Miracle-dz/UniFAR-FTUs huggingface dataset:
E2F1 and E2F2-Mediated Repression of CPT2 Establishes a Lipid-Rich Tumor-Promoting Environment

These findings identify E2F1 and E2F2 transcription factors as metabolic drivers of hepatocellular carcinoma, where deletion of just one is sufficient to prevent disease. Lipid metabolism rearrangements in nonalcoholic fatty liver disease (NAFLD) contribute to disease progression. NAFLD has emerged as a major risk for hepatocellular carcinoma (HCC), where metabolic reprogramming is a hallmark. Identification of metabolic drivers might reveal therapeutic targets to improve HCC treatment. Here, we investigated the contribution of transcription factors E2F1 and E2F2 to NAFLD-related HCC and their involvement in metabolic rewiring during disease progression. In mice receiving a high-fat diet (HFD) and diethylnitrosamine (DEN) administration, E2f1 and E2f2 expressions were increased in NAFLD-related HCC. In human NAFLD, E2F1 and E2F2 levels were also increased and positively correlated. E2f1−/− and E2f2−/− mice were resistant to DEN–HFD-induced hepatocarcinogenesis and associated lipid accumulation. Administration of DEN–HFD in E2f1−/− and E2f2−/− mice enhanced fatty acid oxidation (FAO) and increased expression of Cpt2, an enzyme essential for FAO, whose downregulation is linked to NAFLD-related hepatocarcinogenesis. These results were recapitulated following E2f2 knockdown in liver, and overexpression of E2f2 elicited opposing effects. E2F2 binding to the Cpt2 promoter was enhanced in DEN–HFD-administered mouse livers compared with controls, implying a direct role for E2F2 in transcriptional repression. In human HCC, E2F1 and E2F2 expressions inversely correlated with CPT2 expression. Collectively, these results indicate that activation of the E2F1–E2F2–CPT2 axis provides a lipid-rich environment required for hepatocarcinogenesis. Significance: These findings identify E2F1 and E2F2 transcription factors as metabolic drivers of hepatocellular carcinoma, where deletion of just one is sufficient to prevent disease. Graphical Abstract: http://cancerres.aacrjournals. org/content/canres/81/11/2874/F1.large. jpg. Graphical Abstract
Insights into Nucleation and Growth of Colloidal Quaternary Nanocrystals by Multimodal X-ray Analysis

Copper chalcogenide nanocrystals find applications in photovoltaic inks, bio labels, and thermoelectric materials. We reveal insights in the nucleation and growth during synthesis of anisotropic Cu2ZnSnS4 nanocrystals by simultaneously performing in situ X-ray absorption spectroscopy (XAS) and small-angle X-ray scattering (SAXS). Real-time XAFS reveals that upon thiol injection into the reaction flask, a key copper thiolate intermediate species is formed within fractions of seconds, which decomposes further within a narrow temperature and time window to form copper sulfide nanocrystals. These nanocrystals convert into Cu2ZnSnS4 nanorods by sequentially incorporating Sn and Zn. Real-time SAXS and ex situ TEM of aliquots corroborate these findings. Our work demonstrates how combined in situ X-ray absorption and small-angle X-ray scattering enables the understanding of mechanistic pathways in colloidal nanocrystal formation.
Differentiating sepsis from similar groups of symptoms at triage level in emergency care.

