Miracle-dz/UniFAR-FTUs huggingface dataset:
Expression analysis of BACH1 with clinical variables using the US breast cancer patient cohort

Abstract Background Studies on functional roles of BACH1 reveal that BACH1 promotes cancer metastasis and regulates metabolic networks for metastatic processes. However, little is known about BACH1 protein expression in breast tumors and its relevance to clinical variables as a biomarker for patients with breast tumors. Methods Using a tissue microarray (TMA) of breast tumor tissues isolated from a patient cohort (N = 130) expression of BACH1 and its target gene MCT1 (encoded by SLC16A1) were monitored by immunohistochemistry (IHC) assays and scored for further analyses. We examined the association between scores of BACH1 (Allredscoretotal) or MCT1 (Hscoretotal3x2x1x) with clinical variables including: breast cancer subtypes, tissue types, tumor size, patient’s racial/ethnic background, and age group. Groups were compared using the Mann–Whitney U test (or the non-parametric Kruskal–Wallis test when appropriate) for numerical data. A proportional odds ordinal logistic model was used to examine multiple covariates. Associations between variables were evaluated with the Spearman’s correlation coefficient. Results BACH1 and MCT1 expression were detected in 90.76% (N = 118/130) and 92.30% (N = 120/130) of patients by IHC, respectively, in our study. After dichotomizing tumor size (small: 3–25 in diameter vs. big: 27–85 mm in diameter), BACH1 expression scores were significantly higher ( p = 0.015) in the bigger tumor group (mean [SD]; 4.20 [1.796]) compared with the smaller tumor group (3.920 [1.693]). Of interest, we also observed significantly higher BACH1 scores ( p = 0.004) in tumors from Black women (3.971 [1.514]; N = 69) compared with those of White women (3.02 [1.942]; N = 49). Consistent with mRNA expression analysis, BACH1 expression is most abundant in the basal-like tumors among all subtypes, specifically in Black women, whereas MCT1 expression scores are considerably higher in the basal-like tumors regardless of race. In addition, there was a positive association between BACH1 and MCT1 IHC scores in tumors from Black women, although a weak association between them in tumors from White women. In general, we did not detect associations between MCT1 IHC scores and race, tumor size, tissue types, or patient’s age. Conclusions We found strong associations of BACH1 expression with tumor size and the basal-like subtype, respectively. Importantly, BACH1 expresses significantly higher in tumors from Black women than White women, as well as in the basal-like subtype of breast tumors from Black women. Our study suggests that BACH1 expression could serve as a potential race-associated biomarker indicating poor prognosis.
SIRT1 Regulates Hepatocyte Programmed Cell Death via GSDME – IL18 Axis in Human and Mouse Liver Transplantation

Sirtuin 1 (SIRT1) is a histone/protein deacetylase involved in cellular senescence, inflammation, and stress resistance. We previously reported that myeloid SIRT1 signaling regulates the inflamed liver’s canonical pyroptosis cell death pathway. However, whether/how hepatocyte SIRT1 is engaged in programmed cell death in the cold-stressed liver remains uncertain. Here, we undertook translational studies in human and mouse orthotopic liver transplantation (OLT) to interrogate the significance of hepatocyte-specific SIRT1 signaling in cold-stored donor livers and liver grafts after reperfusion. In the clinical arm of sixty human OLT patients, hepatic SIRT1 levels in cold-preserved donor livers correlated with anti-apoptotic Bcl-2 expression. After reperfusion, improved OLT function was accompanied by hepatic SIRT1 levels negatively associated with cleaved caspase-3 expression. In the experimental arm, we compared FLOX-control with hepatocyte-specific SIRT1-KO livers after orthotopic transplantation into WT mouse recipients, parallel with primary murine hepatocyte cultures subjected to cold activation with/without knockdown of SIRT1, GSDME, and IL18Rβ signaling. Hepatocyte SIRT1 deficiency upregulated apoptosis and GSDME-mediated programmed cell death, which in turn deteriorated the hepatocellular function and shortened OLT survival. Augmented GSDME processing, accompanied by increased secretion of IL18 by stressed hepatocytes, was prominent in SIRT1-deficient, cold-stored livers. Hepatocyte SIRT1 signaling regulated anti-apoptotic Bcl-2/XIAP proteins, suppressed cold stress-triggered apoptosis, and mitigated GSDME licensing to release IL18. Notably, while crosslinking IL18R depressed SIRT1 and Bcl-2/XIAP signaling in vitro, IL18 neutralization in vivo prevented hepatocellular damage and restored the anti-apoptotic phenotype in otherwise injury-prone SIRT1-deficient OLTs. In conclusion, this translational study identifies a novel hepatocyte SIRT1-IL18 signaling circuit as a therapeutic target in the mechanism underpinning hepatocyte death in human and mouse liver transplantation.
Nonthermal processes of fast outflows from astrophysical objects

