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Abstract MuB is a non-specific DNA-binding protein and AAA+ ATPase that significantly influences the DNA transposition process of bacteriophage Mu, especially in target DNA selection for transposition. While studies have established the ATP-dependent formation of MuB filament as pivotal to this process, the high-resolution structure of a full-length MuB protomer and the underlying molecular mechanisms governing its oligomerization remain elusive. Here, we use cryo-EM to obtain a 3.4-Å resolution structure of the ATP(+)-DNA(+)-MuB helical filament, which encapsulates the DNA substrate within its axial channel. The structure categorizes MuB within the initiator clade of the AAA+ protein family and precisely locates the ATP and DNA binding sites. Further investigation into the oligomeric states of MuB show the existence of various forms of the filament. These findings lead to a mechanistic model where MuB forms opposite helical filaments along the DNA, exposing potential target sites on the bare DNA and then recruiting MuA, which stimulates MuB’s ATPase activity and disrupts the previously formed helical structure. When this happens, MuB generates larger ring structures and dissociates from the DNA.

Protein lysine crotonylation is a novel acylation modification discovered in 2011, which plays a key role in the regulation of various biological processes. Thousands of crotonylation sites have been identified in histone and non-histone proteins over the past decades. Crotonylation is conserved and is regulated by a series of enzymes including “writer”, “eraser”, and “reader”. In recent years, crotonylation has received extensive attention due to its breakthrough progress in reproduction, development and pathogenesis of diseases. Here we brief the crotonylation-related enzyme systems, biological functions, and diseases caused by abnormal crotonylation, which provide new ideas for developing disease intervention and treatment regimens.

Nicotinamide phosphoribosyl transferase (NAMPT) is a rate-limiting enzyme in the mammalian nicotinamide adenine dinucleotide (NAD) salvage pathway, and plays a vital role in the regulation of cell metabolic activity, reprogramming, aging and apoptosis. NAMPT synthesizes nicotinamide mononucleotide (NMN) through enzymatic action, which is a key protein involved in host defense mechanism and plays an important role in metabolic homeostasis and cell survival. NAMPT is involved in NAD metabolism and maintains intracellular NAD levels. Sirtuins (SIRTs) are a family of nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylases (HDACs), the members are capable of sensing cellular NAD+ levels. NAMPT-NAD and SIRT constitute a powerful anti-stress defense system. In this paper, the structure, biological function and correlation with diseases of NAMPT are introduced, aiming to provide new ideas for the targeted therapy of related diseases.

The differentiation of vascular endothelial cells and the formation of new blood vessels are inseparable from the energy supply and regulation of metabolism. The budding of blood vessels is a starting point of glycolysis pathway in angiogenesis. Phosphofructokinase-2/fructose 2,6-biophosphatase 3 (PFKFB3), a key rate-limiting enzyme in glycolysis, exhibits strong kinase activity. Inhibition of PFKFB3 can reduce the rate of glycolysis, thereby inhibiting the budding of blood vessels, resulting in inhibition of pathological angiogenesis. In this review, the role of PFKFB3 in the angiogenesis of inflammatory diseases was summarized, and the endothelial inflammatory diseases associated with PFKFB3 were reviewed.

Abstract The Hendra and Nipah viruses (HNVs) are highly pathogenic pathogens without approved interventions for human use. In addition, the interaction pattern between the attachment (G) and fusion (F) glycoproteins required for virus entry remains unclear. Here, we isolate a panel of Macaca-derived G-specific antibodies that cross-neutralize HNVs via multiple mechanisms. The most potent antibody, 1E5, confers adequate protection against the Nipah virus challenge in female hamsters. Crystallography demonstrates that 1E5 has a highly similar binding pattern to the receptor. In cryo-electron microscopy studies, the tendency of 1E5 to bind to the upper or lower heads results in two distinct quaternary structures of G. Furthermore, we identify the extended outer loop β1S2-β1S3 of G and two pockets on the apical region of fusion (F) glycoprotein as the essential sites for G-F interactions. This work highlights promising drug candidates against HNVs and contributes deeper insights into the viruses.

