Miracle-dz/UniFAR-FTUs huggingface dataset:
Modulation of the IGF1R-MTOR pathway attenuates motor neuron toxicity of human ALS SOD1G93A astrocytes

ABSTRACT ALS (amyotrophic lateral sclerosis), the most common motor neuron disease, causes muscle denervation and rapidly fatal paralysis. While motor neurons are the most affected cells in ALS, studies on the pathophysiology of the disease have highlighted the importance of non-cell autonomous mechanisms, which implicate astrocytes and other glial cells. In ALS, subsets of reactive astrocytes lose their physiological functions and become toxic for motor neurons, thereby contributing to disease pathogenesis. Evidence of astrocyte contribution to disease pathogenesis are well established in cellular and animal models of familial ALS linked to mutant SOD1, where astrocytes promote motor neuron cell death. The mechanism underlying astrocytes reactivity in conditions of CNS injury have been shown to involve the MTOR pathway. However, the role of this conserved metabolic signaling pathway, and the potential therapeutic effects of its modulation, have not been investigated in ALS astrocytes. Here, we show elevated activation of the MTOR pathway in human-derived astrocytes harboring mutant SOD1, which results in inhibition of macroautophagy/autophagy, increased cell proliferation, and enhanced astrocyte reactivity. We demonstrate that MTOR pathway activation in mutant SOD1 astrocytes is due to post-transcriptional upregulation of the IGF1R (insulin like growth factor 1 receptor), an upstream positive modulator of the MTOR pathway. Importantly, inhibition of the IGF1R-MTOR pathway decreases cell proliferation and reactivity of mutant SOD1 astrocytes, and attenuates their toxicity to motor neurons. These results suggest that modulation of astrocytic IGF1R-MTOR pathway could be a viable therapeutic strategy in SOD1 ALS and potentially other neurological diseases. Abbreviations: ACM: astrocyte conditioned medium; AKT: AKT serine/threonine kinase; ALS: amyotrophic lateral sclerosis; BrdU: thymidine analog 5-bromo-2’-deoxyuridine; CNS: central nervous system; EIF4EBP1/4EBP1: eukaryotic translation initiation factor 4E binding protein 1; GFAP: glial fibrillary acidic protein; IGF1R: insulin like growth factor 1 receptor; INSR: insulin receptor; iPSA: iPSC-derived astrocytes; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta;MTOR: mechanistic target of rapamycin kinase; NES: nestin; PPK1: 3-phosphoinositide dependent protein kinase 1; PI: propidium iodide; PPP: picropodophyllotoxin; PTEN: phosphatase and tensin homolog; S100B/S100β: S100 calcium binding protein B; SLC1A3/ EAAT1: solute carrier family 1 member 3; SMI-32: antibody to nonphosphorylated NEFH; SOD1: superoxide dismutase 1; TUBB3: tubulin beta 3 class III; ULK1: unc-51 like autophagy activating kinase 1.
How can we manage the cardiac toxicity of immune checkpoint inhibitors?

ABSTRACT Introduction: Cancer immunotherapies with monoclonal antibodies (mAbs) against immune checkpoints (i.e. CTLA-4 and PD-1/PD-L1) have revolutionized antineoplastic treatments. Immune checkpoint inhibitors (ICIs) approved for cancer immunotherapy are mAbs anti-CTLA-4 (ipilimumab), anti-PD-1 (nivolumab, pembrolizumab, and cemiplimab), and anti-PD-L1 (atezolizumab, avelumab, and durvalumab). Treatment with ICIs can be associated with immune-related adverse events (irAEs), including an increased risk of developing myocarditis. These findings are compatible with the observation that, CTLA-4, PD-1, and PD-L1 pathways play a central role in the modulation of autoimmunity. Areas covered: In this paper, we start from examining the pathogenesis of cardiovascular adverse events from ICIs, and then we focus on risk factors and strategies to prevent and manage this cardiotoxicity. Expert opinion: There is a growing need for a multidisciplinary approach of ICI-associated cardiotoxicity, involving oncologists, cardiologists, and immunologists. Prevention and effective management of ICIs cardiotoxicity starts with an in-depth screening and surveillance strategies of high-risk patients, in order to improve early detection and appropriate management in a personalized approach.
The Fe–O coordination in iron phosphate glasses by x-ray diffraction with high energy photons

