Miracle-dz/UniFAR-FTUs huggingface dataset:
Establishment of environmentally sensitive DNA methylation states in the very early human embryo

We have tracked DNA methylation dynamics at metastable epialleles across multiple developmental stages in the early human embryo. The molecular mechanisms responsible for the developmental origins of later disease are currently unknown. We previously demonstrated that women’s periconceptional nutrition predicts their offspring’s DNA methylation at metastable epialleles (MEs). We present a genome-wide screen yielding 687 MEs and track their trajectories across nine developmental stages in human in vitro fertilization embryos. MEs exhibit highly unusual methylation dynamics across the implantation-gastrulation transition, producing a large excess of intermediate methylation states, suggesting the potential for differential programming in response to external signals. Using a natural experiment in rural Gambia, we show that genomic regions sensitive to season of conception are highly enriched for MEs and show similar atypical methylation patterns. MEs are enriched for proximal enhancers and transcription start sites and are influenced by genotype. Together, these observations position MEs as distinctive epigenomic features programmed in the early embryo, sensitive to genetic and periconceptional environment, and with the potential to influence phenotype.
Dialectical behavior therapy skills training affects defense mechanisms in borderline personality disorder: An integrative approach of mechanisms in psychotherapy

Abstract Objective: Borderline personality disorder (BPD) is characterized by immature defense mechanisms. Dialectical behavior therapy (DBT) is an effective treatment for BPD. However, understanding the underlying mechanisms of change is still limited. Using a transtheoretical framework, we investigated the effect of DBT skills training on defense mechanisms. Method: In this randomized controlled trial, 16 of 31 BPD outpatients received DBT skills training adjunctive to individual treatment as usual (TAU), while the remaining 15 received only individual TAU. Pre–post changes of defense mechanisms, assessed with the Defense Mechanism Rating Scale, were compared between treatment conditions using ANCOVAs. Partial correlations and linear regressions were conducted to explore associations between defenses and symptom outcome. Results: Overall defense function improved significantly more in the skills training condition (F(1, 28) = 4.57, p = . 041). Borderline defenses decreased throughout skills training, but not throughout TAU only (F(1, 28) = 5.09, p = . 032). In the skills training condition, an increase in narcissistic defenses was associated with higher symptom scores at discharge (β = 0.58, p = .02). Conclusions: Although DBT does not explicitly target defense mechanisms, skills training may have favorable effects on defense function in BPD. Our findings contribute to an integrative understanding of mechanisms of change in BPD psychotherapy.
3-D Perfusion Imaging Using Principal Curvature Detection Rendering

Three-dimensional contrast-enhanced ultrasound (CEUS) imaging presents a clear advantage over its 2-D counterpart in detecting and characterizing suspicious lesions as it properly surveys the inherent heterogeneity of tumors. However, 3-D CEUS is also slow compared to 2-D CEUS and tends to undersample the microbubble wash-in. This makes it difficult to resolve the feeding vessels, an important oncogenic marker, from the background perfusion cloud. Contrast-enhanced Doppler is helpful in isolating this conduit flow, but requires too many pulses in conventional line-by-line beamforming design. Recent breakthroughs in plane-wave imaging have greatly accelerated the volumetric imaging frame rate, but volumetric Doppler angiography still remains challenging when considering real-time limitations on the Doppler ensemble length. In this work, we demonstrate the feasibility of volumetric CEUS angiography subjected to real-time imaging constraints. Namely, we show how principal curvature detection can significantly improve 3-D rendering of relatively noisy ultrasound angiograms without degrading the spatial resolution while subjected to a reasonable Doppler ensemble size. Singular value decomposition is also shown to be capable of identifying the quasi-stationary capillary perfusion.
Accelerating rates of Arctic carbon cycling revealed by long-term atmospheric CO2 measurements

