Miracle-dz/UniFAR-FTUs huggingface dataset:
Genomic and transcriptomic profiling of carcinogenesis in patients with familial adenomatous polyposis

Objective Familial adenomatous polyposis (FAP) is characterised by the development of hundreds to thousands of adenomas at different evolutionary stages in the colon and rectum that will inevitably progress to adenocarcinomas if left untreated. Here, we investigated the genetic alterations and transcriptomic transitions from precancerous adenoma to carcinoma. Design Whole-exome sequencing, whole-genome sequencing and single-cell RNA sequencing were performed on matched adjacent normal tissues, multiregionally sampled adenomas at different stages and carcinomas from six patients with FAP and one patient with MUTYH-associated polyposis (n=56 exomes, n=56 genomes and n=8,757 single cells). Genomic alterations (including copy number alterations and somatic mutations), clonal architectures and transcriptome dynamics during adenocarcinoma carcinogenesis were comprehensively investigated. Results Genomic evolutionary analysis showed that adjacent lesions from the same patient with FAP can originate from the same cancer-primed cell. In addition, the tricarboxylic acid cycle pathway was strongly repressed in adenomas and was then slightly alleviated in carcinomas. Cells from the ‘normal’ colon epithelium of patients with FAP already showed metabolic reprogramming compared with cells from the normal colon epithelium of patients with sporadic colorectal cancer. Conclusions The process described in the previously reported field cancerisation model also occurs in patients with FAP and can contribute to the formation of adjacent lesions in patients with FAP. Reprogramming of carbohydrate metabolism has already occurred at the precancerous adenoma stage. Our study provides an accurate picture of the genomic and transcriptomic landscapes during the initiation and progression of carcinogenesis, especially during the transition from adenoma to carcinoma.
The Production Possibility of the Antimicrobial Filaments by Co-Extrusion of the PLA Pellet with Chitosan Powder for FDM 3D Printing Technology

The last decades have witnessed a major advancement and development in three-dimensional (3D) printing technology. In the future, the trend’s utilization of 3D printing is expected to play an important role in the biomedical field. This work presents co-extrusion of the polylactic acid (PLA), its derivatives (sPLA), and chitosan with the aim of achieving filaments for printing 3D objects, such as biomedical tools or implants. The physicochemical and antimicrobial properties were evaluated using SEM, FT-IR, DSC, instrumental mechanical test, and based on the ASTM E2149 standard, respectively. The addition of chitosan in the PLA and sPLA filaments increased their porosity and decreased density. The FT-IR analysis showed that PLA and chitosan only formed a physical mixture after extrusion. The addition of chitosan caused deterioration of the mechanical properties of filaments, especially elongation at break and Young’s modulus. The addition of chitosan to the filaments improved their ability to crystallize and provide their antimicrobial properties against Escherichia coli and Staphylococcus aureus.
The inhibition of miR-101a-3p alleviates H/R injury in H9C2 cells by regulating the JAK2/STAT3 pathway

Hypoxia/reoxygenation (H/R) is used as an in vivo model of ischemia/reperfusion injury, and myocardial ischemia can lead to heart disease. Therefore, it is necessary to prevent myocardial H/R injury to avoid the risk of heart disease. The aim of the present study was to investigate whether inhibiting microRNA (miR)-101a-3p attenuated H9C2 cell H/R injury, apoptosis mechanisms and key target proteins. Cell viability and apoptosis were determined by Cell Counting Kit-8 assays and flow cytometry using a cell apoptosis kit, respectively. The contents of creatine kinase (CK) and lactate dehydrogenase (LDH) were detected using colorimetric assays. Dual luciferase assays were carried out to determine if miR-101a-3p inhibited Janus kinase (JAK)2. Western blot analysis and reverse transcription-quantitative PCR were used to determine proteins levels and mRNAs expression. It was found that the inhibition of miR-101a-3p increased the growth of H9C2 cells and decreased H9C2 cell apoptosis during H/R injury. The inhibition of miR-101a-3p reduced the amounts of CK and LDH in H/R model H9C2 cells. The inhibition of miR-101a-3p lowered the levels of Bax, interleukin-6 and tumor necrosis factor-α, but raised the levels of phosphorylated (p)-STAT3 and p-JAK2 in H9C2 cells subjected to H/R injury treatment. miR-101a-3p mimic was found to inhibit H9C2 cell viability, raise p-JAK2 level and slightly increase p-STAT3 during H/R injury. AG490 induced H9C2 cell apoptosis, and decreased the levels of p-JAK2 and p-STAT3 during H/R injury. The data indicated that inhibiting miR-101a-3p reduced H/R damage in H9C2 cells and decreased apoptosis via Bax/Bcl-2 signaling during H/R injury. In addition, it was suggested that the inhibition of miR-101a-3p decreased H/R injury in H9C2 cell by regulating the JAK2/STAT3 signaling pathway.
A YajQ‐LysR‐like, cyclic di‐GMP‐dependent system regulating biosynthesis of an antifungal antibiotic in a crop‐protecting bacterium, Lysobacter enzymogenes

