Increased risk of colorectal cancer (CRC) is associated with altered intestinal microbiota as well as short‐chain fatty acids (SCFAs) reduction of output The energy source of colon cells relies ...mainly on three SCFAs, namely butyrate (BT), propionate, and acetate, while CRC transformed cells rely mainly on aerobic glycolysis to provide energy. This review summarizes recent research results for dysregulated glucose metabolism of SCFAs, which could be initiated by gut microbiome of CRC. Moreover, the relationship between SCFA transporters and glycolysis, which may correlate with the initiation and progression of CRC, are also discussed. Additionally, this review explores the linkage of BT to transport of SCFAs expressions between normal and cancerous colonocyte cell growth for tumorigenesis inhibition in CRC. Furthermore, the link between gut microbiota and SCFAs in the metabolism of CRC, in addition, the proteins and genes related to SCFAs‐mediated signaling pathways, coupled with their correlation with the initiation and progression of CRC are also discussed. Therefore, targeting the SCFA transporters to regulate lactate generation and export of BT, as well as applying SCFAs or gut microbiota and natural compounds for chemoprevention may be clinically useful for CRCs treatment. Future research should focus on the combination these therapeutic agents with metabolic inhibitors to effectively target the tumor SCFAs and regulate the bacterial ecology for activation of potent anticancer effect, which may provide more effective application prospect for CRC therapy.
Short‐chain fatty acids (SCFAs) produced in the human colon are the major products of bacterial fermentation of undigested dietary fiber and starch that escape absorption in the small intestine, and serve as a major source of energy for colonocytes. SCFAs are microbial‐derived metabolites, which are readily absorbed and used as an energy source by colonocytes. Several mechanisms have been proposed to underlie the anticancerous mechanisms of SCFAs. SCFAs reduce epithelial inflammation and trigger cancer cell apoptosis via p21 activity, providing an important defensive capacity against colorectal carcinogenesis.
This is the first randomised controlled trial for assessment of the immunogenicity and safety of a candidate non-replicating adenovirus type-5 (Ad5)-vectored COVID-19 vaccine, aiming to determine an ...appropriate dose of the candidate vaccine for an efficacy study.
This randomised, double-blind, placebo-controlled, phase 2 trial of the Ad5-vectored COVID-19 vaccine was done in a single centre in Wuhan, China. Healthy adults aged 18 years or older, who were HIV-negative and previous severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection-free, were eligible to participate and were randomly assigned to receive the vaccine at a dose of 1 × 1011 viral particles per mL or 5 × 1010 viral particles per mL, or placebo. Investigators allocated participants at a ratio of 2:1:1 to receive a single injection intramuscularly in the arm. The randomisation list (block size 4) was generated by an independent statistician. Participants, investigators, and staff undertaking laboratory analyses were masked to group allocation. The primary endpoints for immunogenicity were the geometric mean titres (GMTs) of specific ELISA antibody responses to the receptor binding domain (RBD) and neutralising antibody responses at day 28. The primary endpoint for safety evaluation was the incidence of adverse reactions within 14 days. All recruited participants who received at least one dose were included in the primary and safety analyses. This study is registered with ClinicalTrials.gov, NCT04341389.
603 volunteers were recruited and screened for eligibility between April 11 and 16, 2020. 508 eligible participants (50% male; mean age 39·7 years, SD 12·5) consented to participate in the trial and were randomly assigned to receive the vaccine (1 × 1011 viral particles n=253; 5 × 1010 viral particles n=129) or placebo (n=126). In the 1 × 1011 and 5 × 1010 viral particles dose groups, the RBD-specific ELISA antibodies peaked at 656·5 (95% CI 575·2–749·2) and 571·0 (467·6–697·3), with seroconversion rates at 96% (95% CI 93–98) and 97% (92–99), respectively, at day 28. Both doses of the vaccine induced significant neutralising antibody responses to live SARS-CoV-2, with GMTs of 19·5 (95% CI 16·8–22·7) and 18·3 (14·4–23·3) in participants receiving 1 × 1011 and 5 × 1010 viral particles, respectively. Specific interferon γ enzyme-linked immunospot assay responses post vaccination were observed in 227 (90%, 95% CI 85–93) of 253 and 113 (88%, 81–92) of 129 participants in the 1 × 1011 and 5 × 1010 viral particles dose groups, respectively. Solicited adverse reactions were reported by 183 (72%) of 253 and 96 (74%) of 129 participants in the 1 × 1011 and 5 × 1010 viral particles dose groups, respectively. Severe adverse reactions were reported by 24 (9%) participants in the 1 × 1011 viral particles dose group and one (1%) participant in the 5 × 1010 viral particles dose group. No serious adverse reactions were documented.
The Ad5-vectored COVID-19 vaccine at 5 × 1010 viral particles is safe, and induced significant immune responses in the majority of recipients after a single immunisation.
National Key R&D Programme of China, National Science and Technology Major Project, and CanSino Biologics.
