Miracle-dz/UniFAR-FTUs huggingface dataset:
Diverse viral proteases activate the NLRP1 inflammasome

The NLRP1 inflammasome is a multiprotein complex that is a potent activator of inflammation. Mouse NLRP1B can be activated through proteolytic cleavage by the bacterial Lethal Toxin (LeTx) protease, resulting in degradation of the N-terminal domains of NLRP1B and liberation of the bioactive C-terminal domain, which includes the caspase activation and recruitment domain (CARD). However, a natural pathogen-derived effector that can activate human NLRP1 remains unknown. Here, we use an evolutionary model to identify several proteases from diverse picornaviruses that cleave human NLRP1 within a rapidly evolving region of the protein, leading to host-specific and virus-specific activation of the NLRP1 inflammasome. Our work demonstrates that NLRP1 acts as a “tripwire” to recognize the enzymatic function of a wide range of viral proteases, and suggests that host mimicry of viral polyprotein cleavage sites can be an evolutionary strategy to activate a robust inflammatory immune response.
Clustered rapid induction of apoptosis limits ZIKV and DENV-2 proliferation in the midguts of Aedes aegypti

Inter-host transmission of pathogenic arboviruses such as dengue virus (DENV) and Zika virus (ZIKV) requires systemic infection of the mosquito vector. Successful systemic infection requires initial viral entry and proliferation in the midgut cells of the mosquito followed by dissemination to secondary tissues and eventual entry into salivary glands 1 . Lack of arbovirus proliferation in midgut cells has been observed in several Aedes aegypti strains 2 , but the midgut antiviral responses underlying this phenomenon are not yet fully understood. We report here that there is a rapid induction of apoptosis (RIA) in the Aedes aegypti midgut epithelium within 2 hours of infection with DENV-2 or ZIKV in both in vivo blood-feeding and ex vivo midgut infection models. Inhibition of RIA led to increased virus proliferation in the midgut, implicating RIA as an innate immune mechanism mediating midgut infection in this mosquito vector. Ayers et al. report rapid induction of apoptosis in the midgut of Aedes aegypti mosquitoes within 2 hours of infection by dengue and Zika viruses, and find that inhibiting apoptosis led to increased virus proliferation in the midgut. These results suggest rapid induction of apoptosis as an innate immune mechanism mediating midgut infection in this mosquito vector.
ADHD in Adolescents: Commentary on the Special Issue of Ripple Effects in Self-Perceptions and Social Relationships

Adolescence is a developmental period that affords both risk as well as enormous opportunity. Ripple effects can extend far and wide and speak to the nuance and complexity in understanding and treating ADHD during the adolescent period. The studies in this special issue provide novel and important insights into the lives of adolescents with ADHD, and they collectively point to important areas for both research and clinical attention. Further, each of the studies underscore the importance of soliciting the perspective of adolescents with ADHD. In this commentary, I consider the value of self-report when working with adolescents with ADHD, the possibility of a self-perception bias in youth with ADHD, challenges in assessing social functioning in adolescence, and implications for school-based assessments and interventions. For treatment specifically, I raise the possibility of a modular intervention approach for adolescents with ADHD and shared decision making that solicits and incorporates the adolescent perspective. The voices of adolescents with ADHD may be crucial for understanding how to lower risk, promote resilience, reduce stigma, and improve our assessments and interventions.
Morphosyntactic Cues for Quantifier Comprehension in Children

ABSTRACT Universal quantifiers, which refer to groups of individuals or events, can express a subtle distinction between collective (unified or simultaneous) and distributive (individuated and separate) events. Indeed, English uses different quantifiers for this distinction (“all” and “each”, respectively). Hebrew, however, has a single universal quantifier. Thus, the collective/distributive distinction associated with the universal quantifier is represented morphosyntactically. This study examined whether Hebrew-speaking children (4–6 year olds) detect the collective/distributive distinction based on morphosyntactic cues alone and whether they show similar performance pattern as adults. Using a novel drawing task, instructions were given in either a collective-preferred form or a distributive form, asking participants to add drawings to pictures of multiple items. Within-subjects (Experiment 1) and between-subjects designs (Experiment 2) were used. Overall, children distinguished between the forms, indicating that they attended the specific morphosyntic cues of these two forms. They produced distributive drawings following the distributive form, similarly to adults. However, they alternated between distributive and collective drawings following the collective-preferred form, unlike adults who mostly gave collective responses. We discuss a possibility for the interplay between the meaning of the universal quantifier and the morphosyntactic cues in children’s performance. This study provides insights into the acquisition of meaning that depends on morphosyntax.
Quantum Thermodynamics of Correlated-Catalytic State Conversion at Small Scale.