Outflows are ubiquitous phenomena in the universe. They have been widely observed in both Galactic and extragalactic objects. In this thesis, we analyze three individual sources. Firstly, we re-analyze the high energy γ-ray data of Fermi-LAT on the giant lobes of Centaurus A. We utilize for the first time the Planck observations to derive the fluxes of the lobes. The multiwavelength SEDs reveal a possible leptonic+hadronic origin of the non-thermal emission. Secondly, we re-analyze Chandra observations of the M87 jet with a total exposure time of 1500 kiloseconds to explore the X-ray emission characteristics along the jet. The variabilities of the nucleus and HST-1, as well as the photon spectra for all knots, are investigated. Fitting the radio to X- ray SEDs assuming a synchrotron origin, we show that a broken power-law electron spectrum allows a satisfactory description of the SEDs for most knots except for B, C and D, for which an additional component is needed. We discuss the implications and suggest that a stratified jet model may account for the differences. Finally, we derive the energy distribution of the ultrarelativistic electron in G1.9+0.3, which is the youngest known SNR in the Galaxy, under the assumption that the detected X-ray with Chandra and NuSTAR are of entirely synchrotron origin. The electron acceleration is found to be an order of magnitude slower than the maximum rate pro- vided by the shock acceleration in the nominal Bohm diffusion regime. We discuss the resultant implications in the context of the contribution of SNRs to the Galactic Cosmic Rays at PeV energies.
Evaluating lumateperone for its use in treating depressive episodes associated with bipolar I or II disorder in adults

ABSTRACT Introduction Lumateperone is a novel antipsychotic medication that has recently received approval by the United States Food and Drug Administration for treatment of major depressive episodes of type I and II bipolar disorder. It is approved for use as monotherapy or as an adjunctive treatment to lithium or valproic acid. Areas covered Clinical trials performed with lumateperone for bipolar disorder were reviewed. Additionally, pharmacodynamic actions of lumateperone are reviewed. Lumateperone is superior to placebo whether used alone or in combination with a mood stabilizer in patients with type I or type II bipolar disorder. It achieves this effect with minimal dopamine blockade-related side effects due to less than 50% dopamine D2 receptor occupancy. While the pharmacodynamic profile of lumateperone is unique, the mechanism of action in bipolar depression remains obscure. Expert opinion Lumateperone is an antipsychotic with full antagonist effects at the post-synaptic D2, and partial agonist effects at the presynaptic D2. This unique profile allows for both antipsychotic and antidepressant effects at the same dose, which does not produce dopamine-related side effects. Consequently, lumateperone is exceptionally well tolerated compared to other antidepressant-acting antipsychotic agents. It is now the only agent approved as an adjunct to the mood stabilizer for bipolar II depression.
Application of SNPs with low minor allele frequencies in missing person identification (MPI) through kinship analysis of DNA mixtures

The need to identify a missing person (MP) through kinship analysis of DNA samples found at a crime scene has become increasingly prevalent. DNA samples from MPs can be severely degraded, contain little DNA and mixed with other contributors, which often makes it difficult to apply conventional methods in practice. This study developed a massively parallel sequencing–based panel that contains 1661 single‐nucleotide polymorphisms (SNPs) with low minor allele frequencies (MAFs) (averaged at 0.0613) in the Chinese Han population, and the strategy for relationship inference from DNA mixtures comprising different numbers of contributors (NOCs) and of varying allele dropout probabilities. Based on the simulated dataset and genotyping results of 42 artificial DNA mixtures (NOC = 2–4), it was observed that the present SNP panel was sufficient for balanced mixtures when referenced to the closest relatives (parents/offspring and full siblings). When the mixture profiles suffered from dropout, incorrect assignments were markedly associated with relatedness, NOC and the dropout level. We, therefore, indicate that SNPs with low MAFs could be reliably interpreted for MP identification through the kinship analysis of complex DNA mixtures. Further studies should be extended to more possible scenarios to test the feasibility of this present approach.
SGLT2 Inhibitors’ Cardiovascular Benefits in Individuals Without Diabetes, Heart Failure, and/or Chronic Kidney Disease: A Systematic Review

