c-FLIP facilitates ZIKV infection by mediating caspase-8/3-dependent apoptosis.

c-FLIP functions as a dual regulator of apoptosis and inflammation, yet its implications in Zika virus (ZIKV) infection remain partially understood, especially in the context of ZIKV-induced congenital Zika syndrome (CZS) where both apoptosis and inflammation play pivotal roles. Our findings demonstrate that c-FLIP promotes ZIKV infection in placental cells and myeloid-derived macrophages, involving inflammation and caspase-8/3-mediated apoptosis. Moreover, our observations reveal that c-FLIP augments ZIKV infection in multiple tissues, including blood cell, spleen, uterus, testis, and the brain of mice. Notably, the partial deficiency of c-FLIP provides protection to embryos against ZIKV-induced CZS, accompanied by a reduction in caspase-3-mediated apoptosis. Additionally, we have found a distinctive parental effect of c-FLIP influencing ZIKV replication in fetal heads. In summary, our study reveals the critical role of c-FLIP as a positive regulator in caspase-8/3-mediated apoptosis during ZIKV infection, significantly contributing to the development of CZS.

Microbiota-derived metabolite promotes HDAC3 activity in the gut.

The coevolution of mammalian hosts and their beneficial commensal microbes has led to development of symbiotic host-microbiota relationships1. Epigenetic machinery permits mammalian cells to integrate environmental signals2; however, how these pathways are fine-tuned by diverse cues from commensal bacteria is not well understood. Here we reveal a highly selective pathway through which microbiota-derived inositol phosphate regulates histone deacetylase 3 (HDAC3) activity in the intestine. Despite the abundant presence of HDAC inhibitors such as butyrate in the intestine, we found that HDAC3 activity was sharply increased in intestinal epithelial cells of microbiota-replete mice compared with germ-free mice. This divergence was reconciled by the finding that commensal bacteria, including Escherichia coli, stimulated HDAC activity through metabolism of phytate and production of inositol-1,4,5-trisphosphate (InsP3). Both intestinal exposure to InsP3 and phytate ingestion promoted recovery following intestinal damage. Of note, InsP3 also induced growth of intestinal organoids derived from human tissue, stimulated HDAC3-dependent proliferation and countered butyrate inhibition of colonic growth. Collectively, these results show that InsP3 is a microbiota-derived metabolite that activates a mammalian histone deacetylase to promote epithelial repair. Thus, HDAC3 represents a convergent epigenetic sensor of distinct metabolites that calibrates host responses to diverse microbial signals.

Shedding light on rechargeable Na/Cl2 battery.

Advancing new ideas of rechargeable batteries represents an important path to meeting the ever-increasing energy storage needs. Recently, we showed rechargeable sodium/chlorine (Na/Cl2) (or lithium/chlorine Li/Cl2) batteries that used a Na (or Li) metal negative electrode, a microporous amorphous carbon nanosphere (aCNS) positive electrode, and an electrolyte containing dissolved aluminum chloride and fluoride additives in thionyl chloride [G. Zhu et al., Nature 596, 525-530 (2021) and G. Zhu et al., J. Am. Chem. Soc. 144, 22505-22513 (2022)]. The main battery redox reaction involved conversion between NaCl and Cl2 trapped in the carbon positive electrode, delivering a cyclable capacity of up to 1,200 mAh g-1 (based on positive electrode mass) at a ~3.5 V discharge voltage [G. Zhu et al., Nature 596, 525-530 (2021) and G. Zhu et al., J. Am. Chem. Soc. 144, 22505-22513 (2022)]. Here, we identified by X-ray photoelectron spectroscopy (XPS) that upon charging a Na/Cl2 battery, chlorination of carbon in the positive electrode occurred to form carbon-chlorine (C-Cl) accompanied by molecular Cl2 infiltrating the porous aCNS, consistent with Cl2 probed by mass spectrometry. Synchrotron X-ray diffraction observed the development of graphitic ordering in the initially amorphous aCNS under battery charging when the carbon matrix was oxidized/chlorinated and infiltrated with Cl2. The C-Cl, Cl2 species and graphitic ordering were reversible upon discharge, accompanied by NaCl formation. The results revealed redox conversion between NaCl and Cl2, reversible graphitic ordering/amorphourization of carbon through battery charge/discharge, and probed trapped Cl2 in porous carbon by XPS.

