Miracle-dz/UniFAR-FTUs huggingface dataset:
Valve-sparing aortic root replacement (David I procedure) in Marfan disease: single-centre 20-year experience in more than 100 patients†

OBJECTIVES Valve-sparing aortic root replacement (VSARR) is recommended for patients with aortic root dilatation and preserved aortic valve cusp morphology. The durability of VSARR in Marfan patients has been questioned. The aim of our study was to establish the long-term outcomes of VSARR in Marfan patients. METHODS Between 1993 and 2015, 582 patients underwent VSARR (David I reimplantation) at our institution. Of these patients, 104 had Marfan disease. Thirteen surgeons performed the procedures in this group. The mean follow-up time was 12 ± 5.4 years (1201 patient-years). RESULTS Early mortality was 0.96%, and long-term survival was 91% at 10 years and 76% at 20 years in Marfan patients. Marfan patients had a significantly better survival compared to non-Marfan patients (P < 0.0001). Freedom from aortic-valve reoperation was 86% at 10 years and 80% at 20 years in Marfan patients. The reoperation rate was similar in Marfan and non-Marfan patients (P = 0.60). Morphological perioperative features (untreated prolapse, commissural plasty, cusp plasty and graft size mismatch) predicted long-term mortality (P = 0.0054). Graft size mismatch and untreated prolapse predicted structural valve deterioration (both P < 0.0001). Long-term valve function in event-free survivors was excellent [mean gradient 4.2 (2.9-6.9), 98% aortic regurgitation ≤ mild]. There were no valve-related thromboembolic or bleeding events. The endocarditis rate was 0.96%. Only 17% of the patients were on oral anticoagulants during the follow-up. CONCLUSIONS VSARR using the David I reimplantation technique results in excellent long-term outcomes in Marfan patients. We present the longest follow-up period so far. The genetic disease does not affect long-term valve function. The durability of the repair is affected by morphological perioperative criteria depending on surgical expertise, and dedicated training is recommended.
A generalized framework for controlling FDR in gene regulatory network inference

Motivation Inference of gene regulatory networks (GRNs) from perturbation data can give detailed mechanistic insights of a biological system. Many inference methods exist, but the resulting GRN is generally sensitive to the choice of method‐specific parameters. Even though the inferred GRN is optimal given the parameters, many links may be wrong or missing if the data is not informative. To make GRN inference reliable, a method is needed to estimate the support of each predicted link as the method parameters are varied. Results To achieve this we have developed a method called nested bootstrapping, which applies a bootstrapping protocol to GRN inference, and by repeated bootstrap runs assesses the stability of the estimated support values. To translate bootstrap support values to false discovery rates we run the same pipeline with shuffled data as input. This provides a general method to control the false discovery rate of GRN inference that can be applied to any setting of inference parameters, noise level, or data properties. We evaluated nested bootstrapping on a simulated dataset spanning a range of such properties, using the LASSO, Least Squares, RNI, GENIE3 and CLR inference methods. An improved inference accuracy was observed in almost all situations. Nested bootstrapping was incorporated into the GeneSPIDER package, which was also used for generating the simulated networks and data, as well as running and analyzing the inferences. Availability and implementation https://bitbucket.org/sonnhammergrni/genespider/src/NB/%2BMethods/NestBoot.m
Interest of neuroimaging of social exclusion in suicide

With one million deaths worldwide, suicide is a major health issue. The frequency of life events preceding suicidal act is high and raises the question of their role in suicidal process. At biological level, dysfunctional neural processing of social exclusion may participate in suicidal risk through an increased perception of social adversity in vulnerable subjects. The purpose of this narrative review is to discuss neuroimaging findings related to social exclusion and loneliness, and to open new perspectives to investigate sensitivity to social stress in suicide.
Atorvastatin, but not pravastatin, inhibits cardiac Akt/mTOR signaling and disturbs mitochondrial ultrastructure in cardiac myocytes

