Miracle-dz/UniFAR-FTUs huggingface dataset:
Mitochondrial respiratory chain and Krebs cycle enzyme function in human donor livers subjected to end-ischaemic hypothermic machine perfusion

Introduction Marginal human donor livers are highly susceptible to ischaemia reperfusion injury and mitochondrial dysfunction. Oxygenation during hypothermic machine perfusion (HMP) was proposed to protect the mitochondria but the mechanism is unclear. Additionally, the distribution and uptake of perfusate oxygen during HMP are unknown. This study aimed to examine the feasibility of mitochondrial function analysis during end-ischaemic HMP, assess potential mitochondrial viability biomarkers, and record oxygenation kinetics. Methods This was a randomised pilot study using human livers retrieved for transplant but not utilised. Livers (n = 38) were randomised at stage 1 into static cold storage (n = 6), hepatic artery HMP (n = 7), and non-oxygen supplemented portal vein HMP (n = 7) and at stage 2 into oxygen supplemented and non-oxygen supplemented portal vein HMP (n = 11 and 7, respectively). Mitochondrial parameters were compared between the groups and between low- and high-risk marginal livers based on donor history, organ steatosis and preservation period. The oxygen delivery efficiency was assessed in additional 6 livers using real-time measurements of perfusate and parenchymal oxygen. Results The change in mitochondrial respiratory chain (complex I, II, III, IV) and Krebs cycle enzyme activity (aconitase, citrate synthase) before and after 4-hour preservation was not different between groups in both study stages (p > 0.05). Low-risk livers that could have been used clinically (n = 8) had lower complex II-III activities after 4-hour perfusion, compared with high-risk livers (73 nmol/mg/min vs. 113 nmol/mg/min, p = 0.01). Parenchymal pO2 was consistently lower than perfusate pO2 (p ≤ 0.001), stabilised in 28 minutes compared to 3 minutes in perfusate (p = 0.003), and decreased faster upon oxygen cessation (75 vs. 36 minutes, p = 0.003). Conclusions Actively oxygenated and air-equilibrated end-ischaemic HMP did not induce oxidative damage of aconitase, and respiratory chain complexes remained intact. Mitochondria likely respond to variable perfusate oxygen levels by adapting their respiratory function during end-ischaemic HMP. Complex II-III activities should be further investigated as viability biomarkers.
Mineralocorticoid receptor antagonists use in patients with heart failure and impaired renal function

Aims Impaired renal function is a major contributor to the low proportion of mineralocorticoid receptor antagonist (MRA) treatment in patients with heart failure with reduced ejection fraction (HFrEF). Our aims were to investigate the impact of MRA treatment on all-cause mortality and worsening renal function (WRF) in patients with HFrEF and moderately impaired renal function. Methods Retrospective data between 2010–2018 on HFrEF patients from a single-centre hospital with estimated glomerular renal function (eGFR) < 60 ml/min/1.73 m2 were analysed. WRF was defined as a decline of by eGFR ≥ 20%. Results 416 patients were included, 131 patients on MRA and 285 without MRA, mean age was 77 years (SD ± 9) and 82 years (SD ± 9), respectively. Median follow-up was 2 years. 128 patients (32%) experienced WRF, 25% in the MRA group and 30% in patients without MRA (p = 0.293). In multivariable analysis, hospitalization for heart failure and systolic blood pressure were associated with WRF (p = 0.015 and p = <0.001), but not use of MRA (p = 0.421). MRA treatment had no impact on the risk of adjusted all-cause mortality (HR 0.93; 95% CI, 0.66–1.32 p = 0.685). WRF was associated with increased adjusted risk of all-cause mortality (HR 1.43; 95% CI, 1.07–1.89 p = 0.014). Use of MRA did not increase the adjusted overall risk of mortality even when experiencing WRF (HR 1.15; 95% CI, 0.81–1.63 p = 0.422). Conclusion In this cohort of elderly HFrEF patients with moderately impaired renal function, MRA did not increase risk for WRF or all-cause mortality.
Lactococcus lactis Mutants Obtained From Laboratory Evolution Showed Elevated Vitamin K2 Content and Enhanced Resistance to Oxidative Stress

