Miracle-dz/UniFAR-FTUs huggingface dataset:
Prognostic significance of aortic valve calcium in relation to coronary artery calcification for long-term, cause-specific mortality: results from the CAC Consortium.

AIMS Aortic valve calcification (AVC) has been shown to be associated with increased cardiovascular disease (CVD) risk; however, whether this is independent of traditional risk factors and coronary artery calcification (CAC) remains unclear. METHODS AND RESULTS From the multicentre CAC Consortium database, 10 007 patients (mean 55.8±11.7 years, 64% male) with concomitant CAC and AVC scoring were included in the current analysis. AVC score was quantified using the Agatston score method and categorized as 0, 1-99, and ≥100. The endpoints were all-cause, CVD, and coronary heart disease (CHD) deaths. AVC (AVC>0) was observed in 1397 (14%) patients. During a median 7.8 (interquartile range: 4.7-10.6) years of study follow-up, 511 (5.1%) deaths occurred; 179 (35%) were CVD deaths, and 101 (19.8%) were CHD deaths. A significant interaction between CAC and AVC for mortality was observed (P<0.001). The incidence of mortality events increased with higher AVC; however, AVC ≥100 was not independently associated with all-cause, CVD, and CHD deaths after adjusting for CVD risk factors and CAC (P=0.192, 0.063, and 0.206, respectively). When further stratified by CAC<100 or ≥100, AVC ≥100 was an independent predictor of all-cause and CVD deaths only in patients with CAC <100, after adjusting for CVD risk factors and CAC [hazard ratio (HR): 1.93, 95% confidence interval (CI): 1.14-3.27; P=0.013 and HR: 2.71, 95% CI: 1.15-6.34; P=0.022, respectively]. CONCLUSION Although the overall prognostic significance of AVC was attenuated after accounting for CAC, high AVC was independently associated with all-cause and CVD deaths in patients with low coronary atherosclerosis burden.
Higher-order interactions in statistical physics and machine learning: A model-independent solution to the inverse problem at equilibrium.

The problem of inferring pairwise and higher-order interactions in complex systems involving large numbers of interacting variables, from observational data, is fundamental to many fields. Known to the statistical physics community as the inverse problem, it has become accessible in recent years due to real and simulated big data being generated. Current approaches to the inverse problem rely on parametric assumptions, physical approximations, e.g., mean-field theory, and ignoring higher-order interactions which may lead to biased or incorrect estimates. We bypass these shortcomings using a cross-disciplinary approach and demonstrate that none of these assumptions and approximations are necessary: We introduce a universal, model-independent, and fundamentally unbiased estimator of all-order symmetric interactions, via the nonparametric framework of targeted learning, a subfield of mathematical statistics. Due to its universality, our definition is readily applicable to any system at equilibrium with binary and categorical variables, be it magnetic spins, nodes in a neural network, or protein networks in biology. Our approach is targeted, not requiring fitting unnecessary parameters. Instead, it expends all data on estimating interactions, hence substantially increasing accuracy. We demonstrate the generality of our technique both analytically and numerically on (i) the two-dimensional Ising model, (ii) an Ising-type model with four-point interactions, (iii) the restricted Boltzmann machine, and (iv) simulated individual-level human DNA variants and representative traits. The latter demonstrates the applicability of this approach to discover epistatic interactions causal of disease in population biomedicine.
Cirrhotic Cardiomyopathy in the Era of Liver Transplantation: Time for Precise Stepwise Evaluation.

