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• The mRNA booster provides additional protection against Omicron-related infections, especially severe infections. • mRNA vaccine effectiveness against Omicron-related infections did significant decrease by more than 6 months after 2-dose vaccination. • After 3 months, the 3-dose mRNA vaccine still provides additional protection against any Omicron infection and severe infection, with respective vaccine efficacy rates of 55.39% (95% CI, 49.63-61.15), and 73.39% (95% CI, 66.88, 79.90). We aimed to systematically evaluate the effectiveness of the currently available mRNA vaccines and boosters for the Omicron variant. We searched for literature published on PubMed, Embase, Web of Science and preprint servers (medRxiv and bioRxiv) from January 1, 2020 to June 20, 2022. The pooled effect estimate was calculated by the random-effects model. We selected 34 eligible studies in the meta-analysis from 4336 records. For the 2-dose vaccinated group, the mRNA vaccine effectiveness (VE) was 34.74%, 36%, and 63.80% against any Omicron infection, symptomatic infection and severe infection, respectively. For the 3-dose vaccinated group, the mRNA VE was 59.80%, 57.47%, and 87.22% against any infection, symptomatic infection and severe infection. For the 3-dose vaccinated group, the relative mRNA VE was 34.74%, 37.36%, and 63.80% against any infection, symptomatic infection and severe infection. Six months after the 2-dose vaccination, VE with any infection, symptomatic infection, and severe infection decreased to 33.4%, 16.79%, and 60.43%. Three months after the 3-dose vaccination, VE for any infection and severe infection decreased to 55.39% and 73.39%. Two-dose mRNA vaccines failed to provide sufficient protection against any Omicron infection and symptomatic infection, while 3-dose mRNA vaccines continued to provide effective protection after 3 months. [ABSTRACT FROM AUTHOR]

Research has been conducted on integrin alphaLbeta2 I domain. The structure of this domain demonstrates open ligand binding conformation and integrin Ig superfamily interface.

Eukaryotic thrombospondin type 3 repeat (TT3R) is an efficient calcium ion (Ca 2+ ) binding motif only found in mammalian thrombospondin family. TT3R has also been found in prokaryotic cellulase Cel5G, which was thought to forfeit the Ca 2+ -binding capability due to the formation of intra-repeat disulfide bonds, instead of the inter-repeat ones possessed by eukaryotic TT3Rs. In this study, we have identified an enormous number of prokaryotic TT3R-containing proteins belonging to several different protein families, including outer membrane protein A (OmpA), an important structural protein connecting the outer membrane and the periplasmic peptidoglycan layer in gram-negative bacteria. Here, we report the crystal structure of the periplasmic region of OmpA from Capnocytophaga gingivalis , which contains a linker region comprising five consecutive TT3Rs. The structure of OmpA-TT3R exhibits a well-ordered architecture organized around two tightly-coordinated Ca 2+ and confirms the presence of abnormal intra-repeat disulfide bonds. Further mutagenesis studies showed that the Ca 2+ -binding capability of OmpA-TT3R is indeed dependent on the proper formation of intra-repeat disulfide bonds, which help to fix a conserved glycine residue at its proper position for Ca 2+ coordination. Additionally, despite lacking inter-repeat disulfide bonds, the interfaces between adjacent OmpA-TT3Rs are enhanced by both hydrophobic and conserved aromatic-proline interactions. [ABSTRACT FROM AUTHOR]

Surface proteins attached by sortases to the cell wall envelope of bacterial pathogens play important roles during infection. Sorting and attachment of these proteins is directed by C-terminal signals. Sortase B of S. aureus recognizes a motif NPQTN, cleaves the polypeptide after the Thr residue, and attaches the protein to pentaglycine cross-bridges. Sortase B of B. anthracis is thought to recognize the NPKTG motif, and attaches surface proteins to m-diaminopimelic acid cross-bridges. We have determined crystal structure of sortase B from B. anthracis and S. aureus at 1.6 and 2.0 Å resolutions, respectively. These structures show a β-barrel fold with α-helical elements on its outside, a structure thus far exclusive to the sortase family. A putative active site located on the edge of the β-barrel is comprised of a Cys-His-Asp catalytic triad and presumably faces the bacterial cell surface. A putative binding site for the sorting signal is located nearby. [Copyright &y& Elsevier]

