Miracle-dz/UniFAR-FTUs huggingface dataset:
Ferroptosis as a target for protection against cardiomyopathy

Significance Nonapoptotic cell death-induced tissue damage has been implicated in a variety of diseases, including neurodegenerative disorder, inflammation, and stroke. In this study, we demonstrate that ferroptosis, a newly defined iron-dependent cell death, mediates both chemotherapy- and ischemia/reperfusion-induced cardiomyopathy. RNA-sequencing analysis revealed up-regulation of heme oxygenase 1 by doxorubicin as a major mechanism of ferroptotic cardiomyopathy. As a result, heme oxygenase 1 degrades heme and releases free iron in cardiomyocytes, which in turn leads to generation of oxidized lipids in the mitochondria membrane. Most importantly, both iron chelation therapy and pharmacologically blocking ferroptosis could significantly alleviate cardiomyopathy in mice. These findings suggest targeting ferroptosis as a strategy for treating deadly heart disease. Heart disease is the leading cause of death worldwide. A key pathogenic factor in the development of lethal heart failure is loss of terminally differentiated cardiomyocytes. However, mechanisms of cardiomyocyte death remain unclear. Here, we discovered and demonstrated that ferroptosis, a programmed iron-dependent cell death, as a mechanism in murine models of doxorubicin (DOX)- and ischemia/reperfusion (I/R)-induced cardiomyopathy. In canonical apoptosis and/or necroptosis-defective Ripk3−/−, Mlkl−/−, or Fadd−/−Mlkl−/− mice, DOX-treated cardiomyocytes showed features of typical ferroptotic cell death. Consistently, compared with dexrazoxane, the only FDA-approved drug for treating DOX-induced cardiotoxicity, inhibition of ferroptosis by ferrostatin-1 significantly reduced DOX cardiomyopathy. RNA-sequencing results revealed that heme oxygenase-1 (Hmox1) was significantly up-regulated in DOX-treated murine hearts. Administering DOX to mice induced cardiomyopathy with a rapid, systemic accumulation of nonheme iron via heme degradation by Nrf2-mediated up-regulation of Hmox1, which effect was abolished in Nrf2-deficent mice. Conversely, zinc protoporphyrin IX, an Hmox1 antagonist, protected the DOX-treated mice, suggesting free iron released on heme degradation is necessary and sufficient to induce cardiac injury. Given that ferroptosis is driven by damage to lipid membranes, we further investigated and found that excess free iron accumulated in mitochondria and caused lipid peroxidation on its membrane. Mitochondria-targeted antioxidant MitoTEMPO significantly rescued DOX cardiomyopathy, supporting oxidative damage of mitochondria as a major mechanism in ferroptosis-induced heart damage. Importantly, ferrostatin-1 and iron chelation also ameliorated heart failure induced by both acute and chronic I/R in mice. These findings highlight that targeting ferroptosis serves as a cardioprotective strategy for cardiomyopathy prevention.
Understanding the Dynamics of T-Cell Activation in Health and Disease Through the Lens of Computational Modeling

T cells in the immune system are activated by binding to foreign peptides (from an external pathogen) or mutant peptide (derived from endogenous proteins) displayed on the surface of a diseased cell. This triggers a series of intracellular signaling pathways, which ultimately dictate the response of the T cell. The insights from computational models have greatly improved our understanding of the mechanisms that control T-cell activation. In this review, we focus on the use of ordinary differential equation–based mechanistic models to study T-cell activation. We highlight several examples that demonstrate the models’ utility in answering specific questions related to T-cell activation signaling, from antigen discrimination to the feedback mechanisms that initiate transcription factor activation. In addition, we describe other modeling approaches that can be combined with mechanistic models to bridge time scales and better understand how intracellular signaling events, which occur on the order of seconds to minutes, influence phenotypic responses of T-cell activation, which occur on the order of hours to days. Overall, through concrete examples, we emphasize how computational modeling can be used to enable the rational design and optimization of immunotherapies.
Statistical medium optimization and DO-STAT fed-batch fermentation for enhanced production of tyrosine phenol lyase in recombinant Escherichia coli