Objectives Conditions that have similar initial presentations as sepsis may make early recognition of sepsis in an emergency room (ER) difficult. We investigated whether selected physiologic and metabolic parameters can be reliably used in the emergency department to differentiate sepsis from other disease states that mimic it, such as dehydration and stroke. Methods Loess regression on retrospective follow-up chart data of patients with sepsis-like symptoms (N = 664) aged 18+ in a large ER in Hungary was used to visualize/identify cutoff points for sepsis risk. A multivariate logistic regression model based on standard triage data was constructed with its corresponding receiver operating characteristic (ROC) curve and compared with another model constructed based on current sepsis guidelines. Results Age, bicarbonate, HR, lactate, pH, and body temperature had U, V, W, or reverse U-shaped associations with identifiable inflexion points, but the cutoff values we identified were slightly different from guideline cutoff values. In contrast to the guidelines, no inflexion points could be observed for the association of sepsis with SBP, DPB, MAP, and RR and therefore were treated as continuous variables. Compared to the guidelines-based model, the triage data-driven final model contained additional variables (age, pH, bicarbonate) and did not include lactate. The data-driven model identified about 85% of sepsis cases correctly, while the guidelines-based model identified only about 70% of sepsis cases correctly. Conclusion Our findings contribute to the growing body of evidence for the necessity of finding improved tools to identify sepsis at early time points, such as in the ER.
Channel-hopping during surface electrical neurostimulation elicits selective, comfortable, distally referred sensations

Objective. Lack of sensation from a hand or prosthesis can result in substantial functional deficits. Surface electrical stimulation of the peripheral nerves is a promising non-invasive approach to restore lost sensory function. However, the utility of standard surface stimulation methods has been hampered by localized discomfort caused by unintended activation of afferents near the electrodes and limited ability to specifically target underlying neural tissue. The objectives of this work were to develop and evaluate a novel channel-hopping interleaved pulse scheduling (CHIPS) strategy for surface stimulation that is designed to activate deep nerves while reducing activation of fibers near the electrodes. Approach. The median nerve of able-bodied subjects was activated by up to two surface stimulating electrode pairs placed around their right wrist. Subjects received biphasic current pulses either from one electrode pair at a time (single-channel), or interleaved between two electrode pairs (multi-channel). Percept thresholds were characterized for five pulse durations under each approach, and psychophysical questionnaires were used to interrogate the perceived modality, quality and location of evoked sensations. Main results. Stimulation with CHIPS elicited enhanced tactile percepts that were distally referred, while avoiding the distracting sensations and discomfort associated with localized charge densities. These effects were reduced after introduction of large delays between interleaved pulses. Significance. These findings demonstrate that our pulse scheduling strategy can selectively elicit referred sensations that are comfortable, thus overcoming the primary limitations of standard surface stimulation methods. Implementation of this strategy with an array of spatially distributed electrodes may allow for rapid and effective stimulation fitting. The ability to elicit comfortable and referred tactile percepts may enable the use of this neurostimulation strategy to provide meaningful and intuitive feedback from a prosthesis, enhance tactile feedback after sensory loss secondary to nerve damage, and deliver non-invasive stimulation therapies to treat various pain conditions.
The Riemannian spatial pattern method: mapping and clustering movement imagery using Riemannian geometry

Objective. Over the last decade, Riemannian geometry has shown promising results for motor imagery classification. However, extracting the underlying spatial features is not as straightforward as for applying common spatial pattern (CSP) filtering prior to classification. In this article, we propose a simple way to extract the spatial patterns obtained from Riemannian classification: the Riemannian spatial pattern (RSP) method, which is based on the backward channel selection procedure. Approach. The RSP method was compared to the CSP approach on ECoG data obtained from a quadriplegic patient while performing imagined movements of arm articulations and fingers. Main results. Similar results were found between the RSP and CSP methods for mapping each motor imagery task with activations following the classical somatotopic organization. Clustering obtained by pairwise comparisons of imagined motor movements however, revealed higher differentiation for the RSP method compared to the CSP approach. Importantly, the RSP approach could provide a precise comparison of the imagined finger flexions which added supplementary information to the mapping results. Significance. Our new RSP method illustrates the interest of the Riemannian framework in the spatial domain and as such offers new avenues for the neuroimaging community. This study is part of an ongoing clinical trial registered with ClinicalTrials.gov, NCT02550522.
Real-world retrospective observational study exploring the effectiveness and safety of antifibrotics in idiopathic pulmonary fibrosis

