Miracle-dz/UniFAR-FTUs huggingface dataset:
Exploring YAP1-centered networks linking dysfunctional CFTR to epithelial–mesenchymal transition

In this work, a systems biology approach identifies potentially dysregulated EMT signaling in CF (including the Hippo, Wnt, TGF-β, p53, and MYC pathways), integrated by YAP1 and TEAD4. Mutations in the CFTR anion channel cause cystic fibrosis (CF) and have also been related to higher cancer incidence. Previously we proposed that this is linked to an emerging role of functional CFTR in protecting against epithelial–mesenchymal transition (EMT). However, the pathways bridging dysfunctional CFTR to EMT remain elusive. Here, we applied systems biology to address this question. Our data show that YAP1 is aberrantly active in the presence of mutant CFTR, interacting with F508del, but not with wt-CFTR, and that YAP1 knockdown rescues F508del-CFTR processing and function. Subsequent analysis of YAP1 interactors and roles in cells expressing either wt- or F508del-CFTR reveal that YAP1 is an important mediator of the fibrotic/EMT processes in CF. Alongside, five main pathways emerge here as key in linking mutant CFTR to EMT, namely, (1) the Hippo pathway; (2) the Wnt pathway; (3) the TGFβ pathway; (4) the p53 pathway; and (5) MYC signaling. Several potential hub proteins which mediate the crosstalk among these pathways were also identified, appearing as potential therapeutic targets for both CF and cancer.
Assessment of a 3D neural spheroid model to detect pharmaceutical-induced neurotoxicity.

Drug-induced neurotoxicity is a leading cause of safety-related attrition for therapeutics in clinical trials, often driven by poor predictive capability of preclinical in vitro and in vivo models of neurotoxicity. Over a dozen different iPSC-derived 3D spheroids have been published in recent years, but their ability to predict neurotoxicity in patients has not been evaluated, nor compared with the predictive power of nonclinical species. To assess the predictive capabilities of the human iPSC-derived neural spheroids (microBrains), we used 84 structurally diverse pharmaceuticals with robust clinical and preclinical datasets with varying degrees of seizurogenic and neurodegenerative liability. Drug-induced changes in neural viability and phenotypic calcium bursts were assessed using 7 endpoints based on calcium oscillation profiles and cellular ATP levels. These endpoints normalized by therapeutic exposure were used to build logistic regression models to establish endpoint cutoffs and evaluate probability for clinical neurotoxicity. The neurotoxicity score calculated from the logistic regression model could distinguish neurotoxic from non-neurotoxic clinical molecules with a specificity as high as 93.33% and a sensitivity of 53.49%, demonstrating a very low false positive rate for the prediction of seizures, convulsions and neurodegeneration. In contrast, nonclinical species showed a higher sensitivity (75%) and much lower specificity (30.4%). The neural spheroids demonstrated higher likelihood ratio positive and inverse likelihood ratio negative compared with nonclinical safety studies. This assay has the potential to be used as a predictive assay to detect neurotoxicity in early drug discovery, aiding in the early identification of compounds that eventually may fail due to neurotoxicity.
3D ceramic microstereolithography applied to sub-millimeter devices manufacturing

In this paper the ceramic micro-stereolithography process is presented for the manufacturing of microwave devices able to work at 100 GHz and higher. A 2D Electromagnetic Band Gap crystal has been manufactured and tested from 110 to 180GHz. Good agreement between the measurement and 3D electromagnetic computations has validated the presented process.
Corticotropin releasing factor (CRF) systems: Promoting cocaine pursuit without distress via incentive motivation