Atmospheric CO2 observations reveal a decrease in Arctic ecosystem carbon residence time over the past four decades. The contemporary Arctic carbon balance is uncertain, and the potential for a permafrost carbon feedback of anywhere from 50 to 200 petagrams of carbon (Schuur et al., 2015) compromises accurate 21st-century global climate system projections. The 42-year record of atmospheric CO2 measurements at Barrow, Alaska (71.29 N, 156.79 W), reveals significant trends in regional land-surface CO2 anomalies (ΔCO2), indicating long-term changes in seasonal carbon uptake and respiration. Using a carbon balance model constrained by ΔCO2, we find a 13.4% decrease in mean carbon residence time (50% confidence range = 9.2 to 17.6%) in North Slope tundra ecosystems during the past four decades, suggesting a transition toward a boreal carbon cycling regime. Temperature dependencies of respiration and carbon uptake suggest that increases in cold season Arctic labile carbon release will likely continue to exceed increases in net growing season carbon uptake under continued warming trends.
Gastrin Protects Against Myocardial Ischemia/Reperfusion Injury via Activation of RISK (Reperfusion Injury Salvage Kinase) and SAFE (Survivor Activating Factor Enhancement) Pathways

Background Ischemia/reperfusion injury (IRI) is one of the most predominant complications of ischemic heart disease. Gastrin has emerged as a regulator of cardiovascular function, playing a key protective role in hypoxia. Serum gastrin levels are increased in patients with myocardial infarction, but the pathophysiogical significance of this finding is unknown. The purpose of this study was to determine whether and how gastrin protects cardiac myocytes from IRI. Methods and Results Adult male Sprague‐Dawley rats were used in the experiments. The hearts in living rats or isolated Langendorff‐perfused rat hearts were subjected to ischemia followed by reperfusion to induce myocardial IRI. Gastrin, alone or with an antagonist, was administered before the induction of myocardial IRI. We found that gastrin improved myocardial function and reduced the expression of myocardial injury markers, infarct size, and cardiomyocyte apoptosis induced by IRI. Gastrin increased the phosphorylation levels of ERK1/2 (extracellular signal‐regulated kinase 1/2), AKT (protein kinase B), and STAT3 (signal transducer and activator of transcription 3), indicating its ability to activate the RISK (reperfusion injury salvage kinase) and SAFE (survivor activating factor enhancement) pathways. The presence of inhibitors of ERK1/2, AKT, or STAT3 abrogated the gastrin‐mediated protection. The protective effect of gastrin was via CCK2R (cholecystokinin 2 receptor) because the CCK2R blocker CI988 prevented the gastrin‐mediated protection of the heart with IRI. Moreover, we found a negative correlation between serum levels of cardiac troponin I and gastrin in patients with unstable angina pectoris undergoing percutaneous coronary intervention, suggesting a protective effect of gastrin in human cardiomyocytes. Conclusions These results indicate that gastrin can reduce myocardial IRI by activation of the RISK and SAFE pathways.
Diversity and Proliferation of Metallo-β-Lactamases: a Clarion Call for Clinically Effective Metallo-β-Lactamase Inhibitors

The worldwide proliferation of life-threatening metallo-β-lactamase (MBL)-producing Gram-negative bacteria is a serious concern to public health. MBLs are compromising the therapeutic efficacies of β-lactams, particularly carbapenems, which are last-resort antibiotics indicated for various multidrug-resistant bacterial infections. ABSTRACT The worldwide proliferation of life-threatening metallo-β-lactamase (MBL)-producing Gram-negative bacteria is a serious concern to public health. MBLs are compromising the therapeutic efficacies of β-lactams, particularly carbapenems, which are last-resort antibiotics indicated for various multidrug-resistant bacterial infections. Inhibition of enzymes mediating antibiotic resistance in bacteria is one of the major promising means for overcoming bacterial resistance. Compounds having potential MBL-inhibitory activity have been reported, but none are currently under clinical trials. The need for developing safe and efficient MBL inhibitors (MBLIs) is obvious, particularly with the continuous spread of MBLs worldwide. In this review, the emergence and escalation of MBLs in Gram-negative bacteria are discussed. The relationships between different class B β-lactamases identified up to 2017 are represented by a phylogenetic tree and summarized. In addition, approved and/or clinical-phase serine β-lactamase inhibitors are recapitulated to reflect the successful advances made in developing class A β-lactamase inhibitors. Reported MBLIs, their inhibitory properties, and their purported modes of inhibition are delineated. Insights into structural variations of MBLs and the challenges involved in developing potent MBLIs are also elucidated and discussed. Currently, natural products and MBL-resistant β-lactam analogues are the most promising agents that can become clinically efficient MBLIs. A deeper comprehension of the mechanisms of action and activity spectra of the various MBLs and their inhibitors will serve as a bedrock for further investigations that can result in clinically useful MBLIs to curb this global menace.
Toward a real liquid biopsy in metastatic breast and prostate cancer: Diagnostic LeukApheresis increases CTC yields in a European prospective multicenter study (CTCTrap)

