Safety and efficacy of lentinan nasal drops in patients infected with the variant of COVID-19: a randomized, placebo-controlled trial.

Objective: Lentinan has antiviral, anti-tumor, immunomodulatory, stimulating interferon production, and other pharmacological effects. Previous animal experiments have shown that lentinan nasal drops can assist [Corona Virus Disease 2019) COVID-19] vaccine to induce high levels of neutralizing antibodies and can effectively resist the invasion of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This study aimed to evaluate the safety and efficacy of lentinan nasal drops in patients infected with Omicron (SARS-CoV-2 variant) through a dose-escalation study and a placebo-controlled trial. Methods: A randomized, placebo-controlled trial. The study was divided into two phases: Phase I: a dose escalation trial in which 24 COVID-19 patients were enrolled, that is, 12 in the escalation dose group (50, 75, and 100 µg/day) and 12 in the standard treatment group. The aim was to evaluate the safety and tolerance of lentinan nasal drops. The second stage was a placebo-controlled study. The optimal dose group of the first stage was used as the therapeutic dose, and the sample size was expanded to verify the anti-COVID-19 efficacy of lentinan nasal drops. Results: In the dose-increasing study, lentinan nasal drops showed good safety, and no serious adverse reactions occurred. The virus shedding time of the 100 µg dose group was significantly shorter than that in the control group (7.75 ± 1.71 VS 13.41 ± 3.8 days) (p = 0.01), and the 100 µg/day lentinan nasal drops were tolerated well. The results of the placebo-controlled study showed that compared with that in the placebo group, the time for COVID-19 antigen to turn negative was significantly shorter in the 100 µg lentinan nasal drop group (p = 0.0298), but no significant difference was observed in symptom improvement between the two groups. In the placebo-controlled study, two patients experienced mild nasal discomfort with nasal drops, but the symptoms relieved themselves. Conclusion: Lentinan nasal drops are tolerated well and can shorten the time of virus clearance.

Identification of tyrphostin AG879 and A9 inhibiting replication of chikungunya virus by screening of a kinase inhibitor library.

Chikungunya virus (CHIKV) is a globally public health threat. There are currently no medications available to treat CHIKV infection. High-throughput screening of 419 kinase inhibitors was performed based on the cytopathic effect method, and six kinase inhibitors with reduced cytopathic effects, including tyrphostin AG879 (AG879), tyrphostin 9 (A9), sorafenib, sorafenib tosylate, regorafenib, and TAK-632, were identified. The anti-CHIKV activities of two receptor tyrosine kinase inhibitors, AG879 and A9, that have not been previously reported, were selected for further evaluation. The results indicated that 50% cytotoxic concentration (CC50) of AG879 and A9 in Vero cells were greater than 30 µM and 6.50 µM, respectively and 50% effective concentration (EC50) were 0.84 µM and 0.36 µM, respectively. The time-of-addition and time-of-removal assays illustrated that both AG879 and A9 function in the middle stage of CHIKV life cycle. Further, AG879 and A9 do not affect viral attachment; however, they inhibit viral RNA replication, and exhibit antiviral activity against CHIKV Eastern/Central/South African and Asian strains, Ross River virus and Sindbis virus in vitro.

The Oral Delivery System of Modified GLP-1 by Probiotics for T2DM.

The glucagon-like peptide-1 (GLP-1) is a peptide with incretin activity and plays an important role in glycemic control as well as the improvement of insulin resistance in type 2 diabetes mellitus (T2DM). However, the short half-life of the native GLP-1 in circulation poses difficulties for clinical practice. To improve the proteolytic stability and delivery properties of GLP-1, a protease-resistant modified GLP-1 (mGLP-1) was constructed with added arginine to ensure the structural integrity of the released mGLP-1 in vivo. The model probiotic Lactobacillus plantarum WCFS1 was chosen as the oral delivery vehicle with controllable endogenous genetic tools driven for mGLP-1 secretory constitutive expression. The feasibility of our design was explored in db/db mice which showed an improvement in diabetic symptoms related to decreased pancreatic glucagon, elevated pancreatic ß-cell proportion, and increased insulin sensitivity. In conclusion, this study provides a novel strategy for the oral delivery of mGLP-1 and further probiotic transformation.

