Genetic determinants of micronucleus formation in vivo.

Genomic instability arising from defective responses to DNA damage1 or mitotic chromosomal imbalances2 can lead to the sequestration of DNA in aberrant extranuclear structures called micronuclei (MN). Although MN are a hallmark of ageing and diseases associated with genomic instability, the catalogue of genetic players that regulate the generation of MN remains to be determined. Here we analyse 997 mouse mutant lines, revealing 145 genes whose loss significantly increases (n = 71) or decreases (n = 74) MN formation, including many genes whose orthologues are linked to human disease. We found that mice null for Dscc1, which showed the most significant increase in MN, also displayed a range of phenotypes characteristic of patients with cohesinopathy disorders. After validating the DSCC1-associated MN instability phenotype in human cells, we used genome-wide CRISPR-Cas9 screening to define synthetic lethal and synthetic rescue interactors. We found that the loss of SIRT1 can rescue phenotypes associated with DSCC1 loss in a manner paralleling restoration of protein acetylation of SMC3. Our study reveals factors involved in maintaining genomic stability and shows how this information can be used to identify mechanisms that are relevant to human disease biology1.

Very-high-energy particle acceleration powered by the jets of the microquasar SS 433.

SS 433 is a binary system containing a supergiant star that is overflowing its Roche lobe with matter accreting onto a compact object (either a black hole or neutron star)1-3. Two jets of ionized matter with a bulk velocity of approximately 0.26c (where c is the speed of light in vacuum) extend from the binary, perpendicular to the line of sight, and terminate inside W50, a supernova remnant that is being distorted by the jets2,4-8. SS 433 differs from other microquasars (small-scale versions of quasars that are present within our own Galaxy) in that the accretion is believed to be super-Eddington9-11, and the luminosity of the system is about 1040 ergs per second2,9,12,13. The lobes of W50 in which the jets terminate, about 40 parsecs from the central source, are expected to accelerate charged particles, and indeed radio and X-ray emission consistent with electron synchrotron emission in a magnetic field have been observed14-16. At higher energies (greater than 100 gigaelectronvolts), the particle fluxes of γ-rays from X-ray hotspots around SS 433 have been reported as flux upper limits6,17-20. In this energy regime, it has been unclear whether the emission is dominated by electrons that are interacting with photons from the cosmic microwave background through inverse-Compton scattering or by protons that are interacting with the ambient gas. Here we report teraelectronvolt γ-ray observations of the SS 433/W50 system that spatially resolve the lobes. The teraelectronvolt emission is localized to structures in the lobes, far from the centre of the system where the jets are formed. We have measured photon energies of at least 25 teraelectronvolts, and these are certainly not Doppler-boosted, because of the viewing geometry. We conclude that the emission-from radio to teraelectronvolt energies-is consistent with a single population of electrons with energies extending to at least hundreds of teraelectronvolts in a magnetic field of about 16 microgauss.

Publisher Correction: Very-high-energy particle acceleration powered by the jets of the microquasar SS 433.

In this Letter, owing to a production error, the penultimate version of the PDF was published. The HTML version was always correct. The PDF has been corrected online.

Discovery of Gamma Rays from the Quiescent Sun with HAWC.

We report the first detection of a TeV γ-ray flux from the solar disk (6.3σ), based on 6.1 years of data from the High Altitude Water Cherenkov (HAWC) observatory. The 0.5-2.6 TeV spectrum is well fit by a power law, dN/dE=A(E/1 TeV)^{-γ}, with A=(1.6±0.3)×10^{-12} TeV^{-1} cm^{-2} s^{-1} and γ=3.62±0.14. The flux shows a strong indication of anticorrelation with solar activity. These results extend the bright, hard GeV emission from the disk observed with Fermi-LAT, seemingly due to hadronic Galactic cosmic rays showering on nuclei in the solar atmosphere. However, current theoretical models are unable to explain the details of how solar magnetic fields shape these interactions. HAWC's TeV detection thus deepens the mysteries of the solar-disk emission.