Background Pirfenidone and nintedanib are the only disease-modifying treatments available for idiopathic pulmonary fibrosis (IPF). Our aim was to test their effectiveness and safety in clinical practice. Methods This is a single-centre retrospective observational study undertaken at a specialised interstitial lung disease centre in England. Data including progression-free survival (PFS), mortality and drug tolerability were compared between patients with IPF on antifibrotic therapies and an untreated control group who had a forced vital capacity percentage (FVC %) predicted within the licensed antifibrotic treatment range. Results 104 patients received antifibrotic therapies and 64 control patients were identified. PFS at 6 months was significantly greater in the antifibrotic group (75.0%) compared with the control group (56.3%) (p=0.012). PFS was not significant at 12 or 18 months when comparing the antifibrotic group with the control group. The 12-month post-treatment mean decline in FVC % predicted (−4.6±6.2%) was significantly less than the 12-month pretreatment decline (−10.4±11.8%) (p=0.039). The 12-month mortality rate was not significantly different between the antifibrotic group (25.3%) and the control group (35.5%) (p=0.132). Baseline Body Mass Index of≤25, baseline diffusion capacity for carbon monoxide percentage predicted of ≤35 and antifibrotic discontinuation within 3 months were independent predictors of 12-month mortality. Antifibrotic discontinuation was significantly higher by 3 and 6 months for patients on pirfenidone than those on nintedanib (p=0.006 and p=0.044, respectively). Discontinuation at 12 months was not significantly different (p=0.381). Conclusions This real-world study revealed that antifibrotics are having promising effects on PFS, lung function and mortality. These findings may favour commencement of nintedanib as first-line antifibrotic therapy, given the lower rates of early treatment discontinuation, although further studies are required to investigate this.
An IFNγ/STAT1/JMJD3 Axis Induces ZEB1 Expression and Promotes Aggressiveness in Lung Adenocarcinoma

Active IFNγ signaling is a common feature of tumors responding to PD-1 checkpoint blockade. IFNγ exhibits both anti- and protumor activities. Here, we show that the treatment of lung adenocarcinoma cells with IFNγ led to a rapid increase of ZEB1 expression and a significant change in epithelial-to-mesenchymal transition (EMT)-associated gene expression pattern. Moreover, functional analyses show that IFNγ promoted cell migration in vitro and metastasis in vivo. We demonstrate that ZEB1 is required for IFNγ-promoted EMT, cell migration, and metastasis, as RNAi-mediated knockdown of ZEB1 abrogated EMT, cell migration, and metastasis induced by IFNγ. We show that IFNγ induced upregulation of JMJD3 significantly reduced H3K27 trimethylation in the promoter of the ZEB1 gene, which led to activation of ZEB1 gene transcription. IFNγ-induced JMJD3 expression was JAK1/2-STAT1 dependent. Inhibition of JMJD3 abrogated IFNγ-induced ZEB1 expression. IFNγ-induced ZEB1 also reduced miR-200 expression. Downregulation of ZEB1 increased miR-200 expression, which led to a reduction of PD-L1 expression induced by IFNγ. It is worth noting that knockdown of ZEB1 did not affect IFNγ-mediated antiproliferation and induction of CXCL9 and CXCL10. Thus, downregulation of ZEB1 may prevent the protumor activity of IFNγ while retaining its antitumor function. This study expands our understanding of IFNγ-mediated signaling and helps to identify therapeutic targets to improve current immunotherapies. Implications: IFNγ increases ZEB1 expression in a STAT1-JMJD3 dependent manner, and consequently promotes cancer cell aggressiveness. This study provides a potential target to minimize the procancer effect of IFNγ while preserving its antitumor function.
The intervening role of anxiety symptoms in associations between Self-Regulation and prosocial behaviors in U.S. Latino/a college students

