In response to the current global health emergency posed by the Zika virus (ZIKV) outbreak and its link to microcephaly and other neurological conditions, we performed a drug repurposing screen of ~6,000 compounds that included approved drugs, clinical trial drug candidates and pharmacologically active compounds, and we identified compounds that either inhibit ZIKV infection or suppress infection-induced caspase-3 activity in different neural cells. A pan-caspase inhibitor, Emricasan, inhibited ZIKV-induced increases in caspase-3 activity and protected human cortical neural progenitors in both monolayer and 3-dimensional organoid cultures. Ten structurally unrelated inhibitors of cyclin-dependent kinases inhibited ZIKV replication. Niclosamide, an FDA approved category B anthelmintic drug, also inhibited ZIKV replication. Finally, combination treatments using one compound from each category (neuroprotective and antiviral) further increased protection of human neural progenitors and astrocytes from ZIKV-induced cell death. Our results demonstrate the efficacy of this screening strategy and identify lead compounds for anti-ZIKV drug development.

SUMMARY Zika virus (ZIKV) directly infects neural progenitors and impairs their proliferation. How ZIKV interacts with the host molecular machinery to impact neurogenesis in vivo is not well understood. Here, by systematically introducing individual proteins encoded by ZIKV into the embryonic mouse cortex, we show that expression of ZIKV-NS2A, but not Dengue virus (DENV)-NS2A, leads to reduced proliferation and premature differentiation of radial glial cells, and aberrant positioning of newborn neurons. Mechanistically, in vitro mapping of protein-interactomes and biochemical analysis suggest interactions between ZIKA-NS2A and multiple adherens junction complex (AJ) components. Functionally, ZIKV-NS2A, but not DENV-NS2A, destabilizes the AJ complex, resulting in impaired AJ formation and aberrant radial glial fiber scaffolding in the embryonic mouse cortex. Similarly, ZIKA-NS2A, but not DENV-NS2A, reduces radial glial cell proliferation and causes AJ deficits in human forebrain organoids. Together, our results reveal pathogenic mechanisms underlying ZIKV infection in the developing mammalian brain.

Zika virus (ZIKV) infection causes microcephaly and has been linked to other brain abnormalities. How ZIKV impairs brain development and function is unclear. Here we systematically profiled transcriptomes of human neural progenitor cells exposed to Asian ZIKVC, African ZIKVM, and dengue virus (DENV). In contrast to the robust global transcriptome changes induced by DENV, ZIKV has a more selective and larger impact on expression of genes involved in DNA replication and repair. While overall expression profiles are similar, ZIKVC, but not ZIKVM, induces upregulation of viral response genes and TP53. P53 inhibitors can block the apoptosis induced by both ZIKVC and ZIKVM in hNPCs, with higher potency against ZIKVC-induced apoptosis. Our analyses reveal virus- and strain-specific molecular signatures associated with ZIKV infection. These datasets will help to investigate ZIKV-host interactions and identify neurovirulence determinants of ZIKV.

Summary 1.Invasive plants often have novel biotic interactions in their introduced ranges. These interactions, including less frequent herbivore attacks, may convey a competitive advantage over native plants. Invasive plants may vary in defence strategies (resistance vs. tolerance) or in response to the type of herbivore (generalists vs. specialists), but no study to date has examined this broad set of traits simultaneously. 2. Here, we examined resistance and tolerance of Chinese tallow (Triadica sebifera) populations from the introduced and native ranges to generalist (Cnidocampa flavescens) and specialist herbivores (Gadirtha inexacta) in the native range. 3. In a field common-garden test of resistance, caterpillars of each species were raised on plants from native and invasive populations. We found the specialist grew larger on and consumed more mass of invasive plant populations than native populations, while the generalist showed the same performance between them. The results were consistent with our laboratory bioassay using excised leaves. Chemical analyses showed that the invasive plants had lower tannin content and higher ratio of carbohydrate to protein than those of their native counterparts, suggesting that plants from invasive populations have altered chemistry that has a larger impact on specialist than on generalist resistance. 4. To test for differences in herbivore tolerance, plants were first defoliated by specialist or generalist herbivory and then allowed to regrow for 100 days in a field common garden. We found that plants from invasive populations had greater herbivore tolerance than native populations, especially for tolerance to generalists. They also grew more rapidly than native counterparts in the absence of herbivory. 5. Synthesis. The results of these experiments indicate that differences in selective pressures between ranges have caused dramatic reductions in resistance to specialist herbivores and those changes in plant secondary chemistry likely underlie these differences. The greater tolerance of invasive populations to herbivory appears to at least partly reflect an increase in growth rate in the introduced range. The greater tolerance to generalist herbivores suggests the intriguing possibility of selection for traits that allow plants to tolerate generalist herbivores more than specialist herbivores.