Abstract Tyrosine phenol lyase (TPL) is a robust biocatalyst for the production of L-dihydroxyphenylalanine (L-DOPA). The improvement of TPL production is conducive to the industrial potential. In this study, the optimization of culture medium of recombinant Escherichia coli harboring TPL from Fusobacterium nucleatum (Fn-TPL) was carried out. Sucrose and combination of yeast extract and peptone were selected as carbon and nitrogen source, respectively. Their optimal concentrations were determined by Box-Behnken design and the synergistic effect between yeast extract and peptone was found to be significant, with p-value < 0.05. The DO-STAT fed-batch fermentation under optimized culture condition was established and the oxygen level was fixed at 20%. Both the biomass and Fn-TPL activity were significantly increased, which were 35.6 g dcw/L and 12292 U/L, respectively. The results obtained significantly promote the industrial production of L-DOPA production.
Anaerobic co-digestion of industrial landfill leachate and glycerin: methanogenic potential, organic matter removal and process optimization

ABSTRACT The objective of this study was to evaluate the performance of the anaerobic co-digestion of different concentrations of industrial landfill leachate associated with crude residual glycerin, in relation to the methanogenic potential, COD removal, accumulated methane production, the effects of the factors (food/microorganism ratio and percentage of glycerin added to the leachate) and their interactions on kinetic parameters of methane production (CH4) using the modified Gompertz model. Co-digestion tests were carried out in bench scale (400 mL of useful volume) under batch mode at 30 ± 1°C during 30-day incubation of anaerobic sewage sludge as inoculum. The parameters glycerin addition to the leachate (v/v) (0%, 1.5%, 5%, 8.5% and 10%) and F/M ratio (0.3, 0.5, 1, 1.5 and 1.7) were investigated using Central Composite Rotational Design method (CCRD). The results indicated significant effect to the response variables: methanogenic potential, COD removal, accumulated production of CH4 and maximum estimated production of CH4, considering a confidence interval of 95% (p < .05). The ideal mixture of 95.13% of leachate with 4.87% of raw glycerin was obtained by desirability test to F/M of 1.61 gCOD of substrate per gVSS (volatile suspended solids) of sludge. Methanogenic potential was 0.19 LNCH4 gTVSrem −1, and the average removal of COD was 92%, resulting in accumulated production and maximum estimated production of CH4 of 74 and 80 mL, respectively. It was noted that the process of co-digestion of the industrial landfill leachate with the crude residual glycerin is promising, due to is potential of complementing and balancing organic materials, nutrients and other components that influence the biological process. Abbreviations: AN: ammoniacal nitrogen; BMP: biochemical methane potential; CCRD: central composite rotational design; COD: chemical oxygen demand; F/M ratio: food/microorganism ratio; FSS: fixed suspended solids; NTP: normal temperature and pressure; TSS: total suspended solids; TA: total alkalinity; TFS: total fixed solids; TKN: total Kjeldahl nitrogen; TP: total phosphorus; TS: total solids; TVA: total volatile acids; TVS: total volatile solids; VSS: volatile suspended solids; WWTP: wastewater treatment plant GRAPHICAL ABSTRACT
Effect of osteochondral graft orientation in a biotribological test system

Autologous osteochondral transplantation (AOT) utilizing autografts is a widely used technique for the treatment of small‐to‐medium cartilage defects occurring in knee and ankle joints. The application of viable cartilage and bone ensures proper integration, early weight bearing, as well as restoration of biomechanical and biotribological properties. However, alignment of the autografts onto the defect site remains a pivotal aspect of reinstating the properties of the joint toward successful autograft integration. This is the first study to perform tests with different orientations of osteochondral grafts in a cartilage‐on‐cartilage test system. The objective was to estimate if there are differences between aligned and 90°‐rotated grafts concerning molecular biological and biomechanical parameters. Tissue viability, assessed by XTT assay indicated lower metabolic activity in tested osteochondral grafts (aligned, p = 0.0148 and 90°‐rotated, p = 0.0760) in favor of a higher anabolic gene expression (aligned, p = 0.0030 and 90°‐rotated, 0.0027). Tissue structure was evaluated by Safranin O histology and microscopic images of the surface. Aligned and 90°‐rotated grafts revealed no apparent differences between proteoglycan content or cracks and fissures on the cartilage surface. Test medium analyzed after tribological tests for their sulfated glycosaminoglycan content revealed no differences (p = 0.3282). During the tests, both the friction coefficient and the relative displacement between the two cartilage surfaces were measured, with no significant difference in both parameters (COF, p = 0.2232 and relative displacement, p = 0.3185). From the methods we deployed, this study can infer that there are no differences between aligned and 90°‐rotated osteochondral grafts after tribological tests in the used ex vivo tissue model. © 2019 The Authors. Journal of Orthopaedic Research® Published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society. J Orthop Res
Single-Trial Cognitive Stress Classification Using Portable Wireless Electroencephalography

