Miracle-dz/UniFAR-FTUs huggingface dataset:
Induction of Wnt signaling antagonists and p21-activated kinase enhances cardiomyocyte proliferation during zebrafish heart regeneration

Abstract Heart regeneration occurs by dedifferentiation and proliferation of pre-existing cardiomyocytes (CMs). However, the signaling mechanisms by which injury induces CM renewal remain incompletely understood. Here, we find that cardiac injury in zebrafish induces expression of the secreted Wnt inhibitors, including Dickkopf 1 (Dkk1), Dkk3, secreted Frizzled-related protein 1 (sFrp1), and sFrp2, in cardiac tissue adjacent to injury sites. Experimental blocking of Wnt activity via Dkk1 overexpression enhances CM proliferation and heart regeneration, whereas ectopic activation of Wnt8 signaling blunts injury-induced CM dedifferentiation and proliferation. Although Wnt signaling is dampened upon injury, the cytoplasmic β-catenin is unexpectedly increased at disarrayed CM sarcomeres in myocardial wound edges. Our analyses indicated that p21-activated kinase 2 (Pak2) is induced at regenerating CMs, where it phosphorylates cytoplasmic β-catenin at Ser 675 and increases its stability at disassembled sarcomeres. Myocardial-specific induction of the phospho-mimetic β-catenin (S675E) enhances CM dedifferentiation and sarcomere disassembly in response to injury. Conversely, inactivation of Pak2 kinase activity reduces the Ser 675-phosphorylated β-catenin (pS675-β-catenin) and attenuates CM sarcomere disorganization and dedifferentiation. Taken together, these findings demonstrate that coordination of Wnt signaling inhibition and Pak2/pS675-β-catenin signaling enhances zebrafish heart regeneration by supporting CM dedifferentiation and proliferation.
Eye-movement patterns to social and non-social cues in early deaf adults

Previous research on covert orienting to the periphery suggested that early profound deaf adults were less susceptible to uninformative gaze-cues, though were equally or more affected by non-social arrow-cues. The aim of this work was to investigate whether spontaneous eye movement behaviour helps explain the reduced impact of the social cue in deaf adults. We tracked the gaze of 25 early profound deaf and 25 age-matched hearing observers performing a peripheral discrimination task with uninformative central cues (gaze vs arrow), stimulus-onset asynchrony (250 vs 750 ms), and cue validity (valid vs invalid) as within-subject factors. In both groups, the cue effect on reaction time (RT) was comparable for the two cues, although deaf observers responded significantly slower than hearing controls. While deaf and hearing observers’ eye movement pattern looked similar when the cue was presented in isolation, deaf participants made significantly more eye movements than hearing controls once the discrimination target appeared. Notably, further analysis of eye movements in the deaf group revealed that independent of the cue type, cue validity affected saccade landing position, while latency was not modulated by these factors. Saccade landing position was also strongly related to the magnitude of the validity effect on RT, such that the greater the difference in saccade landing position between invalid and valid trials, the greater the difference in manual RT between invalid and valid trials. This work suggests that the contribution of overt selection in central cueing of attention is more prominent in deaf adults and helps determine the manual performance, irrespective of the cue type.
Tissue-specific transcriptome profiling of the Arabidopsis inflorescence stem reveals local cellular signatures

Abstract Genome-wide gene expression maps with a high spatial resolution have substantially accelerated plant molecular science. However, the number of characterized tissues and growth stages is still small due to the limited accessibility of most tissues for protoplast isolation. Here, we provide gene expression profiles of the mature inflorescence stem of Arabidopsis thaliana covering a comprehensive set of distinct tissues. By combining fluorescence-activated nucleus sorting and laser-capture microdissection with next-generation RNA sequencing, we characterized the transcriptomes of xylem vessels, fibers, the proximal and distal cambium, phloem, phloem cap, pith, starch sheath, and epidermis cells. Our analyses classified more than 15,000 genes as being differentially expressed among different stem tissues and revealed known and novel tissue-specific cellular signatures. By determining overrepresented transcription factor binding regions in the promoters of differentially expressed genes, we identified candidate tissue-specific transcriptional regulators. Our datasets predict the expression profiles of an exceptional number of genes and allow hypotheses to be generated about the spatial organization of physiological processes. Moreover, we demonstrate that information about gene expression in a broad range of mature plant tissues can be established at high spatial resolution by nuclear mRNA profiling. Tissue-specific gene expression values can be accessed online at https://arabidopsis-stem.cos. uni-heidelberg.de/.
Connecting tree‐ring phenotypes, genetic associations and transcriptomics to decipher the genomic architecture of drought adaptation in a widespread conifer

