Miracle-dz/UniFAR-FTUs huggingface dataset:
Hsa‐miR‐599 inhibits breast cancer progression via BRD4/Jagged1/Notch1 axis

Hsa‐miR‐599 was identified as a tumor suppressor against cancer. This study aimed to explore possible mechanisms of antitumor effect of hsa‐miR‐599 against breast cancer. Tissue specimens were collected from 106 breast cancer cases, and breast cancer cell line MCF‐7 was cultured for in vitro experiments. The expression pattern of hsa‐miR‐599 was measured via quantitative real‐time polymerase chain reaction. Lipofectamine® 2000 reagent was used for cell transfection. Cell viability, motility and apoptosis were detected using MTT assay, transwell assay, and flow cytometer, respectively. Protein analysis was performed via western blot. Hsa‐miR‐599 expression was decreased in breast cancer tissues and cells. Moreover, its expression was negatively correlated with TNM stage (p = 0.004) and lymph node metastasis (p = 0.001). Enhanced hsa‐miR‐599 expression in breast cancer cells could induce the inhibition against cell proliferation, migration and invasion, and strengthen cell apoptosis. BRD4 might be a target of hsa‐miR‐599. Hsa‐miR‐599 combined with BRD4 inhibited breast cancer progression through targeting Jagged1/Notch1 pathway. Hsa‐miR‐599 expression is downregulated in breast cancer. Hsa‐miR‐599 may inactivate BRD4/Jagged1/Notch1 axis, thus suppressing malignant progression of breast cancer.
Changes in CRP and CA19-9 during Preoperative Oncological Therapy Predict Postoperative Survival in Pancreatic Ductal Adenocarcinoma

Introduction: Tumor and systemic inflammatory markers predict survival. This retrospective study aimed to explore the changes in CRP, CA19-9, and other routine laboratory tests during preoperative oncological therapy as prognostic factors in pancreatic ductal adenocarcinoma (PDAC). Methods: Between 2000 and 2016, 68 borderline resectable PDAC patients received preoperative oncological therapy and underwent subsequent surgery at Helsinki University Hospital, Finland. We investigated changes in CRP, CA19-9, CEA, albumin, leukocytes, bilirubin, and platelets and examined the impact on survival. Results: In the multivariate analysis, CRP remaining at ≥3 mg/L after preoperative oncological therapy predicted a poorer postoperative outcome when compared to CRP decreasing to or remaining at <3 mg/L (hazard ratio [HR] 2.766, 95% confidence interval [CI]: 1.300–5.885, p = 0.008). Furthermore, a CA19-9 decrease >90% during preoperative treatment predicted a favorable postoperative outcome (HR 0.297, 95% CI: 0.124–0.708, p = 0.006). In the Kaplan-Meier analysis, the median survival for patients with CRP remaining at <3 mg/L was longer than among patients with an increased CRP level at ≥3 mg/L (42 months vs. 24 months, p = 0.001). Patients with a CA19-9 decrease >90% or level normalization (to ≤37 kU/L) during preoperative treatment exhibited a median survival of 47 months; those with a 50–90% decrease, 15 months; and those with a <50% decrease, 17 months (p < 0.001). Conclusions: Changes in CRP and CA19-9 during preoperative oncological therapy predict postoperative survival.
Trans-2-hexenal downregulates several pathogenicity genes of Pseudogymnoascus destructans, the causative agent of white-nose syndrome in bats

