Miracle-dz/UniFAR-FTUs huggingface dataset:
Regulation of the Dimerization and Activity of SARS-CoV-2 Main Protease through Reversible Glutathionylation of Cysteine 300

SARS-CoV-2 encodes main protease (Mpro), an attractive target for therapeutic interventions. We show Mpro is susceptible to glutathionylation leading to inhibition of dimerization and activity. Activity of glutathionylated Mpro could be restored with reducing agents or glutaredoxin. Analytical studies demonstrated that glutathionylated Mpro primarily exists as a monomer and that a single modification with glutathione is sufficient to block dimerization and loss of activity. Proteolytic digestions of Mpro revealed Cys300 as a primary target of glutathionylation, and experiments using a C300S Mpro mutant revealed that Cys300 is required for inhibition of activity upon Mpro glutathionylation. These findings indicate that Mpro dimerization and activity can be regulated through reversible glutathionylation of Cys300 and provides a novel target for the development of agents to block Mpro dimerization and activity. This feature of Mpro may have relevance to human disease and the pathophysiology of SARS-CoV-2 in bats, which develop oxidative stress during flight.
Aurora B switches relative strength of kinetochore–microtubule attachment modes for error correction

Doodhi et al. reconstitute the yeast kinetochore–microtubule interface in vitro and compare the relative strength of distinct kinetochore–microtubule interaction modes. Their results suggest how Aurora B kinase promotes the exchange of kinetochore–microtubule interactions to eliminate aberrant interactions and establish chromosome biorientation.
Peripheral blood molecular measurable residual disease is sufficient to identify patients with acute myeloid leukaemia with imminent clinical relapse

Longitudinal molecular measurable residual disease (MRD) sampling after completion of therapy serves as a refined tool for identification of imminent relapse of acute myeloid leukaemia (AML) among patients in long‐term haematological complete remission. Tracking of increasing quantitative polymerase chain reaction MRD before cytomorphological reappearance of blasts may instigate individual management decisions and has paved the way for development of pre‐emptive treatment strategies to substantially delay or perhaps even revert leukaemic regrowth. Traditionally, MRD monitoring is performed using repeated bone marrow aspirations, albeit the current European LeukemiaNet MRD recommendations acknowledge the use of peripheral blood as an alternative source for MRD assessment. Persistent MRD positivity in the bone marrow despite continuous morphological remission is frequent in both core binding factor leukaemias and nucleophosmin 1‐mutated AML. In contrast, monthly assessment of MRD in peripheral blood superiorly separates patients with imminent haematological relapse from long‐term remitters and may allow pre‐emptive therapy of AML relapse.
Pazopanib in patients with metastatic renal cell carcinoma: a single-center, real-world, retrospective Chinese study

Background The efficacy and safety of pazopanib in patients diagnosed with metastatic renal cell carcinoma (mRCC) have been demonstrated by a Chinese subgroup analysis of the COMPARZ (Pazopanib Versus Sunitinib in the Treatment of Locally Advanced and/or Metastatic Renal Cell Carcinoma) trial. However, the real-world data are still unknown. This single-center, retrospective study was designed to verify the real-world effects of pazopanib in Chinese patients with mRCC. Methods Patients with mRCC and a clinical decision to initiate pazopanib as first-line therapy were eligible. The primary endpoint was progression-free survival (PFS), with overall survival (OS), objective response rate (ORR), and safety being evaluated as secondary endpoints. The effectiveness according to the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk model, number of risk factors in the intermediate risk group, age, Eastern Cooperative Oncology Group (ECOG) performance status (PS), and the number and site of organ metastasis were also assessed. Results A total of 32 patients were enrolled, including 23 (71.9%) males and 9 (28.1%) females. The median age was 57 years (range 29–75 years). With a median follow-up time of 23.8 months, a median PFS of 18.3 months, and an ORR of 37.5%. Median OS was not reached, and the 1-, 2-, and 3-year overall survival rates were 90.6%, 78.1, and 65.6%, respectively. According to IMDC risk model, 37.5% were placed in the favorable risk (FR) subgroup, 56.2% (the majority) were placed in the intermediate risk (IR) subgroup, and 6.3% were placed in the poor risk (PR) subgroup. Compared with the IR and PR groups, the FR group achieved the best ORR (58.3%) and median PFS (22.1 months). Having 1 risk factor, ECOG PS <2, 1 organ metastasis site, and only lung metastasis associated with a higher ORR and better median PFS. The IMDC risk model and number of metastases were associated with PFS. The most common adverse events were change in hair color (69.0%), diarrhea (63%), and hypertension (50%). Conclusions Pazopanib showed efficacy and safety in real-world Chinese mRCC patients.
Use of Medications for Treating Anxiety or Depression among Testicular Cancer Survivors: A Multi-Institutional Study

