Efficacy, tolerability, and safety of the oral phosphate binder VS-505 (AP301).

BACKGROUND: VS-505 (AP301), an acacia and ferric oxyhydroxide polymer, is a novel fiber-iron-based phosphate binder. This two-part phase 2 study evaluated the tolerability, safety, and efficacy of oral VS-505 administered three times daily with meals in treating hyperphosphatemia in chronic kidney disease (CKD) patients receiving maintenance hemodialysis (MHD). METHODS: In Part 1, patients received dose-escalated treatment with VS-505 2.25, 4.50, and 9.00 g/day for 2 weeks each, guided by serum phosphorus levels. In Part 2, patients received randomized, open-label, fixed-dosage treatment with VS-505 (1.50, 2.25, 4.50, or 6.75 g/day) or sevelamer carbonate 4.80 g/day for 6 weeks. The primary efficacy endpoint was the change in serum phosphorus. RESULTS: The study enrolled 158 patients (Part 1: 25; Part 2: 133), with 130 exposed to VS-505 in total. VS-505 was well tolerated. The most common adverse events were gastrointestinal disorders, mainly feces discolored (56%) and diarrhea (15%; generally during weeks 1‒2 of treatment). Most gastrointestinal disorders resolved without intervention, and none were serious. In Part 1, serum phosphorus significantly improved (mean change -2.0 mg/dL; 95% confidence interval -2.7, -1.4) after VS-505 dose escalation. In Part 2, serum phosphorus significantly and dose-dependently improved in all VS-505 arms, with clinically meaningful reductions with VS-505 4.50 and 6.75 g/day, and sevelamer carbonate 4.80 g/day (mean change -1.6 (-2.2, -1.0), -1.8 (-2.4, -1.2), and -1.4 (-2.2, -0.5) mg/dL, respectively). In both Parts, serum phosphorus reductions occurred within 1 week of VS-505 initiation, returning to baseline within 2 weeks of VS-505 discontinuation. CONCLUSION: VS-505, a novel phosphate binder, was well tolerated with a manageable safety profile, and effectively and dose-dependently reduced serum phosphorus in CKD patients with hyperphosphatemia receiving MHD. Clinical Trial registration number: NCT04551300.

Multiple-microarray analysis for identification of key genes involved in diabetic nephropathy.

The purpose of our study was to discover genes with significantly aberrant expression in diabetic nephropathy (DN) and to determine their potential mechanism. We acquired renal tubules, glomerulus and blood samples data from DN patients and controls from the GEO database. The differentially expressed genes (DEGs) in renal tubules, glomerulus and blood samples between DN patients and controls were studied. Based on these DEGs, we carried out the functional annotation and constructed protein-protein interaction (PPI) network. By comparing DN patients and controls of DEGs, we acquired the shared DGEs in renal tubules, glomerulus and blood samples of DN patients and controls. DN patients compared to controls, we obtained 3000 DEGs, 3064 DEGs, and 2296 DEGs in renal tubules, glomerulus and blood samples, respectively. The PPI networks of top 40 DEGs in renal tubules, glomerulus and blood samples was consisted of 229 nodes and 229 edges, 540 nodes and 606 edges, and 132 nodes and 124 edges, respectively. In total, 21 shared genes were finally found, including CASP3, DHCR24, CXCL1, GYPC, INHBA, LTF, MT1G, MUC1, NINJ1, PFKFB3, PPP1R3C, CCL5, SRSF7, PHLDA2, RBM39, WTAP, BASP1, PLK2, PDK2, PNPLA4, and SNED1. These genes may be associated with the DN process. Our study provides a basis to explore the potential mechanism and identify novel therapeutic targets for DN.

Glutamate-pantothenate pathway promotes antibiotic resistance of Edwardsiella tarda.