Structures of (FeO)x(P2O5)1−x glasses with 0.2 ≤ x ≤ 0.5 are studied by x-ray diffraction using high energy photons from a synchrotron. Scattering intensities are obtained up to Qmax of 250 nm−1. P–O, Fe–O and O–O first-neighbour peaks are well resolved in the pair distribution functions. Constant P–O coordination numbers of 4.0 ± 0.1 with distances of 0.155 ± 0.001 nm are found as expected for PO4 tetrahedra. Mean Fe(II)–O coordination numbers of ~5 with distances of ~0.210 nm are extracted from fitting the Fe–O peaks where the oxygen coordination number of the minor fraction of 5–18% Fe(III) was set to six with Fe–O distances of 0.200 nm. The existence of FeO5 or strongly distorted FeO6 polyhedra instead of densely packed FeO6 octahedra for the Fe(II) sites is attributed to the mixed oxide effect. Fe3+ cations in rigid FeO6 octahedra hinder the Fe2+ cations in forming well defined octahedral environments.
Interaction between LINC-ROR and Stemness State in Gastric Cancer Cells with Helicobacter pylori Infection

Background: LINC-ROR, as a cancer-related lncRNA, has vital roles in stem cell survival, pluripotency, differentiation, and self-renewal in hESCs. However, cancer-related molecular mechanisms, its functional roles, and clinical value of LINC-ROR in GC remain unclear. In this study, we aimed to investigate probable interplay between LINC-ROR with SALL4 stemness regulator and their role with the development of the disease. Methods: The mRNA expression profile of LINC-ROR and SALL4 was assessed in tumoral and adjacent non-cancerous tissues of GC patients, using quantitative real-time PCR. Results: Significant LINC-ROR underexpression and SALL4 overexpression were observed in 55.81% and 75.58% (p < 0.0001) of samples, respectively. The expression of LINC-ROR and SALL4 were significantly correlated with each other (p = 0.044). There was an association between the underexpression of LINC-ROR and sex, stage of tumor progression, tumor type, and location of tumor (p < 0.05), and H. pylori infection with SALL4 expression (p = 0.036). There were also significant correlations between concomitant mRNA expression of SALL4 and LINC-ROR in tumors located at distal noncardiac, positive for H. pylori infection, tumors with invasion into the muscle layer of the stomach, and grade II tumor (p < 0.05). Conclusion: The clinical results of the SALL4-LINC-ROR association propose a probable functional interaction between these markers in tumor maintenance and aggressiveness. Our study can help to understand one of the mechanisms involved in the progression of GC through the function of these regulators.
Impact of combined α-galactosidase and xylanase enzymes on growth performance, nutrients digestibility, chyme viscosity, and enzymes activity of broilers fed corn-soybean diets.

Two experiments were conducted to investigate the effects of a combined α-galactosidase and xylanase preparation on nutrients digestibility and growth performance in broiler chickens. Experiment 1 had 240 broilers allocated to 3 treatments with the dietary supplementation of 0, 300 and 500 g/t of the enzyme combination. Diet and amino acid (AA) digestibility were assessed. Experiment 2 was a 2 × 3 (enzyme × diet) factorial arrangement with 10 replicates of 12 male broilers per replicate. Diets were based on corn-Soybean meal (SBM) diet and had 3 nutritional levels (normal, 2% apparent metabolizable energy (AME) and crude protein (CP) reduction, and 4% AME and CP reduction). Each of these diets was fed with or without enzyme supplementation. Growth performance, chyme viscosity, nutrients digestibility, and endogenous enzymes activity were assessed. In experiment 1, enzyme supplementation improved the digestibility of Ca (P = 0.025) and ileal digestibility of total AA, Pro, Alu, Ile, Lys, His, Thr, Glu, Val, Leu, Tyr and Phe (P < 0.05), and also tended to increase the AME of diets (P < 0.10). In experiment 2, broilers fed the corn-SBM diet with 4% nutrient reduction had better growth performance (P < 0.05), jejunal digesta viscosity at 42 days (P < 0.01), and lower digestibility of gross energy (GE) (P < 0.05) when compared to those fed the normal nutrient diet. Enzyme inclusion increased digestibility of CP (P = 0.044), GE (P = 0.009), raffinose (P < 0.001) and stachyose (P < 0.001), improved average daily gain (P = 0.031), and reduced jejunal digesta viscosity at 42 days (P = 0.011). Besides, similar improvements trend in amylase, trypsin, sucrase, and maltase activity with enzyme inclusion were observed as with energy. These data support that the enzyme supplementation increased nutrients and ileal amino acid digestibility, improved performance and endogenous enzymes activity.
The Effective Use of Digoxin in a Patient with Metastatic Breast Cancer and Anthracycline-induced Cardiomyopathy