Background: This study examined sociodemographic factors, cisplatin-related adverse health outcomes (AHO), and cumulative burden of morbidity (CBMPt) scores associated with medication use for anxiety and/or depression in testicular cancer survivors (TCS). Methods: A total of 1,802 TCS who completed cisplatin-based chemotherapy ≥12 months previously completed questionnaires regarding sociodemographic features and cisplatin-related AHOs [hearing impairment, tinnitus, peripheral sensory neuropathy (PSN), and kidney disease]. A CBMPt score encompassed the number and severity of cisplatin-related AHOs. Multivariable logistic regression models assessed the relationship of individual AHOs and CBMPt with medication use for anxiety and/or depression. Results: A total of 151 TCS (8.4%) used medications for anxiety and/or depression. No cisplatin-related AHOs were reported by 511 (28.4%) participants, whereas 622 (34.5%), 334 (18.5%), 287 (15.9%), and 48 (2.7%), respectively, had very low, low, medium, and high CBMPt scores. In the multivariable model, higher CBMPt scores were significantly associated with medication use for anxiety and/or depression (P < 0.0001). In addition, tinnitus (P = 0.0009), PSN (P = 0.02), and having health insurance (P = 0.05) were significantly associated with greater use of these medications, whereas being employed (P = 0.0005) and vigorous physical activity (P = 0.01) were significantly associated with diminished use. Conclusions: TCS with higher CBMPt scores had a higher probability of using medications for anxiety and/or depression, and conversely, those who were employed and physically active tended to have reduced use of these medications. Impact: Healthcare providers should encourage TCS to increase physical activity to improve both physical and mental health. Rehabilitation programs should assess work-related skills and provide career development counseling/training.
TiO2–BaTiO3 nanocomposite for electron capture in dye‐sensitized solar cells

Different compositions of TiO2–BaTiO3 nanocomposites are synthesized with various weight ratios for dye-sensitized solar cell (DSSC) applications. TiO2 and BaTiO3 nanoparticles (NPs) are synthesized by sol-gel and solvothermal methods, respectively and are employed as the photoanode electrodes. BaTiO3 NPs have pure cubic perovskite crystal structure with an average size of 20-40 nm, while TiO2 NPs show pure anatase phase with 15-30 nm size. The power conversion efficiency (PCE) enhancement of the cells is first attained by controlling the thickness of the films for light harvesting improvement. The fabricated DSSC composed of pure BaTiO3 NPs with an optimal thickness of 25 μm shows efficiency of 6.83%, whereas that made of pure TiO2 NPs with 14 μm thickness has cell efficiency of 7.24%. Further improvement of cell efficiency is achieved by preparation of binary oxide nanocomposites using TiO2 and BaTiO3 NPs with various weight ratios. The highest PCE of 9.40% is obtained for the nanocomposite with TiO2:BaTiO3=85:15 (wt%). The enhancement is assigned to less recombination of photo-generated electrons and higher incident photon to current conversion yield as a result of rapid charge collection and higher dye sensitization.
Top Interface Engineering of Flexible Oxide Thin‐Film Transistors by Splitting Active Layer

The effect of active layer (amorphous indium–gallium–zinc oxide, a‐IGZO) splitting on the performances of back‐channel‐etched (BCE) and etch‐stopper (ES) thin‐film transistors (TFTs) on polyimide substrate is studied. While the performance of BCE TFT is independent of active layer splitting, the performance of ES TFT is improved significantly by splitting the active layer into 2–4 µm width along the channel. The saturation mobility is enhanced from 24.3 to 76.8 cm2 V−1 s−1 and this improvement is confirmed by the operation of a ring oscillator made of the split TFTs also. X‐ray photoelectron spectroscopy (XPS) analysis of the split a‐IGZO indicates the incorporation of F at the island interface and thus improves the top interface quality, leading to a significant improvement of the top channel TFT mobility from 0.25 to 24.22 cm2 V−1 s−1. This improvement is correlated with bonding of In with F at the top interface according to XPS results. The bias stability, hysteresis, and mechanical stability of the ES a‐IGZO TFT are also remarkably improved by splitting a‐IGZO active layer.
[Changes of guanylate cyclase C in colon tissues of rats with intestinal injury associated with severe acute pancreatitis].