Precise Synthesis of Chiral Z-Allylamides by Cobalt-Catalyzed Asymmetric Sequential Hydrogenations.

Asymmetric sequential hydrogenations of conjugated enynes have been developed using a Ph-BPE-CoI catalyst for the precise synthesis of chiral Z-allylamides in high activity (up to 1000 substrate/catalyst (S/C)) and with excellent enantioselectivity (up to >99 % enantiomeric excess (ee)). Mechanism experiments and theoretical calculations support a cationic CoI /CoIII redox catalytic cycle. The catalytic activity difference between cobalt complexes of Ph-BPE and QuinoxP* was explained by the process decomposition of rate-determining step in the second hydrogenation.

High-Throughput Screening of FDA-Approved Drug Library Reveals Ixazomib Is a Broad-Spectrum Antiviral Agent against Arboviruses.

The emergence of significant arboviruses and their spillover transmission to humans represent a major threat to global public health. No approved drugs are available for the treatment of significant arboviruses in circulation today. The repurposing of clinically approved drugs is one of the most rapid and promising strategies in the identification of effective treatments for diseases caused by arboviruses. Here, we screened small-molecule compounds with anti-tick-borne encephalitis virus, West Nile virus, yellow fever virus and chikungunya virus activity from 2580 FDA-approved drugs. In total, 60 compounds showed antiviral efficacy against all four of the arboviruses in Huh7 cells. Among these compounds, ixazomib and ixazomib citrate (inhibitors of 20S proteasome ß5) exerted antiviral effects at a low-micromolar concentration. The time-of-drug-addition assay suggested that ixazomib and ixazomib citrate disturbed multiple processes in viruses' life cycles. Furthermore, ixazomib and ixazomib citrate potently inhibited chikungunya virus replication and relieved virus-induced footpad swelling in a mouse model. These results offer critical information which supports the role of ixazomib as a broad-spectrum agent against arboviruses.

Antiviral efficacy of selective estrogen receptor modulators against SARS-CoV-2 infection in vitro and in vivo reveals bazedoxifene acetate as an entry inhibitor.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the seventh member of the coronavirus family that can infect humans. Recently, more contagious and pathogenic variants of SARS-CoV-2 have been continuously emerging. Clinical candidates with high efficacy and ready availability are still in urgent need. To identify potent anti-SARS-CoV-2 repurposing drugs, we evaluated the antiviral efficacy of 18 selective estrogen receptor modulators (SERMs) against SARS-CoV-2 infection. Six SERMs exhibited excellent anti-SARS-CoV-2 effects in Vero E6 cells and three human cell lines. Clomifene citrate, tamoxifen, toremifene citrate, and bazedoxifene acetate reduced the weight loss of hamsters challenged with SARS-CoV-2, and reduced hamster pulmonary viral load and interleukin-6 expression when assayed at 4 days postinfection. In particular, bazedoxifene acetate was identified to act on the penetration stage of the postattachment step via altering cholesterol distribution and endosome acidification. And, bazedoxifene acetate inhibited pseudoviruses infection of original SARS-CoV-2, Delta variant, Omicron variant, and SARS-CoV. These results offer critical information supporting bazedoxifene acetate as a promising agent against coronaviruses.

Anthropogenic sulfate aerosol pollution in South and East Asia induces increased summer precipitation over arid Central Asia.

Precipitation has increased across the arid Central Asia region over recent decades. However, the underlying mechanisms of this trend are poorly understood. Here, we analyze multi-model simulations from the Precipitation Driver and Response Model Intercomparison Project (PDRMIP) to investigate potential drivers of the observed precipitation trend. We find that anthropogenic sulfate aerosols over remote polluted regions in South and East Asia lead to increased summer precipitation, especially convective and extreme precipitation, in arid Central Asia. Elevated concentrations of sulfate aerosols over remote polluted Asia cause an equatorward shift of the Asian Westerly Jet Stream through a fast response to cooling of the local atmosphere at mid-latitudes. This shift favours moisture supply from low-latitudes and moisture flux convergence over arid Central Asia, which is confirmed by a moisture budget analysis. High levels of absorbing black carbon lead to opposing changes in the Asian Westerly Jet Stream and reduced local precipitation, which can mask the impact of sulfate aerosols. This teleconnection between arid Central Asia precipitation and anthropogenic aerosols in remote Asian polluted regions highlights long-range impacts of anthropogenic aerosols on atmospheric circulations and the hydrological cycle.

