snu-aidas/HVMap-dataset huggingface dataset:
OPA1 gene therapy prevents retinal ganglion cell loss in a Dominant Optic Atrophy mouse model

Dominant optic atrophy (DOA) is a rare progressive and irreversible blinding disease which is one of the most frequent forms of hereditary optic neuropathy. DOA is mainly caused by dominant mutation in the OPA1 gene encoding a large mitochondrial GTPase with crucial roles in membrane dynamics and cell survival. Hereditary optic neuropathies are commonly characterized by the degeneration of retinal ganglion cells, leading to the optic nerve atrophy and the progressive loss of visual acuity. Up to now, despite increasing advances in the understanding of the pathological mechanisms, DOA remains intractable. Here, we tested the efficiency of gene therapy on a genetically-modified mouse model reproducing DOA vision loss. We performed intravitreal injections of an Adeno-Associated Virus carrying the human OPA1 cDNA under the control of the cytomegalovirus promotor. Our results provide the first evidence that gene therapy is efficient on a mouse model of DOA as the wild-type OPA1 expression is able to alleviate the OPA1-induced retinal ganglion cell degeneration, the hallmark of the disease. These results displayed encouraging effects of gene therapy for Dominant Optic Atrophy, fostering future investigations aiming at clinical trials in patients.
Prostate cancer-associated gene expression alterations determined from needle biopsies.

PURPOSE To accurately identify gene expression alterations that differentiate neoplastic from normal prostate epithelium using an approach that avoids contamination by unwanted cellular components and is not compromised by acute gene expression changes associated with tumor devascularization and resulting ischemia. EXPERIMENTAL DESIGN Approximately 3,000 neoplastic and benign prostate epithelial cells were isolated using laser capture microdissection from snap-frozen prostate biopsy specimens provided by 31 patients who subsequently participated in a clinical trial of preoperative chemotherapy. cDNA synthesized from amplified total RNA was hybridized to custom-made microarrays composed of 6,200 clones derived from the Prostate Expression Database. Expression differences for selected genes were verified using quantitative reverse transcription-PCR. RESULTS Comparative analyses identified 954 transcript alterations associated with cancer (q < 0.01%), including 149 differentially expressed genes with no known functional roles. Gene expression changes associated with ischemia and surgical removal of the prostate gland were absent. Genes up-regulated in prostate cancer were statistically enriched in categories related to cellular metabolism, energy use, signal transduction, and molecular transport. Genes down-regulated in prostate cancers were enriched in categories related to immune response, cellular responses to pathogens, and apoptosis. A heterogeneous pattern of androgen receptor expression changes was noted. In exploratory analyses, androgen receptor down-regulation was associated with a lower probability of cancer relapse after neoadjuvant chemotherapy followed by radical prostatectomy. CONCLUSIONS Assessments of tumor phenotypes based on gene expression for treatment stratification and drug targeting of oncogenic alterations may best be ascertained using biopsy-based analyses where the effects of ischemia do not complicate interpretation.
Circulating trimethylamine N‐oxide and the risk of cardiovascular diseases: a systematic review and meta‐analysis of 11 prospective cohort studies

Circulating trimethylamine N-oxide (TMAO), a canonical metabolite from gut flora, has been related to the risk of cardiovascular disorders. However, the association between circulating TMAO and the risk of cardiovascular events has not been quantitatively evaluated. We performed a systematic review and meta-analysis of all available cohort studies regarding the association between baseline circulating TMAO and subsequent cardiovascular events. Embase and PubMed databases were searched for relevant cohort studies. The overall hazard ratios for the developing of cardiovascular events (CVEs) and mortality were extracted. Heterogeneity among the included studies was evaluated with Cochran's Q Test and I2 statistics. A random-effect model or a fixed-effect model was applied depending on the heterogeneity. Subgroup analysis and meta-regression were used to evaluate the source of heterogeneity. Among the 11 eligible studies, three reported both CVE and mortality outcome, one reported only CVEs and the other seven provided mortality data only. Higher circulating TMAO was associated with a 23% higher risk of CVEs (HR = 1.23, 95% CI: 1.07-1.42, I2 = 31.4%) and a 55% higher risk of all-cause mortality (HR = 1.55, 95% CI: 1.19-2.02, I2 = 80.8%). Notably, the latter association may be blunted by potential publication bias, although sensitivity analysis by omitting one study at a time did not significantly change the results. Further subgroup analysis and meta-regression did not support that the location of the study, follow-up duration, publication year, population characteristics or the samples of TMAO affect the results significantly. Higher circulating TMAO may independently predict the risk of subsequent cardiovascular events and mortality.
PDGF-BB secreted by preosteoclasts induces angiogenesis during coupling with osteogenesis

