+) and Rb(+) uptake rates showed high affinity of Hak1 for K(+), while the affinity estimated for Trk1 was two orders of magnitude lower. TRK1 was not transcriptionally regulated and HAK1 was strongly induced in response to very low K(+) and down-regulated by the presence of K(+). This process is clearly dependent on calcineurin. The use of a set of strains carrying mutations affecting intracellular protein trafficking revealed that in response to K(+), Hak1 is endocytosed and degraded in the vacuole, this depending on the ubiquitin ligase Rsp5. This is a first insight into the transcriptional and post-translational mechanisms regulating a high-affinity K(+) transporter (HAK-type transporter) that allows cells to respond and adapt to K(+) availability.

Effect of Metformin on Glycemic Control Regarding Carriers of the SLC22A1/OCT1 (rs628031) Polymorphism and Its Interactions with Dietary Micronutrients in Type 2 Diabetes.

Purpose: Differences in metformin effect on glycemic control in type 2 Diabetes (T2D) have been associated with diet, obesity, years since T2D diagnosis and genetic factors, such as the Met408Val (rs628031) SLC22A1/OCT1 gene polymorphism. This study aimed to analyze the effect of metformin and diet on glycemic control and its association with the Met408Val polymorphism in patients with T2D from western Mexico. Patients and Methods: A total of 240 T2D adult patients were enrolled in this cross-sectional study. Anti-hyperglycemic therapy, dietary intake, body composition and glycemic profile were recorded and the determination of genotypes of SLC22A1/OCT1 gene (rs628031) was performed using an allelic discrimination assay. Results: The type of metformin therapy was 47% monotherapy, 45% dual therapy (metformin+glibenclamide or metformin+insulin) and 8% triple therapy (metformin+glibenclamide+insulin). Individuals with metformin monotherapy had a higher glycemic control frequency (%HbA1c <7.0) compared with the dual and triple treatment schemes (77% vs 35% and 15%, respectively; p<0.001). Interestingly, a high potassium intake was documented in the three anti-hyperglycemic therapies and a lower intake of micronutrients, including calcium, magnesium, and zinc. An interaction was found between calcium intake and carriers of the risk allele A (408Val) with %HbA1c (P interaction=0.028), and potassium intake with the TyG index (P interaction=0.027). In addition, there was a positive correlation between calcium intake and %HbA1c (r=0.682; p=0.010), and potassium intake vs TyG index (r=0.593; p=0.033) in risk allele A (408Val) carriers with metformin monotherapy. Genotype frequencies were GG homozygotes (76.6%), GA heterozygotes (21.5%) and AA homozygotes (1.9%). The allele frequency was 87.4% for the ancestral allele G and 12.6% for the risk allele A. Conclusion: These findings suggest a differing effect of metformin on glycemic control regarding calcium and potassium intake and the Met408Val SLC22A1/OCT1 gene polymorphism in T2D patients.

Low-grade chronic inflammation is attenuated by exercise training in obese adults through down-regulation of ASC gene in peripheral blood: a pilot study.

BACKGROUND: Obesity is characterized by low-grade chronic inflammation and an excess of adipose tissue. The ASC gene encodes a protein that is part of the NLRP3 inflammasome, a cytosolic multiprotein complex that is associated with inflammation and metabolic alterations. To our knowledge, there is no evidence regarding ASC gene activity in obese adults in response to lifestyle modifications. PURPOSE: To evaluate the effect of hypocaloric diet and moderate-intensity structured exercise intervention on ASC gene expression and inflammatory markers in obese adults. METHODS: Thirty-seven obese individuals aged 25 to 50 years were randomized to the hypocaloric diet exercise group or hypocaloric diet group. The participants underwent a 4-month follow-up. Electrical bioimpedance was used for body composition analysis. Biochemical data were analyzed by dry chemistry and insulin levels by ELISA. ASC gene expression from peripheral blood was performed using real-time PCR. Dietary data was collected through questionnaires and analyzed using the Nutritionist Pro™ software. Quantification of cytokines was conducted using Bio-Plex Pro™ Human cytokine. The Astrand-Ryhming test was used to estimate the maximum oxygen volume and design the moderate-intensity structured exercise program ~ 75% heart rate (HR) RESULTS: After the intervention, both study groups significantly improved body composition (decreased weight, fat mass, waist circumference and abdominal obesity, p < 0.05). Besides, the diet-exercise group significantly decreased ASC mRNA expression, MCP-1, and MIP-1ß inflammatory cytokines compared to the diet group (p < 0.05). While in the diet group, MCP-1 and IL-8 exhibited significantly decreased levels (p < 0.05). In the diet-exercise group, a positive correlation between the atherogenic index and waist circumference was found (r = 0.822, p = 0.011), and a negative correlation was observed between the delta of ASC mRNA expression and IL-10 levels at the end of the intervention (r = - 0.627, p = 0.019). CONCLUSION: Low-grade chronic inflammation was attenuated through individualized exercise prescription and our findings highlight the role of the ASC gene in the inflammation of obese adults. TRIAL REGISTRATION: ClinicalTrials.gov , number NCT04315376 . Registered 20 March 2020-retrospectively registered.