Constraints on Lorentz Invariance Violation from HAWC Observations of Gamma Rays above 100 TeV.

Because of the high energies and long distances to the sources, astrophysical observations provide a unique opportunity to test possible signatures of Lorentz invariance violation (LIV). Superluminal LIV enables the decay of photons at high energy. The high altitude water Cherenkov (HAWC) observatory is among the most sensitive gamma-ray instruments currently operating above 10 TeV. HAWC finds evidence of 100 TeV photon emission from at least four astrophysical sources. These observations exclude, for the strongest of the limits set, the LIV energy scale to 2.2×10^{31} eV, over 1800 times the Planck energy and an improvement of 1 to 2 orders of magnitude over previous limits.

Multiple Galactic Sources with Emission Above 56 TeV Detected by HAWC.

We present the first catalog of gamma-ray sources emitting above 56 and 100 TeV with data from the High Altitude Water Cherenkov Observatory, a wide field-of-view observatory capable of detecting gamma rays up to a few hundred TeV. Nine sources are observed above 56 TeV, all of which are likely galactic in origin. Three sources continue emitting past 100 TeV, making this the highest-energy gamma-ray source catalog to date. We report the integral flux of each of these objects. We also report spectra for three highest-energy sources and discuss the possibility that they are PeVatrons.

POT1 germline mutations but not TERT promoter mutations are implicated in melanoma susceptibility in a large cohort of Spanish melanoma families.

BACKGROUND: Germline mutations in telomere-related genes such as POT1 and TERT predispose individuals to familial melanoma. OBJECTIVES: To evaluate the prevalence of germline mutations in POT1 and TERT in a large cohort of Spanish melanoma-prone families (at least two affected first- or second-degree relatives). METHODS: Overall, 228 CDKN2A wild-type melanoma-prone families were included in the study. Screening of POT1 was performed in one affected person from each family and TERT was sequenced in one affected patient from 202 families (26 families were excluded owing to DNA exhaustion/degradation). TERT promoter sequencing was extended to an additional 30 families with CDKN2A mutation and 70 patients with sporadic multiple primary melanoma (MPM) with a family history of other cancers. RESULTS: We identified four families with potentially pathogenic POT1 germline mutations: a missense variant c.233T>C (p.Ile78Thr); a nonsense variant c.1030G>T (p.Glu344*); and two other variants, c.255G>A (r.125_255del) and c.1792G>A (r.1791_1792insAGTA, p.Asp598Serfs*22), which we confirmed disrupted POT1 mRNA splicing. A TERT promoter variant of unknown significance (c.-125C>A) was detected in a patient with MPM, but no germline mutations were detected in TERT promoter in cases of familial melanoma. CONCLUSIONS: Overall, 1·7% of our CDKN2A/CDK4-wild type Spanish melanoma-prone families carry probably damaging mutations in POT1. The frequency of TERT promoter germline mutations in families with melanoma in our population is extremely rare.

Heritability and identification of QTLs and underlying candidate genes associated with the architecture of the grapevine cluster (Vitis vinifera L.).

KEY MESSAGE: We have identified 19 QTLs for rachis architecture, a key and complex trait for grapevine production. Fifty out of 1,173 genes underlying these QTLs are candidates to be further explored. In the table grape industry, the rachis architecture has economic and management implications. Therefore, understanding the genetics of this trait is key for its breeding. The aim of this work was to identify genetic determinants of traits associated with the cluster architecture. Characterisations of eight traits was performed on a 'Ruby Seedless' × 'Sultanina' crossing (F1: n = 137) during three seasons, with and without gibberellic acid (GA3) applications. The genotypic effects and the genotype × GA3 interactions were significant for several traits. Rachis length (rl), lateral shoulder length and node number along the central axis were the most prominent traits. On average, the heritability of these traits was ~71 %, with heritability of rl being 76 % as estimated under different seasons. Quantitative trait loci (QTLs) analyses showed that linkage group 5 (LG5) and LG18 harboured the largest number of QTLs for these traits. According to the variance explained, the main QTL (corresponding to rl) was found on LG9. These QTLs were supported mainly by a paternal additive effect and revealed possible pleiotropic effects. Based on the grapevine reference genome, we identified 1,173 genes located under these QTL confidence intervals. Fifty of the 891 annotated genes of this list were selected for their further characterisation because of their possible participation in the rachis architecture. In conclusion, the QTLs detected indicate that these traits and their GA3 responsiveness have a clear genetic basis. Due to the percentage of the total variance explained, they are good candidates to participate in the genetic determination of the cluster architecture.