Vitamin K2 is an important vitamin for human health. Vitamin K2 enrichment in the human diet is possible by using vitamin K2-producing bacteria such as Lactococcus lactis in food fermentations. Based on previous observations that aerated cultivation conditions improved vitamin K2 content in L. lactis, we performed laboratory evolution on L. lactis MG1363 by cultivating this strain in a shake flask in a sequential propagation regime with transfers to a fresh medium every 72h. After 100 generations of propagation, we selected three evolved strains that showed improved stationary phase survival in oxygenated conditions. In comparison to the original strain MG1363, the evolved strains showed 50–110% increased vitamin K2 content and exhibited high resistance against hydrogen peroxide-induced oxidative stress. Genome sequencing of the evolved strains revealed common mutations in the genes ldh and gapB. Proteomics analysis revealed overproduction of glyceraldehyde 3-phosphate dehydrogenase (GapA), universal stress protein A2 (UspA2), and formamidopyrimidine-DNA glycosylase (MutM) under aerated conditions in evolved strains, proteins with putative functions in redox reactions, universal stress response, and DNA damage repair, all of which could contribute to the enhanced oxidative stress resistance. The mechanisms underlying elevated vitamin K2 content in the evolved strains remain to be elucidated. Two out of the three evolved strains performed similar to the original strain MG1363 in terms of growth and acidification of culture media. In conclusion, this study demonstrated a natural selection approach without genetic manipulations to obtain vitamin K2 overproducers that are highly relevant for food applications and contributed to the understanding of oxidative stress resistance in L. lactis.
Cation Overcrowding Effect on the Oxygen Evolution Reaction

The influence of electrolyte ions on the catalytic activity of electrode/electrolyte interfaces is a controversial topic for many electrocatalytic reactions. Herein, we focus on an effect that is usually neglected, namely, how the local reaction conditions are shaped by nonspecifically adsorbed cations. We scrutinize the oxygen evolution reaction (OER) at nickel (oxy)hydroxide catalysts, using a physicochemical model that integrates density functional theory calculations, a microkinetic submodel, and a mean-field submodel of the electric double layer. The aptness of the model is verified by comparison with experiments. The robustness of model-based insights against uncertainties and variations in model parameters is examined, with a sensitivity analysis using Monto Carlo simulations. We interpret the decrease in OER activity with the increasing effective size of electrolyte cations as a consequence of cation overcrowding near the negatively charged electrode surface. The same reasoning could explain why the OER activity increases with solution pH on the RHE scale and why the OER activity decreases in the presence of bivalent cations. Overall, this work stresses the importance of correctly accounting for local reaction conditions in electrocatalytic reactions to obtain an accurate picture of factors that determine the electrode activity.
Protein Lactylation Critically Regulates Energy Metabolism in the Protozoan Parasite Trypanosoma brucei

Lysine lactylation has been recognized as a novel post-translational modification occurring on histones. However, lactylation in non-histone proteins, especially in proteins of early branching organisms, is not well understood. Energy metabolism and the histone repertoire in the early diverging protozoan parasite Trypanosoma brucei, the causative agent of African trypanosomiasis, markedly diverge from those of conventional eukaryotes. Here, we present the first exhaustive proteome-wide investigation of lactylated sites in T. brucei. We identified 387 lysine-lactylated sites in 257 proteins of various cellular localizations and biological functions. Further, we revealed that glucose metabolism critically regulates protein lactylation in T. brucei although the parasite lacks lactate dehydrogenase. However, unlike mammals, increasing the glucose concentration reduced the level of lactate, and protein lactylation decreased in T. brucei via a unique lactate production pathway. In addition to providing a valuable resource, these foregoing data reveal the regulatory roles of protein lactylation of trypanosomes in energy metabolism and gene expression.
The prognostic value of peripheral total and differential leukocyte count in renal progression: A community-based study

