Different responses to DNA damage determine ageing differences between organs

Organs age differently, causing wide heterogeneity in multimorbidity, but underlying mechanisms are largely elusive. To investigate the basis of organ‐specific ageing, we utilized progeroid repair‐deficient Ercc1^{Δ /−} mouse mutants and systematically compared at the tissue, stem cell and organoid level two organs representing ageing extremes. Ercc1^{Δ /−} intestine shows hardly any accelerated ageing. Nevertheless, we found apoptosis and reduced numbers of intestinal stem cells (ISCs), but cell loss appears compensated by over‐proliferation. ISCs retain their organoid‐forming capacity, but organoids perform poorly in culture, compared with WT. Conversely, liver ages dramatically, even causing early death in Ercc1‐KO mice. Apoptosis, p21, polyploidization and proliferation of various (stem) cells were prominently elevated in Ercc1^{Δ /−} liver and stem cell populations were either largely unaffected (Sox9+), or expanding (Lgr5+), but were functionally exhausted in organoid formation and development in vitro. Paradoxically, while intestine displays less ageing, repair in WT ISCs appears inferior to liver as shown by enhanced sensitivity to various DNA‐damaging agents, and lower lesion removal. Our findings reveal organ‐specific anti‐ageing strategies. Intestine, with short lifespan limiting time for damage accumulation and repair, favours apoptosis of damaged cells relying on ISC plasticity. Liver with low renewal rates depends more on repair pathways specifically protecting the transcribed compartment of the genome to promote sustained functionality and cell preservation. As shown before, the hematopoietic system with intermediate self‐renewal mainly invokes replication‐linked mechanisms, apoptosis and senescence. Hence, organs employ different genome maintenance strategies, explaining heterogeneity in organ ageing and the segmental nature of DNA‐repair‐deficient progerias.     

Big Data to Knowledge: Application of Machine Learning to Predictive Modeling of Therapeutic Response in Cancer

BackgroundIn recent years, the availability of high throughput technologies, establishment of large molecular patient data repositories, and advancement in computing power and storage have allowed elucidation of complex mechanisms implicated in therapeutic response in cancer patients. The breadth and depth of such data, alongside experimental noise and missing values, requires a sophisticated human-machine interaction that would allow effective learning from complex data and accurate forecasting of future outcomes, ideally embedded in the core of machine learning design.ObjectiveIn this review, we will discuss machine learning techniques utilized for modeling of treatment response in cancer, including Random Forests, support vector machines, neural networks, and linear and logistic regression. We will overview their mathematical foundations and discuss their limitations and alternative approaches in light of their application to therapeutic response modeling in cancer.ConclusionWe hypothesize that the increase in the number of patient profiles and potential temporal monitoring of patient data will define even more complex techniques, such as deep learning and causal analysis, as central players in therapeutic response modeling.     

Taxonomical examination and characterization of a methanol-utilizing yeast

The morphological, cultural, and physiological characteristics are described of a yeast, LI70, which uses methanol as its source of energy and carbon; these characteristics have made it possible to identify the strain as Candida boidinii Ramirez. The identification was confirmed by a DNA-DNA genetic homology of 99.43% with the type strain of C. boidinii. Strain LI70 is not pathogenic.     

Confirmation of Childhood Acute Lymphoblastic Leukemia Variants,ARID5B and IKZF1, and Interaction with Parental Environmental Exposures

