Miracle-dz/UniFAR-FTUs huggingface dataset:
Structural Basis of Covalent Inhibitory Mechanism of TMPRSS2-Related Serine Proteases by Camostat

Serine proteases are a large family of enzymes critical for multiple physiological processes and proven diagnostic and therapeutic targets in several clinical indications. The serine protease transmembrane protease serine 2 (TMPRSS2) was recently found to mediate SARS-CoV-2 entry into the host. ABSTRACT Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the viral pathogen causing the coronavirus disease 2019 (COVID-19) global pandemic. No effective treatment for COVID-19 has been established yet. The serine protease transmembrane protease serine 2 (TMPRSS2) is essential for viral spread and pathogenicity by facilitating the entry of SARS-CoV-2 into host cells. The protease inhibitor camostat, an anticoagulant used in the clinic, has potential anti-inflammatory and antiviral activities against COVID-19. However, the potential mechanisms of viral resistance and antiviral activity of camostat are unclear. Herein, we demonstrate high inhibitory potencies of camostat for a panel of serine proteases, indicating that camostat is a broad-spectrum inhibitor of serine proteases. In addition, we determined the crystal structure of camostat in complex with a serine protease (uPA [urokinase-type plasminogen activator]), which reveals that camostat is inserted in the S1 pocket of uPA but is hydrolyzed by uPA, and the cleaved camostat covalently binds to Ser195. We also generated a homology model of the structure of the TMPRSS2 serine protease domain. The model shows that camostat uses the same inhibitory mechanism to inhibit the activity of TMPRSS2, subsequently preventing SARS-CoV-2 spread. IMPORTANCE Serine proteases are a large family of enzymes critical for multiple physiological processes and proven diagnostic and therapeutic targets in several clinical indications. The serine protease transmembrane protease serine 2 (TMPRSS2) was recently found to mediate SARS-CoV-2 entry into the host. Camostat mesylate (FOY 305), a serine protease inhibitor active against TMPRSS2 and used for the treatment of oral squamous cell carcinoma and chronic pancreatitis, inhibits SARS-CoV-2 infection of human lung cells. However, the direct inhibition mechanism of camostat mesylate for TMPRSS2 is unclear. Herein, we demonstrate that camostat uses the same inhibitory mechanism to inhibit the activity of TMPRSS2 as uPA, subsequently preventing SARS-CoV-2 spread.
Immunomodulatory Effects of Lenvatinib Plus Anti–Programmed Cell Death Protein 1 in Mice and Rationale for Patient Enrichment in Hepatocellular Carcinoma

Lenvatinib is an effective drug in advanced HCC. Its combination with the anti‐PD1 (programmed cell death protein 1) immune checkpoint inhibitor, pembrolizumab, has generated encouraging results in phase Ib and is currently being tested in phase III trials. Here, we aimed to explore the molecular and immunomodulatory effects of lenvatinib alone or in combination with anti‐PD1.
Face memory and face perception in autism

It has been argued that autistic individuals have difficulties with face memory but typical face perception. However, only one previous study has examined both face memory and face perception in the same individuals, and this study was conducted with a small group of autistic children. Here, face recognition was examined with a group of autistic adults using two face perception tasks (including one designed to avoid a neurotypical bias) and a standard test of face memory. Self-reported face recognition difficulties in everyday life were also recorded. The group of adults with autism scored lower than a matched neurotypical control group on all face tasks and reported more problems with face recognition in everyday life. On the whole, results suggest difficulties with both face perception and face memory in autistic adults, although it should be noted that a wide range of scores were recorded from the autistic individuals, with some scoring in the neurotypical range. Lay abstract It is well known that some people with autism have difficulties recognizing faces. It is generally thought that this is not because autistic individuals cannot perceive faces, but because autistic individuals have greater problems than people without autism in remembering faces. Here, we worked with a group of autistic adults and a group of non-autistic adults to test their ability to perceive and remember faces. We also asked each person to report any difficulties that they have with recognizing faces in everyday life. We find that, as a group, people with autism have difficulties with both remembering and perceiving faces, and report more problems recognizing faces in everyday life. However, it is worth noting that we observed a wide range of scores in the group of people with autism, with some autistic participants scoring as well as the group of people without autism.
The early COVID-19 pandemic and democratic attitudes