Corticotropin releasing factor (CRF) systems in limbic structures are posited to mediate stress-induced relapse in addiction, traditionally by generating distress states that spur drug consumption as attempts at hedonic self-medication. Yet evidence suggests that activating CRF-expressing neurons in the central amygdala (CeA) or nucleus accumbens (NAc) can magnify incentive motivation in absence of distress, at least for sucrose rewards. However, traditional CRF hypotheses in addiction neuroscience are primarily directed toward drug rewards. The question remains open whether CRF systems can similarly act via incentive motivation mechanisms to promote pursuit of drug rewards, such as cocaine. Here we tested whether optogenetic excitation of CRF-containing neurons in either NAc medial shell, lateral CeA, or dorsolateral BNST of transgenic Crh-Cre+ rats would spur preference and pursuit of a particular laser-paired cocaine reward over an alternative cocaine reward, and whether excitation served as a positively-valenced incentive itself, through laser self-stimulation tests. We report that excitation of CRF-containing neurons in either NAc or CeA recruited mesocorticolimbic circuitry to amplify incentive motivation to pursue the laser-paired cocaine: focusing preference on the laser-paired cocaine reward in a two-choice task, and spurred pursuit as doubled breakpoint in a progressive ratio task. Crucially indicating positive-valence, excitation of CRF neurons in NAc and CeA also was actively sought after by most rats in self-stimulation tasks. Conversely, CRF neuronal activation in BNST was never self-stimulated, but failed to enhance cocaine consumption. Collectively, we find that NAc and CeA CRF-containing neurons can amplify pursuit and consumption of cocaine by positively-valenced incentive mechanisms, without any aversive distress.
Retrospective Study of 23 Patients with Traumatic Posterolateral Tibial Plateau Fracture Treated in a Single Center Between 2017 and 2019 with Lateral Arthrotomy, Reduction, and Plate Fixation Using the Frosch Approach

Background The Frosch approach is a posterolateral surgical procedure performed with or without osteotomy of the fibula for the treatment of posterolateral tibial plateau fractures (PLFs). This retrospective study from a single center aimed to evaluate 23 patients with PLFs who underwent surgical reduction with the Frosch approach between January 2017 and October 2019. Material/Methods Twenty-three patients, 4 with Schatzker type V and 19 with Schatzker type II fractures were enrolled. Postoperative radiographs were performed regularly to measure the medial proximal tibial angle (MTPA), lateral posterior slope angle (LPSA), medial posterior slope angle (MPSA), and articular step-off to evaluate the fracture reduction. At the last follow-up, the Hospital for Special Surgery (HSS) knee score and knee range of motion (ROM) were used to assess knee function. Result Radiograph examinations indicated excellent reduction and fixation of fractures in all patients. The average HSS scores and ROM of the 23 patients were 88.0±3.5 and 131.8±7.8°, respectively, with an average of 30.5±4.6 months of follow-up. Skin numbness occurred in 3 patients but was recovered within 6 months. One patient sustained superficial wound infection, and another patient had superficial adipose tissue liquefaction necrosis. Conclusions This experience from a single center demonstrated the advantage of the Frosch approach in visualizing the posterolateral and lateral tibial plateau from a single surgical incision and resulted in excellent postoperative outcomes at follow-up when evaluated by the HSS score, ROM, and radiographic evaluation of the MTPA, LPSA, and MPSA.
Electronic Health Interventions for Patients With Breast Cancer: Systematic Review and Meta-Analyses

PURPOSE Ongoing supportive care using electronic health (eHealth) interventions has the potential to provide remote support and improve health outcomes for patients with breast cancer. This study aimed to evaluate the effectiveness of eHealth interventions on patient-reported outcomes (quality of life [QOL], self-efficacy, and mental or physical health) for patients during and after breast cancer treatment and patient-reported experience measures (acceptability and engagement). METHODS Systematic review with meta-analyses (random-effects model) of randomized controlled trials was conducted following Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Nine databases were searched using a prespecified search strategy. Patient-directed eHealth interventions for adult patients during or after active breast cancer treatment measuring QOL, self-efficacy, and mental (depressive, anxiety, and distress symptoms) or physical (physical activity, nutrition, and fatigue) health outcomes were included. Data from eligible full-text articles were independently extracted by six observers. RESULTS Thirty-two unique studies (4,790 patients) were included. All were health self-management interventions, and most were multicomponent (videos, forums, and electronic reminder systems) websites. Meta-analyses revealed a significant effect of eHealth interventions on QOL (standardized mean difference [SMD], 0.20 [95% CI, 0.03 to 0.36]), self-efficacy (SMD, 0.45 [95% CI, 0.24 to 0.65]), distress (SMD, –0.41 [95% CI,–0.63 to –0.20]), and fatigue (SMD, –0.37 [95% CI, –0.61 to –0.13]). Twenty-five studies (78.1%) measured patient-reported experience measures. Acceptability (n = 9) was high, with high ratings for satisfaction (range, 71%-100%), usefulness (range, 71%-95%), and ease-of-use (range, 73%-92%). Engagement (n = 25) decreased over time, but disease-focused information and interactive support were most engaging. CONCLUSION eHealth interventions may provide an acceptable and effective strategy for improving QOL, distress, self-efficacy, and fatigue among patients with breast cancer.
Modulation of autoimmune diabetes by N-ethyl-N-nitrosourea- induced mutations in non-obese diabetic mice