Background Systemic inflammation is related to chronic kidney disease (CKD) patients. Elevated peripheral leukocyte count may be a herald of increased systemic inflammation and subclinical disease. Inflammation plays an important role in renal progression. The pattern of total and differential leukocyte count in CKD is not well understood. Besides, the association between total and differential leukocyte count and renal progression is still uncertain. Methods We conducted a community-based cohort study with a follow-up period of two years to evaluate the total and differential leukocyte counts and renal progression association. Results In our study population from the community with a total number of 2128, we found 15.7% (335/2128) CKD patients with a mean estimated glomerular filtration rate (eGFR) around 96 ± 26 ml/min/1.73 m2. The peripheral total leukocyte count and also differential leukocyte count were significantly negatively correlated with eGFR. A total of 56 patients (3%) experienced a rapid progression of the kidney with the definition of eGFR reduction changes of 30% or greater within two years. Univariate analysis indicated that rapid renal progression was significantly associated with male gender, co-morbidity of diabetes mellitus (DM), higher uric acid levels, higher peripheral neutrophil, monocyte, and eosinophil counts. However, only the peripheral neutrophil count was positively and independently associated with rapid renal progression after multivariate analysis. The ROC curve analysis found that the optimal cutoff value of peripheral neutrophil count for rapid progression was 2760/ mm3, with an area under the curve of 0.813. Conclusion Hyperinflammation with higher peripheral total and differential leukocyte count was noted in CKD patients. The peripheral neutrophil count was the only independent factor significantly associated with rapid renal progression. The optimal cutoff point of the peripheral neutrophil count with 2760/mm3 is useful for determining the high-risk population for rapid renal progression with a satisfying sensitivity and specificity.
Impact of persistent D-dimer elevation following recovery from COVID-19

Background Elevated D-dimer is known as predictor for severity of SARS-CoV2-infection. Increased D-dimer is associated with thromboembolic complications, but it is also a direct consequence of the acute lung injury seen in COVID-19 pneumonia. Objectives To evaluate the rate of persistent elevated D-dimer and its association with thromboembolic complications and persistent ground glass opacities (GGO) after recovery from COVID-19. Methods In this post hoc analysis of a prospective multicenter trial, patients underwent blood sampling, measurement of diffusion capacity, blood gas analysis, and multidetector computed tomography (MDCT) scan following COVID-19. In case of increased D-dimer (>0,5 μg/ml), an additional contrast medium-enhanced CT was performed in absence of contraindications. Results were compared between patients with persistent D-dimer elevation and patients with normal D-dimer level. Results 129 patients (median age 48.8 years; range 19–91 years) underwent D-Dimer assessment after a median (IQR) of 94 days (64–130) following COVID-19. D-dimer elevation was found in 15% (19/129) and was significantly more common in patients who had experienced a severe SARS-CoV2 infection that had required hospitalisation compared to patients with mild disease (p = 0.049). Contrast-medium CT (n = 15) revealed an acute pulmonary embolism in one patient and CTEPH in another patient. A significant lower mean pO2 (p = 0.015) and AaDO2 (p = 0.043) were observed in patients with persistent D-Dimer elevation, but the rate of GGO were similar in both patient groups (p = 0.33). Conclusion In 15% of the patients recovered from COVID-19, persistent D-dimer elevation was observed after a median of 3 months following COVID-19. These patients had experienced a more severe COVID and still presented more frequently a lower mean pO2 and AaDO2.
Intraperitoneal administration of human “Neo-Islets”, 3-D organoids of mesenchymal stromal and pancreatic islet cells, normalizes blood glucose levels in streptozotocin-diabetic NOD/SCID mice: Significance for clinical trials

Globally, individuals with autoimmune Type 1 diabetes mellitus (T1DM) continue to depend for survival on insulin injections. While pancreas and intrahepatic pancreatic islet transplants can produce insulin-independence and ameliorate serious complications, both therapies depend on potentially toxic anti-rejection drugs. Furthermore, the scarcity of pancreas donors and islet transplant failures limit the general availability of such interventions. Recently, fetal and induced Pluripotent Stem Cells have been successfully differentiated to generate insulin producing β-like cells that generate euglycemia in diabetic mice. However, their clinical use still depends on anti-rejection drugs or immune-isolating encapsulation systems. We reported recently that allogeneic “Neo-Islets” (NI), 3-D organoids of Mesenchymal Stromal and Islet Cells are immune protected and permanently correct autoimmune diabetes in NOD mice by omental engraftment and endocrine cell redifferentiation. This new “endocrine pancreas” delivers islet hormones physiologically into the hepatic portal vein. Furthermore, treatment of insulin-dependent dogs with allogeneic canine NIs (ongoing FDA-approved Pilot Study) consistently improved glycemic control without the need for antirejection drugs. As there remains a critical need for curative therapies of T1DM, we engineered human NIs and tested their ability, after i.p. administration, to reestablish euglycemia in streptozotocin (STZ)-diabetic NOD/SCID mice. This diabetes model reproduces, in part, the clinical situation in which recipients of allogeneic biotherapies must take potent anti-rejection drugs that similarly create a life-long immune-compromised status. The present study demonstrates that human NI therapy (2x10e5/kg bw NIs/mouse) of STZ-diabetic NOD/SCID mice (n = 6), compared to controls (n = 6) significantly improved glycemic control, and most importantly, that a second dose given to the initial group normalized blood glucose levels long-term. Conclusion: Despite the limitations of the utilized diabetic NOD/SCID mouse model, the obtained data show that human NIs are curative, an observation that has high translational relevance and significantly supports the planned conduct of clinical trials with human NIs.
Sex differences in the response to circadian disruption in diurnal sand rats