COPII Sec23 proteins form isoform-specific endoplasmic reticulum exit sites with differential effects on polarized growth.

Coat Protein complex II (COPII), a coat protein complex that forms vesicles on the endoplasmic reticulum (ER), mediates trafficking to the Golgi. While metazoans have few genes encoding each COPII component, plants have expanded these gene families, leading to the hypothesis that plant COPII has functionally diversified. In the moss Physcomitrium (Physcomitrella) patens, the Sec23/24 gene families are each composed of seven genes. Silencing Sec23/24 revealed isoform-specific contributions to polarized growth, with the closely related Sec23D/E and Sec24C/D essential for protonemal development. Focusing on Sec23, we discovered that Sec23D/E mediate ER-to Golgi transport and are essential for tip growth, with Sec23D localizing to presumptive ER exit sites. In contrast, Sec23A, B, C, F, and G are dispensable and do not quantitatively affect ER-to-Golgi trafficking. However, Δsec23abcfg plants exhibited reduced secretion of plasma membrane cargo. Of the four highly expressed protonemal Sec23 genes, Sec23F/G are members of a divergent Sec23 clade specifically retained in land plants. Notably, Sec23G accumulates on ER-associated foci that are significantly larger, do not overlap with, and are independent of Sec23D. While Sec23D/E form ER exit sites and function as bona fide COPII components essential for tip-growing protonemata, Sec23G and the closely related Sec23F have likely functionally diversified, forming separate and independent ER exit sites and participating in Golgi-independent trafficking pathways.

A near-infrared fluorescent probe with a substantial Stokes shift designed for the detection and imaging of ß-galactosidase within living cells and animals.

ß-Galactosidase serves as a pivotal biomarker for both cancer and cellular aging. The advancement of fluorescent sensors for tracking ß-galactosidase activity is imperative in the realm of cancer diagnosis. We have designed a near-infrared fluorescent probe (PTA-gal) for the detection of ß-galactosidase in living systems with large Stokes shifts. PTA-gal exhibits remarkable sensitivity and selectivity in detecting ß-galactosidase, producing near-infrared fluorescent signals with a remarkably low detection limit (2.2 × 10-5 U/mL) and a high quantum yield (0.30). Moreover, PTA-gal demonstrates biocompatibility and can effectively detect ß-galactosidase in cancer cells as well as within living animals.

A mutation-sensitive, multiplexed and amplification-free detection of nucleic acids by stretching single-molecule tandem hairpin probes.

The detection of nucleic acid sequences in parallel with the discrimination of single nucleotide variations (SNVs) is critical for research and clinical applications. A few limitations make the detection technically challenging, such as too small variation in probe-hybridization energy caused by SNVs, the non-specific amplification of false nucleic acid fragments and the few options of dyes limited by spectral overlaps. To circumvent these limitations, we developed a single-molecule nucleic acid detection assay without amplification or fluorescence termed THREF (hybridization-induced tandem DNA hairpin refolding failure) based on multiplexed magnetic tweezers. THREF can detect DNA and RNA sequences at femtomolar concentrations within 30 min, monitor multiple probes in parallel, quantify the expression level of miR-122 in patient tissues, discriminate SNVs including the hard-to-detect G-U or T-G wobble mutations and reuse the probes to save the cost. In our demonstrative detections using mock clinic samples, we profiled the let-7 family microRNAs in serum and genotyped SARS-CoV-2 strains in saliva. Overall, the THREF assay can discriminate SNVs with the advantages of high sensitivity, ultra-specificity, multiplexing, reusability, sample hands-free and robustness.

Exchange Bias Induced by the Spin-Glass-Like State in a Te-Rich FeGeTe van der Waals Ferromagnet.