Treatment of childhood acute lymphoblastic leukemia in central America: a lower-middle income countries experience.

BACKGROUND: Five Asociación de Hemato-Oncología de Centroamérica (AHOPCA) countries have used an adapted BFM-based protocol for childhood acute lymphoblastic leukemia (ALL). PROCEDURE: In the AHOPCA-ALL 2008 protocol, patients were stratified by age, white blood cell count, immunophenotype, central nervous system involvement, day 8 prednisone response, and morphologic bone marrow response to induction therapy. Patients at Standard Risk (SR) received a three-drug induction regimen, a reinduction phase, and maintenance with protracted intrathecal therapy. Those at Intermediate (IR) and High Risk (HR) received, in addition, daunorubicin during induction therapy, a consolidation phase and two or three reinduction phases respectively. RESULTS: From August 2008 through July 2012, 1,313 patients were enrolled: 353 in SR, 548 in IR, 412 in HR. During induction therapy, 3.0% of patients died, 2.7% abandoned treatment, 1.1% had resistant ALL, and 93.2% achieved morphological complete remission (CR). Deaths and abandonment in first CR occurred in 2.7% and in 7.0% of patients, respectively. The relapse rate at a median observation time of 2.1 years was 15.0%. At 3 years, the event-free survival (EFS) and overall survival (OS), with abandonment considered as an event, were 59.4% (SE 1.7) and 68.2% (SE 1.6). Three-year EFS was 68.5% (SE 3.0), 62.1% (SE 2.6), and 47.8% (SE 3.2) for SR, IR, and HR groups. Adolescents had a significantly higher relapse rate (P = 0.001). CONCLUSIONS: This experience shows that common international studies are feasible in lower-middle income countries. Toxic deaths, abandonment of treatment, and relapses remain major obstacles to the successful treatment. Alternative treatment strategies may be beneficial.

Cisgenesis and intragenesis: new tools for improving crops.

Genetically Modified Organisms (GMO) could be the answer for many relevant problems affecting crops. However, improving crops through GMO is also often associated with safety concerns, environmental risks and health issues due to the presence of foreign DNA. These limitations have prompted the development of alternative technologies. Recently, cisgenesis and intragenesis have been developed as new tools aimed to modify crops. While cisgenesis involves genetic modification using a complete copy of natural genes with their regulatory elements that belong exclusively to sexually compatible plants, intragenesis refers to the transference of new combinations of genes and regulatory sequences belonging to that particular species. So far, application of cisgenesis and intragenesis as alternatives to conventional transgenesis are limited to a few species, mainly due to the lack of knowledge of the regulatory sequences required. The grape is one of the most cultivated crops worldwide and is the most economically relevant crop in Chile. Its genomic sequence has been completed, making available new sources of information to improve grape traits by genetic manipulation. This review is focused on the current alternatives to transgenesis in plants, including new approaches to develop marker-free crops, their application to economically relevant crops and future perspectives in the area. Also, the identification of grapevine promoters with a wide range of expression profiles is shown. The expression pattern of these genes was analyzed in different tissues and developmental stages, as well as under several stresses and stimuli, giving a broad range of expression patterns, including genes expressed exclusively during ripening, in response to sugars, senescence and biotic stress, among others. Genes with strong and constitutive expression were also identified. Functional analysis using reporter genes has been conducted in order to confirm the promoter's transcription activity, opening new possibilities for developing cisgenic/intragenic grapevines.