Liver cirrhosis (LC) is an important cause of mortality. Access to liver transplantation (LT) has significantly improved the prognosis of LC. A rigorous pre-transplant cardiac evaluation is mandatory, since cardiac dysfunction is considered the main cause of mortality after LT. Notwithstanding, the most updated pre-LT evaluation guidelines provide only an algorithm for the evaluation of major cardiovascular diseases, with no specific recommendations concerning cirrhotic cardiomyopathy (CCM), which is linked to various complications in LC, especially the development of heart failure after invasive procedures and surgical interventions, including LT. CCM is characterized by a cardiac dysfunction that includes systolic and/or diastolic dysfunction and/or electrophysiological abnormalities, in the absence of other known cardiac diseases. The role of the novel methods, tissue Doppler imaging and speckle tracking echocardiography, might be essential in the early detection of cardiac dysfunction, with prognosis implications in LC. All these new methods were only recently included in the CCM diagnosis algorithm. This review summarizes the old and novel techniques used for the diagnosis of CCM, with their diagnosis and prognostic role. It also highlights the strengths and the weaknesses of the new provided CCM diagnostic consensus, and proposes a step-by- step novel diagnostic algorithm, in order to better detect cardiac dysfunction.cirrhotic cardiomyopathy.
Scaling Up Cloud Point Extraction of Aromatic Contaminants from Wastewater in a Continuous Rotating Disk Contactor. II. Effect of Operating Temperature and Added Electrolyte

Abstract When a nonionic surfactant solution is heated above the cloud point, phase separation occurs. Two isotropic phases are formed: a micellar‐rich or coacervate phase and a micellar‐dilute phase. The organic contaminant dissolved in the wastewater tends to solubilize into the micelles and concentrate in the coacervate phase, resulting in a low concentration of contaminant in the dilute phase. In this work, this cloud point extraction (CPE) was scaled up from batch to continuous operation in a multistage rotating disk contactor to remove toluene from wastewater. The surfactant partition ratio, toluene partition ratio, and the concentration of surfactant and toluene in the coacervate phase increase with increasing temperature. The addition of NaCl shows corresponding results to an increase in temperature since NaCl can depress the cloud point. The overall volumetric mass transfer coefficient and the number of transfer unit increase, whereas the height of transfer unit decreases when temperature is raised or NaCl is added to solution.
A new picrotoxane-type sesquiterpene from Dendrobium nobile Lindl

Abstract A picrotoxane-type sesquiterpene, dendroterpene E (1), together with five benzene derivatives (2–6), were isolated from the stems of Dendrobium nobile Lindl. Their structures were elucidated by spectroscopic analysis and X-ray diffraction analysis. Compound 1 was a new picrotoxane-type sesquiterpene with a C-9/C-1/O/C-11 oxetane ring, which was first encountered in this type of compounds. Compounds 1–3 exhibited inhibitory activities against α-glycosidase. Graphical Abstract
One of us or one of them? The effects of the model’s and observer’s characteristics on placebo analgesia induced by observational learning

Previous studies have proved that observational learning can induce placebo analgesia, but the factors that influence observationally induced placebo analgesia have not yet been extensively examined. The primary goal of this study was to investigate the effect of information about the role that the observed person (model) plays in the experiment on the magnitude of the observationally induced placebo effect. This study also examined the contribution of the observer’s empathy, conformity and fear of pain to the placebo analgesia induced by observational learning. The effects induced in two experimental groups and one control group were compared. Participants in the experimental groups observed a model introduced as either another participant taking part in the study or a coworker of the experimenter. The model rated the intensity of pain induced by electrocutaneous stimuli preceded by color stimuli. One-half of all participants watched a model rating pain stimuli preceded by the color orange as higher than stimuli preceded by the color blue; for the other half, the ratings were the opposite. There was no observation in the control group. Subsequently, all participants received pain stimuli of the same intensity preceded by orange and blue stimuli and rated the intensity of the experienced pain. Placebo analgesia was found in both experimental groups. However, the way the observed model was introduced to participants did not affect the magnitude of placebo analgesia. Thus, the study showed that the role played by the model is not crucial for observationally induced placebo analgesia. The examined observer’s individual characteristics did not predict the magnitude of placebo effect.
A Novel Platform to Test In Vivo Single Gene Dependencies in t(8,21) and t(15,17) AML Confirms Zeb2 as Leukemia Target

