snu-aidas/HVMap-dataset huggingface dataset:
Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial.

BACKGROUND AN1792 (beta-amyloid [Abeta]1-42) immunization reduces Abeta plaque burden and preserves cognitive function in APP transgenic mice. The authors report the results of a phase IIa immunotherapy trial of AN1792(QS-21) in patients with mild to moderate Alzheimer disease (AD) that was interrupted because of meningoencephalitis in 6% of immunized patients. METHODS This randomized, multicenter, placebo-controlled, double-blind trial of IM AN1792 225 microg plus the adjuvant QS-21 50 microg (300 patients) and saline (72 patients) included patients aged 50 to 85 years with probable AD, Mini-Mental State Examination (MMSE) 15 to 26. Injections were planned for months 0, 1, 3, 6, 9, and 12. Safety and tolerability were evaluated, and pilot efficacy (AD Assessment Scale-Cognitive Subscale [ADAS-Cog], MRI, neuropsychological test battery [NTB], CSF tau, and Abeta42) was assessed in anti-AN1792 antibody responder patients (immunoglobulin G titer > or = 1:2,200). RESULTS Following reports of meningoencephalitis (overall 18/300 [6%]), immunization was stopped after one (2 patients), two (274 patients), or three (24 patients) injections. Of the 300 AN1792(QS-21)-treated patients, 59 (19.7%) developed the predetermined antibody response. Double-blind assessments were maintained for 12 months. No significant differences were found between antibody responder and placebo groups for ADAS-Cog, Disability Assessment for Dementia, Clinical Dementia Rating, MMSE, or Clinical Global Impression of Change, but analyses of the z-score composite across the NTB revealed differences favoring antibody responders (0.03 +/- 0.37 vs -0.20 +/- 0.45; p = 0.020). In the small subset of subjects who had CSF examinations, CSF tau was decreased in antibody responders (n = 11) vs placebo subjects (n = 10; p < 0.001). CONCLUSION Although interrupted, this trial provides an indication that Abeta immunotherapy may be useful in Alzheimer disease.
Human papillomavirus and Papanicolaou tests to screen for cervical cancer.

BACKGROUND Screening for cervical cancer based on testing for human papillomavirus (HPV) increases the sensitivity of detection of high-grade (grade 2 or 3) cervical intraepithelial neoplasia, but whether this gain represents overdiagnosis or protection against future high-grade cervical epithelial neoplasia or cervical cancer is unknown. METHODS In a population-based screening program in Sweden, 12,527 women 32 to 38 years of age were randomly assigned at a 1:1 ratio to have an HPV test plus a Papanicolaou (Pap) test (intervention group) or a Pap test alone (control group). Women with a positive HPV test and a normal Pap test result were offered a second HPV test at least 1 year later, and those who were found to be persistently infected with the same high-risk type of HPV were then offered colposcopy with cervical biopsy. A similar number of double-blinded Pap smears and colposcopies with biopsy were performed in randomly selected women in the control group. Comprehensive registry data were used to follow the women for a mean of 4.1 years. The relative rates of grade 2 or 3 cervical intraepithelial neoplasia or cancer detected at enrollment and at subsequent screening examinations were calculated. RESULTS At enrollment, the proportion of women in the intervention group who were found to have lesions of grade 2 or 3 cervical intraepithelial neoplasia or cancer was 51% greater (95% confidence interval [CI], 13 to 102) than the proportion of women in the control group who were found to have such lesions. At subsequent screening examinations, the proportion of women in the intervention group who were found to have grade 2 or 3 lesions or cancer was 42% less (95% CI, 4 to 64) and the proportion with grade 3 lesions or cancer was 47% less (95% CI, 2 to 71) than the proportions of control women who were found to have such lesions. Women with persistent HPV infection remained at high risk for grade 2 or 3 lesions or cancer after referral for colposcopy. CONCLUSIONS The addition of an HPV test to the Pap test to screen women in their mid-30s for cervical cancer reduces the incidence of grade 2 or 3 cervical intraepithelial neoplasia or cancer detected by subsequent screening examinations. (ClinicalTrials.gov number, NCT00479375 [ClinicalTrials.gov].).
Chronic Exercise Increases Both Inducible and Endothelial Nitric Oxide Synthase Gene Expression in Endothelial Cells of Rat Aorta

