Dengue fever is an emerging arboviral disease for which no vaccine or antiviral treatment exists and that causes thousands of fatalities each year. To develop an in vivo test system for antidengue drugs, AG129 mice, which are deficient for the interferon- alpha / beta and - gamma receptors, were injected with unadapted dengue virus, resulting in a dose-dependent transient viremia lasting several days and peaking on day 3 after infection. Additionally, nonstructural protein 1, increased levels of proinflammatory cytokines, and neutralizing IgM and IgG antibodies were found, and mice had splenomegaly. Oral administration of the antiviral compounds 7-deaza-2'-C-methyl-adenosine, N-nonyl-deoxynojirimycin, or 6-O-butanoyl castanospermine significantly reduced viremia in a dose-dependent manner, even after delayed treatment, leading to a reduction of splenomegaly and proinflammatory cytokine levels. The results validate this dengue viremia mouse model as a suitable system for testing antidengue drugs and indicate that antiviral treatment during the acute phase of dengue fever can reduce the severity of the disease.

The infusion of coronavirus disease 2019 (COVID-19) patients with mesenchymal stem cells (MSCs) potentially improves clinical symptoms, but the underlying mechanism remains unclear. We conducted a randomized, single-blind, placebo-controlled (29 patients/group) phase II clinical trial to validate previous findings and explore the potential mechanisms. Patients treated with umbilical cord-derived MSCs exhibited a shorter hospital stay (P = 0.0198) and less time required for symptoms remission (P = 0.0194) than those who received placebo. Based on chest images, both severe and critical patients treated with MSCs showed improvement by day 7 (P = 0.0099) and day 21 (P = 0.0084). MSC-treated patients had fewer adverse events. MSC infusion reduced the levels of C-reactive protein, proinflammatory cytokines, and neutrophil extracellular traps (NETs) and promoted the maintenance of SARS-CoV-2-specific antibodies. To explore how MSCs modulate the immune system, we employed single-cell RNA sequencing analysis on peripheral blood. Our analysis identified a novel subpopulation of VNN2+ hematopoietic stem/progenitor-like (HSPC-like) cells expressing CSF3R and PTPRE that were mobilized following MSC infusion. Genes encoding chemotaxis factors — CX3CR1 and L-selectin — were upregulated in various immune cells. MSC treatment also regulated B cell subsets and increased the expression of costimulatory CD28 in T cells in vivo and in vitro. In addition, an in vivo mouse study confirmed that MSCs suppressed NET release and reduced venous thrombosis by upregulating kindlin-3 signaling. Together, our results underscore the role of MSCs in improving COVID-19 patient outcomes via maintenance of immune homeostasis.

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The four serotypes of dengue virus (DENV-1 to -4) represent the most prevalent mosquito-borne viral pathogens in humans. No clinically approved vaccine or antiviral is currently available for DENV. Here we report a spiropyrazolopyridone compound that potently inhibits DENV both in vitro and in vivo. The inhibitor was identified through screening of a 1.8-million-compound library by using a DENV-2 replicon assay. The compound selectively inhibits DENV-2 and -3 (50% effective concentration [EC 50 ], 10 to 80 nM) but not DENV-1 and -4 (EC 50 , >20 M). Resistance analysis showed that a mutation at amino acid 63 of DENV-2 NS4B (a nonenzymatic transmembrane protein and a component of the viral replication complex) could confer resistance to compound inhibition. Genetic studies demonstrate that variations at amino acid 63 of viral NS4B are responsible for the selective inhibition of DENV-2 and -3. Medicinal chemistry improved the physicochemical properties of the initial "hit" (compound 1), leading to compound 14a, which has good in vivo pharmacokinetics. Treatment of DENV-2-infected AG129 mice with compound 14a suppressed viremia, even when the treatment started after viral infection. The results have proven the concept that inhibitors of NS4B could potentially be developed for clinical treatment of DENV infection. Compound 14a represents a potential preclinical candidate for treatment of DENV-2-and -3-infected patients. IMPORTANCE Dengue virus (DENV) threatens up to 2.5 billion people and is now spreading in many regions Emerging infectious pathogens represent a major threat to public health. Vaccines and therapeutics are two key countermeasures against these pathogens. Many viruses of the genus Flavivirus within the family Flaviviridae are arthropod-borne human pathogens, among which the four serotypes of dengue virus (DENV) alone cause 390 million human infections each year (1). Several promising DENV vaccines are currently in clinical development (2). The most advanced vaccine (CYD-TDV) exhibited good efficacy against DENV-1, -3, and -4 but weak protection against DENV-2 (3-5). For antiviral development, four compounds have been tested in dengue clinical trials, including balapiravir (a nucleoside inhibitor) (6), celgosivir (a cellular ␣-glucosidase inhibitor) (7), chloroquine (a malaria drug with antiviral and immunomodulatory activities) (8), and prednisolone (a corticosteroid drug) (9). None of them showed any antiviral activity or clinical benefits in dengue patients. Notably, all these compounds were repurposed from existing drugs or compounds previously developed for other viruses. Bona fide inhibitors specifically designed for DENV have never advanced to clinical trials (10).In this paper, we report the identification of a novel class of small-molecule anti-DENV agents, the spiropyrazolopyridones, using phenotypic screening. These inhibitors block DENV replication by targeting nonstructural protein 4B (NS4B), a nonenzymatic transmembrane protein functioning as an essential component of the viral r...