Cobalt-Catalyzed Chemo- and Enantioselective Hydrogenation of Conjugated Enynes.

Asymmetric hydrogenation is one of the most powerful methods for the preparation of single enantiomer compounds. However, the chemo- and enantioselective hydrogenation of the relatively inert unsaturated group in substrates possessing multiple unsaturated bonds remains a challenge. We herein report a protocol for the highly chemo- and enantioselective hydrogenation of conjugated enynes while keeping the alkynyl bond intact. Mechanism studies indicate that the accompanying Zn2+ generated from zinc reduction of the CoII complex plays a critical role to initiate a plausible CoI /CoIII catalytic cycle. This approach allows for the highly efficient generation of chiral propargylamines (up to 99.9 % ee and 2000 S/C) and further useful chemical transformations.

Embryonic Expression of NrasG 12 D Leads to Embryonic Lethality and Cardiac Defects.

Ras proteins control a complex intracellular signaling network. Gain-of-function mutations in RAS genes lead to RASopathy disorders in humans, including Noonan syndrome (NS). NS is the second most common syndromic cause of congenital heart disease. Although conditional expression of the NrasG12D/ + mutation in adult hematopoietic system is leukemogenic, its effects on embryonic development remain unclear. Here, we report that pan-embryonic expression of endogenous NrasG12D/ + by Mox2-Cre in mice caused embryonic lethality from embryonic day (E) 15.5 and developmental defects predominantly in the heart. At E13.5, NrasG12D/ + ; Mox2Cre/ + embryos displayed a moderate expansion of hematopoietic stem and progenitor cells without a significant impact on erythroid differentiation in the fetal liver. Importantly, the mutant embryos exhibited cardiac malformations resembling human congenital cardiac defects seen in NS patients, including ventricular septal defects, double outlet right ventricle, the hypertrabeculation/thin myocardium, and pulmonary valve stenosis. The mutant heart showed dysregulation of ERK, BMP, and Wnt pathways, crucial signaling pathways for cardiac development. Endothelial/endocardial-specific expression of NrasG12D/ + caused the cardiac morphological defects and embryonic lethality as observed in NrasG12D/ + ; Mox2Cre/ + mutants, but myocardial-specific expression of NrasG12D/ + did not. Thus, oncogenic NrasG12D mutation may not be compatible with embryonic survival.

Integrative investigation of dust emissions by dust storms and dust devils in North Africa.

Dust aerosols in North Africa account for >50% of the global total; however dust emission areas are still unclear. Based on the analysis of dust storms simulated with the numerical Weather Research and Forecast (WRF) model, satellite aerosol index (AI), and the dust data observed at 300 meteorological stations over 20 years, the spatio-temporal distribution characteristics of dust storm, dust devil and AI are compared and analyzed. The results show that: 1) There are two dust emission mechanisms: the dynamically-dominated dust storm and thermally-dominated dust devil; 2) Dust storms occur most frequently in Spring and are concentrated in the areas of Grand Erg Occidental Desert to the Erg Chech-Adrar Desert, the northern part of Grand Erg Oriental, the Atouila Desert to the Ouarane Desert, the Mediterranean coast, the eastern side of Nubian Desert and Bodélé Depression; 3) Dust devils occur most frequently from April to August and are mainly concentrated in the central part of North Africa, especially in the southwest of Hoggar Mountains to the west of Air Mountains, the border area of Egypt - Sudan - Libya and the vicinity of Tibesti Plateau; 4) The spatio-temporal distribution of AI is correlated more with the dust devils emission whereas the annual average contributions by dust storms and dust devils are 61.3% and 38.7%, respectively. This study discovers a new area of dust emissions by dust devils, and provides a better explanation for the spatio-temporal distribution of AI in North Africa.