The effect of a topical anesthetic on the sensitivity of calf dehorning wounds.

The objective was to determine the effect of a topical local anesthetic on the sensitivity of dehorning wounds in calves. Thirty 2-mo-old Holstein-Friesian calves were randomly allocated to sham dehorning control (CON), scoop dehorning without treatment with topical anesthetic (SnoTA), or scoop dehorning with an application of a topical anesthetic (STA). Sensitivity was measured by providing mechanical stimulation to the dehorned wound and peri-wound area using von Frey monofilaments calibrated at 10 and 300 g. Calf responses were categorized as absent, minor, moderate, or severe. Sensitivity measurements were performed before treatment and at various time points up to 24h posttreatment. Sham dehorned calves displayed unchanging absent or minor responses to stimulation. Regardless of whether topical anesthetic was applied, scoop dehorned calves were more likely to display minor, moderate, or severe responses than sham dehorned control calves, and responses tended to be most extreme at 4h postdehorning. Calves in the STA group tended to be less likely to display minor, moderate, or severe responses than calves in the SnoTA group at most time points (exception at 4h postdehorning). Responses were significantly more likely to be less severe in STA calves than in SnoTA calves at 40 min and 1.5h following dehorning. Thus, the use of the topical anesthetic for calves reduced the short-term sensitivity of scoop dehorning wounds.

Temporal and spatial dissimilarities in an intertidal fish assemblage in the South Pacific Ocean: The role of the ENSO process and intrinsic habitat conditions in emerging patterns.

An intertidal fish assemblage was studied in central Chile for 15 years in three localities: Isla Negra, El Tabo, and Las Cruces. Analyses of their multivariate dissimilarities were carried out considering temporal and spatial factors. Temporal factors included intra-annual and year-to-year variability. Spatial factors included locality, intertidal tidepool height, and each tidepool considered as a unique unit. Complementary to this, we tested the hypothesis that the El Niño Southern Oscillation (ENSO) would help explain year-to-year dissimilarities in the multivariate structure of this fish assemblage for the 15 years of data. To this end, the ENSO was regarded as a continuous inter-annual process as well as a set of discrete events. Additionally, dissimilarities in the temporal dynamics of the fish assemblage were evaluated considering each locality and tidepool unique units. Results indicated the following: (i) The most representative species for the whole area and period of the study were Scartichthys viridis (44 %), Helcogrammoides chilensis (17 %), Girella laevifrons (10 %), Graus nigra (7 %), Auchenionchus microcirrhis (5 %), and Helcogrammoides cunninghami (4 %); (ii) there is intra-annual (i.e., seasonality) and year-to-year multivariate variability in fish assemblage dissimilarities throughout the entire area of study, including all the tidepools and localities; (iii) when considering the spatial factor specifically, each tidepool unit, as well as their heights and localities, presented their own unique temporal year-to-year dynamics. The latter can be explained by the ENSO factor, also considering the intensity of the El Niño and La Niña events. In summary, the multivariate structure of the intertidal fish assemblage was statistically dissimilar when comparing neutral periods with El Niño and La Niña events. This structure was observed for the entire area of study, for each locality, and primarily for each tidepool as a unique unit. Fish physiological mechanisms underlying the identified patterns are discussed.

Tackling the lack of diversity in cancer research.

Despite the clear benefit of studying biological samples from diverse genetic backgrounds and geographical locations, our current knowledge of disease is mostly derived from the study of European-descent individuals. In the cancer field, this is reflected in the poor representation of African and Amerindian/Latino samples in most large public data repositories. This lack of diversity is due to several reasons, but here we focus on (1) the lack of support for studies on non-European populations that are performed in low- and middle-income countries (LMICs), and (2) unequal partnerships between scientists in LMICs and those in high-income countries. We argue that expanding access to research funding, increasing the participation of underrepresented scientists in editorial boards and international conferences, facilitating the publication of studies conducted in these countries, and properly acknowledging LMIC researchers' contributions in publications and grant applications will promote equity for scientists working in LMICs. We envisage that this will translate to more impactful research in these countries, which will include more samples from diverse populations. For the cancer field, this will broaden our understanding of pathomechanisms and may help to improve the treatment of patients from all backgrounds.