Chronic exercise upregulates endothelial nitric oxide synthase (eNOS) gene expression. Whether the expression of inducible nitric oxide synthase (iNOS) is affected by exercise is unknown. We therefore investigated the effects of chronic exercise on iNOS and eNOS expression in isolated rat aortic endothelial and smooth muscle cells separately. Five-week-old male Wistar rats were randomly divided into control and exercise groups. After 10 weeks of running training, animals were sacrificed under ether anesthesia. The standard curve quantitative competitive reverse transcriptase-polymerase chain reaction method was used to quantify NOS mRNA expression in isolated endothelial/smooth muscle cells. To evaluate the functional role of iNOS, we examined phenylephrine-induced vascular responses with or without pretreatment with aminoguanidine. We found that (1) expression of iNOS and eNOS mRNA in endothelial cells was increased by chronic exercise and (2) chronic exercise blunted phenylephrine-induced vascular responses, probably by increasing NO release via iNOS. Our results show that chronic exercise increases both iNOS and eNOS gene expression in endothelium. These alterations may be partially responsible for the change in vascular response after exercise.
CRISPR–Cas9 genome editing induces a p53-mediated DNA damage response

Here, we report that genome editing by CRISPR–Cas9 induces a p53-mediated DNA damage response and cell cycle arrest in immortalized human retinal pigment epithelial cells, leading to a selection against cells with a functional p53 pathway. Inhibition of p53 prevents the damage response and increases the rate of homologous recombination from a donor template. These results suggest that p53 inhibition may improve the efficiency of genome editing of untransformed cells and that p53 function should be monitored when developing cell-based therapies utilizing CRISPR–Cas9. CRISPR–Cas9-induced DNA damage triggers p53 to limit the efficiency of gene editing in immortalized human retinal pigment epithelial cells.
Comparative Structural Analysis of Lipid Binding START Domains

BACKGROUND Steroidogenic acute regulatory (StAR) protein related lipid transfer (START) domains are small globular modules that form a cavity where lipids and lipid hormones bind. These domains can transport ligands to facilitate lipid exchange between biological membranes, and they have been postulated to modulate the activity of other domains of the protein in response to ligand binding. More than a dozen human genes encode START domains, and several of them are implicated in a disease. PRINCIPAL FINDINGS We report crystal structures of the human STARD1, STARD5, STARD13 and STARD14 lipid transfer domains. These represent four of the six functional classes of START domains. SIGNIFICANCE Sequence alignments based on these and previously reported crystal structures define the structural determinants of human START domains, both those related to structural framework and those involved in ligand specificity. ENHANCED VERSION This article can also be viewed as an enhanced version in which the text of the article is integrated with interactive 3D representations and animated transitions. Please note that a web plugin is required to access this enhanced functionality. Instructions for the installation and use of the web plugin are available in Text S1.
Staphylococcus aureus infection dynamics

Staphylococcus aureus is a human commensal that can also cause systemic infections. This transition requires evasion of the immune response and the ability to exploit different niches within the host. However, the disease mechanisms and the dominant immune mediators against infection are poorly understood. Previously it has been shown that the infecting S. aureus population goes through a population bottleneck, from which very few bacteria escape to establish the abscesses that are characteristic of many infections. Here we examine the host factors underlying the population bottleneck and subsequent clonal expansion in S. aureus infection models, to identify underpinning principles of infection. The bottleneck is a common feature between models and is independent of S. aureus strain. Interestingly, the high doses of S. aureus required for the widely used "survival" model results in a reduced population bottleneck, suggesting that host defences have been simply overloaded. This brings into question the applicability of the survival model. Depletion of immune mediators revealed key breakpoints and the dynamics of systemic infection. Loss of macrophages, including the liver Kupffer cells, led to increased sensitivity to infection as expected but also loss of the population bottleneck and the spread to other organs still occurred. Conversely, neutrophil depletion led to greater susceptibility to disease but with a concomitant maintenance of the bottleneck and lack of systemic spread. We also used a novel microscopy approach to examine abscess architecture and distribution within organs. From these observations we developed a conceptual model for S. aureus disease from initial infection to mature abscess. This work highlights the need to understand the complexities of the infectious process to be able to assign functions for host and bacterial components, and why S. aureus disease requires a seemingly high infectious dose and how interventions such as a vaccine may be more rationally developed.
Strategies for optimizing maternal nutrition to promote infant development