Abstract The E3 ligase-degron interaction determines the specificity of the ubiquitin‒proteasome system. We recently discovered that FEM1B, a substrate receptor of Cullin 2-RING ligase (CRL2), recognizes C-degrons containing a C-terminal proline. By solving several cryo-EM structures of CRL2FEM1B bound to different C-degrons, we elucidate the dimeric assembly of the complex. Furthermore, we reveal distinct dimerization states of unmodified and neddylated CRL2FEM1B to uncover the NEDD8-mediated activation mechanism of CRL2FEM1B. Our research also indicates that, FEM1B utilizes a bipartite mechanism to recognize both the C-terminal proline and an upstream aromatic residue within the substrate. These structural findings, complemented by in vitro ubiquitination and in vivo cell-based assays, demonstrate that CRL2FEM1B-mediated polyubiquitination and subsequent protein turnover depend on both FEM1B-degron interactions and the dimerization state of the E3 ligase complex. Overall, this study deepens our molecular understanding of how Cullin-RING E3 ligase substrate selection mediates protein turnover.

Abstract Nipah virus (NiV) is a World Health Organization priority pathogen and there are currently no approved drugs for clinical immunotherapy. Through the use of a naïve human phage-displayed Fab library, two neutralizing antibodies (NiV41 and NiV42) targeting the NiV receptor binding protein (RBP) were identified. Following affinity maturation, antibodies derived from NiV41 display cross-reactivity against both NiV and Hendra virus (HeV), whereas the antibody based on NiV42 is only specific to NiV. Results of immunogenetic analysis reveal a correlation between the maturation of antibodies and their antiviral activity. In vivo testing of NiV41 and its mature form (41-6) show protective efficacy against a lethal NiV challenge in hamsters. Furthermore, a 2.88 Å Cryo-EM structure of the tetrameric RBP and antibody complex demonstrates that 41-6 blocks the receptor binding interface. These findings can be beneficial for the development of antiviral drugs and the design of vaccines with broad spectrum against henipaviruses.

Abstract Developing X-ray scintillators that are water-dispersible, compatible with polymeric matrices, and processable to flexible substrates is an important challenge. Herein, Tb3+-doped Na5Lu9F32 is introduced as an X-ray scintillating material with steady-state X-ray light yields of 15,800 photons MeV−1, which is generated as nanocrystals on halloysite nanotubes. The obtained product exhibits good water-dispersibility and highly sensitive luminescence to X-rays. It is deposited onto a polyurethane foam to afford a composite foam material with dose-dependent radioluminescence. Moreover, the product is dispersed into polymer matrixes in aqueous solution to prepare rigid or flexible scintillator screen for X-ray imaging. As a third example, it is incorporated multilayer hydrogels for information camouflage and multilevel encryption. Encrypted information can be recognized only by X-ray irradiation, while the false information is read out under UV light. Altogether, we demonstrate that the water-dispersible scintillators are highly promising for aqueous processing of radioluminescent, X-ray imaging, and information encrypting materials.

Background: Psoriasis is a prevalent skin disease affecting approximately 1%–3% of the population and imposes significant medical, social and economic burdens. Psoriasis involves multiple organs and is often complicated with obesity, diabetes, dyslipidemia, and hypertension. Because of the benefits of lipid-lowering agents and antidiabetic medications for psoriasis, metabolic abnormalities possibly play a pathogenic role in psoriasis.Objective: This review focuses on the impacts of a variety of metabolic disorders on psoriasis and the underlying mechanisms.Results: In psoriasis, enhanced glycolysis, glutamine metabolism and altered fatty acid composition in the psoriatic lesion and plasma result in the excessive proliferation of keratinocytes and secretion of inflammatory cytokines. Altered metabolism is associated with the activation of MTORC signaling pathway and transcription factors such as HIF and S6K1. Therefore, MTORC1 can be a target for the treatment of psoriasis. Additionally, there are diabetes drugs and lipid-lowering drugs including TZDs, GLP-1 RAs, Metformin, statins and fibrates, which improve both metabolic levels and psoriasis symptoms.

