Repair, abort, ignore? Strategies for dealing with UV damage

DNA repair is a prominent member of the nuclear transactions triad (replication, transcription, and repair). Sophisticated mechanisms govern the cellular process of decision-making (to repair or not to repair, to proceed with cell cycle or not and, eventually, to let the cell survive or die) and the temporal and spatial distribution of the DNA repair activities. UV radiation is a very common and virtually unavoidable mutagen whose carcinogenic potential seems to accumulate over time. Various strategies have been developed to avoid or decrease UV damage to cellular DNA, based on prevention of exposure as well as on post-irradiation measures. It is, however, important to acknowledge that the individual capacity for DNA repair varies during the life of the individual and must, therefore, be assessed so as to determine whether the individual is coping with environmental UV damage. Assessment of individual repair capacity might greatly modify the existing therapeutic strategies for common cancers and ought to become a routine part of health prophylaxis

ATM in focus:a damage sensor and cancer target

The ability of a cell to conserve and maintain its native DNA sequence is fundamental for the survival and normal functioning of the whole organism and protection from cancer development. Here we review recently obtained results and current topics concerning the role of the ataxia-telangiectasia mutated (ATM) protein kinase as a damage sensor and its potential as therapeutic target for treating cancer. This monograph discusses DNA repair mechanisms activated after DNA double-strand breaks (DSBs), i.e. non-homologous end joining, homologous recombination and single strand annealing and the role of ATM in the above types of repair. In addition to DNA repair, ATM participates in a diverse set of physiological processes involving metabolic regulation, oxidative stress, transcriptional modulation, protein degradation and cell proliferation. Full understanding of the complexity of ATM functions and the design of therapeutics that modulate its activity to combat diseases such as cancer necessitates parallel theoretical and experimental efforts. This could be best addressed by employing a systems biology approach, involving mathematical modelling of cell signalling pathways

Penalization Framework For Autonomous Agents Using Answer Set Programming

This paper presents a framework for enforcing penalties on intelligent agents that do not comply with authorization or obligation policies in a changing environment. A framework is proposed to represent and reason about penalties in plans, and an algorithm is proposed to penalize an agent's actions based on their level of compliance with respect to authorization and obligation policies. Being aware of penalties an agent can choose a plan with a minimal total penalty, unless there is an emergency goal like saving a human's life. The paper concludes that this framework can reprimand insubordinate agents.Comment: In Proceedings ICLP 2023, arXiv:2308.1489

Targeting ATM pathway for therapeutic intervention in cancer

The Ataxia Telangiectasia Mutated gene encodes the ATM protein, a key element in the DNA damage response (DDR) signalling pathway responsible for maintaining genomic integrity within the cell. The ATM protein belongs to a family of large protein kinases containing the phosphatidylinositol-3 catalytic domain, including ATM, ATR and PI3K. ATM provides the crucial link between DNA damage, cell cycle progression and cell death by first sensing double stranded DNA breaks and subsequently phosphorylating and activating other downstream proteins functioning in DNA damage repair, cell cycle arrest and apoptotic pathways,. Mammalian cells are constantly challenged by genotoxic agents from a variety of sources and therefore require a robust sensing and repair mechanism to maintain DNA integrity or activate alternative cell fate pathways. This review covers the role of ATM in DDR signalling and describes the interaction of the ATM kinase with other proteins in order to fulfil its various functions. Special emphasis is given to how the growing knowledge of the DDR can help identify drug targets for cancer therapy, thus providing a rationale for exploiting the ATM pathway in anticancer drug development. Moreover, we discuss how a network modelling approach can be used to identify and characterise ATM inhibitors and predict their therapeutic potential

Advocating the need of a systems biology approach for personalised prognosis and treatment of B-CLL patients

The clinical course of B-CLL is heterogeneous. This heterogeneity leads to a clinical dilemma: can we identify those patients who will benefit from early treatment and predict the survival? In recent years, mathematical modelling has contributed significantly in understanding the complexity of diseases. In order to build a mathematical model for determining prognosis of B-CLL one has to identify, characterise and quantify key molecules involved in the disease. Here we discuss the need and role of mathematical modelling in predicting B-CLL disease pathogenesis and suggest a new systems biology approach for a personalised therapy of B-CLL patients

The alternate GNB3 splice variant, Gβ3s, exhibits an altered signalling response to EGF stimulation, which leads to enhanced cell migration

