Miracle-dz/UniFAR-FTUs huggingface dataset:
Relationship between Measures of HIV Reactivation and Decline of the Latent Reservoir under Latency-Reversing Agents

ABSTRACT Antiretroviral-free HIV remission requires substantial reduction of the number of latently infected cells and enhanced immune control of viremia. Latency-reversing agents (LRAs) aim to eliminate latently infected cells by increasing the rate of reactivation of HIV transcription, which exposes these cells to killing by the immune system. As LRAs are explored in clinical trials, it becomes increasingly important to assess the effect of an increased HIV reactivation rate on the decline of latently infected cells and to estimate LRA efficacy in increasing virus reactivation. However, whether the extent of HIV reactivation is a good predictor of the rate of decline of the number of latently infected cells is dependent on a number of factors. Our modeling shows that the mechanisms of maintenance and clearance of the reservoir, the life span of cells with reactivated HIV, and other factors may significantly impact the relationship between measures of HIV reactivation and the decline in the number of latently infected cells. The usual measures of HIV reactivation are the increase in cell-associated HIV RNA (CA RNA) and/or plasma HIV RNA soon after administration. We analyze two recent studies where CA RNA was used to estimate the impact of two novel LRAs, panobinostat and romidepsin. Both drugs increased the CA RNA level 3- to 4-fold in clinical trials. However, cells with panobinostat-reactivated HIV appeared long-lived (half-life > 1 month), suggesting that the HIV reactivation rate increased by approximately 8%. With romidepsin, the life span of cells that reactivated HIV was short (2 days), suggesting that the HIV reactivation rate may have doubled under treatment. IMPORTANCE Long-lived latently infected cells that persist on antiretroviral treatment (ART) are thought to be the source of viral rebound soon after ART interruption. The elimination of latently infected cells is an important step in achieving antiretroviral-free HIV remission. Latency-reversing agents (LRAs) aim to activate HIV expression in latently infected cells, which could lead to their death. Here, we discuss the possible impact of the LRAs on the reduction of the number of latently infected cells, depending on the mechanisms of their loss and self-renewal and on the life span of the cells that have HIV transcription activated by the LRAs.
Depth enhancement with improved exemplar-based inpainting and joint trilateral guided filtering

Heavy noises and large amounts of holes exist in depth images captured by sensors, such as Kinect, which would severely hinder the application of depth information. In this paper, a novel depth enhancement algorithm with improved exemplar-based inpainting and joint trilateral guided filtering is proposed. The improved examplar-based inpainting method is applied to fill the holes in the depth images, in which the level set distance component is introduced in the priority evaluation function. Then a joint trilateral guided filter is adopted to denoise and smooth the inpainted results. Experimental results reveal that the proposed algorithm can achieve better enhancement results compared with the existing methods in terms of subjective and objective quality measurements.
BK Polyomavirus: Clinical Aspects, Immune Regulation, and Emerging Therapies

SUMMARY BK polyomavirus (BKV) causes frequent infections during childhood and establishes persistent infections within renal tubular cells and the uroepithelium, with minimal clinical implications. However, reactivation of BKV in immunocompromised individuals following renal or hematopoietic stem cell transplantation may cause serious complications, including BKV-associated nephropathy (BKVAN), ureteric stenosis, or hemorrhagic cystitis. Implementation of more potent immunosuppression and increased posttransplant surveillance has resulted in a higher incidence of BKVAN. Antiviral immunity plays a crucial role in controlling BKV replication, and our increasing knowledge about host-virus interactions has led to the development of improved diagnostic tools and clinical management strategies. Currently, there are no effective antiviral agents for BKV infection, and the mainstay of managing reactivation is reduction of immunosuppression. Development of immune-based therapies to combat BKV may provide new and exciting opportunities for the successful treatment of BKV-associated complications.
BMP7 Induces Uterine Receptivity and Blastocyst Attachment