Statins, which reduce LDL‐cholesterol by inhibition of 3‐hydroxy‐3‐methylglutaryl–coenzyme A reductase, are among the most widely prescribed drugs. Skeletal myopathy is a known statin‐induced adverse effect associated with mitochondrial changes. We hypothesized that similar effects would occur in cardiac myocytes in a lipophilicity‐dependent manner between 2 common statins: atorvastatin (lipophilic) and pravastatin (hydrophilic). Neonatal cardiac ventricular myocytes were treated with atorvastatin and pravastatin for 48 h. Both statins induced endoplasmic reticular (ER) stress, but only atorvastatin inhibited ERK1/2T202/Y204, AktSer473, and mammalian target of rapamycin signaling; reduced protein abundance of caveolin‐1, dystrophin, epidermal growth factor receptor, and insulin receptor‐β; decreased Ras homolog gene family member A activation; and induced apoptosis. In cardiomyocyte‐equivalent HL‐1 cells, atorvastatin, but not pravastatin, reduced mitochondrial oxygen consumption. When male mice underwent atorvastatin and pravastatin administration per os for up to 7 mo, only long‐term atorvastatin, but not pravastatin, induced elevated serum creatine kinase; swollen, misaligned, size‐variable, and disconnected cardiac mitochondria; alteration of ER structure; repression of mitochondria‐ and endoplasmic reticulum–related genes; and a 21% increase in mortality in cardiac‐specific vinculin‐knockout mice during the first 2 months of administration. To our knowledge, we are the first to demonstrate in vivo that long‐term atorvastatin administration alters cardiac ultrastructure, a finding with important clinical implications. ——Godoy, J. C. , Niesman, I. R. , Busija, A.R. , Kassan, A. , Schilling, J. M. , Schwarz, A. , Alvarez, E. A. , Dalton, N. D. , Drummond, J. C. , Roth, D.M. , Kararigas, G. , Patel, H. H. , Zemljic‐Harpf, A. E. Atorvastatin, but not pravastatin, inhibits cardiac Akt/mTOR signaling and disturbs mitochondrial ultrastructure in cardiac myocytes. FASEB J. 33, 1209–1225 (2019). www.fasebj. org
Clinical and epidemiological characteristics of hepatitis C virus-infected people who inject drugs: a Greek descriptive analysis

Background It is estimated that 17,000 people who inject drugs (PWID) in Greece have hepatitis C virus (HCV) viremia. The aim of our study was to explore the characteristics of the HCV-infected, direct acting antiviral (DAA)-naïve PWID. Methods This is a retrospective analysis of PWID with HCV infection. We selected data from six liver clinics during the period from 1st May 2014 to 31st May 2017 in order to record the characteristics of infected PWID. Results We included 800 PWID with HCV infection (78.5% male, mean age 42±10 years) who had not received DAAs before 1st June 2017. One third of the patients had comorbidities (diabetes mellitus, arterial hypertension and psychological disorders); 70% were smokers, 27% alcohol users, 67% unemployed, 29% married, and 34% had education >12 years; 65% were attending addiction programs; 57% were receiving methadone and 36% buprenorphine. Sporadic or systemic drug use was reported by 37% while 1.4% and 2.9% had HIV and HBV coinfection, respectively. The genotype distribution was 20.5%, 4.6%, 3.3%, 61% and 10% for genotypes 1a, 1b, 2, 3 and 4, respectively. Mean (±SD) liver stiffness was 9±7 kPa and 21% of the patients had cirrhosis. Half of the patients were in the F0-F1 stage of liver disease, defined as stiffness ≤7 kPa. Conclusions Our real-life data suggest that HCV genotype 3 remains the predominant genotype among PWID. One third of PWID had comorbidities and one-fifth cirrhosis. Half of PWID had early-stage liver disease and remained without access to DAAs according to the Greek prioritization criteria.
Hyper expression of MTBP may be an adverse signal for the survival of some malignant tumors

