Explore the vast range of titles available.

Endogenous retroviruses (ERVs) are remnants of ancient retroviral infections of the germ line that can remain capable of replication within the host genome. In the soma, DNA methylation and repressive chromatin keep the majority of this parasitic DNA transcriptionally silent. However, it is unclear how the host organism adapts to recognize and silence novel invading retroviruses that enter the germ line. Krueppel-Associated Box (KRAB)-associated protein 1 (KAP1) is a transcriptional regulatory factor that drives the epigenetic repression of many different loci in mammalian genomes. Here, we use published experimental data to provide evidence that human KAP1 is recruited to endogenous retroviral DNA by KRAB-containing zinc-finger transcription factors (TFs). Many of these zinc-finger genes exist in clusters associated with human chromosome 19. We demonstrate that these clusters are located at hotspots for copy number variation (CNV), generating a large and continuing diversity of zinc-finger TFs with new generations. These zinc-finger genes possess a wide variety of DNA binding affinities, but their role as transcriptional repressors is conserved. We also perform a computational study of the different ERVs that invaded the human genome during primate evolution. We find candidate zinc-finger repressors that arise in the genome for each ERV family that enters the genomes of primates. In particular, we show that those repressors that gained their binding affinity to retrovirus sequences at the same time as their targets invaded the human lineage are preferentially located on chromosome 19 (P-value: 3 × 10(-3)).

A brief review of experimental methods for testing blast effects on structures is presented. Methods are classified in four groups: field tests, shock tubes, pendulum systems, and new techniques (blast simulator). Description of each method is given together with overall specification of possible instruments used in each test. In today’s modern era of computers which are becoming powerful tool implemented in all aspects of life and also scientific research, comparison of experimental and numerical techniques is also given. Comparison of data obtained from different experimental methods show that careful planning and execution leads to reliable results in terms of pressure, impulse, stress, and damage quantification.

Background A Phase II proof of concept (POC) randomized clinical trial was conducted to evaluate the effects of rasagiline, a monoamine oxidase B (MAO‐B) inhibitor approved for Parkinson disease, in mild to moderate Alzheimer's disease (AD). The primary objective was to determine if 1 mg of rasagiline daily for 24 weeks is associated with improved regional brain metabolism (fluorodeoxyglucose–positron emission tomography [FDG‐PET]) compared to placebo. Secondary objectives included measurement of effects on tau PET and evaluation of directional consistency of clinical end points. Methods This was a double‐blind, parallel group, placebo‐controlled, community‐based, three‐site trial of 50 participants randomized 1:1 to receive oral rasagiline or placebo (NCT02359552). FDG‐PET was analyzed for the presence of an AD‐like pattern as an inclusion criterion and as a longitudinal outcome using prespecified regions of interest and voxel‐based analyses. Tau PET was evaluated at baseline and longitudinally. Clinical outcomes were analyzed using an intention‐to‐treat (ITT) model. Results Fifty patients were randomized and 43 completed treatment. The study met its primary end point, demonstrating favorable change in FDG‐PET differences in rasagiline versus placebo in middle frontal (P < 0.025), anterior cingulate (P < 0.041), and striatal (P < 0.023) regions. Clinical measures showed benefit in quality of life (P < 0.04). Digit Span, verbal fluency, and Neuropsychiatric Inventory (NPI) showed non‐significant directional favoring of rasagiline; no effects were observed in Alzheimer's Disease Assessment Scale‐Cognitive Subscale (ADAS‐cog) or activities of daily living. Rasagiline was generally well tolerated with low rates of adverse events and notably fewer neuropsychiatric symptoms in the active treatment group. Discussion These outcomes illustrate the potential benefits of rasagiline on clinical and neuroimaging measures in patients with mild to moderate AD. Rasagiline appears to affect neuronal activity in frontostriatal pathways, with associated clinical benefit potential warranting a more fully powered trial. This study illustrated the potential benefit of therapeutic repurposing and an experimental medicine proof‐of‐concept design with biomarkers to characterize patient and detect treatment response.

