Miracle-dz/UniFAR-FTUs huggingface dataset:
Stage-Dependent Impact of RIPK1 Inhibition on Atherogenesis: Dual Effects on Inflammation and Foam Cell Dynamics

Objective: Atherosclerosis is an arterial occlusive disease with hypercholesterolemia and hypertension as common risk factors. Advanced-stage stenotic plaque, which features inflammation and necrotic core formation, is the major reason for clinical intervention. Receptor interacting serine/threonine-protein kinase 1 (RIPK1) mediates inflammation and cell death and is expressed in atherosclerotic lesions. The role of RIPK1 in advanced-stage atherosclerosis is unknown. Approach and Results: To investigate the effect of RIPK1 inhibition in advanced atherosclerotic plaque formation, we used ApoESA/SA mice, which exhibit hypercholesterolemia, and develop angiotensin-II mediated hypertension upon administration of doxycycline in drinking water. These mice readily develop severe atherosclerosis, including that in coronary arteries. Eight-week-old ApoESA/SA mice were randomized to orally receive a highly selective RIPK1 inhibitor (RIPK1i, GSK547) mixed with a western diet, or control diet. RIPK1i administration reduced atherosclerotic plaque lesion area at 2 weeks of treatment, consistent with suppressed inflammation (MCP-1, IL-1β, TNF-α) and reduced monocyte infiltration. However, administration of RIPK1i unexpectedly exacerbated atherosclerosis at 4 weeks of treatment, concomitant with increased macrophages and lipid deposition in the plaques. Incubation of isolated macrophages with oxidized LDL resulted in foam cell formation in vitro. RIPK1i treatment promoted such foam cell formation while suppressing the death of these cells. Accordingly, RIPK1i upregulated the expression of lipid metabolism-related genes (Cd36, Ppara, Lxrα, Lxrb, Srebp1c) in macrophage foam cells with ABCA1/ABCG1 unaltered. Furthermore, RIPK1i treatment inhibited ApoA1 synthesis in the liver and reduced plasma HDL levels. Conclusion: RIPK1 modulates the development of atherosclerosis in a stage-dependent manner, implicating both pro-atherosclerotic (monocyte infiltration and inflammation) and anti-atherosclerotic effects (suppressing foam cell accumulation and promoting ApoA1 synthesis). It is critical to identify an optimal therapeutic duration for potential clinical use of RIPK1 inhibitor in atherosclerosis or other related disease indications.
Comparative Dynamic Transcriptome Reveals the Delayed Secondary-Cell-Wall Thickening Results in Altered Lint Percentage and Fiber Elongation in a Chromosomal Segment Substitution Line of Cotton (Gossypium hirsutum L.)

Lint percentage (LP) is an important yield component in cotton that is usually affected by initial fiber number and cell wall thickness. To explore how fiber cell wall development affects LP, phenotypic identification and dynamic transcriptome analysis were conducted using a single segment substitution line of chromosome 15 (SL15) that harbors a major quantitative trait locus (QTL) for LP. Compared to its recurrent parent LMY22, SL15 did not differ in initial fiber number, but the fiber cell wall thickness and single-fiber weight decreased significantly, altering LP. The comparative transcriptome profiles revealed that the secondary cell wall (SCW) development phase of SL15 was relatively delayed. Meanwhile, the expression of genes related to cell expansion decreased more slightly in SL15 with fiber development, resulting in relatively higher expression at SL15_25D than at LMY22_25D. SCW development-related genes, such as GhNACs and GhMYBs, in the putative NAC-MYB-CESA network differentially expressed at SL15_25D, along with the lower expression of CESA6, CSLC12, and CSLA2. The substituted chromosomal interval was further investigated, and found 6 of 146 candidate genes were differentially expressed in all four cell development periods including 10, 15, 20 and 25 DPA. Genetic variation and co-expression analysis showed that GH_D01G0052, GH_D01G0099, GH_D01G0100, and GH_D01G0140 may be important candidate genes associated with qLP-C15-1. Our results provide novel insights into cell wall development and its relationship with LP, which is beneficial for lint yield and fiber quality improvement.
A Multi-Center Validated Subtyping Model of Esophageal Cancer Based on Three Metabolism-Related Genes