Summary YajQ, a binding protein of the universal bacterial second messenger cyclic di‐GMP (c‐di‐GMP), affects virulence in several bacterial pathogens, including Xanthomonas campestris. In this bacterium, YajQ interacts with the transcription factor LysR. Upon c‐di‐GMP binding, the whole c‐di‐GMP‐YajQ‐LysR complex is found to dissociate from DNA, resulting in virulence gene regulation. Here, we identify a YajQ‐LysR‐like system in the bacterial biocontrol agent Lysobacter enzymogenes OH11 that secretes an antifungal antibiotic, heat‐stable antifungal factor (HSAF) against crop fungal pathogens. We show that the YajQ homologue, CdgL (c‐di‐GMP receptor interacting with LysR) affects expression of the HSAF biosynthesis operon by interacting with the transcription activator LysR. The CdgL‐LysR interaction enhances the apparent affinity of LysR to the promoter region upstream of the HSAF biosynthesis operon, which increases operon expression. Unlike the homologues CdgL (YajQ)‐LysR system in X. campestris, we show that c‐di‐GMP binding to CdgL seems to weaken CdgL‐LysR interactions and promote the release of CdgL from the LysR‐DNA complex, which leads to decreased expression. Together, this study takes the YajQ‐LysR‐like system from bacterial pathogens to a crop‐protecting bacterium that is able to regulate antifungal HSAF biosynthesis via disassembly of the c‐di‐GMP receptor–transcription activator complex.
Professional and Volunteer Refugee Aid Workers–Depressive Symptoms and Their Predictors, Experienced Traumatic Events, PTSD, Burdens, Engagement Motivators and Support Needs

In 2016, the Department of Psychosomatic Medicine and Psychotherapy of the University Hospital of Erlangen started conducting training for professional and voluntary aid workers. In total, 149 aid workers took part in the training courses, of which 135 completed the corresponding questionnaires. Engagement motivators, perceived distress in refugee work and training needs were examined. Moreover, depressive symptoms, the prevalence of traumatic experiences and symptoms of posttraumatic stress disorder were explored. Participants named helping others as the highest motivating factor for their work with refugees and communication problems as the main burden. Thirteen aid workers (10.1%) showed clinically relevant depressive symptoms. In total, 91.4% of refugee aid workers had experienced at least one traumatic event personally or as a witness but only three (3.6%) fulfilled the psychometric requirements of a PTSD diagnosis. These three participants all belonged to the professional aid workers (6.3%). More severe symptoms of depression were significantly associated with female gender (β = 0.315, p = 0.001), higher perceived burdens of refugee work (β = 0.294, p = 0.002), and a larger number of experienced traumatic events (β = 0.357, p < 0.001). According to our results, we recommend psychological trainings and regular screenings for psychological stress in order to counteract possible mental illnesses.
Berberine ameliorates lipopolysaccharide-induced inflammatory responses in mouse inner medullary collecting duct-3 cells by downregulation of NF-κB pathway

The major role of inner medullary collecting duct (IMCD) cells is to maintain water and sodium homeostasis. In addition to the major role, it also participates in the protection of renal and systemic inflammation. Although IMCD cells could take part in renal and systemic inflammation, investigations on renal inflammation in IMCD cells have rarely been reported. Although berberine (BBR) has been reported to show diverse pharmacological effects, its anti-inflammatory and protective effects on IMCD cells have not been studied. Therefore, in the present study, we examined the anti-inflammatory and protective effects of BBR in mouse IMCD-3 (mIMCD-3) cells against lipopolysaccharide (LPS). An MTT assay was carried out to investigate the toxicity of BBR on mIMCD-3 cells. Reverse transcription quantitative-PCR and western blotting were performed to analysis pro-inflammatory molecules and cytokines. Mechanisms of BBR were examined by western blotting and immunocytochemistry. According to previous studies, pro-inflammatory molecules, such as inducible nitric oxide synthase and cyclooxygenase-2, and pro-inflammatory cytokines, such as interleukin (IL)-1β, IL-6 and tumor necrosis factor-α are increased in LPS-exposed mIMCD-3 cells. However, the production of these pro-inflammatory molecules is significantly inhibited by treatment with BBR. In addition, BBR inhibited translocation of nuclear factor (NF)-κB p65 from the cytosol to the nucleus, and degradation of inhibitory κ-Bα in LPS-exposed mIMCD-3 cells. In conclusion, BBR could inhibit renal inflammatory responses via inhibition of NF-κB signaling and ultimately contribute to amelioration of renal injury during systemic inflammation.
Molecular Mechanisms and Genetics of Oxidative Stress in Alzheimer’s Disease