ABSTRACT Most animal model studies on physiological functions and pathologies are conducted in males. However, diseases such as depression, type 2 diabetes (T2DM) and cardiovascular disease, all show different prevalence and characteristics in females and males. Moreover, most mammal studies are conducted in nocturnal mice and rats, while modelling diurnal humans. We therefore used male and female fat sand rats (Psammomys obesus), which are diurnal in the wild, as an animal model for T2DM, to explore the effects of mild circadian disruption on behavior, glucose tolerance, cholesterol and heart weight. We found significant differences between the sexes: on average, in response to short photoperiods (SP) acclimation, males showed higher levels of depression-like behavior, lower glucose tolerance, and increased plasma cholesterol levels compared with females, with no effect on heart/body weight ratio. Females, however did show an increase in heart/body weight ratio in response to SP acclimation. We also found that regardless of sex, arrhythmic animals showed higher blood glucose levels, cholesterol levels, heart/body weight ratio, and depressive-like behavior compared with rhythmic animals. Hence, we suggest that the expression of the Circadian Syndrome could be different between males and females. Additional work with females is required to clearly delineate the specific effects in both sexes, and promote sex-based health care, prevention measures and therapies.
Quantitative proteomic analysis of hepatic tissue in allotetraploid hybridized from red crucian carp and common carp identified crucial proteins and pathways associated with metabolism and growth rate

Allotetraploid is a new species produced by distant hybridization between red crucian carp (Carassius auratus red var., abbreviated as RCC) and common carp (Cyprinus carpio L., abbreviated as CC). There is a significant difference in growth rate between allotetraploid and its parents. However, the underlying molecular mechanism is largely unknown. In this study, to find direct evidence associated with metabolism and growth rate in protein level, we performed quantitative proteomics analysis on liver tissues between allotetraploid and its parents. A total of 2502 unique proteins were identified and quantified by SWATH‐MS in our proteomics profiling. Subsequently, comprehensive bioinformatics analyses including gene ontology enrichment analysis, pathway and network analysis, and protein–protein interaction analysis (PPI) were conducted based on differentially expressed proteins (DEPs) between allotetraploid and its parents. The results revealed several significant DEPs involved in metabolism pathways in liver. More specifically, the integrative analysis highlighted that the DEPs ACSBG1, OAT, and LDHBA play vital roles in metabolism pathways including “pentose phosphate pathway,” “TCA cycle,” and “glycolysis and gluconeogenesis. ” These could directly affect the growth rate in fresh water fishes by regulating the metabolism, utilization, and exchange of substance and energy. Since the liver is the central place for metabolism activity in animals, we firstly established the comprehensive and quantitative proteomics knowledge base for liver tissue from freshwater fishes, our study may serve as an irreplaceable reference for further studies regarding fishes’ culture and growth.
Gene-Level Germline Contributions to Clinical Risk of Recurrence Scores in Black and White Patients with Breast Cancer