Abstract As boreal forests face significant threats from climate change, understanding evolutionary trajectories of coniferous species has become fundamental to adapting management and conservation to a drying climate. We examined the genomic architecture underlying adaptive variation related to drought tolerance in 43 populations of a widespread boreal conifer, white spruce (Picea glauca [Moench] Voss), by combining genotype–environment associations, genotype–phenotype associations, and transcriptomics. Adaptive genetic variation was identified by correlating allele frequencies for 6,153 single nucleotide polymorphisms from 2,606 candidate genes with temperature, precipitation and aridity gradients, and testing for significant associations between genotypes and 11 dendrometric and drought‐related traits (i.e., anatomical, growth response and climate‐sensitivity traits) using a polygenic model. We identified a set of 285 genes significantly associated with a climatic factor or a phenotypic trait, including 110 that were differentially expressed in response to drought under greenhouse‐controlled conditions. The interlinked phenotype–genotype–environment network revealed eight high‐confidence genes involved in white spruce adaptation to drought, of which four were drought‐responsive in the expression analysis. Our findings represent a significant step toward the characterization of the genomic basis of drought tolerance and adaptation to climate in conifers, which is essential to enable the establishment of resilient forests in view of new climate conditions.
Ion Implantation as an Approach for Structural Modifications and Functionalization of Ti3C2Tx MXenes.

MXenes are a young family of two-dimensional transition metal carbides, nitrides, and carbonitrides with highly controllable structure, composition, and surface chemistry to adjust for target applications. Here, we demonstrate the modifications of two-dimensional MXenes by low-energy ion implantation, leading to the incorporation of Mn ions in Ti3C2Tx (where Tx is a surface termination) thin films. Damage and structural defects caused by the implantation process are characterized at different depths by XPS on Ti 2p core-level spectra, by ToF-SIMS, and with electron energy loss spectroscopy analyses. Results show that the ion-induced alteration of the damage tolerant Ti3C2Tx layer is due to defect formation at both Ti and C sites, thereby promoting the functionalization of these sites with oxygen groups. This work contributes to the inspiring approach of tailoring 2D MXene structure and properties through doping and defect formation by low-energy ion implantation to expand their practical applications.
The effects of the activation of hostile and non-hostile schemas on intent attribution processes in non-aggressive individuals: An ERP study

ABSTRACT We investigated the influences of hostile and non-hostile schemas activations in non-aggressive individuals on their intent attribution processes in various social contexts. 38 non-aggressive participants were randomly assigned to one of two groups, one primed with negative words, to be conditioned as temporarily hostile (TH), and the other with positive words, be conditioned as temporarily non-hostile (TNH). They were asked to read social scenarios composed of positive or negative behaviors of others whose intentions are ambiguous followed by a disambiguation of others’ real intentions (hostile vs non-hostile) behind their behaviors. Neural activity related to spontaneous intent attribution processes was measured using electroencephalography (EEG). The results showed that when non-hostile intentions were revealed following ambiguous-negative behaviors of others, the N400 effect was observed only in the TH group. Similarly, when hostile intentions were revealed following ambiguous-positive behaviors of others, the N400 effect was observed only in the TNH group. In other words, non-aggressive individuals were led to attribute either hostile or non-hostile intentions to the same ambiguous behaviors of others depending on which concepts or thoughts (hostile vs non hostile) were activated and accessible in memory by priming at the time of social interactions.
Inflammatory Mechanisms in Parkinson’s Disease: From Pathogenesis to Targeted Therapies