Osteogenesis during bone modeling and remodeling is coupled with angiogenesis. A recent study showed that a specific vessel subtype, strongly positive for CD31 and endomucin (CD31hiEmcnhi), couples angiogenesis and osteogenesis. Here, we found that platelet-derived growth factor-BB (PDGF-BB) secreted by preosteoclasts induces CD31hiEmcnhi vessel formation during bone modeling and remodeling. Mice with depletion of PDGF-BB in the tartrate-resistant acid phosphatase–positive cell lineage show significantly lower trabecular and cortical bone mass, serum and bone marrow PDGF-BB concentrations, and fewer CD31hiEmcnhi vessels compared to wild-type mice. In the ovariectomy (OVX)-induced osteoporotic mouse model, serum and bone marrow levels of PDGF-BB and numbers of CD31hiEmcnhi vessels are significantly lower compared to sham-operated controls. Treatment with exogenous PDGF-BB or inhibition of cathepsin K to increase the number of preosteoclasts, and thus the endogenous levels of PDGF-BB, increases CD31hiEmcnhi vessel number and stimulates bone formation in OVX mice. Thus, pharmacotherapies that increase PDGF-BB secretion from preosteoclasts offer a new therapeutic target for treating osteoporosis by promoting angiogenesis and thus bone formation.
ERCC1 and MUS81–EME1 promote sister chromatid separation by processing late replication intermediates at common fragile sites during mitosis

Chromosomal instability (CIN) is a hallmark of tumour initiation and progression. Some genomic regions are particularly unstable under replication stress, notably common fragile sites (CFSs) whose rearrangements in tumour cells contribute to cancer development. Recent work has shown that the Fanconi anaemia (FANC) pathway plays a role in preventing defective chromosome segregation and CIN under conditions of replication stress. Strikingly, FANCD2 is recruited to regions hosting CFSs on metaphase chromosomes. To decipher the mechanisms protecting CFSs in G2/M, we searched for proteins that co-localize with FANCD2 on mitotic chromosomes, and identified XPF–ERCC1 and MUS81–EME1, two structure-specific endonucleases. We show that depletion of either ERCC1 or MUS81–EME1 affects accurate processing of replication intermediates or under-replicated DNA that persist at CFSs until mitosis. Depletion of these endonucleases also leads to an increase in the frequency of chromosome bridges during anaphase that, in turn, favours accumulation of DNA damage in the following G1 phase.
Transtheoretical model-based multiple behavior intervention for weight management: effectiveness on a population basis.

BACKGROUND The increasing prevalence of overweight and obesity underscores the need for evidence-based, easily disseminable interventions for weight management that can be delivered on a population basis. The Transtheoretical Model (TTM) offers a promising theoretical framework for multiple behavior weight management interventions. METHODS Overweight or obese adults (BMI 25-39.9; n=1277) were randomized to no-treatment control or home-based, stage-matched multiple behavior interventions for up to three behaviors related to weight management at 0, 3, 6, and 9 months. All participants were re-assessed at 6, 12, and 24 months. RESULTS Significant treatment effects were found for healthy eating (47.5% versus 34.3%), exercise (44.90% versus 38.10%), managing emotional distress (49.7% versus 30.30%), and untreated fruit and vegetable intake (48.5% versus 39.0%) progressing to Action/Maintenance at 24 months. The groups differed on weight lost at 24 months. Co-variation of behavior change occurred and was much more pronounced in the treatment group, where individuals progressing to Action/Maintenance for a single behavior were 2.5-5 times more likely to make progress on another behavior. The impact of the multiple behavior intervention was more than three times that of single behavior interventions. CONCLUSIONS This study demonstrates the ability of TTM-based tailored feedback to improve healthy eating, exercise, managing emotional distress, and weight on a population basis. The treatment produced a high level of population impact that future multiple behavior interventions can seek to surpass.
Macrophages in the Pathogenesis of Atherosclerosis