The class of possible thermodynamic conversions can be extended by introducing an auxiliary system called catalyst, which assists in state conversion while its own state remains unchanged. We reveal a complete characterization of catalytic state conversion in quantum and single-shot thermodynamics by allowing an infinitesimal correlation between the system and the catalyst. Specifically, we prove that a single thermodynamic potential, which provides the necessary and sufficient condition for the correlated-catalytic state conversion, is given by the standard nonequilibrium free energy defined with the Kullback-Leibler divergence. This resolves the conjecture raised by Wilming, Gallego, and Eisert [Entropy 19, 241 (2017)ENTRFG1099-430010.3390/e19060241] and by Lostaglio and Müller [Phys. Rev. Lett. 123, 020403 (2019)PRLTAO0031-900710.1103/PhysRevLett.123. 020403] in the positive. Moreover, we show that, with the aid of the work storage, any quantum state can be converted into another by paying the work cost equal to the nonequilibrium free energy difference. Our result would serve as a step towards establishing resource theories of catalytic state conversion in the fully quantum regime.
The effect of parasitic co-infections on immune responses in Gabon : particular emphasis on malaria and helminths

The work presented in this thesis aimed at increasing our understanding of the effect of helminths on Plasmodium spp. immune response in co-infected individuals living in endemic countries. It presents data from studies conducted in rural and semi urban areas of Lambarene (Gabon) where the burden of malaria and helminths is particularly important. Although scarce previous studies have indicated an effect of helminths on malaria outcomes and immune response to Plasmodium spp. parasite in co-infected subjects. However it is still debated how consistent is this effect across study sites and teams and what its immunological basis is.
Postzygotic Somatic Mutations in the Human Brain Expand the Threshold-Liability Model of Schizophrenia

The search for what causes schizophrenia has been onerous. This research has included extensive assessment of a variety of genetic and environmental factors using ever emerging high-resolution technologies and traditional understanding of the biology of the brain. These efforts have identified a large number of schizophrenia-associated genes, some of which are altered by mutational and epi-mutational mechanisms in a threshold liability model of schizophrenia development. The results, however, have limited predictability and the actual cause of the disease remains unknown. This current state asks for conceptualizing the problem differently in light of novel insights into the nature of mutations, the biology of the brain and the fine precision and resolution of emerging technologies. There is mounting evidence that mutations acquired during postzygotic development are more common than germline mutations. Also, the postzygotic somatic mutations including epimutations (PZMs), which often lead to somatic mosaicism, are relatively common in the mammalian brain in comparison to most other tissues and PZMs are more common in patients with neurodevelopmental mental disorders, including schizophrenia. Further, previously inaccessible, detection of PZMs is becoming feasible with the advent of novel technologies that include single-cell genomics and epigenomics and the use of exquisite experimental designs including use of monozygotic twins discordant for the disease. These developments allow us to propose a working hypothesis and expand the threshold liability model of schizophrenia that already encompasses familial genetic, epigenetic and environmental factors to include somatic de novo PZMs. Further, we offer a test for this expanded model using currently available genome sequences and methylome data on monozygotic twins discordant for schizophrenia (MZD) and their parents. The results of this analysis argue that PZMs play a significant role in the development of schizophrenia and explain extensive heterogeneity seen across patients. It also offers the potential to convincingly link PZMs to both nervous system health and disease, an area that has remained challenging to study and relatively under explored.
Metabolomic and Lipidomic Profiling of Preoperative CSF in Elderly Hip Fracture Patients With Postoperative Delirium

