Abstract
Chemical modification of transcripts with 5′ caps occurs in all organisms. Here, we report a systems-level mass spectrometry-based technique, CapQuant, for quantitative analysis of an ...organism's cap epitranscriptome. The method was piloted with 21 canonical caps—m7GpppN, m7GpppNm, GpppN, GpppNm, and m2,2,7GpppG—and 5 ‘metabolite’ caps—NAD, FAD, UDP-Glc, UDP-GlcNAc, and dpCoA. Applying CapQuant to RNA from purified dengue virus, Escherichia coli, yeast, mouse tissues, and human cells, we discovered new cap structures in humans and mice (FAD, UDP-Glc, UDP-GlcNAc, and m7Gpppm6A), cell- and tissue-specific variations in cap methylation, and high proportions of caps lacking 2′-O-methylation (m7Gpppm6A in mammals, m7GpppA in dengue virus). While substantial Dimroth-induced loss of m1A and m1Am arose with specific RNA processing conditions, human lymphoblast cells showed no detectable m1A or m1Am in caps. CapQuant accurately captured the preference for purine nucleotides at eukaryotic transcription start sites and the correlation between metabolite levels and metabolite caps.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to evolve and adapt after its emergence in late 2019. As the causative agent of the coronavirus disease 2019 (COVID-19), the ...replication and pathogenesis of SARS-CoV-2 have been extensively studied by the research community for vaccine and therapeutics development. Given the importance of viral spike protein in viral infection/transmission and vaccine development, the scientific community has thus far primarily focused on studying the structure, function, and evolution of the spike protein. Other viral proteins are understudied. To fill in this knowledge gap, a few recent studies have identified nonstructural protein 6 (nsp6) as a major contributor to SARS-CoV-2 replication through the formation of replication organelles, antagonism of interferon type I (IFN-I) responses, and NLRP3 inflammasome activation (a major factor of severe disease in COVID-19 patients). Here, we review the most recent progress on the multiple roles of nsp6 in modulating SARS-CoV-2 replication and pathogenesis.
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•This paper reviews the structural model and function of SARS-CoV-2 nsp6 protein.•SARS-CoV-2 nsp6 is a membrane protein essential for the formation of replication organelles.•SARS-CoV-2 nsp6 antagonizes type-I interferon responses and NLRP3 inflammasome activation.•SARS-CoV-2 variants accumulate specific nsp6 mutations to modulate viral pathogenesis.
Infections with mosquito-borne flaviviruses, such as Dengue virus, ZIKV virus, and West Nile virus, pose significant threats to public health. Flaviviruses cause up to 400 million infections each ...year, leading to many forms of diseases, including fatal hemorrhage, encephalitis, congenital abnormalities, and deaths. Currently, there are no clinically approved antiviral drugs for the treatment of flavivirus infections. The non-structural protein NS4B is an emerging target for drug discovery due to its multiple roles in the flaviviral life cycle. In this review, we summarize the latest knowledge on the structure and function of flavivirus NS4B, as well as the progress on antiviral compounds that target NS4B.
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•This review summarizes the latest knowledge on the structure and function of flavivirus NS4B protein.•Flavivirus NS4B is a membrane protein essential for viral replication and host immune response•Flavivirus NS4B interacts with various viral and host proteins in infected cells
Two doses of the BNT162b2 mRNA vaccine are highly effective against SARS-CoV-2. Here, we tested the antibody neutralization against Omicron SARS-CoV-2 after 2 and 3 doses of BNT162b2. Serum from ...vaccinated individuals was serially tested for its ability to neutralize wild-type SARS-CoV-2 (USA-WA1/2020) and an engineered USA-WA1/2020 bearing the Omicron spike glycoprotein. At 2 or 4 weeks post dose 2, the neutralization geometric mean titers (GMTs) against the wild-type and Omicron-spike viruses were 511 and 20, respectively; at 1 month post dose 3, the neutralization GMTs increased to 1,342 and 336; and at 4 months post dose 3, the neutralization GMTs decreased to 820 and 171. The data support a 3-dose vaccination strategy and provide a glimpse into the durability of the neutralization response against Omicron.