Methyl esters of 23,24-Dinor-5α-cholan-22-oic acids as brassinosteroid Analogues. Synthesis, evaluation of plant growth promoting activity and Molecular docking.

Five new brassinosteroid analogues were synthetized from 3ß-acetoxy-23,24-dinorchol-4-en-22-oic acid. All the obtained compound showed significant activity in the Rice Lamina Inclination Test. Interestingly the effects of the methyl ester of 3ß-hydroxy-6-oxo-23,24-dinorcholan-22-oic acid (14) at concentrations of 1 × 10-7 and 1 × 10-6 M proved to be higher than those produced by brassinolide. In silico Molecular Docking and Induced fit docking (IFD) simulations for the compounds with the highest biological activity data were carried out to investigate the binding mode interactions into the brassinolide-binding groove which revealed that the compound 14 had high binding energy values and a good affinity.

PKR-like ER kinase (PERK) Haplotypes Are Associated with Depressive Symptoms in People with HIV.

Background: Depression is a debilitating and difficult-to-treat condition in people with HIV (PWH) despite viral suppression on antiretroviral therapy (ART). Depression is associated with activation of the PKR-like ER kinase (PERK) pathway, which regulates protein synthesis in response to metabolic stress. We evaluated common PERK haplotypes that influence PERK expression in relation to depressed mood in PWH. Methods: PWH from 6 research centers were enrolled in the study. Genotyping was conducted using targeted sequencing with TaqMan. The major PERK haplotypes A, B, and D were identified. Depressive symptom severity was assessed using the Beck Depression Inventory-II (BDI-II). Covariates including genetically-defined ancestry, demographics, HIV disease/treatment parameters and antidepressant treatments were assessed. Data were analyzed using multivariable regression models. Results: A total of 287 PWH with a mean (SD) age of 57.1±7.8 years were enrolled. Although the largest ethnic group was non-Hispanic white (n=129, 45.3%), African-American (n=124, 43.5%) and Hispanic (n=30, 10.5%) made up over half the sample. 20.3% were female and 96.5% were virally suppressed. Mean BDI-II was 9.6±9.5, and 28.9% scored above the cutoff for mild depression (BDI-II>13). PERK haplotype frequencies were AA57.8%, AB25.8%, AD 10.1%, and BB4.88%. PERK haplotypes were differentially represented according to genetic ancestry (p=6.84e-6). BDI-II scores were significantly higher in participants with the AB haplotype (F=4.45, p=0.0007).This finding was robust to consideration of potential confounds. Conclusion: PERK haplotypes were associated with depressed mood in PWH.Consequently, pharmacological targeting of PERK-related pathways might amelioratedepression in PWH.

Pulsar glitches: the crust is not enough.

Pulsar glitches are traditionally viewed as a manifestation of vortex dynamics associated with a neutron superfluid reservoir confined to the inner crust of the star. In this Letter we show that the nondissipative entrainment coupling between the neutron superfluid and the nuclear lattice leads to a less mobile crust superfluid, effectively reducing the moment of inertia associated with the angular momentum reservoir. Combining the latest observational data for prolific glitching pulsars with theoretical results for the crust entrainment, we find that the required superfluid reservoir exceeds that available in the crust. This challenges our understanding of the glitch phenomenon, and we discuss possible resolutions to the problem.

[Incidence of intravenous colistin nephrotoxicity in hospitalized patients]. / Incidencia de nefrotoxicidad inducida por colistina intravenosa en pacientes hospitalizados.