Objective To investigate dysregulated molecules in preoperative cerebrospinal fluid (CSF) of elderly hip fracture patients with postoperative delirium (POD), in order to identify potential pathological mechanisms and biomarkers for pre-stage POD. Materials and Methods This nested case control study used untargeted metabolomic and lipidomic analysis to profile the preoperative CSF of patients (n = 40) who developed POD undergone hip fracture surgery (n = 10) and those who did not (n = 30). Thirty Non-POD patients were matched to 10 POD patients by age (± 2 years) and Mini Mental State Examination score (± 2 points). CSF was collected after successful spinal anesthesia and banked for subsequent analysis. On the first two postoperative days, patients were assessed twice daily using the Confusion Assessment Method-Chinese Revision. CSF samples from the two groups were analyzed to investigate possible relevant pathological mechanisms and identify candidate biomarkers. Results Demographic characteristics of the groups were matched. Eighteen metabolites and thirty-three lipids were dysregulated in the preoperative CSF of POD patients. Pathway enrichment analysis revealed perturbations in D-glutamine and D-glutamate metabolism; glycerophospholipid metabolism; alanine, aspartate and glutamate metabolism; sphingolipid metabolism; histidine metabolism; and arginine biosynthesis at the pre-delirium stage. Receiver operating characteristic curve analysis indicated that phosphatidylethanolamine (PE, 40:7e), with an area under the curve value of 0.92, is a potential biomarker for POD. Conclusion Multiple pathological mechanisms in the POD group were involved before surgery, including neuroinflammation, oxidative stress, and energy metabolism disorders induced by hypoxia, as well as neurotransmitter imbalances such as increased dopamine and glutamate, and decreased glutamine. These metabolic abnormalities potentially increase the fragility of the brain, thus contributing to POD. PE (40:7e) might be a potential biomarker for POD. Not only do our results provide potential biomarkers for POD, but also provide information for deep pathological research. Clinical Trial Registration www.ClinicalTrials. gov, identifier ChiCTR1900021533.
Prognostic Role of Ammonia in Critical Care Patients Without Known Hepatic Disease

Background and Aims: Hyperammonemia usually develops because of hepatic disease, but it may occur in patients with non-hepatic hyperammonemia (NHH). But, studies on the prognosis and possible risk factors of this disorder are lacking. The aim of this study was to find possible prognostic and risk factors for NHH in critically ill patients. Methods: Data were extracted from MIMIC III Database. Survival was analyzed by the Kaplan-Meier method. Univariate and multivariate analyses were performed to identify prognostic factors. Results: Valproic acid, carbamazepine, corticosteroids, recent orthopedic surgery, epilepsy, disorders of urea cycle metabolism, and obesity were found to be risk factors for NHH. Patients in the hyperammonemia group had a higher 30 day mortality than those in the non-hyperammonemia group. After final regression analysis, ammonia was found to be independent predictors of mortality. Conclusion: Ammonia was an independent prognostic predictor of 30 day mortality for critical care patients without liver disease.
Beneficial Cardiac Structural and Functional Adaptations After Lumbosacral Spinal Cord Epidural Stimulation and Task-Specific Interventions: A Pilot Study

Cardiac myocyte atrophy and the resulting decreases to the left ventricular mass and dimensions are well documented in spinal cord injury. Therapeutic interventions that increase preload can increase the chamber size and improve the diastolic filling ratios; however, there are no data describing cardiac adaptation to chronic afterload increases. Research from our center has demonstrated that spinal cord epidural stimulation (scES) can normalize arterial blood pressure, so we decided to investigate the effects of scES on cardiac function using echocardiography. Four individuals with chronic, motor-complete cervical spinal cord injury were implanted with a stimulator over the lumbosacral enlargement. We assessed the cardiac structure and function at the following time points: (a) prior to implantation; (b) after scES targeted to increase systolic blood pressure; (c) after the addition of scES targeted to facilitate voluntary (i.e., with intent) movement of the trunk and lower extremities; and (d) after the addition of scES targeted to facilitate independent, overground standing. We found significant improvements to the cardiac structure (left ventricular mass = 10 ± 2 g, p < 0.001; internal dimension during diastole = 0.1 ± 0.04 cm, p < 0.05; internal dimension during systole = 0.06 ± 0.03 cm, p < 0.05; interventricular septum dimension = 0.04 ± 0.02 cm, p < 0.05), systolic function (ejection fraction = 1 ± 0.4%, p < 0.05; velocity time integral = 2 ± 0.4 cm, p < 0.001; stroke volume = 4.4 ± 1.5 ml, p < 0.01), and diastolic function (mitral valve deceleration time = -32 ± 11 ms, p < 0.05; mitral valve deceleration slope = 50 ± 25 cm s–1, p < 0.05; isovolumic relaxation time = −6 ± 1.9 ms, p < 0.05) with each subsequent scES intervention. Despite the pilot nature of this study, statistically significant improvements to the cardiac structure, systolic function, and diastolic function demonstrate that scES combined with task-specific interventions led to beneficial cardiac remodeling, which can reverse atrophic changes that result from spinal cord injury. Long-term improvements to cardiac function have implications for increased quality of life and improved cardiovascular health in individuals with spinal cord injury, decreasing the risk of cardiovascular morbidity and mortality.
Chronic Physical Activity for Attention Deficit Hyperactivity Disorder and/or Autism Spectrum Disorder in Children: A Meta-Analysis of Randomized Controlled Trials