ABSTRACT Genetic association studies of type 1 diabetes (T1D) in humans, and in congenic non-obese diabetic (NOD) mice harboring DNA segments from T1D-resistant mice, face the challenge of assigning causation to specific gene variants among many within loci that affect disease risk. Here, we created random germline mutations in NOD/NckH mice and used automated meiotic mapping to identify mutations modifying T1D incidence and age of onset. In contrast with association studies in humans or congenic NOD mice, we analyzed a relatively small number of genetic changes in each pedigree, permitting implication of specific mutations as causative. Among 844 mice from 14 pedigrees bearing 594 coding/splicing changes, we identified seven mutations that accelerated T1D development, and five that delayed or suppressed T1D. Eleven mutations affected genes not previously known to influence T1D (Xpnpep1, Herc1, Srrm2, Rapgef1, Ppl, Zfp583, Aldh1l1, Col6a1, Ccdc13, Cd200r1, Atrnl1). A suppressor mutation in Coro1a validated the screen. Mutagenesis coupled with automated meiotic mapping can detect genes in which allelic variation influences T1D susceptibility in NOD mice. Variation of some of the orthologous/paralogous genes may influence T1D susceptibility in humans.
Cytotoxic Polyprenylated Benzoylphloroglucinol Derivatives from the Branches of Garcinia schomburgkiana

Abstract Five undescribed polyprenylated benzoylphloroglucinol derivatives ( 1 – 5 ), named garschomcinols A – E, and five known analogues ( 6 – 10 ) were isolated from the branches of Garcinia schomburgkiana . Their structures were determined on the basis of 1D and 2D NMR and HRESIMS analyses. The absolute configuration of the bicyclo [3.3. 1]nonane core structure of the polyprenylated benzoylphloroglucinols was assigned by comparison of its experimental electronic circular dichroism data with that of related compounds. All isolated compounds were evaluated for their cytotoxicity in vitro against five cancer cell lines. Compound 6 showed potent cytotoxicity against five cancer cell lines including KB, HeLa S3, HT-29, MCF-7, and Hep G2 with IC 50 values in the range of 5.05 – 7.03 µM.
Phospho‐specific plasma p‐tau181 assay detects clinical as well as asymptomatic Alzheimer's disease

Plasma phosphorylated‐tau‐181 (p‐tau181) reliably detects clinical Alzheimer's disease (AD) as well as asymptomatic amyloid‐β (Aβ) pathology, but is consistently quantified with assays using antibody AT270, which cross‐reacts with p‐tau175. This study investigates two novel phospho‐specific assays for plasma p‐tau181 and p‐tau231 in clinical and asymptomatic AD.
Specificity of phonological representations in school-age high-functioning ASD children

Abstract Purpose Well-specified phonological representations are important for the development of spoken and written language. This study investigates the types of speech errors and the quality of phonological representations in Greek-speaking school-age children with high-functioning autism spectrum disorder (HF-ASD), as well as the relationship between stored phonological representations and speech output in this sample, according to Stackhouse and Wells’ (1997) model. Method All participants completed a phonological and a naming test, and a non-word repetition task. A receptive phonological task was administered to a subgroup of HF-ASD and typically developing (TD) participants. According to performance in the phonological test, the HF-ASD children were categorised as ASD with Speech Sound Disorder (SSD) or ASD without SSD. Result The HF-ASD children made significantly more speech errors and showed significant difficulties in the repetition of non-words and the stored phonological representations compared to the TD group but had the same naming abilities with their TD peers. The ASD children with SSD and without SSD performed alike in the receptive task, indicating that both groups had unspecified phonological representations. Conclusion These results support the hypothesis of distinct phonological representations for speech input and output and highlight the need of using receptive tasks to evaluate underlying phonological knowledge, a process which could allow clinicians to identify the level of speech breakdown.
Systematic expression profiling of dprs and DIPs reveals cell surface codes in Drosophila larval motor and sensory neurons.