Although cellular metabolic states have been shown to modulate bacterial susceptibility to antibiotics, the interaction between glutamate (Glu) and chloramphenicol (CAP) resistance remains unclear because of the specificity of antibiotics and bacteria. We found that the level of Glu was upregulated in the CAP-resistant strain of Edwardsiella tarda according to a comparative metabolomics approach based on LC-MS/MS. Furthermore, we verified that exogenous metabolites related to Glu, the tricarboxylic acid (TCA) cycle, and glutathione (GSH) metabolism could promote CAP resistance in survival assays. If GSH metabolism or the TCA cycle is inhibited by L-buthionine sulfoximine or propanedioic acid, the promotion of CAP resistance by Glu in the corresponding pathway disappears. According to metabolomic analysis, exogenous Glu could change pantothenate metabolism, affecting GSH biosynthesis and the TCA cycle. These results showed that the glutamate-pantothenate pathway could promote CAP resistance by being involved in the synthesis of GSH, entering the TCA cycle by direct deamination, or indirectly affecting the metabolism of the two pathways by pantothenate. These results extend our knowledge of the effect of Glu on antibiotic resistance and suggest that the potential effect, which may aggravate antibiotic resistance, should be considered before Glu and GSH administration in the clinic.

Sub-pm linewidth, high pulse energy, high beam quality microsecond-pulse Ti:sapphire laser at 766.699†nm.

In this letter, a sub-pm linewidth, high pulse energy and high beam quality microsecond-pulse 766.699 nm Ti:sapphire laser pumped by a frequency-doubled Nd:YAG laser is demonstrated. At an incident pump energy of 824 mJ, the maximum output energy of 132.5 mJ at 766.699 nm with linewidth of 0.66 pm and a pulse width of 100 µs is achieved at a repetition rate of 5 Hz. To the best of our knowledge, this is the highest pulse energy at 766.699 nm with pulse width of hundred micro-seconds for a Ti:sapphire laser. The beam quality factor M2 is measured to be 1.21. It could be precisely tuned from 766.623 to 766.755 nm with a tuning resolution of 0.8 pm. The wavelength stability is measured to be less than ±0.7 pm over 30 min. The sub-pm linewidth, high pulse energy and high beam quality Ti:sapphire laser at 766.699 nm can be used to create a polychromatic laser guide star together with a home-made 589 nm laser in the mesospheric sodium and potassium layer for the tip-tilt correction resulting in the near-diffraction limited imagery on a large telescope.

Efficacy and Safety of Sevelamer Carbonate in Chinese Nondialysis Chronic Kidney Disease Patients with Hyperphosphatemia: A Randomized, Double-Blind, Parallel-Group Study.

Introduction: Previous studies suggested that sevelamer carbonate is well tolerated with a favorable efficacy and safety profile in both dialysis and nondialysis patients in Europe; however, the efficacy remains controversial, and few studies have examined sevelamer carbonate therapy in other ethnic nondialysis CKD patients. This study assessed the efficacy and safety of sevelamer carbonate in Chinese nondialysis CKD patients with hyperphosphatemia. Methods: The multicenter, randomized, double-blind, parallel-group, placebo-controlled, and phase 3 clinical trial enrolled 202 Chinese nondialysis CKD patients with serum phosphorus ≥1.78 mmol/L. Patients were randomly assigned 1:1 to receive sevelamer carbonate (2.4-12 g per day) or placebo for 8 weeks. The primary outcome was the change in serum phosphorous between baseline and week 8. Results: Totally 482 Chinese patients were screened and 202 were randomized (sevelamer carbonate, n = 101; placebo, n = 101). The mean serum phosphorous decreased significantly in patients treated with sevelamer carbonate compared with placebo (-0.22 ± 0.47 vs. 0.05 ± 0.44 mmol/L, p < 0.0001). Significantly (p < 0.0001), decreases of serum total cholesterol, low-density lipoprotein cholesterol, and calcium-phosphorus (Ca × P) product levels from baseline to week 8 were shown in sevelamer carbonate group compared with placebo group. Serum intact parathyroid hormone was not significantly changed in the sevelamer carbonate group (p = 0.83). Patients in the sevelamer carbonate group experienced similar adverse events as the placebo group. Conclusion: Sevelamer carbonate is an effective and well-tolerated phosphate binder in advanced nondialysis CKD Chinese patients with hyperphosphatemia.

