Miracle-dz/UniFAR-FTUs huggingface dataset:
Cysteine depletion induces pancreatic tumor ferroptosis in mice

Ferroptotic cell death and cancer Cell death can occur through different mechanisms, several of which are being explored as potential targets for cancer treatment. One form of cell death that has attracted recent interest is ferroptosis, which is triggered by high intracellular levels of lipid reactive oxygen species. Pancreatic cancer cells have high levels of reactive oxygen species but manage to avoid ferroptosis by importing extracellular cysteine. Studying mice bearing pancreatic tumors, Badgley et al. found that administration of a drug inhibiting cysteine import induced tumor-selective ferroptosis and inhibited tumor growth. Further work will be required to determine whether this therapeutic strategy will be effective in human pancreatic cancer, a tumor type for which new treatments are urgently needed. Science, this issue p. 85 A drug that lowers intracellular cysteine levels inhibits growth of pancreatic tumors in mice by inducing a specific form of cell death. Ferroptosis is a form of cell death that results from the catastrophic accumulation of lipid reactive oxygen species (ROS). Oncogenic signaling elevates lipid ROS production in many tumor types and is counteracted by metabolites that are derived from the amino acid cysteine. In this work, we show that the import of oxidized cysteine (cystine) via system xC– is a critical dependency of pancreatic ductal adenocarcinoma (PDAC), which is a leading cause of cancer mortality. PDAC cells used cysteine to synthesize glutathione and coenzyme A, which, together, down-regulated ferroptosis. Studying genetically engineered mice, we found that the deletion of a system xC– subunit, Slc7a11, induced tumor-selective ferroptosis and inhibited PDAC growth. This was replicated through the administration of cyst(e)inase, a drug that depletes cysteine and cystine, demonstrating a translatable means to induce ferroptosis in PDAC.
Adiponectin and Lipid Profile Levels in Type-2 Diabetic Obese Patients in Kerbala Province

Background: The association between obesity and type-2 diabetes mellitus may be partly mediated by altered secretion of adipokines by adipose tissue. Adiponectin is an adipokines with anti-inflammatory and insulin sensitizing properties; it is secretion is down regulated in obesity. The correlation of plasma adiponectin with the risk of type-2 diabetes mellitus and hyperlipidemia is unclear. Objective: To study the association between plasma adiponectin level with lipid profile in type-2 diabetic obese patients in Kerbala province: Iraq. Material and method: A total number of 110 sample subjects with different age, and different gender were classified according to diabetes mellitus and obesity. Fasting serum adiponectin was measured by ELISA method. Measurements of fasting lipid profile also have been performed. Results and discussion: It was obtained that adiponectin level was lowered significantly in diabetic group, obese group, and diabetic obese group as compared with control group. Serum adiponectin was correlate negatively with serum total cholesterol, serum TG, and with body fat percent (BF %), while it was correlated positively with HDL-C. Serum total cholesterol levels was correlated positively with each of serum TG, LDL-C levels and with BF%, while serum TG levels was negatively correlated with serum HDL-C and positively correlated with each of BMI and BF %. Serum LDL-C was positively correlated with BF %, while BF % correlates positively with age. Conclusion: According to the presented data, adiponectin as hormone play an important role in the prevention of hyperlipidemia, and consequently atherosclerosis and its complications. Kerbala Journal of Pharmaceutical Sciences Number 2 خّٞلاذٞظىا ً٘يؼيى ءلاثشم خيجٍ ــ 3122 158 و هٍتكوىبٌدلأا ثاٌىتسم ةرىص يركسنا ىضرم ًف نىهذنا – ءلابرك تظفاحم ًف ءاوذبنا ًواثنا عىىنا بهطمنا ذبع رهزأ , طاٍخنا ًظفح قراط مٍهاربإ تمعط لآ داىخ مضاف و
WAITING TIMES IN THE UNIVERSITY HOSPITAL