Abstract To explore the relationship between mouse double minute 2 binding protein (MTBP) and the prognosis of cancer patients, a databank-based reanalysis was conducted and a clinical observation about lung adenocarcinoma was taken to verify the result of data analysis. We reanalyzed all the downloaded data in order to make a conclusion about the relationship between MTBP and the prognosis of cancer patients. At last, we collected 112 lung cancer patients with MTBP information to verify the results of data analysis (GSE30219). The overall Kaplan–Meier curve results of 6 eligible data groups were shown in Fig. 1. The Kaplan–Meier curve result of GSE16011 was shown in Fig. 1A (concordance index = 59.48, Log-Rank Equal Curves [P = 5.942e−05], R2 = 0.045/1, risk groups hazard ratio = 1.69 [conf. int. 1.3–2.9], P = 7.344e−05), while the stratification results were displayed independently in Figs. 2 and 3. The similar results could be seen in other 5 data groups. The tissue sections of 112 patients with lung adenocarcinoma were collected and immunohistochemically stained. The hyper expression rate of MTBP in adenocarcinoma was 23.21% (26/112). The results showed that patients with hyper expression of MTBP had significantly worse prognosis than the control group, and the survival curves were clearly separated from each other (Fig. 4B, P = .000). Hyper expression of MTBP maybe an adverse event for the survival of some cancer patients, especially in glioblastoma, kidney cancer, and lung cancer patients, which has been verified in 112 lung cancer patients with MTBP status.
Change in Public Concern and Responsive Behaviors Toward Air Pollution Under the Dome

This study evaluates the effect of the documentary Under the Dome on the concern and responsive behaviors of the public regarding air pollution in China, with two surveys conducted before and after watching the documentary. Employing difference‐in‐differences regression, this study answers two research questions: (1) Does Under the Dome change public concern about air pollution? (2) Does Under the Dome change public behaviors in response to air pollution, including protective behaviors (i.e., wearing face masks) and mitigation behaviors (i.e., reducing car driving)? We find that the information campaign (1) protects against the decline of public concern about air pollution in Beijing and (2) moderates the degree to which people's perceived severity, perceived susceptibility, and sense of self‐efficacy influence protective behaviors and moderates the degree to which people's belief in the cooperative behaviors by others influences mitigation behaviors. This study provides evidence that information campaigns of the Under the Dome type are effective in raising public awareness; however, the information campaign did not directly influence public protective and mitigation behaviors.
Unsupervised Bilingual Segmentation using MDL for Machine Translation

In statistical machine translation systems, a problem arises from the weak performance in alignment due to differences in word form or granularity across different languages. To address this problem, in this paper, we pro-pose a unsupervised bilingual segmentation method using the minimum description length (MDL) principle. Our work aims at improving translation quality using a proper segmentation model (lexicon). For generating bilingual lexica, we implement a heuristic and iterative algorithm. Each entry in this bilingual lexicon is required to hold a proper length and the ability to ﬁt the data well. The results show that this bilingual segmentation signiﬁ-cantly improved the translation quality on the Chinese–Japanese and Japanese–Chinese sub-tasks.
Detection and prevention of malicious cryptocurrency mining on internet-connected devices

As technology evolves, more and more devices are connected to the Internet. The popularity and increasing significance of cryptocurriences are drawing attention, and crybercriminals are trying to utilize the resources and steal the processing power of these devices. It is highly likely that there are billions of devices that are maliciously mining cryptocurrency for the benefit of a cybercriminal without noticing the damage they may be causing. This paper is proposed because there is a huge need to professionally defend and protect against the misuse of assets in order to avoid losses, both financially and operationally, and how it is possible to mitigate with this rising trend.
Irisin promotes cardiac progenitor cell‐induced myocardial repair and functional improvement in infarcted heart

Irisin, a newly identified hormone and cardiokine, is critical for modulating body metabolism. New evidence indicates that irisin protects the heart against myocardial ischemic injury. However, whether irisin enhances cardiac progenitor cell (CPC)‐induced cardiac repair remains unknown. This study examines the effect of irisin on CPC‐induced cardiac repair when these cells are introduced into the infarcted myocardium. Nkx2.5+ CPC stable cells were isolated from mouse embryonic stem cells. Nkx2.5 + CPCs (0.5 × 10 6) were reintroduced into the infarcted myocardium using PEGlylated fibrin delivery. The mouse myocardial infarction model was created by permanent ligation of the left anterior descending (LAD) artery. Nkx2.5 + CPCs were pretreated with irisin at a concentration of 5 ng/ml in vitro for 24 hr before transplantation. Myocardial functions were evaluated by echocardiographic measurement. Eight weeks after engraftment, Nkx2.5 + CPCs improved ventricular function as evident by an increase in ejection fraction and fractional shortening. These findings are concomitant with the suppression of cardiac hypertrophy and attenuation of myocardial interstitial fibrosis. Transplantation of Nkx2.5 + CPCs promoted cardiac regeneration and neovascularization, which were increased with the pretreatment of Nkx2.5 + CPCs with irisin. Furthermore, irisin treatment promoted myocyte proliferation as indicated by proliferative markers Ki67 and phosphorylated histone 3 and decreased apoptosis. Additionally, irisin resulted in a marked reduction of histone deacetylase 4 and increased p38 acetylation in cultured CPCs. These results indicate that irisin promoted Nkx2.5 + CPC‐induced cardiac regeneration and functional improvement and that irisin serves as a novel therapeutic approach for stem cells in cardiac repair.
Maternal Deprivation Enhances Contextual Fear Memory via Epigenetically Programming Second-Hit Stress-Induced Reelin Expression in Adult Rats