How does a public health crisis like a global pandemic affect political opinions in fragile democratic contexts? Research in political science suggests several possible public reactions to crisis, from retrospective anti-incumbency to rally ‘round the flag effects to democratic erosion and authoritarianism. Which of these obtains depends on the nature of the crisis. We examine whether and how the onset of the global pandemic shifted public opinion toward the president, elections, and democracy in Haiti. We embedded two experiments in a phone survey administered to a nationally representative sample of Haitians in April-June 2020. We find that the early pandemic boosted presidential approval and intentions to vote for the incumbent president, consistent with a rally effect. These results show that a rally effect occurs even in the most unlikely of places–an unstable context in which the incumbent president is struggling to maintain order and support. At the same time, we find scant evidence that the onset of the pandemic eroded democratic attitudes, even in a context in which democracy rests on uncertain grounds.
Disease-Image-Specific Learning for Diagnosis-Oriented Neuroimage Synthesis With Incomplete Multi-Modality Data

Incomplete data problem is commonly existing in classification tasks with multi-source data, particularly the disease diagnosis with multi-modality neuroimages, to track which, some methods have been proposed to utilize all available subjects by imputing missing neuroimages. However, these methods usually treat image synthesis and disease diagnosis as two standalone tasks, thus ignoring the specificity conveyed in different modalities, i.e., different modalities may highlight different disease-relevant regions in the brain. To this end, we propose a disease-image-specific deep learning (DSDL) framework for joint neuroimage synthesis and disease diagnosis using incomplete multi-modality neuroimages. Specifically, with each whole-brain scan as input, we first design a Disease-image-Specific Network (DSNet) with a spatial cosine module to implicitly model the disease-image specificity. We then develop a Feature-consistency Generative Adversarial Network (FGAN) to impute missing neuroimages, where feature maps (generated by DSNet) of a synthetic image and its respective real image are encouraged to be consistent while preserving the disease-image-specific information. Since our FGAN is correlated with DSNet, missing neuroimages can be synthesized in a diagnosis-oriented manner. Experimental results on three datasets suggest that our method can not only generate reasonable neuroimages, but also achieve state-of-the-art performance in both tasks of Alzheimer’s disease identification and mild cognitive impairment conversion prediction.
Genomic epidemiology of the first epidemic wave of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Palestine

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the novel coronavirus responsible for the COVID-19 pandemic, continues to cause a significant public-health burden and disruption globally. Genomic epidemiology approaches point to most countries in the world having experienced many independent introductions of SARS-CoV-2 during the early stages of the pandemic. However, this situation may change with local lockdown policies and restrictions on travel, leading to the emergence of more geographically structured viral populations and lineages transmitting locally. Here, we report the first SARS-CoV-2 genomes from Palestine sampled from early March 2020, when the first cases were observed, through to August of 2020. SARS-CoV-2 genomes from Palestine fall across the diversity of the global phylogeny, consistent with at least nine independent introductions into the region. We identify one locally predominant lineage in circulation represented by 50 Palestinian SARS-CoV-2, grouping with genomes generated from Israel and the UK. We estimate the age of introduction of this lineage to 05/02/2020 (16/01/2020–19/02/2020), suggesting SARS-CoV-2 was already in circulation in Palestine predating its first detection in Bethlehem in early March. Our work highlights the value of ongoing genomic surveillance and monitoring to reconstruct the epidemiology of COVID-19 at both local and global scales.
Crystal structure of the Aurivillius phases in the system Bi4Ti3O12—PbTiO3

