Sealing of chromosomal DNA nicks during nucleotide excision repair requires XRCC1 and DNA ligase III alpha in a cell-cycle-specific manner

Impaired gap filling and sealing of chromosomal DNA in nucleotide excision repair (NER) leads to genome instability. XRCC1-DNA ligase IIIa (XRCC1-Lig3) plays a central role in the repair of DNA single-strand breaks but has never been implicated in NER. Here we show that XRCC1-Lig3 is indispensable for ligation of NER-induced breaks and repair of UV lesions in quiescent cells. Furthermore, our results demonstrate that two distinct complexes differentially carry out gap filling in NER. XRCC1-Lig3 and DNA polymerase d colocalize and interact with NER components in a UV- and incision-dependent manner throughout the cell cycle. In contrast, DNA ligase I and DNA polymerase are recruited to UV-damage sites only in proliferating cells. This study reveals an unexpected and key role for XRCC1-Lig3 in maintenance of genomic integrity by NER in both dividing and nondividing cells and provides evidence for cell-cycle regulation of NER-mediated repair synthesis in vivo

Test-retest reliability of TRIMP in collegiate ice hockey players

The utility of the heart rate derived variable TRaining IMPulse (TRIMP) for assessing internal training load in ice hockey players is not clear. Having a reliable measure of internal training load during on-ice training sessions would help coaches program exercise training. This study determined the reliability of TRIMP during on-ice training sessions in ice hockey players. Twelve Division I collegiate male ice hockey players (aged 18–23 years) had their heart rate (HR) data recorded during two on-ice practice sessions separated by two weeks. TRIMP and other descriptive HR variables were compared between sessions. TRIMP demonstrated moderate reliability during on-ice sessions. Systematic error, quantified as standardized change in means was negligible (–0.19); random error quantified as the percent typical error (%TE) was moderate (12.2%); and, test-retest correlation was very strong (0.75). TRIMP is suitable for quantifying training load during intermittent work in hockey athletes. The results from our study can be used to determine the threshold for meaningful change in TRIMP, which may aid in informing decisions by coaches and strength training staff regarding on-ice training session difficulty and composition

Reprint of “The clinical impact of deficiency in DNA non-homologousend-joining”

DNA non-homologous end-joining (NHEJ) is the major DNA double strand break (DSB) repair pathway inmammalian cells. Defects in NHEJ proteins confer marked radiosensitivity in cell lines and mice models,since radiation potently induces DSBs. The process of V(D)J recombination functions during the devel-opment of the immune response, and involves the introduction and rejoining of programmed DSBs togenerate an array of diverse T and B cells. NHEJ rejoins these programmed DSBs. Consequently, NHEJdeficiency confers (severe) combined immunodeficiency – (S)CID – due to a failure to carry out V(D)Jrecombination efficiently. NHEJ also functions in class switch recombination, another step enhancing Tand B cell diversity. Prompted by these findings, a search for radiosensitivity amongst (S)CID patientsrevealed a radiosensitive sub-class, defined as RS-SCID. Mutations in NHEJ genes, defining human syn-dromes deficient in DNA ligase IV (LIG4 Syndrome), XLF-Cernunnos, Artemis or DNA-PKcs, have beenidentified in such patients. Mutations in XRCC4 or Ku70,80 in patients have not been identified. RS-SCIDpatients frequently display additional characteristics including microcephaly, dysmorphic facial featuresand growth delay. Here, we overview the clinical spectrum of RS-SCID patients and discuss our currentunderstanding of the underlying biology

Therapeutic opportunities within the DNA damage response

The DNA damage response (DDR) is essential for maintaining the genomic integrity of the cell, and its disruption is one of the hallmarks of cancer. Classically, defects in the DDR have been exploited therapeutically in the treatment of cancer with radiation therapies or genotoxic chemotherapies. More recently, protein components of the DDR systems have been identified as promising avenues for targeted cancer therapeutics. Here, we present an in-depth analysis of the function, role in cancer and therapeutic potential of 450 expert-curated human DDR genes. We discuss the DDR drugs that have been approved by the US Food and Drug Administration (FDA) or that are under clinical investigation. We examine large-scale genomic and expression data for 15 cancers to identify deregulated components of the DDR, and we apply systematic computational analysis to identify DDR proteins that are amenable to modulation by small molecules, highlighting potential novel therapeutic targets

The Northwest Africa (NWA) 5790 meteorite:A mesostasis-rich nakhlite with little or no Martian aqueous alteration