Abstract White-nose syndrome is an emergent wildlife disease that has killed millions of North American bats. It is caused by Pseudogymnoascus destructans, a cold-loving, invasive fungal pathogen that grows on bat tissues and disrupts normal hibernation patterns. Previous work identified trans-2-hexenal as a fungistatic volatile compound that potentially could be used as a fumigant against P. destructans in bat hibernacula. To determine the physiological responses of the fungus to trans-2-hexenal exposure, we characterized the P. destructans transcriptome in the presence and absence of trans-2-hexenal. Specifically, we analyzed the effects of sublethal concentrations (5 μmol/L, 10 μmol/L, and 20 μmol/L) of gas-phase trans-2-hexenal of the fungus grown in liquid culture. Among the three treatments, a total of 407 unique differentially expressed genes (DEGs) were identified, of which 74 were commonly affected across all three treatments, with 44 upregulated and 30 downregulated. Downregulated DEGs included several probable virulence genes including those coding for a high-affinity iron permease, a superoxide dismutase, and two protein-degrading enzymes. There was an accompanying upregulation of an ion homeostasis gene, as well as several genes involved in transcription, translation, and other essential cellular processes. These data provide insights into the mechanisms of action of trans-2-hexenal as an anti-fungal fumigant that is active at cold temperatures and will guide future studies on the molecular mechanisms by which six carbon volatiles inhibit growth of P. destructans and other pathogenic fungi.
Epigenetic age prediction

Advanced age is the main common risk factor for cancer, cardiovascular disease and neurodegeneration. Yet, more is known about the molecular basis of any of these groups of diseases than the changes that accompany ageing itself. Progress in molecular ageing research was slow because the tools predicting whether someone aged slowly or fast (biological age) were unreliable. To understand ageing as a risk factor for disease and to develop interventions, the molecular ageing field needed a quantitative measure; a clock for biological age. Over the past decade, a number of age predictors utilising DNA methylation have been developed, referred to as epigenetic clocks. While they appear to estimate biological age, it remains unclear whether the methylation changes used to train the clocks are a reflection of other underlying cellular or molecular processes, or whether methylation itself is involved in the ageing process. The precise aspects of ageing that the epigenetic clocks capture remain hidden and seem to vary between predictors. Nonetheless, the use of epigenetic clocks has opened the door towards studying biological ageing quantitatively, and new clocks and applications, such as forensics, appear frequently. In this review, we will discuss the range of epigenetic clocks available, their strengths and weaknesses, and their applicability to various scientific queries.
Psychiatric disorders: A plea for complexity

A patient arrives in consultation experiencing a complex mix of symptoms: anhedonia (without mood symptoms), anxiety and repetitive behaviors, leading him to order and check everything, which he describes as the consequences of a desire to neutralize his feeling of distress. He complains of the harmful effects associated with each of these symptoms. However, the clinician cannot identify or explain to her patient any obvious dysfunction underlying this whole set. For her, it appears obvious that each isolated symptom constitutes a perturbation of the whole system— which she can explain pedagogically to the patient. More precisely, she explains the entire picture to the patient by drawing together all of these interacting symptoms: his ‘disorder’ is built by such a cluster of harmful dysfunctions, in which each influences the others directly. Finally, she offers care and support by considering these idiosyncratic interactions. This clinical vignette illustrates how the definition of a disorder can be a complex topic in psychiatry. The main debates about it have crystallized at the level of dysfunction and harm, and traditionally discuss naturalism (i.e. concepts of disorders are predominantly driven by dysfunctions), normativism (i.e. concepts of disorders are identified according to a subjective harm) and hybrid proposals (Wakefield, 1992)—which all capture only part of what is important about explanations of diseases. In order to avoid many of these difficulties, the conception of complex systems describes that a psychiatric disorder is related to an embedded mechanism in its environment (Wolkenhauer, 2020), i.e. to a network of interrelated elements. In psychiatry, a medical discipline in which the usefulness of a diagnostic, prognostic or predictive biomarker has not been formally established for clinical practice, most of the daily elements of the clinician correspond to clinical manifestations. Thus, in alignment with symptom network theory (Borsboom, 2017), a psychiatric disorder could be defined as the disturbance of a mechanism composed of a stable and strongly connected set of clinical manifestations, i.e. stable and strongly connected sets of harmful dysfunctions. In this way, as we can see with the previous clinical vignette, such a network of harmful dysfunctions would be described as a psychiatric disorder in which these harmful dysfunctions are strongly fixed in a stable state, requiring therapeutic force to restore health. In a precise and personalized psychiatric view, such a definition allows researchers and physicians to integrate elements of different natures (e.g. environmental or biological) resulting from various levels of analysis.
Theratyping cystic fibrosis in vitro in ALI culture and organoid models generated from patient-derived nasal epithelial conditionally reprogrammed stem cells

