Lessons from the meiotic recombination landscape of the ZMM deficient budding yeast Lachancea waltii

Meiotic recombination has been deeply characterized in a few model species only, notably in the budding yeast Saccharomyces cerevisiae. Interestingly, most members of the ZMM pathway that implements meiotic crossover interference in S. cerevisiae have been lost in Lachancea yeast species after the divergence of Lachancea kluyveri from the rest of the clade. This suggests major differences in the control of crossover distribution. After investigating meiosis in L. kluyveri, we determined the meiotic recombination landscape of Lachancea waltii and identified several characteristics that should help understand better the underlying mechanisms. Such characteristics include systematic regions of loss of heterozygosity (LOH) in L. waltii hybrids, compatible with dysregulated Spo11-mediated DNA double strand breaks (DSB) independently of meiosis. They include a higher recombination rate in L. waltii than in L. kluyveri despite the lack of multiple ZMM pro-crossover factors. L. waltii exhibits an elevated frequency of zero-crossover bivalents as L. kluyveri but opposite to S. cerevisiae. L. waltii gene conversion tracts lengths are comparable to those observed in S. cerevisiae and shorter than in L. kluyveri despite the lack of Mlh2, a factor limiting conversion tracts size in S. cerevisiae. L. waltii recombination hotspots are not shared with either S. cerevisiae or L. kluyveri, showing that meiotic recombination hotspots can evolve at a rather limited evolutionary scale within budding yeasts. Finally, in line with the loss of several ZMM genes, we found only residual crossover interference in L. waltii likely coming from the modest interference existing between recombination precursors.

Polymorphic variants in genes related to stress coping are associated with the awake bruxism

Background Chronic stress is one of the leading predisposing factors in bruxism aetiology, but the influence of genetic factors is also suggested. We aimed to study whether sequence variants in genes involved in stress regulation pathways: NTRK2 and BDNF, may be associated with awake bruxism susceptibility, clinical presentation, and patients’ perceived stress level. Methods The study group included 104 patients with probable awake bruxism and 191 population controls. Patients underwent dental examination concerning the symptoms of bruxism and psychological testing. Genotyping was performed using HRMA and sequencing. Statistical analyses were conducted, and P values below 0.05 were considered statistically significant. Results We observed a positive correlation of measured stress level and pathological teeth attrition in the anterior segment (r = 0.45, P < 0.001), enamel attritions (r = 0.44, P < 0.001), tongue impressions (r = 0.50, P < 0.001) and posterior teeth attrition (r = 0.27, P = 0.005). Moreover, the c.196A variant (p.66Met) of the BDNF gene and c.1397-31392G allele of the NTRK2 gene were present with elevated frequency, comparing to controls. Conclusions This study hence the thesis that perceived stress level is a substantial contributing factor to awake bruxism occurrence and its clinical manifestations. Moreover, sequence variants in genes related to stress coping may be correlated with awake bruxism’s susceptibility via elevated perceived stress level.

Micronuclei and other nuclear abnormalities in phorate exposed fish, Channa punctatus

Aim: The present study aims to establish morphology-based nuclear abnormalities (NAs) including micronuclei (MN) as effective and sensitive genotoxic endpoint biomarkers in fish against the sub-lethal exposure of phorate. Methodology: Fish, Channa punctatus (35 ± 3.0 g; 14.5 ± 1.0 cm) were randomly exposed in two sets, treated group 1 and 2 (0.0375 mg l-1 and 0.075 mg l-1 of phorate, respectively) along with a simultaneous control (0 mg l-1). The blood was sampled after 30 days. Results: A significant (p < 0.05) induction in reactive oxygen species (ROS) coupled with elevated frequency of blood cells showing micronuclei along with the gross appearance of notched nuclei, curved nuclei, blebbed nuclei, kidney-shaped nuclei, V-shaped nuclei, nuclear buds, nucleoplasmic bridges, dumbbell nuclei, and condensed/rounded nuclei were recorded in a dose-dependent manner. Interpretation: A significant (p < 0.05) induction in reactive oxygen species (ROS) coupled with elevated frequency of blood cells showing micronuclei along with the gross appearance of notched nuclei, curved nuclei, blebbed nuclei, kidney-shaped nuclei, V-shaped nuclei, nuclear buds, nucleoplasmic bridges, dumbbell nuclei, and condensed/rounded nuclei were recorded in a dose-dependent manner.