The crystal structure of four Aurivillius phases within the pseudo-binary system Bi4Ti3O12—PbTiO3 is examined using a 3 + 1D approach where these phases are treated as commensurately modulated layered structures. The structure of PbBi4Ti4O15, Pb2Bi4Ti5O18, Pb3Bi4Ti6O21 and PbBi8Ti7O27 are refined by the Rietveld method using XRPD data from single phased powders. The structure of Pb3Bi4Ti6O21 and PbBi8Ti7O27 is reported for the first time. When the lead content increases, the structure gets less distorted and approaches the prototype paraelectric phase in an apparent close relation with the onset of a “relaxor-like” ferroelectric behaviour. For these relaxor compounds, SAED investigation evidences the existence of a disorder in the form of micro-twinning.
Sphingosine Kinase Inhibition Enhances Dimerization of Calreticulin at the Cell Surface in Mitoxantrone-Induced Immunogenic Cell Death

Agents that induce immunogenic cell death (ICD) alter the cellular localization of calreticulin (CRT), causing it to become cell surface–exposed within the plasma membrane lipid raft microdomain [cell surface–exposed CRT (ectoCRT)] where it serves as a damage associated-molecular pattern that elicits an antitumor immune response. We have identified the sphingolipid metabolic pathway as an integral component of the process of ectoCRT exposure. Inhibition of the sphingosine kinases (SphKs) enhances mitoxantrone-induced production of hallmarks of ICD, including ectoCRT production, with an absolute mean difference of 40 MFI (95% CI: 19–62; P = 0.0014) and 1.3-fold increase of ATP secretion with an absolute mean difference of 87 RLU (95% CI: 55–120; P < 0.0001). Mechanistically, sphingosine kinase inhibition increases mitoxantrone-induced accumulation of ceramide species, including C16:0 ceramide 2.8-fold with an absolute mean difference of 1.390 pmol/nmol Pi (95% CI: 0.798–1.983; P = 0.0023). We further examined the localization of ectoCRT to the lipid raft microdomain and demonstrate that ectoCRT forms disulfide-bridged dimers. Together, our findings suggest that ceramide accumulation impinges on the homeostatic function of the endoplasmic reticulum to induce ectoCRT exposure and that structural alterations of ectoCRT may underlie its immunogenicity. Our findings further suggest that inhibition of the SphKs may represent a means to enhance the therapeutic immunogenic efficacy of ICD-inducing agents while reducing overt toxicity/immunosuppressive effects by allowing for the modification of dosing regimens or directly lowering the dosages of ICD-inducing agents employed in therapeutic regimens. SIGNIFICANCE STATEMENT This study demonstrates that inhibition of sphingosine kinase enhances the mitoxantrone-induced cell surface exposure of a dimeric form of the normally endoplasmic reticulum resident chaperone calreticulin as part of the process of a unique form of regulated cell death termed immunogenic cell death. Importantly, inhibition of sphingosine kinase may represent a means to enhance the therapeutic efficacy of immunogenic cell death–inducing agents, such as mitoxantrone, while reducing their overt toxicity and immunosuppressive effects, leading to better therapeutic outcomes for patients.
Fibrosis-4 Index vs Nonalcoholic Fatty Liver Disease Fibrosis Score in Identifying Advanced Fibrosis in Subjects With Nonalcoholic Fatty Liver Disease: A Meta-Analysis

INTRODUCTION: In subjects with nonalcoholic fatty liver disease (NAFLD), advanced fibrosis (AF) carries the highest risk of adverse liver-related events. To reduce the number of unnecessary biopsies, several noninvasive tools (NITs) for the risk stratification of fibrosis have been developed. We conducted this meta-analysis to assess the performance of the fibrosis-4 index (FIB-4) and NAFLD fibrosis scores (NFS), the 2 most common NITs, for the appropriate selection of subjects with AF for biopsy. METHODS: Four databases were searched until December 2020 (CRD42021224766). Original articles reporting data on the performance of FIB-4 and NFS, interpreted according to standard cutoffs in subjects with biopsy-proven NAFLD, were included. Separate data extractions were performed according to the lower cutoff, the higher cutoff, and the dual threshold approach. The numbers of subjects classified as true-negative, true-positive, false-negative, and false-positive were extracted. Summary operating points were estimated using a random-effects model. RESULTS: Eighteen studies evaluating 12,604 subjects were included. Participants were adult outpatients with biopsy-proven NAFLD or nonalcoholic steatohepatitis. Overall, a weak-to-moderate performance was found for both scores. The head-to-head comparison showed FIB-4 to be associated with a higher performance in ruling in and NFS in ruling out AF in the single threshold approach, whereas, with the dual threshold approach, a lower prevalence of indeterminate findings was found for FIB-4. DISCUSSION: This meta-analysis suggested that currently available NITs have a limited performance in identifying AF among subjects with NAFLD. Further studies are needed to optimize existing thresholds or develop new NITs.
Dinuclear Coinage-Metal Complexes of Bis(NHC) Ligands: Structural Features and Dynamic Behavior of a Cu–Cu Complex