OBJECTIVE: The increase in infections with multidrug resistant bacteria has forced to return to the use of colistin, antibiotic with known nephrotoxicity. The aim of the study is to determine the incidence of colistin nephrotoxicity nowadays. METHODS: Retrospective-observational-unicentric study was collected hospitalized patients in intravenous colistin treatment during the years 2018-2019. Nephrotoxicity was defined according to the RIFLE scale. The variables to determine it were serum creatinine (sCr) and glomerular filtration (GF). The variables analyzed were age, sex, treatment duration, loading and cumulative dose, empirical/targeted treatment, chronic kidney disease, concomitant use of intravenous contrast and nephrotoxic drugs. RESULTS: A total of 90 patients (60% men) were included, with an average age of 58.2±18.1 years. The mean duration of treatment was 9±8.3 days, with an average cumulative dose of 69.8±71MU. There were no differences between sCr and GF at the beginning and end of treatment. The incidence of nephrotoxicity was 1.73 cases/100 days of treatment (prevalence of 15.56%). CONCLUSIONS: Colistin nephrotoxicity has an important incidence, without developing severe illness.

Clinical Evaluation of Lithium Disilicate Veneers Manufactured by CAD/CAM Compared with Heat-pressed Methods: Randomized Controlled Clinical Trial.

CLINICAL RELEVANCE: Lithium disilicate veneers for esthetic restorations show great accuracy and similarity, regardless of the type of fabrication technique.

[Impact of a quality improvement plan on the validation of drug prescriptions on the safety of the hospitalised patient]. / Impacto de un plan de mejora de calidad en la validación de la prescripción de fármacos sobre la seguridad de los pacientes hospitalizados.

BACKGROUND AND OBJECTIVES: Medication errors are the most common adverse events in healthcare. Pharmaceutical validation (PV) seeks to reduce them. The aims of this study were to assess the impact of the introduction of an automated tool for the validation (VPAT) of the high clinical relevance drugs prescription (HCRD) over time of pharmaceutical intervention (PI), and to quantify the number of medication errors detected before and after its implementation. MATERIAL AND METHODS: A two phase retrospective-observational single centre study was designed. A pre-intervention phase (Pre-P): PV of beds with Unit Dose Dispensing (October 2015 - February 2016), was followed by a post-intervention phase (Post-P): PV using a VPAT of HCRD in hospital patients (October 2016 - February 2017). HCRD were selected from the list of high-risk drugs of Institute for Safe Medication Practices. The data was obtained from the PI record (Access®) and the computerised prescription. The variables collected were: age and gender of the patients included, data of drugs prescription, and time to PI. RESULTS: A total of 477 PI were analysed in 404 patients, with a mean age of 65.9±19.5 years (53.22% women). The mean time up to PI was 25.6±24.72h in the Pre-P, and 18.87±20.44h in the Post-P (P=0.01). In Pre-P, 106 PI were performed (35.85% prevention of adverse reactions) compared to 371 PI (39.62% medication reconciliation) in Post-P. CONCLUSIONS: The VPAT enabled a greater number of medication errors to be detected and intervened in hospitalised patients, with a significantly reduced time to PI.

Adapted Three-step Restorative Technique: Recovering Dental Substrate Compromised by Complex Erosive Wear in a Young Patient.

CLINICAL RELEVANCE: This article presents the dental restoration of a young female patient complaining of erosive dental wear using a three-step restorative technique, an alternative approach with some novel adjustments. SUMMARY: For successful tooth wear treatment, determining the etiological systemic and local factors is the main priority before deciding on effective and long-term preventive and/or therapeutic restorative approaches. In addition to professional intervention, achieving optimal outcomes requires patients to control their diet and/or gastric issues, thus minimizing the wear process. However, continuous wear constitutes the most challenging scenario, mainly when it affects young patients' dentitions. This article describes the dental restoration of posterior teeth with reestablishment of occlusal vertical dimension before treating the anterior teeth, while educating the patient and providing medical monitoring. The three-step restorative technique seems to be properly applicable in cases of significant dental compromise due mainly to erosive wear and is based on direct procedures, which can assure a reliable and feasible approach.