Metabolic reprogramming is a hallmark of malignancy. Understanding the characteristics of metabolic reprogramming in esophageal squamous cell carcinoma (ESCC) helps uncover novel targets for cancer progression. In this study, 880 metabolism-related genes were identified from microarray data and then filtered to divide patients into two subgroups using consensus clustering, which exhibits significantly different overall survival. After a differential analysis between two subtypes, 3 genes were screened out to construct a two subtypes decision model on the training cohort (GSE53624), defined as high-risk and low-risk subtypes. These risk models were then verified in two public databases (GSE53622 and TCGA-ESCC), an independent cohort of 49 ESCC patients by RT-qPCR and an external cohort of 95 ESCC patients by immunohistochemistry analysis (IHC). Furthermore, the immune cell infiltration of regulatory T cells (Tregs) and plasma cells showed a significant difference between the high and low-risk subtypes in the IHC experiment with 119 ESCC patients. In conclusion, our study indicated that three metabolism-related prognostic genes could stratify patients into subgroups and were associated with immune infiltration, clinical features and clinical outcomes.
Bioengineering Methods in MicroRNA-Mediated Direct Reprogramming of Fibroblasts Into Cardiomyocytes

Ischemic heart disease is the major cause of mortality worldwide. Despite the most recent pharmacological progresses, cardiac regeneration is yet not possible, and heart transplantation is the only therapeutic option for end-stage heart failure. Traditional cardiac regenerative medicine approaches, such as cell therapies and tissue engineering, have failed in the obtainment of human functional cardiac tissue, mainly due to unavailability of high quantities of autologous functional cardiomyocytes (CMs), low grafting efficiency, and/or arrhythmic events. Direct reprogramming (DR) of fibroblasts into induced CMs (iCMs) has emerged as a new promising approach for myocardial regeneration by in situ transdifferentiation or providing additional CM source for cell therapy. Among available DR methods, non-viral transfection with microRNAs (miRcombo: miR-1, miR-133, miR-208, and miR-499) appears promising for future clinical translation. MiRcombo transfection of fibroblasts could be significantly improved by the development of safe nanocarriers, efficiently delivering their cargo to target cells at the required stoichiometric ratio and overall dose in due times. Newly designed in vitro 3D culture microenvironments, providing biomimetic biophysical and biochemical stimuli to miRcombo-transfected cells, significantly increase the yield of fibroblast transdifferentiation into iCMs, enhancing CM gene expression. Epigenetic regulation of gene expression programs, critical to cell lineage commitment, can also be promoted by the administration of specific anti-inflammatory and anti-fibrotic soluble factors, helping in suppressing fibroblast signature. The aim of this mini-review is to introduce the readers to a relatively unknown field of cardiac research integrating bioengineering tools as relevant for the progress of miRNA-mediated cardiac DR.
Steering Does Affect Biophysical Responses in Asynchronous, but Not Synchronous Submaximal Handcycle Ergometry in Able-Bodied Men

Real-life daily handcycling requires combined propulsion and steering to control the front wheel. Today, the handcycle cranks are mostly mounted synchronously unlike the early handcycle generations. Alternatively, arm cycle ergometers do not require steering and the cranks are mostly positioned asynchronously. The current study aims to evaluate the effects of combining propulsion and steering requirements on synchronous and asynchronous submaximal handcycle ergometry. We hypothesize that asynchronous handcycling with steering results in the mechanically least efficient condition, due to compensation for unwanted rotations that are not seen in synchronous handcycling, regardless of steering. Sixteen able-bodied male novices volunteered in this lab-based experiment. The set-up consisted of a handcycle ergometer with 3D force sensors at each crank that also allows “natural” steering. Four submaximal steady-state (60 rpm, ~35 W) exercise conditions were presented in a counterbalanced order: synchronous with a fixed steering axis, synchronous with steering, asynchronous with a fixed axis and asynchronous with steering. All participants practiced 3 × 4 mins with 30 mins rest in between every condition. Finally, they did handcycle for 4 mins in each of the four conditions, interspaced with 10 mins rest, while metabolic outcomes, kinetics and kinematics of the ergometer were recorded. The additional steering component did not influence velocity, torque and power production during synchronous handcycling and therefore resulted in an equal metabolically efficient handcycling configuration compared to the fixed condition. Contrarily, asynchronous handcycling with steering requirements showed a reduced mechanical efficiency, as velocity around the steering axis increased and torque and power production were less effective. Based on the torque production around the crank and steering axes, neuromuscular compensation strategies seem necessary to prevent steering movements in the asynchronous mode. To practice or test real-life daily synchronous handcycling, a synchronous crank set-up of the ergometer is advised, as exercise performance in terms of mechanical efficiency, metabolic strain, and torque production is independent of steering requirements in that mode. Asynchronous handcycling or arm ergometry demands a different handcycle technique in terms of torque production and results in higher metabolic responses than synchronous handcycling, making it unsuitable for testing.
Automated Monitoring of Cattle Heat Stress and Its Mitigation