This work used a low-cost wireless electroencephalography (EEG) headset to quantify the human response to different cognitive stress states on a single-trial basis. We used a Stroop-type color–word interference test to elicit mild stress responses in 18 subjects while recording scalp EEG. Signals recorded from thirteen scalp locations were analyzed using an algorithm that computes the root mean square voltages in the theta (4–8 Hz), alpha (8–13 Hz), and beta (13–30 Hz) bands immediately following the initiation of Stroop stimuli; the mean of the Teager energy in each of these three bands; and the wideband EEG signal line-length and number of peaks. These computational features were extracted from the EEG signals on thirteen electrodes during each stimulus presentation and used as inputs to logistic regression, quadratic discriminant analysis, and k-nearest neighbor classifiers. Two complementary analysis methodologies indicated classification accuracies over subjects of around 80% on a balanced dataset for the logistic regression classifier when information from all electrodes was taken into account simultaneously. Additionally, we found evidence that stress responses were preferentially time-locked to stimulus presentation, and that certain electrode–feature combinations worked broadly well across subjects to distinguish stress states.
Differential modulation of cognitive control networks by monetary reward and punishment

Abstract Incentives are primary determinants of if and how well an organism will perform a given behavior. Here, we examined how incentive valence and magnitude influence task switching, a critical cognitive control process, and test the predictions that the anterior cingulate cortex (ACC) and the ventral striatum (vStr) function as key nodes linking motivation and control systems in the brain. Our results indicate that reward and punishment incentives have both common and distinct effects on cognitive control at the behavioral and neurobiological levels. For example, reward incentives led to greater activity in the ACC during the engagement of control relative to punishments. Furthermore, the neural responses to reward and punishment differed as a function of individual sensitivity to each incentive valence. Functional connectivity analyses suggest a role for vStr in signaling motivational value during cognitive control and as a potential link between motivation and control networks. Overall, our findings suggest that similar changes in observed behavior (e.g. response accuracy) under reward and punishment incentives are mediated by, at least partially, distinct neurobiological substrates.
Efektifitas Terapi Audio Murrotal Al-Qur’an Terhadap Perubahan Kadar Serotonin Dan Perkembangan Perilaku Pada Balita Dengan Autis

Latar belakang : Masa balita merupakan masa keemasan ( golden age ), masa pertumbuhan dan perkembangan yang paling pesat pada otak manusia dan merupakan masa yang sangat peka bagi otak anak dalam menerima berbagai masukan dari lingkungan sekitarnya. Di Indonesia menurut Badan Pusat Statistik (2010) dengan jumlah penduduk lebih dari 237,5 juta dan laju pertumbuhan penduduk sebesar 1,14% dengan jumlah penyandang autis mencapai 2,4 juta orang. Jumlah penderita autis di Indonesia diperkirakan mengalami penambahan sekitar 500 orang setiap tahun. Autis terjadi karena adanya gangguan pada perkembangan otak sehingga menimbulkan adanya gangguan pada komunikasi verbal dan non verbal, interaksi sosial dan perilaku emosi. Salah satu penyebab terjadinya peningkatan insiden autis adalah adanya disfungsi serotonin pada awal perkembangan otak manusia. Serotonin termasuk dalam salah satu neurotransmitters yang mempunyai peranan penting terhadap perkembangan otak yang dapat berpengaruh terhadap gangguan perkembangan perilaku pada penderita autis. Terapi audio murrotal (surah Ar Rahman) merupakan salah satu terapi komplementer yang cukup efektif untuk meningkatkan perkembangan anak autis. Adanya potensi suara dan melodi dari terapi audio murrotal (Surah Ar Rahman) dapat membentuk emosi, psikologi, kognitif dan sosial individu yang dapat digunakan sebagai upaya preventif dan promotif pada gangguan perkembangan peilaku pada anak autis. Penelitian ini bertujuan untuk mengetahui pengaruh terapi audio murrotal (surah Ar rahman) terhadap perubahan kadar serotonindan perkembangan perilaku pada balita dengan autis. Metode penelitian : Penelitian ini merupakan jenis penelitian true -eksperimen dengan menggunakan rancangan randomized Pre & post test control group. Sampel akan diambil dengan tehnik randomisasi yang berjumlah 24 orang yang terdiri dari 12 orang kelompok intervensi (terapi audio murrotal dengan tekanan lembut) dan 12 orang kelompok kontrol. Perubahan kadar serotonin yang diukur dengan uji laboratoriumdan perkembangan perilaku akan diukur menggunkan ceklist CARS. Pengaruh terapi audio murrotal (surah Ar rahman) terhadap perubahan kadar serotonin pada autis yang akan dianalisis dengan menggunakan uji t-test. kata kunci : terapi audio murrotal (Surah ar Rahman), kadar serotonin, perkembangan perilaku, balita autis.
Mesenchymal Cell‐Derived Juxtacrine Wnt1 Signaling Regulates Osteoblast Activity and Osteoclast Differentiation