Chiral Bicyclic Imidazole-Catalyzed Acylative Dynamic Kinetic Resolution for the Synthesis of Chiral Phthalidyl Esters.

Utilizing a chiral bicyclic imidazole organocatalyst and adopting a continuous injection process, an alternative route has been developed for the efficient synthesis of chiral phthalidyl ester prodrugs via dynamic kinetic resolution of 3-hydroxyphthalides through enantioselective acylation (up to 99 % ee). The computational studies suggest a general base catalytic mechanism differing from the widely accepted nucleophilic catalytic mechanism. The structure analysis of the key transition states shows that the CH-π interactions and not the previously considered cation/π-π interactions between the catalyst and substrate is the dominant factor giving rise to the observed stereocontrol.

Ezrin is essential for the entry of Japanese encephalitis virus into the human brain microvascular endothelial cells.

Japanese encephalitis virus (JEV) remains the predominant cause of viral encephalitis worldwide. It reaches the central nervous system upon crossing the blood-brain barrier through pathogenic mechanisms that are not completely understood. Here, using a high-throughput siRNA screening assay combined with verification experiments, we found that JEV enters the primary human brain microvascular endothelial cells (HBMEC) through a caveolae-mediated endocytic pathway. The role of ezrin, an essential host factor for JEV entry based on our screening, in caveolae-mediated JEV internalization was investigated. We observed that JEV internalization in HBMEC is largely dependent on ezrin-mediated actin cytoskeleton polymerization. Moreover, Src, a protein predicted by a STRING database search, was found to be required in JEV entry. By a variety of pharmacological inhibition and immunoprecipitation assays, we found that Src, ezrin, and caveolin-1 were sequentially activated and formed a complex during JEV infection. A combination of in vitro kinase assay and subcellular analysis demonstrated that ezrin is essential for Src-caveolin-1 interactions. In vivo, both Src and ezrin inhibitors protected ICR suckling mice against JEV-induced mortality and diminished mouse brain viral load. Therefore, JEV entry into HBMEC requires the activation of the Src-ezrin-caveolin-1 signalling axis, which provides potential targets for restricting JEV infection.

A Physics-Based DNI Model Assessing All-Sky Circumsolar Radiation.

By investigating the long-term observations at Atmospheric Radiation Measurement (ARM) Southern Great Plains (SGP), we find that the routinely used Beer-Bouguer-Lambert law and the models that empirically separate direct normal irradiance (DNI) from measurements of global horizontal irradiance (GHI) have dramatic and unexpected bias in computing cloudy-sky DNI. This bias has led to tremendous uncertainty in estimating the electricity generation by solar energy conversion systems. To effectively reduce the bias, this study proposes a physical solution of all-sky DNI that computes solar radiation in the infinite-narrow beam along the sun direction and the scattered radiation falls within the circumsolar region. In sharp contrast with the other DNI models, this method uses a finite-surface integration algorithm that computes solar radiation in differential solid angles and efficiently infers its contribution to a surface perpendicular to the sun direction. The new model substantially reduces the uncertainty in DNI by a factor of 2-7.

Cobalt-Catalyzed Asymmetric Hydrogenation of C=N Bonds Enabled by Assisted Coordination and Nonbonding Interactions.

An efficient cobalt-catalyzed asymmetric hydrogenation of C=N bonds has been realized. Chiral hydrazines were obtained in high yields and with excellent enantioselectivities (95-98 % ee). The hydrogenation went smoothly at up to 2000 substrate/catalyst and on a gram scale. The success of this reaction relies on the presence of an NHBz group in the substrates, with the reactivity and enantioselectivity improved by an assisted coordination to the cobalt atom and a nonbonding interaction with the ligand. Furthermore, this reaction has practical applications for the synthesis of several useful chiral nitrogen-containing compounds.

Endophilin-A2-mediated endocytic pathway is critical for enterovirus 71 entry into caco-2 cells.