Question Cystic fibrosis (CF) is due to pathogenic variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Recent improvements have enabled pharmacological therapy aiming at restoring mutated CFTR expression and function. CFTR “modulators” have revolutionised the CF therapeutic landscape, particularly the last approved, Trikafta. This drug combination is indicated by the United States Food and Drug Administration and very recently by the European Medicines Agency for genotypes carrying at least one copy of CFTR with the F508del pathogenic variant. However, several genotypes are not yet eligible for Trikafta treatment. Materials/patients and methods We exploited an innovative cellular approach allowing highly efficient in vitro expansion of airway epithelial stem cells (AESCs) through conditional reprogramming from nasal brushing of CF patients. This approach, coupled to the development of AESC-derived personalised disease models, as organoids and air–liquid interface (ALI) cultures, revealed highly suitable for CFTR pharmacological testing. Results and answer to the question We fully validated the experimental models and implemented the CFTR functional assays and biochemical CFTR protein characterisation, which allowed the evaluation of the efficacy of clinically available modulators in restoring CFTR maturation and function of each patient-derived “avatar” (theratyping). F508del homozygous genotypes, used as controls, confirmed the higher clinical activity of Trikafta in comparison with older modulators. In addition, Trikafta showed its efficacy on three rare genotypes previously not eligible for treatment with modulators, opening the way to clinical translation. Finally, encouraging results for innovative drug combinations were obtained. Despite approval of Trikafta, a fraction of cystic fibrosis patients with rare genotypes are still lacking modulator therapies. Conditionally reprogrammed nasal cell-based in vitro models may allow theratyping for each patient for personalised treatment. https://bit.ly/3ylOJ28
Synergistic interaction between sensory inputs and propriospinal signalling underlying quadrupedal locomotion

Stimulation of hindlimb afferent fibres can both stabilize and increase the activity of fore‐ and hindlimb motoneurons during fictive locomotion. The increase in motoneuron activity is at least partially due to the production of doublets of action potentials in a subpopulation of motoneurons. These results were obtained using an in vitro brainstem/spinal cord preparation of neonatal rat.
Development of postural stability in children with autism spectrum disorder: a cross-sectional study

ABSTRACT The purpose was to investigate the effects of age on postural stability for children with autism spectrum disorder (ASD). Twenty-nine children with mild ASD were assigned into one of the three groups: 6–8 years (U8), 9–11 years (U11) and 12–14 years (U14). Participants stood barefoot with both feet on a force platform and maintained stationary for 15 seconds during eyes-open and eyes-closed conditions. Center of pressure data were collected and variables were calculated, including displacements, total distances, sway areas, and sample entropy. The variables were compared among the three groups using a mixed-model ANOVA. The age group effect was significant for mediolateral center of pressure displacement (p = 0.04) and sway distance (p = 0.02). Post-hoc comparisons revealed that U8 exhibited greater mediolateral displacement and total distance compared to U14, regardless of test conditions. The U14 group exhibited improved mediolateral postural stability compared to U8, whereas no differences were found between U8 and U11 or between U11 and U14. This may suggest that children with ASD could slowly develop postural stability but only demonstrate significant changes over a long period of time. Early intervention programs aimed to improve complexity of postural control could be beneficial.
Wearable myoelectric interface enables high‐dose, home‐based training in severely impaired chronic stroke survivors

High‐intensity occupational therapy can improve arm function after stroke, but many people lack access to such therapy. Home‐based therapies could address this need, but they don’t typically address abnormal muscle co‐activation, an important aspect of arm impairment. An earlier study using lab‐based, myoelectric computer interface game training enabled chronic stroke survivors to reduce abnormal co‐activation and improve arm function. Here, we assess feasibility of doing this training at home using a novel, wearable, myoelectric interface for neurorehabilitation training (MINT) paradigm.
The role of limestone and dolomite tailings’ particle size in retention of heavy metals from liquid waste

