Miracle-dz/UniFAR-FTUs huggingface dataset:
Recent advances in the histo‐molecular pathology of human prion disease

Prion diseases are progressive neurodegenerative disorders affecting humans and other mammalian species. The term prion, originally put forward to propose the concept that a protein could be infectious, refers to PrPSc, a misfolded isoform of the cellular prion protein (PrPC) that represents the pathogenetic hallmark of these disorders. The discovery that other proteins characterized by misfolding and seeded aggregation can spread from cell to cell, similarly to PrPSc, has increased interest in prion diseases. Among neurodegenerative disorders, however, prion diseases distinguish themselves for the broader phenotypic spectrum, the fastest disease progression and the existence of infectious forms that can be transmitted through the exposure to diseased tissues via ingestion, injection or transplantation. The main clinicopathological phenotypes of human prion disease include Creutzfeldt–Jakob disease, by far the most common, fatal insomnia, variably protease‐sensitive prionopathy, and Gerstmann–Sträussler–Scheinker disease. However, clinicopathological manifestations extend even beyond those predicted by this classification. Because of their transmissibility, the phenotypic diversity of prion diseases can also be propagated into syngenic hosts as prion strains with distinct characteristics, such as incubation period, pattern of PrPSc distribution and regional severity of histopathological changes in the brain. Increasing evidence indicates that different PrPSc conformers, forming distinct ordered aggregates, encipher the phenotypic variants related to prion strains. In this review, we summarize the most recent advances concerning the histo‐molecular pathology of human prion disease focusing on the phenotypic spectrum of the disease including co‐pathologies, the characterization of prion strains by experimental transmission and their correlation with the physicochemical properties of PrPSc aggregates.
Cutting Edge: HDAC3 Protects Double-Positive Thymocytes from P2X7 Receptor–Induced Cell Death

Intricate life-versus-death decisions are programmed during T cell development, and the regulatory mechanisms that coordinate their activation and repression are still under investigation. In this study, HDAC3-deficient double-positive (DP) thymocytes exhibit a severe decrease in numbers. The thymic cortex is rich in ATP, which is released by macrophages that clear apoptotic DP thymocytes that fail to undergo positive selection. We demonstrate that HDAC3 is required to repress expression of the purinergic receptor P2X7 to prevent DP cell death. HDAC3-deficient DP thymocytes upregulate the P2X7 receptor, increasing sensitivity to ATP-induced cell death. P2rx7/HDAC3-double knockout mice show a partial rescue in DP cell number. HDAC3 directly binds to the P2rx7 enhancer, which is hyperacetylated in the absence of HDAC3. In addition, RORγt binds to the P2rx7 enhancer and promotes P2X7 receptor expression in the absence of HDAC3. Therefore, HDAC3 is a critical regulator of DP thymocyte survival and is required to suppress P2X7 receptor expression.
Circ_Lrp6, a Circular RNA Enriched in Vascular Smooth Muscle Cells, Acts as a Sponge Regulating miRNA-145 Function

Rationale: microRNAs (miRNAs) modulate gene expression by repressing translation of targeted genes. Previous work has established a role for miRNAs in regulating vascular smooth muscle cell (VSMC) activity. Whether circular RNAs are involved in the modulation of miRNA activity in VSMCs is unknown. Objective: We aimed to identify circular RNAs interacting with miRNAs enriched in VSMCs and modulating the cells’ activity. Methods and Results: RNA sequencing and bioinformatics identified several circular RNAs enriched in VSMCs; however, only one, possessing multiple putative binding sites for miR-145, was highly conserved between mouse and man. This circular RNA gemmed from alternative splicing of Lrp6 (lipoprotein receptor 6), a gene highly expressed in vessels and implicated in vascular pathologies and was thus named circ_Lrp6. Its role as a miR-145 sponge was confirmed by determining reciprocal interaction through RNA immunoprecipitation, stimulated emission depletion microscopy, and competitive luciferase assays; functional inhibition of miR-145 was assessed by measuring expression of the target genes ITG&bgr;8 (integrin-&bgr;8), FASCIN (fascin actin-bundling protein 1), KLF4 (Kruppel-like factor 4), Yes1 (YES proto-oncogene 1), and Lox (lysyl oxidase). The interaction was preferentially localized to P-bodies, sites of mRNA degradation. Using loss- and gain-of-function approaches, we found that circ_Lrp6 hindered miR-145-mediated regulation of VSMC migration, proliferation, and differentiation. Differential expression of miR-145 and circ_Lrp6 in murine and human vascular diseases suggests that the ratio of circ_Lrp6 bound to miR-145 versus unbound could play a role in vascular pathogenesis. Viral delivery of circ_Lrp6 shRNA prevented intimal hyperplasia in mouse carotids. Conclusions: circ_Lrp6 is an intracellular modulator and a natural sponge for miR-145, counterbalancing the functions of the miRNA in VSMCs.
Computational Modeling of Realistic Cell Membranes