The Association Between Use of Rivastigmine and Pneumonia: Systematic Analysis of FDA Adverse Event Reporting System

Background: Pneumonia is an inflammatory condition induced by infection of the lungs and is frequently a cause of morbidity and mortality among patients with Alzheimer’s disease (AD). Some studies have shown a correlation between acetylcholinesterase inhibitor use and elevated pneumonia risk. Objective: The purpose of this study was to perform a comparative analysis of the number of reported pneumonia cases in individuals prescribed rivastigmine relative to the association between pneumonia risk for other therapeutics including over-the-counter drugs and other AD therapeutics, as reported to the FDA Adverse Event Reporting System (FAERS) database. Methods: A disproportionality analysis was conducted to investigate the association between using rivastigmine and risk of pneumonia. Age, gender, dosage, route of administration, temporality, and geographic distribution of reported cases were also assessed. Results: Patients prescribed rivastigmine were more likely to report pneumonia as an adverse event than many drugs except galantamine. Males were found to be 46%more likely than females to report pneumonia as an adverse event while likelihood of pneumonia diagnosis increases 3–5-fold in patients older than 65 years of age. Conclusion: The observed elevated frequency of aspiration pneumonia in patients prescribed rivastigmine may be due to an induced cholinergic crisis that is selective for the medulla oblongata, resulting in gastrointestinal distress, impaired swallowing, heightened salivation, and labored breathing. The observed elevated frequency of infectious pneumonia in patients prescribed rivastigmine may also be linked to overstimulation of neurons in the medulla oblongata and downstream suppression of localized inflammatory responses.

The impact of artificial selection for Wolbachia-mediated dengue virus blocking on phage WO

Wolbachia is currently at the forefront of global efforts to control arbovirus transmission from the vector Aedes aegypti. The use of Wolbachia relies on two phenotypes—cytoplasmic incompatibility (CI), conferred by cifA and cifB genes in prophage WO, and Wolbachia-mediated pathogen blocking (WMPB). These traits allow for local, self-sustaining reductions in transmission of dengue (DENV) following release of Wolbachia-infected A. aegypti. Here, aided by previous artificial selection experiment that generated Low and High pathogen blocking lines, we examined the potential link between WMPB and phage WO. We found no evidence that Wolbachia or phage WO relative densities predict DENV blocking strength across selected lines. However, selection resulted in reduced phage WO relative density for the Low WMPB line. The Low blocking line was previously shown to have reduced fitness as a result of selection. Through subsequent genomic analyses, we demonstrate that SNP variation underpinning selection for low blocking led to elevated frequency of potential deleterious SNPs on chromosome 1. The key region on chromosome 1 contains genes relating to cell cycle regulation, oxidative stress, transcriptional pausing, among others, that may have cascading effects on Wolbachia intracellular environment. We hypothesize that reduction in phage WO may be driven by changes in the loci directly under selection for blocking, or by the accumulation of predicted deleterious alleles in linkage disequilibrium with blocking loci resulting from hitchhiking. For the Low line with fewer phage WO, we also detected reduced expression of cifA and cifB CI genes, with patterns of expression varying between somatic and reproductive tissues. In conclusion, we propose that artificial selection for WMPB trait had corresponding impacts on phage WO densities, and also the transcription of CI-causing genes. Future studies may include a more detailed analysis of the regions the A. aegypti chromosome 1’s ability to affect WMPB and other Wolbachia-associated intrinsic factors such as phage WO.