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•Two doses of BNT162b2 are not sufficient to elicit robust neutralization against Omicron•Three doses of BNT162b2 confer substantial neutralization against Omicron•Neutralization against Omicron remains robust at 4 months after dose 3 of BNT162b2
Through serially testing BNT162b2-vaccinated human sera against SARS-CoV-2 and its Omicron variant, Xia et al. found that 2 doses of BNT162b2 are insufficient to elicit robust neutralization against Omicron. Three doses increase the magnitude and breadth of neutralization against Omicron and remains robust for up to 4 months post dose 3.
The frequently observed forest decline in water‐limited regions may be associated with impaired tree hydraulics, but the precise physiological mechanisms remain poorly understood. We compared ...hydraulic architecture of Mongolian pine (Pinus sylvestris var. mongolica) trees of different size classes from a plantation and a natural forest site to test whether greater hydraulic limitation with increasing size plays an important role in tree decline observed in the more water‐limited plantation site. We found that trees from plantations overall showed significantly lower stem hydraulic efficiency. More importantly, plantation‐grown trees showed significant declines in stem hydraulic conductivity and hydraulic safety margins as well as syndromes of stronger drought stress with increasing size, whereas no such trends were observed at the natural forest site. Most notably, the leaf to sapwood area ratio (LA/SA) showed a strong linear decline with increasing tree size at the plantation site. Although compensatory adjustments in LA/SA may mitigate the effect of increased water stress in larger trees, they may result in greater risk of carbon imbalance, eventually limiting tree growth at the plantation site. Our results provide a potential mechanistic explanation for the widespread decline of Mongolian pine trees in plantations of Northern China.
Hydraulic failure has been proposed as an important reason causing tree die‐off in vast areas of water‐limited land across the globe, especially under the influence of climate change, but the underlying mechanisms remain poorly understood. Decline has been more frequently observed in larger trees, and significant changes in hydraulic architecture are also commonly found with increasing tree size, suggesting a mechanistic linkage between tree decline and hydraulic limitations mediated by variation in tree size. Here, we compared hydraulic architecture of Pinus sylvestris var. mongolica trees between a plantation and a natural forest site across different tree size classes to test whether greater hydraulic limitation in larger trees is responsible for tree decline in the more water‐limited plantation site. We observed clear contrasts in hydraulic‐related characteristics between trees of the 2 sites and found clear trends of change in these traits with increasing tree size at the plantation site but not at the natural forest site, which provide a potential mechanistic explanation for the widespread decline of this species in plantations of Northern China.
Cerebral organoids, three-dimensional cultures that model organogenesis, provide a new platform to investigate human brain development. High cost, variability, and tissue heterogeneity limit their ...broad applications. Here, we developed a miniaturized spinning bioreactor (SpinΩ) to generate forebrain-specific organoids from human iPSCs. These organoids recapitulate key features of human cortical development, including progenitor zone organization, neurogenesis, gene expression, and, notably, a distinct human-specific outer radial glia cell layer. We also developed protocols for midbrain and hypothalamic organoids. Finally, we employed the forebrain organoid platform to model Zika virus (ZIKV) exposure. Quantitative analyses revealed preferential, productive infection of neural progenitors with either African or Asian ZIKV strains. ZIKV infection leads to increased cell death and reduced proliferation, resulting in decreased neuronal cell-layer volume resembling microcephaly. Together, our brain-region-specific organoids and SpinΩ provide an accessible and versatile platform for modeling human brain development and disease and for compound testing, including potential ZIKV antiviral drugs.
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•A miniaturized spinning bioreactor for cost-effective culturing of organoids•Generation of brain-region-specific organoids from human iPSCs•ZIKV causes decrease of neuronal cell-layer volume resembling microcephaly•Both African and Asian ZIKV infect neural progenitors in organoids
Zika virus preferentially infects neural progenitors in early stage cortical organoids generated using cost-effective miniaturized spinning bioreactors, resulting in suppressed proliferation, increased cell death, and macroscopic features resembling microcephaly.