Cell membranes contain a large variety of lipid types and are crowded with proteins, endowing them with the plasticity needed to fulfill their key roles in cell functioning. The compositional complexity of cellular membranes gives rise to a heterogeneous lateral organization, which is still poorly understood. Computational models, in particular molecular dynamics simulations and related techniques, have provided important insight into the organizational principles of cell membranes over the past decades. Now, we are witnessing a transition from simulations of simpler membrane models to multicomponent systems, culminating in realistic models of an increasing variety of cell types and organelles. Here, we review the state of the art in the field of realistic membrane simulations and discuss the current limitations and challenges ahead.
Persistence of Fusarium oxysporum f. sp. fragariae in soil through asymptomatic colonization of rotation crops

Asymptomatic plant colonization is hypothesized to enhance persistence of pathogenic forms of Fusarium oxysporum in the absence of a susceptible host. However, a correlation between pathogen populations on living plant tissues and soilborne populations after tillage has not been demonstrated. Living and dead tissues of broccoli, lettuce, spinach, wheat, cilantro, raspberry, and strawberry plants inoculated with Fusarium oxysporum f. sp. fragariae (the cause of Fusarium wilt of strawberry) were assayed to quantify the incidence of infection and extent of colonization by this pathogen. All crops could be infected by F. oxysporum f. sp. fragariae, but the extent of colonization varied between plant species. Pathogen population densities on non-living crown tissues incorporated into the soil matrix were typically greater than those observed on living tissues. Crop-dependent differences in the inoculum density of F. oxysporum f. sp. fragariae in soil were only observed after decomposition of crop residue. Forty-four weeks after plants were incorporated into the soil, F. oxysporum f. sp. fragariae soil population densities were positively correlated with population densities on plant tissue fragments recovered at the same timepoint. Results indicate that asymptomatic colonization can have a significant, long-term impact on soilborne populations of Fusarium wilt pathogens. Cultural practices, such as crop rotation, should be leveraged to favor pathogen population decline by planting hosts that do not support extensive population growth on living or decomposing tissues.
Perceptually Validated Cross-Renderer Analytical BRDF Parameter Remapping

Material appearance of rendered objects depends on the underlying BRDF implementation used by rendering software packages. A lack of standards to exchange material parameters and data (between tools) means that artists in digital 3D prototyping and design, manually match the appearance of materials to a reference image. Since their effect on rendered output is often non-uniform and counter intuitive, selecting appropriate parameterisations for BRDF models is far from straightforward. We present a novel BRDF remapping technique, that automatically computes a mapping (BRDF Difference Probe) to match the appearance of a source material model to a target one. Through quantitative analysis, four user studies and psychometric scaling experiments, we validate our remapping framework and demonstrate that it yields a visually faithful remapping among analytical BRDFs. Most notably, our results show that even when the characteristics of the models are substantially different, such as in the case of a phenomenological model and a physically-based one, our remapped renderings are indistinguishable from the original source model.
Editorial Comment.