Inflammation is a critical factor contributing to the progressive neurodegenerative process observed in Parkinson’s disease (PD). Microglia, the immune cells of the central nervous system, are activated early in PD pathogenesis and can both trigger and propagate early disease processes via innate and adaptive immune mechanisms such as upregulated immune cells and antibody-mediated inflammation. Downstream cytokines and gene regulators such as microRNA (miRNA) coordinate later disease course and mediate disease progression. Biomarkers signifying the inflammatory and neurodegenerative processes at play within the central nervous system are of increasing interest to clinical teams. To be effective, such biomarkers must achieve the highest sensitivity and specificity for predicting PD risk, confirming diagnosis, or monitoring disease severity. The aim of this review was to summarize the current preclinical and clinical evidence that suggests that inflammatory processes contribute to the initiation and progression of neurodegenerative processes in PD. In this article, we further summarize the data about main inflammatory biomarkers described in PD to date and their potential for regulation as a novel target for disease-modifying pharmacological strategies.
Learning latent heterogeneity for type 2 diabetes patients using longitudinal health markers in electronic health records

Electronic health records (EHRs) from type 2 diabetes (T2D) patients consist of longitudinally and sparsely measured health markers at clinical encounters. Our goal is to use such data to learn latent patterns that can inform patient's health status related to T2D while accounting for challenges in retrospectively collected EHRs. To handle challenges such as correlated longitudinal measurements, irregular and informative encounter times, and mixed marker types, we propose multivariate generalized linear models to learn latent patient subgroups. In our model, covariate effects were time‐dependent and latent Gaussian processes were introduced to model between‐marker correlations over time. Using inferred latent processes, we integrated the irregularly measured health markers of mixed types into composite scores and applied hierarchical clustering to learn latent subgroup structures among T2D patients. Application to an EHR dataset of T2D patients showed different trends of age, sex, and race effects on hypertension/high blood pressure, total cholesterol, glycated hemoglobin, high‐density lipoprotein, and medications. The associations among these markers varied over time during the study window. Clustering results revealed four subgroups, each with distinct health status. The same patterns were further confirmed using new EHR records of the same cohort. We developed a novel latent model to integrate longitudinal health markers in EHRs and characterize patient latent heterogeneities. Analysis indicated that there were distinct subgroups of T2D patients, suggesting that effective healthcare managements for these patients should be performed separately for each subgroup.
Projected Estimates of Opioid Mortality After Community-Level Interventions

Key Points Question Using simulated urban and rural communities, what evidence-based practices are associated with a reduction in opioid overdose mortality of at least 40% by 2022? Findings In this decision analytical model using simulated urban and rural communities, no single intervention or approach was associated with a 40% reduction in overdose mortality in any community. Achieving a 40% reduction required increasing capacity for treating with medications for opioid use disorder, improving retention on medications, and increased naloxone distribution. Meaning These findings suggest that reducing opioid overdose may require substantial, coordinated effort with a focus on improving initiation with medications, retention in care, and increased naloxone distribution.
Long non‐coding RNA TINCR suppresses metastatic melanoma dissemination by preventing ATF4 translation

Transition from proliferative‐to‐invasive phenotypes promotes metastasis and therapy resistance in melanoma. Reversion of the invasive phenotype, however, is challenged by the poor understanding of mechanisms underlying its maintenance. Here, we report that the lncRNA TINCR is down‐regulated in metastatic melanoma and its silencing increases the expression levels of invasive markers, in vitro migration, in vivo tumor growth, and resistance to BRAF and MEK inhibitors. The critical mediator is ATF4, a central player of the integrated stress response (ISR), which is activated in TINCR‐depleted cells in the absence of starvation and eIF2α phosphorylation. TINCR depletion increases global protein synthesis and induces translational reprogramming, leading to increased translation of mRNAs encoding ATF4 and other ISR proteins. Strikingly, re‐expression of TINCR in metastatic melanoma suppresses the invasive phenotype, reduces numbers of tumor‐initiating cells and metastasis formation, and increases drug sensitivity. Mechanistically, TINCR interacts with mRNAs associated with the invasive phenotype, including ATF4, preventing their binding to ribosomes. Thus, TINCR is a suppressor of the melanoma invasive phenotype, which functions in nutrient‐rich conditions by repressing translation of selected ISR RNAs.
Default mode network activity in depression subtypes