Abstract Objective The present study aimed to investigate the intervening role of anxiety symptoms in relations between self-regulation and multiple forms of prosocial behaviors in U.S. Latino/a college students. Participants The sample is based on data from a cross-sectional study on college students’ health and adjustment. Participants were 249 (62% women; M age =20 years; 86% U.S. born) college students who self-identified as Latino/a. Methods College students self-reported on their self-regulation, anxiety symptoms, and types and targets of prosocial behaviors using online surveys. Path analyses were conducted to test direct and indirect associations among the study variables. Results Self-regulation was directly and indirectly associated with several types of prosocial behaviors via anxiety symptoms. The hypothesized associations also differed by the target of helping. Conclusions Our findings underscore a strengths-based view of the coping and mental health resources that predict positive well-being among U.S. Latino/a college students.
Infectious keratitis after corneal crosslinking: systematic review

Infectious keratitis after corneal crosslinking is low. The use of topical steroids, bandage contact lenses, and/or a history of atopic or herpetic disease are associated with infection. Corneal crosslinking is a U.S. Food and Drug Administration-–approved therapy to stiffen the cornea and prevent progression of corneal ectasia in patients with keratoconus. The standard procedure involves removal of the corneal epithelium (epithelial-off) prior to treatment. Variations to the standard procedure include accelerated crosslinking and transepithelial procedures. This study reviewed what is known regarding the risk for infection after epithelial-off crosslinking, the spectrum of pathogens, and clinical outcomes. 26 publications were identified. All eyes were fit with a bandage contact lens postoperatively. Available data indicate that the overall frequency of infectious keratitis after epithelium-off crosslinking is low. Bacterial infections are the most common, with a mean time of presentation of 4.8 days postoperatively. The use of steroids and bandage contact lenses in the immediate postoperative period and/or a history of atopic or herpetic disease were associated with infection. These patients require intense postoperative care with prophylactic antiviral therapy when appropriate.
Navigating the uncertainties of COVID-19 associated aspergillosis (CAPA): A comparison with influenza associated aspergillosis (IAPA)

Abstract Invasive pulmonary aspergillosis (IPA) is increasingly recognized as a life-threatening superinfection of severe respiratory viral infections, such as influenza. The pandemic of Coronavirus Disease 2019 (COVID-19) due to emerging SARS-CoV-2 rose concern about the eventuality of IPA complicating COVID-19 in intensive care unit mechanically-ventilated patients. While the association between severe influenza and IPA has been demonstrated, it remains unclear whether SARS-CoV-2 infection represents a specific risk factor for IPA. A variable incidence of such complication has been previously reported, which can be partly attributed to differences in diagnostic strategy and IPA definitions, and possibly local environmental/epidemiological factors. In this article, we discuss the similarities and differences between influenza-associated pulmonary aspergillosis (IAPA) and COVID-19-associated pulmonary aspergillosis (CAPA). Compared to IAPA, the majority of CAPA cases have been classified as putative rather than proven/probable IPA, in the absence of positive serum galactomannan or histopathologic evidence of angio-invasion. Discrimination between Aspergillus airways colonization and CAPA is difficult. Distinct physiopathology and cytokine profiles of influenza and COVID-19 may explain these discrepancies. Whether CAPA represents a distinct entity is still debatable and many questions remain unanswered, such as its actual incidence, the predisposing role of corticosteroids or immunomodulatory drugs, and the indications for antifungal therapy.
Muscle-Tendon Behavior and Kinetics in Gastrocnemius Medialis During Forefoot and Rearfoot Strike Running.

The present study aimed to clarify the effect of the foot strike pattern on muscle-tendon behavior and kinetics of the gastrocnemius medialis during treadmill running. Seven male participants ran with 2 different foot strike patterns (forefoot strike [FFS] and rearfoot strike [RFS]), with a step frequency of 2.50 Hz and at a speed of 2.38 m/s for 45 seconds on a treadmill with an instrumented force platform. The fascicle behavior of gastrocnemius medialis was captured using a B-mode ultrasound system with a sampling rate of 75 Hz, and the mechanical work done and power exerted by the fascicle and tendon were calculated. At the initial contact, the fascicle length was significantly shorter in the FFS than in the RFS (P = .001). However, the fascicular velocity did not differ between strike patterns. Higher tendon stretch and recoil were observed in the FFS (P < .001 and P = .017, respectively) compared with the RFS. The fascicle in the positive phase performed the same mechanical work in both the FFS and RFS; however, the fascicle in the negative phase performed significantly greater work in the FFS than in the RFS (P = .001). RFS may be advantageous for requiring less muscular work and elastic energy in the series elastic element compared with the FFS.
Moral foundations theory, political identity, and the depiction of morality in children’s movies