In atherosclerosis, the accumulation of apolipoprotein B-lipoproteins in the matrix beneath the endothelial cell layer of blood vessels leads to the recruitment of monocytes, the cells of the immune system that give rise to macrophages and dendritic cells. Macrophages derived from these recruited monocytes participate in a maladaptive, nonresolving inflammatory response that expands the subendothelial layer due to the accumulation of cells, lipid, and matrix. Some lesions subsequently form a necrotic core, triggering acute thrombotic vascular disease, including myocardial infarction, stroke, and sudden cardiac death. This Review discusses the central roles of macrophages in each of these stages of disease pathogenesis.
Overweight prevalence among youth in the United States: Why so many different numbers?

Several recent publications have presented different estimates for the prevalence of overweight among youth in the United States. Prevalence estimates range from 11–24%, despite describing the same results from the third National Health and Nutrition Examination Survey (NHANES III). This paper discusses the variety and evolution of different overweight prevalence estimates. Issues of definition, measurements, criteria selection and comparison groups are considered and implications for estimates of the prevalence of overweight among youth are explored. Reference percentiles for body mass index (BMI) from several publications are compared. The differences in published estimates from NHANES III are noted and explained.
Senescence and aging: the critical roles of p53

p53 functions as a transcription factor involved in cell-cycle control, DNA repair, apoptosis and cellular stress responses. However, besides inducing cell growth arrest and apoptosis, p53 activation also modulates cellular senescence and organismal aging. Senescence is an irreversible cell-cycle arrest that has a crucial role both in aging and as a robust physiological antitumor response, which counteracts oncogenic insults. Therefore, via the regulation of senescence, p53 contributes to tumor growth suppression, in a manner strictly dependent by its expression and cellular context. In this review, we focus on the recent advances on the contribution of p53 to cellular senescence and its implication for cancer therapy, and we will discuss p53’s impact on animal lifespan. Moreover, we describe p53-mediated regulation of several physiological pathways that could mediate its role in both senescence and aging.
Asymmetric cryo-EM reconstruction of phage MS2 reveals genome structure in situ

In single-stranded ribonucleic acid (RNA) viruses, virus capsid assembly and genome packaging are intertwined processes. Using cryo-electron microscopy and single particle analysis we determined the asymmetric virion structure of bacteriophage MS2, which includes 178 copies of the coat protein, a single copy of the A-protein and the RNA genome. This reveals that in situ, the viral RNA genome can adopt a defined conformation. The RNA forms a branched network of stem-loops that almost all allocate near the capsid inner surface, while predominantly binding to coat protein dimers that are located in one-half of the capsid. This suggests that genomic RNA is highly involved in genome packaging and virion assembly.
Harnessing transposons for cancer gene discovery

Recently, it has become possible to mobilize the Tc1/mariner transposon, Sleeping Beauty (SB), in mouse somatic cells at frequencies high enough to induce cancer. Tumours result from SB insertional mutagenesis of cancer genes, thus facilitating the identification of the genes and signalling pathways that drive tumour formation. A conditional SB transposition system has also been developed that makes it possible to limit where SB mutagenesis occurs, providing a means to selectively model many types of human cancer. SB mutagenesis has already identified a large collection of known cancer genes in addition to a plethora of new candidate cancer genes and potential drug targets.
MicroRNA-Containing T-Regulatory-Cell-Derived Exosomes Suppress Pathogenic T Helper 1 Cells