In women, the window of implantation is limited to a brief 2- to 3-day period characterized by optimal levels of circulating ovarian hormones and a receptive endometrium. Although the window of implantation is assumed to occur 8 to 10 days after ovulation in women, molecular markers of endometrial receptivity are necessary to determine optimal timing prior to embryo transfer. Previous studies showed that members of the bone morphogenetic protein (BMP) family are expressed in the uterus necessary for female fertility; however, the role of BMP7 during implantation and in late gestation is not known. To determine the contribution of BMP7 to female fertility, we generated Bmp7flox/flox-Pgr-cre+/- [BMP7 conditional knockout (cKO)] mice. We found that absence of BMP7 in the female reproductive tract resulted in subfertility due to uterine defects. At the time of implantation, BMP7 cKO females displayed a nonreceptive endometrium with elevated estrogen-dependent signaling. These implantation-related defects also affected decidualization and resulted in decreased expression of decidual cell markers such as Wnt4, Cox2, Ereg, and Bmp2. We also observed placental abnormalities in pregnant Bmp7 cKO mice, including excessive parietal trophoblast giant cells and absence of a mature placenta at 10.5 days post coitum. To establish possible redundant roles of BMP5 and BMP7 during pregnancy, we generated double BMP5 knockout/BMP7 cKO [BMP5/7 double knockout (DKO)] mice; however, we found that the combined deletion had no additive disruptive effect on fertility. Our studies indicate that BMP7 is an important factor during the process of implantation that contributes to healthy embryonic development.
Repeat E anchors Xist RNA to the inactive X chromosomal compartment through CDKN1A-interacting protein (CIZ1)

Significance The long noncoding Xist RNA coats and silences one X chromosome in female cells. How Xist localizes in cis to the inactive X compartment is not clear. Here, we reveal a required interaction between CIZ1 protein and Xist Repeat E motifs. Stochastic optical reconstruction microscopy (STORM) shows a tight association of CIZ1 with Xist RNA at the single-molecule level. Deletion of either CIZ1 or Repeat E causes dispersal of Xist RNA throughout the nucleoplasm, as well as loss of the heterochromatin mark H3K27me3 from the inactive X chromosome. We have thus identified a critical factor for stable association of Xist RNA with the inactive X chromosome. X chromosome inactivation is an epigenetic dosage compensation mechanism in female mammals driven by the long noncoding RNA, Xist. Although recent genomic and proteomic approaches have provided a more global view of Xist’s function, how Xist RNA localizes to the inactive X chromosome (Xi) and spreads in cis remains unclear. Here, we report that the CDKN1-interacting zinc finger protein CIZ1 is critical for localization of Xist RNA to the Xi chromosome territory. Stochastic optical reconstruction microscopy (STORM) shows a tight association of CIZ1 with Xist RNA at the single-molecule level. CIZ1 interacts with a specific region within Xist exon 7–namely, the highly repetitive Repeat E motif. Using genetic analysis, we show that loss of CIZ1 or deletion of Repeat E in female cells phenocopies one another in causing Xist RNA to delocalize from the Xi and disperse into the nucleoplasm. Interestingly, this interaction is exquisitely sensitive to CIZ1 levels, as overexpression of CIZ1 likewise results in Xist delocalization. As a consequence, this delocalization is accompanied by a decrease in H3K27me3 on the Xi. Our data reveal that CIZ1 plays a major role in ensuring stable association of Xist RNA within the Xi territory.
Programming microphysiological systems for children’s health protection