Climate change related global warming is likely to continue, despite all mitigation measures taken by humans, due to the lag effect of long-term anthropogenic activities. Warming of the atmosphere can impact worldwide cattle production directly by compromising health, welfare and productivity, and indirectly by reducing the quality and quantity of animal feed. Under warm thermal conditions, cattle adjust their physiological and behavioural responses as an integral part of thermoregulation to maintain internal body temperature within a safe range. However, a greater intensity and duration of heat exposure can exceed thermoregulatory capacity leading to an increase in internal body temperature beyond the normal limit that ultimately evokes different animal responses to heat. In cattle, response to heat stress can be visually observed as elevated respiration rate or panting, but continuous visual monitoring is labour intensive, time consuming and subjective. Therefore, different weather-based indices have been developed such as the temperature humidity index (THI) and heat load index (HLI) which are commonly used weather-based indices for monitoring cattle heat stress at commercial level. However, the thermal comfort level of cattle based on weather-based indices has limited use at a microclimatic and individual animal level. Varying sensor-based approaches have shown promise to shift the focus of heat stress management to the individual level. Monitoring individual animal response and mitigation strategies for isolated heat-susceptible cattle could save on heat management costs whilst improving animal welfare and productivity. Here we review the technologies that enable automatic, continuous, and real-time cattle heat stress monitoring and mitigation under commercial conditions. Future platforms for autonomous monitoring and mitigation of heat stress in cattle are likely to be based on minimally-invasive smart technologies either singly, or in an integrated system, enabling real-time solutions to animal responses under various production systems and environmental conditions.
Canonical and Non-canonical TGFβ Signaling Activate Autophagy in an ULK1-Dependent Manner

The mechanism(s) in which transforming growth factor beta 1 (TGFβ) modulates autophagy in cancer remain unclear. Here, we characterized the TGFβ signaling pathways that induce autophagy in non-small cell lung cancer cells, using cells lines stably expressing GFP-LC3-RFP-LC3ΔG constructs that measure autophagic flux. We demonstrated that TGFβ1 increases Unc 51-like kinase 1 (ULK1) protein levels, 5′ adenosine monophosphate-activated protein kinase (AMPK)-dependent ULK1 phosphorylation at serine (S) 555 and ULK1 complex formation but decreases mechanistic target of rapamycin (mTOR) activity on ULK1. Further analysis revealed that the canonical Smad4 pathway and the non-canonical TGFβ activated kinase 1/tumor necrosis factor receptor-associated factor 6/P38 mitogen activated protein kinase (TAK1-TRAF6-P38 MAPK) pathway are important for TGFβ1-induced autophagy. The TAK1-TRAF6-P38 MAPK pathway was essential for downregulating mTOR S2448 phosphorylation, ULK1 S555 phosphorylation and autophagosome formation. Furthermore, although siRNA-mediated Smad4 silencing did not alter mTOR-dependent ULK1 S757 phosphorylation, it did reduce AMPK-dependent ULK1 S555 phosphorylation and autophagosome formation. Additionally, Smad4 silencing and inhibiting the TAK1-TRAF6-P38 MAPK pathway decreased autophagosome-lysosome co-localization in the presence of TGFβ. Our results suggest that the Smad4 and TAK1-TRAF6-P38 MAPK signaling pathways are essential for TGFβ-induced autophagy and provide specific targets for the inhibition of TGFβ in tumor cells that utilize autophagy in their epithelial-mesenchymal transition program.
Comparative Transcriptome Analysis of Male Sterile Anthers Induced by High Temperature in Wheat (Triticum aestivum L.)