INTRODUCTION The “A/T/N” (amyloid/tau/neurodegeneration) framework provides a biological basis for Alzheimer's disease (AD) diagnosis and can encompass additional changes such as inflammation (“I”). A spectrum of T/N/I imaging and plasma biomarkers was acquired in a phase 2 clinical trial of rasagiline in mild to moderate AD patients. We evaluated these to understand biomarker distributions and relationships within this population. METHODS Plasma biomarkers of pTau‐181, neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), other inflammation‐related proteins, imaging measures including fluorodeoxyglucose (FDG) positron emission tomography (PET), flortaucipir PET, and volumetric magnetic resonance imaging (MRI), and cognitive endpoints were analyzed to assess characteristics and relationships for the overall population (N = 47 at baseline and N = 21 for longitudinal cognitive comparisons) and within age‐decade subgroups (57‐69, 70‐79, 80‐90 years). RESULTS Data demonstrate wide clinical and biomarker heterogeneity in this population influenced by age and sex. Plasma pTau‐181 and GFAP correlate with tau PET, most strongly in left inferior temporal cortex (p = 0.0002, p = 0.0006, respectively). In regions beyond temporal cortex, tau PET uptake decreased with age for the same pTau‐181 or GFAP concentrations. FDG PET and brain volumes correlate with tau PET in numerous regions (such as inferior temporal: p = 0.0007, p = 0.00001, respectively). NfL, GFAP, and all imaging modalities correlate with baseline MMSE; subsequent MMSE decline is predicted by baseline parahippocampal and lateral temporal tau PET (p = 0.0007) and volume (p = 0.0006). Lateral temporal FDG PET (p = 0.006) and volume (p = 0.0001) are most strongly associated with subsequent ADAS‐cog decline. NfL correlates with FDG PET and baseline MMSE but not tau PET. Inflammation biomarkers are intercorrelated but correlated with other biomarkers in only the youngest group. DISCUSSION Associations between plasma biomarkers, imaging biomarkers, and cognitive status observed in this study provide insight into relationships among biological processes in mild to moderate AD. Findings show the potential to characterize AD patients regarding likely tau pathology, neurodegeneration, prospective clinical decline, and the importance of covariates such as age. Highlights Plasma pTau‐181 and GFAP correlated with regional and global tau PET in mild to moderate AD. NfL correlated with FDG PET and cognitive endpoints but not plasma pTau‐181 or tau PET. Volume and FDG PET showed strong relationships to tau PET, one another, and cognitive status. Temporal volumes most strongly predicted decline in both MMSE and ADAS‐cog. Volume and plasma biomarkers can enrich for elevated tau PET with age a significant covariate.

Piwi-interacting RNAs (piRNAs) are a recently discovered class of 24- to 30-nt noncoding RNAs whose best-understood function is to repress transposable elements (TEs) in animal germ lines. In humans, TE-derived sequences comprise ∼45% of the genome and there are several active TE families, including LINE-1 and Alu elements, which are a significant source of de novo mutations and intrapopulation variability. In the “ping-pong model,” piRNAs are thought to alternatively cleave sense and antisense TE transcripts in a positive feedback loop. Because piRNAs are poorly conserved between closely related species, including human and chimpanzee, we took a population genomics approach to study piRNA function and evolution. We found strong statistical evidence that piRNA sequences are under selective constraint in African populations. We then mapped the piRNA sequences to human TE sequences and found strong correlations between the age of each LINE-1 and Alu subfamily and the number of piRNAs mapping to the subfamily. This result supports the idea that piRNAs function as repressors of TEs in humans. Finally, we observed a significant depletion of piRNA matches in the reverse transcriptase region of the consensus human LINE-1 element but not of the consensus mouse LINE-1 element. This result suggests that reverse transcriptase might have an endogenous role specific to humans. Overall, our results elucidate the function and evolution of piRNAs in humans and highlight the utility of population genomics analysis for studying this rapidly evolving genetic system.

Introduction Allopregnanolone (ALLO), an endogenous neurosteroid, promoted neurogenesis and oligogenesis and restored cognitive function in animal models of Alzheimer's disease (AD). Based on these discovery research findings, we conducted a randomized‐controlled phase 1b/2a multiple ascending dose trial of ALLO in persons with early AD (NCT02221622) to assess safety, tolerability, and pharmacokinetics. Exploratory imaging outcomes to determine whether ALLO impacted hippocampal structure, white matter integrity, and functional connectivity are reported. Methods Twenty‐four individuals participated in the trial (n = 6 placebo; n = 18 ALLO) and underwent brain magnetic resonance imaging (MRI) before and after 12 weeks of treatment. Hippocampal atrophy rate was determined from volumetric MRI, computed as rate of change, and qualitatively assessed between ALLO and placebo sex, apolipoprotein E (APOE) ε4 allele, and ALLO dose subgroups. White matter microstructural integrity was compared between placebo and ALLO using fractional and quantitative anisotropy (QA). Changes in local, inter‐regional, and network‐level functional connectivity were also compared between groups using resting‐state functional MRI. Results Rate of decline in hippocampal volume was slowed, and in some cases reversed, in the ALLO group compared to placebo. Gain of hippocampal volume was evident in APOE ε4 carriers (range: 0.6% to 7.8% increased hippocampal volume). Multiple measures of white matter integrity indicated evidence of preserved or improved integrity. ALLO significantly increased fractional anisotropy (FA) in 690 of 690 and QA in 1416 of 1888 fiber tracts, located primarily in the corpus callosum, bilateral thalamic radiations, and bilateral corticospinal tracts. Consistent with structural changes, ALLO strengthened local, inter‐regional, and network level functional connectivity in AD‐vulnerable regions, including the precuneus and posterior cingulate, and network connections between the default mode network and limbic system. Discussion Indicators of regeneration from previous preclinical studies and these exploratory MRI‐based outcomes from this phase 1b/2a clinical cohort support advancement to a phase 2 proof‐of‐concept efficacy clinical trial of ALLO as a regenerative therapeutic for mild AD (REGEN‐BRAIN study; NCT04838301).