The Combination of Fasting, Acute Resistance Exercise, and Protein Ingestion Led to Different Responses of Autophagy Markers in Gastrocnemius and Liver Samples.

The present study verified the responses of proteins related to the autophagy pathway after 10 h of fast with resistance exercise and protein ingestion in skeletal muscle and liver samples. The rats were distributed into five experimental groups: control (CT; sedentary and without gavage after fast), exercise immediately (EXE-imm; after fast, rats were submitted to the resistance protocol and received water by gavage immediately after exercise), exercise after 1 h (EXE-1h; after fast, rats were submitted to the resistance protocol and received water by gavage 1 h after exercise), exercise and supplementation immediately after exercise (EXE/Suppl-imm; after fast, rats were submitted to the resistance protocol and received a mix of casein: whey protein 1:1 (w/w) by gavage immediately after exercise), exercise and supplementation 1 h after exercise (EXE/Suppl-1h; after fast, rats were submitted to the resistance protocol and received a mix of casein: whey protein 1:1 (w/w) by gavage 1 h after exercise). In summary, the current findings show that the combination of fasting, acute resistance exercise, and protein blend ingestion (immediately or 1 h after the exercise stimulus) increased the serum levels of leucine, insulin, and glucose, as well as the autophagy protein contents in skeletal muscle, but decreased other proteins related to the autophagic pathway in the liver. These results deserve further mechanistic investigations since athletes are combining fasting with physical exercise to enhance health and performance outcomes.

GSK3-ß Stimulates Claspin Degradation via ß-TrCP Ubiquitin Ligase and Alters Cancer Cell Survival.

: Claspin is essential for activating the DNA damage checkpoint effector kinase Chk1, a target in oncotherapy. Claspin functions are tightly correlated to Claspin protein stability, regulated by ubiquitin-dependent proteasomal degradation. Here we identify Glycogen Synthase Kinase 3-ß (GSK3-ß) as a new regulator of Claspin stability. Interestingly, as Chk1, GSK3-ß is a therapeutic target in cancer. GSK3-ß inhibition or knockdown stabilizes Claspin, whereas a GSK3-ß constitutively active form reduces Claspin protein levels by ubiquitination and proteasome-mediated degradation. Our results also suggest that GSK3-ß modulates the interaction of Claspin with ß-TrCP, a critical E3 ubiquitin ligase that regulates Claspin stability. Importantly, GSK3-ß knock down increases Chk1 activation in response to DNA damage in a Claspin-dependent manner. Therefore, Chk1 activation could be a pro-survival mechanism that becomes activated upon GSK3-ß inhibition. Importantly, treating triple negative breast cancer cell lines with Chk1 or GSK3-ß inhibitors alone or in combination, demonstrates that Chk1/GSK3-ß double inhibition restrains cell growth and triggers more apoptosis compared to individual treatments, thereby revealing novel possibilities for a combination therapy for cancer.

Claspin - checkpoint adaptor and DNA replication factor.

Claspin was discovered as a Chk1-interacting protein necessary for Chk1 phosphorylation and activation by the upstream kinase, ATR, in response to DNA synthesis inhibition in Xenopus oocyte extracts. Subsequent investigations have defined a molecular model in which Claspin acts as an adaptor or scaffold protein to facilitate activation of Chk1 by ATR within a multiprotein complex that forms on single-stranded DNA at stalled replication forks and sites of DNA damage. Interestingly, Claspin is an unstable protein whose degradation via the proteasome is tightly regulated via ubiquitination and controlled by multiple ubiquitin ligases and deubiquitinases. As a result, Claspin levels fluctuate during the cell cycle, contributing to the regulation of checkpoint proficiency and playing a key role in terminating checkpoint-mediated cell cycle arrest. In addition to its role in signalling genotoxic stress, Claspin is required to maintain normal rates of replication fork progression during unperturbed DNA replication and may contribute to the regulation of replication origin firing. Consistent with this, Claspin can bind directly to DNA, with particular affinity for branched or forked molecules, and it interacts with multiple protein components of the replisome. As expected for a protein with key roles in checkpoint signalling and genome duplication, aberrations of Claspin expression and structure have been observed in cancer. Claspin is furthermore targeted to facilitate viral replication and plays a role in suppressing cellular DNA synthesis in response to nongenotoxic endoplasmic reticulum stress. Here, we review the functions and regulation of Claspin with a focus on areas of active research.