Alzheimer’s disease is the most common neurodegenerative disorder that can cause dementia in elderly over 60 years of age. One of the disease hallmarks is oxidative stress which interconnects with other processes such as amyloid-β deposition, tau hyperphosphorylation, and tangle formation. This review discusses current thoughts on molecular mechanisms that may relate oxidative stress to Alzheimer’s disease and identifies genetic factors observed from in vitro, in vivo, and clinical studies that may be associated with Alzheimer’s disease-related oxidative stress.
Circulating pentraxin-3 and preeclampsia: a meta-analysis of 17 case-control studies

Abstract Introduction Change of circulating pentraxin-3 (PTX-3), a novel marker of inflammation, has been observed in women with preeclampsia (PE). However, results of previous studies were inconsistent. We performed a meta-analysis to evaluate the difference of circulating PTX-3 between women with PE and normal pregnancies. Methods Case-control studies comparing circulating PTX-3 level between women with PE and normal pregnancies were identified via search of PubMed and Embase databases according to a predefined search strategy and inclusion criteria by two independent authors. Meta-analysis was performed with a random-effect model to incorporate heterogeneity. Results Seventeen studies including 814 women with PE and 949 women with normal pregnancy were included. Results showed that women with PE had significantly higher circulating PTX-3 at diagnosis as compared to women with normal pregnancy (standardized mean difference [SMD]: = 1.74, 95% CI: 1.20–2.29, p < .001; I 2 = 94%). The results were consistent regardless of study characteristics including study location, maternal age, sample size, early or late onset of PE, blood sample for PTX-3 measurement, or NOS quality scores. Moreover, higher circulating PTX-3 was also observed before the diagnosis of PE (SMD = 0.65, 95% CI: 0.02–1.29, p = .04; I 2 = 87%). Conclusion Women with PE have higher circulating PTX-3 than women with normal pregnancy. The elevated PTX-3 could be observed before the clinical onset of PE. Future studies are needed to determine whether PTX-3 is an active molecular in the pathogenesis of PE.
Improved volumetric myelin imaging in human brain using 3D dual echo inversion recovery‐prepared UTE with complex echo subtraction

Inversion recovery‐based UTE (IR‐UTE) sequences have been proposed to directly image myelin with extremely short T2∗ (~0.3 ms). In this study, we demonstrate the feasibility of complex echo subtraction to improve 3D IR‐UTE imaging of myelin in white matter of the brain in vivo.
Coaxial electrospinning of PEEU/gelatin to fiber meshes with enhanced mesenchymal stem cell attachment and proliferation1.

Microfibers with a core-shell structure can be produced by co-axial electrospinning, allowing for the functionalization of the outer layer with bioactive molecules. In this study, a thermoplastic, degradable polyesteretherurethane, consisting of poly(p-dioxanone) (PPDO) and poly(ɛ-caprolactone) (PCL) segments with different PPDO to PCL weight ratios, were processed into fiber meshes by co-axial electrospinning with gelatin. The prepared PEEU fibers have a diameter of 1.3±0.5 μm and an elastic modulus of around 5.1±1.0 MPa as measured by tensile testing in a dry state at 37°C, while the PEEU/Gelatin core-shell fibers with a gelatin content of 12±6 wt% and a diameter of 1.5±0.5 μm possess an elastic modulus of 15.0±1.1 MPa in a dry state at 37 °C but as low as 0.7±0.7 MPa when hydrated at 37 °C. Co-axial electrospinning allowed for the homogeneous distribution of the gelatin shell along the whole microfiber. Gelatin with conjugated FITC remained stable on the PEEU fibers after 7 days incubation in PBS at 37 °C. The gelatin coating on PEEU fibers lead to enhanced human adipose tissue derived mesenchymal stem cell (hADSC) attachment and a proliferation rate 81.7±34.1 % higher in cell number in PEEU50/Gelatin fibers after 7 days of cell culture when compared to PEEU fibers without coating. In this work, we demonstrate that water-soluble gelatin can be incorporated as the outer shell of a polymer fiber via molecular entanglement, with a sustained presence and role in enhancing stem cell attachment and proliferation.
The formation of hybrid complexes between isoenzymes of glyceraldehyde‐3‐phosphate dehydrogenase regulates its aggregation state, the glycolytic activity and sphingolipid status in Saccharomyces cerevisiae