The authors evaluated the effect of 5-ARI administration after PCa diagnosis in the multicenter PASS. They found no difference in pathological disease upgrading at surveillance biopsy between the 107 and 902 men who did and did not use 5ARIs, respectively, during a median of 3.6 years of followup. On a limited secondary analysis in only 9 men who received 5-ARIs and went on to radical prostatectomy the investigators found no difference in the rate of adverse pathology between the groups. The biological relationship between 5-ARI use and PCa is poorly understood. Two major randomized trials have evaluated the influence of 5ARI use on PCa diagnosis, demonstrating a reduction in the incidence of low risk cancer and a slight increase in high grade cancer detection (references 1 and 2 in article). However, the latter finding is likely to have been an artifact of increased biopsy sensitivity due to smaller prostate volume. Long-term registration trials have confirmed that there is no excess prostate cancer mortality in men who receive 5-ARIs. The current study showed no difference in disease reclassification, while in the REDEEM trial a randomized comparison of dutasteride to placebo in 302 men on AS demonstrated a reduction in PCa progression (HR 0.62, p <0.01) (reference 9 in article). Ultimately additional studies with longer followup will be required to clarify the effect of 5-ARIs on disease progression in the AS population. For now 5-ARIs administered during AS appear warranted in men with lower urinary tract symptoms due to BPH. Patients should be educated about the limited long-term data on PCa progression.
CPR-Content 15-1

DOI: 10.2174/1573396315666190118101953 Abstract: Neonates represent a vulnerable population for infections and neonatal sepsis is a major cause of mortality and morbidity worldwide. Therefore, antimicrobials are the most commonly prescribed drugs in the Neonatal Intensive Care Unit Setting but unfortunately are quite often used inappropriately with various short and long-term effects. The rational use of antimicrobials is of paramount importance in this population and structured antimicrobial stewardship interventions should be in place. These interventions are slightly different from those used in adults and older children due to the particularities of the neonatal medicine. The aim of this review is to provide an update in the field and identify areas for further consideration and future research.
Central adiposity in relation to risk of liver cancer in Chinese adults: A prospective study of 0.5 million people

Central adiposity is associated with liver cancer risk beyond general adiposity in Western populations. However, there is little prospective evidence in East Asian populations who are more likely to have central adiposity at given BMI levels. The prospective China Kadoorie Biobank recruited 512,713 adults aged 30–79 years from 10 diverse areas. During 10 years follow‐up, 2,847 incident cases of liver cancer were identified. Cox regression was used to estimate adjusted hazard ratios (HR) for liver cancer associated with central adiposity, excluding individuals with cancers and liver diseases at baseline and the first 5 years of follow‐up (1,049 incident liver cancer cases). Overall, mean waist circumference (WC) was 82.2 (SD 9.8) cm in men and 79.1 (9.5) cm in women. Central adiposity showed positive associations with liver cancer risk. Associations were strongest for WC and waist‐to‐hip ratio (WHR), with adjusted HRs per 1‐SD of 1.09 (95%CI 1.01–1.18) and 1.12 (1.02–1.23), respectively. The positive associations became stronger when additionally adjusting for BMI (1.26 [1.09–1.46] and 1.14 [1.02–1.28]). The positive association of central obesity (WC ≥90 cm in men and ≥ 80 cm in women) with liver cancer increased progressively with the number of other presenting metabolic risk factors (physical inactivity, diabetes, and hypertension), with HRs of 1.07 (0.90–1.28), 1.17 (1.00–1.38), and 1.91 (1.40–2.59) in those with one, two, and three factors (p for trend 0.006). In this relatively lean Chinese population, there were positive associations of central adiposity with risk of liver cancer, with WHR and WC showing the strongest associations.
Allele frequency dynamics in a pedigreed natural population