Actin remodeling proteins are important in immune diseases and regulate cell cytoskeletal responses. These responses play a pivotal role in maintaining the delicate balance of biological events, protecting against acute or chronic inflammation in a range of diseases. Cofilin (CFL) and actin depolymerization factor (ADF) are potent actin-binding proteins that cut and depolymerize actin filaments to generate actin cytoskeleton dynamics. Although the molecular mechanism by which actin induces actin cytoskeletal reconstitution has been studied for decades, the regulation of actin in the inflammatory process has only recently become apparent. In this paper, the functions of the actin cytoskeleton and ADF/cofilin superfamily members are briefly introduced, and then focus on the role of CFL1 in inflammatory response.

Abstract Background Mitochondrial outer membrane permeabilisation (MOMP) plays a pivotal role in cellular death and immune activation. A deeper understanding of the impact of tumour MOMP on immunity will aid in guiding more effective immunotherapeutic strategies. Methods A comprehensive pan‐cancer dataset comprising 30 cancer‐type transcriptomic cohorts, 20 immunotherapy transcriptomic cohorts and three immunotherapy scRNA‐seq datasets was collected and analysed to determine the influence of tumour MOMP activity on clinical prognosis, immune infiltration and immunotherapy effectiveness. Leveraging 65 scRNA‐Seq datasets, the MOMP signature (MOMP.Sig) was developed to accurately reflect tumour MOMP activity. The clinical predictive value of MOMP.Sig was explored through machine learning models. Integration of the MOMP.Sig model and a pan‐cancer immunotherapy CRISPR screen further investigated potential targets to overcome immunotherapy resistance, which subsequently underwent clinical validation. Results Our research revealed that elevated MOMP activity reduces mortality risk in cancer patients, drives the formation of an anti‐tumour immune environment and enhances the response to immunotherapy. This finding emphasises the potential clinical application value of MOMP activity in immunotherapy. MOMP.Sig, offering a more precise indicator of tumour cell MOMP activity, demonstrated outstanding predictive efficacy in machine‐learning models. Moreover, with the assistance of the MOMP.Sig model, FOXO1 was identified as a core modulator that promotes immune resistance. Finally, these findings were successfully validated in clinical immunotherapy cohorts of skin cutaneous melanoma and triple‐negative breast cancer patients. Conclusions This study enhances our understanding of MOMP activity in immune modulation, providing valuable insights for more effective immunotherapeutic strategies across diverse tumours.

Abstract Histamine receptors are a group of G protein-coupled receptors (GPCRs) that play important roles in various physiological and pathophysiological conditions. Antihistamines that target the histamine H1 receptor (H1R) have been widely used to relieve the symptoms of allergy and inflammation. Here, to uncover the details of the regulation of H1R by the known second-generation antihistamines, thereby providing clues for the rational design of newer antihistamines, we determine the cryo-EM structure of H1R in the apo form and bound to different antihistamines. In addition to the deep hydrophobic cavity, we identify a secondary ligand-binding site in H1R, which potentially may support the introduction of new derivative groups to generate newer antihistamines. Furthermore, these structures show that antihistamines exert inverse regulation by utilizing a shared phenyl group that inserts into the deep cavity and block the movement of the toggle switch residue W4286.48. Together, these results enrich our understanding of GPCR modulation and facilitate the structure-based design of novel antihistamines.

Abstract Many AAA+ (ATPases associated with diverse cellular activities) proteins function as protein or DNA remodelers by threading the substrate through the central pore of their hexameric assemblies. In this ATP-dependent translocating state, the substrate is gripped by the pore loops of the ATPase domains arranged in a universal right-handed spiral staircase organization. However, the process by which a AAA+ protein is activated to adopt this substrate-pore-loop arrangement remains unknown. We show here, using cryo-electron microscopy (cryo-EM), that the activation process of the Lon AAA+ protease may involve a pentameric assembly and a substrate-dependent incorporation of the sixth protomer to form the substrate-pore-loop contacts seen in the translocating state. Based on the structural results, we design truncated monomeric mutants that inhibit Lon activity by binding to the native pentamer and demonstrated that expressing these monomeric mutants in Escherichia coli cells containing functional Lon elicits specific phenotypes associated with lon deficiency, including the inhibition of persister cell formation. These findings uncover a substrate-dependent assembly process for the activation of a AAA+ protein and demonstrate a targeted approach to selectively inhibit its function within cells.