Human genetic evidence demonstrates that WNT1 mutations cause osteogenesis imperfecta (OI) and early‐onset osteoporosis, implicating WNT1 as a major regulator of bone metabolism. However, its main cellular source and mechanisms of action in bone remain elusive. We generated global and limb bud mesenchymal cell–targeted deletion of Wnt1 in mice. Heterozygous deletion of Wnt1 resulted in mild trabecular osteopenia due to decreased osteoblast function. Targeted deletion of Wnt1 in mesenchymal progenitors led to spontaneous fractures due to impaired osteoblast function and increased bone resorption, mimicking the severe OI phenotype in humans with homozygous WNT1 mutations. Importantly, we showed for the first time that Wnt1 signals strictly in a juxtacrine manner to induce osteoblast differentiation and to suppress osteoclastogenesis, in part via canonical Wnt signaling. In conclusion, mesenchymal cell‐derived Wnt1, acting in short range, is an essential regulator of bone homeostasis and an intriguing target for therapeutic interventions for bone diseases. © 2019 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc.
X-ray irradiation induces subtle changes in the genome-wide distribution of DNA hydroxymethylation with opposing trends in genic and intergenic regions

ABSTRACT DNA hydroxymethylation has gained attention as an intermediate in the process of DNA demethylation. More recently, 5-hydroxymethylcytosine has been recognized as an independent epigenetic mark that can persist over time and that exerts influence on gene regulation and other biological processes. Deregulation of this DNA modification has been linked to tumorigenesis and a variety of other diseases. The impact of irradiation on DNA hydroxymethylation is poorly understood. In this study we exposed lung fibroblasts (IMR90) to 0.5 Gy and 2 Gy of X-rays, respectively. We characterized radiation induced changes of DNA hydroxymethylation 1 h, 6 h, 24 h and 120 h after exposure employing immunoprecipitation and subsequent deep sequencing of the genomic fraction enriched for hydroxymethylated DNA. Transcriptomic response to irradiation was analyzed for time points 6 h and 24 h post exposure by means of RNA sequencing. Irradiated and sham-irradiated samples shared the same overall distribution of 5-hydroxymethylcytosines with respect to genomic features such as promoters and exons. The frequency of 5-hydroxymethylcytosine peaks differentially detected in irradiated samples increased in genic regions over time, while the opposing trend was observed for intergenic regions. Onset and extent of this effect was dose dependent. Moreover, we demonstrated a biased distribution of 5-hmC alterations at CpG islands and sites occupied by the DNA binding protein CTCF. In summary, our study provides new insights into the epigenetic response to irradiation. Our data highlight genomic features more prone to irradiation induced changes of DNA hydroxymethylation, which might impact early and late onset effects of irradiation.
Optimal virtual monoenergetic image in “TwinBeam” dual‐energy CT for organs‐at‐risk delineation based on contrast‐noise‐ratio in head‐and‐neck radiotherapy