Anthracyclines have cardiotoxic side effects. Cardioprotective drugs such as angiotensin-converting enzyme inhibitors and beta-blockers are therefore recommended for patients with anthracycline-induced cardiomyopathy. We herein present a 54-year-old woman with recurrent metastatic breast cancer who developed heart failure (HF) with a left ventricular ejection fraction (LVEF) of 22% after undergoing epirubicin chemotherapy. However, her HF symptoms and low LVEF persisted despite 5 months of cardioprotective therapy and additional oral pimobendan. Pimobendan was discontinued because of ventricular arrhythmia and hypotension. After the start of low-dose (0.125 mg daily) digoxin, her LVEF increased to 42%, and her HF symptoms improved with no adverse events.
ENHANCEMENT OF TOTAL PHENOLICS AND ANTIOXIDANT PROPERTIES OF SOME TROPICAL GREEN LEAFY VEGETABLES BY STEAM COOKING

ABSTRACT This study sought to evaluate the effect of steam cooking on the vitamin C, total phenolics, total flavonoid and antioxidant properties (1,1-diphenyl-2-picrylhydrazyl [DPPH] free radical and 2,2-azinobis(3-ethylbenzo-thiazoline-6-sulfonate) [ABTS*] radical scavenging abilities, reducing property and Fe2+ chelating ability) of some tropical green leafy vegetables: Talinum triangulare, Ocimum gratissimum, Amaranthus hybridus, Telfairia occidentalis, Ipomea batata, Cnidoscolus aconitifolius, Baselia alba and Senecio biafrae leaves. The results of the study revealed that cooking causes a significant (P < 0.05) decrease in the vitamin C (raw [321.4–842.0], cooked [198.2–638.4 mg/100 g]) content. Conversely, there was a significant (P < 0.05) increase in the total phenol (raw [146.9–693.8], cooked [272.9–1037.5 mg/100 g]), total flavonoid (raw [8.2–53.0], cooked [12.9–57.4 mg/100 g]), DPPH radical scavenging ability (raw [15.7–61.8], cooked [52.8–92.7%]), reducing property (raw: 28.3–61.8; cooked: 43.9–71.6 mg/100 g ascorbic acid equivalent [AAE]), Fe2+ chelating ability (raw [17.4–75.4], cooked [22.8–89.2%]) and ABTS* scavenging ability (raw [17.4–87.3], cooked [57.5–113.2 mmol/100 g trolox equivalent antioxidant capacity]). In view of this, it could be concluded that steam cooking decreases the vitamin C content of all the vegetables, while it increased the phenolic content and antioxidant activities. PRACTICAL APPLICATIONS Consumption of fruits and vegetables has been known to be a practical approach toward the prevention and management of several degenerative diseases. Most green leafy vegetables are not eaten in their unprocessed form but are rather cooked by steaming before consumption in tropical Africa. It is well reported that vitamin C is lost during the cooking of vegetables, but recently, phenolics have been shown to be the main phytochemicals present in foods and that they play crucial roles in the management of several degenerative diseases. Cooking is an indispensable prerequisite in order to obtain safe and high-quality food products. Cooked vegetables have much better hygienic quality, and due to chemical reactions during cooking, they become more digestible and have an increased nutritional value. However, steam cooking may affect the antioxidant status of tropical green leafy vegetables due to the release of more phenolic compounds and destruction or creation of redox-active metabolites.
Point‐of‐Care Ultrasound Pronator Quadratus Hematoma Sign for Detection of Clinically Non‐Angulated Pediatric Distal Forearm Fractures

Point‐of‐care ultrasound (POCUS) diagnosis of distal forearm fractures relies on the identification of buckling or breach of hyperechoic bone cortex. We describe the pronator quadratus hematoma (PQH) formation visualized on POCUS, the PQH sign, as it may aid diagnosis of pediatric distal forearm cortical breach fractures.
Emergency Physicians’ Workstation Design: An Observational Study of Interruptions and Perception of Collaboration During Shift-End Handoffs