Simple Summary Mouse models are extensively used to study human diseases, including cancer. They are particularly useful to evaluate the role of specific genes in the tumorigenic process. The platform we present allows to effectively induce in vivo silencing of any potential candidate gene in two acute myeloid leukemia mouse models, with the scope of furthering the understanding of this gene’s role in the biology of leukemia. Abstract The increased usage of high-throughput technologies in cancer research, including genetic and drug screens, generates large sets of candidate targets that need to be functionally validated for their roles in tumor development. Thus, reliable and robust in vivo model systems are needed to perform reverse genetic experiments. Ideally, these models should allow for a conditional silencing of the target and an unambiguous identification of engineered cancer cells. Here, we present a platform consisting of: (i) t(8;21) and t(15;17) driven acute myeloid leukemia (AML) transgenic mice with constitutive expression of green fluorescent protein (GFP) and inducible expression of Cre recombinase, and (ii) REX, a modified pSico lentiviral vector for inducible shRNA expression and red fluorescent protein (RFP) as a selection marker. In this system, leukemic cells from transgenic mice are transduced with REX, flow sorted, and transplanted into syngeneic hosts. Gene interference is induced in established tumors by tamoxifen treatment. Dual-color cell fluorescence guides the in vivo identification of shRNA interfered AML cells, monitoring engraftment and disease progression. We tested the platform by inducing knockdown of Zeb2, a gene upregulated by AML1-ETO and PML-RARα oncogenes in pre-leukemic hematopoietic stem cell compartment, and observed a significant delay in leukemia onset. This proves the power and utility of the platform and confirms Zeb2 contribution to the pathogenesis of AML.
Performance of human papillomavirus DNA detection in residual specimens taken for Chlamydia trachomatis and Neisseria gonorrhoeae nucleic acid amplification testing in men who have sex with men

Objectives Rectal swab specimens, either alone or pooled with first-void urine (FVU) and pharyngeal swab specimens, are used to test for Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) infection in men who have sex with men (MSM). Following introduction of human papillomavirus (HPV) vaccination for MSM attending UK sexual health services (SHSs), HPV testing of residual CT/NG test specimens has been proposed to monitor HPV prevalence in this population. Performance of HPV detection in such specimens has not been evaluated previously. Methods MSM attending a UK SHS provided three specimens: (1) rectal swab for CT/NG, (2) pooled rectal/pharyngeal/FVU specimen for CT/NG and (3) dedicated anal swab for HPV. Specimen 3 and residual material from specimens 1 and 2 were tested for type-specific HPV DNA. HPV detection was by an in-house multiplex PCR and luminex-based genotyping assay. Results A total of 129 MSM were recruited with a mean age of 38.1 years; 24% were HIV-positive. Of the 129 MSM, 92 (71%) had any type-specific HPV DNA in ≥1 specimen; 80 (62%) had high risk (HR) HPV. Of 123 participants with sufficient residual pooled and dedicated specimens, 70 (56.9%) had detectable HPV on both, and 40 (32.5%) were negative on both; overall concordance was 89% (95% CI 83% to 94%), and kappa statistic was 0.78 (95% CI 0.66 to 0.89). Pooled samples had a 4.1% (95% CI −1.9% to 10.0%) higher test positivity rate than dedicated samples.Of 125 participants with sufficient residual rectal and specimens, 74 (59.2%) had detectable HPV on both, and 36 (28.8%) were negative on both; overall concordance was 88% (95% CI 81% to 93%), and kappa statistic was 0.74 (95% CI 0.61 to 0.86). Residual rectal samples had 5.6% (95%CI −0.6% to 11.8%) higher test positivity than dedicated samples. Conclusions We observed high concordance between the dedicated and residual STI test specimens. Our data support the strategy of testing residual specimens for HPV prevalence monitoring in MSM to evaluate the impact of the targeted vaccination programme.
A robust two-stage sleep spindle detection approach using single-channel EEG