Evaluation of safety, effectiveness and treatment patterns of sodium zirconium cyclosilicate in management of hyperkalaemia in China: a real-world study protocol.

INTRODUCTION: Hyperkalaemia (HK) is a potentially life-threatening electrolyte imbalance associated with several adverse clinical outcomes. The efficacy and negative effects of currently existing treatment options have made HK management questionable. Sodium zirconium cyclosilicate (SZC), a novel highly selective potassium binder, is approved for the treatment of HK. The present study will be aimed to assess the safety, effectiveness and treatment patterns of SZC in Chinese patients with HK in a real-world clinical setting as it is required by China's drug review and approval process. METHODS AND ANALYSIS: This is a multicentre, prospective cohort study which plans to enrol 1000 patients taking SZC or willing to take SZC from approximately 40 sites in China. Patients ≥18 years of age at the time of signing the written informed consent and with documented serum potassium levels ≥5.0 mmol/L within 1 year before study enrolment day will be included. Eligible patients will receive SZC treatment and will be followed up for 6 months from enrolment day. The primary objective will be to evaluate the safety of SZC for the management of HK in Chinese patients in terms of adverse events (AEs), serious AEs as well as discontinuation of SZC. The secondary objectives will include understanding the SZC dosage information in terms of its effectiveness and treatment patterns under real-world clinical practice and assessing effectiveness of SZC during the observational period. ETHICS AND DISSEMINATION: This study protocol was approved by the Ethics Committee of the First Affiliated Hospital of Dalian Medical University (approval number: YJ-JG-YW-2020). All the participating sites have received the ethics approval. Results will be disseminated through national and international presentations and peer-reviewed publications. TRIAL REGISTRATION NUMBER: NCT05271266.

Revisiting the mechanisms of mid-Tertiary uplift of the NE Tibetan Plateau.

Contrasting views exist on timing and mechanisms of Tertiary crustal uplift in the NE Tibetan Plateau based on different approaches, with many models attributing surface uplift to crustal shortening. We carry out a comprehensive investigation of mid-Tertiary stratigraphy, sedimentology, and volcanism in the West Qinling, Hoh Xil and Qaidam basin, and the results challenge previous views. It was held that the discordance between Oligocene and Miocene strata is an angular unconformity in the West Qinling, but our field observations show that it is actually a disconformity, indicative of vertical crustal uplifting rather than crustal shortening at the Oligocene to Miocene transition. Widespread occurrence of synsedimentary normal faults in mid-Tertiary successions implicates supracrustal stretching. Miocene potassic-ultrapassic and mafic-ultramafic volcanics in the Hoh Xil and West Qinling suggest a crucial role of deep thermomechanical processes in generating crust- and mantle-sourced magmatism. Also noticeable are the continuity of mid-Tertiary successions and absence of volcanics in the Qaidam basin. Based on a holistic assessment of stratigraphic-sedimentary processes, volcanic petrogenesis, and spatial variations of lithospheric thicknesses, we speculate that small-sale mantle convection might have been operating beneath northeast Tibet in the mid-Tertiary. It is assumed that northward asthenospheric flow was impeded by thicker cratonic lithosphere of the Qaidam and Alxa blocks, thereby leading to edge convection. The edge-driven convection could bring about surface uplift, induce supracrustal stretching, and trigger vigorous volcanism in the Hoh Xil and West Qinling in the mid-Tertiary period. This mechanism satisfactorily explains many key geologic phenomena that are hardly reconciled by previous models.

Deep Encrypted Traffic Detection: An Anomaly Detection Framework for Encryption Traffic Based on Parallel Automatic Feature Extraction.

With an increasing number of network attacks using encrypted communication, the anomaly detection of encryption traffic is of great importance to ensure reliable network operation. However, the existing feature extraction methods for encrypted traffic anomaly detection have difficulties in extracting features, resulting in their low efficiency. In this paper, we propose a framework of encrypted traffic anomaly detection based on parallel automatic feature extraction, called deep encrypted traffic detection (DETD). The proposed DETD uses a parallel small-scale multilayer stack autoencoder to extract local traffic features from encrypted traffic and then adopts an L1 regularization-based feature selection algorithm to select the most representative feature set for the final encrypted traffic anomaly detection task. The experimental results show that DETD has promising robustness in feature extraction, i.e., the feature extraction efficiency of DETD is 66% higher than that of the conventional stacked autoencoder, and the anomaly detection performance is as high as 99.998%, and thus DETD outperforms the deep full-range framework and other neural network anomaly detection algorithms.

