BRCA1 deficiency specific base substitution mutagenesis is dependent on translesion synthesis and regulated by 53BP1

Defects in BRCA1, BRCA2 and other genes of the homology-dependent DNA repair (HR) pathway cause an elevated rate of mutagenesis, eliciting specific mutation patterns including COSMIC signature SBS3. Using genome sequencing of knock-out cell lines we show that Y family translesion synthesis (TLS) polymerases contribute to the spontaneous generation of base substitution and short insertion/deletion mutations in BRCA1 deficient cells, and that TLS on DNA adducts is increased in BRCA1 and BRCA2 mutants. The inactivation of 53BP1 in BRCA1 mutant cells markedly reduces TLS-specific mutagenesis, and rescues the deficiency of template switch–mediated gene conversions in the immunoglobulin V locus of BRCA1 mutant chicken DT40 cells. 53BP1 also promotes TLS in human cellular extracts in vitro. Our results show that HR deficiency–specific mutagenesis is largely caused by TLS, and suggest a function for 53BP1 in regulating the choice between TLS and error-free template switching in replicative DNA damage bypass.

Présentation atypique de la trichotillomanie : un cas clinique avec revue de la littérature

Trichotillomania is a chronic mental illness with an elevated rate of psychiatric comorbidities. Patients with Trichotillomania often have a low insight putting them at risk for serious health problems such as depression, social dysfunction, body damage, malnutrition, even death in severe cases if untreated. Not all patients have access to health care, most of them live in difficult environments with different cultural variations and attitudes toward mental illness making them more vulnerable. The literature suggests that there is a variety of psychotherapies and medications that may help in managing Trichotillomania. The present case is of a woman with no prior history of mental illness, who was brought by her father for behavioral issues. During her evaluation we observed various symptoms associated with different pathologies, exemplifying the difficulties to diagnose individuals with Trichotillomania and to prepare a treatment plan for them

The Likelihood of Early Guilty Pleas Following Digitally Recorded Victim Statements for Family Violence

This study follows 4715 Family Harm cases for which charges are laid (from around 15,000 events from 2018–2020). Comparisons are made between cases where a digitally recorded victim video statement (VVS) is taken to those who (1) make a written statement, (2) refuse to make any statement and (3) present at the public counter and make a written statement. Findings indicate that VVS increases the rates of an early guilty plea by 95% (OR = 1.95, LCL = 1.34, UCL = 2.7) compared to those who decline a VVS and have a written statement. No difference is observed for those presenting to report an event at a public counter. A more modest effect is observed comparing those who refuse a statement altogether (OR = 1.28, LCL = 1.03, UCL = 1.60). A VVS is nearly twice as likely to lead to an early guilty plea. It is reasoned that there is a poor rate of guilty pleas for written statements, rather than an elevation in rates for VVS. Age and gender are unrelated to the elevated rate of pleading guilty to a VVS. Event seriousness is inversely related to pleading guilty, whereas having many prior convictions or being remanded increases the likelihood of the guilty plea.

Impact of Perioperative Absolute Neutrophil Count on Central Line-Associated Bloodstream Infection in Children With Acute Lymphoblastic and Myeloid Leukemia

BackgroundThere is lack of evidence concerning safety of placement of tunneled central venous catheters (TCVCs) in neutropenic children with acute leukemias. Here, we evaluate the impact of absolute neutrophil count (ANC) at the time of TCVC placement on development of central line-associated bloodstream infections (CLABSI) in children with lymphoblastic (ALL) or myeloid leukemia (AML).Materials and MethodsA retrospective observational study of children undergoing TCVC placement at a tertiary referral hospital between January 2000 and December 2019 was performed. Traditional and competing-risks regression models were used to estimate the effect of perioperative ANC on development of CLABSI.ResultsA total of 350 children (median age 6.4 [IQR: 3.1–10.9] years) underwent 498 consecutive TCVC implantations in neutropenic (n = 172, 34.5%) and non-neutropenic conditions (n = 326, 65.5%). The median length of observation per TCVC was 217.1 (IQR: 116.1–260.5) days with a total of 99,681 catheter days (CD). There were no differences in early (within first 30 days after TCVC placement) and overall CLABSI rates between neutropenic and non-neutropenic patients (HR 1.250, p = 0.502; HR 1.633, p = 0.143). We identified female sex (HR 2.640, p = 0.006) and the use of TCVC for treatment of relapsed leukemia (HR 4.347, p < 0.0001) as risk factors for early CLABSI and the use of double-lumen catheters (HR 2.607, p = 0.003) and use of TCVCs during leukemia relapse (HR 2.004, p = 0.005) for overall study period.ConclusionThe placement of TCVC in children with neutropenia undergoing anticancer therapy for acute leukemia is safe and not associated with an elevated rate of CLABSI.