Abstract Depression continues to carry a major disease burden worldwide, with limitations on the success of traditional pharmacological or psychological treatments. Recent approaches have therefore focused upon the neurobiological underpinnings of depression, and on the “individualization” of depression symptom profiles. One such model of depression has divided the standard diagnostic criteria into four “depression subtypes”, with neurological and behavioral pathways. At the same time, attention has been focused upon the region of the brain known as the “default mode network” (DMN) and its role in attention and problem-solving. However, to date, no review has been published of the links between the DMN and the four subtypes of depression. By searching the literature studies from the last 20 years, 62 relevant papers were identified, and their findings are described for the association they demonstrate between aspects of the DMN and the four depression subtypes. It is apparent from this review that there are potential positive clinical and therapeutic outcomes from focusing upon DMN activation and connectivity, via psychological therapies, transcranial magnetic stimulation, and some emerging pharmacological models.
Optimal Carotid Plaque Features on Computed Tomography Angiography Associated With Ischemic Stroke

Background Stenosis has historically been the major factor used to determine carotid stroke sources. Recent evidence suggests that specific plaque features detected on imaging may be more highly associated with ischemic stroke than stenosis. We sought to determine computed tomography angiography (CTA) imaging features of carotid plaque that optimally discriminate ipsilateral stroke sources. Methods and Results In this institutional review board–approved retrospective cross‐sectional study, 494 ipsilateral carotid CTA‐brain magnetic resonance imaging pairs were available for analysis after excluding patients with alternative stroke sources. Carotid CTA and clinical markers were recorded, a multivariable Poisson regression model was fitted, and backward elimination was performed with a 2‐sided threshold of P<0.10. Discriminatory value was determined using receiver operating characteristic analysis, area under the curve, and bootstrap validation. The final CTA carotid‐source stroke prediction model included intraluminal thrombus (prevalence ratio, 2.8 [P<0.001]; 95% CI, 1.6–4.9), maximum soft plaque thickness (prevalence ratio, 1.2 [P<0.001]; 95% CI, 1.1–1.4), and the rim sign (prevalence ratio, 2.0 [P=0.007]; 95% CI, 1.2–3.3). The final discriminatory value (area under the curve=78.3%) was higher than intraluminal thrombus (56.4%, P<0.001), maximum soft plaque thickness (76.4%, P=0.007), or rim sign alone (69.9%, P=0.001). Furthermore, NASCET (North American Symptomatic Carotid Endarterectomy Trial) stenosis categories (cutoffs of 50% and 70%) had lower stroke discrimination (area under the curve=67.4%, P<0.001). Conclusions Optimal discrimination of ipsilateral carotid sources of stroke requires information on intraluminal thrombus, maximum soft plaque thickness, and the rim sign. These results argue against the sole use of carotid stenosis to determine stroke sources on CTA, and instead suggest these alternative markers may better diagnose vulnerable carotid plaque and guide treatment decisions.
Factor Structure, Measurement Invariance, and Concurrent Validity of the Penn State Worry Questionnaire Across Development, Psychopathology, and Culture

The Penn State Worry Questionnaire (PSWQ) is a widely used assessment of excessive worry. American undergraduate samples have predominately been used to evaluate its factor structure, which may not generalize to other developmental, cultural, and psychopathology populations. The present study tested the PSWQ’s factor structure across three diverse samples: American undergraduate students (n = 3,243), Dutch high school students (n = 3,906), and American adults with psychopathology (n = 384). Exploratory, confirmatory, and multigroup confirmatory factor analyses were conducted. Measurement invariance and concurrent validity were also tested. Method-factor and two-factor models were largely equivalent and superior to a one-factor model. Invariance tests supported configural and metric invariance but only partial scalar invariance. Positively worded items but not negatively worded items demonstrated concurrent validity with anxiety and depression symptom measures and diagnoses. Overall, the PSWQ appears to measure a unitary construct. Present results warrant further testing of the PSWQ across diverse samples.
Multi‐institutional validation of novel models for predicting the prognosis of patients with huge hepatocellular carcinoma

