Miracle-dz/UniFAR-FTUs huggingface dataset:
GM-CSF: A Double-Edged Sword in Cancer Immunotherapy

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a cytokine that drives the generation of myeloid cell subsets including neutrophils, monocytes, macrophages, and dendritic cells in response to stress, infections, and cancers. By modulating the functions of innate immune cells that serve as a bridge to activate adaptive immune responses, GM-CSF globally impacts host immune surveillance under pathologic conditions. As with other soluble mediators of immunity, too much or too little GM-CSF has been found to promote cancer aggressiveness. While too little GM-CSF prevents the appropriate production of innate immune cells and subsequent activation of adaptive anti-cancer immune responses, too much of GM-CSF can exhaust immune cells and promote cancer growth. The consequences of GM-CSF signaling in cancer progression are a function of the levels of GM-CSF, the cancer type, and the tumor microenvironment. In this review, we first discuss the secretion of GM-CSF, signaling downstream of the GM-CSF receptor, and GM-CSF’s role in modulating myeloid cell homeostasis. We then outline GM-CSF’s anti-tumorigenic and pro-tumorigenic effects both on the malignant cells and on the non-malignant immune and other cells in the tumor microenvironment. We provide examples of current clinical and preclinical strategies that harness GM-CSF’s anti-cancer potential while minimizing its deleterious effects. We describe the challenges in achieving the Goldilocks effect during administration of GM-CSF-based therapies to patients with cancer. Finally, we provide insights into how technologies that map the immune microenvironment spatially and temporally may be leveraged to intelligently harness GM-CSF for treatment of malignancies.
Advancing Hydroinformatics and Water Data Science Instruction: Community Perspectives and Online Learning Resources

Hydroinformatics and water data science topics are increasingly common in university graduate settings through dedicated courses and programs as well as incorporation into traditional water science courses. The technical tools and techniques emphasized by hydroinformatics and water data science involve distinctive instructional styles, which may be facilitated by online formats and materials. In the broader hydrologic sciences, there has been a simultaneous push for instructors to develop, share, and reuse content and instructional modules, particularly as the COVID-19 pandemic necessitated a wide scale pivot to online instruction. The experiences of hydroinformatics and water data science instructors in the effectiveness of content formats, instructional tools and techniques, and key topics can inform educational practice not only for those subjects, but for water science generally. This paper reports the results of surveys and interviews with hydroinformatics and water data science instructors. We address the effectiveness of instructional tools, impacts of the pandemic on education, important hydroinformatics topics, and challenges and gaps in hydroinformatics education. Guided by lessons learned from the surveys and interviews and a review of existing online learning platforms, we developed four educational modules designed to address shared topics of interest and to demonstrate the effectiveness of available tools to help overcome identified challenges. The modules are community resources that can be incorporated into courses and modified to address specific class and institutional needs or different geographic locations. Our experience with module implementation can inform development of online educational resources, which will advance and enhance instruction for hydroinformatics and broader hydrologic sciences for which students increasingly need informatics experience and technical skills.
Cross-Talk of Multiple Types of RNA Modification Regulators Uncovers the Tumor Microenvironment and Immune Infiltrates in Soft Tissue Sarcoma