Purpose: To explore the effects of physical activity (PA) intervention on executive function (EF) and motor skills (MS) among children with attention deficit hyperactivity disorder and/or autism spectrum disorder (ASD). Methods: Relevant studies were sourced from PubMed, Web of Science, EMBASE, Cochrane Library, CNKI and Wanfang Data. Only randomized controlled trials (RCT) were included based upon the following criteria: (1) participants were children and clinically diagnosed with ADHD/ASD, (2) intervention strategies were identified as chronic physical activity, and (3) EF (e.g., cognitive flexibility) and/or MS (e.g., gross motor skills) were measured at baseline and post-intervention and compared with an eligible control group. Results: Eleven studies involving 346 participants were finally identified. PA elicited significant improvements in EF and MS in children with ADHD/ASD. Regarding changes in the EF of participants, PA showed a great improvement in overall EF [standardized mean difference (SMD): 0.90, 95% confidence interval (CI) 0.49–1.30, p < 0.00001], inhibitory control (SMD: 1.30, 95% CI 0.58–2.02, p = 0.0004) and cognitive flexibility (SMD: 0.85, 95% CI 0.42–1.29, p = 0.0001), but no significant improvement in working memory (SMD: 0.28, 95% CI −0.15–0.71, p = 0.20). Significant improvements were also found with respect to gross motor skills (SMD: 0.80, 95% CI 0.30–1.30, p = 0.002), but no significant changes were found in fine motor skills (SMD: 0.30, 95% CI −0.91–1.52, p = 0.62). Conclusion: Chronic PA interventions may promote EF and MS in children with ADHD/ASD, especially in inhibitory control, cognitive flexibility, and gross motor skills. However, PA interventions seemed to have insignificant effects on working memory and fine motor skills to children with ADHD/ASD. PROSPERO registration number: CRD42019118622
Strategies to Target Estrogen-Related Tumor Promoting Mechanisms in Lung Cancer

Despite clinical advancements with targeted and immune therapies, lung cancer remains the leading cause of cancer related deaths in the United States. Scant improvements in the five-year survival rate over the past decade necessitate the development of more efficacious therapeutic approaches. Epidemiological reports and preclinical studies have demonstrated involvement of the estrogen pathway, mediated through estrogen receptor β-1 (ERβ), in the development and promotion of lung tumorigenesis. Strategies for targeting the estrogen pathway include anti-estrogens and aromatase inhibitors (AIs), either as single agents or combined with other therapies. The primary objective of this study was to identify and target interactions between the estrogen signaling pathway and the fibroblast growth factor (FGF) pathway and identify additional estrogen-related tumor promoting mechanisms in non-small cell lung cancer (NSCLC). Fibroblast growth factor receptor 1 (FGFR1) was significantly over-expressed in ERβ high tumors, while the decoy receptor, fibroblast growth factor receptor like-1 (FGFR5), was down-regulated. NSCLC cell lines lacking FGFR1 amplification expressed multiple FGFRs and secreted several FGFs. β-estradiol (E2) treatment significantly enhanced FGF2 release, an effect blocked by the anti-estrogen fulvestrant. Furthermore, co-targeting the E2 and FGF pathways with fulvestrant and the pan-FGFR inhibitor AZD4547 resulted in greater anti-tumor effects both in vitro and in vivo compared to single pathway inhibition. These results demonstrate crosstalk between the two pathways in NSCLC, and suggest clinical utility of a pan-FGFR inhibitor in combination with an anti-estrogen in a subset of NSCLC patients. Previous reports of aromatase expression in pulmonary tumor macrophages, and up-regulation of anti-oxidant signaling with AIs, indicate a potential interaction between estrogen signaling and inflammation in lung cancer. Utilizing an in vivo NSCLC xenograft model, the AIs exemestane and letrozole significantly inhibited tumor proliferation, reduced Ki67 expression, altered tumor histology, and increased anti-inflammatory signaling. Finally, we demonstrated fulvestrant enhanced therapeutic sensitivity and inhibited the migration of NSCLC cells resistant to the heat shock protein 90 (HSP90) inhibitor ganetespib, but not through a reversal of epithelial-mesenchymal transition. Together, the results of this study highlight the pervasive role of estrogen signaling in lung cancer and provide rationale for combinatorial strategies involving hormonal agents for lung cancer treatment.
Asymptotically Optimal and Near-Optimal Aperiodic Quasi-Complementary Sequence Sets Based on Florentine Rectangles