Stereocilia, the mechanosensory organelles on the apical surface of hair cells, are necessary to detect sound and carry out mechano-electrical transduction. An electron-dense matrix is located at the distal tips of stereocilia and plays crucial roles in the regulation of stereocilia morphology. Mutations of the components in this tip complex density (TCD) have been associated with profound deafness. However, the mechanism underlying the formation of the TCD is largely unknown. Here, we discover that the specific multivalent interactions among the Whirlin-myosin 15 (Myo15)-Eps8 complex lead to the formation of the TCD-like condensates through liquid-liquid phase separation. The reconstituted TCD-like condensates effectively promote actin bundling. A deafness-associated mutation of Myo15 interferes with the condensates formation and consequently impairs actin bundling. Therefore, our study not only suggests that the TCD in hair cell stereocilia may form via phase separation but it also provides important clues for the possible mechanism underlying hearing loss. • Stereocilia tip complex proteins Whirlin, Myo15, and Eps8 form phase separation • Multivalent interactions are essential for tip complex condensate formation • Whirlin-Myo15-Eps8 condensates promote actin bundling • Deafness-associated Myo15 mutation impairs condensate formation and actin bundling Lin et al. report that the specific multivalent interactions among Whirlin-Myo15-Eps8 tip complex in hair cell stereocilia lead to the formation of highly dense condensates through liquid-liquid phase separation. The condensates effectively promote actin bundling, while the deafness-associated mutation of Myo15 interferes with condensate formation and consequently impairs actin bundling. [ABSTRACT FROM AUTHOR]

Summary Exocytosis of synaptic vesicles and dense-core vesicles requires both the Munc13 and CAPS (Ca2+-dependent activator proteins for secretion) proteins. CAPS contains a soluble N -ethylmaleimide-sensitive factor attachment protein receptor (SNARE)-binding region (called the DAMH domain), which has been found to be essential for SNARE-mediated exocytosis. Here we report a crystal structure of the CAPS-1 DAMH domain at 2.9-Å resolution and reveal a dual role of CAPS-1 in SNARE complex formation. CAPS-1 plays an inhibitory role dependent on binding of the DAMH domain to the MUN domain of Munc13-1, which hinders the ability of Munc13 to catalyze opening of syntaxin-1, inhibiting SNARE complex formation, and a chaperone role dependent on interaction of the DAMH domain with the syntaxin-1/SNAP-25 complex, which stabilizes the open conformation of Syx1, facilitating SNARE complex formation. Our results suggest that CAPS-1 facilitates SNARE complex formation via the DAMH domain in a manner dependent on sequential and cooperative interaction with Munc13-1 and SNARE proteins. Graphical Abstract Highlights • A structure of the DAMH domain of CAPS is presented • CAPS hinders the ability of Munc13to catalyze opening of syntaxin-1 • CAPS stabilizes the open state of syntaxin-1 to facilitate SNARE complex formation CAPS and Munc13, as major priming factors for exocytosis, play an important role in SNARE-mediated membrane fusion. Zhou et al. present the crystal structure of the DAMH domain of CAPS and reveal a molecular link between the roles of CAPS and Munc13 in SNARE complex formation. [ABSTRACT FROM AUTHOR]

The enzyme prephenate dehydrogenase catalyzes the oxidative decarboxylation of prephenate to 4-hydroxyphenylpyruvate for the biosynthesis of tyrosine. Prephenate dehydrogenases exist as either monofunctional or bifunctional enzymes. The bifunctional enzymes are diverse, since the prephenate dehydrogenase domain is associated with other enzymes, such as chorismate mutase and 3-phosphoskimate 1-carboxyvinyltransferase. We report the first crystal structure of a monofunctional prephenate dehydrogenase enzyme from the hyperthermophile Aquifex aeolicus in complex with NAD+. This protein consists of two structural domains, a modified nucleotide-binding domain and a novel helical prephenate binding domain. The active site of prephenate dehydrogenase is formed at the domain interface and is shared between the subunits of the dimer. We infer from the structure that access to the active site is regulated via a gated mechanism, which is modulated by an ionic network involving a conserved arginine, Arg250. In addition, the crystal structure reveals for the first time the positions of a number of key catalytic residues and the identity of other active site residues that may participate in the reaction mechanism; these residues include Ser126 and Lys246 and the catalytic histidine, His147. Analysis of the structure further reveals that two secondary structure elements, β3 and β7, are missing in the prephenate dehydrogenase domain of the bifunctional chorismate mutase-prephenate dehydrogenase enzymes. This observation suggests that the two functional domains of chorismate mutase-prephenate dehydrogenase are interdependent and explains why these domains cannot be separated. [ABSTRACT FROM AUTHOR]

The nuclear protooncoprotein SKI negatively regulates transforming growth factor-β (TGF-β) signaling in cell growth and differentiation. It directly interacts with the Smads and, by various mechanisms, represses the transcription of TGF-β-responsive genes. SKI is a multidomain protein that includes a domain bearing high sequence similarity with the retinal determination protein Dachshund (the Dachshund homology domain, DHD). The SKI-DHD has been implicated in SMAD-2/3, N-CoR, SKIP, and PML-RARalpha binding. The 1.65 Å crystal structure of the Dachshund homology domain of human SKI is reported here. The SKI-DHD adopts a mixed α/β structure which includes features found in the forkhead/winged-helix family of DNA binding proteins, although SKI-DHD is not a DNA binding domain. Residues that form a contiguous surface patch on SKI-DHD are conserved within the Ski/Sno family and with Dachshund, suggesting that this domain may mediate intermolecular interactions common to these proteins. [Copyright &y& Elsevier]