Genome wide association studies (GWAS) have established association of ARID5B and IKZF1 variants with childhood acute lymphoblastic leukemia (ALL). Epidemiological studies suggest that environmental factors alone appear to make a relatively minor contribution to disease risk. The polygenic nature of childhood ALL predisposition together with the timing of environmental triggers may hold vital clues for disease etiology. This study presents results from an Australian GWAS of childhood ALL cases (n = 358) and population controls (n = 1192). Furthermore, we utilised family trio (n = 204) genotypes to extend our investigation to gene-environment interaction of significant loci with parental exposures before conception, and child’s sex and age. Thirteen SNPs achieved genome wide significance in the population based case/control analysis; ten annotated to ARID5B and three to IKZF1. The most significant SNPs in these regions were ARID5B rs4245595 (OR 1.63, CI 1.38–1.93, P = 2.13×10⁻⁹), and IKZF1 rs1110701 (OR 1.69, CI 1.42–2.02, p = 7.26×10⁻⁹). There was evidence of gene-environment interaction for risk genotype at IKZF1, whereby an apparently stronger genetic effect was observed if the mother took folic acid or if the father did not smoke prior to pregnancy (respective interaction P-values: 0.04, 0.05). There were no interactions of risk genotypes with age or sex (P-values >0.2). Our results evidence that interaction of genetic variants and environmental exposures may further alter risk of childhood ALL however, investigation in a larger population is required. If interaction of folic acid supplementation and IKZF1 variants holds, it may be useful to quantify folate levels prior to initiating use of folic acid supplements.     

Phagocytosis Dynamics Depends on Target Shape

A complete understanding of phagocytosis requires insight into both its biochemical and physical aspects. One of the ways to explore the physical mechanism of phagocytosis is to probe whether and how the target properties (e.g., size, shape, surface states, stiffness, etc.) affect their uptake. Here we report an imaging-based method to explore phagocytosis kinetics, which is compatible with real-time imaging and can be used to validate existing reports using fixed and stained cells. We measure single-event engulfment time from a large number of phagocytosis events to compare how size and shape of targets determine their engulfment. The data shows an increase in the average engulfment time for increased target size, for spherical particles. The uptake time data on nonspherical particles confirms that target shape plays a more dominant role than target size for phagocytosis: Ellipsoids with an eccentricity of 0.954 and much smaller surface areas than spheres were taken up five times more slowly than spherical targets.     

Effects of melatonin ingestion on physical performance and biochemical responses following exhaustive running exercise in soccer players

Antioxidant supplementation has become a common practice among athletes to boost sport achievement. Likewise, melatonin (MEL) has been ingested as an ergogenic aid to improve physical performance. To date, no study has checked whether the multiple beneficial effects of MEL have an outcome during a maximum running exercise until exhaustion. Therefore, the present study aimed to evaluate the effect of MEL ingestion on physical performance and biochemical responses (i.e., oxidative stress) during exhaustive exercise. In a double blind randomized study, thirteen professional soccer players [age: 17.5 ± 0.8 years, body mass: 70.3 ± 3.9 kg, body height: 1.80 ± 0.08 m; maximal aerobic speed (MAS): 16.85 ± 0.63 km/h; mean ± standard deviation], members of a first league squad, performed a running exercise until exhaustion at 100% of MAS, after either MEL or placebo ingestion. Physical performance was assessed, and blood samples were obtained at rest and following the exercise. Compared to placebo, MEL intake prevented the increase in oxidative stress markers (i.e., malondialdehyde), alleviated the alteration of antioxidant status (i.e., glutathione peroxidase, uric acid and total bilirubin) and decreased post-exercise biomarkers of muscle damage (i.e., creatine kinase and lactate dehydrogenase) (p < 0.05). However, physical performance was not affected by MEL ingestion (p > 0.05). In conclusion, acute MEL intake before a maximal running exercise protected athletes from oxidative stress and cellular damage but without an effect on physical performance.     

Electrochemical sensing of trimethylamine based on polypyrrole-flavin-containing monooxygenase (FMO3) and ferrocene as redox probe for evaluation of fish freshness

