A DNA repair-independent role for alkyladenine DNA glycosylase in alkylation-induced unfolded protein response.

Alkylating agents damage DNA and proteins and are widely used in cancer chemotherapy. While cellular responses to alkylation-induced DNA damage have been explored, knowledge of how alkylation affects global cellular stress responses is sparse. Here, we examined the effects of the alkylating agent methylmethane sulfonate (MMS) on gene expression in mouse liver, using mice deficient in alkyladenine DNA glycosylase (Aag), the enzyme that initiates the repair of alkylated DNA bases. MMS induced a robust transcriptional response in wild-type liver that included markers of the endoplasmic reticulum (ER) stress/unfolded protein response (UPR) known to be controlled by XBP1, a key UPR effector. Importantly, this response is significantly reduced in the Aag knockout. To investigate how AAG affects alkylation-induced UPR, the expression of UPR markers after MMS treatment was interrogated in human glioblastoma cells expressing different AAG levels. Alkylation induced the UPR in cells expressing AAG; conversely, AAG knockdown compromised UPR induction and led to a defect in XBP1 activation. To verify the requirements for the DNA repair activity of AAG in this response, AAG knockdown cells were complemented with wild-type Aag or with an Aag variant producing a glycosylase-deficient AAG protein. As expected, the glycosylase-defective Aag does not fully protect AAG knockdown cells against MMS-induced cytotoxicity. Remarkably, however, alkylation-induced XBP1 activation is fully complemented by the catalytically inactive AAG enzyme. This work establishes that, besides its enzymatic activity, AAG has noncanonical functions in alkylation-induced UPR that contribute to cellular responses to alkylation

Identification of Novel Human Damage Response Proteins Targeted through Yeast Orthology

Studies in Saccharomyces cerevisiae show that many proteins influence cellular survival upon exposure to DNA damaging agents. We hypothesized that human orthologs of these S. cerevisiae proteins would also be required for cellular survival after treatment with DNA damaging agents. For this purpose, human homologs of S. cerevisiae proteins were identified and mapped onto the human protein-protein interaction network. The resulting human network was highly modular and a series of selection rules were implemented to identify 45 candidates for human toxicity-modulating proteins. The corresponding transcripts were targeted by RNA interference in human cells. The cell lines with depleted target expression were challenged with three DNA damaging agents: the alkylating agents MMS and 4-NQO, and the oxidizing agent t-BuOOH. A comparison of the survival revealed that the majority (74%) of proteins conferred either sensitivity or resistance. The identified human toxicity-modulating proteins represent a variety of biological functions: autophagy, chromatin modifications, RNA and protein metabolism, and telomere maintenance. Further studies revealed that MMS-induced autophagy increase the survival of cells treated with DNA damaging agents. In summary, we show that damage recovery proteins in humans can be identified through homology to S. cerevisiae and that many of the same pathways are represented among the toxicity modulators

Effects of Ethanol and NAP on Cerebellar Expression of the Neural Cell Adhesion Molecule L1

The neural cell adhesion molecule L1 is critical for brain development and plays a role in learning and memory in the adult. Ethanol inhibits L1-mediated cell adhesion and neurite outgrowth in cerebellar granule neurons (CGNs), and these actions might underlie the cerebellar dysmorphology of fetal alcohol spectrum disorders. The peptide NAP potently blocks ethanol inhibition of L1 adhesion and prevents ethanol teratogenesis. We used quantitative RT-PCR and Western blotting of extracts of cerebellar slices, CGNs, and astrocytes from postnatal day 7 (PD7) rats to investigate whether ethanol and NAP act in part by regulating the expression of L1. Treatment of cerebellar slices with 20 mM ethanol, 10−12 M NAP, or both for 4 hours, 24 hours, and 10 days did not significantly affect L1 mRNA and protein levels. Similar treatment for 4 or 24 hours did not regulate L1 expression in primary cultures of CGNs and astrocytes, the predominant cerebellar cell types. Because ethanol also damages the adult cerebellum, we studied the effects of chronic ethanol exposure in adult rats. One year of binge drinking did not alter L1 gene and protein expression in extracts from whole cerebellum. Thus, ethanol does not alter L1 expression in the developing or adult cerebellum; more likely, ethanol disrupts L1 function by modifying its conformation and signaling. Likewise, NAP antagonizes the actions of ethanol without altering L1 expression