Frequently, the number of circulating tumor cells (CTC) isolated in 7.5 mL of blood is too small to reliably determine tumor heterogeneity and to be representative as a “liquid biopsy”. In the EU FP7 program CTCTrap, we aimed to validate and optimize the recently introduced Diagnostic LeukApheresis (DLA) to screen liters of blood. Here we present the results obtained from 34 metastatic cancer patients subjected to DLA in the participating institutions. About 7.5 mL blood processed with CellSearch® was used as “gold standard” reference. DLAs were obtained from 22 metastatic prostate and 12 metastatic breast cancer patients at four different institutions without any noticeable side effects. DLA samples were prepared and processed with different analysis techniques. Processing DLA using CellSearch resulted in a 0–32 fold increase in CTC yield compared to processing 7.5 mL blood. Filtration of DLA through 5 μm pores microsieves was accompanied by large CTC losses. Leukocyte depletion of 18 mL followed by CellSearch yielded an increase of the number of CTC but a relative decrease in yield (37%) versus CellSearch DLA. In four out of seven patients with 0 CTC detected in 7.5 mL of blood, CTC were detected in DLA (range 1–4 CTC). The CTC obtained through DLA enables molecular characterization of the tumor. CTC enrichment technologies however still need to be improved to isolate all the CTC present in the DLA.
Real-world performance and utility of a noninvasive gene expression assay to evaluate melanoma risk in pigmented lesions

About 3 million surgical pigmented skin lesion biopsies are performed each year in the USA alone to diagnose fewer than 200 000 new cases of invasive melanoma and melanoma in situ using the current standard of care that includes visual assessment and histopathology. A recently described noninvasive adhesive patch-based gene expression rule-out test [pigmented lesion assay (PLA)] may be helpful in identifying high-risk pigmented skin lesions to aid with surgical biopsy decisions. The main objective of this utility study was to determine the real-world clinical performance of PLA use and assess how the PLA changes physician behavior in an observational cohort analysis of 381 patients assessed with the PLA. All (100%) of 51 PLA(+) test results were clinically managed with surgical biopsy. Of these, 19 (37%) were melanomas, corresponding to a number needed to biopsy of 2.7 and a biopsy ratio of 1.7. All melanomas were histopathologically classified as melanoma in situ or stage 1. Nearly all (99%) of 330 PLA(−) test results were clinically managed with surveillance. None of the three follow-up biopsies performed in the following 3–6 months, were diagnosed as melanoma histopathologically. The estimated sensitivity and specificity of the PLA from these data sets are 95 and 91%, respectively. Overall, 93% of PLA results positive for both LINC00518 and PRAME were diagnosed histopathologically as melanoma. PRAME-only and LINC00518-only lesions were melanomas histopathologically in 50 and 7%, respectively. The PLA alters clinical management of pigmented lesions and shows high clinical performance. The likelihood of positive histopathologic diagnosis of melanoma is higher in PLA results that are positive for both LINC00518 and PRAME.
Prognostic relevance of proliferation-related miRNAs in pancreatic neuroendocrine neoplasms.