Amperometric and impedimetric biosensor for detecting trimethylamine (TMA) which represents good parameters for estimating fish freshness has been developed. The biosensor is based on a conducting polypyrrole substituted with ferrocenyl, where flavin-containing monooxygenase 3 (FMO3) enzyme was immobilised by covalent bonding. FMO3 catalyzes the monooxygenation TMA to trimethylamine N-oxide (TMO). For catalysis FMO require flavin adenine (FAD) as a prosthetic group, NADPH as a cofactor and molecular oxygen as cosubstrate. Ferrocenyl group substituted on the polypyrrole matrix will serve as redox probe for monitoring the response of the biosensor to TMA. The construction of the biosensor was characterized by FT-IR, cyclic voltammetry and impedance measurements. Detection is done through the analysis of the current of oxidation signal of the ferrocenyl groups and compared to the measurement of impedance related to the electrical properties of the layers. Amperometric and impedimetric response were measured as a function of TMA concentration in range of 0.4 μgm L(-1)-80 μgm L(-1) (6.5 μmol L(-1)-1.5 mmol L(-1)). Amperometric measurements show a decrease in current response which is in correlation with the increase of the charge transfer resistance demonstrated by impedance. Calibration curve obtained by impedance spectroscopy shows a high sensitivity with a dynamic range from (0.4 μgm L(-1) to 80 μgm L(-1)). We demonstrated, using ferrocene as redox probe for catalytic reaction of FMO3, that high sensitivity and dynamic range was obtained. The biosensor was stable during 16 days. The biosensor shows high selectivity and its sensitivity to TMA in real samples was evaluated using fish extract after deterioration during storage.     

Effect of nocturnal melatonin intake on cellular damage and recovery from repeated sprint performance during an intensive training schedule

ABSTRACT

An optimal recovery between training sessions is of similar if not greater importance as the training content and program of the training, itself. One of the most used strategies for improving recovery is the ingestion of supplements. The present study aimed to evaluate the effect of 5 mg oral melatonin supplementation on the recovery from repeated sprint (RSA) of performance and biochemical responses (i.e. oxidative stress, leukocytosis cellular damage) after an intensive training camp (TC). Twenty soccer players performed an RSA test before and after an intensive six-day TC associated with nocturnal melatonin (n = 10) or placebo (n = 10) ingestion. Resting and post-RSA test blood samples were obtained before and after the TC. Compared to placebo, melatonin intake decreased resting oxidative stress markers (i.e, advanced oxidation protein products), leukocytosis (i.e. white blood cells (WBC), neutrophils (NE)) and biomarkers of cellular damage (i.e. creatine kinase (CK)). It also lowered post-exercise leukocytosis (i.e. WBC, NE, lymphocytes (LY), monocytes (MO)) and biomarkers of cellular damage (i.e. CK, aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT)) and raised the activity of the main antioxidant enzymes (i.e. glutathione peroxidase (GPx), glutathione reductase (GR)). In addition, compared to placebo, melatonin reduced the deterioration of the best and total time during the RSA test after the TC. In conclusion, nocturnal melatonin supplementation during an intensive TC alleviated oxidative stress, leukocytosis and cellular damage and improved recovery of RSA performance in soccer players.     

Adaptation of <Emphasis Type="Italic">Salmonella enterica</Emphasis> Hadar under static magnetic field: effects on outer membrane protein pattern

Background  

Salmonella enterica serovar Hadar (S. Hadar) is a highly prevalent foodborne pathogen and therefore a major cause of human gastroenteritis worldwide. Outer membrane proteins whose production is often regulated by environmental conditions also play important roles in the adaptability of bacterial pathogens to various environments.     

Th17-related cytokines in inflammatory bowel diseases: friends or foes?

T helper (Th)17 cells and other interleukin (IL)-17-producing cells are supposed to play critical roles in several human immune-mediated diseases, including Crohn's disease (CD) and ulcerative colitis (UC), the main forms of inflammatory bowel diseases (IBD) in man. Th17 cells infiltrate massively the inflamed intestine of IBD patients and in vitro and in vivo studies have shown that Th17-type cytokines may trigger and amplify multiple inflammatory pathways. Nonetheless, some Th17-related cytokines, such as interleukin (IL)-17A and IL-22, may target gut epithelial cells and promote the activation of counter-regulatory mechanisms. This observation together with the demonstration that Th17 cells are not stable and can be converted into either regulatory T cells or Th1 cells if stimulated by immune-suppressive (e.g. TGF-β1) or inflammatory (e.g. IL-12, IL-23) cytokines have contributed to advance our understanding of mechanisms that regulate mucosal homeostasis and inflammation in the gut.