Foxp3(+) T regulatory (Treg) cells prevent inflammatory disease but the mechanistic basis of suppression is not understood completely. Gene silencing by RNA interference can act in a cell-autonomous and non-cell-autonomous manner, providing mechanisms of intercellular regulation. Here, we demonstrate that non-cell-autonomous gene silencing, mediated by miRNA-containing exosomes, is a mechanism employed by Treg cells to suppress T-cell-mediated disease. Treg cells transferred microRNAs (miRNA) to various immune cells, including T helper 1 (Th1) cells, suppressing Th1 cell proliferation and cytokine secretion. Use of Dicer-deficient or Rab27a and Rab27b double-deficient Treg cells to disrupt miRNA biogenesis or the exosomal pathway, respectively, established a requirement for miRNAs and exosomes for Treg-cell-mediated suppression. Transcriptional analysis and miRNA inhibitor studies showed that exosome-mediated transfer of Let-7d from Treg cell to Th1 cells contributed to suppression and prevention of systemic disease. These studies reveal a mechanism of Treg-cell-mediated suppression mediated by miRNA-containing exosomes.
Estimating risk curves for first-degree relatives of patients with Alzheimer’s disease: The REVEAL study

Purpose: The REVEAL study is a randomized, controlled study of the psychological and behavioral impact of APOE disclosure in a risk assessment protocol provided to first degree relatives of patients with Alzheimer’s disease. The protocol presents risk information as cumulative incidence curves. This article describes how these curves were estimated. Methods: Curves were calculated using Bayes’ rule to compute the posterior survival curves incorporating APOE information. Results: A combination of survival data from the MIRAGE study and gender- and age-specific APOE odds ratios were used to create risk curves for males and females within each of the 6 APOE genotypes. Conclusion: Utilizing comparative genotype relative risk information and survival data from family studies, estimates of gender-, age-, and genotype-specific risk can be generated for use in a risk assessment research study that features genotype disclosure.
Prostaglandin E2 promotes intestinal tumor growth via DNA methylation

Although aberrant DNA methylation is considered to be one of the key ways by which tumor-suppressor and DNA-repair genes are silenced during tumor initiation and progression, the mechanisms underlying DNA methylation alterations in cancer remain unclear. Here we show that prostaglandin E(2) (PGE(2)) silences certain tumor-suppressor and DNA-repair genes through DNA methylation to promote tumor growth. These findings uncover a previously unrecognized role for PGE(2) in the promotion of tumor progression.
Microenvironmental regulation of tumor progression and metastasis

Cancers develop in complex tissue environments, which they depend on for sustained growth, invasion and metastasis. Unlike tumor cells, stromal cell types within the tumor microenvironment (TME) are genetically stable and thus represent an attractive therapeutic target with reduced risk of resistance and tumor recurrence. However, specifically disrupting the pro-tumorigenic TME is a challenging undertaking, as the TME has diverse capacities to induce both beneficial and adverse consequences for tumorigenesis. Furthermore, many studies have shown that the microenvironment is capable of normalizing tumor cells, suggesting that re-education of stromal cells, rather than targeted ablation per se, may be an effective strategy for treating cancer. Here we discuss the paradoxical roles of the TME during specific stages of cancer progression and metastasis, as well as recent therapeutic attempts to re-educate stromal cells within the TME to have anti-tumorigenic effects.
Bezafibrate in men with lower extremity arterial disease: randomised controlled trial.

OBJECTIVE To assess the effect of bezafibrate on the risk of coronary heart disease and stroke in men with lower extremity arterial disease. DESIGN Double blind placebo controlled randomised trial. SETTING 85 general practices and nine hospital vascular clinics. PARTICIPANTS 1568 men, mean age 68.2 years (range 35 to 92) at recruitment. INTERVENTIONS Bezafibrate 400 mg daily (783 men) or placebo (785 men). MAIN OUTCOME MEASURES Combination of coronary heart disease and of stroke. All coronary events, fatal and non-fatal coronary events separately, and strokes alone (secondary end points). RESULTS Bezafibrate did not reduce the incidence of coronary heart disease and stroke. There were 150 and 160 events in the active and placebo groups respectively (relative risk 0.96, 95% confidence interval 0.76 to 1.21). There were 90 and 111 major coronary events in the active and placebo groups respectively (0.81, 0.60 to 1.08), of which 64 and 65 were fatal (0.95, 0.66 to 1.37) and 26 and 46 non-fatal (0.60, 0.36 to 0.99). Beneficial effects on non-fatal events were greatest in men aged <65 years at entry, in whom benefit was also seen for all coronary events (0.38, 0.20 to 0.72). There were no significant effects in older men. There were 60 strokes in those on active treatment and 49 in those on placebo (1.34, 0.80 to 2.01). There were 204 and 195 deaths from all causes in the two groups respectively (1.03, 0.83 to 1.26). Bezafibrate reduced the severity of intermittent claudication for up to three years. CONCLUSIONS Bezafibrate has no effect on the incidence of coronary heart disease and of stroke combined but may reduce the incidence of non-fatal coronary events, particularly in those aged <65 years at entry, in whom all coronary events may also be reduced.
Auditory Cortex Tracks Both Auditory and Visual Stimulus Dynamics Using Low-Frequency Neuronal Phase Modulation