BACKGROUND The growing appreciation of the multi-faceted importance of optimal maternal nutrition to the health and development of the infant and young child is tempered by incompletely resolved strategies for combatting challenges. OBJECTIVE To review the importance of maternal nutrition and strategies being employed to optimize outcomes. METHODS Selected data from recent literature with special focus on rationale for and currently published results of maternal nutrition supplements, including lipid based nutrition supplements. RESULTS 1) An impelling rationale for improving the maternal and in utero environment of low resource populations has emerged to achieve improved fetal and post-natal growth and development. 2) Based partly on population increases in adult height over one-two generations, much can be achieved by reducing poverty. 3) Maternal, newborn and infant characteristics associated with low resource environments include evidence of undernutrition, manifested by underweight and impaired linear growth. 4) Apart from broad public health and educational initiatives, to date, most specific efforts to improve fetal growth and development have included maternal nutrition interventions during gestation. 5) The relatively limited but real benefits of both iron/folic acid (IFA) and multiple micronutrient (MMN) maternal supplements during gestation have now been reasonably defined. 6) Recent investigations of a maternal lipid-based primarily micronutrient supplement (LNS) have not demonstrated a consistent benefit beyond MMN alone. 7) However, effects of both MMN and LNS appear to be enhanced by commencing early in gestation. CONCLUSIONS Poor maternal nutritional status is one of a very few specific factors in the human that not only contributes to impaired fetal and early post-natal growth but for which maternal interventions have demonstrated improved in utero development, documented primarily by both improvements in low birth weights and by partial corrections of impaired birth length. A clearer definition of the benefits achievable by interventions specifically focused on correcting maternal nutrition deficits should not be limited to improvements in the quality of maternal nutrition supplements, but on the cumulative quantity and timing of interventions (also recognizing the heterogeneity between populations). Finally, in an ideal world these steps are only a prelude to improvements in the total environment in which optimal nutrition and other health determinants can be achieved.
Metformin reverses established lung fibrosis in a bleomycin model

Fibrosis is a pathological result of a dysfunctional repair response to tissue injury and occurs in a number of organs, including the lungs1. Cellular metabolism regulates tissue repair and remodelling responses to injury2-4. AMPK is a critical sensor of cellular bioenergetics and controls the switch from anabolic to catabolic metabolism5. However, the role of AMPK in fibrosis is not well understood. Here, we demonstrate that in humans with idiopathic pulmonary fibrosis (IPF) and in an experimental mouse model of lung fibrosis, AMPK activity is lower in fibrotic regions associated with metabolically active and apoptosis-resistant myofibroblasts. Pharmacological activation of AMPK in myofibroblasts from lungs of humans with IPF display lower fibrotic activity, along with enhanced mitochondrial biogenesis and normalization of sensitivity to apoptosis. In a bleomycin model of lung fibrosis in mice, metformin therapeutically accelerates the resolution of well-established fibrosis in an AMPK-dependent manner. These studies implicate deficient AMPK activation in non-resolving, pathologic fibrotic processes, and support a role for metformin (or other AMPK activators) to reverse established fibrosis by facilitating deactivation and apoptosis of myofibroblasts.
Mesenchymal Stromal Cells: From Discovery to Manufacturing and Commercialization