Objective Pancreatic neuroendocrine neoplasms (PanNENs) are rare tumors arising from the endocrine pancreas, however their prognosis differs significantly upon their proliferative state which is characterized by histopathological grading. MiRNAs are small, noncoding RNAs posttranscriptionally regulating gene expression. Our aim was to identify miRNAs with altered expression upon proliferation which can be used as prognostic biomarkers in PanNENs. Methods MiRNA expression profiles of 40 PanNENs were downloaded from Gene Expression Omnibus and were reanalyzed upon tumor grades (discovery cohort). Results of the reanalysis were confirmed by qRT-PCR analysis of 5 miRNAs on an independent validation cohort of sixty three primary PanNEN samples. Cox proportional hazards survival regression model was fit for both univariate and multivariate analysis to determine the miRNAs' effect on progression-free and overall survival. Results 19 miRNAs displayed differential expression between tumor grades. The altered expression of 3 out of 5 chosen miRNAs was successfully validated; hsa-miR-21, hsa-miR-10a and hsa-miR-106b were up-regulated in more proliferative PanNENs compared to grade 1 tumors. In univariate analysis, higher expression of tissue hsa-miR-21, hsa-miR-10a and hsa-miR-106b expression of primary PanNENs predicted worse progression-free and overall survival, however multivariate analysis only confirmed the expression of hsa-miR-21 as an independent prognostic factor. Conclusions The expression of hsa-miR-106b, hsa-miR-10a and especially hsa-miR-21 has prognostic relevance regarding progression-free and overall survival in patients with PanNENs.
Effects of oils and solid fats on blood lipids: a systematic review and network meta-analysis[S]

The aim of this network meta-analysis (NMA) is to compare the effects of different oils/solid fats on blood lipids. Literature searches were performed until March 2018. Inclusion criteria were as follows: i) randomized trial (≥3 weeks study length) comparing at least two of the following oils/solid fats: safflower, sunflower, rapeseed, hempseed, flaxseed, corn, olive, soybean, palm, and coconut oil, and lard, beef-fat, and butter; ii) outcomes LDL-cholesterol (LDL-C), total cholesterol (TC), HDL-cholesterol (HDL-C), and triacylglycerols (TGs). A random dose-response (per 10% isocaloric exchange) NMA was performed and surface under the cumulative ranking curve (SUCRA) was estimated. Fifty-four trials were included in the NMA. Safflower oil had the highest SUCRA value for LDL-C (82%) and TC (90%), followed by rapeseed oil (76% for LDL-C, 85% for TC); whereas, palm oil (74%) had the highest SUCRA value for TG, and coconut oil (88%) for HDL-C. Safflower, sunflower, rapeseed, flaxseed, corn, olive, soybean, palm, and coconut oil as well beef fat were more effective in reducing LDL-C (−0.42 to −0.23 mmol/l) as compared with butter. Despite limitations in these data, our NMA findings are in line with existing evidence on the metabolic effects of fat and support current recommendations to replace high saturated-fat food with unsaturated oils.
Assessment of Kidney Function in Mouse Models of Glomerular Disease

The use of murine models to mimic human kidney disease is becoming increasingly common. Our research is focused on the assessment of glomerular function in diabetic nephropathy and podocyte-specific VEGF-A knock-out mice; therefore, this protocol describes the full kidney work-up used in our lab to assess these mouse models of glomerular disease, enabling a vast amount of information regarding kidney and glomerular function to be obtained from a single mouse. In comparison to alternative methods presented in the literature to assess glomerular function, the use of the method outlined in this paper enables the glomerular phenotype to be fully evaluated from multiple aspects. By using this method, the researcher can determine the kidney phenotype of the model and assess the mechanism as to why the phenotype develops. This vital information on the mechanism of disease is required when examining potential therapeutic avenues in these models. The methods allow for detailed functional assessment of the glomerular filtration barrier through measurement of the urinary albumin creatinine ratio and individual glomerular water permeability, as well as both structural and ultra-structural examination using the Periodic Acid Schiff stain and electron microscopy. Furthermore, analysis of the genes dysregulated at the mRNA and protein level enables mechanistic analysis of glomerular function. This protocol outlines the generic but adaptable methods that can be applied to all mouse models of glomerular disease.
Genetic analysis of carcass and meat quality traits in Nelore cattle.