Perovskite photovoltaics are strong potential candidates to drive low‐power off‐grid electronics for indoor applications. Compared with rigid devices, flexible perovskite devices can provide a more ...suitable surface for indoor small electronic devices, enabling them have a broader indoor application prospect. However, the mechanical stability of flexible perovskite photovoltaics is an urgent issue solved. Herein, a kind of 3D crosslinking agent named borax is selected to carry out grain boundary penetration treatment on perovskite film to realize full‐dimensional stress release. This strategy improves the mechanical and phase stabilities of perovskite films subjected to external forces or large temperature changes. The fabricated perovskite photovoltaics deliver a champion power conversion efficiency (PCE) of 21.63% under AM 1.5G illumination, which is the highest one to date. The merit of low trap states under weak light makes the devices present a superior indoor PCE of 31.85% under 1062 lux (LED, 2956 K), which is currently the best flexible perovskite indoor photovoltaic device. This work provides a full‐dimensional grain boundary stress release strategy for highly stable flexible perovskite indoor photovoltaics.
A grain boundary stress release strategy is proposed for high‐stability flexible perovskite indoor photovoltaics by the grain boundary penetration with borax 3D stretchable molecules. The full‐dimensional grain boundary stress release enables the flexible perovskite photovoltaics deliver a champion power conversion efficiency (PCE) of 21.63% under AM 1.5G illumination and an indoor PCE of 31.85% under 1062 lux.
The catalytic activity of nanocrystal catalysts depends strongly on their structures. Herein, we report three distinct structures of Fe3O4 nanocrystals, cluster spheres, octahedra, and triangular ...plates, prepared by a similar hydrothermal procedure. Additionally, the three Fe3O4 nanostructures were used as peroxidase nanomimetics and the correlation between the catalytic activities and the structures was first explored by using 3,3′,5,5′‐tetramethylbenzidine and H2O2 as peroxidase substrates. The results showed that the peroxidase‐like activities of the Fe3O4 nanocrystals were structure dependent and followed the order cluster spheres>triangular plates>octahedra; this order was closely related to their preferential exposure of catalytically active iron atoms or crystal planes. Such investigation is of great significance for peroxidase nanomimetics with enhanced activity and utilization.
A question of shape: Three distinct structures of Fe3O4 nanocrystals, cluster spheres, octahedra, and triangular plates, have been fabricated by a similar hydrothermal procedure. These different Fe3O4 nanostructures had different specific surface areas and exposed crystal planes, and thus exhibited different levels of peroxidase‐like activities, in the order of cluster spheres> triangular plates>octahedra (see figure).
ELONGATED HYPOCOTYL 5 (HY5), a basic domain/leucine zipper (bZIP) transcription factor, acts as a master regulator of transcription to promote photomorphogenesis. At present, it's unclear whether HY5 ...uses additional mechanisms to inhibit hypocotyl elongation. Here, we demonstrate that HY5 enhances the activity of GSK3-like kinase BRASSINOSTEROID-INSENSITIVE 2 (BIN2), a key repressor of brassinosteroid signaling, to repress hypocotyl elongation. We show that HY5 physically interacts with and genetically acts through BIN2 to inhibit hypocotyl elongation. The interaction of HY5 with BIN2 enhances its kinase activity possibly by the promotion of BIN2 Tyr
autophosphorylation, and subsequently represses the accumulation of the transcription factor BRASSINAZOLE-RESISTANT 1 (BZR1). Leu
of HY5 is found to be important for the HY5-BIN2 interaction and HY5-mediated regulation of BIN2 activity, without affecting the transcriptional activity of HY5. HY5 levels increase with light intensity, which gradually enhances BIN2 activity. Thus, our work reveals an additional way in which HY5 promotes photomorphogenesis, and provides an insight into the regulation of GSK3 activity.
Summary
The continuing nitrogen (N) deposition observed worldwide alters ecosystem nutrient cycling and ecosystem functioning. Litter decomposition is a key process contributing to these changes, but ...the numerous mechanisms for altered decomposition remain poorly identified.
We assessed these different mechanisms with a decomposition experiment using litter from four abundant species (Achnatherum sibiricum, Agropyron cristatum, Leymus chinensis and Stipa grandis) and litter mixtures representing treatment‐specific community composition in a semi‐arid grassland under long‐term simulation of six different rates of N deposition.
Decomposition increased consistently with increasing rates of N addition in all litter types. Higher soil manganese (Mn) availability, which apparently was a consequence of N addition‐induced lower soil pH, was the most important factor for faster decomposition. Soil C : N ratios were lower with N addition that subsequently led to markedly higher bacterial to fungal ratios, which also stimulated litter decomposition.
Several factors contributed jointly to higher rates of litter decomposition in response to N deposition. Shifts in plant species composition and litter quality played a minor role compared to N‐driven reductions in soil pH and C : N, which increased soil Mn availability and altered microbial community structure. The soil‐driven effect on decomposition reported here may have long‐lasting impacts on nutrient cycling, soil organic matter dynamics and ecosystem functioning.