Quasi-complementary sequence sets (QCSSs) can be seen as a generalized version of complete complementary codes (CCCs), which enables multicarrier communication systems to support more users. The contribution of this work is two-fold. First, we propose a systematic construction of Florentine rectangles. Secondly, we propose several sets of CCCs and QCSSs, using Florentine rectangles. The CCCs and QCSSs are constructed over <inline-formula> <tex-math notation="LaTeX">$\mathbb {Z}_{N}$ </tex-math></inline-formula>, where <inline-formula> <tex-math notation="LaTeX">$N\geq 2$ </tex-math></inline-formula> is any integer. The cross-correlation magnitude of any two of the constructed CCCs is upper bounded by <inline-formula> <tex-math notation="LaTeX">$N$ </tex-math></inline-formula>. By combining the proposed CCCs, we propose asymptotically optimal and near-optimal QCSSs with new parameters.
scATAC-Seq reveals epigenetic heterogeneity associated with an EMT-like process in male germline stem cells and its regulation by G9a

Epithelial-mesenchymal transition (EMT) is a phenomenon in which epithelial cells acquire mesenchymal traits. It contributes to organogenesis and tissue homeostasis, as well as stem cell differentiation. Emerging evidence indicates that heterogeneous expression of EMT gene markers presents in sub-populations of germline stem cells (GSCs). However, the functional implications of such heterogeneity are largely elusive. Here, we unravelled an EMT-like process in GSCs by in vitro extracellular matrix (ECM) model and single-cell genomics approaches. Through modulating ECM, we demonstrated that GSCs exist in interconvertible epithelial-like and mesenchymal-like cell states. GSCs gained higher migratory ability after transition to a mesenchymal-like cell state, which was largely mediated by the TGF-β signaling pathway. Dynamics of epigenetic regulation at the single-cell level was also found to align with the EMT-like process. Chromatin accessibility profiles generated by single-cell sequencing assay for transposase-accessible chromatin (scATAC-seq) clustered GSCs into epithelial-like and mesenchymal-like states, which were associated with differentiation status. The high-resolution data revealed novel regulators in the EMT-like process, including transcription factors Zeb1 and Hesl. We further identified putative enhancer-promoter interactions and cis-co-accessibility networks at loci such as Tgfbl, Notchl and Lin28a. Importantly, we demonstrated that histone methyltransferase G9a promoted the GSC EMT-like process in vitro and contributed to neonatal germ cell migration in vivo. Our work thus provides the foundation for understanding the EMT-like process and a comprehensive resource for future investigation of epigenetic regulatory networks in GSCs.
ComboLoss for Facial Attractiveness Analysis with Squeeze-and-Excitation Networks

Loss function is crucial for model training and feature representation learning, conventional models usually regard facial attractiveness recognition task as a regression problem, and adopt MSE loss or Huber variant loss as supervision to train a deep convolutional neural network (CNN) to predict facial attractiveness score. Little work has been done to systematically compare the performance of diverse loss functions. In this paper, we firstly systematically analyze model performance under diverse loss functions. Then a novel loss function named ComboLoss is proposed to guide the SEResNeXt50 network. The proposed method achieves state-of-the-art performance on SCUT-FBP, HotOrNot and SCUT-FBP5500 datasets with an improvement of 1.13%, 2.1% and 0.57% compared with prior arts, respectively. Code and models are available at this https URL.