Enterovirus 71 (EV71) is typically transmitted by the oral-faecal route and initiates infection upon crossing the intestinal mucosa. Our limited understanding of the mechanisms by which it crosses the intestinal mucosa has hampered the development of effective therapeutic options. Here, using an RNA interference screen combined with chemical inhibitors or the overexpression of dominant negative proteins, we found that EV71 entry into Caco-2 cells, a polarized human intestinal epithelial cell line, does not involve clathrin- and caveolae-dependent endocytic pathways or macropinocytosis but requires GTP-binding protein dynamin 2 and cytoskeleton remodelling. The use of siRNAs targeting endophilin family members revealed that endophlin-A2 is essential for the uptake of EV71 particles by Caco-2 cells. Subcellular analysis revealed that internalized EV71 virions largely colocalized with endophilin-A2 at cytomembrane ruffles and in the perinuclear area. Combined with viral entry kinetics, these data suggest that EV71 enters Caco-2 cells mainly via an endophilin-A2-mediated endocytic (EME) pathway. Finally, we showed that internalized EV71 virions were transported to endosomal sorting complex required for transport (ESCRT)-related multivesicular bodies (MVBs). These data provide attractive therapeutic targets to block EV71 infection.

Selective Asymmetric Hydrogenation of Four-Membered Exo-α,ß-Unsaturated Cyclobutanones Using RuPHOX-Ru as a Catalyst.

The selective asymmetric hydrogenation of four-membered exo-α,ß-unsaturated cyclobutanones has been achieved for the first time using RuPHOX-Ru as a catalyst, providing four-membered exo-cyclic chiral allylic alcohols in high yields and with up to 99.9% ee. The reaction could be performed on a gram scale with a relatively low catalyst loading (up to 10000 S/C), and the resulting products can be transformed to several biologically active molecules.

Pd-catalyzed asymmetric allylic substitution cascade using α-(pyridin-1-yl)-acetamides formed in situ as nucleophiles.

A Pd-catalyzed asymmetric allylic substitution cascade reaction, using α-(pyridin-1-yl)-acetamides (formed in situ) as nucleophiles, has been developed, generating chiral piperidine-containing amino acid derivatives via a one-pot procedure in high yields and with up to 96% ee. The products can be easily converted into potential bioactive compounds, unnatural chiral amino acids and dipeptides.

Synthesis of Chiral α-Aminosilanes through Palladium-Catalyzed Asymmetric Hydrogenation of Silylimines.

The asymmetric hydrogenation of silylimines was first developed by using a palladium complex of a P-stereogenic diphosphine ligand as the catalyst, affording the valuable chiral α-aminosilanes with quantitative conversions and excellent enantioselectivities (up to 99% ee).

Downregulating Notch counteracts KrasG12D-induced ERK activation and oxidative phosphorylation in myeloproliferative neoplasm.

The Notch signaling pathway contributes to the pathogenesis of a wide spectrum of human cancers, including hematopoietic malignancies. Its functions are highly dependent on the specific cellular context. Gain-of-function NOTCH1 mutations are prevalent in human T-cell leukemia, while loss of Notch signaling is reported in myeloid leukemias. Here, we report a novel oncogenic function of Notch signaling in oncogenic Kras-induced myeloproliferative neoplasm (MPN). We find that downregulation of Notch signaling in hematopoietic cells via DNMAML expression or Pofut1 deletion significantly blocks MPN development in KrasG12D mice in a cell-autonomous manner. Further mechanistic studies indicate that inhibition of Notch signaling upregulates Dusp1, a dual phosphatase that inactivates p-ERK, and downregulates cytokine-evoked ERK activation in KrasG12D cells. Moreover, mitochondrial metabolism is greatly enhanced in KrasG12D cells but significantly reprogrammed by DNMAML close to that in control cells. Consequently, cell proliferation and expanded myeloid compartment in KrasG12D mice are significantly reduced. Consistent with these findings, combined inhibition of the MEK/ERK pathway and mitochondrial oxidative phosphorylation effectively inhibited the growth of human and mouse leukemia cells in vitro. Our study provides a strong rational to target both ERK signaling and aberrant metabolism in oncogenic Ras-driven myeloid leukemia.