RNA molecules serve a wide range of functions that are closely linked to their structures. The basic structural units of RNA consist of single- and double-stranded regions. In order to carry out advanced functions such as catalysis and ligand binding, certain types of RNAs can adopt higher-order structures. The analysis of RNA structures has progressed alongside advancements in structural biology techniques, but it comes with its own set of challenges and corresponding solutions. In this review, we will discuss recent advances in RNA structure analysis techniques, including structural probing methods, X-ray crystallography, nuclear magnetic resonance, cryo-electron microscopy, and small-angle X-ray scattering. Often, a combination of multiple techniques is employed for the integrated analysis of RNA structures. We also survey important RNA structures that have been recently determined using various techniques.

Objective To investigate the prognostic impact of initial lung cancer (LC) on second primary breast cancer after LC (LC-BC) and further develop a nomogram for predicting the survival of patients.Methods All patients diagnosed with LC-BC and first primary BC (BC-1) during 2000–2017 were collected from Surveillance, Epidemiology, and End Results database. Pathological features, treatment strategies and survival outcomes were compared between LC-BC and BC-1 before and after propensity score matching (PSM). Cox regression analysis was performed to identify the prognostic factors associated with LC in patients with LC-BC. Additionally, least absolute shrinkage and selection operator regression analysis was used to select clinical characteristics for nomogram construction, which were subsequently evaluated using the concordance index (C-index), calibration curve and decision curve analysis (DCA).Results 827 429 patients with BC-1 and 1445 patients with LC-BC were included in the analysis. Before and after PSM, patients with BC-1 had a better prognosis than individuals with LC-BC in terms of both overall survival (OS) and breast cancer-specific survival (BCSS). Furthermore, characteristics such as more regional lymph node dissection, earlier stage and the lack of chemotherapy and radiation for LC were found to have a stronger predictive influence on LC-BC. The C-index values (OS, 0.748; BCSS, 0.818), calibration curves and DCA consistently demonstrated excellent predictive accuracy of the nomogram.Conclusion In conclusion, patients with LC-BC have a poorer prognosis than those with BC-1, and LC traits can assist clinicians estimate survival of patients with LC-BC more accurately.

Precursor ribosomal RNA (pre-rRNA) processing is a key step in ribosome biosynthesis and involves numerous RNases. A HEPN (higher eukaryote and prokaryote nucleotide binding) nuclease Las1 and a polynucleotide kinase Grc3 assemble into a tetramerase responsible for rRNA maturation. Here, we report the structures of full-length Saccharomyces cerevisiae and Cyberlindnera jadinii Las1-Grc3 complexes, and C. jadinii Las1. The Las1-Grc3 structures show that the central coiled-coil domain of Las1 facilitates pre-rRNA binding and cleavage, while the Grc3 C-terminal loop motif directly binds to the HEPN active center of Las1 and regulates pre-rRNA cleavage. Structural comparison between Las1 and Las1-Grc3 complex exhibits that Grc3 binding induces conformational rearrangements of catalytic residues associated with HEPN nuclease activation. Biochemical assays identify that Las1 processes pre-rRNA at the two specific sites (C2 and C2′), which greatly facilitates rRNA maturation. Our structures and specific pre-rRNA cleavage findings provide crucial insights into the mechanism and pathway of pre-rRNA processing in ribosome biosynthesis.

Abstract Group I introns are catalytic RNAs that coordinate two consecutive transesterification reactions for self-splicing. To understand how the group I intron promotes catalysis and coordinates self-splicing reactions, we determine the structures of L-16 Tetrahymena ribozyme in complex with a 5′-splice site analog product and a 3′-splice site analog substrate using cryo-EM. We solve six conformations from a single specimen, corresponding to different splicing intermediates after the first ester-transfer reaction. The structures reveal dynamics during self-splicing, including large conformational changes of the internal guide sequence and the J5/4 junction as well as subtle rearrangements of active-site metals and the hydrogen bond formed between the 2′-OH group of A261 and the N2 group of guanosine substrate. These results help complete a detailed structural and mechanistic view of this paradigmatic group I intron undergoing the second step of self-splicing.