Despite the growing body of evidence regarding the beneficial cardiovascular effects of sodium–glucose cotransporter‐2 (SGLT2) inhibitors, clinical data in individuals without diabetes, heart failure (HF), and/or chronic kidney disease (CKD) is limited. A systematic review of the literature was conducted in PubMed, Scopus, Web of Science, Cochrane Library, and Google Scholar, from database inception until May 4, 2023, to explore new evidence of SGLT2 inhibitors’ cardiovascular benefits in individuals without diabetes, HF, and/or CKD. A total of 1156 individuals from 14 studies (13 randomized controlled trials and 1 nonrandomized study) were included. The results showed the benefits of SGLT2 inhibitors on blood pressure, weight, and body mass index in this population with an acceptable safety profile. The current evidence supports the potential role of SGLT2 inhibitors as primary prevention in individuals without diabetes, HF, and/or CKD. This review may shed light on the use of SGLT2 inhibitors in conditions such as stage A HF and metabolic syndrome. The literature trend is going toward uncovering SGLT2 inhibitors’ role in stage B HF, different types of myocardial infarction, and cardiac arrhythmias.
Amphiphilic peptide Mastoparan‐B induces conformational changes within the AdeB efflux pump, down‐regulates adeB gene expression, and restores antibiotic susceptibility in an MDR strain of Acinetobacter baumannii

Mastoparan B (MP‐B) is an amphiphilic peptide with a potent antimicrobial activity against most Gram‐negative bacteria. However, there is little information available on the inhibition of the Acinetobacter baumannii resistance‐nodulation‐cell‐division (RND) efflux pump using this antimicrobial peptide. Here, we carried out a series of in‐silico experiments to find the mechanisms underlying the anti‐efflux activity of MP‐B using a multi‐drug resistant (MDR) strain of A. baumannii (AB). According to our findings, MP‐B demonstrated a potent antibacterial activity against an MDR‐AB (minimum inhibitory concentration [MIC] = 1 μg/mL) followed by a 20‐fold reduction in the adeB gene expression in the presence of sub‐MIC of this peptide. Using Groningen Machine for Chemicals Simulation (GROMACS) via PyMOL Graphical User Interface (GUI), (we observed that, the AdeB transporter had conserved helix‐turn‐helix regions and a tight pore rich in Phe and Ala residues. To understand how inhibition of the AdeB is achieved, we generated 20 apo‐MP‐B poses using the InterPep and SiteMap tools. The high‐quality model was created by homology modeling and used for docking via AutoDock/Vina to identify the MP‐B binding sites. We established that the most apo‐MP‐B formed H‐bonds to the backbone of five amino acids in the Helix‐5. As a result, the dihedral angles of the involved amino acids shift by 9.0–9.6 Ǻ, causing a change in the conformation of the AdeB protein. This led to helix conformation stereoisomerization and block the AdeB activity. MP‐B presumably has dual mechanisms. (1) It blocks the AdeB transporter by changing its conformation. (2) MP‐B influences the adeB gene expression by binding to G‐protein which laterally controls efflux regulators like MarA, RamA, SoxS, and Rob proteins.
Metachronous colorectal cancer metastasis: Who, what, when and what to do about it

Metachronous colorectal cancer (CRC) metastasis occurs due to micrometastatic disease, in up to 23% of patients who have undergone curative‐intent treatment. Metachronous metastasis tends to occur within 2 years of initial treatment. Diagnosis relies on posttreatment surveillance strategies. Care for patients with metachronous CRC metastasis is complex and requires careful multidisciplinary consideration. Those with isolated and technically resectable diseases are recommended to undergo metastasectomy with adjunct chemotherapy, however, survival, even after curative‐intent resection, is poor.
Post-tuberculosis lung disease and chronic obstructive pulmonary disease