Mutation saturation for fitness effects at human CpG sites

Whole exome sequences have now been collected for millions of humans, with the related goals of identifying pathogenic mutations in patients and establishing reference repositories of data from unaffected individuals. As a result, we are approaching an important limit, in which datasets are large enough that, in the absence of natural selection, every highly mutable site will have experienced at least one mutation in the genealogical history of the sample. Here, we focus on CpG sites that are methylated in the germline and experience mutations to T at an elevated rate of ~10-7 per site per generation; considering synonymous mutations in a sample of 390,000 individuals, ~99% of such CpG sites harbor a C/T polymorphism. Methylated CpG sites provide a natural mutation saturation experiment for fitness effects: as we show, at current sample sizes, not seeing a non-synonymous polymorphism is indicative of strong selection against that mutation. We rely on this idea in order to directly identify a subset of CpG transitions that are likely to be highly deleterious, including ~27% of possible loss-of-function mutations, and up to 20% of possible missense mutations, depending on the type of functional site in which they occur. Unlike methylated CpGs, most mutation types, with rates on the order of 10-8 or 10-9, remain very far from saturation. We discuss what these findings imply for interpreting the potential clinical relevance of mutations from their presence or absence in reference databases and for inferences about the fitness effects of new mutations.

Uncovering bleomycin-induced genomic alterations and underlying mechanisms in yeast

Bleomycin (BLM) is a widely used chemotherapeutic drug. BLM-treated cells showed an elevated rate of mutations, but the underlying mechanisms remained unclear. In this study, the global genomic alterations in BLM-treated cells were explored in the yeast Saccharomyces cerevisiae . Using genetic assay and whole-genome sequencing, we found that the mutation rate could be greatly elevated in S. cerevisiae cells that underwent Zeocin TM (a BLM member) treatment. One-base deletion and T to G substitution at the 5’-GT-3’ motif was the most striking signature of Zeocin TM -induced mutations. This was mainly the result of translesion DNA synthesis involving Rev1 and polymerase ζ. Zeocin TM treatment led to the frequent loss of heterozygosity and chromosomal rearrangements in the diploid strains. The breakpoints of recombination events were significantly associated with certain chromosomal elements. Lastly, we identified multiple genomic alterations that contributed to BLM resistance in the Zeocin TM -treated mutants. Overall, this study provides new insights into the genotoxicity and evolutional effects of BLM. Importance Bleomycin is an antitumor antibiotic that can mutate genomic DNA. Using yeast models in combination with genome sequencing, the mutational signatures of Zeocin TM (a member of the bleomycin family) are disclosed. Translesion-synthesis polymerases are crucial for the viability of Zeocin TM -treated yeast cells at the sacrifice of a higher mutation rate. We also confirmed that multiple genomic alterations were associated with the improved resistance to Zeocin TM , providing novel insights into how bleomycin resistance is developed in cells.

Treatment of epilepsy associated with primary and metastatic brain tumors

There is a number of unsolved issues in management of epilepsy associated with primary and metastatic brain tumors (BTs). In particular, no consensus approaches to treatment of patients with epilepsy associated with BTs have been proposed regarding use of current anti-epileptic drugs (AEDs). The review presents the relevant data on epidemiology, features of clinically manifested epilepsy at varying stages of BTs, aspects of drug-drug interaction between AEDs and anti-tumor agents, AED-related effects on cognitive functions as well as quality of life in patients with epilepsy associated with BTs. Levetiracetam and valproic acid comprise the first-line drugs for treating seizures in patients with BTs. It is unreasonable to use AEDs acting as hepatic microsomal enzyme inducers for therapy of epileptic seizures in BTs, because it may decrease efficacy of chemotherapy agents and glucocorticoids along with elevated rate of side effects. Perampanel acting as a selective noncompetitive AMPA receptor antagonist, may be one of the drugs of choice for the adjunctive therapy of epileptic seizures associated with BTs.