Polyacrylic Acid/Polyaniline-Coated Multimode Interferometer for Ammonia Detection.

A coaxial optical fiber interferometer (COFI) is proposed here for ammonia sensing, which comprises two light-carrying single-mode fibers (SMF) fused to a section of no-core fiber (NCF), thus forming an optical interferometer. The outer surface of the COFI is coated with a layer of polyacrylic acid (PAA)/polyaniline (PAni) film. The refractive index (RI) of the sensitive layer varies when PAA/PAni interacts with ammonia, which leads to the resonance wavelength shift. The surface morphology and structure of the PAA/PAni composites were characterized by using a scanning electron microscope (SEM) and Fourier-transform infrared (FTIR) spectroscopy. When the sensor was exposed to an ammonia atmosphere of different concentrations at room temperature, the sensing performance of the PAA/PAni composite film was superior to that of a sensitive film formed by single-component PAA or PAni. According to the experimental results, the composite film formed by 5 wt% PAA mixed with 2 wt% PAni shows better performance when used for ammonia sensing. A maximum sensitivity of 9.8 pm/ppm was obtained under the ammonia concentration of 50 ppm. In addition, the sensor shows good performance in response time (100 s) and recovery time (180 s) and has good stability and selectivity. The proposed optical fiber ammonia sensor is adapted to monitor leakage in its production, storage, transportation, and application.

Extracellular vesicles from Zika virus-infected cells display viral E protein that binds ZIKV-neutralizing antibodies to prevent infection enhancement.

Mosquito-borne flaviviruses including Zika virus (ZIKV) represent a public health problem in some parts of the world. Although ZIKV infection is predominantly asymptomatic or associated with mild symptoms, it can lead to neurological complications. ZIKV infection can also cause antibody-dependent enhancement (ADE) of infection with similar viruses, warranting further studies of virion assembly and the function of envelope (E) protein-specific antibodies. Although extracellular vesicles (EVs) from flavivirus-infected cells have been reported to transmit infection, this interpretation is challenged by difficulties in separating EVs from flavivirions due to their similar biochemical composition and biophysical properties. In the present study, a rigorous EV-virion separation method combining sequential ultracentrifugation and affinity capture was developed to study EVs from ZIKV-infected cells. We find that these EVs do not transmit infection, but EVs display abundant E proteins which have an antigenic landscape similar to that of virions carrying E. ZIKV E-coated EVs attenuate antibody-dependent enhancement mediated by ZIKV E-specific and DENV-cross-reactive antibodies in both cell culture and mouse models. We thus report an alternative route for Flavivirus E protein secretion. These results suggest that modulation of E protein release via virions and EVs may present a new approach to regulating flavivirus-host interactions.

Interannual and seasonal relationships between photosynthesis and summer soil moisture in the Ili River basin, Xinjiang, 2000-2018.

Soil moisture (SM) is essential for controlling terrestrial carbon uptake, as it directly provides moisture for photosynthesis, especially in arid and semiarid regions. We selected the arid and semiarid Ili River basin (IRB) of Xinjiang as the study area, and investigated the spatial and temporal characteristics and interrelationships with SM and photosynthesis from 2000 to 2018 using the ERA5 products and solar-induced chlorophyll fluorescence (SIF). SM and photosynthesis showed a decreasing trend during the study period. Compared with those in spring and autumn, the variation of summer SM and SIF was more consistent with the interannual variation. Anomaly analysis showed that negative SM anomalies were most profound in 2012-2015, 2008, and 2014. Additionally, we quantified the effect of seasonal SM deficits on photosynthesis by performing model-based experiments. The results indicated that the gross primary productivity (GPP) simulated by the P-model could capture the characteristics of photosynthesis in the IRB, which had a high correlation with SIF (R2 = 0.82, p < 0.001). In 2012-2015, 2008, and 2014, SM deficits caused more GPP reduction in the summers than in the springs or the autumns. The trends were mainly visible in the northern IRB, where GPP was below 40 % of the multi-year mean, and SM was below 23 %. GPP decreased more significantly in grassland than in the forest under the influence of SM deficit. This study reveals seasonal differences in the effects of SM deficit on photosynthesis and emphasizes that the summer SM deficit was the main factor responsible for decreases in GPP in the IRB during the study period. These findings contribute to a better understanding of the relationships between photosynthesis and environmental factors, and provide a reference for an accurate assessment of the regional carbon cycle.