Integrating information across sensory domains to construct a unified representation of multi-sensory signals is a fundamental characteristic of perception in ecological contexts. One provocative hypothesis deriving from neurophysiology suggests that there exists early and direct cross-modal phase modulation. We provide evidence, based on magnetoencephalography (MEG) recordings from participants viewing audiovisual movies, that low-frequency neuronal information lies at the basis of the synergistic coordination of information across auditory and visual streams. In particular, the phase of the 2-7 Hz delta and theta band responses carries robust (in single trials) and usable information (for parsing the temporal structure) about stimulus dynamics in both sensory modalities concurrently. These experiments are the first to show in humans that a particular cortical mechanism, delta-theta phase modulation across early sensory areas, plays an important "active" role in continuously tracking naturalistic audio-visual streams, carrying dynamic multi-sensory information, and reflecting cross-sensory interaction in real time.
Increased sensitivity of antigen-experienced T cells through the enrichment of oligomeric T cell receptor complexes.

Although memory T cells respond more vigorously to stimulation and they are more sensitive to low doses of antigen than naive T cells, the molecular basis of this increased sensitivity remains unclear. We have previously shown that the T cell receptor (TCR) exists as different-sized oligomers on the surface of resting T cells and that large oligomers are preferentially activated in response to low antigen doses. Through biochemistry and electron microscopy, we now showed that previously stimulated and memory T cells have more and larger TCR oligomers at the cell surface than their naive counterparts. Reconstitution of cells and mice with a point mutant of the CD3ζ subunit, which impairs TCR oligomer formation, demonstrated that the increased size of TCR oligomers was directly responsible for the increased sensitivity of antigen-experienced T cells. Thus, we propose that an "avidity maturation" mechanism underlies T cell antigenic memory.
Dynamic interactions of cortactin and membrane type 1 matrix metalloproteinase at invadopodia: defining the stages of invadopodia formation and function.

Metastatic tumor cells that actively migrate and invade surrounding tissues rely on invadopodia to degrade extracellular matrix (ECM) barriers. Invadopodia are membrane protrusions that localize enzymes required for ECM degradation. Little is known about the formation, function, and regulation of invadopodia. Here, we show that invadopodia have two distinct aspects: (a) structural for organizing the cellular actin cytoskeleton to form membrane protrusions and (b) functional for using proteolytic enzyme(s) for ECM degradation. Small interfering RNA (siRNA) inhibition established that organization of invadopodia structure requires cortactin, whereas protease inhibitor studies identified membrane type 1 matrix metalloproteinase (MT1-MMP) as the key invadopodial enzyme responsible for gelatin matrix degradation in the breast carcinoma cell line MDA-MB-231. The inhibition of invadopodial structure assembly by cortactin depletion resulted in a block of matrix degradation due to failure of invadopodia formation. Either protease inhibition or MT1-MMP siRNA depletion moderately decreased the formation of invadopodial structures that were identified as actin-cortactin accumulations at the ventral cell membrane adherent to matrix. The invadopodia that were able to form upon MT1-MMP inhibition or depletion retained actin-cortactin accumulations but were unable to degrade matrix. Examination of cells at different time points as well as live-cell imaging revealed four distinct invadopodial stages: membrane cortactin aggregation at membranes adherent to matrix, MT1-MMP accumulation at the region of cortactin accumulation, matrix degradation at the invadopodia region, and subsequent cortactin dissociation from the area of continued MT1-MMP accumulation associated with foci of degraded matrix. Based on these results, we propose a stepwise model of invadopodia formation and function.