Over the last decades, mesenchymal stromal cells (MSC) have been the focus of intense research by academia and industry due to their unique features. MSC can be easily isolated and expanded through in vitro culture by taking full advantage of their self-renewing capacity. In addition, MSC exert immunomodulatory effects and can be differentiated into various lineages, which makes them highly attractive for clinical applications in cell-based therapies. In this review, we attempt to provide a brief historical overview of MSC discovery, characterization, and the first clinical studies conducted. The current MSC manufacturing platforms are reviewed with special attention regarding the use of bioreactors for the production of GMP-compliant clinically relevant cell numbers. The first commercial MSC-based products are also addressed, as well as the remaining challenges to the widespread use of MSC-derived products.
Delta–Notch—and then? Protein interactions and proposed modes of repression by Hes and Hey bHLH factors

Hes and Hey genes are the mammalian counterparts of the Hairy and Enhancer-of-split type of genes in Drosophila and they represent the primary targets of the Delta-Notch signaling pathway. Hairy-related factors control multiple steps of embryonic development and misregulation is associated with various defects. Hes and Hey genes (also called Hesr, Chf, Hrt, Herp or gridlock) encode transcriptional regulators of the basic helix-loop-helix class that mainly act as repressors. The molecular details of how Hes and Hey proteins control transcription are still poorly understood, however. Proposed modes of action include direct binding to N- or E-box DNA sequences of target promoters as well as indirect binding through other sequence-specific transcription factors or sequestration of transcriptional activators. Repression may rely on recruitment of corepressors and induction of histone modifications, or even interference with the general transcriptional machinery. All of these models require extensive protein-protein interactions. Here we review data published on protein-protein and protein-DNA interactions of Hairy-related factors and discuss their implications for transcriptional regulation. In addition, we summarize recent progress on the identification of potential target genes and the analysis of mouse models.
The Long Noncoding RNA CAREL Controls Cardiac Regeneration.

BACKGROUND Adult mammalian heart loses regeneration ability following ischemic injury due to the loss of cardiomyocyte mitosis. However, the molecular mechanisms underlying the post-mitotic nature of cardiomyocytes remain largely unknown. OBJECTIVES The purpose of this study was to define the essential role of long noncoding ribonucleic acids (lncRNAs) in heart regeneration during postnatal and adult injury. METHODS Myh6-driving cardiomyocyte-specific lncRNA-CAREL transgenic mice and adenovirus-mediated in vivo silencing of endogenous CAREL were used in this study. The effect of CAREL on cardiomyocyte replication and heart regeneration after apical resection or myocardial infarction was assessed by detecting mitosis and cytokinesis. RESULTS An lncRNA CAREL was found significantly up-regulated in cardiomyocytes from neonatal mice (P7) in parallel with loss of regenerative capacity. Cardiac-specific overexpression of CAREL in mice reduced cardiomyocyte division and proliferation and blunted neonatal heart regeneration after injury. Conversely, silencing of CAREL in vivo markedly promoted cardiac regeneration and improved heart functions after myocardial infarction in neonatal and adult mice. CAREL acted as a competing endogenous ribonucleic acid for miR-296 to derepress the expression of Trp53inp1 and Itm2a, the target genes of miR-296. Consistently, overexpression of miR-296 significantly increased cardiomyocyte replication and cardiac regeneration after injury. Decline of cardiac regenerative ability in CAREL transgenic mice was also rescued by miR-296. A short fragment containing the conserved sequence of CAREL reduced the proliferation of human induced pluripotent stem cell-derived cardiomyocytes as the full-length CAREL. CONCLUSIONS LncRNA CAREL regulates cardiomyocyte proliferation and heart regeneration in postnatal and adult heart after injury by acting as a competing endogenous ribonucleic acid on miR-296 that targets Trp53inp1 and Itm2a.
BCAP links IL-1R to the PI3K–mTOR pathway and regulates pathogenic Th17 cell differentiation