Binuclear complexes of copper, silver, and gold bearing a 2,2′-bipyridine analogue, the pyridazine annelated bis(N-heterocyclic carbene) ligand (vegi) 1, were prepared and structurally characterized. They all feature the shortest metal–metal distances that have been measured so far in complexes with this structural motif bearing neutral bidentate ligands, indicative of d10–d10 interactions. While in the silver complex the linear coordination of each silver atom with two carbene ligands results in a planar complex, the ligand planes are twisted by 70° in the Cu complex 4 and by 31° in the gold complex 3. The copper complex shows a solvent-dependent equilibrium between the [Cu2L2]2+ complex and a [Cu2L3]2+ complex along with solvated CuPF6.
Proof‐of‐concept evidence for trimodal simultaneous investigation of human brain function

The link between spatial (where) and temporal (when) aspects of the neural correlates of most psychological phenomena is not clear. Elucidation of this relation, which is crucial to fully understand human brain function, requires integration across multiple brain imaging modalities and cognitive tasks that reliably modulate the engagement of the brain systems of interest. By overcoming the methodological challenges posed by simultaneous recordings, the present report provides proof‐of‐concept evidence for a novel approach using three complementary imaging modalities: functional magnetic resonance imaging (fMRI), event‐related potentials (ERPs), and event‐related optical signals (EROS). Using the emotional oddball task, a paradigm that taps into both cognitive and affective aspects of processing, we show the feasibility of capturing converging and complementary measures of brain function that are not currently attainable using traditional unimodal or other multimodal approaches. This opens up unprecedented possibilities to clarify spatiotemporal integration of brain function.
Changes in the Hepatitis B Surface Antigen Level According to the HBeAg Status and Drug Used in Long-term Nucleos(t)ide Analog-treated Chronic Hepatitis B Patients.

Backgrounds/Aims The HBsAg levels have been used to monitor the chronic hepatitis B (CHB) treatment response to antiviral therapy. On the other hand, it is unclear if the HBsAg quantification levels at each treatment point differ according to the HBeAg status and drug in CHB patients. This study compared the changes in HBsAg in CHB patients according to the HBeAg status and treatment drugs. Methods CHB patients with at least 1 year of follow-up treatment with one drug, either entecavir (ETV) or tenofovir (TDF), were enrolled in this study. The mean HBsAg levels were measured annually for up to 6 years. A linear mixed model was used to compare the HBsAg quantification levels during the follow-up period. An independent samples t-test was used to analyze the differences in the HBsAg quantification levels at each treatment time point. Results Ninety-seven patients were enrolled in this study; 59 among them were HBeAg-positive. Two patients in the TDF group achieved HBsAg seroconversion. The HBsAg level decreased during the follow-up in the ETV and TDF groups. The HBsAg level was lower in the TDF group than the ETV group during the follow-up. On the other hand, subgroup analysis showed that this trend was the same only in the HBeAg-negative patients, not in the HBeAg-positive patients. In the HBeAg-negative patients, HBsAg level in the TDF group was significantly lower than that in the ETV group at 36, 48, and 72 months. The change in HBsAg level from the baseline increased at a decreasing rate during the follow-up in both groups. Furthermore, the change in the HBsAg level in the TDF group was significantly larger than that of the ETV group at 36 months in the HBeAg-negative patients. Conclusions Although TDF might be more efficient than ETV in reducing the HBsAg level in HBeAg-negative patients in a few years, HBsAg seroconversion occurred very rarely. A further large-scale, long-term study will be needed to confirm the antiviral effects on the HBsAg level.
QSAR analysis of the acute toxicity of avermectins towards Tetrahymena pyriformis