Epigenetic Modifications as Outcomes of Exercise Interventions Related to Specific Metabolic Alterations: A Systematic Review.

BACKGROUND: Chronic diseases arise as a consequence of an unhealthy lifestyle primarily characterized by physical inactivity and unbalanced diets. Regular physical activity can improve health, and there is consistent evidence that these improvements may be the result of epigenetic modifications. OBJECTIVE: To identify epigenetic modificationsas outcomes of exercise interventions related to specific metabolic alterations. METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) methodology for manuscript research and preparation was followed using PubMed and EBSCO databases for literature review. Out of 2,638 articles identified, only 34 articles met the inclusion criteria. RESULTS: The sections of the review were organized by metabolic alterations in which studies were grouped according to healthy, diseased, and trained individuals. Resistance exercise in humans induced epigenetic changes in pathways associated with energy metabolism and insulin sensitivity, contributing to healthy skeletal muscle. Endurance exercise also caused modifications in biomarkers associated to metabolic alterations through changes in DNA methylation and the expression of specific miRNAs. However, both resistance and endurance exercise are necessary to obtain a better physiological adaptation and a combination of both seems to be needed to properly tackle the increasing prevalence of non-communicable pathologies. CONCLUSION: Given the heterogeneity and complexity of the existing literature, it is currently not possible to propose a specific recommendation about the type, intensity, or duration of exercise that could be beneficial for different subsets of the population (healthy, diseased, and/or trained). Nevertheless, this review highlights the importance of exercise for health and shows the need to perform more research in this emerging area to identify epigenetic biomarkers that could serve as indicators of exercise adaptations.

Control of DNA Replication Initiation by Ubiquitin.

Eukaryotic cells divide by accomplishing a program of events in which the replication of the genome is a fundamental part. To ensure all cells have an accurate copy of the genome, DNA replication occurs only once per cell cycle and is controlled by numerous pathways. A key step in this process is the initiation of DNA replication in which certain regions of DNA are marked as competent to replicate. Moreover, initiation of DNA replication needs to be coordinated with other cell cycle processes. At the molecular level, initiation of DNA replication relies, among other mechanisms, upon post-translational modifications, including the conjugation and hydrolysis of ubiquitin. An example is the precise control of the levels of the DNA replication initiation protein Cdt1 and its inhibitor Geminin by ubiquitin-mediated proteasomal degradation. This control ensures that DNA replication occurs with the right timing during the cell cycle, thereby avoiding re-replication events. Here, we review the events that involve ubiquitin signalling during DNA replication initiation, and how they are linked to human disease.

Associations of the lipid genetic variants Thr54 ( FABP2) and -493T ( MTTP) with total cholesterol and low-density lipoprotein cholesterol levels in Mexican subjects.

Objective Mexico has one of the world's highest rates of obesity, which is influenced by lipid-genetic and lifestyle factors. This study aimed to determine whether FABP2 (Ala54Thr) and MTTP (-493 G/T) genetic polymorphisms are associated with metabolic disorders in Mexican subjects. Methods A total of 523 subjects participated in a cross-sectional study. Genotyping for FABP2 and MTTP was performed using real-time RT-PCR. Biochemical and anthropometric data were evaluated. Results The genetically at-risk group (Thr54/-493T) was associated with significantly higher total and low-density lipoprotein cholesterol levels (difference between genetically at-risk group and wild-type group: 10.6 mg/dL and 8.94 mg/dL, respectively). Carriers within the genetically at-risk group had a significantly higher prevalence rate of hypercholesterolaemia (42.5% vs. 32.0%) and higher LDL-C levels (37.6% vs. 26.4%) than did non-carriers. Conclusions Subjects who are genetically at risk (Thr54/-493T) have higher total cholesterol levels, low-density lipoprotein cholesterol levels, and prevalence rate of hypercholesterolaemia. These findings highlight the importance of basing nutritional intervention strategies for preventing and treating chronic diseases on individual genetic characteristics.