OBJECTIVE To explore the dynamic changes of guanylate cyclase C (GC-C) in the colon tissues of rats with intestinal injury associated with severe acute pancreatitis (SAP). OBJECTIVE Thirty-six SD rats were randomized equally into two groups to receive either sham operation or retrograde pumping of 5% sodium taurocholate (0.1 mL/100 g) into the pancreaticobiliary duct following laparotomy to induce SAP. At 12, 24, and 48 h after modeling, 6 rats from each group were euthanized and the colon tissues were collected for Western blotting, immunohistochemistry and RT-PCR to determine the changes in GC-C expression, and the lowest GC-C expression was deemed to indicate the most serious intestinal injury and the time window for intervention. Another 18 SD rats were randomized into 3 groups for sham operation, SAP modeling or intragastric administration of linaclotide (a GC-C agonist) solution once daily at the dose of 10 μg/kg. At 12 h after modeling, the pathological changes in the pancreas and colon were observed with HE staining; the serum level of AMY, DAO, D-Lac and TNF-α were measured with ELISA, and the expressions of GC-C and claudin-1 were detected using Western blotting, immunohistochemical and transmission electron microscopy. OBJECTIVE The expression of GC-C was significantly reduced in the colon of rats in SAP group, and its lowest expression occurred at 12 h after modeling (P < 0.05) followed by gradual increase over time. Claudin-1 showed a similar trend in the colon. Compared with the sham-operated rats, the rats in SAP and Linaclotide groups showed significantly increased pathological scores of the colon tissues (P < 0.05) and serum levels of AMY, DAO, D-Lac and TNF-α and decreased expressions of GC-C and claudin-1 in the colon (P < 0.05). Compared with those in SAP group, the rats in linaclotide group had significantly lower colonic histopathological scores, lower serum levels of AMY, DAO, D-Lac and TNF-α, and higher expression levels of GC-C and claudin-1 in the colon tissue. OBJECTIVE In rats with SAP-related intestinal injury, the expression of GC-C in the colon tissue decreases to the lowest level at 12 h after SAP onset followed by gradual increase. activating GC-C can increase the expression levels of GC-C and claudin-1 and alleviate intestinal injury, suggesting the role of GC-C in maintaining intestinal barrier integrity by regulating the expression of tight junction proteins.
Geometries in Soft Matter From Geometric Frustration, Liquid Droplets to Electrostatics in Solution

This thesis explores geometric aspects of soft matter systems. The topics covered fall into three categories: (i) geometric frustrations, including the interplay of geometry and topological defects in two dimensional systems, and the frustration of a planar sheet attached to a curved surface; (ii) geometries of liquid droplets, including the curvature driven instabilities of toroidal liquid droplets and the self-propulsion of droplets on a spatially varying surface topography; (iii) the study of the electric double layer structure around charged spherical interfaces by a geometric method. In (i), we study the crystalline order on capillary bridges with varying Gaussian curvature. Energy requires the appearance of topological defects on the surface, which are natural spots for biological activity and chemical functionalization. We further study how liquid crystalline order deforms flexible structured vesicles. In particular we find faceted tetrahedral vesicle as the ground state, which may lead to the design of supra-molecular structures with tetrahedral symmetry and new classes of nano-carriers. Furthermore, by a simple paper model we explore the geometric frustration on a planar sheet when brought to a negative curvature surface in a designed elasto-capillary system. In (ii), motivated by the idea of realizing crystalline order on a stable toroidal droplet and a beautiful experiment on toroidal droplets, we study the Rayleigh instability and the shrinking instability of thin and fat toroidal droplets, where the toroidal geometry plays an essential role. In (iii), by a geometric mapping we construct an approximate analytic spherical solution to the nonlinear Poisson-Boltzmann equation, and identify the applicability regime of the solution. The derived geometric solution enables further analytical study of spherical electrostatic systems such as colloidal suspensions. Geometries in Soft Matter From Geometric Frustration, Liquid Droplets to Electrostatics in Solution
Stress-dependent activation of myosin in the heart requires thin filament activation and thick filament mechanosensing

Significance The efficiency of the heart as a pump depends on an autoregulatory mechanism, the Frank–Starling law of the heart, that potentiates the strength of contraction in response to an increase in ventricular filling. Disruption of this mechanism compromises the ability of the heart to pump blood, potentially leading to heart failure. We used fluorescent probes on myosin in heart muscle cells to investigate the molecular basis of the Frank–Starling mechanism. Our results show that the stronger contraction of heart muscle at longer lengths is due to a calcium-dependent interfilament signaling pathway that links stress sensing in the myosin-containing filaments with calcium activation of the actin-containing filaments. This pathway can potentially be targeted for treating heart failure. Myosin-based regulation in the heart muscle modulates the number of myosin motors available for interaction with calcium-regulated thin filaments, but the signaling pathways mediating the stronger contraction triggered by stretch between heartbeats or by phosphorylation of the myosin regulatory light chain (RLC) remain unclear. Here, we used RLC probes in demembranated cardiac trabeculae to investigate the molecular structural basis of these regulatory pathways. We show that in relaxed trabeculae at near-physiological temperature and filament lattice spacing, the RLC-lobe orientations are consistent with a subset of myosin motors being folded onto the filament surface in the interacting-heads motif seen in isolated filaments. The folded conformation of myosin is disrupted by cooling relaxed trabeculae, similar to the effect induced by maximal calcium activation. Stretch or increased RLC phosphorylation in the physiological range have almost no effect on RLC conformation at a calcium concentration corresponding to that between beats. These results indicate that in near-physiological conditions, the folded myosin motors are not directly switched on by RLC phosphorylation or by the titin-based passive tension at longer sarcomere lengths in the absence of thin filament activation. However, at the higher calcium concentrations that activate the thin filaments, stretch produces a delayed activation of folded myosin motors and force increase that is potentiated by RLC phosphorylation. We conclude that the increased contractility of the heart induced by RLC phosphorylation and stretch can be explained by a calcium-dependent interfilament signaling pathway involving both thin filament sensitization and thick filament mechanosensing.
Amber codon is genetically unstable in generation of premature termination codon (PTC)-harbouring Foot-and-mouth disease virus (FMDV) via genetic code expansion