Conspecific and heterospecific aboveground and belowground herbivores often occur together in nature and their interactions may determine community structure. Here we show how aboveground adults and belowground larvae of the tallow tree specialist beetle Bikasha collaris and multiple heterospecific aboveground species interact to determine herbivore performance. Conspecific aboveground adults facilitate belowground larvae, but other aboveground damage inhibits larvae or has no effect. Belowground larvae increase conspecific adult feeding, but decrease heterospecific aboveground insect feeding and abundance. Chemical analyses and experiments with plant populations varying in phenolics show that all these positive and negative effects on insects are closely related to root and shoot tannin concentrations. Our results show that specific plant herbivore responses allow herbivore facilitation and inhibition to co-occur, likely shaping diverse aboveground and belowground communities. Considering species-specific responses of plants is critical for teasing apart inter- and intraspecific interactions in aboveground and belowground compartments.

Many invasive plants have enhanced mutualistic arbuscular mycorrhizal (AM) fungal associations, however, mechanisms underlying differences in AM fungal associations between introduced and native populations of invasive plants have not been explored. Here we test the hypothesis that variation in root exudate chemicals in invasive populations affects AM fungal colonization and then impacts plant performance. We examined flavonoids (quercetin and quercitrin) in root exudates of native and introduced populations of the invasive plant Triadica sebifera and tested their effects on AM fungi and plant performance. We found that plants from introduced populations had higher concentrations of quercetin in root exudates, greater AM fungal colonization and higher biomass. Applying root exudates more strongly increased AM fungal colonization of target plants and AM fungal spore germination when exudate donors were from introduced populations. The role of root exudate chemicals was further confirmed by decreased AM fungal colonization when activated charcoal was added into soil. Moreover, addition of quercetin into soil increased AM fungal colonization, indicating quercetin might be a key chemical signal stimulating AM fungal associations. Together these results suggest genetic differences in root exudate flavonoids play an important role in enhancing AM fungal associations and invasive plants’ performance, thus considering root exudate chemicals is critical to unveiling mechanisms governing shifting plant-soil microbe interactions during plant invasions.

Abstract:In the present study, we investigated the anti-fatigue activity in male Kunming mice of extracts of stem bark from Acanthopanax senticosus (ASSE) using a forced swimming test. Mice were divided into four groups (three ASSE administered groups and the control group). The control group were gavaged with distilled water and ASSE administered groups were gavaged with ASSE (100, 200 and 400 mg/kg). After four weeks, a forced swimming test was performed and the biochemical parameters related to fatigue were examined. The results suggested that ASSE could extend the swimming time to exhaustion of the mice, as well as increase the tissue glycogen contents, while decreasing the blood lactate and serum urea nitrogen contents. This indicated that ASSE had anti-fatigue activity and could elevate the exercise tolerance.

Chicken essence (CE) is a liquid nutritional supplement made from cooking whole chickens. In traditional Chinese medicine, CE is used to support health, promote healing, increase metabolism, and relieve fatigue. However, few studies have examined the effect of CE on exercise performance and physical fatigue. We aimed to evaluate the potential beneficial effects of CE on fatigue and ergogenic functions following physical challenge in mice. Male ICR mice were divided into four groups to receive vehicle or CE by oral gavage at 0, 845, 1690, or 4225 mg/kg/day for 4 weeks. Exercise performance and anti-fatigue function were evaluated by forelimb grip strength, exhaustive swimming time, and levels of physical fatigue-related biomarkers serum lactate, ammonia, glucose, and creatine kinase (CK) after physical challenge. CE supplementation dose-dependently elevated endurance and grip strength. CE supplementation significantly decreased lactate, ammonia, and CK levels after physical challenge. Tissue glycogen content, an important energy source for exercise, was significantly increased with CE supplementation. In addition, CE supplementation had few subchronic toxic effects. The supplementation with CE can have a wide spectrum of bioactivities on health promotion, performance improvement and anti-fatigue.