In complex nervous systems, neurons must identify their correct partners to form synaptic connections. The prevailing model to ensure correct recognition posits that cell surface proteins (CSPs) in individual neurons act as identification tags. Thus, knowing what cells express which CSPs would provide insights into neural development, synaptic connectivity, and nervous system evolution. Here, we investigated expression of dprs and DIPs, two CSP subfamilies belonging to the immunoglobulin superfamily, in Drosophila larval motor neurons (MNs), muscles, glia, and sensory neurons (SNs), using a collection of GAL4 driver lines. We found that dprs are more broadly expressed than DIPs in MNs and SNs, and each examined neuron expresses a unique combination of dprs and DIPs. Interestingly, many dprs and DIPs are not robustly expressed, but instead, are found in gradient and temporal expression patterns. In addition, the unique expression patterns of dprs and DIPs revealed three uncharacterized MNs. This study sets the stage for exploring the functions of dprs and DIPs in Drosophila MNs and SNs and provides genetic access to subsets of neurons.
Ketoprofen, piroxicam and indomethacin‐suppressed quorum sensing and virulence factors in Acinetobacter baumannii

Quorum sensing (QS) inhibition is a promising strategy to suppress bacterial virulence and control infection caused by Gram‐negative and Gram‐positive bacteria. This study explores the QS inhibiting activity of the non‐steroidal anti‐inflammatory drugs (NSAIDs) in Acinetobacter baumannii.
Balancing non‐discriminatory donor selection and blood safety in the Netherlands: Evaluation of an individual risk assessment of sexual behavior

To better balance the safety of the blood supply and the inclusion of men who have sex with men (MSM), further improvements are needed to the risk management strategy employed in the Netherlands to reduce transfusion‐transmissible infections (TTIs). A gender‐neutral individual risk assessment could provide a solution by determining donor eligibility based on sexual behaviors known to increase the risk of TTIs. Our objective is to estimate the proportion of blood donors that would be deferred by such an assessment, as well as their discomfort answering such questions.
Proprotein convertase subtilisin/kexin type 9 is associated with atherosclerosis in patients with Behcet’s disease

ABSTRACT Objectives The incidence of cardiovascular disease is increased in patients with Behcet’s disease (BD). Proprotein convertase subtilisin/kexin type 9 (PCSK9) causes the acceleration of atherosclerosis. We aimed to investigate whether there is a relationship between PCSK9 with carotid artery intima-media thickness (cIMT), a marker of subclinical atherosclerosis, and BD disease activity. Methods Fifty-eight patients with BD and 58 age-, gender-, and body mass index (BMI)-matched healthy control subjects were included in the study. The disease activity of the patients was estimated. Individuals’ cIMT values were measured, and PCSK9 levels were studied. Results Patients with BD’ cIMT (0.51 ± 0.1 vs 0.41 ± 0.1 mm, p < .001) and PCSK9 (623.2 ± 101.7 ± 10.1 vs 528.3 ± 242.7 ng/ml, p = .007), values were significantly higher than the control group. In stepwise regression analysis, there was an independent relationship between cIMT with PCSK9 (β = 0.179, p < .050). There was no independent relationship between disease activities with PCSK9. Based on the ROC curve analysis, the PCSK9 optimal cutoff value for cIMT was 595.1 ng/ml, sensitivity 66.7%, specificity 64.7% (AUC = 0.672; 95% CI: 0.530–0.815, p = .040). Conclusion There is a strong independent association between subclinical atherosclerosis and PCSK9 in patients with BD. There may be no independent association between PCSK9 and disease activity.
SAMS-1 coordinates HLH-30/TFEB and PHA-4/FOXA activities through histone methylation to mediate dietary restriction-induced autophagy and longevity