The toll-like receptor (TLR) and interleukin (IL)-1 family of receptors share several signaling components, including the most upstream adapter, MyD88. We previously reported the discovery of B cell adapter for phosphoinositide 3-kinase (BCAP) as a novel toll-IL-1 receptor homology domain-containing adapter that regulates inflammatory responses downstream of TLR signaling. Here we find that BCAP plays a critical role downstream of both IL-1 and IL-18 receptors to regulate T helper (Th) 17 and Th1 cell differentiation, respectively. Absence of T cell intrinsic BCAP did not alter development of naturally arising Th1 and Th17 lineages but led to defects in differentiation to pathogenic Th17 lineage cells. Consequently, mice that lack BCAP in T cells had reduced susceptibility to experimental autoimmune encephalomyelitis. More importantly, we found that BCAP is critical for IL-1R-induced phosphoinositide 3-kinase-Akt-mechanistic target of rapamycin (mTOR) activation, and minimal inhibition of mTOR completely abrogated IL-1β-induced differentiation of pathogenic Th17 cells, mimicking BCAP deficiency. This study establishes BCAP as a critical link between IL-1R and the metabolic status of activated T cells that ultimately regulates the differentiation of inflammatory Th17 cells.
Adapting the WHO package of essential noncommunicable disease interventions, Samoa

Problem Samoa has been struggling to address the burden of noncommunicable diseases at the health system, community and individual levels. Approach The World Health Organization (WHO) package of essential noncommunicable disease interventions for primary health care in low-resource settings was adopted in seven villages throughout Samoa in 2015. The National Steering Committee Members designed and implemented a screening process, and local facilitators and health-care workers collected health and lifestyle data. The WHO/International Society of Hypertension risk assessment was used on villagers older than 40 years to identify people at high risk of noncommunicable disease. Local setting Samoa is a small island developing state with increasing morbidity and mortality due to noncommunicable diseases. A national representative survey indicated that 50.1% (595/1188) of the Samoan adult population is at high risk of such diseases. High numbers of noncommunicable diseases are undiagnosed or untreated, because of shortage of health-care staff and lack of awareness of risk factors. Relevant changes The teams collected data from 2234 adults. For people older than 40 years, 6.7% (54/804) were identified as being at high-risk and were encouraged to seek treatment or manage risk factors. Community members developed an awareness programme to improve understanding of lifestyle risk factors. Lessons learnt Engaging community members was crucial in conducting a successful screening campaign. By identifying those villagers at high risk of developing noncommunicable diseases, early intervention was possible. Education improved awareness of the symptom-free nature of early-stage noncommunicable diseases.
The Dual Immunoregulatory function of Nlrp12 in T Cell-Mediated Immune Response: Lessons from Experimental Autoimmune Encephalomyelitis

Although the etiology of multiple sclerosis (MS) remains enigmatic, the role of T cells is unquestionably central in this pathology. Immune cells respond to pathogens and danger signals via pattern-recognition receptors (PRR). Several reports implicate Nlrp12, an intracellular PRR, in the development of a mouse MS-like disease, called Experimental Autoimmune Encephalomyelitis (EAE). In this study, we used induced and spontaneous models of EAE, as well as in vitro T cell assays, to test the hypothesis that Nlrp12 inhibits Th1 response and prevents T-cell mediated autoimmunity. We found that Nlrp12 plays a protective role in induced EAE by reducing IFNγ/IL-4 ratio in lymph nodes, whereas it potentiates the development of spontaneous EAE (spEAE) in 2D2 T cell receptor (TCR) transgenic mice. Looking into the mechanism of Nlrp12 activity in T cell response, we found that it inhibits T cell proliferation and suppresses Th1 response by reducing IFNγ and IL-2 production. Following TCR activation, Nlrp12 inhibits Akt and NF-κB phosphorylation, while it has no effect on S6 phosphorylation in the mTOR pathway. In conclusion, we propose a model that can explain the dual immunoregulatory function of Nlrp12 in EAE. We also propose a model explaining the molecular mechanism of Nlrp12-dependent regulation of T cell response.