Channel-independent function of UNC-9/Innexin in spatial arrangement of GABAergic synapses in C. elegans.

Precise synaptic connection of neurons with their targets is essential for the proper functioning of the nervous system. A plethora of signaling pathways act in concert to mediate the precise spatial arrangement of synaptic connections. Here we show a novel role for a gap junction protein in controlling tiled synaptic arrangement in the GABAergic motor neurons in Caenorhabditis elegans, in which their axons and synapses overlap minimally with their neighboring neurons within the same class. We found that while EGL-20/Wnt controls axonal tiling, their presynaptic tiling is mediated by a gap junction protein UNC-9/Innexin, that is localized at the presynaptic tiling border between neighboring dorsal D-type GABAergic motor neurons. Strikingly, the gap junction channel activity of UNC-9 is dispensable for its function in controlling tiled presynaptic patterning. While gap junctions are crucial for the proper functioning of the nervous system as channels, our finding uncovered the novel channel-independent role of UNC-9 in synapse patterning.

Rapid-Response and Wide-Range pH Sensors Enabled by Self-Assembled Functional PAni/PAA Layer on No-Core Fiber.

The measurement of pH has received great attention in diverse fields, such as clinical diagnostics, environmental protection, and food safety. Optical fiber sensors are widely used for pH sensing because of their great advantages. In this work, an optical fiber pH sensor is fabricated, by combining the merits of the multimode interference configuration and pH-sensitive polyaniline/polyacrylic acid (PAni/PAA) coatings, which was successfully in situ deposited on the no-core fiber (NCF) by the layer-by-layer (LBL) self-assembly method. The sensors' performance was experimentally characterized when used for pH detection. It has a high sensitivity of 0.985 nm/pH and a great linear response in a universal pH range of 2-12. The response time and recovery time is measured to be less than 10 s. In addition, its temperature sensitivity is tested to be about 0.01 nm/°C with a low temperature crosstalk effect, which makes it promising for detecting pH in the liquid phase with temperature variation. The sensors also demonstrated easy fabrication, good stability, and repeatability, which are adapted to pH detection in most practical applications.

Polyelectrolyte/Graphene Oxide Nano-Film Integrated Fiber-Optic Sensors for High-Sensitive and Rapid-Response Humidity Measurement.

Optical fiber humidity sensors have sparked enormous interests in many fields because of their excellent features. However, it remains a great challenge to balance sensitivity, humidity response, temperature crosstalk, and wet hysteresis for real-world application. To overcome this trade-off, an optical fiber humidity sensor is developed here by coating functional graphene oxide (GO)/polyelectrolyte nanocomposite film on the excessively tilted fiber grating (ex-TFG), in which GO/polyelectrolyte nanocomposite film is employed for enhancing the hydrophilicity and accelerating the adsorption/desorption of water molecule, while the ex-TFG is utilized for improving the sensitivity of refractive index and eliminating the crosstalk of temperature. By this design, optical fiber humidity sensors achieve high sensitivity, rapid response and recovery, low hysteresis, and temperature crosstalk as well as excellent repeatability and stability in large relative humidity (RH) range. Our work provides a promising platform for effective RH monitoring systems that can be widely applied in rapid diagnostics, pharmacy, precision medicine, and so forth.

Allergen protease-activated stress granule assembly and gasdermin D fragmentation control interleukin-33 secretion.