Abstract Purpose Dual‐energy computed tomography (DECT) using TwinBeam CT (TBCT) is a new option for radiation oncology simulators. TBCT scanning provides virtual monoenergetic images which are attractive in treatment planning since lower energies offer better contrast for soft tissues, and higher energies reduce noise. A protocol is needed to achieve optimal performance of this feature. In this study, we investigated the TBCT scan schema with the head‐and‐neck radiotherapy workflow at our clinic and selected the optimal energy with best contrast‐noise‐ratio (CNR) in organs‐at‐risks (OARs) delineation for head‐and‐neck treatment planning. Methods and materials We synthesized monochromatic images from 40 keV to 190 keV at 5 keV increments from data acquired by TBCT. We collected the Hounsfield unit (HU) numbers of OARs (brainstem, mandible, spinal cord, and parotid glands), the HU numbers of marginal regions outside OARs, and the noise levels for each monochromatic image. We then calculated the CNR for the different OARs at each energy level to generate a serial of spectral curves for each OAR. Based on these spectral curves of CNR, the mono‐energy corresponding to the max CNR was identified for each OAR of each patient. Results Computed tomography scans of ten patients by TBCT were used to test the optimal monoenergetic image for the CNR of OAR. Based on the maximized CNR, the optimal energy values were 78.5 ± 5.3 keV for the brainstem, 78.0 ± 4.2 keV for the mandible, 78.5 ± 5.7 keV for the parotid glands, and 78.5 ± 5.3 keV for the spinal cord. Overall, the optimal energy for the maximum CNR of these OARs in head‐and‐neck cancer patients was 80 keV. Conclusion We have proposed a clinically feasible protocol that selects the optimal energy level of the virtual monoenergetic image in TBCT for OAR delineation based on the CNR in head‐and‐neck OAR. This protocol can be applied in TBCT simulation.
The molecular evolution of feathers with direct evidence from fossils

Significance During the dinosaur–bird transition, feathers of bird ancestors must have been molecularly modified to become biomechanically suitable for flight. We report molecular moieties in fossil feathers that shed light on that transition. Pennaceous feathers attached to the right forelimb of the Jurassic dinosaur Anchiornis were composed of both feather β-keratins and α-keratins, but were dominated by α-keratins, unlike mature feathers of extant birds, which are dominated by β-keratins. Data suggest that the pennaceous feathers of Anchiornis had some, but not all, of the ultrastructural and molecular characteristics of extant feathers, and may not yet have attained molecular modifications required for powered flight. Dinosaur fossils possessing integumentary appendages of various morphologies, interpreted as feathers, have greatly enhanced our understanding of the evolutionary link between birds and dinosaurs, as well as the origins of feathers and avian flight. In extant birds, the unique expression and amino acid composition of proteins in mature feathers have been shown to determine their biomechanical properties, such as hardness, resilience, and plasticity. Here, we provide molecular and ultrastructural evidence that the pennaceous feathers of the Jurassic nonavian dinosaur Anchiornis were composed of both feather β-keratins and α-keratins. This is significant, because mature feathers in extant birds are dominated by β-keratins, particularly in the barbs and barbules forming the vane. We confirm here that feathers were modified at both molecular and morphological levels to obtain the biomechanical properties for flight during the dinosaur–bird transition, and we show that the patterns and timing of adaptive change at the molecular level can be directly addressed in exceptionally preserved fossils in deep time.
Incidental significant arrhythmia in scleroderma associates with cardiac magnetic resonance measure of fibrosis and hs-TnI and NT-proBNP

Abstract Objectives To screen for significant arrhythmias with an implantable loop recorder (ILR) in patients with SSc and no known cardiovascular disease, and identify associated disease phenotype, blood and cardiovascular magnetic resonance (CMR) biomarkers. Methods Twenty patients with SSc with no history of primary SSc heart disease, traditional cardiovascular disease, diabetes or maximum one traditional cardiovascular risk factor underwent clinical assessment, contrast-enhanced CMR and ILR insertion. Results ILR data were available for 19 patients: 63% female, mean (s.d.) age of 53 (12) years, 32% diffuse SSc. Eight patients had significant arrhythmias over 3 years: one complete heart block, two non-sustained ventricular tachycardia [all three dcSSc, two anti-topoisomerase antibodies (Scl70) positive, three interstitial lung disease and two previous digital ulceration] and five atrial arrhythmias of which four were with limited SSc. These required interventions with one permanent pacemaker implantation, four anti-arrhythmic pharmacotherapy, one anticoagulation. Patients with significant arrhythmia had higher baseline high-sensitivity troponin I and N-terminal pro-brain natriuretic peptide [mean difference (95% CI) 117 (−11, 245) and 92 (−30, 215) ng/l, respectively], and CMR-extracellular volume [mean (s.d.) 32 (2) vs 29 (4)%]. Late gadolinium enhancement was observed in five patients, only one with significant arrhythmia. Conclusion This first ILR study identified potentially life-threatening arrhythmias in asymptomatic SSc patients attributable to a primary SSc heart disease. Disease phenotype, CMR-extracellular volume (indicating diffuse fibrosis) and cardiac biomarkers may identify at-risk patients that would benefit from ILR screening. Future studies can inform a risk model and provide insights into SSc-associated arrhythmia pathogenesis.