ABSTRACT The foot-and-mouth disease virus (FMDV) is the causative agent of FMD, a highly infectious and devastating viral disease of domestic and wild cloven-hoofed animals. FMD affects livestock and animal products’ national and international trade, causing severe economic losses and social consequences. Currently, inactivated vaccines play a vital role in FMD control, but they have several limitations. The genetic code expansion technology provides powerful strategies for generating premature termination codon (PTC)-harbouring virus as a live but replication-incompetent viral vaccine. However, this technology has not been explored for the design and development of new FMD vaccines. In this study, we first expanded the genetic code of the FMDV genome via a transgenic cell line containing an orthogonal translation machinery. We demonstrated that the transgenic cells stably integrated the orthogonal pyltRNA/pylRS pair into the genome and enabled efficient, homogeneous incorporation of unnatural amino acids into target proteins in mammalian cells. Next, we constructed 129 single-PTC FMDV mutants and four dual-PTC FMDV mutants after considering the tolerance, location, and potential functions of those mutated sites. Amber stop codons individually substituted the selected amino acid codons in four viral proteins (3D, L, VP1, and VP4) of FMDV. We successfully rescued PTC-FMDV mutants, but the amber codon unexpectedly showed a highly degree of mutation rate during PTC-FMDV packaging and replication. Our findings highlight that the genetic code expansion technology for the generation of PTC-FMD vaccines needs to be further improved and that the genetic stability of amber codons during the packaging and replication of FMDV is a concern.
SS3D: Sequence similarity in 3D for comparison of protein families

Homologous proteins are often compared by pairwise sequence alignment, and structure superposition if the atomic coordinates are available. Unification of sequence and structure data is an important task in structural biology. Here, we present Sequence Similarity 3D (SS3D), a new method for integrating sequence and structure information for comparison of homologous proteins. SS3D quantifies the spatial similarity of residues within a given radius of homologous through-space contacts. The spatial alignments are scored using the well-known BLOSUM and PAM substitution matrices. In this work, we present the SS3D method, and demonstrate its utility through case studies comparing members of several protein families: GPCR, p53, kelch, SUMO, and SARS coronavirus spike protein. We show that SS3D can more clearly highlight biologically important regions of similarity and dissimilarity compared to pairwise sequence alignments or structure superposition alone. SS3D is written in C++, and is available with a manual and tutorial at https://github.com/0x462e41/SS3D/.
Real people or mere numbers? The influence of kill-save ratios and identifiability on moral judgements (¿Personas reales o meros números? La influencia de la proporción vidas sacrificadas/vidas salvadas y la identificabilidad en los juicios morales)

ABSTRACT In moral dilemmas, decision-making can be based on more utilitarian or deontological reasoning. In two experimental studies, we manipulated the number of people to be sacrificed (1 to save 5 vs. 3 to save 5) and whether personalizing information about them was presented. Results provide the first evidence of how the effects of kill-save ratios and identifiability of the potential victims are contingent on one another. Specifically, this research shows that when individuating information about the potential victims is present in a trolley dilemma, participants are more reluctant to sacrifice three persons to save five than to sacrifice one person to save five. When such individuating information is not present, the acceptability of sacrificing the victims does not depend on their number.
Variational-autoencoder-based Environment for Interactive Sketch Tutoring Aiming for Kids

Sketching is a type of artistic skills that most people can acquire during their childhood. In this paper, we present a web-based GUI environment which interactively teaches users how to sketch. Based on neural-network variational autoencoder (VAE), the environment uses generated strokes to guide users, however, the drawing quality cannot naively meet standards required for tutoring purposes. We conducted qualitative analysis, investigated the influence of latent variable on the drawing quality, and choose transformer as decoder. The proposed technique enhances the interactive drawing quality, and has the potential to build a sketch-tutoring software for young children.