The present study did not originate under any of project and no funding was raised for research. However, we would like to thank especially Professor Angeliki Moutsatsou and the personal of the Laboratory of Inorganic and Analytical Chemistry of the Chemical Engineering School in the National Technical University of Athens for their various support during the experimental work required for the successful realization of the present study.
Orientational changes of white matter fibers in Alzheimer's disease and amnestic mild cognitive impairment

White matter abnormalities represent early neuropathological events in neurodegenerative diseases such as Alzheimer's disease (AD), investigating these white matter alterations would likely provide valuable insights into pathological changes over the course of AD. Using a novel mathematical framework called “Director Field Analysis” (DFA), we investigated the geometric microstructural properties (i.e., splay, bend, twist, and total distortion) in the orientation of white matter fibers in AD, amnestic mild cognitive impairment (aMCI), and cognitively normal (CN) individuals from the Alzheimer's Disease Neuroimaging Initiative 2 database. Results revealed that AD patients had extensive orientational changes in the bilateral anterior thalamic radiation, corticospinal tract, inferior and superior longitudinal fasciculus, inferior fronto‐occipital fasciculus, and uncinate fasciculus in comparison with CN. We postulate that these orientational changes of white matter fibers may be partially caused by the expansion of lateral ventricle, white matter atrophy, and gray matter atrophy in AD. In contrast, aMCI individuals showed subtle orientational changes in the left inferior longitudinal fasciculus and right uncinate fasciculus, which showed a significant association with the cognitive performance, suggesting that these regions may be preferential vulnerable to breakdown by neurodegenerative brain disorders, thereby resulting in the patients' cognitive impairment. To our knowledge, this article is the first to examine geometric microstructural changes in the orientation of white matter fibers in AD and aMCI. Our findings demonstrate that the orientational information of white matter fibers could provide novel insight into the underlying biological and pathological changes in AD and aMCI.
Culture‐free biphasic approach for sensitive detection of Escherichia coli O157:H7 from beef samples

Foodborne illnesses are a major threat to public health also leading to significant mortality and financial and reputational damage to industry. It is very important to detect pathogen presence in food products early, rapidly, and accurately to avoid potential outbreaks and economic loss. However, “gold standard” culture methods, including enrichment of pathogens, can take up to several days. Moreover, the food matrix often interferes with nucleic acid amplification methods of detection, requiring DNA extraction from the sample for successful molecular detection of pathogens. Here, we introduce a “biphasic” amplification method that can achieve high sensitivity detection with background noise from ground beef food samples without culture or other extraction methods in 2.5 h. Homogenized ground beef is dried resulting in an increase in porosity of the dried food matrix to allowing amplification enzymes and primers to access the target DNA and initiate the reaction within the dried food matrix. Using Loop Mediated Isothermal Amplification, we demonstrate the detection of 1–3 cfu of Escherichia coli bacteria in 30 mg of dried food matrix. Our approach significantly lowers the time to result to less than a few hours and have a pronounced impact on reduction of instrumentation complexity and costs.
Bacterial translation machinery for deliberate mistranslation of the genetic code