We have experimentally investigated the mechanism of the exchange bias in 2D van der Waals (vdW) ferromagnets by means of the anomalous Hall effect (AHE) together with the dynamical magnetization property. The temperature dependence of the AC susceptibility with its frequency response indicates a glassy transition of the magnetic property for the Te-rich FeGeTe vdW ferromagnet. We also found that the irreversible temperature dependence in the anomalous Hall voltage follows the de Almeida-Thouless line. Moreover, the freezing temperature of the spin-glass-like phase is found to correlate with the disappearance temperature of the exchange bias. These important signatures suggest that the emergence of magnetic exchange bias in the 2D van der Waals ferromagnets is induced by the presence of the spin-glass-like state in FeGeTe. The unprecedented insights gained from these findings shed light on the underlying principles governing exchange bias in vdW ferromagnets, contributing to the advancement of our understanding.

Extracellular Vesicle ASC: A Novel Mediator for Lung-Brain Axis in Preterm Brain Injury.

Bronchopulmonary dysplasia (BPD) and neurodevelopmental impairment (NDI) are among the most common morbidities affecting preterm infants. Although BPD is a predictor of poor NDI, it is currently uncertain how BPD contributes to brain injury in preterm infants. Extracellular vesicles (EVs) are involved in inter-organ communication in diverse pathological processes. Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is pivotal in inflammasome assembly and activation of inflammatory response. We assessed expression profiles of alveolar macrophage (AM) markers, CD11b, CD11c, and CD206, and ASC in EVs isolated from the plasma of preterm infants at risk for BPD at 1 week of age. We found that infants on higher fraction inspired oxygen (FiO2) therapy (HO2, ≥30%) had increased levels of AM-derived EV-ASC compared with infants on lower FiO2 (LO2, <30%). To assess the function of these EVs, we performed adoptive transfer experiments by injecting them into the circulation of newborn mice. We discovered that mice that received EVs from infants on HO2 had increased lung inflammation, decreased alveolarization, and disrupted vascular development, the hallmarks of BPD. Importantly, these EVs crossed the blood-brain barrier and the EVs from infants on HO2 caused inflammation, reduced cell survival, and increased cell death with features of pyroptosis and necroptosis in the hippocampus. These results highlight a novel role for AM-derived EV-ASC in mediating the lung-to-brain crosstalk that is critical in the pathogenesis of BPD and brain injury and identify potential novel targets for preventing and treating BPD and brain injury in preterm infants.

Polar Crystals Using Molecular Chirality: Pseudosymmetric Crystallization toward Polarization Switching Materials.

Polar compounds with switchable polarization properties are applicable in various devices such as ferroelectric memory and pyroelectric sensors. However, a strategy to prepare polar compounds has not been established. We report a rational synthesis of a polar CoGa crystal using chiral cth ligands (SS-cth and RR-cth, cth = 5,7,7,12,14,14-hexamethyl-1,4,8,11-tetraazacyclotetradecane). Both the original homo metal Co crystal and Ga crystal exhibit a centrosymmetric isostructure, where the dipole moment of metal complexes with the SS-cth ligand and those with the RR-cth ligand are canceled out. To obtain a polar compound, the Co valence tautomeric complex with SS-cth in the homo metal Co crystal is replaced with the Ga complex with SS-cth by mixing Co valence tautomeric complexes with RR-cth and Ga complexes with SS-cth. The CoGa crystal exhibits polarization switching between the pseudononpolar state at a low temperature and the polar state at a high temperature because only Co complexes exhibit changes in electric dipole moment due to metal-to-ligand charge transfer. Following the same strategy, the polarization-switchable CoZn complex was synthesized. The CoZn crystal exhibits polarization switching between the polar state at a low temperature and the pseudononpolar state at a high temperature, which is the opposite temperature dependence to that of the CoGa crystal. These results revealed that the polar crystal can be synthesized by design, using a chiral ligand. Moreover, our method allows for the control of temperature-dependent polarization changes, which contrasts with typical ferroelectric compounds, in which the polar ferroelectric phase typically occurs at low temperatures.

Electrically Detectable Photoinduced Polarization Switching in a Molecular Prussian Blue Analogue.