Effect of garlic on cardiovascular disorders: a review

Garlic and its preparations have been widely recognized as agents for prevention and treatment of cardiovascular and other metabolic diseases, atherosclerosis, hyperlipidemia, thrombosis, hypertension and diabetes. Effectiveness of garlic in cardiovascular diseases was more encouraging in experimental studies, which prompted several clinical trials. Though many clinical trials showed a positive effect of garlic on almost all cardiovascular conditions mentioned above, however a number of negative studies have recently cast doubt on the efficary of garlic specially its cholesterol lowering effect of garlic. It is a great challenge for scientists all over the world to make a proper use of garlic and enjoy its maximum beneficial effect as it is the cheapest way to prevent cardiovascular disease. This review has attempted to make a bridge the gap between experimental and clinical study and to discuss the possible mechanisms of such therapeutic actions of garlic

Mesoscale engineering of photonic glass for tunable luminescence

The control of optical behavior of active materials through manipulation of microstructure has led to the development of high-performance photonic devices with enhanced integration density, improved quantum efficiencies and controllable colour output. However, the achievement of robust light-harvesting materials with tunable, broadband and flatten emission remains a long-standing goal, owing to the limited inhomogeneous broadening in ordinary hosts. Here, we describe an effective strategy for management of photon emission by manipulation of mesoscale heterogeneities in optically active materials. Importantly, this unique approach enables control of dopant-dopant and dopant-host interactions at the extended mesoscale. This allows generating intriguing optical phenomena such as high activation ratio of dopant (close to 100 %), dramatically inhomogeneous broadening (up to 480 nm), notable emission enhancement, and moreover, simultaneously extending emission bandwidth and flattening spectral shape in glass and fiber. Our results highlight that the findings connect the understanding and manipulation at the mesoscale realm to functional behavior at the macroscale, and the approach to managing the dopants based on mesoscale engineering may provide new opportunity for construction of robust fiber light source.National Natural Science Foundation of China (Grant IDs: 11474102, 51202180), the Chinese Program for New Century Excellent Talents in University (Grant ID: NCET-13-0221), Guangdong Natural Science Funds for Distinguished Young Scholar (Grant ID: S2013050014549), Fundamental Research Funds for the Central University, Scientific Research Foundation for the Returned Overseas Chinese Scholars, State Education Ministry, World Premier International Research Center Initiative (WPI), MEXT, JapanThis is the author accepted manuscript. It is currently under an indefinite embargo pending publication by Nature Publishing Group

Pooled analysis of WHO Surgical Safety Checklist use and mortality after emergency laparotomy

Background The World Health Organization (WHO) Surgical Safety Checklist has fostered safe practice for 10 years, yet its place in emergency surgery has not been assessed on a global scale. The aim of this study was to evaluate reported checklist use in emergency settings and examine the relationship with perioperative mortality in patients who had emergency laparotomy. Methods In two multinational cohort studies, adults undergoing emergency laparotomy were compared with those having elective gastrointestinal surgery. Relationships between reported checklist use and mortality were determined using multivariable logistic regression and bootstrapped simulation. Results Of 12 296 patients included from 76 countries, 4843 underwent emergency laparotomy. After adjusting for patient and disease factors, checklist use before emergency laparotomy was more common in countries with a high Human Development Index (HDI) (2455 of 2741, 89.6 per cent) compared with that in countries with a middle (753 of 1242, 60.6 per cent; odds ratio (OR) 0.17, 95 per cent c.i. 0.14 to 0.21, P <0001) or low (363 of 860, 422 per cent; OR 008, 007 to 010, P <0.001) HDI. Checklist use was less common in elective surgery than for emergency laparotomy in high-HDI countries (risk difference -94 (95 per cent c.i. -11.9 to -6.9) per cent; P <0001), but the relationship was reversed in low-HDI countries (+121 (+7.0 to +173) per cent; P <0001). In multivariable models, checklist use was associated with a lower 30-day perioperative mortality (OR 0.60, 0.50 to 073; P <0.001). The greatest absolute benefit was seen for emergency surgery in low- and middle-HDI countries. Conclusion Checklist use in emergency laparotomy was associated with a significantly lower perioperative mortality rate. Checklist use in low-HDI countries was half that in high-HDI countries.Peer reviewe