Background . Prolonged waiting times for the admission to the hospital are important factor of patient dissatisfaction with health care in the hospital. Methods . Questionnaire (check-list) was used to measure time intervals of the individual phases of health care from admission in the out-patient department to the admission to the ward. Check-list was filled in by nurses both in the out-patient department and hospital wards. In the study we included 572 patients of which 505 were admitted to the hospital. Results . Average waiting time from admission in out-patient department to placement in the bed in hospital ward was 93.6 minutes. Shortest waiting time was observed in urgent patients, longest in non booked patients. On average patients waited 54.8 minutes from admisssion till the end of examination of the admitting physician and 17.5 minutes from entering the hospital ward to placement in their bed. Majority, 68% of patients were admitted in the morning shift, 23% in the afternoon, and 9% in the night shift. Non-admitted patients waited on average 202 minutes before completion of their workup and release from the out-patient department. Conclusions . Our study revealed bottle-necks in the admitting procedure and supported efforts for simplification and hence shortening. Besides changes in admitting procedure, reorganization of laboratory service and changes in the existing hospital information system are also indicated.
Evolutionarily conserved non-protein-coding regions in the chicken genome harbor functionally important variation

The availability of genomes for many species has advanced our understanding of the non-protein-coding fraction of the genome. Comparative genomics has proven to be an invaluable approach for the systematic, genome-wide identification of conserved non-protein-coding elements (CNEs). However, for many non-mammalian model species, including chicken, our capability to interpret the functional importance of variants overlapping CNEs has been limited by current genomic annotations, which rely on a single information type (e.g. conservation). We here studied CNEs in chicken using a combination of population genomics and comparative genomics. To investigate the functional importance of variants found in CNEs we develop a ch(icken) Combined Annotation-Dependent Depletion (chCADD), a variant effect prediction tool first introduced for humans and later on for mouse and pig. We show that 73 Mb of the chicken genome has been conserved across more than 280 million years of vertebrate evolution. The vast majority of the conserved elements are in non-protein-coding regions, which display SNP densities and allele frequency distributions characteristic of genomic regions constrained by purifying selection. By annotating SNPs with the chCADD score we are able to pinpoint specific subregions of the CNEs to be of higher functional importance, as supported by SNPs found in these subregions are associated with known disease genes in humans, mice, and rats. Taken together, our findings indicate that CNEs harbor variants of functional significance that should be object of further investigation along with protein-coding mutations. We therefore anticipate chCADD to be of great use to the scientific community and breeding companies in future functional studies in chicken.
Pyronaridine Tetraphosphate Efficacy Against Ebola Virus Infection in Guinea Pig

The recent outbreaks of the Ebola virus (EBOV) in Africa have brought global visibility to the shortage of available therapeutic options to treat patients infected with this or closely related viruses. We have recently computationally identified three molecules which have all demonstrated statistically significant efficacy in the mouse model of infection with mouse adapted Ebola virus (ma-EBOV). One of these molecules is the antimalarial pyronaridine tetraphosphate (IC50 range of 0.82-1.30 µM against three strains of EBOV and IC50 range of 1.01-2.72 µM against two strains of Marburg virus (MARV)) which is an approved drug in the European Union and used in combination with artesunate. To date, no small molecule drugs have shown statistically significant efficacy in the guinea pig model of EBOV infection. Pharmacokinetics and range-finding studies in guinea pigs directed us to a single 300mg/kg or 600mg/kg oral dose of pyronaridine 1hr after infection. Pyronaridine resulted in statistically significant survival of 40% at 300mg/kg and protected from a lethal challenge with EBOV. In comparison, oral favipiravir (300 mg/kg dosed once a day) had 43.5 % survival. The in vitro metabolism and metabolite identification of pyronaridine and another of our EBOV active molecules, tilorone, which suggests significant species differences which may account for the efficacy or lack thereof, respectively in guinea pig. In summary, our studies with pyronaridine demonstrates its utility for repurposing as an antiviral against EBOV and MARV, providing justification for future testing in non-human primates. Importance There is currently no antiviral small molecule drug approved for treating Ebola Virus infection. We have previously used machine learning models to identify new uses for approved drugs and demonstrated their activity against the Ebola virus in vitro and in vivo. We now describe the pharmacokinetic properties of the antimalarial pyronaridine in the guinea pig. In addition, we show that this drug is effective against multiple strains of EBOV and MARV in vitro and in the guinea pig model of Ebola virus infection. These combined efforts indicate the need to further test this molecule in larger animal efficacy studies prior to clinical use in humans. These findings also may be useful for repurposing this drug for use against other viruses in future.
The effect of a novel powerful ABA mimic on the improvement of color in grapes and its mechanism