Microphysiological systems (MPS) and computer simulation models that recapitulate the underlying biology and toxicology of critical developmental transitions are emerging tools for developmental effects assessment of drugs/chemicals. Opportunities and challenges exist for their application to alternative, more public health relevant and efficient chemical toxicity testing methods. This is especially pertinent to children’s health research and the evaluation of complex embryological and reproductive impacts of drug/chemical exposure. Scaling these technologies to higher throughput is a key challenge and drives the need for in silico models for quantitative prediction of developmental toxicity to inform safety assessments. One example is cellular agent-based models, constructed from extant embryology, that produce data useful to simulate critical developmental transitions and thereby predict phenotypic consequences of disruption in silico. Biologically inspired MPS models built from human induced pluripotent stem (iPS)-derived cells and synthetic matrices that recapitulate organ-specific physiologies and native tissue architectures are providing exciting new research opportunities to advance the assessment of developmental toxicity and offer the possibility of deriving a full ‘human on a chip’ system, or a ‘Homunculus. ’ Impact statement This ‘commentary’ summarizes research needs and opportunities for engineered MPS models for developmental and reproductive toxicity testing. Emerging concepts can be taken forward to a virtual tissue modeling framework for assessing chemical (and non-chemical) stressors on human development. These models will advance children’s health research, both basic and translational and new ways to evaluate complex embryological and reproductive impacts of drug and chemical exposures to inform safety assessments.
Random measurement error: Why worry? An example of cardiovascular risk factors

With the increased use of data not originally recorded for research, such as routine care data (or ‘big data’), measurement error is bound to become an increasingly relevant problem in medical research. A common view among medical researchers on the influence of random measurement error (i.e. classical measurement error) is that its presence leads to some degree of systematic underestimation of studied exposure-outcome relations (i.e. attenuation of the effect estimate). For the common situation where the analysis involves at least one exposure and one confounder, we demonstrate that the direction of effect of random measurement error on the estimated exposure-outcome relations can be difficult to anticipate. Using three example studies on cardiovascular risk factors, we illustrate that random measurement error in the exposure and/or confounder can lead to underestimation as well as overestimation of exposure-outcome relations. We therefore advise medical researchers to refrain from making claims about the direction of effect of measurement error in their manuscripts, unless the appropriate inferential tools are used to study or alleviate the impact of measurement error from the analysis.
Optimization of intra‐voxel incoherent motion measurement in diffusion‐weighted imaging of breast cancer

Purpose The purpose of this study was to optimize intra‐voxel incoherent motion (IVIM) measurement in diffusion‐weighted imaging (DWI) of breast cancer by separating perfusion and diffusion effects through the determination of an optimal threshold b‐value, thus benign and cancerous breast tissues can be accurately differentiated using IVIM‐derived diffusion and perfusion parameters. Materials and Methods Twenty‐eight patients, with biopsy‐confirmed breast cancers, were studied with a 3T MRI scanner, using T1‐weighted dynamic contrast‐enhanced MRI images, and diffusion‐weighted images with nine b‐values, ranging from 0 to 1000 s/mm2. IVIM‐derived parameter maps for tissue diffusion coefficients D, perfusion fraction f, and pseudo‐diffusion coefficients D* were computed using the segmented fitting method with optimized threshold b‐value, and the sum of squared residuals (SSR) were calculated for IVIM‐derived parameters in different breast lesions. Results The IVIM analysis method developed in this work can separate perfusion and diffusion effects with the optimal threshold b‐value of 300 s/mm2, and the results of diffusion and perfusion parameters from IVIM analysis can be used to differentiate pathological changes in breast tissues. It was found that the averages and standard deviations of the diffusion and perfusion parameters, D, f, D*, are the following, for malignant, benign and normal breast tissues respectively: D (0.813 ± 0.225 × 10−3 mm2/s, 1.437 ± 0.538 × 10−3 mm2/s, 1.838 ± 0.213 × 10−3 mm2/s), f (10.73 ± 3.44%, 7.86 ± 3.70%, 8.92 ± 3.72%), D* (15.23 ± 12.17×10−3 mm2/s, 12.02 ± 3.19 × 10−3 mm2/s, 12.03 ± 7.21 × 10−3 mm2/s). Conclusion IVIM‐derived diffusion and perfusion parameter maps depend highly on the choice of threshold b‐value. Using the methodology developed in this work, and with the optimized threshold b‐value, the diffusion and perfusion parameters of breast tissues can be accurately assessed, making IVIM MRI a technique of choice for differential diagnosis of breast cancer.
Loss of BRCA1 in the Cells of Origin of Ovarian Cancer Induces Glycolysis: A Window of Opportunity for Ovarian Cancer Chemoprevention