Background: Frequent external interruptions and lack of collaboration among team members are known to be common barriers in end-of-shift handoffs between physicians in the emergency department. In spite of being the primary location for this crucial and cognitively demanding task, workstations are not designed to limit barriers and support handoffs. Objective: The purpose of this study is to examine handoff characteristics, actual and perceived interruptions, and perceived collaboration among emergency physicians performing end-of-shift handoffs in physician workstations with varying levels of enclosures—(a) open-plan workstation, (b) enclosed workstation, and (c) semi-open workstation. Method: Handoff and interruption characteristics were captured through in-person observations of 60 handoffs using an iPad-based tool. Additionally, physicians participating in the handoffs responded to a survey pertaining to their perception of interruptions and collaboration with clinicians during each phase. Other organizational and demographic data were obtained from the hospital database, surveys, and observations. Results: Physicians working in the open workstation experienced a significantly higher number of interruptions/hour (18.08 int/hr) as compared to the semi-open (13.62 int/hr) and enclosed workstations (11.41 int/hr). Most physicians perceived that they were interrupted in the semi-open and open workstations. In addition, majority of physicians in the enclosed pod perceived high collaboration with clinicians involved in and present in the workstation during handoff. Conclusion: This correlational study showed positive outcomes experienced by physician working in the enclosed workstation as compared to the open and semi-open workstations.
Thermally-Induced Structural Changes in Wool

As wool is heated in a vacuum, the following succession of events occurs: ordinary drying, removal of strongly-bound water at 150°C, a possible glass transition in the amorphous protein at about 160°, slow formation of amide crosslinks at about 160°, melting of a small part of the ordered wool protein at 215°, rapid formation of amide cross links above 215° in the newly formed amorphous material, melting of the major ordered part of the wool protein at 235°, disulfide bond cleavage at 230-250°C, and general pyrolysis above 250°C.
Saturation of thylakoid‐associated fatty acids facilitates bioenergetic coupling in a marine diatom allowing for thermal acclimation

In a rapidly warming world, we ask, “What limits the potential of marine diatoms to acclimate to elevated temperatures? ,” a group of ecologically successful unicellular eukaryotic photoautotrophs that evolved in a cooler ocean and are critical to marine food webs. To this end, we examined thermal tolerance mechanisms related to photosynthesis in the sequenced and transformable model diatom Phaeodactylum tricornutum. Data from transmission electron microscopy (TEM) and fatty acid methyl ester‐gas chromatography mass spectrometry (FAME‐GCMS) suggest that saturating thylakoid‐associated fatty acids allowed rapid (on the order of hours) thermal tolerance up to 28.5°C. Beyond this critical temperature, thylakoid ultrastructure became severely perturbed. Biophysical analyses revealed that electrochemical leakage through the thylakoid membranes was extremely sensitive to elevated temperature (Q10 of 3.5). Data suggest that the loss of the proton motive force (pmf) occurred even when heat‐labile photosystem II (PSII) was functioning, and saturation of thylakoid‐associated fatty acids was active. Indeed, growth was inhibited when leakage of pmf through thylakoid membranes was insufficiently compensated by proton input from PSII. Our findings provide a mechanistic understanding of the importance of rapid saturation of thylakoid‐associated fatty acids for ultrastructure maintenance and a generation of pmf at elevated temperatures. To the extent these experimental results apply, the ability of diatoms to generate a pmf may be a sensitive parameter for thermal sensitivity diagnosis in phytoplankton.
Assessment Of Tumour Infiltrating Lymphocytes And Pd-l1 Expression In Adenoid Cystic Carcinoma Of The Salivary Gland.

PURPOSE Early phase clinical studies are ongoing to evaluate the role of immune checkpoint inhibitors in adenoid cystic carcinoma (ACC) despite a paucity of information on the immune microenvironment. This study aims to better characterize the immune microenvironment of ACC tumours and evaluate survival outcomes based on tumour infiltrating lymphocyte (TIL) and programmed death-ligand 1 (PD-L1) expression. METHODS Patient characteristics, treatment and outcome data were collected for 24 ACC patients. The CD8+(cluster of differentiation 8) TIL and PD-L1 expression were quantified by immunohistochemistry. Marker expression and survival outcomes were evaluated by Kaplan-Meier analysis. RESULTS All cases were negative for PD-L1 expression; four cases had focal high, eight cases had focal moderate and 12 cases had low TIL expression. Based on TIL expression, there was no difference in disease-free or overall survival. CONCLUSION Adenoid cystic carcinoma tumours were found to be associated with a poor immunogenic microenvironment, with absent PD-L1 expression and low CD8+ TILs. There was no association between TIL expression and survival. These data suggest that PD-L1 and TIL expression are unlikely to be useful as predictive biomarkers for response to immunotherapy.
Inclusion of Synovial Tissue–Derived Characteristics in a Nomogram for the Prediction of Treatment Response in Treatment‐Naive Rheumatoid Arthritis Patients