Pigment content is an important quality attribute in the grape industry, and anthocyanins are the major fruit pigments. iso-PhABA is a novel and excellent ABA analog capable of the antimetabolic inactivation of ABA. In this study, we found that iso-PhABA improved the coloration of grape berries more obviously than ABA at concentrations of 2 mg/L and 5 mg/L in two grape varieties in China. iso-PhABA treatment enhanced the anthocyanin content in the two grape varieties; specifically, the anthocyanin and delphinidin contents increased in both the ‘Jufeng’ and ‘Xiahei’ varieties. An enzymatic activity test showed that iso-PhABA significantly promoted four key enzyme activities catalyzing anthocyanin biosynthesis. We also determined the affinity between iso-PhABA and ABA receptors using ABA as a control. The results indicated that iso-PhABA had significantly to moderately higher affinities for some ABA receptors, including PYR1, PYL2, PYL1, PYL3 and PYL10, which resulted in higher inhibition of the PP2C HAB1 in the presence of iso-PhABA than in the presence of ABA. iso-PhABA treatment increased the content of soluble sugars and grape yield without any apparent accompanying adverse effects on the quality of the grapes.
Supertertiary protein structure affects an allosteric network

Significance Protein function can be allosterically regulated by changes in structure or dynamics. PDZ domains are classic examples for studies of allostery in single protein domains. However, PDZ domains are often found in multidomain proteins; in particular, PDZ3 is located in a supramodule containing three domains. The allosteric network in PDZ3 has never been studied in the presence of the adjacent domains. Here we map the allosteric network for a PDZ3:ligand complex, both in isolation and in the context of a supramodule. We demonstrate that the allosteric network is highly dependent on this supertertiary structure, with broad implications for studies of allostery in single domains. The notion that protein function is allosterically regulated by structural or dynamic changes in proteins has been extensively investigated in several protein domains in isolation. In particular, PDZ domains have represented a paradigm for these studies, despite providing conflicting results. Furthermore, it is still unknown how the association between protein domains in supramodules, consitituting so-called supertertiary structures, affects allosteric networks. Here, we experimentally mapped the allosteric network in a PDZ:ligand complex, both in isolation and in the context of a supramodular structure, and show that allosteric networks in a PDZ domain are highly dependent on the supertertiary structure in which they are present. This striking sensitivity of allosteric networks to the presence of adjacent protein domains is likely a common property of supertertiary structures in proteins. Our findings have general implications for prediction of allosteric networks from primary and tertiary structures and for quantitative descriptions of allostery.
Different theta frameworks coexist in the hippocampus and are coordinated during memory-guided exploration and novelty detection