In the past 37 years, human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) has undergone various major transmission routes in China, with the world most complex co-circulating ...HIV-1 subtypes, even the prevalence is still low. In response to the first epidemic outbreak of HIV in injecting drug users and the second one by illegal commercial blood collection, China issued the Anti-Drug Law and launched the Blood Donation Act and nationwide nucleic acid testing, which has avoided 98,232 to 211,200 estimated infections and almost ended the blood product-related infection. China has been providing free antiretroviral therapy (ART) since 2003, which covered >80% of the identified patients and achieved a viral suppression rate of 91%. To bend the curve of increasing the disease burden of HIV and finally end the epidemic, China should consider constraining HIV spread through sexual transmission, narrowing the gaps in identifying HIV cases, and the long-term effectiveness and safety of ART in the future.
The E3 ligase CONSTITUTIVELY PHOTOMORPHOGENIC 1 (COP1) has been known to mediate key signaling factors for degradation via the ubiquitin/26S proteasome pathway in both plants and animals. Here, we ...report a noncanonical function of Arabidopsis COP1, the central repressor of photomorphogenesis, in the form of a COP1/ SUPPRESSOR of phyA-105 (SPA) complex. We show that the COP1/SPA complex associates with and stabilizes PHYTOCHROME INTERACTING FACTOR 3 (PIF3) to repress photomorphogenesis in the dark. We identify the GSK3-like kinase BRASSINOSTEROID-INSENSITIVE 2 (BIN2) as a kinase of PIF3, which induces PIF3 degradation via 26S proteasome during skotomorphogenesis. Mutations on two typical BIN2 phosphorylation motifs of PIF3 lead to a strong stabilization of the protein in the dark. We further show that the COP1/SPA complex promotes PIF3 stability by repressing BIN2 activity. Intriguingly, without affecting BIN2 expression, the COP1/SPA complex modulates BIN2 activity through interfering with BIN2–PIF3 interaction, thereby inhibiting BIN2-mediated PIF3 phosphorylation and degradation. Taken together, our results suggest another paradigm for COP1/SPA complex action in the precise control of skotomorphogenesis.
Abstract We demonstrated that three different types of water-soluble fullerenes materials can intercept all of the major physiologically relevant ROS. C60 (C(COOH)2 )2 , C 60OH 22 , and Gd@C 82OH 22 ...can protect cells against H2 O2 -induced oxidative damage, stabilize the mitochondrial membrane potential and reduce intracellular ROS production with the following relative potencies: Gd@C 82OH 22 ≥ C 60OH 22 > C60 (C(COOH)2 )2 . Consistent with their cytoprotective abilities, these derivatives can scavenge the stable 2,2-diphenyl-1-picryhydrazyl radical (DPPH), and the reactive oxygen species (ROS) superoxide radical anion (O2 − ), singlet oxygen, and hydroxyl radical (HO ), and can also efficiently inhibit lipid peroxidation in vitro . The observed differences in free radical-scavenging capabilities support the hypothesis that both chemical properties, such as surface chemistry induced differences in electron affinity, and physical properties, such as degree of aggregation, influence the biological and biomedical activities of functionalized fullerenes. This represents the first report that different types of fullerene derivatives can scavenge all physiologically relevant ROS. The role of oxidative stress and damage in the etiology and progression of many diseases suggests that these fullerene derivatives may be valuable in vivo cytoprotective and therapeutic agents.
Abnormal tumor microenvironment (TME) facilitates tumor proliferation and metastasis and establishes physiological barriers for effective transport of therapeutics inside the tumor, posing great ...challenges for cancer treatment. We designed a core‐satellite size transformable nanoframework (denoted as T‐PFRT) that can synchronously adapt to and remold TME for augmenting photodynamic therapy to inhibit tumor growth and prevent tumor metastasis. Upon matrix metalloproteinase 2 (MMP2)‐responsive dissociation of the nanoframework in TME, the core structure loaded with TGFβ signaling pathway inhibitor and oxygen‐carrying hemoglobin aims to stroma remodeling and hypoxia relief, allowing photosensitizer‐encapsulated satellite particles to penetrate to deep‐seated tumor for oxygen‐fueled photodynamic therapy. T‐PFRT could overcome the stroma and hypoxia barriers for delivering therapeutics and gain excellent therapeutic outcomes in the treatment of primary and metastatic tumors.
We designed a core‐satellite nanoframework (T‐PFRT) that can synchronously adapt to and remold tumor microenvironment (TME) via MMP2‐triggered size transformation, TGFβ inhibition‐mediated stroma remodeling and hemoglobin‐enabled hypoxia relief. By coordinating TME normalization with photodynamic therapy (PDT), superior therapeutic outcomes could be gained in the treatment of primary and metastatic tumors.
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