Global warming will have a negative effect on agricultural production as high temperature (HT) stress can seriously threaten plant growth and reproduction. Male sterility caused by HT may be exploited by the creation of a male-sterile line, which has great potential for application in crop heterosis. Therefore, it is important to understand the molecular mechanisms of anther abortion induced by HT in wheat, which remain unclear at present. In this study, we performed phenotype improve language in the abstract and comparative transcriptome analysis of the male sterile anthers induced by HT in wheat. Compared with Normal anthers, the cytological analysis indicated that HT-induced male sterile anthers were smaller and had no starch accumulation in pollen grains, which is consistent with the results observed by scanning electron microscopy (SEM). The 9601 differentially expressed genes (DEGs) identified by transcriptome sequencing compared with the Normal anthers were noticeably involved in the following pathways: starch and sucrose metabolism, phosphatidylinositol (PI) signaling system, peroxidase activity and response to oxidative stress, and heme binding. In addition, TUNEL assays were performed and the results further confirmed the excessive accumulation of reactive oxygen species (ROS) in sterile anthers. Moreover, a total of 38 hub genes were obtained from the protein-protein interaction network analysis of these pathways, including genes, for example, heat shock protein 90 (HSP90), thioredoxin-like protein 1, peroxidase (POD), calreticulin, UDP glucose pyrophosphorylase (UGPase), sucrose synthase, phosphatidylinositol-4-phosphate 5-Kinase (PIP5K), cytochrome c, and Cystathionine beta-synthase X6-like (CBSX6-like). These findings provide insights for predicting the functions of the candidate genes, and the comprehensive analysis of our results is helpful for studying the abortive interaction mechanism induced by HT in wheat.
The Roles of Macrophages in Heart Regeneration and Repair After Injury

Although great advances have been made, the problem of irreversible myocardium loss due to the limited regeneration capacity of cardiomyocytes has not been fully solved. The morbidity and mortality of heart disease still remain high. There are many therapeutic strategies for treating heart disease, while low efficacy and high cost remain challenging. Abundant evidence has shown that both acute and chronic inflammations play a crucial role in heart regeneration and repair following injury. Macrophages, a primary component of inflammation, have attracted much attention in cardiac research in recent decades. The detailed mechanisms of the roles of macrophages in heart regeneration and repair are not completely understood, in part because of their complex subsets, various functions, and intercellular communications. The purpose of this review is to summarize the progress made in the understanding of macrophages, including recent reports on macrophage differentiation, polarization and function, and involvement in heart regeneration and repair. Also, we discuss progress in treatments, which may suggest directions for future research.
Association Between Plasma Amyloid-β and Neuropsychological Performance in Patients With Cognitive Decline

Objective: To investigate the association between plasma amyloid-β (Aβ) levels and neuropsychological performance in patients with cognitive decline using a highly sensitive nano-biosensing platform. Methods: We prospectively recruited 44 patients with cognitive decline who underwent plasma Aβ analysis, amyloid positron emission tomography (PET) scanning, and detailed neuropsychological tests. Patients were classified into a normal control (NC, n = 25) or Alzheimer’s disease (AD, n = 19) group based on amyloid PET positivity. Multiple linear regression was performed to determine whether plasma Aβ (Aβ40, Aβ42, and Aβ42/40) levels were associated with neuropsychological test results. Results: The plasma levels of Aβ42/40 were significantly different between the NC and AD groups and were the best predictor of amyloid PET positivity by receiver operating characteristic curve analysis [area under the curve of 0.952 (95% confidence interval, 0.892–1.000)]. Although there were significant differences in the neuropsychological performance of cognitive domains (language, visuospatial, verbal/visual memory, and frontal/executive functions) between the NC and AD groups, higher levels of plasma Aβ42/40 were negatively correlated only with verbal and visual memory performance. Conclusion: Our results demonstrated that plasma Aβ analysis using a nano-biosensing platform could be a useful tool for diagnosing AD and assessing memory performance in patients with cognitive decline.
Immune-Related Adverse Events Associated With Immune Checkpoint Inhibitors for Advanced Non-small Cell Lung Cancer: A Network Meta-Analysis of Randomized Clinical Trials