Sodium-dependent vitamin C transporters are responsible for vitamin C uptake and tissue distribution in mammals. Here, authors present cryo-EM structures of mouse SVCT1 in both the apo and substrate-bound states, revealing the structural basis of substrate recognition and transport.

Geopolymers show great potential in complex wastewater treatment to improve water quality. In this work, general geopolymers, porous geopolymers and geopolymer microspheres were prepared by the suspension curing method using three solid waste products, coal gangue, fly ash and blast furnace slag. The microstructure, morphology and surface functional groups of the geopolymers were studied by SEM, XRD, XRF, MIP, FTIR and XPS. It was found that the geopolymers possess good adsorption capacities for both organic and inorganic pollutants. With methylene blue and potassium dichromate as the representative pollutants, in order to obtain the best removal rate, the effects of the adsorbent type, dosage of adsorbent, concentration of methylene blue and potassium dichromate and pH on the adsorption process were studied in detail. The results showed that the adsorption efficiency of the geopolymers for methylene blue and potassium dichromate was in the order of general geopolymers < porous geopolymers < geopolymer microspheres, and the removal rates were up to 94.56% and 79.46%, respectively. Additionally, the competitive adsorption of methylene blue and potassium dichromate in a binary system was also studied. The mechanism study showed that the adsorption of methylene blue was mainly through pore diffusion, hydrogen bond formation and electrostatic adsorption, and the adsorption of potassium dichromate was mainly through pore diffusion and redox reaction. These findings demonstrate the potential of geopolymer microspheres in adsorbing organic and inorganic pollutants, and, through five cycles of experiments, it is demonstrated that MGP exhibits excellent recyclability.

Hybrid nucleic acid origami has potential for biomedical delivery of mRNA and fabrication of artificial ribozymes. Here, the authors use chemical footprinting and cryo-electron microscopy to reveal insights into nucleic acid origami used to fold messenger and ribosomal RNA into 3D polyhedral structures.

This study identifies the evolutionarily conserved Exportin 4 as an essential regulator in the nuclear export of circRNAs. Defective circRNA export results in R-loop formation and DNA damage in cells, as well as testis and neurological defects in mice.

The S280 ultra-high strength stainless steel was subjected to isothermal constant strain rate compression experiments under the conditions of deformation temperature 1000–1150 °C and strain rate 0.001–10 s−1 by Thermecmaster-Z thermal simulation testing machine. The flow behavior of S280 ultra-high strength stainless steel was analyzed; the dynamic recrystallization critical strain model, dynamic recrystallization volume fraction model, dynamic recrystallization grain size and average grain size model of the steel were established, and its dynamic recrystallization behavior was numerically simulated. The results show that the flow stress of S280 ultra-high strength stainless steel increases with the increase of strain rate and the decrease of deformation temperature. The distribution of dynamic recrystallization volume fraction and average grain size in each deformation region after thermal compression is not uniform, and the dynamic recrystallization volume fraction increases with the increase of deformation temperature and decrease of strain rate; the average grain size increases with the increase of deformation temperature and strain rate. The numerical simulation results are in good agreement with the experimental results, which can provide a theoretical basis for the microstructure control of the steel during thermal deformation.

Structural biology, complemented by biochemistry experiments and RNA-binding assays show that the Gemin5 C-terminal region adopts a decamer architecture. Gemin5 decamerization is essential for its role in regulating mRNA translation.