Osteopathology and selenium deficiency co-occurring in a population of endangered Patagonian huemul (Hippocamelus bisulcus)

Background: About 1,000 endangered Patagonian huemul deer (Hippocamelus bisulcus) remain in Chile and 350-500 in Argentina. Most groups (&gt;100) are not recovering, and prevalence of osteopathology in Argentina was at least 57%. Here I describe relevant cases of osteopathology from a Chilean population which, however, recently also provided data on trace mineral status, supporting the initial hypothesis that nutrition may be a primary etiologic factor. Additionally, recent data on bone chemical composition of Argentine cases and soil analyses are discussed. Results: Fluoride levels in Argentine cases with osteopathology were low and fluorosis was discarded as an etiological factor. Selenium deficiency occurred in 73% of huemul from the Chilean population which exhibited several cases with osteopathology. The pathophysiognomy included extensive erosion; tooth loss;  porosification; perforations of palate, maxillar and mandibular bone with frequent exposure of tooth roots; and fractured mandibula. Areas currently used by remaining huemul have mainly acidic volcanic soils, which reduces selenium bioavailability: mean soil selenium levels from areas typically used by extant huemul were very deficient (0.19 ppm), corroborating documented overt selenium deficiency in local livestock and plants. The area of extant huemul is known to result in primary iodine deficiency in livestock which is aggravated by selenium deficiency. Conclusions: Currently the most parsimonious explanation for frequent osteopathology and lack of numerical recovery are the combined effects of selenium and iodine deficiencies based on: osteopathology in a population of selenium deficient huemul; selenium deficient livestock, plants and soils; acidic soils; and regional primary iodine deficiency. The nexus between mineral nutrition and population dynamics of huemul may be due to constraints on their movements to fertile lowlands, including the elimination of historic migratory traditions, and concomitant elimination of source populations

Breaking barriers: using the behavior change wheel to develop a tailored intervention to overcome workplace inhibitors to breaking up sitting time

© The Author(s). 2019. Background: The workplace is a prominent domain for excessive sitting. The consequences of increased sitting time include adverse health outcomes such as cardiovascular disease and poor mental wellbeing. There is evidence that breaking up sitting could improve health, however, any such intervention in the workplace would need to be informed by a theoretical evidence-based framework. The aim of this study was to use the Behaviour Change Wheel (BCW) to develop a tailored intervention to break up and reduce workplace sitting in desk-based workers. Methods: The BCW guide was followed for this qualitative, pre-intervention development study. Semi-structured interviews were conducted with 25 office workers (26–59years, mean age 40.9 [SD=10.8] years; 68% female) who were purposively recruited from local council offices and a university in the East of England region. The interview questions were developed using the Theoretical Domains Framework (TDF). Transcripts were deductively analysed using the COM-B (Capability, Opportunity, Motivation – Behaviour) model of behaviour. The Behaviour Change Technique Taxonomy Version 1 (BCTv1) was thereafter used to identify possible strategies that could be used to facilitate change in sitting behaviour of office workers in a future intervention. Results: Qualitative analysis using COM-B identified that participants felt that they had the physical Capability to break up their sitting time, however, some lacked the psychological Capability in relation to the knowledge of both guidelines for sitting time and the consequences of excess sitting. Social and physical Opportunity was identified as important, such as a supportive organisational culture (social) and the need for environmental resources (physical). Motivation was highlighted as a core target for intervention, both reflective Motivation, such as beliefs about capability and intention and automatic in terms of overcoming habit through reinforcement. Seven intervention functions and three policy categories from the BCW were identified as relevant. Finally, 39 behaviour change techniques (BCTs) were identified as potential active components for an intervention to break up sitting time in the workplace. Conclusions: The TDF, COM-B model and BCW can be successfully applied through a systematic process to understand the drivers of behaviour of office workers to develop a co-created intervention that can be used to break up and decrease sitting in the workplace. Intervention designers should consider the identified BCW factors and BCTs when developing interventions to reduce and break up workplace sitting