Background Soft-tissue sarcoma (STS) represents a rare and diverse cohort of solid tumors, and encompasses over 100 various histologic and molecular subtypes. In recent years, RNA modifications including m6A, m5C, m1A, and m7G have been demonstrated to regulate immune response and tumorigenesis. Nevertheless, the cross-talk among these RNA modification regulators and related effects upon the tumor microenvironment (TME), immune infiltrates, and immunotherapy in STS remain poorly understood. Methods In this study, we comprehensively investigated transcriptional and genetic alterations of 32 RNA modification regulators in STS patients from The Cancer Genome Atlas (TCGA) cohort and validated them in the Gene Expression Omnibus (GEO) cohort. Single-cell transcriptomes were introduced to identify regulators within specific cell types, with own sequencing data and RT-qPCR conducted for biological validation. Distinct regulator clusters and regulator gene subtypes were identified by using unsupervised consensus clustering analysis. We further built the regulator score model based on the prognostic regulator-related differentially expressed genes (DEGs), which could be used to quantitatively assess the risk for individual STS patients. The clinical and biological characteristics of different regulator score groups were further examined. Results A total of 455 patients with STS were included in this analysis. The network of 32 RNA modification regulators demonstrated significant correlations within multiple different RNA modification types. Distinct regulator clusters and regulator gene subtypes were characterized by markedly different prognoses and TME landscapes. The low regulator score group in the TCGA-SARC cohort was characterized by poor prognosis. The robustness of the scoring model was further confirmed by the external validation in GSE30929 and GSE17674. The regulator score was negatively correlated with CD4+ T cell, Th2 cell, and Treg cell recruitment and most immunotherapy-predicted pathways, and was also associated with immunotherapy efficacy. Conclusions Overall, our study is the first to demonstrate the cross-talk of RNA modification regulators and the potential roles in TME and immune infiltrates in STS. The individualized assessment based on the regulator score model could facilitate and optimize personalized treatment.
Simulation of the Potential Suitable Distribution of the Endangered Cremastra appendiculata in China Under Global Climate Change

Predicting the spatial distribution of species in relation to suitable areas under global climate change could provide some references for conservation and long-term management strategies for the species. In this study, the MaxEnt was optimized by adjusting the feature combination and regulation magnification parameters with the ENMeval data package. Based on 127 Cremastra appendiculata spatial distribution locations and 14 environmental factors, the potential distribution areas of C. appendiculata under the present and future climate conditions (2050s, 2070s) were simulated, and the dominant environmental factors influencing the spatial distribution of C. appendiculata were analyzed. The feature combination (FC) and the regularization multiplier (RM) were selected as per the Akaike information criterion (AIC). The model showed complexity and degree of over-fitting (delta AICc = 0, omission rate = 0.106, the difference in the curve values between the training and testing areas was 0.021) after establishing the optimal model (FC = LQH and RM = 2.5), and the results indicated that the optimal model performed well in simulating the potential spatial distribution of C. appendiculata (the area under the receiver operating characteristic curve = 0.933). The results showed that the suitable habitat of C. appendiculata currently in China is 187.60 × 104 km2, while the highly suitable habitat is 118.47 × 104 km2, the moderately suitable habitat is 53.25 × 10 4 km2, and the poorly suitable habitat is 15.88 × 104 km2. There is an increasing trend in the suitable habitat of C. appendiculata under six climate scenarios, including SSP1-2.6, SSP2-4.5, and SSP5-8.5 in the 2050s and the 2070s, and that habitat will extend to the northwest as a whole. The highly suitable habitat of C. appendiculata in nature reserves is 0.47 × 104 km2; consequently, there is a large gap in the protection of C. appendiculata. The distribution of C. appendiculata was influenced by the temperature, precipitation, and normalized vegetation index.
Educational Intervention for Management of Acute Trauma Pain: A Proof-of-Concept Study in Post-surgical Trauma Patients

Objective Despite years of research and the development of countless awareness campaigns, the number of deaths related to prescription opioid overdose is steadily rising. Often, naive patients undergoing trauma-related surgery are dispensed opioids while in the hospital, resulting in an escalation to long-term opioid misuses. We explored the impact of an educational intervention to modify perceptions of opioid needs at the bedside of trauma inpatients in post-surgery pain management. Materials and Methods Twenty-eight inpatients with acute post-surgical pain completed this proof-of-concept study adopting an educational intervention related to opioids and non-pharmacological strategies in the context of acute post-surgical pain. An education assessment survey was developed to measure pre- and post-education perceptions of opioid needs to manage pain. The survey statements encompassed the patient’s perceived needs for opioids and other pharmacological and non-pharmacological therapeutics to manage acute pain. The primary outcome was the change in the patient’s perceived need for opioids. The secondary (explorative) outcome was the change in Morphine Milligram Equivalents (MME) used on the day of the educational intervention while inpatients and prescribed at the time of the hospital discharge. Results After the educational intervention, patients reported less agreement with the statement, “I think a short course of opioids (less than 5 days) is safe. ” Moreover, less agreement on using opioids to manage trauma-related pain was positively associated with a significant reduction in opioids prescribed at discharge after the educational intervention. The educational intervention might have effectively helped to cope with acute trauma-related pain while adjusting potential unrealistic expectancies about pain management and, more in general, opioid-related needs. Conclusion These findings suggest that trauma patients’ expectations and understanding of the risks associated with the long-term use of opioids can be modified by a short educational intervention delivered by health providers during the hospitalization. Establishing realistic expectations in managing acute traumatic pain may empower patients with the necessary knowledge to minimize the potential of continuous long-term opioid use, opioid misuse, and the development of post-trauma opioid abuse and/or addiction.
DMSO_A_287281 589..600