Light, a nondestructive and remotely controllable external stimulus, effectively triggers a variety of electron-transfer phenomena in metal complexes. One prime example includes using light in molecular cyanide-bridged [FeCo] bimetallic Prussian blue analogues, where it switches the system between the electron-transferred metastable state and the system's ground state. If this process is coupled to a ferroelectric-type phase transition, the generation and disappearance of macroscopic polarization, entirely under light control, become possible. In this research, we successfully executed a nonpolar-to-polar phase transition in a trinuclear cyanide-bridged [Fe2Co] complex crystal via directional electron transfer. Intriguingly, by exposing the crystal to the wavelength of light─785 nm─without any electric field─we can drive this ferroelectric phase transition to completely depolarize the crystal, during which a measurable electric current response can be detected. These discoveries signify an important step toward the realization of fully light-controlled ferroelectric memory devices.

Two-Dimensional Spin-Crossover Molecular Solid Solutions with Tunable Transition Temperatures across 90 K.

Spin-crossover (SCO) materials exhibit remarkable potential as bistable switches in molecular devices. However, the spin transition temperatures (Tc) of known compounds are unable to cover the entire ambient temperature spectrum, largely limiting their practical utility. This study reports an exemplary two-dimensional SCO solid solution system, [FeIII(H0.5LCl)2-2x(H0.5LF)2x]·H2O (H0.5LX = 5-X-2-hydroxybenzylidene-hydrazinecarbothioamide, X = F or Cl, x = 0 to 1), in which the adjacent layers are adhered via hydrogen bonding. Notably, the Tc of this system can be fine-tuned across 90 K (227-316 K) in a linear manner by modulating the fraction x of the LF ligand. Elevating x results in strengthened hydrogen bonding between adjacent layers, which leads to enhanced intermolecular interactions between adjacent SCO molecules. Single-crystal diffraction analysis and periodic density functional theory calculations revealed that such a special kind of alteration in interlayer interactions strengthens the FeIIIN2O2S2 ligand field and corresponding SCO energy barrier, consequently resulting in increased Tc. This work provides a new pathway for tuning the Tc of SCO materials through delicate manipulation of molecular interactions, which could expand the application of bistable molecular solids to a much wider temperature regime.

Increased Apolipoprotein A1 Expression Correlates with Tumor-Associated Neutrophils and T Lymphocytes in Upper Tract Urothelial Carcinoma.

An increased neutrophil-to-lymphocyte ratio (NLR) is a poor prognostic biomarker in various types of cancer, because it reflects the inhibition of lymphocytes in the circulation and tumors. In urologic cancers, upper tract urothelial carcinoma (UTUC) is known for its aggressive features and lack of T cell infiltration; however, the association between neutrophils and suppressed T lymphocytes in UTUC is largely unknown. In this study, we examined the relationship between UTUC-derived factors and tumor-associated neutrophils or T lymphocytes. The culture supernatant from UTUC tumor tissue modulated neutrophils to inhibit T cell proliferation. Among the dominant factors secreted by UTUC tumor tissue, apolipoprotein A1 (Apo-A1) exhibited a positive correlation with NLR. Moreover, tumor-infiltrating neutrophils were inversely correlated with tumor-infiltrating T cells. Elevated Apo-A1 levels in UTUC were also inversely associated with the population of tumor-infiltrating T cells. Our findings indicate that elevated Apo-A1 expression in UTUC correlates with tumor-associated neutrophils and T cells. This suggests a potential immunomodulatory effect on neutrophils and T cells within the tumor microenvironment, which may represent therapeutic targets for UTUC treatment.

IC100, a humanized therapeutic monoclonal anti-ASC antibody alleviates oxygen-induced retinopathy in mice.