The glycolytic enzyme glyceraldehyde‐3‐phosphate dehydrogenase (GAPDH) has been traditionally considered a housekeeping protein involved in energy generation. However, evidence indicates that GAPDHs from different origins are tightly regulated and that this regulation may be on the basis of glycolysis‐related and glycolysis‐unrelated functions. In Saccharomyces cerevisiae, Tdh3 is the main GAPDH, although two other isoenzymes encoded by TDH1 and TDH2 have been identified. Like other GAPDHs, Tdh3 exists predominantly as a tetramer, although dimeric and monomeric forms have also been isolated. Mechanisms of Tdh3 regulation may thus imply changes in its oligomeric state or be based in its ability to interact with Tdh1 and/or Tdh2 to form hybrid complexes. However, no direct evidence of the existence of these interactions has been provided and the exact function of Tdh1,2 is unknown. Here, we show that Tdh1,2 immunopurified with a GFP‐tagged version of Tdh3 and that lack of this interaction stimulates the Tdh3’s aggregation. Furthermore, we found that the combined knockout of TDH1 and TDH2 promotes the loss of cell’s viability and increases the growing rate, glucose consumption and CO2 production, suggesting a higher glycolytic flux in the mutant cells. Consistent with this, the tdh3 strain, which displays impaired in vitro GAPDH activity, exhibited the opposite phenotypes. Quite remarkably, tdh1 tdh2 mutant cells show increased sensitivity to aureobasidin A, an inhibitor of the inositolphosphoryl ceramide synthase, while cells lacking Tdh3 showed improved tolerance. The results are in agreement with a link between glycolysis and sphingolipid (SLs) metabolism. Engineering Tdh activity could be thus exploited to alter the SLs status with consequences in different aspects of yeast biotechnology.
Human Induced Pluripotent Stem Cell-Derived Non-Cardiomyocytes Modulate Cardiac Electrophysiological Maturation Through Connexin 43-Mediated Cell-Cell Interactions

The functional maturation status of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) has a notable impact upon their use in pharmacological studies, disease modeling, and therapeutic applications. Non-cardiomyocytes (non-CMs) produced in the differentiation process have previously been identified as having an extrinsic influence upon hiPSC-CM development, yet the underlying mechanisms are not fully understood. Herein, we aimed to modulate electrophysiological properties of hiPSC-CMs within co-cultures containing varied proportions of non-CMs and investigate the nature of interactions between these different cell types. Therefore, we sorted cardiac differentiations on day 10 and subsequently replated the cells at ratios of 7:3, 1:1, 3:7, and 1:9 non-CMs to CMs. After a month of co-culture, we evaluated electrophysiological properties through the genetically encoded voltage indicator ArcLight. We ultimately identified that co-cultures with approximately 70%–90% CM purity demonstrated the highest action potential (AP) amplitude and maximum upstroke velocity by day 40 of differentiation, indicative of enhanced electrophysiological maturation, as well as more ventricular-like AP morphologies. Notably, these findings were distinct from those observed for co-cultures of hiPSC-CMs and dermal fibroblasts. We determined that the co-culture phenotypes could not be attributed to paracrine effects of non-CMs due to the inability of conditioned media to recapitulate the observed effects. This led to the further observation of a distinctive expression pattern of connexin 43 (Cx43) at cell-cell interfaces between both CMs and non-CMs. Depletion of Cx43 by short hairpin RNA (shRNA) specifically in the non-CM population within a co-culture environment was able to recapitulate electrophysiological phenotypes of a purer hiPSC-CM population. Collectively, our data demonstrate that abundant non-CM content exerts a significant negative influence upon the electrophysiological maturation of hiPSC-CMs through Cx43-mediated cell-cell-contacts, and thus should be considered regarding the future production of purpose-built hiPSC-CM systems.
Reporting of Clinical Trial Interventions Published in Leading Otolaryngology-Head and Neck Surgery Journals.