This study applied a synovitis score obtained during routine care from ultrasound (US)–guided biopsies of synovial tissue (ST) in patients with rheumatoid arthritis (RA) and patients with other inflammatory and noninflammatory joint diseases to identify pretreatment synovial biomarkers associated with disease characteristics, and to integrate the findings into a multiparameter nomogram for use in baseline prediction of diagnosis and treatment response in treatment‐naive rheumatoid arthritis (RA) patients.
Shaping the BRCAness mutational landscape by alternative double-strand break repair, replication stress and mitotic aberrancies

Abstract Tumours with mutations in the BRCA1/BRCA2 genes have impaired double-stranded DNA break repair, compromised replication fork protection and increased sensitivity to replication blocking agents, a phenotype collectively known as ‘BRCAness’. Tumours with a BRCAness phenotype become dependent on alternative repair pathways that are error-prone and introduce specific patterns of somatic mutations across the genome. The increasing availability of next-generation sequencing data of tumour samples has enabled identification of distinct mutational signatures associated with BRCAness. These signatures reveal that alternative repair pathways, including Polymerase θ-mediated alternative end-joining and RAD52-mediated single strand annealing are active in BRCA1/2-deficient tumours, pointing towards potential therapeutic targets in these tumours. Additionally, insight into the mutations and consequences of unrepaired DNA lesions may also aid in the identification of BRCA-like tumours lacking BRCA1/BRCA2 gene inactivation. This is clinically relevant, as these tumours respond favourably to treatment with DNA-damaging agents, including PARP inhibitors or cisplatin, which have been successfully used to treat patients with BRCA1/2-defective tumours. In this review, we aim to provide insight in the origins of the mutational landscape associated with BRCAness by exploring the molecular biology of alternative DNA repair pathways, which may represent actionable therapeutic targets in in these cells.
Estimated Prevalence of Harmful Alcohol Consumption in Pregnant and Nonpregnant Women in Saxony-Anhalt (NorthEast Germany) Using Biomarkers.

BACKGROUND Alcohol consumption is commonly accepted in Western societies and is a known risk factor in pregnancy, which could lead to fetal alcohol spectrum disorders (FASDs). Prevalence of alcohol consumption during pregnancy is mostly unknown. Prevalence estimates in publications based on questionnaires are limited by possible underreporting due to social stigmatization. The aim of this study was to estimate the prevalence of harmful alcohol consumption in a large cohort of pregnant women using different biomarkers related to alcohol consumption and compare the findings with those of non-pregnant women METHODS: Routine parameters known to be influenced by alcohol consumption (γ-glutamyltransferase, GGT; carbohydrate-deficient transferrin, CDT/%CDT; mean corpuscular/cell volume, MCV; combined parameter of GGT and %CDT, GGT-CDT) were analyzed in serum samples of 2,182 pregnant women and 743 non-pregnant, age-matched females. Data were tested for (i) differences between pregnant and non-pregnant women and (ii) changes across the 3 trimesters of pregnancy. RESULTS Prevalence rates differ greatly according to the parameter and cutoff, which reflects the limitations of assessing alcohol consumption with biomarkers. The prevalence of harmful alcohol consumption on the basis of a single or several elevated parameters was 13.8% (95% CI: 12.4 to 15.2) in pregnant women and 18.6% (95% CI: 15.8 to 21.4) in non-pregnant women, though 85.0% of the elevated measurements were attributable to an isolated elevation in %CDT only. Using GGT-CDT as the parameter with the highest specificity according to the literature, the estimated prevalence of harmful alcohol consumption in pregnancy is 0.5% (95% CI: 0.2 to 0.7). CONCLUSION Estimated prevalence rates differ greatly with respect to the biomarkers and cutoffs used. The use of CDT/%CDT alone appears to overestimate harmful alcohol consumption during pregnancy.
Playing pool on the beta-plane: how weak initial perturbations predetermine the long-term evolution of coherent vortices

Abstract This study explores the long-term impact of a weak initial departure from circular symmetry in coherent equivalent-barotropic vortices on their dynamics and evolution. An algorithm is developed which makes it possible to construct models of vortices that initially propagate with prescribed velocity. These solutions are used as the initial conditions for a series of numerical simulations. Simulations indicate that seemingly minor perturbations of dipolar form can control the propagation of vortices for extended periods, during which they translate over distances greatly exceeding their size. The numerical results are contrasted with the linear model, which assumes that the non-axisymmetric component of circulation in the vortex interior is relatively weak. The linear solutions reflect the self-propagation tendencies of coherent vortices to a much lesser degree, which underscores the role of fundamentally nonlinear mechanisms at play. The remarkable ability of quasi-monopolar vortices to retain the memory of weak initial perturbations helps to rationalize the wide range of the observed propagation velocities of coherent long-lived vortices in the ocean.