Significance Aminoacyl-transfer RNA (tRNA) synthetases (aaRSs) are essential enzymes that mediate accurate expression of the genetic code. More than 96% of analyzed species possess duplicated aaRSs genes, which are presumed to encode canonical aaRSs. However, in this study, we show that some of these seemingly canonical aaRSs are in fact repurposed for deliberate mistranslation of the genetic code, enabling organisms to encode two amino acids using a single sense codon. This finding, along with the abundance of duplicated aaRSs genes, suggests that the deliberate mistranslation of sense codons may be more common than previously thought. More broadly, our work illustrates that extant genomes have many exciting functionalities that are currently hidden under a disguise of canonical tRNA synthetases and tRNAs. Inaccurate expression of the genetic code, also known as mistranslation, is an emerging paradigm in microbial studies. Growing evidence suggests that many microbial pathogens can deliberately mistranslate their genetic code to help invade a host or evade host immune responses. However, discovering different capacities for deliberate mistranslation remains a challenge because each group of pathogens typically employs a unique mistranslation mechanism. In this study, we address this problem by studying duplicated genes of aminoacyl-transfer RNA (tRNA) synthetases. Using bacterial prolyl-tRNA synthetase (ProRS) genes as an example, we identify an anomalous ProRS isoform, ProRSx, and a corresponding tRNA, tRNAProA, that are predominately found in plant pathogens from Streptomyces species. We then show that tRNAProA has an unusual hybrid structure that allows this tRNA to mistranslate alanine codons as proline. Finally, we provide biochemical, genetic, and mass spectrometric evidence that cells which express ProRSx and tRNAProA can translate GCU alanine codons as both alanine and proline. This dual use of alanine codons creates a hidden proteome diversity due to stochastic Ala→Pro mutations in protein sequences. Thus, we show that important plant pathogens are equipped with a tool to alter the identity of their sense codons. This finding reveals the initial example of a natural tRNA synthetase/tRNA pair for dedicated mistranslation of sense codons.
DOAC discontinuation among patients with atrial fibrillation according to gender and cohabitation status; A Nationwide Cohort Study.

AIMS The aim of this study was to evaluate the risk of discontinuing treatment with direct oral anticoagulants (DOACs) among patients with atrial fibrillation (AF) according to cohabitation status and gender. METHODS AND RESULTS Using the Danish national registers, we identified 32,364 patients with AF aged 40-90 years in treatment with DOAC. The study period was from 2013 to 2017, and patients were followed for two years, or until death, outcome, or emigration. The main outcome was discontinuation of DOAC-treatment for at least 30 days.The absolute two-year risk of DOAC discontinuation was highest among men living alone (35.7%, 95% Confidence interval (CI): 37.3% to 34.1%). Men living alone had a 4.6% (95% CI: 6.4% to 2.8%) higher absolute risk of discontinuation and a 12% (HR 1.12, 95% CI: 1.04 to 1.20) higher relative risk of discontinuation compared to men living with a partner. Female patients living alone likewise had a higher absolute risk of DOAC discontinuation (2.6%, 95% CI: 4.4% to 0.09%) compared to female patients living with a partner, yet no statistically significant difference in relative risk. In an analysis evaluating gender, we found male gender to be associated with a significantly higher relative risk of DOAC-discontinuation (HR: 1.33, 95% CI: 1.26 to 1.40) compared to female gender (p-value for interaction with cohabitant status, P = 0.5996). CONCLUSION In this nationwide population study, male gender and living alone was associated with a higher risk of DOAC discontinuation among patients with AF.
Use of antioxidant nanoparticles to reduce oxidative stress in blood storage

Oxidative damage by free radicals has a negative effect on blood quality during storage. Antioxidant nanoparticles can prevent oxidative stress. We use SOD‐CAT‐Alb‐PEG‐PLGA‐ nanoparticles to reduce the effects of oxidative stress in blood storage. Electrospray was employed to prepare nanoparticles. Nanoparticles entered the test bags and were kept for 35 days from the time of donation under standard conditions. On target days, experiments were performed on the samples taken. The examination included blood smear, red blood cells count, hemoglobin, hematocrit, K, Fe, glutathione peroxidase, glutathion reductase, glucose‐6‐phosphate dehydrogenase, prooxidant‐antioxidant balance, malondialdehyde, and flow cytometric assay for phosphatidylserine. The repeated measures analysis was performed on samples every week. Morphological changes were less in the test group compared to the control. The quantitative hemolysis profile test showed significant changes in the test and control groups (p < 0.05) in consecutive weeks except for K and Fe. Oxidative stress parameters too showed a significant change during the target days of the examination (p < 0.05). Also, the phosphatidylserine expression was increased in control groups more than test in consecutive weeks (p < 0.05). It seems that the use of antioxidant nanoparticles improves the quality of stored red blood cells and can prevent posttransfusion complications and blood loss by reducing oxidative stress.