OBJECTIVES/HYPOTHESIS Randomized controlled trials (RCTs) play a crucial role in advancing patient care within otolaryngology-head and neck surgery (OTL-HNS), yet studies have shown the reporting of these trials needs improvement. Here, we evaluate the completeness of intervention reporting of RCTs in OTL-HNS and evaluate whether the publication of the Template for Intervention Description and Replication (TIDieR) checklist has influenced intervention reporting. STUDY DESIGN Retrospective Cross-Sectional Analysis. METHODS We searched PubMed for RCTs published in top OTL-HNS journals in two cohorts, one before the release of the TIDieR and one afterward. A sample of 300 RCTs was randomly selected and screened for inclusion. Once the dataset was finalized, we extracted trial characteristics and assessed each trial's adherence to the TIDieR checklist. We then used descriptive characteristics, a generalized estimated equation, time-series analysis, and a two-sample t test to analyze our data. RESULTS After screening was completed, 173 RCTs were included in our analysis. Of these RCTs, 103 (59.5%) showed <60% adherence to the TIDieR checklist. We found a slight increase in adherence to TIDieR items after the checklist was released, although this was not statistically significant (P = .91). In addition, we found that trials with a crossover study design or multiple interventions and those that provided a Consolidated Standards for Reporting Trials statement were associated with greater adherence to the TIDieR checklist. CONCLUSIONS The majority of OTL-HNS RCTs included in our analysis showed suboptimal reporting factors related to the TIDieR checklist. Requiring a TIDieR statement and automating the journal requirements process for all OTL-HNS clinical trials would be a worthwhile, efficient approach to improving research quality and ultimately patient care within OTL-HNS. LEVEL OF EVIDENCE NA Laryngoscope, 2019.
Design of L-Cysteine Functionalized UiO-66 MOFs for Selective Adsorption of Hg(II) in Aqueous Medium.

Mercury ions can cause a series of hazards to humans and the environment, even in trace amounts. Here, we designed a novel adsorbent (Cys-UiO-66) by functionalizing NH2-UiO-66 with L-cysteine for selective removal of Hg(II) from solution. The Cys-UiO-66 was characterized by different instruments. The adsorption property of Cys-UiO-66 was evaluated by batch methods. The maximum adsorption capacity was 350.14 mg/g at pH 5.0. Furthermore, the adsorption isotherm and kinetics models were in accord with the Langmuir and Pseudo-second-order models respectively, evidencing that the adsorption behavior was dominated by monolayer chemisorption. The Cys-UiO-66 had better affinity for Hg(II) than other coexisting ions in wastewater and could be regenerated at least five cycles. The results prove that Cys-UiO-66 is a talented and efficient sorbent for mercury ions.
Organic anion transporting polypeptide 1A2 mediates fentanyl uptake in cultured cells.

Individual differences in the response to fentanyl, which may be caused by different concentrations of the drug in the central nervous system, can complicate analgesic treatment. It has been reported that the organic anion transporting polypeptide (OATP) at the blood‑brain barrier (BBB) in Sprague‑Dawley rats may serve an important role in the transport of fentanyl across the BBB. However, whether human OATP can transport fentanyl has thus far not been reported. The present study aimed to establish a 293 cell line stably overexpressing OATP1A2, and to determine whether OATP1A2 is able to transport fentanyl across the plasma membrane. Initially, 293 cells were transfected with an OATP1A2‑expressing plasmid (referred to as 293‑OATP1A2 cells), and single colonies were selected and characterized following geneticin treatment. Subsequently, reverse transcription‑quantitative polymerase chain reaction and western blot analyses were conducted to verify the transfection efficiency. Furthermore, treatment of 293‑OATP1A2 cells with different concentrations of fexofenadine (FEX) and fentanyl was performed to investigate the transport function of OATP1A2 in 293 cells. FEX and fentanyl uptake experiments were also performed with naringenin, an inhibitor of OATP1A2. The results indicated that FEX and fentanyl uptake was significantly increased in 293‑OATP1A2 cells compared with that in the control‑transfected cells. The 293‑OATP1A2‑mediated uptake of FEX at concentration of 100 nM FEX was ~10‑fold higher than that of 293‑VC cells. The 293‑OATP1A2‑mediated uptake of fentanyl (100 nM) was 5.1‑fold higher compared with that in 293‑VC cells. In 293‑OATP1A2 cells, the uptake of FEX without OATP1A2 inhibitor naringenin (100 µg/ml) was 2.8‑fold higher compared with that in the presence of naringenin, and the uptake of fentanyl without naringenin was 7.3‑fold higher compared with that in the presence of naringenin (100 µg/ml). In conclusion, 293 cells that overexpressed OATP1A2 were successfully constructed, and OATP1A2 was revealed to mediate fentanyl uptake in the cultured cells.