Objective: This network meta-analysis will provide a complete toxicity profile, toxicity profile, and safety ranking of immune checkpoint inhibitors (ICIs) for treatment of advanced non-small cell lung cancer (NSCLC). Methods: We found 12 phase II or III randomized clinical trials (RCTs) including 8,453 patients with NSCLC by searching Pubmed, Embase, and ClinicalTrials.gov. Risk ratios (RRs) and 95% confidence interval (CI) were used to compare the rate of immune-related adverse events (irAEs) for different ICIs-based treatments using pairwise and network meta-analysis with random effects. Results: For dermatologic irAEs, the corresponding ranking of incidences of the seven groups from high to low was: nivolumab + ipilimumab (97.4%), pembrolizumab (80.1%), nivolumab (67.1%), pembrolizumab + platinum (43.3%), atezolizumab + platinum (39.9%), durvalumab (17.5%), platinum-based chemotherapy (4.7%). For colitis, the corresponding ranking of incidences of the six groups from high to low was: atezolizumab + platinum (77.1%), nivolumab (67.3%), pembrolizumab (60.5%), durvalumab (45.2%), pembrolizumab + platinum (41.4%), platinum-based chemotherapy (8.5%). For endocrine irAEs, the corresponding ranking of incidences of the seven groups from high to low was: nivolumab + ipilimumab (79.1%), durvalumab (69.1%), pembrolizumab (61.9%), atezolizumab + platinum (60.4%),nivolumab (45.7%), pembrolizumab + platinum (33.5%), platinum-based chemotherapy (0.3%). For pneumonitis, the corresponding ranking of incidences of the seven groups from high to low was: pembrolizumab (99.3%), pembrolizumab + platinum (65.1%), durvalumab (62.2%), atezolizumab + platinum (56%), nivolumab (35.9%), platinum-based chemotherapy (18.1%),atezolizumab (13.3%). For hepatitis, the corresponding ranking of incidences of the six groups from high to low was: pembrolizumab (71.2%), pembrolizumab + platinum (64.3%), durvalumab (56.4%), atezolizumab + platinum (53.8%), nivolumab (44.5%), platinum-based chemotherapy (9.8%). Conlusion: In addition to platinum-based chemotherapy, durvalumab for dermatologic and liver irAEs, pembrolizumab for gastrointestinal irAEs, pembrolizumab + platinum for endocrine irAEs, and atezolizumab for pneumonitis may be associated with lower rates of irAEs than other immune-based regimens. Nivolumab + ipilimumab for dermatologic and endocrine irAEs, atezolizumab + platinum for colitis, and pembrolizumab for pneumonitis and hepatitis may be associated with higher rates of irAEs.
Dissociative Symptoms in Bipolar Disorder: Impact on Clinical Course and Treatment Response

Background: Dissociative symptoms are under recognized and scarcely studied by clinicians and researchers in patients with bipolar disorder (BD). We examined the relationship between dissociative symptoms and the psychotic features in patients with BD and assessed clinical and socio-demographic characteristics more frequently associated with dissociative symptoms and treatment response. Methods: Participants were 100 adult outpatients with BD. They were screened with semi-structured interview to collect socio-demographic and clinical characteristics; the Dissociative Experiences Scale-II (DES-II) and the ALDA scale were used to assess dissociative psychopathologies and response to treatment with mood stabilizers, respectively. Results: DES score (mean 31.7 ± 21.7) correlated with clinical variables, BD features, and course of illness. Psychotic symptoms, mixed features, and previous suicide attempts significantly predicted DES score [F(3, 47) = 39.880, p < 0.001, R2 corrected = 0.713]. Dissociative symptoms were inversely correlated with poor response to treatment (r = −0.593; p < 0.001). Limitations: Cross-sectional design with a small sample and backward clinical assessment of psychotic symptoms. Conclusions: Dissociative phenomena are closely related to the presence of psychotic symptoms, mixed features, and previous suicide attempts in BD, especially in BD-I. Given the close association between dissociative and psychotic symptoms, this association could represent a diagnostic indicator of BD-I that may guide the clinician to plan the most appropriate treatment.