The PIWI-interacting RNA (piRNA) pathway is essential for retrotransposon silencing. In piRNA-deficient mice, L1-overexpressing male germ cells exhibit excessive DNA damage and meiotic defects. It ...remains unknown whether L1 expression simply highlights piRNA deficiency or actually drives the germ-cell demise. Specifically, the sheer abundance of genomic L1 copies prevents reliable quantification of new insertions. Here, we developed a codon-optimized L1 transgene that is controlled by an endogenous mouse L1 promoter. Importantly, DNA methylation dynamics of a single-copy transgene were indistinguishable from those of endogenous L1s. Analysis of Mov10l1
−/− testes established that de novo methylation of the L1 transgene required the intact piRNA pathway. Consistent with loss of DNA methylation and programmed reduction of H3K9me2 at meiotic onset, the transgene showed 1,400-fold increase in RNA expression and consequently 70-fold increase in retrotransposition in postnatal day 14 Mov10l1
−/− germ cells compared with the wild-type. Analysis of adult Mov10l1
−/− germ-cell fractions indicated a stage-specific increase of retrotransposition in the early meiotic prophase. However, extrapolation of the transgene data to endogenous L1s suggests that it is unlikely insertional mutagenesis alone accounts for the Mov10l1
−/− phenotype. Indeed, pharmacological inhibition of reverse transcription did not rescue the meiotic defect. Cumulatively, these results establish the occurrence of productive L1 mobilization in the absence of an intact piRNA pathway but leave open the possibility of processes preceding L1 integration in triggering meiotic checkpoints and germ-cell death. Additionally, our data suggest that many heritable L1 insertions originate from individuals with partially compromised piRNA defense.
Assay for Transposase Accessible Chromatin by sequencing (ATAC-seq) accurately depicts the chromatin regulatory state and altered mechanisms guiding gene expression in disease. However, bulk ...sequencing entangles information from different cell types and obscures cellular heterogeneity. To address this, we developed Cellformer, a deep learning method that deconvolutes bulk ATAC-seq into cell type-specific expression across the whole genome. Cellformer enables cost-effective cell type-specific open chromatin profiling in large cohorts. Applied to 191 bulk samples from 3 brain regions, Cellformer identifies cell type-specific gene regulatory mechanisms involved in resilience to Alzheimer's disease, an uncommon group of cognitively healthy individuals that harbor a high pathological load of Alzheimer's disease. Cell type-resolved chromatin profiling unveils cell type-specific pathways and nominates potential epigenetic mediators underlying resilience that may illuminate therapeutic opportunities to limit the cognitive impact of the disease. Cellformer is freely available to facilitate future investigations using high-throughput bulk ATAC-seq data.
We present a general approach to describe slowly driven quantum systems both in real and imaginary time. We highlight many similarities, qualitative and quantitative, between real and imaginary time ...evolution. We discuss how the metric tensor and the Berry curvature can be extracted from both real and imaginary time simulations as a response of physical observables. For quenches ending at or near the quantum critical point, we show the utility of the scaling theory for detecting the location of the quantum critical point by comparing sweeps at different velocities. We briefly discuss the universal relaxation to equilibrium of systems after a quench. We finally review recent developments of quantum Monte Carlo methods for studying imaginary time evolution. We illustrate our findings with explicit calculations using the transverse-field Ising model in one dimension.
Type I spiral ganglion neurons (SGNs) convey sound information to the central auditory pathway by forming synapses with inner hair cells (IHCs) in the mammalian cochlea. The molecular mechanisms ...regulating the formation of the post-synaptic density (PSD) in the SGN afferent terminals are still unclear. Here, we demonstrate that brain-specific angiogenesis inhibitor 1 (BAI1) is required for the clustering of AMPA receptors GluR2–4 (glutamate receptors 2–4) at the PSD. Adult Bai1-deficient mice have functional IHCs but fail to transmit information to the SGNs, leading to highly raised hearing thresholds. Despite the almost complete absence of AMPA receptor subunits, the SGN fibers innervating the IHCs do not degenerate. Furthermore, we show that AMPA receptors are still expressed in the cochlea of Bai1-deficient mice, highlighting a role for BAI1 in trafficking or anchoring GluR2–4 to the PSDs. These findings identify molecular and functional mechanisms required for sound encoding at cochlear ribbon synapses.
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•In the mouse cochlea, BAI1 is expressed in the afferent spiral ganglion neurons (SGNs)•AMPA receptors are absent in the SGN afferent terminals of adult Bai1-deficient mice•Functional IHC ribbon synapses fail to relay sound information to SGNs in mice lacking BAI1•Bai1-deficient mice have highly elevated hearing thresholds
Carlton et al. show that BAI1 is essential for activating SGN afferent terminals at cochlear IHC ribbon synapses. In Bai1-deficient mice, IHC-SGN synapses are formed but AMPA receptors that are normally in the post-synaptic density are either missing or uncoupled from the pre-synaptic ribbons, leading to highly raised hearing thresholds.