ABSTRACT Dietary restriction (DR) is known to promote autophagy to exert its longevity effect. While SAMS-1 (S-adenosyl methionine synthetase-1) has been shown to be a key mediator of the DR response, little is known about the roles of S-adenosyl methionine (SAM) and SAM-dependent methyltransferase in autophagy and DR-induced longevity. In this study, we show that DR and SAMS-1 repress the activity of SET-2, a histone H3K4 methyltransferase, by limiting the availability of SAM. Consequently, the reduced H3K4me3 levels promote the expression and activity of two transcription factors, HLH-30/TFEB and PHA-4/FOXA, which both regulate the transcription of autophagy-related genes. We then find that HLH-30/TFEB and PHA-4/FOXA act collaboratively on their common target genes to mediate the transcriptional response of autophagy-related genes and consequently the lifespan of the animals. Our study thus shows that the SAMS-1-SET-2 axis serves as a nutrient-sensing module to epigenetically coordinate the activation of HLH-30/TFEB and PHA-4/FOXA transcription factors to control macroautophagy/autophagy and longevity in response to DR. Abbreviations: ChIP: chromatin immunoprecipitation; ChIP-seq: chromatin immuno precipitation-sequencing; COMPASS: complex of proteins associated with Set1; DR: dietary restriction; GO: gene ontology; SAM: S-adenosyl methionine; SAMS-1: S-adenosyl methionine synthetase-1; TSS: transcription start site; WT: wild-type.
Strong ACE-2 expression in the choroidal vessels: do high choroid plexuses serve as a gateway for SARS-CoV-2 infection on the human brain?

OBJECTIVE Previous studies have confirmed the key mechanism by which SARS-CoV-2 enters human cells. It is well established that ACE2 is the receptor that can mark the beginning of the infection. In light of this, the organs that express higher levels of ACE2 are generally considered at higher risk, while those with lower levels should be somehow more protected. This - if related to the scarcity of ace2-expressing cells in the brain - seems to contrast with the presence of a variety of neurological symptoms that follow infection with ace2. The aim of this work was to analyze ACE2 expression in the human brain, focusing on the choroid plexuses. PATIENTS AND METHODS Twenty brain samples were obtained at autopsy from ten human fetuses and from ten adult subjects. All samples were selected to contain the choroid plexus. Specimens were fixed in 10% formalin, routinely processed and paraffin embedded. 5-micron sections were stained with Hematoxylin and Eosin (H&E) and immunostained with a commercial anti-human ACE2 rabbit monoclonal antibody at 1:100 dilution. RESULTS We analyzed 20 samples by immunohistochemistry, and we noted that, as far as fetal samples are concerned, a strong reactivity for ACE2 was detected in the myxoid stroma of the choroid plexuses and in the endothelial cells in fetuses. The complete absence of the ACE2 marker was detected in epithelial cells, neurons and glial cells of the cerebral cortex, both in fetuses and in adults. Whereas a strong but selective reactivity for ACE2 was also detected in adult choroid plexuses, mainly localized in the endothelial cells of the choroid capillaries. CONCLUSIONS Our study shows a strong expression of ACE in the fetal and adult brain choroid plexuses. This new histopathological finding may clarify the susceptibility of the human brain to SARS-COV-2 infection. Our data indicate the choroid plexus as the entry gate of virus for in the human brain; therefore, the entrance of SARS-CoV-2 into the cerebrospinal fluid through the choroid plexuses might represent the mechanism utilized by this coronavirus to cause direct injury to brain cells.
Structure and Mechanism of a Cold-Adapted Bacterial Lipase

The structural origin of enzyme cold-adaptation has been the subject of considerable research efforts in recent years. Comparative studies of orthologous mesophilic–psychrophilic enzyme pairs found in nature are an obvious strategy for solving this problem, but they often suffer from relatively low sequence identity of the enzyme pairs. Small bacterial lipases adapted to distinctly different temperatures appear to provide an excellent model system for these types of studies, as they may show a very high degree of sequence conservation. Here, we report the first crystal structures of lipase A from the psychrophilic bacterium Bacillus pumilus, which confirm the high structural similarity to the mesophilic Bacillus subtilis enzyme, as indicated by their 81% sequence identity. We further employ extensive QM/MM calculations to delineate the catalytic reaction path and its energetics. The computational prediction of a rate-limiting deacylation step of the enzymatic ester hydrolysis reaction is verified by stopped-flow experiments, and steady-state kinetics confirms the psychrophilic nature of the B. pumilus enzyme. These results provide a useful benchmark for examining the structural basis of cold-adaptation and should now make it possible to disentangle the effects of the 34 mutations between the two enzymes on catalytic properties and thermal stability.