BACKGROUND: Retinopathy of prematurity (ROP), which often presents with bronchopulmonary dysplasia (BPD), is among the most common morbidities affecting extremely premature infants and is a leading cause of severe vision impairment in children worldwide. Activations of the inflammasome cascade and microglia have been implicated in playing a role in the development of both ROP and BPD. Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is pivotal in inflammasome assembly. Utilizing mouse models of both oxygen-induced retinopathy (OIR) and BPD, this study was designed to test the hypothesis that hyperoxia induces ASC speck formation, which leads to microglial activation and retinopathy, and that inhibition of ASC speck formation by a humanized monoclonal antibody, IC100, directed against ASC, will ameliorate microglial activation and abnormal retinal vascular formation. METHODS: We first tested ASC speck formation in the retina of ASC-citrine reporter mice expressing ASC fusion protein with a C-terminal citrine (fluorescent GFP isoform) using a BPD model that causes both lung and eye injury by exposing newborn mice to room air (RA) or 85% O2 from postnatal day (P) 1 to P14. The retinas were dissected on P14 and retinal flat mounts were used to detect vascular endothelium with AF-594-conjugated isolectin B4 (IB4) and citrine-tagged ASC specks. To assess the effects of IC100 on an OIR model, newborn ASC citrine reporter mice and wildtype mice (C57BL/6 J) were exposed to RA from P1 to P6, then 75% O2 from P7 to P11, and then to RA from P12 to P18. At P12 mice were randomized to the following groups: RA with placebo PBS (RA-PBS), O2 with PBS (O2-PBS), O2 + IC100 intravitreal injection (O2-IC100-IVT), and O2 + IC100 intraperitoneal injection (O2-IC100-IP). Retinal vascularization was evaluated by flat mount staining with IB4. Microglial activation was detected by immunofluorescence staining for allograft inflammatory factor 1 (AIF-1) and CD206. Retinal structure was analyzed on H&E-stained sections, and function was analyzed by pattern electroretinography (PERG). RNA-sequencing (RNA-seq) of the retinas was performed to determine the transcriptional effects of IC100 treatment in OIR. RESULTS: ASC specks were significantly increased in the retinas by hyperoxia exposure and colocalized with the abnormal vasculature in both BPD and OIR models, and this was associated with increased microglial activation. Treatment with IC100-IVT or IC100-IP significantly reduced vaso-obliteration and intravitreal neovascularization. IC100-IVT treatment also reduced retinal microglial activation, restored retinal structure, and improved retinal function. RNA-seq showed that IC100 treatment corrected the induction of genes associated with angiogenesis, leukocyte migration, and VEGF signaling caused by O2. IC100 also corrected the suppression of genes associated with cell junction assembly, neuron projection, and neuron recognition caused by O2. CONCLUSION: These data demonstrate the crucial role of ASC in the pathogenesis of OIR and the efficacy of a humanized therapeutic anti-ASC antibody in treating OIR mice. Thus, this anti-ASC antibody may potentially be considered in diseases associated with oxygen stresses and retinopathy, such as ROP.

Chorioamnionitis accelerates granule cell and oligodendrocyte maturation in the cerebellum of preterm nonhuman primates.

BACKGROUND: Preterm birth is often associated with chorioamnionitis and leads to increased risk of neurodevelopmental disorders, such as autism. Preterm birth can lead to cerebellar underdevelopment, but the mechanisms of disrupted cerebellar development in preterm infants are not well understood. The cerebellum is consistently affected in people with autism spectrum disorders, showing reduction of Purkinje cells, decreased cerebellar grey matter, and altered connectivity. METHODS: Preterm rhesus macaque fetuses were exposed to intra-amniotic LPS (1 mg, E. coli O55:B5) at 127 days (80%) gestation and delivered by c-section 5 days after injections. Maternal and fetal plasma were sampled for cytokine measurements. Chorio-decidua was analyzed for immune cell populations by flow cytometry. Fetal cerebellum was sampled for histology and molecular analysis by single-nuclei RNA-sequencing (snRNA-seq) on a 10× chromium platform. snRNA-seq data were analyzed for differences in cell populations, cell-type specific gene expression, and inferred cellular communications. RESULTS: We leveraged snRNA-seq of the cerebellum in a clinically relevant rhesus macaque model of chorioamnionitis and preterm birth, to show that chorioamnionitis leads to Purkinje cell loss and disrupted maturation of granule cells and oligodendrocytes in the fetal cerebellum at late gestation. Purkinje cell loss is accompanied by decreased sonic hedgehog signaling from Purkinje cells to granule cells, which show an accelerated maturation, and to oligodendrocytes, which show accelerated maturation from pre-oligodendrocytes into myelinating oligodendrocytes. CONCLUSION: These findings suggest a role of chorioamnionitis on disrupted cerebellar maturation associated with preterm birth and on the pathogenesis of neurodevelopmental disorders among preterm infants.

The associates of anxiety among lung cancer patients: Dehydroepiandrosterone (DHEA) as a potential biomarker.