The objective of this study was to estimate genetic parameters for carcass and meat quality traits, as well as their genetic correlations using pedigree and genomic information. A total of 3,716; 3,702; 3,439; 3,705; and 3,714 records of 12th-13th rib LM area (LMA), backfat thickness (BF), HCW, marbling score (MARB), and Warner-Bratzler peak shear force (WBSF), respectively, were used. Animals were genotyped with BovineHD BeadChip and GeneSeek Genomic Profiler Indicus HD - GGP75Ki panel. The (co)variance components were estimated by Bayesian inference using a multitrait ssGBLUP analysis. The animal model included fixed effects of contemporary group (defined by the combination of farm and year of birth, and management group at yearling) and age of animal at slaughtering as a covariate (linear). Direct additive genetic and residual effects were fitted as random. The posterior means and SD of heritabilities for LMA, BF, HCW, MARB, and WBSF were 0.28 (0.03), 0.21 (0.04), 0.21 (0.04), 0.12 (0.04), and 0.11 (0.03), respectively. The posterior means for genetic correlations between LMA and meat quality were positive and moderate with MARB (0.38 ± 0.12) and negative with WBSF (-0.47 ± 0.12). Low genetic correlations were estimated between BF and WBSF (-0.03 ± 0.16) and between HCW and MARB (-0.04 ± 0.14), indicating that these traits are not controlled by the same set or linked genes. Carcass traits (LMA, BF, and HCW) presented moderate heritability providing quick response to the selection purpose. The estimates of heritability for meat quality traits (MARB and WBSF) were low and indicate that the rate of genetic improvement for these traits would be slow. Genetic correlations indicated that selection for carcass traits would not be strongly antagonistic for improving meat quality.
Low Temperature-Enhanced Flavonol Synthesis Requires Light-Associated Regulatory Components in Arabidopsis thaliana

Plants are continuously exposed to a myriad of stresses, which lead to the formation of secondary metabolites including flavonoids. Studies suggest that low temperature exposure leads to enhanced flavonoid accumulation in Arabidopsis thaliana. In addition, flavonoid biosynthesis is regulated by light through various regulatory factors. Therefore, plants may possess the capability to integrate light and low temperature signals for survival under freezing conditions. However, the detailed molecular mechanism and the regulatory factors associated with light- and low temperature- responsive flavonoid biosynthesis remain largely unknown. Here, we report a strict requirement for light for the low temperature-enhanced flavonol biosynthesis. Low temperature-induced expression of biosynthetic genes as well as flavonol accumulation was hampered in ELONGATED HYPOCOTYL (hy5) and myb11myb111myb12 triple mutants as compared with the wild type in Arabidopsis. Overexpression of AtHY5 in the hy5 mutant restored induction of gene expression and flavonol accumulation in response to low temperature in light. Metabolite and gene expression analysis also suggests a negative role for CONSTITUTIVE PHOTOMORPHOGENIC1 (COP1) in accumulation of flavonols in response to low temperature. Overexpression of AtMYB12 enhanced accumulation of flavonols under low temperature in a light-dependent manner. Together, our analysis suggests the requirement for HY5 and flavonol-specific MYB regulatory factors for low temperature-induced flavonol synthesis.
A novel RFLP-ARMS TaqMan PCR-based method for detecting the BRAF V600E mutation in melanoma

To enable the rapid and sensitive screening of the BRAF V600E mutation in clinical samples, a novel method combining restriction fragment length polymorphism (RFLP) analysis with the popular amplification refractory mutation system (ARMS) TaqMan quantitative (qPCR) genotyping method in a single reaction tube was developed. A total of 2 primer pairs were designed to enrich for and genotype the BRAF mutational hotspot (RFLP primers and ARMS primers) and a restriction enzyme was used to remove the wild-type alleles. The analysis revealed that this method detected mutant alleles in mixed samples containing >0.1% mutant sequences. In a survey of 53 melanoma samples, this method detected 21 mutation-positive samples. This novel RFLP-ARMS TaqMan qPCR protocol may prove useful for detecting mutations in clinical samples containing only a small proportion of mutant alleles.
Exendin‐4 enhances radiation response of prostate cancer

Exendin‐4, one of the most widely used antidiabetic drugs, has recently been reported to have potential antitumor effects in cancers. Prostate cancer (PC) is one of the most common cancers in male patients with type 2 diabetes mellitus, and radiotherapy plays a vital role in the therapy of PC. Whether exendin‐4 has the potential to enhance PC response to ionizing radiation (IR) remains unknown. We aimed to explore whether exendin‐4 radiosensitizes PC cells.