Lost in post-translational modification—Dengue virus writes its own sequel

Elevated frequency of afucosylated IgG1 antibodies during dengue virus infection is associated with prior infection and predicts severe disease.

me31B regulates stem cell homeostasis by preventing excess dedifferentiation in the Drosophila male germline

Tissue-specific stem cells maintain tissue homeostasis by providing a continuous supply of differentiated cells throughout the life of organisms. Differentiated/differentiating cells can revert back to a stem cell identity via dedifferentiation to help maintain the stem cell pool beyond the lifetime of individual stem cells. Although dedifferentiation is important to maintain the stem cell population, it is speculated to underlie tumorigenesis. Therefore, this process must be tightly controlled. Here we show that a translational regulator me31B plays a critical role in preventing excess dedifferentiation in the Drosophila male germline: in the absence of me31B, spermatogonia (SGs) dedifferentiate into germline stem cells (GSCs) at a dramatically elevated frequency. Our results show that the excess dedifferentiation is likely due to misregulation of nos, a key regulator of germ cell identity and GSC maintenance. Taken together, our data reveal negative regulation of dedifferentiation to balance stem cell maintenance with differentiation.

me31B regulates stem cell homeostasis by preventing excess dedifferentiation in the Drosophila male germline

Tissue-specific stem cells maintain tissue homeostasis by providing a continuous supply of differentiated cells throughout the life of organisms. Differentiated/differentiating cells can revert back to a stem cell identity via dedifferentiation to help maintain the stem cell pool beyond the lifetime of individual stem cells. Although dedifferentiation is important to maintain the stem cell population, it is speculated to underlie tumorigenesis. Therefore, this process must be tightly controlled. Here we show that a translational regulator me31B plays a critical role in preventing excess dedifferentiation in the Drosophila male germline: in the absence of me31B, spermatogonia (SGs) dedifferentiate into germline stem cells (GSCs) at a dramatically elevated frequency. Our results show that the excess dedifferentiation is likely due to misregulation of nos, a key regulator of germ cell identity and GSC maintenance. Taken together, our data reveal negative regulation of dedifferentiation to balance stem cell maintenance with differentiation.

Everyday Executive Function and Self-Awareness in Agenesis of the Corpus Callosum

Objective: Agenesis of the corpus callosum (AgCC) is associated with a range of cognitive deficits, including mild to moderate problems in higher order executive functions evident in neuropsychological assessments. Previous research has also suggested a lack of self-awareness in persons with AgCC. Method: We investigated daily executive functioning and self-awareness in 36 individuals with AgCC by analyzing self-ratings on the Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A), as well as ratings on the same instrument from close relatives. Discrepancies between self- and informant-ratings were compared to the normative sample and exploratory analyses examined possible moderating effects of participant and informant characteristics. Results: Significant deficiencies were found in the Behavioral Regulation and Metacognitive indices for both the self and informant results, with elevated frequency of metacognition scores in the borderline to clinical range. Informants also endorsed elevated frequency of borderline to clinically significant behavioral regulation scores. The proportion of AgCC participants whose self-ratings indicated less metacognitive impairment than informant-ratings was greater than in the normative sample. Self-ratings of behavioral regulation impairment decreased with age and informant-ratings of metacognition were higher in males than females. Conclusions: These findings provide evidence that individuals with AgCC experience mild to moderate executive functioning problems in everyday behavior which are observed by others. Results also suggest a lack of self-understanding or insight into the severity of these problems in the individuals with AgCC, particularly with respect to their metacognitive functioning.

Dysregulation of REV-ERBα impairs GABAergic function and promotes epileptic seizures in preclinical models

To design potentially more effective therapies, we need to further understand the mechanisms underlying epilepsy. Here, we uncover the role of Rev-erbα in circadian regulation of epileptic seizures. We first show up-regulation of REV-ERBα/Rev-erbα in brain tissues from patients with epilepsy and a mouse model. Ablation or pharmacological modulation of Rev-erbα in mice decreases the susceptibility to acute and chronic seizures, and abolishes diurnal rhythmicity in seizure severity, whereas activation of Rev-erbα increases the animal susceptibility. Rev-erbα ablation or antagonism also leads to prolonged spontaneous inhibitory postsynaptic currents and elevated frequency in the mouse hippocampus, indicating enhanced GABAergic signaling. We also identify the transporters Slc6a1 and Slc6a11 as regulators of Rev-erbα-mediated clearance of GABA. Mechanistically, Rev-erbα promotes the expressions of Slc6a1 and Slc6a11 through transcriptional repression of E4bp4. Our findings propose Rev-erbα as a regulator of synaptic function at the crosstalk between pathways regulating the circadian clock and epilepsy.