Mutations in the breast cancer susceptibility gene 1 (BRCA1) are associated with an increased risk of developing epithelial ovarian cancer. However, beyond the role of BRCA1 in DNA repair, little is known about other mechanisms by which BRCA1 impairment promotes carcinogenesis. Given that altered metabolism is now recognized as important in the initiation and progression of cancer, we asked whether the loss of BRCA1 changes metabolism in the cells of origin of ovarian cancer. The findings show that silencing BRCA1 in ovarian surface epithelial and fallopian tube cells increased glycolysis. Furthermore, when these cells were transfected with plasmids carrying deleterious BRCA1 mutations (5382insC or the P1749R), there was an increase in hexokinase-2 (HK2), a key glycolytic enzyme. This effect was mediated by MYC and the STAT3. To target the metabolic phenotype induced by loss of BRCA1, a drug-repurposing approach was used and aspirin was identified as an agent that counteracted the increase in HK2 and the increase in glycolysis induced by BRCA1 impairment. Evidence from this study indicates that the tumor suppressor functions of BRCA1 extend beyond DNA repair to include metabolic endpoints and identifies aspirin as an ovarian cancer chemopreventive agent capable of reversing the metabolic derangements caused by loss of BRCA1. Cancer Prev Res; 10(4); 255–66. ©2017 AACR.
Survival, Persistence, and Isolation of the Emerging Multidrug-Resistant Pathogenic Yeast Candida auris on a Plastic Health Care Surface

ABSTRACT The emerging multidrug-resistant pathogenic yeast Candida auris represents a serious threat to global health. Unlike most other Candida species, this organism appears to be commonly transmitted within health care facilities and causes health care-associated outbreaks. To better understand the epidemiology of this emerging pathogen, we investigated the ability of C. auris to persist on plastic surfaces common in health care settings compared with that of Candida parapsilosis, a species known to colonize the skin and plastics. Specifically, we compiled comparative and quantitative data essential to understanding the vehicles of spread and the ability of both species to survive and persist on plastic surfaces under controlled conditions (25°C and 57% relative humidity), such as those found in health care settings. When a test suspension of 104 cells was applied and dried on plastic surfaces, C. auris remained viable for at least 14 days and C. parapsilosis for at least 28 days, as measured by CFU. However, survival measured by esterase activity was higher for C. auris than C. parapsilosis throughout the 28-day study. Given the notable length of time Candida species survive and persist outside their host, we developed methods to more effectively culture C. auris from patients and their environment. Using our enrichment protocol, public health laboratories and researchers can now readily isolate C. auris from complex microbial communities (such as patient skin, nasopharynx, and stool) as well as environmental biofilms, in order to better understand and prevent C. auris colonization and transmission.
A CONCEPT PROOF OF POTENTIAL OF EXPERIMENTAL DRIED MUCILAGE ISOLATED FROM THE SEEDS OF OCIMUM BASILICUM AS A DISINTEGRANT Research Article

In an attempt to avoid complexities associated with development of synthetic and semi synthetic excipients, comparatively less explored area of herbal products was tried. The present investigation was undertaken with a view to develop fast disintegrating tablet of Paracetamol using dried mucilage (DM) prepared by drying the mucilage isolated from the seeds of Ocimum basilicum as novel disintegrating agent. Selection of dried mucilage as a novel excipients can be justified because of its desired functionality. The fast disintegrating tablets of paracetamol were prepared by adopting conventional wet granulation technology. The tablets were evaluated for characteristics such as weight variation, crushing strength, disintegration time and dissolution rate and compared with characteristics of fast disintegrating tablets of paracetamol prepared by using established disintegrants crosscarmellose sodium, crosspovidone and sodium starch glycolate. Fast disintegrating formulations prepared by using established disintegrants and dried mucilage as novel disintegrating agent exhibited fast disintegration of tablets followed by dissolution of the active (paracetamol). There was no sign of interaction between the dried mucilage and paracetamol as revealed in results of preliminary interaction studies. The statistical analysis of experimental data of disintegration studies suggested that Paracetamol tablets prepared by using dried mucilage as disintegrating agent resulted in rapid disintegration of the tablet comparable to established disintegrants.
The Role of CXCR3 in Neurological Diseases