Northwest Africa (NWA) 5790 is the most recently discovered member of the nakhlite group. Its mineralogy differs from the other nakhlites with a high abundance mesostasis (38.1 ± 3.6 vol%) and scarcity of olivine (4.0 ± 2.2 vol%). Furthermore, zoning of augite phenocrysts, and other petrographic and chemical characteristics suggest that NWA 5790 samples the chilled margin of its parent lava flow/sill. NWA 5790 contains calcite and rare clay minerals that are evidence for its exposure to liquid water. The calcite forms a cement to coatings of dust on the outer surface of the find and extends into the interior of the meteorite within veins. The presence of microbial remains within the coating confirms that the dust and its carbonate cement are terrestrial in origin, consistent with the carbon and oxygen isotope composition of the calcite. The clay minerals are finely crystalline and comprise ~0.003 vol% of the meteorite. δD values of the clay minerals range from -212 ± 109‰ to -96 ± 132‰, and cannot be used to distinguish between a terrestrial or Martian origin. As petrographic results are also not definitive, we conclude that secondary minerals produced by Martian groundwaters are at best very rare within NWA 5790. The meteorite has therefore sampled a region of the lava flow/sill with little or no exposure to the aqueous solutions that altered other nakhlites. This isolation could relate to the scarcity of olivine in NWA 5790 because dissolution of olivine in other nakhlites by Martian groundwaters enhanced their porosity and permeability, and provided solutes for secondary minerals

Designing lenalidomide cocrystals with an extended-release profile for improved pulmonary drug delivery †

Lenalidomide is a poorly soluble immunomodulatory drug that has been the subject of several cocrystal studies aiming to improve oral bioavailability by enhancing solubility. In contrast, for application in pulmonary fibrosis, reduced solubility may extend the retention time and reduce potential side effects of inhalable formulations. In this article, we present a proof-of-principle study on a low-solubility cocrystal of lenalidomide and melamine. The structure of the hydrated cocrystal was determined by single crystal X-ray diffraction and revealed a 3-dimensional hydrogen-bonding network between lenalidomide, melamine and channel-included solvent. The cocrystal has a lower maximum solubility than pure lenalidomide, making it more suitable for inhalable formulation approaches. A preliminary study shows that the cocrystal can be micronized with lactose as a model excipient with particle sizes in the appropriate order of magnitude for use in an inhalable formulation

Evidence for methane in Martian meteorites

The putative occurrence of methane in the Martian atmosphere has had a major influence on the exploration of Mars, especially by the implication of active biology. The occurrence has not been borne out by measurements of atmosphere by the MSL rover Curiosity but, as on Earth, methane on Mars is most likely in the subsurface of the crust. Serpentinization of olivine-bearing rocks, to yield hydrogen that may further react with carbon-bearing species, has been widely invoked as a source of methane on Mars, but this possibility has not hitherto been tested. Here we show that some Martian meteorites, representing basic igneous rocks, liberate a methane-rich volatile component on crushing. The occurrence of methane in Martian rock samples adds strong weight to models whereby any life on Mars is/was likely to be resident in a subsurface habitat, where methane could be a source of energy and carbon for microbial activity

Cardiorespiratory fitness is associated with physical literacy in a large sample of Canadian children aged 8 to 12 years

Background The associations between cardiorespiratory fitness (CRF) and physical literacy in children are largely unknown. The aim of this study was to assess the relationships between CRF, measured using the 20-m shuttle run test (20mSRT), and components of physical literacy among Canadian children aged 8–12 years. Methods A total of 9393 (49.9% girls) children, with a mean (SD) age of 10.1 (±1.2) years, from a cross-sectional surveillance study were included for this analysis. The SRT was evaluated using a standardized 15 m or 20 m protocol. All 15 m SRTs were converted to 20mSRT values using a standardized formula. The four domains of physical literacy (Physical Competence, Daily Behaviour, Motivation and Confidence, and Knowledge and Understanding) were measured using the Canadian Assessment of Physical Literacy. Tertiles were identified for 20mSRT laps, representing low, medium, and high CRF for each age and gender group. Cohen’s d was used to calculate the effect size between the low and high CRF groups. Results CRF was strongly and favourably associated with all components of physical literacy among school-aged Canadian children. The effect size between low and high CRF tertile groups was large for the Physical Competence domain (Cohen’s d range: 1.11–1.94) across age and gender groups, followed by moderate to large effect sizes for Motivation and Confidence (Cohen’s d range: 0.54–1.18), small to moderate effect sizes for Daily Behaviour (Cohen’s d range: 0.25–0.81), and marginal to moderate effect sizes for Knowledge and Understanding (Cohen’s d range: 0.08–0.70). Conclusions This study identified strong favourable associations between CRF and physical literacy and its constituent components in children aged 8–12 years. Future research should investigate the sensitivity and specificity of the 20mSRT in screening those with low physical literacy levels