A major research finding in the field of Biological Psychiatry is that symptom-based categories of mental disorders map poorly onto dysfunctions in brain circuits or neurobiological pathways. Many of ...the identified (neuro) biological dysfunctions are "transdiagnostic", meaning that they do not reflect diagnostic boundaries but are shared by different ICD/DSM diagnoses. The compromised biological validity of the current classification system for mental disorders impedes rather than supports the development of treatments that not only target symptoms but also the underlying pathophysiological mechanisms. The Biological Classification of Mental Disorders (BeCOME) study aims to identify biology-based classes of mental disorders that improve the translation of novel biomedical findings into tailored clinical applications.
BeCOME intends to include at least 1000 individuals with a broad spectrum of affective, anxiety and stress-related mental disorders as well as 500 individuals unaffected by mental disorders. After a screening visit, all participants undergo in-depth phenotyping procedures and omics assessments on two consecutive days. Several validated paradigms (e.g., fear conditioning, reward anticipation, imaging stress test, social reward learning task) are applied to stimulate a response in a basic system of human functioning (e.g., acute threat response, reward processing, stress response or social reward learning) that plays a key role in the development of affective, anxiety and stress-related mental disorders. The response to this stimulation is then read out across multiple levels. Assessments comprise genetic, molecular, cellular, physiological, neuroimaging, neurocognitive, psychophysiological and psychometric measurements. The multilevel information collected in BeCOME will be used to identify data-driven biologically-informed categories of mental disorders using cluster analytical techniques.
The novelty of BeCOME lies in the dynamic in-depth phenotyping and omics characterization of individuals with mental disorders from the depression and anxiety spectrum of varying severity. We believe that such biology-based subclasses of mental disorders will serve as better treatment targets than purely symptom-based disease entities, and help in tailoring the right treatment to the individual patient suffering from a mental disorder. BeCOME has the potential to contribute to a novel taxonomy of mental disorders that integrates the underlying pathomechanisms into diagnoses.
Retrospectively registered on June 12, 2019 on ClinicalTrials.gov (TRN: NCT03984084).
During pregnancy, metabolic changes that develop in women may increase the risk of diseases and conditions that may also harm the life of the growing fetus. The aim of the present study was to ...identify and compare the metabolic profile (MP) during pregnancy in two birth cohorts in 2010 in the cities of Ribeirão Preto (RP) and São Luís (SL), Brazil. Pregnant women (1393 in RP and 1413 in SL) were studied; information was obtained through questionnaires in addition to anthropometric, biochemical, and blood pressure measurements. Data are presented as means and proportions. To compare the characteristics of pregnant women in both cities, chi-squared and Student's t-tests were applied, with 5% significance level. Ribeirão Preto presented higher mean values than SL for pre-gestational body mass index (24.5 vs 23 kg/m2, P<0.001), systolic (108.4 vs 102.8 mmHg, P<0.001) and diastolic (65.9 vs 61.8 mmHg, P<0.001) blood pressure, total cholesterol (226.3 vs 213.7 mg/dL, P<0.001) and fractions, and glycemia (84.5 vs 80.2 mg/dL, P<0.001), except for triglycerides (P=0.135). Women from RP also showed higher rates of pre-gestational overweight and obesity compared with SL (40.1 vs 25.8%). In the present study, pregnant women in RP had a worse gestational metabolic profile than those in SL, with higher pre-gestational excess weight, indicating that nutritional transition was more advanced in the more developed city.
Given the increase of women with excess weight or obesity and its possible effects on birth weight, the present study aimed to investigate the association between pregestational maternal body mass ...index (BMI) and birth weight in a birth cohort from Ribeirão Preto, SP, Brazil. This was a prospective study conducted on 1362 mother-child pairs involving singleton births. The women were evaluated using standardized questionnaires during the second trimester of pregnancy and at the time of childbirth. Information about the newborns was obtained from their medical records. The dependent variable was birth weight, categorized as low, adequate, or high. The independent variable was pregestational maternal BMI, categorized as malnutrition, adequate weight, overweight, and obesity. A multinomial regression model was used to estimate the crude and adjusted relative risk (RR) of low and high birth weight. A high frequency of pregestational excess weight (39.6%) was detected and found to be independently associated with high birth weight (RR=2.13, 95%CI: 1.19-3.80 for overweight and RR=3.34, 95%CI: 1.80-6.19 for obese pregnant women). There was no association between pregestational malnutrition and low birth weight (RR=1.70; 95%CI: 0.81-3.55). The present data showed a high rate of women with excess pregestational weight, supporting the hypothesis that pregestational BMI may contribute to high birth weight babies and indicating the need for actions aiming to prevent excessive weight in women at reproductive age.
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