Purpose: The purpose of the study is to quantitatively assess the association between C-reactive protein (CRP) and all-cause, cardiovascular disease (CVD), and cancer mortality; a dose-response meta-analysis was performed on data from cohort studies in general population.Methods: The published relevant articles were searched for in PubMed, Web of Science, and Embase until September 21, 2019. The pooled relative risk (RR) was estimated by random effects of generalized least square regression models. The dose-response relationship was modeled using restricted cubic splines.Results: Twenty-two articles were screened for the meta-analysis. Compared with the low CRP group, the pooled RR in the moderate CRP group was 1.30 (95% confidence interval (CI), 1.20-1.41) for all-cause mortality and 1.43 (95% CI, 1.22-1.68) for CVD mortality; the pooled RR in the high CRP group was 1.75 (95% CI, 1.59-1.92) for all-cause mortality, 2.02 (95% CI, 1.70-2.41) for CVD mortality, and 1.32 (95% CI, 1.21-1.45) for cancer mortality.Conclusions: This meta-analysis demonstrated the relationships between CRP and mortality were nonlinear for all-cause and CVD mortality and were linear for cancer and noncardiovascular mortality. [ABSTRACT FROM AUTHOR]

Summary The membrane-associated guanylate kinase (MAGUK) scaffold proteins share a signature guanylate kinase (GK) domain. Despite their diverse functional roles in cell polarity control and synaptic signaling, the currently known mode of action of MAGUK GK is via its binding to phosphorylated short peptides from target proteins. Here, we discover that the GK domain of DLG MAGUK binds to an unphosphorylated and autonomously folded domain within the stalk region (MAGUK binding stalk [MBS] domain) of a kinesin motor KIF13B with high specificity and affinity. The structure of DLG4 GK in complex with KIF13B MBS reveals the molecular mechanism governing this atypical GK/target recognition mode and provides insights into DLG/KIF13B complex-mediated regulation of diverse cellular processes such as asymmetric cell division. We further show that binding to non-phosphorylated targets is another general property of MAGUK GKs, thus expanding the mechanisms of action of the MAGUK family proteins. [ABSTRACT FROM AUTHOR]

The biodegradable hydrogels with a 3D network structure have potential applications in bone tissue engineering. Here, inspired by natural bone, the novel organic-inorganic composites (GelMPC-x) with high compressive strength are designed via adding magnesium oxide/calcium dihydrogen phosphate (MPC) powders into the oxidized dextran/gelatin (OD/Gel) hydrogel. GelMPC-x composites can trigger the gelation of OD/Gel hydrogel through an acid-alkaline reaction between magnesium oxide and calcium dihydrogen phosphate, thus forming an organic-inorganic double network. The cross-linked network between oxidized dextran and gelatin, and the multiple weak interactions between OD/Gel hydrogel and MPC enable the composites to have remarkable compressive strength (77–652 kPa) at the strain of 44 %. More importantly, the composites with appropriate MPC content possess superior injectability, high porosity, and excellent cytocompatibility. This work provides guidelines for the preparation of oxidized dextran-based composite hydrogels with enhanced mechanical performance. [Display omitted] [ABSTRACT FROM AUTHOR]

Summary: RapA, as abundant as σ70 in the cell, is an RNA polymerase (RNAP)-associated Swi2/Snf2 protein with ATPase activity. It stimulates RNAP recycling during transcription. We report a structure of RapA that is also a full-length structure for the entire Swi2/Snf2 family. RapA contains seven domains, two of which exhibit novel protein folds. Our model of RapA in complex with ATP and double-stranded DNA (dsDNA) suggests that RapA may bind to and translocate on dsDNA. Our kinetic template-switching assay shows that RapA facilitates the release of sequestered RNAP from a posttranscrption/posttermination complex for transcription reinitiation. Our in vitro competition experiment indicates that RapA binds to core RNAP only but is readily displaceable by σ70. RapA is likely another general transcription factor, the structure of which provides a framework for future studies of this bacterial Swi2/Snf2 protein and its important roles in RNAP recycling during transcription. [Copyright &y& Elsevier]