Objective. Sleep spindles in the electroencephalogram (EEG) are significant in sleep analysis related to cognitive functions and neurological diseases, and thus are of great clinical interests. An automatic sleep spindle detection algorithm could help decrease the workload of visual inspection by sleep clinicians. Approach. We propose a robust two-stage approach for sleep spindle detection using single-channel EEG. In the pre-detection stage, a stable number of sleep spindle candidates are discovered using the Teager energy operator with adaptive parameters, where the number of true sleep spindles are ensured as many as possible to maximize the detection sensitivity. In the refinement stage, representative features are designed and a bagging classifier is exploited to further recognize the true spindles from all candidates, in order to remove the false detection in the first stage. Main results. Using the union of all experts’ annotations as the ground truth, its performance outperforms state-of-the-art works in terms of F1-score (F1) on two public databases (F1: 0.814 for Montreal archive of sleep studies dataset and 0.690 for DREAMS dataset). The annotation consistency between the proposed method and certain selected expert as the trainer could exceed the consistency between two human experts. Significance. The proposed sleep spindle detection method is based on single-channel EEG thus introduces as less interference to the subjects as possible. It is robust to subject variations between databases and is capable of learning certain annotation rules, which is expected to help facilitate the manual labeling of certain experts. In addition, this method is fast enough for real-time applications.
Mitochondrial Dysfunction in Pancreatic Alpha and Beta Cells Associated with Type 2 Diabetes Mellitus

Type 2 diabetes mellitus is a complex multifactorial disease of epidemic proportions. It involves genetic and lifestyle factors that lead to dysregulations in hormone secretion and metabolic homeostasis. Accumulating evidence indicates that altered mitochondrial structure, function, and particularly bioenergetics of cells in different tissues have a central role in the pathogenesis of type 2 diabetes mellitus. In the present study, we explore how mitochondrial dysfunction impairs the coupling between metabolism and exocytosis in the pancreatic alpha and beta cells. We demonstrate that reduced mitochondrial ATP production is linked with the observed defects in insulin and glucagon secretion by utilizing computational modeling approach. Specifically, a 30–40% reduction in alpha cells’ mitochondrial function leads to a pathological shift of glucagon secretion, characterized by oversecretion at high glucose concentrations and insufficient secretion in hypoglycemia. In beta cells, the impaired mitochondrial energy metabolism is accompanied by reduced insulin secretion at all glucose levels, but the differences, compared to a normal beta cell, are the most pronounced in hyperglycemia. These findings improve our understanding of metabolic pathways and mitochondrial bioenergetics in the pathology of type 2 diabetes mellitus and might help drive the development of innovative therapies to treat various metabolic diseases.
Profiling of Silk Sericin from Cocoons of Three Southern African Wild Silk Moths with a Focus on Their Antimicrobial and Antioxidant Properties

Silk sericin was extracted from the cocoons of three Southern African wild silk moth species, namely Gonometapostica, G. rufobrunnae (Lepidoptera: Lasiocampidae), and Argema mimosae (Lepidoptera: Saturniidae); these three sericin extracts were analysed to determine the relationship that exists between their chemical structures and their functional properties. The relationship was investigated by utilising several methods that include the determination of the amino acid composition, and characterisation of the secondary structures with Fourier transformation infrared spectroscopy (FTIR) and X-ray diffraction (XRD). The antibacterial properties of these three sericin extracts were evaluated by an agar well diffusion assay with three Gram-positive bacteria (Bacillus subtilis, Staphylococcus aureus, and Staphylococcus epidermidis) as test microorganisms; and, lastly, the antioxidant properties of the three sericin extracts were determined using several scavenging methods that include the 2,2-diphenyl-1-picrylhydrazyl radical (DPPH), 2,2′-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS˙+), and the ferric reducing antioxidant power (FRAP) assay. The amino acid composition in the silk sericin extracts from G. postica, G. rufobrunnea, and Argema mimosa in terms of the polar/non-polar ratio (P/NP) was found to be 65:35, 56:44, and 59:41, respectively. The FTIR spectra of these three silk sericin extracts showed distinct major bands such as amide A (3265 cm−1), amide B (3062 cm−1), amide I (1644 cm−1), amide II (1538 cm−1), and amide III (1244 cm−1). The XRD patterns of the silk sericin extracts revealed both amorphous and α-helical structures, with small crystalline regions. All three silk sericin extracts presented potent antibacterial efficacy against the three Gram-positive bacteria and were found to have excellent antioxidant activities against the tested free radicals.
Acute Conditioning of Antigen-Expanded CD8+ T Cells via the GSK3β-mTORC Axis Differentially Dictates Their Immediate and Distal Responses after Antigen Rechallenge