Background: Neurological diseases have become an obvious challenge due to insufficient therapeutic intervention. Therefore, novel drugs for various neurological disorders are in desperate need. Recently, compelling evidence has demon-strated that chemokine receptor CXCR3, which is a G protein-coupled receptor in the CXC chemokine receptor family, may play a pivotal role in the development of neurological diseases. The aim of this review is to provide evidence for the potential of CXCR3 as a therapeutic target for neurological diseases. Methods: English journal articles that focused on the invovlement of CXCR3 in neurological diseases were searched via PubMed up to May 2017. Moreover, reference lists from identified articles were included for overviews. Results: The expression level of CXCR3 in T cells was significantly elevated in several neurological diseases, including multiple sclerosis (MS), glioma, Alzheimer’s disease (AD), chronic pain, human T-lymphotropic virus type 1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and bipolar disorder. CXCR3 antagonists showed therapeutic effects in these neurological diseases. Conclusion: These studies provided hard evidence that CXCR3 plays a vital role in the pathogenesis of MS, glioma, AD, chronic pain, HAM/TSP and bipolar disorder. CXCR3 is a crucial molecule in neuroinflammatory and neurodegenerative diseases. It regulates the activation of infiltrating cells and resident immune cells. However, the exact functions of CXCR3 in neurological diseases are inconclusive. Thus, it is important to understand the topic of chemokines and the scope of their ac-tivity in neurological diseases.
Triglyceride-rich lipoprotein lipolysis products increase blood-brain barrier transfer coefficient and induce astrocyte lipid droplets and cell stress.

Elevation of blood triglycerides, primarily as triglyceride-rich lipoproteins (TGRL), has been linked to cerebrovascular inflammation, vascular dementia, and Alzheimer's disease (AD). Brain microvascular endothelial cells and astrocytes, two cell components of the neurovascular unit, participate in controlling blood-brain barrier (BBB) permeability and regulating neurovascular unit homeostasis. Our studies showed that infusion of high physiological concentrations of TGRL lipolysis products (TGRL + lipoprotein lipase) activate and injure brain endothelial cells and transiently increase the BBB transfer coefficient (Ki = permeability × surface area/volume) in vivo. However, little is known about how blood lipids affect astrocyte lipid accumulation and inflammation. To address this, we first demonstrated TGRL lipolysis products increased lipid droplet formation in cultured normal human astrocytes. We then evaluated the transcriptional pathways activated in astrocytes by TGRL lipolysis products and found upregulated stress and inflammatory-related genes including activating transcription factor 3 (ATF3), macrophage inflammatory protein-3α (MIP-3α), growth differentiation factor-15 (GDF15), and prostaglandin-endoperoxide synthase 2 (COX2). TGRL lipolysis products also activated the JNK/cJUN/ATF3 pathway, induced endoplasmic reticulum stress protein C/EBP homologous protein (CHOP), and the NF-κB pathway, while increasing secretion of MIP-3α, GDF15, and IL-8. Thus our results demonstrate TGRL lipolysis products increase the BBB transfer coefficient (Ki), induce astrocyte lipid droplet formation, activate cell stress pathways, and induce secretion of inflammatory cytokines. Our observations are consistent with evidence for lipid-induced neurovascular injury and inflammation, and we, therefore, speculate that lipid-induced astrocyte injury could play a role in cognitive decline.
Validation of Systemic Lupus Erythematosus Diagnosis as the Primary Cause of Renal Failure in the US Renal Data System

Using American College of Rheumatology (ACR) and Systemic Lupus International Collaborating Clinics (SLICC) criteria for systemic lupus erythematosus (SLE) classification as gold standards, we determined sensitivity, specificity, positive and negative predictive values (PPV and NPV) of having SLE denoted as the primary cause of end‐stage renal disease (ESRD) in the US Renal Data System (USRDS).