It has recently been reported that the duplication of the GNB3 gene has been shown to be directly linked to an obesity phenotype, both in humans and also in a humanised mouse model. Moreover, the common human GNB3 c.825C>T polymorphism (rs5443) causes this ubiquitously expressed gene to be aberrantly spliced approximately 50% of the time leading to the production of both a normal Gβ3 protein and a truncated, possibly less stable subunit, known as Gβ3s. The presence of the GNB3 825T allele has previously been shown to be associated with predisposition to hypertension, obesity, various cancers, Alzheimers, age related cognitive function, erectile dysfunction as well as a marker for pharmacogenetic drug action. Great controversy, however, currently exists as to whether these phenotypes associated with the 825T allele are a) mainly due to the presence of the smaller, possibly more active, Gβ3s subunit or b) merely down to the haploinsufficiency of the normal GNB3 transcript, due to its frequent aberrant splicing. In order to try and address these two conflicting hypothesis, we report on the identification and characterisation of signalling alterations unique to the presence of Gβ3s protein subunit. Moreover we also show the physiological consequences associated with altered signalling, directly induced by the Gβ3s subunit. For this, we used both an EBV transformed lymphoblast cell line homozygote for GNB3 825T/825T (TT) and a stable Gβ3s expressing recombinant COS-7 clone. In both of these cell lines that express the Gβ3s subunit, we found enhanced cytosolic calcium influx upon stimulation with EGF, TGFα and VEGF ligands, as compared to “normal” GNB3 controls with the 825C/825C (CC) genotype. This aberrant calcium influx also led to an increase in ERK, but not AKT1, phosphorylation. Despite the lack of AKT1 activation, we paradoxically observed a significant increase in phosphorylation of its downstream substrates, namely mTOR and p70S6k (KS6B2). Moreover we observed a decrease in phospho FoxO3a only in Gβ3s expressing cells, but not in the “normal” GNB3 (CC) control cell line. The presence of the Gβ3s subunit also appeared to alter the distinct localisation patterns of both Foxo3a and AKT1, while also increasing the colocalisation of mTOR and p70S6K. Subsequent growth factor stimulation studies revealed that EGF treatment, of Gβ3s expressing cells, appeared to cause a significant decrease in cAMP levels, which, in turn resulted in both enhanced caveolin-1a phosphorylation, and an increase in actin stress fibre formation. The identification of these distinct Gβ3s specific signalling alterations were indicative of a more aggressive migratory phenotype. This led us to further investigate and confirm that the presence of the Gβ3s subunit also appears to cause significantly enhanced migration and robust scratch wound healing kinetics, as compared to cells harbouring only the normal copy of the gene. These data therefore present convincing evidence that the Gβ3s subunit is stable, functional and its presence can significantly alter signalling pathways, in different cell types

Water Exchange across the Blood-Brain Barrier in Obstructive Sleep Apnea: An MRI Diffusion-Weighted Pseudo-Continuous Arterial Spin Labeling Study

Obstructive sleep apnea (OSA) subjects show brain injury in sites that control autonomic, cognitive, and mood functions that are deficient in the condition. The processes contributing to injury may include altered blood-brain barrier (BBB) actions. Our aim was to examine BBB function, based on diffusion-weighted pseudo-continuous arterial spin labeling (DW-pCASL) procedures, in OSA compared to controls. We performed DW-pCASL imaging in nine OSA and nine controls on a 3.0-Tesla MRI scanner. Global mean gray and white matter arterial transient time (ATT, an index of large artery integrity), water exchange rate across the BBB (Kw, BBB function), DW-pCASL ratio, and cerebral blood flow (CBF) values were compared between OSA and control subjects. RESULTS: Global mean gray and white matter ATT (OSA vs. controls; gray matter, 1.691 ± .120 vs. 1.658 ± .109 second, P = .49; white matter, 1.700 ± .115 vs. 1.650 ± .114 second, P = .44), and CBF values (gray matter, 57.4 ± 15.8 vs. 58.2 ± 10.7 ml/100 g/min, P = .67; white matter, 24.2 ± 7.0 vs. 24.6 ± 6.7 ml/100 g/min, P = .91) did not differ significantly, but global gray and white matter Kw (gray matter, 158.0 ± 28.9 vs. 220.8 ± 40.6 min-1, P = .002; white matter, 177.5 ± 57.2 vs. 261.1 ± 51.0 min-1, P = .006), and DW-pCASL ratio (gray matter, .727 ± .076 vs. .823 ± .069, P = .011; white matter, .722 ± .144 vs. .888 ± .100, P = .004) values were significantly reduced in OSA over controls. OSA subjects show compromised BBB function, but intact large artery integrity. The BBB alterations may introduce neural damage contributing to abnormal functions in OSA, and suggest a need to repair BBB function with strategies commonly used in other fields

Lower Back Injuries in National Collegiate Athletic Association Football Players: A 5-Season Epidemiological Study

Background: Low back injuries are common in collegiate football players and can frequently lead to persistent pain, reinjuries, and time lost from participation. Purpose: To describe the epidemiology of back injuries in National Collegiate Athletic Association (NCAA) football players during the 2009/2010 through 2013/2014 academic years utilizing the NCAA Injury Surveillance Program (ISP) database. Study Design: Descriptive epidemiology study. Methods: A convenience sample of NCAA varsity football teams was utilized to determine the rates and patterns of back injuries as well as to generate national injury estimates. The rates and distribution of back injuries were identified within the context of mechanism of injury, injury chronicity, and time lost from sport. Injury rates were calculated as the number of injuries divided by the total number of athlete-exposures (AEs). Incidence rate ratios were calculated to compare the rates of injury between season, event type, mechanism of injury, injury chronicity, and time lost from sport. Results: Nationally, there were 267 low back injuries reported in the database. These were used to estimate 7076 back injuries over the 5-year period, approximately 82% of which were new injuries. The injuries occurred at a rate of 2.70 per 10,000 AEs. Overall, injuries were 3.12 times more likely to occur in competitions than in practices. Athletes were 4.67 times more likely to sustain a back injury during the preseason compared with the postseason but were 1.41 times more likely to sustain a low back injury during the preseason compared with the regular season. Both contact and noncontact were reported equally as the mechanism of injury (37.8% and 38.3%, respectively), and unspecified low back pain was the most common injury (64.2%). Only 1.6% of patients required surgery for their injury, and the majority of athletes (59.6%) returned to play within 24 hours. Conclusion: There was a relatively high rate of lumbar back injuries at the collegiate level (2.70/10,000 AEs), the majority of which were new injuries. About 18% of reported injuries were reinjuries. Although very few required surgery, a careful examination and work-up should be conducted to evaluate each injury. Regimented physical therapy and reconditioning programs are recommended to avert reinjuries.NCAAOpen access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]