Hippocampal firing is organized in theta sequences controlled by internal memory-related processing and by external sensory cues. How these computations are segregated or integrated, depending on the cognitive needs, is not fully understood. Although theta activity in the hippocampus is most commonly studied as a unique coherent oscillation, it is the result of a complex interaction between different rhythm generators. Here we investigated the coordination between theta generators as a possible mechanism to couple or decouple internally and externally driven computations. We separated and quantified three different theta current generators from the hippocampus of freely behaving rats, one originating in CA3 with current sinks in CA1 str. radiatum and two with current sinks in CA1 str. lacunosum-moleculare and dentate molecular layer, mainly driven by entorhinal cortex (EC) layers 3 and 2, respectively. These theta generators followed non fully coherent dynamics and presented epochs of higher and lower phase coupling, suggesting a flexible interaction between them. Selective optogenetic inhibition in CA3 depressed the str. radiatum generator without affecting the EC-driven theta oscillations, indicating that theta rhythm generators can be modulated independently. In addition, band-specific gamma interactions with theta oscillations selectively occurred with the corresponding pathway-specific theta current generator, supporting the existence of different theta-gamma coding frameworks to organize neuronal firing in the hippocampus. Importantly, we found that epochs of highly synchronized theta rhythmicity across generators preferentially occurred during memory-guided exploration and mismatch novelty detection in familiar environments, two conditions in which internally generated memory representations need to be coordinated with the incoming sensory information about external cues. We propose a mechanism for segregating and integrating hippocampal computations based on the coexistence of different theta-gamma frameworks that flexibly couple or decouple accommodating the cognitive needs.
Activity-dependent tuning of intrinsic excitability in mouse and human neurogliaform cells

The ability to modulate the efficacy of synaptic communication between neurons constitutes an essential property critical for normal brain function. Animal models have proved invaluable in revealing a wealth of diverse cellular mechanisms underlying varied plasticity modes. However, to what extent these processes are mirrored in humans is largely uncharted thus questioning their relevance to human circuit function. In this study, we focus on neurogliaform cells, a specialized form of neuron that possess physiological features enabling them to impart a widespread inhibitory influence on neural activity. We demonstrate that this prominent neuronal subtype, embedded in both mouse and human neural circuits, undergo remarkably similar activity-dependent modulation manifesting as epochs of enhanced intrinsic excitability. In principle, these evolutionary conserved plasticity routes likely tune the extent of neurogliaform cell mediated inhibition thus constituting canonical circuit mechanisms relevant for human cognitive processing and behavior.
The Nucleocapsid Protein of SARS-CoV-2 Abolished Pluripotency in Human Induced Pluripotent Stem Cells

The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is raging across the world, leading to a global mortality rate of 3.4% (estimated by World Health Organization in March 2020). As a potential vaccine and therapeutic target, the nucleocapsid protein of SARS-CoV-2 (nCoVN) functions in packaging the viral genome and viral self-assembly. To investigate the biological effects of nCoVN to human stem cells, genetically engineered human induced pluripotent stem cells (iPSC) expressing nCoVN (iPSC-nCoVN) were generated by lentiviral expression systems, in which the expression of nCoVN could be induced by the doxycycline. The proliferation rate of iPSC-nCoVN was decreased. Unexpectedly, the morphology of iPSC started to change after nCoVN expression for 7 days. The pluripotency marker TRA-1-81 were not detectable in iPSC-nCoVN after a four-day induction. Meanwhile, iPSC-nCoVN lost the ability for differentiation into cardiomyocytes with a routine differentiation protocol. The RNA-seq data of iPSC-nCoVN (induction for 30 days) and immunofluorescence assays illustrated that iPSC-nCoVN were turning to fibroblast-like cells. Our data suggested that nCoVN disrupted the pluripotent properties of iPSC and turned them into other types of cells, which provided a new insight to the pathogenic mechanism of SARS-CoV-2.
Nuclear envelope–vacuole contacts mitigate nuclear pore complex assembly stress