Simple Summary Expanded, antigen-experienced CD8+ T cells are utilized in immunotherapy to treat infections and cancers. Antigen rechallenge of these cells leads to their re-expansion. The effector functions of re-expanded CD8+ T cells are critical for their therapeutic efficacy. We found that acute conditioning of the cells, before antigen rechallenge, impacts their effector function after re-expansion. Our data showed that acute pharmacological modulation of the GSK3β-mTORC axis with TWS119 or rapamycin, but not Torin1, before antigen rechallenge promotes the effector functions of re-expanded CD8+ T cells. These findings suggest that acute conditioning of the GSK3β-mTORC axis in expanded CD8+ T cells, before antigen rechallenge, can promote the therapeutic performance of re-expanded CD8+ T cells. Abstract CD8+ T cells protect against tumors and intracellular pathogens. The inflammatory cytokines IL-2, IL-15, and IL-7 are necessary for their expansion. However, elevated serum levels of these cytokines are often associated with cancer, poorer prognosis of cancer patients, and exhaustion of antigen-expanded CD8+ T cells. The impact of acute conditioning of antigen-expanded CD8+ T cells with these cytokines is unknown. Here, we generated antigen-expanded CD8+ T cells using dendritic cells and PC-3 cells. The cells were acutely (18–24 h) conditioned with IL-2 and either the GSK3β inhibitor TWS119, the mTORC1 inhibitor rapamycin, or the mTORC1/2 inhibitor Torin1, then their immediate and post-re-expansion (distal) cytokine responses after antigen rechallenge were evaluated. We found that acute IL-2 conditioning upregulated the immediate antigen-induced cytokine response of the tested cells. Following their re-expansion, however, the cells showed a decreased cytokine response. These IL-2 conditioning-mediated impacts were counteracted with TWS119 or rapamycin but not with Torin1. Our data revealed that the acute conditioning of antigen-expanded CD8+ T cells with IL-2 modulates the GSK3β-mTORC signaling axis. This modulation differentially affected the immediate and distal cytokine responses of the cells. The acute targeting of this signaling axis could, therefore, represent a novel strategy for the modulation of antigen-expanded CD8+ T cells.
Impact of COVID‐19 in patients with concurrent co‐infections: A systematic review and meta‐analyses

The burden and impact of secondary superadded infections in critically ill coronavirus disease 2019 (COVID‐19) patients is widely acknowledged. However, there is a dearth of information regarding the impact of COVID‐19 in patients with tuberculosis, HIV, chronic hepatitis, and other concurrent infections. This review was conducted to evaluate the consequence of severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) infection in patients with concurrent co‐infections based on the publications reported to date. An extensive comprehensive screening was conducted using electronic databases up to 3rd September 2020 after obtaining registration with PROSPERO (CRD420202064800). The observational studies or interventional studies in English, evaluating the impact of SARS‐CoV‐2 in patients with concurrent infections are included for the meta‐analyses. Our search retrieved 20 studies, with a total of 205,702 patients. Patients with tuberculosis (RR = 2.10; 95% CI, 1.75–2.51; I2 = 0%), influenza (RR = 2.04; 95% CI, 0.15–28.25, I2 = 99%) have an increased risk of mortality during a co‐infection with SARS‐CoV‐2. No significant impact is found in people living with HIV (RR = 0.99; 95% CI, 0.82–1.19; I2 = 30%), Chronic hepatitis (RR = 1.15; 95% CI, 0.73–1.81; I2 = 10%). Several countries (Brazil, Paraguay, Argentina, Peru, Colombia, and Singapore) are on the verge of a dengue co epidemic (cumulative 878,496 and 5,028,380 cases of dengue and COVID‐19 respectively). The impact of COVID‐19 in patients of concurrent infections with either tuberculosis or influenza is detrimental. The clinical outcomes of COVID‐19 in HIV or chronic hepatitis patients are comparable to COVID‐19 patients without these concurrent infections.