Interleukin-33 (IL-33), an epithelial cell-derived cytokine that responds rapidly to environmental insult, has a critical role in initiating airway inflammatory diseases. However, the molecular mechanism underlying IL-33 secretion following allergen exposure is not clear. Here, we found that two cell events were fundamental for IL-33 secretion after exposure to allergens. First, stress granule assembly activated by allergens licensed the nuclear-cytoplasmic transport of IL-33, but not the secretion of IL-33. Second, a neo-form murine amino-terminal p40 fragment gasdermin D (Gsdmd), whose generation was independent of inflammatory caspase-1 and caspase-11, dominated cytosolic secretion of IL-33 by forming pores in the cell membrane. Either the blockade of stress granule assembly or the abolishment of p40 production through amino acid mutation of residues 309-313 (ELRQQ) could efficiently prevent the release of IL-33 in murine epithelial cells. Our findings indicated that targeting stress granule disassembly and Gsdmd fragmentation could reduce IL-33-dependent allergic airway inflammation.

New indication of Chuankezhi injection for steroid-resistant focal segmental glomerulosclerosis and its mechanism of action.

Background: Chuankezhi (CKZ) injection is a traditional Chinese medicine (TCM) injection extracted from Chinese herbs Epimedium sagittatum (Yin Yang Huo) and Morinda officinalis (Bai Ji Tian). Studies have shown that CKZ has a positive effect on improving diabetic nephropathy and regulating immune function. Focal segmental glomerulosclerosis (FSGS) is a kind of refractory nephropathy, which has been confirmed as closely associated with immunity. Whether CKZ is effective against FSGS and how it works warrant further study. This study aimed to verify the efficacy of CKZ in rats with steroid-resistant (SR) FSGS and explore its mechanism of action. Methods: We established an SR FSGS model in male Sprague Dawley (SD) rats by injecting adriamycin into the tail vein. Based on group intervention and comparison, the primary efficacy parameters of FSGS were observed, including general condition, 24-hour urine protein, serum albumin, cholesterol, triglyceride, and renal pathological changes. Network pharmacological analysis and molecular docking were used to predict the mechanism of action of CKZ. Finally, we used quantitative polymerase chain reaction (qPCR) and western blot (WB) to detect messenger RNA (mRNA) expression and protein phosphorylation at specific targets in rat kidney tissue to validate the predicted results. Results: Intramuscular injection of CKZ had a dose-dependent effect in SR FSGS model rats, including lowering urine protein, increasing serum albumin, lowering cholesterol and triglyceride, and treating pathological lesions in the kidney. Network pharmacological analysis and Molecular docking revealed that 5 active components (Icariin, Icariside II, Epimedin C, Icaritin, and Noricaritin) might be the critical components. The findings also revealed that Akt was perhaps the critical target gene, the PI3K-Akt signaling pathway was perhaps the critical pathway, and reversible protein phosphorylation was probably the critical biological process. The qPCR and WB analyses showed that CKZ significantly increased the relative mRNA expression and protein phosphorylation of PI3K and Akt, respectively. Conclusions: This study showed that intramuscular injection of CKZ has a significant therapeutic effect in SR FSGS rats, which may be associated with the activation of PI3K-Akt signaling by CKZ.

An intein-split transactivator for intersectional neural imaging and optogenetic manipulation.

The cell-type-specific recording and manipulation is instrumental to disentangle causal neural mechanisms in physiology and behavior and increasingly requires intersectional control; however, current approaches are largely limited by the number of intersectional features, incompatibility of common effectors and insufficient gene expression. Here, we utilized the protein-splicing technique mediated by intervening sequences (intein) and devised an intein-based intersectional synthesis of transactivator (IBIST) to selectively control gene expression of common effectors in multiple-feature defined cell types in mice. We validated the specificity and sufficiency of IBIST to control fluorophores, optogenetic opsins and Ca2+ indicators in various intersectional conditions. The IBIST-based Ca2+ imaging showed that the IBIST can intersect five features and that hippocampal neurons tune differently to distinct emotional stimuli depending on the pattern of projection targets. Collectively, the IBIST multiplexes the capability to intersect cell-type features and controls common effectors to effectively regulate gene expression, monitor and manipulate neural activities.