ABSTRACT Avermectins have been effectively used in medicine, veterinary medicine, and agriculture as antiparasitic agents for many years. However, there are still no reliable data on the main ecotoxicological characteristics of most individual avermectins. Although many QSAR models have been proposed to describe the acute toxicity of organic compounds towards Tetrahymena pyriformis (T. pyriformis), avermectins are outside the applicability domain of these models. The influence of the molecular structures of various organic compounds on the acute toxicity towards T. pyriformis was studied using the OCHEM web platform (https://ochem.eu). A data set of 1792 toxicants was used to create models. The QSAR (Quantitative Structure-Activity Relationship) models were developed using the molecular descriptors Dragon, ISIDA, CDK, PyDescriptor, alvaDesc, and SIRMS and machine learning methods, such as Least Squares Support Vector Machine and Transformer Convolutional Neural Network. The HYBOT descriptors and Random Forest were used for a comparative QSAR investigation. Since the best predictive ability was demonstrated by the Transformer Convolutional Neural Network model, it was used to predict the toxicity of individual avermectins towards T. pyriformis. During a structural interpretation of the developed QSAR model, we determined the significant molecular transformations that increase and decrease the acute toxicity of organic compounds.
Constructing a new prognostic signature of gastric cancer based on multiple data sets

ABSTRACT In order to explore new prediction methods and key genes for gastric cancer. Firstly, we downloaded the 6 original sequencing data of gastric cancer on the Illumina HumanHT-12 platform from Array Expression and Gene Expression Omnibus, and used bioinformatics methods to identify 109 up-regulated genes and 271 down-regulated genes. Further, we performed univariate Cox regression analysis of prognostic-related genes, then used Lasso regression to remove collinearity, and finally used multivariate Cox regression to analyze independent prognostic genes (MT1M, AKR1C2, HEYL, KLK11, EEF1A2, MMP7, THBS1, KRT17, RPESP, CMTM4, UGT2B17, CGNL1, TNFRSF17, REG1A). Based on these, we constructed a prognostic risk proportion signature, and found that patients with high-risk gastric cancer have a high degree of malignancy. Subsequently, we used the GSE15459 data set to verify the signature. By calculating the area under the recipient operator characteristic curve of 5-year survival rate, the test set and verification set are 0.739 and 0.681, respectively, suggesting that the prognostic signature has a moderate prognostic ability. The nomogram is used to visualize the prognostic sig-nature, and the calibration curve verification showed that the prediction accuracy is higher. Finally, we verified the expression and prognosis of the hub gene, and suggested that HEYL, MMP7, THBS1, and KRT17 may be potential prognostic biomarkers.
Sensitivity and specificity of the INECO frontal screening (IFS) in the detection of patients with traumatic brain injury presenting executive deficits

Abstract Executive dysfunction (EF) is a common feature of adult traumatic brain injury (TBI), especially in moderate to severe cases. Assessing EF usually requires the administration of an extensive neuropsychological battery, which is time consuming and expensive. The INECO frontal screening (IFS) is a brief, easy-to-administer screening test which has previously shown to be useful in the detection of executive deficits in different psychiatric and neurological populations. The aim of the present study was to assess the usefulness of the IFS in the detection of executive dysfunction in TBI patients. Twenty-eight TBI patients and thirty-two healthy controls were assessed with a battery that included classical executive tests and the IFS. Our results indicated that with a cutoff score of 26.25 points, the IFS showed good sensitivity and specificity in the detection of executive impairments in TBI patients. It also showed good positive and negative predicted values. Our results suggest that the IFS can be considered a useful tool for identifying executive dysfunction in patients with TBI.
Hijab Pornography: A Content Analysis of Internet Pornographic Videos

A content analysis was conducted to explore sexual indicators of aggression, objectification, exploitation, and agency in 50 “hijab” pornographic videos. Our findings suggest that women were the target of aggressive acts in all videos, with gagging (42%) and spanking (38%) being the most common. Also, in comparison with men, women were more likely to be objectified and exploited, and less likely to possess agency. Limitations of the current study and directions for future research are detailed.