This study identifies race-specific genetic associations with breast cancer risk of recurrence scores and suggests mediation of these associations by PAM50 subtype and expression, with implications for clinical interpretation of these scores. Continuous risk of recurrence scores (CRS) based on tumor gene expression are vital prognostic tools for breast cancer. Studies have shown that Black women (BW) have higher CRS than White women (WW). Although systemic injustices contribute substantially to breast cancer disparities, evidence of biological and germline contributions is emerging. In this study, we investigated germline genetic associations with CRS and CRS disparity using approaches modeled after transcriptome-wide association studies (TWAS). In the Carolina Breast Cancer Study, using race-specific predictive models of tumor expression from germline genetics, we performed race-stratified (N = 1,043 WW, 1,083 BW) linear regressions of three CRS (ROR-S: PAM50 subtype score; proliferation score; ROR-P: ROR-S plus proliferation score) on imputed tumor genetically regulated tumor expression (GReX). Bayesian multivariate regression and adaptive shrinkage tested GReX-prioritized genes for associations with tumor PAM50 expression and subtype to elucidate patterns of germline regulation underlying GReX-CRS associations. At FDR-adjusted P < 0.10, 7 and 1 GReX prioritized genes among WW and BW, respectively. Among WW, CRS were positively associated with MCM10, FAM64A, CCNB2, and MMP1 GReX and negatively associated with VAV3, PCSK6, and GNG11 GReX. Among BW, higher MMP1 GReX predicted lower proliferation score and ROR-P. GReX-prioritized gene and PAM50 tumor expression associations highlighted potential mechanisms for GReX-prioritized gene to CRS associations. Among patients with breast cancer, differential germline associations with CRS were found by race, underscoring the need for larger, diverse datasets in molecular studies of breast cancer. These findings also suggest possible germline trans-regulation of PAM50 tumor expression, with potential implications for CRS interpretation in clinical settings. Significance: This study identifies race-specific genetic associations with breast cancer risk of recurrence scores and suggests mediation of these associations by PAM50 subtype and expression, with implications for clinical interpretation of these scores.
Implementation of HIV non-occupational post-exposure prophylaxis for men who have sex with men in 2 cities of Southwestern China

Abstract Non-occupational post-exposure prophylaxis (nPEP) has often relied on the joint work of emergency physicians and infectious disease specialists in busy emergency departments and human immunodeficiency virus (HIV)/sexually transmitted infections clinics abroad, where adherence education and follow-up are invariably reactive. In our pilot study, community-based organizations (CBOs) were invited to together implement the nPEP tailored to men who have sex with men (MSM) in 2 cities of Guangxi in Southwestern China, of which experiences and lessons drawn from would be provided to the promotion of nPEP in China. The study population enrolled MSM individuals prescribed nPEP from September 2017 to December 2019. One-to-one follow-ups by CBOs were applied through the treatment. Predictors of treatment completion were assessed by logistic regression. Of 271 individuals presented for nPEP, 266 MSM with documented treatment completion or non-completion, 93.6% completed the 28-day course of medication. Completion was associated with reporting side effects (aOR = .10; 95% CI: 0.02–0.38; P = .001). The follow-up rate of 91.9% was achieved based on the definition of loss to follow-up. No documented nPEP failures were found, although 1 MSM subsequently seroconverted to HIV due to ongoing high-risk behavior. CBOs’ engagement in HIV nPEP, especially the “one-to-one” follow-up supports by peer educators partly ensure adherence and retention to nPEP. Tailored interventions are needed to address the subsequent high-risk behaviors among the MSM population.
Clinicopathological features and prognosis of male breast cancer

Objective We aimed to describe the differences in clinicopathological characteristics and overall survival (OS) between male and female breast cancer patients, and to develop a prognostic nomogram to predict survival in patients with male breast cancer (MBC). Methods Using the Surveillance, Epidemiology, and End Results database, we compared age, race, histological type, histological grade, tumor size, lymph node status, metastases, estrogen/progesterone receptor (ER/PR) and HER-2 status between male and female patients, and analyzed their relationships with OS. We established a nomogram and produced a calibration curve to observe its predictive effect. Results Age, race, T stage, N stage, bone and lung metastases, and histological type and grade differed between male and female patients. OS in male patients was related to age, tumor size, metastatic site, ER/PR status, and histological grade, but not to race or lymph node status. A nomogram was established, which showed good predictive performance for survival in MBC patients (area under the curve = 0.7). Conclusion MBC has a worse prognosis than female breast cancer, mainly characterized by late onset age, late staging, high proportion of invasive non-specific histological types, high histological grade, and luminal breast cancer.