Abstract The burden of chronic airway diseases, including chronic obstructive pulmonary disease (COPD), continues to increase, especially in low- and middle-income countries. Post-tuberculosis lung disease (PTLD) is characterized by chronic lung changes after the "cure" of pulmonary tuberculosis (TB), which may be associated with the pathogenesis of COPD. However, data on its prevalence, clinical manifestations, computed tomography features, patterns of lung function impairment, and influencing factors are limited. The pathogenic mechanisms underlying PTLD remain to be elucidated. This review summarizes the recent advances in PTLD and TB-associated COPD. Research is urgently needed both for the prevention and management of PTLD.
Research progress of plant‐derived natural alkaloids in central nervous system diseases

Central nervous system (CNS) disease is one of the most important causes of human death. Because of their complex pathogenesis, more and more attention has been paid to them. At present, drug treatment of the CNS is the main means; however, most drugs only relieve symptoms, and some have certain toxicity and side effects. Natural compounds derived from plants can provide safer and more effective alternatives. Alkaloids are common nitrogenous basic organic compounds found in nature, which exist widely in many kinds of plants and have unique application value in modern medicine. For example, Galantamine and Huperzine A from medicinal plants are widely used drugs on the market to treat Alzheimer's disease. Therefore, the main purpose of this review is to provide the available information on natural alkaloids with the activity of treating central nervous system diseases in order to explore the trends and perspectives for the further study of central nervous system drugs. In this paper, 120 alkaloids with the potential effect of treating central nervous system diseases are summarized from the aspects of sources, structure types, mechanism of action and structure–activity relationship.
Young type 1 diabetes subjects sway more than healthy persons when somatosensory system is challenged in static standing postural stability tests

In type 1 diabetes, it is important to prevent diabetes‐related complications and postural instability may be one clinically observable manifestation early on. This study was set to investigate differences between type 1 diabetics and healthy controls in variables of instrumented posturography assessment to inform about the potential of the assessment in early detection of diabetes‐related complications. Eighteen type 1 diabetics with no apparent complications (HbA1c = 58 ± 9 mmol/L, diabetes duration = 15 ± 7 years) and 35 healthy controls underwent six 1‐min two feet standing postural stability tests on a force plate. Study groups were comparable in age and anthropometric and performed the test with eyes open, eyes closed (EC), and EC head up with and without unstable padding. Type 1 diabetics exhibited greater sway (path length, p = 0.044 and standard deviation of velocity, p = 0.039) during the EC test with the unstable pad. Also, power spectral density indicated greater relative power (p = 0.043) in the high‐frequency band in the test with EC head up on the unstable pad and somatosensory activity increased more (p = 0.038) when the unstable pad was added to the EC test. Type 1 diabetes may induce subtle changes in postural control requiring more active balancing when stability is challenged. Postural assessment using a portable easy‐to‐use force plate shows promise in detecting a diabetes‐related decline in postural control that may be used as a sensitive biomarker of early‐phase diabetes‐related complications.
Extraction of Human Heart Conduction Network from Diffusion Tensor MRI

Modeling of the Conduction Network of the heart has been addressed in much research for simulating the heart’s electrical stimulation. The previous models estimate the Conduction Network depending on the early activation points of Durrer et. al. measurements and/or some dissection data where this gives an approximation to the real network. However, there are some considerable differences between Conduction Networks of different human hearts in which lead to a lake of accuracy of the provided models. A new approach is presented in this paper, where the Conduction Network can be built as a case-based structure and according to the literature this is the first method to achieve this. The method that is developed is based on the biological properties of the heart tissues as well as the working methodology of the Magnetic Resonance Imaging (MRI) scanner. Results of the produced structure were much similar to some dissection data and by employing the reconstructed Conduction Network in an inhomogeneous human model; the produced results were much similar to the measured ones.
Hypertension and NAFLD risk: Insights from the NHANES 2017–2018 and Mendelian randomization analyses