Prevalence of attention deficit/hyperactivity disorder in Mexican university students

Introduction: Attention-Deficit/Hyperactivity Disorder (ADHD) in adulthood causes relevant deterioration in daily functioning. Specifically, in educational scenarios, complications including an elevated rate of failed courses and desertion have been found. The reported prevalence of ADHD in adults varies widely, therefore studying specific populations becomes important. Objective: to determine the prevalence of ADHD in students at a public university using screening tools to determine the presence of current and retrospective symptomatology during childhood and to describe their sociodemographic characteristics. Method: the study was conducted with a probabilistic sample of undergraduate students (N = 1837), to whom the Adult Self Report Scale for ADHD (ASRS-6) and the Wender Utha Rating Scale (WURS) were administered to determine current and childhood ADHD symptoms. Results: the prevalence of ADHD in the studied population was 16.2%, with a significantly higher frequency in males (22.14%) than in females (13%). ADHD was most prevalent in Biology students (23.7%) and least in Nursery students (9.9%). Discussion and conclusion: results indicate a higher frequency of ADHD in Mexican undergraduate students than that reported in adult populations of other countries, but consistent with previous reports of Mexican undergraduate students and children. The association of ADHD and difficulties in academic, work, and social achievement in the studied population should be further investigated.

Effects of Metformin on Spontaneous Ca2+ Signals in Cultured Microglia Cells under Normoxic and Hypoxic Conditions

Microglial functioning depends on Ca2+ signaling. By using Ca2+ sensitive fluorescence dye, we studied how inhibition of mitochondrial respiration changed spontaneous Ca2+ signals in soma of microglial cells from 5–7-day-old rats grown under normoxic and mild-hypoxic conditions. In microglia under normoxic conditions, metformin or rotenone elevated the rate and the amplitude of Ca2+ signals 10–15 min after drug application. Addition of cyclosporin A, a blocker of mitochondrial permeability transition pore (mPTP), antioxidant trolox, or inositol 1,4,5-trisphosphate receptor (IP3R) blocker caffeine in the presence of rotenone reduced the elevated rate and the amplitude of the signals implying sensitivity to reactive oxygen species (ROS), and involvement of mitochondrial mPTP together with IP3R. Microglial cells exposed to mild hypoxic conditions for 24 h showed elevated rate and increased amplitude of Ca2+ signals. Application of metformin or rotenone but not phenformin before mild hypoxia reduced this elevated rate. Thus, metformin and rotenone had the opposing fast action in normoxia after 10–15 min and the slow action during 24 h mild-hypoxia implying activation of different signaling pathways. The slow action of metformin through inhibition of complex I could stabilize Ca2+ homeostasis after mild hypoxia and could be important for reduction of ischemia-induced microglial activation.

Pervasive positive selection on virus receptors driven by host-virus conflicts in mammals

Viruses hijack cellular proteins known as viral receptors to initiate their infection. Viral receptors are subject to two conflicting directional forces, namely negative selection to maintain their cellular function and positive selection resulted from everchanging host-virus arms race. Much remains unclear how viral receptors evolved in mammals, and whether viral receptors from different mammal groups experienced different strength of natural selection. Here, we perform evolutionary analyses of 92 viral receptors in five major orders of mammals, including Carnivora, Cetartiodactyla, Chiroptera, Primates, and Rodentia. In all the five mammal orders, signals of positive selection are detected for a high proportion of viral receptors (from 41% in Carnivora to 65% in Rodentia). Many positively selected residues overlap host-virus interaction interface. Compared with control genes, we find viral receptors underwent elevated rate of adaptive evolution in all the five mammal orders, suggesting that host-virus conflicts are the main driver of the adaptive evolution of viral receptors in mammals. Interestingly, the overall strength of natural selection acting on viral receptors driven by host-virus arms race is largely homogenous and correlated among different mammal orders with bats and rodents, zoonosis reservoirs of importance, unexceptional. Taken together, our findings indicate host-virus conflicts have driven the elevated rate of adaptive evolution in viral receptors across mammals, and might have important implications in zoonosis surveillance and prediction. Importance Viral receptors are cellular proteins hijacked by viruses to help their infections. A complete picture on the evolution of viral receptors in mammals is still lacking. Here, we perform a comprehensive evolutionary analysis of the evolution of 92 viral receptors in five mammal orders, including Carnivora, Cetartiodactyla, Chiroptera, Primates, and Rodentia. We find that positive selection pervasively occurred during the evolution of viral receptors, and viral receptors exhibit at an elevated rate of adaptive evolution than control genes in all the five mammal orders, suggesting host-virus conflicts are a major driver of the adaptive evolution of viral receptors. Interestingly, the strength of positive selection acting on viral receptors is similar among the five mammal orders. Our study might have important implications in understanding the evolution of host-virus interaction.