Dietary glycemic index, glycemic load, and cause-specific mortality: two population-based prospective cohort studies.

BACKGROUND: Epidemiological studies on the relationship between dietary glycemic index (GI), glycemic load (GL) and all-cause and cause-specific mortality yielded conflict results. We aimed to assess these associations in Chinese. METHODS: We conducted this study based on two prospective cohort studies in Shanghai. Dietary information was collected using validated cohort-specific food frequency questionnaires. We used Cox regression model to estimate the hazard ratios (HR) for mortality associated with GI and GL. RESULTS: After median follow-up periods of 12.8 years for 59,770 men and 18.2 years for 74,735 women, 8,711 deaths in men and 10,501 deaths in women were documented. After we controlled the potential confounders, dietary GI, GL, and carbohydrate intake were associated with a higher risk of cardiovascular disease (CVD) mortality (P values for trend = 0.025, 0.001, and 0.001). Dietary GI was associated with lower risk of total and cause-specific mortality in men in the second quartile (Q) (all-cause mortality: HR Q2 vs. Q1 = 0.89, 95%CI: 0.84, 0.95). Dietary GL was associated with lower risk of cancer mortality but higher risk of CVD mortality in men. In women, dietary GI was associated with mortality due to all-cause (HRMax Q4 vs. Q1 = 1.10, 95%CI: 1.04, 1.06), cancer (HRMax Q4 vs. Q1 = 1.12, 95%CI: 1.02, 1.23), and CVD (HRMax Q4 vs. Q1 = 1.10, 95%CI: 1.00, 1.22). CONCLUSIONS: The present study indicates that diet with higher GI and GL was associated with an increased risk of CVD mortality in Chinese adults. The association may vary for men and women, which need further investigating in other Asian populations.

Targeted inhibition of Zika virus infection in human cells by CRISPR-Cas13b.

Zika virus (ZIKV) outbreaks occurred in recent years on an unprecedented scale, which caused fever and severe complications like Guillain-Barré syndrome in adults and fetal abnormalities. No vaccines or other effective treatments against ZIKV are available to date. The CRISPR-Cas13 family has the unique ability to target single-strand RNA molecules and mediate RNA cleavage. In the present study, we sought to exploit CRISPR-Cas13b for developing an anti-ZIKV system in mammalian cells. We first generated a ZIKV infection and reporting system by: (1) fusing mCherry to the ZIKV capsid protein for reporting infection by fluorescence; and (2) deriving a 293T cell line (293T-DC-SIGN) stably expressing DC-SIGN (Dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin) that became highly susceptible to ZIKV infection. The CRISPR Cas13b expression was reported to be in the cytoplasm of 293T-DC-SIGN cells using a Cas13b-GFP fusion expression vector. Fourteen CRISPR RNAs (crRNAs) were designed to target the most conserved regions of the ZIKV genome through bioinformatics analysis of 1138 ZIKV genome sequences. Five crRNAs were found to have significant effects (p < 0.001; two-sided t test) for Cas13b-targeted inhibition on ZIKV infection in 293T-DC-SIGN cells. Our study demonstrated an exciting example of using the CRISPR-Cas13b system for the treatment and prevention of ZIKV infection, highlighting CRISPR-Cas13 as a promising therapeutic anti-RNA virus strategy.

Protocol for in utero injection to investigate Zika virus-related fetal microcephaly in mice.

Zika virus (ZIKV) is linked to congenital defects including microcephaly. An infection model that can recapitulate most microcephaly-related phenotypes is crucial for understanding ZIKV pathogenesis. Here, we present a protocol to generate ZIKV from an infectious clone through a reverse genetic system and subsequently perform embryonic brain infection with the rescued ZIKV in pregnant mice. We optimized several aspects of the procedures including virus rescue and in utero injection. This protocol facilitates reproducible investigation of virus-induced cortical development defects. For complete details on the use and execution of this protocol, please refer to Zeng et al. (2020).