As the population ages, the medical and socioeconomic impact of age-related bone disorders will further increase. An imbalance between osteogenesis and adipogenesis of mesenchymal stem cells (MSCs) can lead to various bone and metabolic diseases such as osteoporosis. Thus, understanding the molecular mechanisms underlying MSC osteogenic and adipogenic differentiation is important for the discovery of novel therapeutic paradigms for these diseases. miR-10b has been widely reported in tumorigenesis, cancer invasion and metastasis. However, the effects and potential mechanisms of miR-10b in the regulation of MSC adipogenic and osteogenic differentiation have not been explored. In this study, we found that the expression of miR-10b was positively correlated with bone formation marker genes ALP, RUNX2 and OPN, and negatively correlated with adipogenic markers CEBPα, PPARγ and AP2 in clinical osteoporosis samples. Overexpression of miR-10b enhanced osteogenic differentiation and inhibited adipogenic differentiation of human adipose-derived mesenchymal stem cells (hADSCs) in vitro, whereas downregulation of miR-10b reversed these effects. Furthermore, miR-10b promoted ectopic bone formation in vivo. Target prediction and dual luciferase reporter assays identified SMAD2 as a potential target of miR-10b. Silencing endogenous SMAD2 expression in hADSCs enhanced osteogenesis but repressed adipogenesis. Pathway analysis indicated that miR-10b promotes osteogenic differentiation and bone formation via the TGF-β signaling pathway, while suppressing adipogenic differentiation may be primarily mediated by other pathways. Taken together, our findings imply that miR-10b acts as a critical regulator for balancing osteogenic and adipogenic differentiation of hADSCs by repressing SMAD2 and partly through the TGF-β pathway. Our study suggests that miR-10b is a novel target for controlling bone and metabolic diseases.

Previous research has demonstrated the role of servant leadership, a leadership style emphasizing serving others, in promoting frontline employees’ service performance. It is unclear, however, how servant leadership by leaders at different organizational levels would exert such an influence. Integrating insights from both social learning theory and the trickle-down paradigm of leadership, we develop a cross-level model in which we argue that servant leadership by high-level managers could cascade downward through the organizational hierarchy to influence frontline employees’ service performance and that this trickle-down effect is contingent on the extent to which subordinates identify their leaders as embodying the organization. Using a matched sample of 92 supervisors and 568 frontline employees across 92 sub-branches of a large banking company, we found that servant leadership by high-level managers could indeed promote employees’ in-role and extra-role service performance through its effect on low-level supervisors’ servant leadership. We also found that this trickle-down effect was stronger when high-level managers and low-level supervisors were perceived by their subordinates as more fully embodying the organization. Implications, limitations and future directions are discussed.

Purpose The purpose of this paper is to investigate how and when service-oriented high-performance work systems (HPWS) impact employees’ service performance. Design/methodology/approach Survey data was obtained from 568 frontline service employees and their supervisors across 92 branches of a large bank in China. The hypotheses were tested with hierarchical linear modeling. Findings The results suggested that service-oriented HPWS affected employee service performance via its simultaneous impact on employees’ service ability, customer orientation, and service climate perception. Moreover, the indirect effects of HPWS on service performance via service ability and customer orientation were significant only when service-oriented HPWS consensus was high. Practical implications To elicit employees’ provision of excellent service, organizations should invest in service-oriented HRM practices to improve all of their service ability, customer orientation, and service climate perception, making them able to, willing to, and having the chance to perform high-quality service performance. Organizations should also pay attention to the variability in employees’ HRM perceptions within the same group. Originality/value The research contributes to the extant literature by presenting a more complete understanding of how service-oriented HPWS elicits employee service performance, and when this HPWS is and is not effective.