Significance Evolution is change in the genetic composition of populations. In nature, individuals reproduce, die, and move among populations, leading to changes in the population frequency of the alleles they carry. Here we study an extensive family tree (pedigree) for an exhaustively sampled natural population of Florida Scrub-Jays to directly characterize the mechanisms underlying how genetic material is transmitted to future generations. We link individual fitness with long-term genetic contributions and quantify the relative roles of evolutionary processes governing allele frequency change. This study clearly illustrates how short-term evolutionary change occurs within a natural population. A central goal of population genetics is to understand how genetic drift, natural selection, and gene flow shape allele frequencies through time. However, the actual processes underlying these changes—variation in individual survival, reproductive success, and movement—are often difficult to quantify. Fully understanding these processes requires the population pedigree, the set of relationships among all individuals in the population through time. Here, we use extensive pedigree and genomic information from a long-studied natural population of Florida Scrub-Jays (Aphelocoma coerulescens) to directly characterize the relative roles of different evolutionary processes in shaping patterns of genetic variation through time. We performed gene dropping simulations to estimate individual genetic contributions to the population and model drift on the known pedigree. We found that observed allele frequency changes are generally well predicted by accounting for the different genetic contributions of founders. Our results show that the genetic contribution of recent immigrants is substantial, with some large allele frequency shifts that otherwise may have been attributed to selection actually due to gene flow. We identified a few SNPs under directional short-term selection after appropriately accounting for gene flow. Using models that account for changes in population size, we partitioned the proportion of variance in allele frequency change through time. Observed allele frequency changes are primarily due to variation in survival and reproductive success, with gene flow making a smaller contribution. This study provides one of the most complete descriptions of short-term evolutionary change in allele frequencies in a natural population to date.
Superficial Layers Suppress the Deep Layers to Fine-tune Cortical Coding

The descending microcircuit from layer 2/3 (L2/3) to layer 5 (L5) is one of the strongest excitatory pathways in the cortex, presumably forming a core component of its feedforward hierarchy. To date, however, no experiments have selectively tested the impact of L2/3 activity on L5 during active sensation. We used optogenetic, cell-type-specific manipulation of L2/3 neurons in the barrel cortex of actively sensing mice (of either sex) to elucidate the significance of this pathway to sensory coding in L5. Contrary to standard models, activating L2/3 predominantly suppressed spontaneous activity in L5, whereas deactivating L2/3 mainly facilitated touch responses in L5. Somatostatin interneurons are likely important to this suppression because their optogenetic deactivation significantly altered the functional impact of L2/3 onto L5. The net effect of L2/3 was to enhance the stimulus selectivity and expand the range of L5 output. These data imply that the core cortical pathway increases the selectivity and expands the range of cortical output through feedforward inhibition. SIGNIFICANCE STATEMENT The primary sensory cortex contains six distinct layers that interact to form the basis of our perception. While rudimentary patterns of connectivity between the layers have been outlined quite extensively in vitro, functional relationships in vivo, particularly during active sensation, remain poorly understood. We used cell-type-specific optogenetics to test the functional relationship between layer 2/3 and layer 5. Surprisingly, we discovered that L2/3 primarily suppresses cortical output from L5. The recruitment of somatostatin-positive interneurons is likely fundamental to this relationship. The net effect of this translaminar suppression is to enhance the selectivity and expand the range of receptive fields, therefore potentially sharpening the perception of space.
Atypical Cowpox Virus Infection in Smallpox-Vaccinated Patient, France

We report a case of atypical cowpox virus infection in France in 2016. The patient sought care for thoracic lesions after injury from the sharp end of a metallic guardrail previously stored in the ground. We isolated a cowpox virus from the lesions and sequenced its whole genome. The patient reported that he had been previously vaccinated against smallpox. We describe an alternative route of cowpox virus infection and raise questions about the immunological status of smallpox-vaccinated patients for circulating orthopoxviruses.
Relationship of Ganciclovir Therapeutic Drug Monitoring with Clinical Efficacy and Patient Safety

