Abstract
Background
The high cost and insufficient supply of human papillomavirus (HPV) vaccines have slowed the pace of controlling cervical cancer. A phase III clinical trial was conducted to ...evaluate the efficacy, safety, and immunogenicity of a novel Escherichia coli-produced bivalent HPV-16/18 vaccine.
Methods
A multicenter, randomized, double-blind trial started on November 22, 2012 in China. In total, 7372 eligible women aged 18–45 years were age-stratified and randomly assigned to receive three doses of the test or control (hepatitis E) vaccine at months 0, 1, and 6. Co-primary endpoints included high-grade genital lesions and persistent infection (over 6 months) associated with HPV-16/18. The primary analysis was performed on a per-protocol susceptible population of individuals who were negative for relevant HPV type-specific neutralizing antibodies (at day 0) and DNA (at day 0 through month 7) and who received three doses of the vaccine. This report presents data from a prespecified interim analysis used for regulatory submission.
Results
In the per-protocol cohort, the efficacies against high-grade genital lesions and persistent infection were 100.0% (95% confidence interval = 55.6% to 100.0%, 0 of 3306 in the vaccine group vs 10 of 3296 in the control group) and 97.8% (95% confidence interval = 87.1% to 99.9%, 1 of 3240 vs 45 of 3246), respectively. The side effects were mild. No vaccine-related serious adverse events were noted. Robust antibody responses for both types were induced and persisted for at least 42 months.
Conclusions
The E coli-produced HPV-16/18 vaccine is well tolerated and highly efficacious against HPV-16/18–associated high-grade genital lesions and persistent infection in women.
Sortase‐mediated hydrazinolysis of proteins with hydrazine or its derivatives was developed for the production of recombinant protein hydrazides. This process provides an alternative approach for ...protein semisynthesis through the use of recombinant protein hydrazides as thioester surrogates. It also provides an alternative method for C‐terminal modification of proteins with functional units as well as for the preparation of C‐to‐C fusion proteins.
Takes all sort(ase)s: Sortase A mediated hydrazinolysis reactions of proteins with hydrazine or its derivatives were developed as an efficient process for the production of recombinant protein hydrazides. This reaction provides an alternative approach for the semichemical synthesis as well as C‐terminal modification of proteins.
Just add oil: A new detergent‐free method was developed to synthesize lipidated proteins using a light‐activatable solubilizing side chain (in dashed circle, see scheme) to assist the ligation of the ...lipopeptides. This method allows the efficient preparation of a phosphatidylethanolamine‐conjugated autophagosomal marker protein (LC3‐II) as well as labeled derivatives of LC3‐II, which can be used to study autophagy regulation.
CRISPR-Cas9 has emerged as a powerful technology that relies on Cas9/sgRNA ribonucleoprotein complexes (RNPs) to target and edit DNA. However, many therapeutic targets cannot currently be accessed ...due to the lack of carriers that can deliver RNPs systemically. Here, we report a generalizable methodology that allows engineering of modified lipid nanoparticles to efficiently deliver RNPs into cells and edit tissues including muscle, brain, liver, and lungs. Intravenous injection facilitated tissue-specific, multiplexed editing of six genes in mouse lungs. High carrier potency was leveraged to create organ-specific cancer models in livers and lungs of mice though facile knockout of multiple genes. The developed carriers were also able to deliver RNPs to restore dystrophin expression in DMD mice and significantly decrease serum PCSK9 level in C57BL/6 mice. Application of this generalizable strategy will facilitate broad nanoparticle development for a variety of disease targets amenable to protein delivery and precise gene correction approaches.
Sex‐biased dispersal: a review of the theory Li, Xiang‐Yi; Kokko, Hanna
Biological reviews of the Cambridge Philosophical Society,
April 2019, Letnik:
94, Številka:
2
Journal Article
Recenzirano
Odprti dostop
ABSTRACT
Dispersal is ubiquitous throughout the tree of life: factors selecting for dispersal include kin competition, inbreeding avoidance and spatiotemporal variation in resources or habitat ...suitability. These factors differ in whether they promote male and female dispersal equally strongly, and often selection on dispersal of one sex depends on how much the other disperses. For example, for inbreeding avoidance it can be sufficient that one sex disperses away from the natal site. Attempts to understand sex‐specific dispersal evolution have created a rich body of theoretical literature, which we review here. We highlight an interesting gap between empirical and theoretical literature. The former associates different patterns of sex‐biased dispersal with mating systems, such as female‐biased dispersal in monogamous birds and male‐biased dispersal in polygynous mammals. The predominant explanation is traceable back to Greenwood's () ideas of how successful philopatric or dispersing individuals are at gaining mates or the resources required to attract them. Theory, however, has developed surprisingly independently of these ideas: models typically track how immigration and emigration change relatedness patterns and alter competition for limiting resources. The limiting resources are often considered sexually distinct, with breeding sites and fertilizable females limiting reproductive success for females and males, respectively. We show that the link between mating system and sex‐biased dispersal is far from resolved: there are studies showing that mating systems matter, but the oft‐stated association between polygyny and male‐biased dispersal is not a straightforward theoretical expectation. Here, an important understudied factor is the extent to which movement is interpretable as an extension of mate‐searching (e.g. are matings possible en route or do they only happen after settling in new habitat – or can females perhaps move with stored sperm). We also point out other new directions for bridging the gap between empirical and theoretical studies: there is a need to build Greenwood's influential yet verbal explanation into formal models, which also includes the possibility that an individual benefits from mobility as it leads to fitness gains in more than one final breeding location (a possibility not present in models with a very rigid deme structure). The order of life‐cycle events is likewise important, as this impacts whether a departing individual leaves behind important resources for its female or male kin, or perhaps both, in the case of partially overlapping resource use.