The effect of dispersion state of graphene on mechanical properties of graphene/epoxy composites was investigated. The graphene sheets were exfoliated from graphite oxide (GO) via thermal reduction ...(thermally reduced GO, RGO). Different dispersions of RGO sheets were prepared with and without ball mill mixing. It was found that the composites with highly dispersed RGO showed higher glass transition temperature (Tg) and strength than those with poorly dispersed RGO, although no significant differences in both the tensile and flexural moduli are caused by the different dispersion levels. In particular, the Tg was increased by nearly 11°C with the addition of 0.2wt.% well dispersed RGO to epoxy. As expected, the highly dispersed RGO also produced one or two orders of magnitude higher electrical conductivity than the corresponding poorly dispersed RGO. Furthermore, an improved quasi-static fracture toughness (KIC) was measured in the case of good dispersion. The poorly and highly dispersed RGO at 0.2wt.% loading resulted in about 24% and 52% improvement in KIC of cured epoxy thermosets, respectively. RGO sheets were observed to bridge the micro-crack and debond/delaminate during fracture process due to the poor filler/matrix and filler/filler interface, which should be the key elements of the toughening effect.
Fabric-based triboelectric nanogenerators (TENGs) are promising candidates as wearable energy-harvesting devices and self-powered sensors. Booting the power generation performance is an eternal ...pursuit for TENGs. Herein, an efficient approach was proposed to enhance the triboelectric performance of commercial velvet fabric by enriching the fiber surface with hierarchical structures and amide bonds through chemical grafting of carbon nanotube (CNT) and poly(ethylenimine) (PEI) via a polyamidation reaction. With an optimized modifier concentration, the fabric-based TENG easily achieved over 10 times improvement in output voltage and current at a low modifier content of less than 1 wt %. The modified-fabric-based TENG was fully washable and exhibited excellent robustness and long-term stability. With a maximum power density of 3.2 W/m2 achieved on a 5 × 106 Ω external resistor, the TENG was able to serve as a power source for various small electronics such as pedometer, digital watch, calculator, and digital timer. In addition, the TENG demonstrated capability in self-powered tactile and pressure sensing and promising potential in human–computer interface applications. The approach proposed provides a feasible path for boosting the triboelectric performance of fabric-based TENGs and gives insights into the design of fabric-based nanogenerators and smart textiles.
Antiviral therapeutics with profiles of high potency, low resistance, panserotype, and low toxicity remain challenging, and obtaining such agents continues to be an active area of therapeutic ...development. Due to their unique three-dimensional structural features, spirooxindoles have been identified as privileged chemotypes for antiviral drug development. Among them, spiro-pyrazolopyridone oxindoles have been recently reported as potent inhibitors of dengue virus NS4B, leading to the discovery of an orally bioavailable preclinical candidate (R)-44 with excellent in vivo efficacy in a dengue viremia mouse model. This review highlights recent advances in the development of biologically active spirooxindoles for their antiviral potential, primarily focusing on the structure–activity relationships (SARs) and modes of action, as well as future directions to achieve more potent analogues toward a viable antiviral therapy.
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•The prepared hydrogel showed a great self-healing ability and spontaneously self-healed within 15 s.•The prepared hydrogel was highly transparent, with transmittance reaching as high ...as 90%.•The developed hydrogel sensor was able to sense very subtle external pressure such as water drop.•The sensor worked stably on the detection of human motions such as finger, knee or elbow movements.
Wearable sensors have emerged as favored novel devices for human healthcare. Current sensors, however, suffer from low sensitivity, non-transparency, and lack of self-healing ability. In this study, we synthesized a polyvinyl alcohol/cellulose nanofibril (PVA/CNF) hydrogel with dual-crosslinked networks for highly transparent, stretchable, and self-healing pressure and strain sensors. The hydrogel contains dynamic borate bonds, metal–carboxylate coordination bonds, and hydrogen bonds, all of which contribute to the hydrogel’s superior dimensional stability, mechanical strength and flexibility, and spontaneous self-healing ability as compared to traditional PVA hydrogels. The developed hydrogel has a moderate modulus of 11.2 kPa, and a high elongation rate of 1900%. It spontaneously self-heals within 15 s upon contact without any external stimuli, has a high transmittance of over 90%, and has excellent compatibility with human fibroblasts. The capacitive sensor developed based on the PVA/CNF hydrogel has high sensitivity to very subtle pressure changes, such as small water droplets. When used as a strain sensor, it was capable of detecting and monitoring various human motions such as finger, knee, elbow, and head movements, breathing, and gentle tapping. The developed hydrogel and sensors not only show great potential in electronic skin, personal healthcare, and wearable devices, but may also inspire the development of transparent, intelligent skin-like sensors.
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