Abstract Background Early-life stress increases the risk for posttraumatic stress disorder. However, the epigenetic mechanism of early-life stress-induced susceptibility to posttraumatic stress disorder in adulthood remains unclear. Methods Rat pups were exposed to maternal deprivation during postnatal days 1 to 14 for 3 hours daily and treated with the DNA methyltransferase inhibitor zebularine, L-methionine, or vehicle 7 days before contextual fear conditioning, which was used as a second stress and to mimic the reexperiencing symptom of posttraumatic stress disorder in adulthood. Long-term potentiation, dendritic spine density, DNA methyltransferase mRNA, Reelin gene methylation, and Reelin protein expression in the hippocampal CA1 were measured. Results Maternal deprivation enhanced contextual fear memory in adulthood. Meanwhile, maternal deprivation decreased DNA methyltransferase mRNA and Reelin gene methylation in the hippocampal CA1 on postnatal days 22 and 90. Reelin protein expression was increased in the hippocampal CA1 following contextual fear conditioning in adulthood. Furthermore, compared with rats that experienced maternal deprivation alone, rats also exposed to contextual fear conditioning showed an enhanced induction of hippocampal long-term potentiation and increased dendritic spine density in the hippocampal CA1 following contextual fear conditioning in adulthood. Zebularine pretreatment led to an enhancement of contextual fear memory, hypomethylation of the Reelin gene, and increased Reelin protein expression in adult rats, while L-methionine had the opposite effects. Conclusions Maternal deprivation can epigenetically program second-hit stress-induced Reelin expression and enhance the susceptibility to contextual fear memory in adulthood. These findings provide a new framework for understanding the cumulative stress hypothesis.
Hepatic Mitochondrial Defects in a Nonalcoholic Fatty Liver Disease Mouse Model Are Associated with Increased Degradation of Oxidative Phosphorylation Subunits*

2H2O-metabolic labeling approach was used to assess hepatic mitochondrial proteome dynamics in a diet-induced mouse model of non-alcoholic fatty liver disease (NAFLD). A Western-diet (WD) stimulated degradation of oxidative phosphorylation subunits in NAFLD mice liver. These changes were associated with decreased mitochondria content, impaired activities of electron transport chain complexes and ATP synthesis. Increased mitophagy contributed to enhanced degradation of mitochondrial proteins. Graphical Abstract Highlights Stability of oxidative phosphorylation subunits are reduced in a diet-induced mouse model of NAFLD. These changes are associated with impaired activities of electron transport chain complexes and ATP synthesis. Increased mitophagy contributed to enhanced degradation of mitochondrial proteins. Nonalcoholic fatty liver disease (NAFLD) is associated with hepatic mitochondrial dysfunction characterized by reduced ATP synthesis. We applied the 2H2O-metabolic labeling approach to test the hypothesis that the reduced stability of oxidative phosphorylation proteins contributes to mitochondrial dysfunction in a diet-induced mouse model of NAFLD. A high fat diet containing cholesterol (a so-called Western diet (WD)) led to hepatic oxidative stress, steatosis, inflammation and mild fibrosis, all markers of NAFLD, in low density cholesterol (LDL) receptor deficient (LDLR−/−) mice. In addition, compared with controls (LDLR−/− mice on normal diet), livers from NAFLD mice had reduced citrate synthase activity and ATP content, suggesting mitochondrial impairment. Proteome dynamics study revealed that mitochondrial defects are associated with reduced average half-lives of mitochondrial proteins in NAFLD mice (5.41 ± 0.46 versus 5.15 ± 0.49 day, p < 0.05). In particular, the WD reduced stability of oxidative phosphorylation subunits, including cytochrome b-c1 complex subunit 1 (5.9 ± 0.1 versus 3.4 ± 0.8 day), ATP synthase subunit α (6.3 ± 0.4 versus 5.5 ± 0.4 day) and ATP synthase F(0) complex subunit B1 of complex V (8.5 ± 0.6 versus 6.5 ± 0.2 day) (p < 0.05). These changes were associated with impaired complex III and F0F1-ATP synthase activities. Markers of mitophagy were increased, but proteasomal degradation activity were reduced in NAFLD mice liver, suggesting that ATP deficiency because of reduced stability of oxidative phosphorylation complex subunits contributed to inhibition of ubiquitin-proteasome and activation of mitophagy. In conclusion, the 2H2O-metabolic labeling approach shows that increased degradation of hepatic oxidative phosphorylation subunits contributed to mitochondrial impairment in NAFLD mice.
Hereditary transthyretin amyloidosis: baseline characteristics of patients in the NEURO-TTR trial