The clinical utility of ganciclovir therapeutic drug monitoring (TDM) is unknown. We retrospectively analyzed adult patients treated for cytomegalovirus (CMV) infection with ganciclovir with TDM between 2005 and 2015. ABSTRACT The clinical utility of ganciclovir therapeutic drug monitoring (TDM) is unknown. We retrospectively analyzed adult patients treated for cytomegalovirus (CMV) infection with ganciclovir with TDM between 2005 and 2015. The primary outcome was an association between ganciclovir TDM and clinical efficacy endpoints within 30 days, defined by viral load and symptomatology. Secondary outcomes included safety endpoints, evaluated within 7 days of the last administered dose of ganciclovir. Of 175 patients evaluated, 82 patients with CMV infection were included in our analysis with a median (interquartile range) baseline CMV viral load of 5,500 (3,000 to 15,200) copies/ml. The majority achieved undetectable or reduced CMV viral load below the lower limit of quantification (74.4%) with improvement in symptomatology (70.7%) at 30 days. Among patients with detectable CMV viremia at 30 days, the viral load had declined to a median of 1,000 (1,000 to 3,090) copies/ml. We did not observe significant associations between the efficacy outcomes and ganciclovir trough (P = 0.20 and P = 0.20, respectively) or peak concentrations (P = 0.14 and P = 0.14, respectively). Similarly, there was no significant association between ganciclovir trough or peak concentrations and safety endpoints, including leukopenia (P = 0.48 and P = 0.69), neutropenia (P = 0.59 and P = 0.69), thrombocytopenia (P = 0.29 and P = 0.37), anemia (P = 0.51 and P = 0.35), nephrotoxicity (P = 0.41 and P = 0.57), and neurotoxicity (P = 0.22 and P = 0.48). We did not observe any associations between ganciclovir TDM and clinical efficacy or safety endpoints. Routine ganciclovir TDM may be of limited value. Future studies may be warranted to identify specific populations with unpredictable pharmacokinetic and pharmacodynamics profiles in whom ganciclovir TDM may be of benefit.
Current limitations of neuropsychological tests and assessment procedures

Abstract Objective: Neuropsychological tests are used for a wide variety of purposes: assessing basic cognitive abilities or disabilities; determining cognitive patterns associated with brain disorders or injury; exploring brain-behavior relationships; and, in some cases, addressing psycho-legal issues. This paper will focus on the limitations of current neuropsychological tests for these purposes. Method: Current limits of neuropsychological tests and assessment procedures are reviewed and recommendations for improvements are made. The relationship between the conceptual basis of neuropsychological tests and modern theories of brain functional organization is discussed. In addition, psycho-legal concerns are briefly outlined. Conclusions: Existing tests and techniques can be improved. Normative data for some neuropsychological tests are based on small samples or have limited validity or reliability data. A variety of neuropsychological tests are available but particular cognitive domains are underrepresented, particularly those involving high-level cognitive skills and social skills. Progress is being made in the availability of tests in multiple languages, but the restricted range of languages and cultural influences demands more attention. Standard test procedures often deviate from real-world activities. In this modern age, some tests have become too familiar because of the Internet. Understanding of complex neural networks activated by cognitive tasks is only beginning to be appreciated. Procedures for determining psycho-legal issues need improvements in some areas.
Regulated Assembly of LPS, Its Structural Alterations and Cellular Response to LPS Defects

Distinguishing feature of the outer membrane (OM) of Gram-negative bacteria is its asymmetry due to the presence of lipopolysaccharide (LPS) in the outer leaflet of the OM and phospholipids in the inner leaflet. Recent studies have revealed the existence of regulatory controls that ensure a balanced biosynthesis of LPS and phospholipids, both of which are essential for bacterial viability. LPS provides the essential permeability barrier function and act as a major virulence determinant. In Escherichia coli, more than 100 genes are required for LPS synthesis, its assembly at inner leaflet of the inner membrane (IM), extraction from the IM, translocation to the OM, and in its structural alterations in response to various environmental and stress signals. Although LPS are highly heterogeneous, they share common structural elements defining their most conserved hydrophobic lipid A part to which a core polysaccharide is attached, which is further extended in smooth bacteria by O-antigen. Defects or any imbalance in LPS biosynthesis cause major cellular defects, which elicit envelope responsive signal transduction controlled by RpoE sigma factor and two-component systems (TCS). RpoE regulon members and specific TCSs, including their non-coding arm, regulate incorporation of non-stoichiometric modifications of LPS, contributing to LPS heterogeneity and impacting antibiotic resistance.