Summary: The N-terminal domain of thrombospondin-1 (TSPN-1) mediates the protein''s interaction with (1) glycosaminoglycans, calreticulin, and integrins during cellular adhesion, (2) low-density lipoprotein receptor-related protein during uptake and clearance, and (3) fibrinogen during platelet aggregation. The crystal structure of TSPN-1 to 1.8 Å resolution is a β sandwich with 13 antiparallel β strands and 1 irregular strand-like segment. Unique structural features of the N- and C-terminal regions, and the disulfide bond location, distinguish TSPN-1 from the laminin G domain and other concanavalin A-like lectins/glucanases superfamily members. The crystal structure of the complex of TSPN-1 with heparin indicates that residues R29, R42, and R77 in an extensive positively charged patch at the bottom of the domain specifically associate with the sulfate groups of heparin. The TSPN-1 structure and identified adjacent linker region provide a structural framework for the analysis of the TSPN domain of various molecules, including TSPs, NELLs, many collagens, TSPEAR, and kielin. [Copyright &y& Elsevier]

• Metal salt could alter electro-assisted enzymatic hydrolysis of broken rice. • Metal salt affected the hydrolysis mainly by altering α-amylase activity. • Interactions between starch and metal ion showed no effect on the hydrolysis. • Ca2+ and Mg2+ showed more positive effects on the hydrolysis than Mn2+ and Cu2+. This study aimed to evaluate the effects of metal salts on α-amylase-catalyzed hydrolysis of broken rice under a moderate electric field (MEF) by monitoring changes in hydrolysis efficiency, temperature, α-amylase activity, starch-metal ion interaction, and the structural and physicochemical properties of hydrolysates. Results showed that metal salts affected the hydrolysis mainly by altering α-amylase activity rather than by inducing thermal effect or interacting with starch. Reducing sugar content reached 125.0 g/L, while α-amylase activity increased by 18.16% when treated with 0.12 mmol/L Ca2+. Holes on hydrolysates treated with Ca2+ and Mg2+ were larger than those treated with Mn2+ and Cu2+. No M–O bond was formed after the hydrolysis. The crystallinity was slightly increased with the hydrolysis and the values for Ca2+- and Mg2+-treated samples were larger. The water and oil absorption capacity of the hydrolysate treated with Ca2+ was the highest. This study extended the knowledge of the roles of metal ions on MEF-assisted enzymatic hydrolysis and will contribute to the development of an innovative technology for starch modification. [ABSTRACT FROM AUTHOR]

Rab35, a master regulator of membrane trafficking, regulates diverse cellular processes and is associated with various human diseases. Although a number of effectors have been identified, the molecular basis of Rab35-effector interactions remains unclear. Here, we provide the high-resolution crystal structures of Rab35 in complex with its two specific effectors ACAP2 and RUSC2, respectively. In the Rab35/ACAP2 complex structure, Rab35 binds to the terminal ankyrin repeat and a C-terminal extended α helix of ACAP2, revealing a previously uncharacterized binding mode both for Rabs and ankyrin repeats. In the Rab35/RUSC2 complex structure, Arg1015 of RUSC2 functions as a "pseudo-arginine finger" that stabilizes the GTP-bound Rab35, thus facilitating the assembly of Rab35/RUSC2 complex. The structural analysis allows us to design specific Rab35 mutants capable of eliminating Rab35/ACAP2 and Rab35/RUSC2 interactions, but not interfering with other effector bindings. The atomic structures also offer possible explanations to disease-associated mutants identified at the Rab35-effector interfaces. • Rab35 specifically binds to ACAP2 and RUSC2, respectively • Rab35/ACAP2 and Rab35/RUSC2 complex structures were solved • A pseudo-arginine finger in RUSC2 stabilizes the Rab35/RUSC2 assembly • Rab35 mutants selectively abolished Rab35/ACAP2 and Rab35/RUSC2 interactions Lin et al. determined the crystal structures of active Rab35 in complex with its specific effectors ACAP2 and RUSC2, respectively. The atomic structures not only elucidate the molecular basis of Rab35-effector interactions, but also enable the design of specific Rab35 mutants capable of abolishing Rab35/ACAP2 and Rab35/RUSC2 interactions. [ABSTRACT FROM AUTHOR]

Summary CsdA has been proposed to be essential for the biogenesis of ribosome and gene regulation after cold shock. However, the structure of CsdA and the function of its long C-terminal regions are still unclear. Here, we solved all of the domain structures of CsdA and found two previously uncharacterized auxiliary domains: a dimerization domain (DD) and an RNA-binding domain (RBD). Small-angle X-ray scattering experiments helped to track the conformational flexibilities of the helicase core domains and C-terminal regions. Biochemical assays revealed that DD is indispensable for stabilizing the CsdA dimeric structure. We also demonstrate for the first time that CsdA functions as a stable dimer at low temperature. The C-terminal regions are critical for RNA binding and efficient enzymatic activities. CsdA_RBD could specifically bind to the regions with a preference for single-stranded G-rich RNA, which may help to bring the helicase core to unwind the adjacent duplex. [ABSTRACT FROM AUTHOR]