The intricacy of nuclear pore complex (NPC) biogenesis imposes risks of failure that can cause defects in nuclear transport and nuclear envelope morphology, however, cellular mechanisms utilized to alleviate NPC assembly stress are not well-defined. In the budding yeast Saccharomyces cerevisiae, we demonstrate that NVJ1- and MDM1-enriched nuclear envelope (NE)-vacuole contacts increase when NPC assembly is compromised in several nup mutants, including nup116ΔGLFG cells. These interorganelle nucleus-vacuole junctions (NVJs) cooperate with lipid droplets to maintain viability and enhance NPC formation in assembly mutants. Additionally, NVJs function with ATG1 to promote vacuole-dependent remodeling in nup116ΔGLFG cells, which also correlates with proper NPC formation. Importantly, NVJs significantly improve the physiology of NPC assembly mutants, despite having only negligible effects when NPC biogenesis is unperturbed. Collectively, these results define how NE-vacuole interorganelle contacts coordinate responses to mitigate deleterious cellular effects caused by disrupted NPC assembly. Summary How cells respond to deleterious effects imposed by disrupted nuclear pore complex (NPC) assembly are not well-defined. The authors demonstrate nuclear envelope-vacuole interactions expand in response to perturbed NPC assembly to promote viability, nuclear envelope remodeling, and proper NPC biogenesis.
Transcriptome Analysis Uncovers a Link Between Copper Metabolism, and Both Fungal Fitness and Antifungal Sensitivity in the Opportunistic Yeast Candida albicans

Copper homeostasis is an important determinant for virulence of many human pathogenic fungi such as the highly prevalent yeast Candida albicans. However, beyond the copper transporter Ctr1, little is known regarding other genes and biological processes that are affected by copper. To gain insight into the cellular processes that are modulated by copper abundance in C. albicans, we monitored the global gene expression dynamic under both copper depletion and excess using RNA-seq. Beyond copper metabolism, other different transcriptional programs related to fungal fitness such as stress responses, antifungal sensitivity, host invasion and commensalism were modulated in response to copper variations. We have also investigated the transcriptome of the mutant of the copper utilization regulator, mac1, and identified potential direct targets of this transcription factor under copper starvation. We also showed that Mac1 was required for the invasion and adhesion to host cells and antifungal tolerance. This study provides a framework for future studies to examine the link between copper metabolism and essential functions that modulate fungal virulence and fitness inside the host.
TERL: Classification of Transposable Elements by Convolutional Neural Networks

Transposable elements (TEs) are the most represented sequences occurring in eukaryotic genomes. They are capable of transpose and generate multiple copies of themselves throughout genomes. These sequences can produce a variety of effects on organisms, such as regulation of gene expression. There are several types of these elements, which are classified in a hierarchical way into classes, subclasses, orders and superfamilies. Few methods provide the classification of these sequences into deeper levels, such as superfamily level, which could provide useful and detailed information about these sequences. Most methods that classify TE sequences use handcrafted features such as k-mers and homology based search, which could be inefficient for classifying non-homologous sequences. Here we propose a pipeline, transposable elements representation learner (TERL), that use four preprocessing steps, a transformation of one-dimensional nucleic acid sequences into two-dimensional space data (i.e., image-like data of the sequences) and apply it to deep convolutional neural networks (CNNs). CNN is used to classify TE sequences because it is a very flexible classification method, given it can be easily retrained to classify different categories and any other DNA sequences. This classification method tries to learn the best representation of the input data to correctly classify it. CNNs can also be accelerated via GPUs to provide fast results. We have conducted six experiments to test the performance of TERL against other methods. Our approach obtained macro mean accuracies and F1-score of 96.4% and 85.8% for the superfamily sequences from RepBase and 95.7% and 91.5% for the order sequences from RepBase respectively. We have also obtained macro mean accuracies and F1-score of 95.0% and 70.6% for sequences from seven databases into superfamily level and 89.3% and 73.9% for the order level respectively. We surpassed accuracy, recall and specificity obtained by other methods on the experiment with the classification of order level sequences from seven databases and surpassed by far the time elapsed of any other method for all experiments. We also show a way to preprocess sequences and prepare train and test sets. Therefore, TERL can learn how to predict any hierarchical level of the TEs classification system, is on average 162 times and four orders of magnitude faster than TEclass and PASTEC respectively and on a real-world scenario obtained better accuracy, recall, and specificity than the other methods.