Cleavage of transfer (t)RNA and ribosomal (r)RNA are critical and conserved steps of translational control for cells to overcome varied environmental stresses. However, enzymes that are responsible ...for this event have not been fully identified in high eukaryotes. Here, we report a mammalian tRNA/rRNA-targeting endoribonuclease: SLFN13, a member of the Schlafen family. Structural study reveals a unique pseudo-dimeric U-pillow-shaped architecture of the SLFN13 N'-domain that may clamp base-paired RNAs. SLFN13 is able to digest tRNAs and rRNAs in vitro, and the endonucleolytic cleavage dissevers 11 nucleotides from the 3'-terminus of tRNA at the acceptor stem. The cytoplasmically localised SLFN13 inhibits protein synthesis in 293T cells. Moreover, SLFN13 restricts HIV replication in a nucleolytic activity-dependent manner. According to these observations, we term SLFN13 RNase S13. Our study provides insights into the modulation of translational machinery in high eukaryotes, and sheds light on the functional mechanisms of the Schlafen family.
Phycocyanobilin (PCB) is a linear open-chain tetrapyrrole chromophore that captures and senses light and a variety of biological activities, such as anti-oxidation, anti-cancer, and ...anti-inflammatory. In this paper, the biological activities of PCB are reviewed, and the related mechanism of PCB and its latest application in disease treatment are introduced. PCB can resist oxidation by scavenging free radicals, inhibiting the activity of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, and delaying the activity of antioxidant enzymes. In addition, PCB can also be used as an excellent anti-inflammatory agent to reduce the proinflammatory factors IL-6 and IFN-γ and to up-regulate the production of anti-inflammatory cytokine IL-10 by inhibiting the inflammatory signal pathways NF-κB and mitogen-activated protein kinase (MAPK). Due to the above biological activities of phycocyanobilin PCB, it is expected to become a new effective drug for treating various diseases, such as COVID-19 complications, atherosclerosis, multiple sclerosis (MS), and ischaemic stroke (IS).
Interferon regulatory factor (IRF) 3 and IRF7 are master regulators of type I interferon (IFN‐I)‐dependent antiviral innate immunity. Upon viral infection, a positive feedback loop is formed, wherein ...IRF7 promotes further induction of IFN‐I in the later stage. Thus, it is critical to maintain a suitably low level of IRF7 to avoid the hyperproduction of IFN‐I. In this study, we find that early expression of IFN‐I‐dependent STAT1 promotes the expression of XAF1 and that XAF1 is associated specifically with IRF7 and inhibits the activity of XIAP. XAF1‐knockout and XIAP‐transgenic mice display resistance to viral infection, and this resistance is accompanied by increases in IFN‐I production and IRF7 stability. Mechanistically, we find that the XAF1‐XIAP axis controls the activity of KLHL22, an adaptor of the BTB‐CUL3‐RBX1 E3 ligase complex through a ubiquitin‐dependent pathway. CUL3‐KLHL22 directly targets IRF7 and catalyzes its K48‐linked ubiquitination and proteasomal degradation. These findings reveal unexpected functions of the XAF1‐XIAP axis and KLHL22 in the regulation of IRF7 stability and highlight an important target for antiviral innate immunity.
Synopsis
A XAF1‐XIAP‐KLHL22 axis functions as a major regulator to control IRF7 protein abundance and helps maintaining proper IFN‐I production.
XAF1‐KO and XIAP transgenic mice display resistance to viral infection.
XAF1‐KO and XIAP transgenic mice show increased IFN‐I production and IRF7 stability.
KLHL22 directly targets IRF7, catalyzes its K48‐linked ubiquitination and promotes its proteasomal degradation.
The XAF1‐XIAP axis controlls the activity of KLHL22 through ubiquitin‐dependent pathways.
A XAF1‐XIAP‐KLHL22 axis functions as a major regulator to control IRF7 protein abundance and helps maintaining proper IFN‐I production.
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