Abstract Background: Hypertension and non-alcoholic fatty liver disease (NAFLD) share several pathophysiologic risk factors, and the exact relationship between the two remains unclear. Our study aims to provide evidence concerning the relationship between hypertension and NAFLD by analyzing data from the National Health and Nutrition Examination Survey (NHANES) 2017–2018 and Mendelian randomization (MR) analyses. Methods: Weighted multivariable-adjusted logistic regression was applied to assess the relationship between hypertension and NAFLD risk by using data from the NHANES 2017–2018. Subsequently, a two-sample MR study was performed using the genome-wide association study (GWAS) summary statistics to identify the causal association between hypertension, systolic blood pressure (SBP), diastolic blood pressure (DBP), and NAFLD. The primary inverse variance weighted (IVW) and other supplementary MR approaches were conducted to verify the causal association between hypertension and NAFLD. Sensitivity analyses were adopted to confirm the robustness of the results. Results: A total of 3144 participants were enrolled for our observational study in NHANES. Weighted multivariable-adjusted logistic regression analysis suggested that hypertension was positively related to NAFLD risk (odds ratio [OR] = 1.677; 95% confidence interval [CI], 1.159–2.423). SBP ≥130 mmHg and DBP ≥80 mmHg were also significantly positively correlated with NAFLD. Moreover, hypertension was independently connected with liver steatosis (β = 7.836 [95% CI, 2.334–13.338]). The results of MR analysis also supported a causal association between hypertension (OR = 7.203 [95% CI, 2.297–22.587]) and NAFLD. Similar results were observed for the causal exploration between SBP (OR = 1.024 [95% CI, 1.003–1.046]), DBP (OR = 1.047 [95% CI, 1.005–1.090]), and NAFLD. The sensitive analysis further confirmed the robustness and reliability of these findings (all P >0.05). Conclusion: Hypertension was associated with an increased risk of NAFLD.
Tutorial on survival modeling with applications to omics data

Abstract Motivation Identification of genomic, molecular and clinical markers prognostic of patient survival is important for developing personalized disease prevention, diagnostic and treatment approaches. Modern omics technologies have made it possible to investigate the prognostic impact of markers at multiple molecular levels, including genomics, epigenomics, transcriptomics, proteomics and metabolomics, and how these potential risk factors complement clinical characterization of patient outcomes for survival prognosis. However, the massive sizes of the omics datasets, along with their correlation structures, pose challenges for studying relationships between the molecular information and patients’ survival outcomes. Results We present a general workflow for survival analysis that is applicable to high-dimensional omics data as inputs when identifying survival-associated features and validating survival models. In particular, we focus on the commonly used Cox-type penalized regressions and hierarchical Bayesian models for feature selection in survival analysis, which are especially useful for high-dimensional data, but the framework is applicable more generally. Availability and implementation A step-by-step R tutorial using The Cancer Genome Atlas survival and omics data for the execution and evaluation of survival models has been made available at https://ocbe-uio.github. io/survomics.
Shear viscosity scaling of granular suspensions across dilute to dense regimes

In this letter, following an extensive experimental validation, we perform constant-volume shearing simulations of non-Brownian granular suspensions using the discrete element method coupled with the lattice Boltzmann method. We choose a wide range of solid fractions, shear rates, fluid viscosities, particle sizes, and inter-particle frictional coefficients to obtain a scaling solution for the viscous behavior of suspensions in both dilute and dense regimes. This letter demonstrates that, with a proposed dilute-dense transitional solid fraction, $\phi_d$, there exists a strong correlation between the inverse relative viscosity and the shear stress. This work incorporates both the $\phi$-dependence and the $\dot{\gamma}$-dependence of suspension viscosity in a universal framework, which provides a scaling solution for granular suspensions across dilute and dense regimes and sheds light on the dilute-dense transition mechanisms.
Discovering User Types: Mapping User Traits by Task-Specific Behaviors in Reinforcement Learning

When assisting human users in reinforcement learning (RL), we can represent users as RL agents and study key parameters, called \emph{user traits}, to inform intervention design. We study the relationship between user behaviors (policy classes) and user traits. Given an environment, we introduce an intuitive tool for studying the breakdown of"user types": broad sets of traits that result in the same behavior. We show that seemingly different real-world environments admit the same set of user types and formalize this observation as an equivalence relation defined on environments. By transferring intervention design between environments within the same equivalence class, we can help rapidly personalize interventions.