Abstract Background: Hereditary transthyretin (ATTRm) amyloidosis is a rare, progressive and fatal disease with a range of clinical manifestations. Objective: This study comprehensively evaluates disease characteristics in a large, diverse cohort of patients with ATTRm amyloidosis. Methods: Adult patients (N = 172) with Stage 1 or Stage 2 ATTRm amyloidosis who had polyneuropathy were screened and enrolled across 24 investigative sites and 10 countries in the NEURO-TTR trial (www.clinicaltrials.gov, NCT01737398). Medical and disease history, quality of life, laboratory data, and clinical assessments were analyzed. Results: The NEURO-TTR patient population was diverse in age, disease severity, TTR mutation, and organ involvement. Twenty-seven different TTR mutations were present, with Val30Met being the most common (52%). One third of patients reported early onset disease (before age 50) and the average duration of neuropathy symptoms was 5.3 years. Symptoms affected multiple organs and systems, with nearly 70% of patients exhibiting broad involvement of weakness, sensory loss, and autonomic disturbance. Over 60% of patients had cardiomyopathy, with highest prevalence in the United States (72%) and lowest in South America/Australasia (33%). Cardiac biomarker NT-proBNP correlated with left ventricular wall thickness (p<.001). Quality of life, measured by Norfolk QoL-DN and SF-36 patient-reported questionnaires, was significantly impaired and correlated with disease severity. Conclusions: Baseline data from the NEURO-TTR trial demonstrates ATTRm amyloidosis as a systemic disease with deficits in multiple organs and body systems, leading to decreased quality of life. We report concomitant presentation of polyneuropathy and cardiomyopathy in most patients, and early involvement of multiple body systems.
Importance of polyphosphate in the Leishmania life cycle

Protozoan parasites contain negatively charged polymers of a few up to several hundreds of phosphate residues. In other organisms, these poly-phosphate (polyP) chains serve as an energy source and phosphate reservoir, and have been implicated in adaptation to stress and virulence of pathogenic organisms. In this study, we confirmed first that the polyP polymerase vacuolar transporter chaperone 4 (VTC4) is responsible for polyP synthesis in Leishmania parasites. During Leishmania in vitro culture, polyP is accumulated in logarithmic growth phase and subsequently consumed once stationary phase is reached. However, polyP is not essential since VTC4-deficient (vtc4-) Leishmania proliferated normally in culture and differentiated into infective metacyclic parasites and into intracellular and axenic amastigotes. In in vivo mouse infections, L. major VTC4 knockout showed a delay in lesion formation but ultimately gave rise to strong pathology, although we were unable to restore virulence by complementation to confirm this phenotype. Knockdown of VTC4 did not alter the course of L. guyanensis infections in mice, suggesting that polyP was not required for infection, or that very low levels of it suffice for lesion development. At higher temperatures, Leishmania promastigotes highly consumed polyP, and both knockdown or deletion of VTC4 diminished parasite survival. Thus, although polyP was not essential in the life cycle of the parasite, our data suggests a role for polyP in increasing parasite survival at higher temperatures, a situation faced by the parasite when transmitted to humans.