OBJECTIVE: Anxiety is a prevalent comorbidity in lung cancer (LC) patients associated with a decline in quality of life. Dehydroepiandrosterone (DHEA), a neuroactive steroid, levels rise in response to stress. Prior research on the association between DHEA and anxiety has yielded contradictory results and no study has investigated this association in LC patients. METHODS: A total of 213 patients with LC were recruited from a general hospital. Data on demographic and cancer-related variables were collected. Using the Chinese version of the Hospital Anxiety and Depression Scale (HADS), the degree of anxiety was determined. Cortisol, DHEA, and Dehydroepiandrosterone sulfate (DHEA-S) levels in saliva were measured. Adjusting for confounding variables, a multivariate regression analysis was conducted. RESULTS: 147 men and 66 women comprised our group with an average age of 63.75 years. After accounting for demographic and treatment-related factors, anxiety levels were significantly correlated with, post-traumatic stress symptoms (PTSSs) (ß = 0.332, p < 0.001) and fatigue (ß = 0.247, p = 0.02). Association between anxiety and three factors, including DHEA, PTSSs, and fatigue, was observed in patients with advanced cancer stages (III and IV) (DHEA ß = 0.319, p = 0.004; PTSS ß = 0.396, p = 0.001; fatigue ß = 0.289, p = 0.027) and those undergoing chemotherapy (DHEA ß = 0.346, p = 0.001; PTSS ß = 0.407, p = 0.001; fatigue ß = 0.326, p = 0.011). CONCLUSIONS: The association between anxiety and DHEA remained positive in advanced cancer stages and chemotherapy patients. Further study is necessary to determine whether DHEA is a potential biomarker of anxiety in LC patients.

Fabrication of Luminescent Triple-Cross-Linked Gelatin/Alginate Hydrogels through Freezing-Drying-Swelling and Freezing-Thawing Processes.

Lanthanide-containing luminescent hydrogels have shown potential for sensing and imaging applications. Nonetheless, integrating lanthanide ions or complexes into the polymer matrix often results in the poor stability and mechanical strength of the hydrogels. This work presents an innovative approach to fabricating luminescent hydrogels with three dynamic cross-links: imine bond, boronate ester bond, and metal-ligand coordination. Europium(III) (Eu3+) ions are incorporated into a dual-cross-linked matrix composed of phenylboronic acid-polyethylenimine-modified gelatin (PPG) and alginate dialdehyde (ADA) through a combined treatment involving freeze-drying-swelling (FDS) and freeze-thawing (FT) processes. The FDS process facilitates the formation of additional europium-carboxylate cross-links within the polymeric network to enhance its luminescence and stability, while the FT process strengthens the network physically. The impact of the FDS-FT cycle number on the microstructures and properties of PPG/ADA-Eu3+ hydrogels is thoroughly investigated, and their potential for monitoring bacterial growth and detecting copper(II) ions is also demonstrated.

Prognostic factors of intravesical recurrence after radical nephroureterectomy for upper tract urothelial carcinoma.

PURPOSE: To evaluate predictive factors of increasing intravesical recurrence (IVR) rate in patients with upper tract urothelial carcinoma (UTUC) after receiving radical nephroureterectomy (RNUx) with bladder cuff excision (BCE). MATERIALS AND METHODS: A total of 2114 patients were included from the updated data of the Taiwan UTUC Collaboration Group. It was divided into two groups: IVR-free and IVR after RNUx, with 1527 and 587 patients, respectively. To determine the factors affecting IVR, TNM stage, the usage of pre-operative ureteroscopy, and pathological outcomes were evaluated. The Kaplan-Meier estimator was used to estimate the rates of prognostic outcomes in overall survival (OS), cancer-specific survival (CSS), disease-free survival (DFS), and bladder recurrence-free survival (BRFS), and the survival curves were compared using the stratified log-rank test. RESULTS: Based on our research, ureter tumor, female, smoking history, age (< 70 years old), multifocal tumor, history of bladder cancer were determined to increase the risk of IVR after univariate analysis. The multivariable analysis revealed that female (BRFS for male: HR 0.566, 95% CI 0.469-0.681, p < 0.001), ureter tumor (BRFS: HR 1.359, 95% CI 1.133-1.631, p = 0.001), multifocal (BRFS: HR 1.200, 95% CI 1.001-1.439, p = 0.049), history of bladder cancer (BRFS: HR 1.480, 95% CI 1.118-1.959, p = 0.006) were the prognostic factors for IVR. Patients who ever received ureterorenoscopy (URS) did not increase the risk of IVR. CONCLUSION: Patients with ureter tumor and previous bladder UC history are important factors to increase the risk of IVR after RNUx. Pre-operative URS manipulation is not associated with higher risk of IVR and diagnostic URS is feasible especially for insufficient information of image study. More frequent surveillance regimen may be needed for these patients.