1Department of Human Nutrition, Adigrat University, Adigrat, Ethiopia; 2Department of Nutrition and Dietetics, Faculty of Public Health, Jimma University, Jimma, Ethiopia; 3Tigray Health Research Institute, Mekelle, Ethiopia Background: Metabolic Syndrome (MetS) is becoming a big public health problem in developing countries like Ethiopia. Developing countries have an almost two-fold higher risk of death due to non-communicable diseases (NCDs) compared to high-income countries. This study aimed to assess the magnitude and factors associated with MetS among adult residents of Mekelle city. Methods: A population-based cross-sectional study was carried out among 266 randomly selected adults from July to September 2019. Data were collected on socio-demographic, clinical, anthropometric, and lifestyle characteristics using a structured questionnaire adapted from the WHO STEPs survey tool. Fasting Blood Glucose (FBG) and lipid profiles were tested using a blood sample. Bivariate and multivariable logistic regression analyses were used to identify factors associated with MetS and variables were considered statistically significant at p ≤0.05. Results: The findings of this study showed the magnitude of MetS was 21.8%. The proportion of MetS was relatively higher among women (24.6%) than men (18.5%). Raised blood pressure was the most prominent (42.5%) component of MetS followed by central obesity (41.7%). The magnitude of the other components of MetS was 38.0%, 21.4%, and 14.3% for elevated triglyceride, raised FBG, and low HDL-C, respectively. Advanced age, medium and high monthly income, walking less than 10 minutes per day, raised Body Mass Index (BMI), higher waist to hip ratio, and elevated total cholesterol were significantly associated with a higher risk of metabolic syndrome. Conclusion: In this study, we found a high prevalence of metabolic syndrome and its components, which highlights an urgent need for a public health strategy for its prevention, early diagnosis, and management.
Molecular Mechanisms of Epigenetic Regulation, Inflammation, and Cell Death in ADPKD

Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder, which is caused by mutations in the PKD1 and PKD2 genes, characterizing by progressive growth of multiple cysts in the kidneys, eventually leading to end-stage kidney disease (ESKD) and requiring renal replacement therapy. In addition, studies indicate that disease progression is as a result of a combination of factors. Understanding the molecular mechanisms, therefore, should facilitate the development of precise therapeutic strategies for ADPKD treatment. The roles of epigenetic modulation, interstitial inflammation, and regulated cell death have recently become the focuses in ADPKD. Different epigenetic regulators, and the presence of inflammatory markers detectable even before cyst growth, have been linked to cyst progression. Moreover, the infiltration of inflammatory cells, such as macrophages and T cells, have been associated with cyst growth and deteriorating renal function in humans and PKD animal models. There is evidence supporting a direct role of the PKD gene mutations to the regulation of epigenetic mechanisms and inflammatory response in ADPKD. In addition, the role of regulated cell death, including apoptosis, autophagy and ferroptosis, have been investigated in ADPKD. However, there is no consensus whether cell death promotes or delays cyst growth in ADPKD. It is therefore necessary to develop an interactive picture between PKD gene mutations, the epigenome, inflammation, and cell death to understand why inherited PKD gene mutations in patients may result in the dysregulation of these processes that increase the progression of renal cyst formation.
Effect of Sacubitril/Valsartan on Reducing the Risk of Arrhythmia: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Background and Objective Relevant data of PARADIGM-HF reveals sacubitril/valsartan (SV) therapy led to a greater reduction in the risks of arrhythmia, and sudden cardiac death than angiotensin converting enzyme inhibitor (ACEI)/angiotensin receptor inhibitor (ARB) therapy in HFrEF, however, inconsistent results were reported in subsequent studies. Here, we conduct a meta-analysis of related randomized controlled trials (RCTs) to evaluate the protective effect of SV on reducing the risk of arrhythmias. Methods and Results RCTs focused on the difference in therapeutic outcomes between SV and ACEI/ARB were searched from PUBMED, EMBASE, ClinicalTrials.gov, and Cochrane Library. The results were extracted from each individual study, expressed as binary risk, 95% confidence interval (CI) and relative risk (RR). Sixteen RCTs including 22, 563 patients met the study criteria. Compared with ACEI/ARB therapy, SV therapy did significantly reduce in the risks of severe arrhythmias among patients with heart failure with reduced ejection fraction (HFrEF) (RR 0.83, 95% CI 0.73–0.95, p = 0.006), ventricular tachycardia (VT) among patients with HFrEF (RR 0.69, 95% CI 0.51–0.92, p = 0.01), cardiac arrest among patients with heart failure (HF) (RR 0.52, 95% CI 0.37–0.73, p = 0.0002), cardiac arrest among patients with HFrEF (RR 0.49, 95% CI 0.32–0.76, p = 0.001), cardiac arrest or ventricular fibrillation (VF) among patients with HF (RR 0.63, 95% CI 0.48–0.83, p = 0.001), and cardiac arrest or VF among patients with HFrEF (RR 0.65, 95% CI 0.47–0.89, p = 0.008), but reduced the risks of arrhythmias (RR 0.87, 95% CI 0.74–1.01, p = 0.07), atrial arrhythmias (RR 0.98, 95% CI 0.83–1.16, p = 0.85), and atrial fibrillation (RR 0.98, 95% CI 0.82–1.17, p = 0.82) among all patients with no significant between-group difference. The merged result was robust after sensitivity analysis, and there was no publication bias. Conclusion Our meta-analysis provides evidence that, compared with ACEI/ARB, SV can additionally reduce the risks of most arrhythmias, just the significant differences are revealed in reducing the risks of VT, severe arrhythmias, and cardiac arrest in patients with HFrEF. Besides, the positive effect of SV on VF according to statistical result of combining VF with cardiac arrest in patients with HFrEF is credibility.
Beyond LIF Neurons on Neuromorphic Hardware

Neuromorphic systems aim to provide accelerated low-power simulation of Spiking Neural Networks (SNNs), typically featuring simple and efficient neuron models such as the Leaky Integrate-and-Fire (LIF) model. Biologically plausible neuron models developed by neuroscientists are largely ignored in neuromorphic computing due to their increased computational costs. This work bridges this gap through implementation and evaluation of a single compartment Hodgkin-Huxley (HH) neuron and a multi-compartment neuron incorporating dendritic computation on the SpiNNaker, and SpiNNaker2 prototype neuromorphic systems. Numerical accuracy of the model implementations is benchmarked against reference models in the NEURON simulation environment, with excellent agreement achieved by both the fixed- and floating-point SpiNNaker implementations. The computational cost is evaluated in terms of timing measurements profiling neural state updates. While the additional model complexity understandably increases computation times relative to LIF models, it was found a wallclock time increase of only 8× was observed for the HH neuron (11× for the mutlicompartment model), demonstrating the potential of hardware accelerators in the next-generation neuromorphic system to optimize implementation of complex neuron models. The benefits of models directly corresponding to biophysiological data are demonstrated: HH neurons are able to express a range of output behaviors not captured by LIF neurons; and the dendritic compartment provides the first implementation of a spiking multi-compartment neuron model with XOR-solving capabilities on neuromorphic hardware. The work paves the way for inclusion of more biologically representative neuron models in neuromorphic systems, and showcases the benefits of hardware accelerators included in the next-generation SpiNNaker2 architecture.
Estimating the Impact of a Seasonal Fishing Moratorium on the East China Sea Ecosystem From 1997 to 2018