Children’s movies often provide messages about morally appropriate and inappropriate conduct. In two studies, we draw on Moral Foundations Theory (MFT) to derive predictions about actual depictions of morality, and people’s preferences for different moral depictions, within children’s movies. According to MFT, people’s moral concerns include individualizing foundations of care and fairness and binding foundations of loyalty, authority, and sanctity. Prior work reveals that although there are political differences in the endorsement of these two broad categories—whereby stronger political conservatism predicts stronger binding concerns and weaker individualizing concerns—there nonetheless is broad agreement across political identity in the importance of individualizing concerns. We therefore predicted that heroes would value individualizing foundations more than villains, and that despite political differences in preferences for moral messages, there would be more agreement in the importance of messages promoting individualizing concerns. In Study 1, we coded heroes and villains from popular children’s movies for their valuation of moral foundations. Heroes valued individualizing concerns more, and binding concerns less, than villains did. Participants in Study 2 considered moral dilemmas faced by children’s movie characters, and rated their preferences for resolutions that promoted either individualizing or binding foundations. Although liberals preferred individualizing-promoting resolutions and conservatives preferred binding-promoting resolutions, there was stronger agreement across political identity in the importance of individualizing concerns. Despite political differences in moral preferences, popular depictions of children’s movie characters and people’s self-reported moral endorsement suggest a shared belief in the importance of the individualizing moral virtues of care and fairness. Movies are often infused with moral messages. From their exploration of overarching themes, their ascription of particular traits to heroic and villainous characters, and their resolution of pivotal moral dilemmas, movies provide viewers with depictions of morally virtuous (and morally suspect) behavior. Moral messaging in children’s movies is of particular importance, since it is targeted at an audience for which morality is actively developing. What moral messages do filmmakers (and consumers, including parents) want children’s movies to depict? Are these preferences related to people’s political identity? And what are the actual moral depictions presented in movies? In the present two studies, we draw on an influential theory of moral judgment—Moral Foundations Theory—to develop and test predictions about the depiction of morality in children’s movies.
Functional regulation of the structure-specific endonuclease FEN1 by the human cytomegalovirus protein IE1 suggests a role for the re-initiation of stalled viral replication forks

Flap endonuclease 1 (FEN1) is a member of the family of structure-specific endonucleases implicated in regulation of DNA damage response and DNA replication. So far, knowledge on the role of FEN1 during viral infections is limited. Previous publications indicated that poxviruses encode a conserved protein that acts in a manner similar to FEN1 to stimulate homologous recombination, double-strand break (DSB) repair and full-size genome formation. Only recently, cellular FEN1 has been identified as a key component for hepatitis B virus cccDNA formation. Here, we report on a novel functional interaction between Flap endonuclease 1 (FEN1) and the human cytomegalovirus (HCMV) immediate early protein 1 (IE1). Our results provide evidence that IE1 manipulates FEN1 in an unprecedented manner: we observed that direct IE1 binding does not only enhance FEN1 protein stability but also phosphorylation at serine 187. This correlates with nucleolar exclusion of FEN1 stimulating its DSB-generating gap endonuclease activity. Depletion of FEN1 and inhibition of its enzymatic activity during HCMV infection significantly reduced nascent viral DNA synthesis demonstrating a supportive role for efficient HCMV DNA replication. Furthermore, our results indicate that FEN1 is required for the formation of DSBs during HCMV infection suggesting that IE1 acts as viral activator of FEN1 in order to re-initiate stalled replication forks. In summary, we propose a novel mechanism of viral FEN1 activation to overcome replication fork barriers at difficult-to-replicate sites in viral genomes.