The population of patients with huge hepatocellular carcinoma (H‐HCC diameter > 10.0 cm) is an odd group that is not well adjudicated in the current staging systems, whose prognosis after curative resection varies. We aimed to develop novel models to predict the long‐term outcomes of patients with H‐HCC without portal vein tumor thrombus after hepatectomy. There were 1076 H‐HCC patients enrolled who underwent curative liver resection in five institutions in China. In total, 670 patients were recruited from our center and randomly divided into the training cohort (n = 502) and internal validation (n = 168) cohorts. Additionally, 406 patients selected from other four centers as the external validation cohort. Novel models were constructed based on independent preoperative and postoperative predictors of postsurgical recurrence (PSR) and postsurgical mortality (PSM) determined in multivariable cox regression analysis. The predictive accuracy and discriminative ability of the model were measured using Harrell's concordance index (C index) and calibration curve and compared with five conventional HCC staging systems. PSR model and PSM model were constructed based on tumor number, microscopic vascular invasion, tumor differentiation, preoperative alpha‐fetoprotein level, albumin‐bilirubin grade, liver segment invasion, neutrophil‐to‐lymphocyte ratio or platelet‐to‐neutrophil ratio, and surgical margin or intraoperative blood transfusion. The C‐indexes were 0.84 (95% CI, 0.78‐0.90) and 0.85 (95% CI, 0.78‐0.91) for the PSR and PSM models, respectively, which were substantially higher than those of the five conventional HCC staging systems (0.63‐0.75 for PSR; 0.66‐0.77 for PSM). The two novel models achieved more accurate prognostic predictions of PSR and PSM for H‐HCC patients after curative liver resection.
Graphene Oxide‐Doped Gellan Gum–PEGDA Bilayered Hydrogel Mimicking the Mechanical and Lubrication Properties of Articular Cartilage

Articular cartilage (AC) is a specialized connective tissue able to provide a low‐friction gliding surface supporting shock‐absorption, reducing stresses, and guaranteeing wear‐resistance thanks to its structure and mechanical and lubrication properties. Being an avascular tissue, AC has a limited ability to heal defects. Nowadays, conventional strategies show several limitations, which results in ineffective restoration of chondral defects. Several tissue engineering approaches have been proposed to restore the AC's native properties without reproducing its mechanical and lubrication properties yet. This work reports the fabrication of a bilayered structure made of gellan gum (GG) and poly (ethylene glycol) diacrylate (PEGDA), able to mimic the mechanical and lubrication features of both AC superficial and deep zones. Through appropriate combinations of GG and PEGDA, cartilage Young's modulus is effectively mimicked for both zones. Graphene oxide is used as a dopant agent for the superficial hydrogel layer, demonstrating a lower friction than the nondoped counterpart. The bilayered hydrogel's antiwear properties are confirmed by using a knee simulator, following ISO 14243. Finally, in vitro tests with human chondrocytes confirm the absence of cytotoxicity effects. The results shown in this paper open the way to a multilayered synthetic injectable or surgically implantable filler for restoring AC defects.
Study by grazing incident diffraction and surface spectroscopy of amalgams from ancient mirrors

Characterization of four amalgam surfaces, with different alteration degrees from Andalusia historical mirrors, has been carried out by grazing-incidence X-ray diffraction (GIXRD), and other spectroscopic techniques (SEM/EDX, XPS, and REELS). The combination of all these techniques allows determining the corrosion state of the amalgams. The results show that the amalgams are composed in all cases of a binary alloy of tin and mercury. As mercury has high vapour pressure at RT, it slowly segregates and eventually evaporates, it leaves finely divided particles of tin that easily can be oxidize, forming tin monoxide (SnO) and tin dioxide (SnO2). In one of the samples, most of the amalgam remains unoxidized, since Hg0.1Sn0. 9 and metallic Sn phases are the major components; in two other samples, Hg0.1Sn0. 9 and Sn phases are not detected while SnO2 and SnO phases appear. Finally, in the last studied sample, only SnO2 phase is detected. The surface analyses of these samples by XPS show that, for most of them an unique chemical species (Sn4+) is found.