Semantic representations are processed along a posterior-to-anterior gradient reflecting a shift from perceptual (e.g., it has eight legs ) to conceptual (e.g., venomous spiders are rare ) information. One critical region is the anterior temporal lobe (ATL): patients with semantic variant primary progressive aphasia (svPPA), a clinical syndrome associated with ATL neurodegeneration, manifest a deep loss of semantic knowledge. We test the hypothesis that svPPA patients perform semantic tasks by over-recruiting areas implicated in perceptual processing. We compared MEG recordings of svPPA patients and healthy controls during a categorization task. While behavioral performance did not differ, svPPA patients showed indications of greater activation over bilateral occipital cortices and superior temporal gyrus, and inconsistent engagement of frontal regions. These findings suggest a pervasive reorganization of brain networks in response to ATL neurodegeneration: the loss of this critical hub leads to a dysregulated (semantic) control system, and defective semantic representations are seemingly compensated via enhanced perceptual processing.

Introduction Amyloid measurement provides important confirmation of pathology for Alzheimer's disease (AD) clinical trials. However, many amyloid positive (Am+) early‐stage subjects do not worsen clinically during a clinical trial, and a neurodegenerative measure predictive of decline could provide critical information. Studies have shown correspondence between perfusion measured by early amyloid frames post‐tracer injection and fluorodeoxyglucose (FDG) positron emission tomography (PET), but with limitations in sensitivity. Multivariate machine learning approaches may offer a more sensitive means for detection of disease related changes as we have demonstrated with FDG. Methods Using summed dynamic florbetapir image frames acquired during the first 6 minutes post‐injection for 107 Alzheimer's Disease Neuroimaging Initiative subjects, we applied optimized machine learning to develop and test image classifiers aimed at measuring AD progression. Early frame amyloid (EFA) classification was compared to that of an independently developed FDG PET AD progression classifier by scoring the FDG scans of the same subjects at the same time point. Score distributions and correlation with clinical endpoints were compared to those obtained from FDG. Region of interest measures were compared between EFA and FDG to further understand discrimination performance. Results The EFA classifier produced a primary pattern similar to that of the FDG classifier whose expression correlated highly with the FDG pattern (R‐squared 0.71), discriminated cognitively normal (NL) amyloid negative (Am–) subjects from all Am+ groups, and that correlated in Am+ subjects with Mini‐Mental State Examination, Clinical Dementia Rating Sum of Boxes, and Alzheimer's Disease Assessment Scale–13‐item Cognitive subscale (R = 0.59, 0.63, 0.73) and with subsequent 24‐month changes in these measures (R = 0.67, 0.73, 0.50). Discussion Our results support the ability to use EFA with a multivariate machine learning–derived classifier to obtain a sensitive measure of AD‐related loss in neuronal function that correlates with FDG PET in preclinical and early prodromal stages as well as in late mild cognitive impairment and dementia. Highlights The summed initial post‐injection minutes of florbetapir positron emission tomography  correlate with fluorodeoxyglucose. A machine learning classifier enabled sensitive detection of early prodromal Alzheimer's disease. Early frame amyloid (EFA) classifier scores correlate with subsequent change in Mini‐Mental State Examination, Clinical Dementia Rating Sum of Boxes, and Alzheimer's Disease Assessment Scale–13‐item Cognitive subscale. EFA classifier effect sizes and clinical prediction outperformed region of interest standardized uptake value ratio. EFA classification may aid in stratifying patients to assess treatment effect.

The future compact linear collider (CLIC) offers a possibility for a rich precision physics programme, in particular in the Higgs sector through the energy staging. This is the first paper addressing the measurement of the standard model Higgs boson decay into two muons at 1.4 TeV CLIC. With respect to similar studies at future linear colliders, this paper includes several novel contributions to the statistical uncertainty of the measurement. The latter includes the equivalent photon approximation employed to describe and interactions whenever the virtuality of the mediated photon is smaller than 4 GeV and realistic forward electron tagging based on energy deposition maps in the forward calorimeters, as well as several processes with the Beamstrahlung photons that results in irreducible contribution to the signal. In addition, coincidence of the Bhabha scattering with the signal and background processes is considered, altering the signal selection efficiency. The study is performed using a fully simulated CLIC_ILD detector model. It is shown that the branching ratio for the Higgs decay into a pair of muons BR( ) times the Higgs production cross-section in WW-fusion can be measured with 38 % statistical accuracy at , assuming an integrated luminosity of 1.5 ab [Formula omitted] with unpolarised beams. If 80 % electron beam polarisation is considered, the statistical uncertainty of the measurement is reduced to 25 %. Systematic uncertainties are negligible in comparison to the statistical uncertainty.

A prototype of a luminometer, designed for a future e+e- collider detector, and consisting at present of a four-plane module, was tested in the CERN PS accelerator T9 beam. The objective of this beam test was to demonstrate a multi-plane tungsten/silicon operation, to study the development of the electromagnetic shower and to compare it with MC simulations. The Molière radius has been determined to be 24.0 ± 0.6 (stat.) ± 1.5 (syst.) mm using a parametrization of the shower shape. Very good agreement was found between data and a detailed Geant4 simulation.