Molecular Contrastive Pretraining with Collaborative Featurizations.

Molecular pretraining, which learns molecular representations over massive unlabeled data, has become a prominent paradigm to solve a variety of tasks in computational chemistry and drug discovery. Recently, prosperous progress has been made in molecular pretraining with different molecular featurizations, including 1D SMILES strings, 2D graphs, and 3D geometries. However, the role of molecular featurizations with their corresponding neural architectures in molecular pretraining remains largely unexamined. In this paper, through two case studies─chirality classification and aromatic ring counting─we first demonstrate that different featurization techniques convey chemical information differently. In light of this observation, we propose a simple and effective MOlecular pretraining framework with COllaborative featurizations (MOCO). MOCO comprehensively leverages multiple featurizations that complement each other and outperforms existing state-of-the-art models that solely rely on one or two featurizations on a wide range of molecular property prediction tasks.

Measurements of the gravitational constant using two independent methods.

The Newtonian gravitational constant, G, is one of the most fundamental constants of nature, but we still do not have an accurate value for it. Despite two centuries of experimental effort, the value of G remains the least precisely known of the fundamental constants. A discrepancy of up to 0.05 per cent in recent determinations of G suggests that there may be undiscovered systematic errors in the various existing methods. One way to resolve this issue is to measure G using a number of methods that are unlikely to involve the same systematic effects. Here we report two independent determinations of G using torsion pendulum experiments with the time-of-swing method and the angular-acceleration-feedback method. We obtain G values of 6.674184 × 10-11 and 6.674484 × 10-11 cubic metres per kilogram per second squared, with relative standard uncertainties of 11.64 and 11.61 parts per million, respectively. These values have the smallest uncertainties reported until now, and both agree with the latest recommended value within two standard deviations.

Sphingosylphosphorylcholine alleviates pressure overload-induced myocardial remodeling in mice via inhibiting CaM-JNK/p38 signaling pathway.

Apoptosis plays a critical role in the development of heart failure, and sphingosylphosphorylcholine (SPC) is a bioactive sphingolipid naturally occurring in blood plasma. Some studies have shown that SPC inhibits hypoxia-induced apoptosis in myofibroblasts, the crucial non-muscle cells in the heart. Calmodulin (CaM) is a known SPC receptor. In this study we investigated the role of CaM in cardiomyocyte apoptosis in heart failure and the associated signaling pathways. Pressure overload was induced in mice by trans-aortic constriction (TAC) surgery. TAC mice were administered SPC (10 µM·kg-1·d-1) for 4 weeks post-surgery. We showed that SPC administration significantly improved survival rate and cardiac hypertrophy, and inhibited cardiac fibrosis in TAC mice. In neonatal mouse cardiomyocytes, treatment with SPC (10 µM) significantly inhibited Ang II-induced cardiomyocyte hypertrophy, fibroblast-to-myofibroblast transition and cell apoptosis accompanied by reduced Bax and phosphorylation levels of CaM, JNK and p38, as well as upregulated Bcl-2, a cardiomyocyte-protective protein. Thapsigargin (TG) could enhance CaM functions by increasing Ca2+ levels in cytoplasm. TG (3 µM) annulled the protective effect of SPC against Ang II-induced cardiomyocyte apoptosis. Furthermore, we demonstrated that SPC-mediated inhibition of cardiomyocyte apoptosis involved the regulation of p38 and JNK phosphorylation, which was downstream of CaM. These results offer new evidence for SPC regulation of cardiomyocyte apoptosis, potentially providing a new therapeutic target for cardiac remodeling following stress overload.