Fisheries management policies (FMPs) have been implemented in coastal countries to ensure a sustainable supply of seafood and the recovery of species diversity. Because of the depletion of fishery stocks, China has introduced a series of FMPs since 1995, including a seasonal fishing moratorium (SFM), a zero-growth strategy, and a minimum mesh size for fishing nets. Here, we built two mass balance models for 1997–2000 (M1997) and 2018–2019 (M2018) using Ecopath with Ecosim 6.6 to illustrate the interannual changes over the past two decades in the East China Sea (ECS). We then simulated two dynamic scenarios from 1997 to 2018, SFM (M2018SFM) and no SFM (M2018no-SFM), to test the role of the SFM under fishing pressure in the ECS. Ecopath showed that the ECS ecosystem is becoming more mature, although it is still unstable, featuring lower total primary production/total respiration, longer cycles, faster organic material circulation speed, and a higher omnivorous degree. This suggests a slow recovery for the ECS ecosystem in the past two decades. The biomass of fish in the ECS—especially the planktivores, dominated by small-sized Benthosema pterotum—significantly increased in M2018 versus M1997, but there were fewer medium- and large-sized fish. The keystone species switched from the planktivores/piscivores dominated by Decapterus maruadsi in M1997 to planktivores in M2018. Ecosim illustrated that the SFM has positive effects on fishery resources recovery, especially for commercial fishes (i.e., large yellow croakers and hairtails), as reflected by the significantly higher predicted biomass of fish in M2018SFM compared to M2018no-SFM and M1997, although the bioaccumulation was consumed by the intense fishing pressure after the SFM. However, the M2018SFM prediction for nektons was still lower than the actual value, especially for planktivores, which display a sharp increase in biomass. This should be partly attributable to the policy of the minimum mesh size (<5 cm was banned), which benefits B. pterotum due to its 3.5 cm maximum body size. Therefore, a series of FMPs, rather than only the SFM, functioned together in the ECS ecosystem. However, the mixed trophic impact indicated a negative impact if the fisheries were further developed. Fishery management in the ECS needs to be strengthened by extending the SFM and reducing fishing pressure after the SFM.
p66Shc Deficiency in Chronic Lymphocytic Leukemia Promotes Chemokine Receptor Expression Through the ROS-Dependent Inhibition of NF-κB

The microenvironment of lymphoid organs is central to the pathogenesis of chronic lymphocytic leukemia (CLL). Within it, tumor cells find a favourable niche to escape immunosurveillance and acquire pro-survival signals. We have previously reported that a CLL-associated defect in the expression of the pro-apoptotic and pro-oxidant adaptor p66Shc leads to enhanced homing to and accumulation of leukemic cells in the lymphoid microenvironment. The p66Shc deficiency-related impairment in intracellular reactive oxygen species (ROS) production in CLL cells is causally associated to the enhanced expression of the chemokine receptors CCR2, CXCR3 and CCR7, that promote leukemic cell homing to both lymphoid and non-lymphoid organs, suggesting the implication of a ROS-modulated transcription factor(s). Here we show that the activity of the ROS-responsive p65 subunit of the transcription factor NF-κB was hampered in the CLL-derived cell line MEC-1 expressing a NF-κB-luciferase reporter following treatment with H2O2. Similar results were obtained when intracellular ROS were generated by expression of p66Shc, but not of a ROS-defective mutant, in MEC-1 cells. NF-κB activation was associated with increased expression of the chemokine receptors CCR2, CXCR3 and CCR7. Reconstitution of p66Shc in CLL cells normalized intracellular ROS and hampered NF-κB activation, which led to a decrease in the expression of these homing receptors. Our data provide direct evidence that the p66Shc-deficiency-related ROS depletion in CLL cells concurs to NF-κB hyperactivation and homing receptor overexpression, providing a mechanistic basis for the enhanced ability of these cells to accumulate in the pro-survival lymphoid niche.