Psoriasis is a chronic inflammatory skin disease. The histopathological features of psoriasis include excessive proliferation of keratinocytes and infiltration of immune cells. The S100 proteins are a group of EF-hand Ca2+-binding proteins, including S100A2, -A7, -A8/A9, -A12, -A15, which expression levels are markedly upregulated in psoriatic skin. These proteins exert numerous functions such as serving as intracellular Ca2+ sensors, transduction of Ca2+ signaling, response to extracellular stimuli, energy metabolism, and regulating cell proliferation and apoptosis. Evidence shows a crucial role of S100 proteins in the development and progress of inflammatory diseases, including psoriasis. S100 proteins can possibly be used as potential therapeutic target and diagnostic biomarkers. This review focuses on the pathogenic role of S100 proteins in psoriasis.

Objective: Tumor sprouting can reflect independent risk factors for tumor malignancy and a poor clinical prognosis. However, there are significant differences and difficulties associated with manually identifying tumor sprouting. This study used the Faster region convolutional neural network (RCNN) model to build a colorectal cancer tumor sprouting artificial intelligence recognition framework based on pathological sections to automatically identify the budding area to assist in the clinical diagnosis and treatment of colorectal cancer. Methods: We retrospectively collected 100 surgical pathological sections of colorectal cancer from January 2019 to October 2019. The pathologists used LabelImg software to identify tumor buds and to count their numbers. Finally, 1,000 images were screened, and the total number of tumor buds was approximately 3,226; the images were randomly divided into a training set and a test set at a ratio of 6:4. After the images in the training set were manually identified, the identified buds in the 600 images were used to train the Faster RCNN identification model. After the establishment of the artificial intelligence identification detection platform, 400 images in the test set were used to test the identification detection system to identify and predict the area and number of tumor buds. Finally, by comparing the results of the Faster RCNN system and the identification information of pathologists, the performance of the artificial intelligence automatic detection platform was evaluated to determine the area and number of tumor sprouting in the pathological sections of the colorectal cancers to achieve an auxiliary diagnosis and to suggest appropriate treatment. The selected performance indicators include accuracy, precision, specificity, etc. ROC (receiver operator characteristic) and AUC (area under the curve) were used to quantify the performance of the system to automatically identify tumor budding areas and numbers. Results: The AUC of the receiver operating characteristic curve of the artificial intelligence detection and identification system was 0.96, the image diagnosis accuracy rate was 0.89, the precision was 0.855, the sensitivity was 0.94, the specificity was 0.83, and the negative predictive value was 0.933. After 400 test sets, pathological image verification showed that there were 356 images with the same positive budding area count, and the difference between the positive area count and the manual detection count in the remaining images was less than 3. The detection system based on tumor budding recognition in pathological sections is comparable to that of pathologists’ accuracy; however, it took significantly less time (0.03±0.01)s for the pathologist (13±5)s to diagnose the sections with the assistance of the AI model. Conclusion: This system can accurately and quickly identify the tumor sprouting area in the pathological sections of colorectal cancer and count their numbers, which greatly improves the diagnostic efficacy, and effectively avoids the need for confirmation by different pathologists. The use of the AI reduces the burden of pathologists in reading sections and it has a certain clinical diagnosis and treatment value.

Abstract Cryo-electron microscopy (cryo-EM) has emerged as an unprecedented tool to resolve protein structures at atomic resolution. Structural insights of biological samples not accessible by conventional X-ray crystallography and NMR can be explored with cryo-EM because measurements are carried out under near-native crystal-free conditions, and large protein complexes with conformational and compositional heterogeneity are readily resolved. RNA has remained underexplored in cryo-EM, despite its essential role in various biological processes. This review highlights current challenges and recent progress in using cryo-EM single-particle analysis to determine protein-free RNA structures, enabled by improvement in sample preparation and integration of multiple structural and biochemical methods.

The Gleeble-3800 thermal simulator is used to perform isothermal and constant strain rate compression tests on SP700 titanium alloy under the conditions of deformation temperature of 700–950 °C and strain rate of 0.001–1 s−1. The processing map technology can be obtained based on dynamic material model, through this technology, its thermal deformation behavior can be studied and the appropriate processing parameter range can be optimized by combining the changes in the strain rate sensitivity exponent m, strain hardening exponent n and deformation activation energy Q. The results show that the flow stress of SP700 titanium alloy is sensitive to deformation temperature and strain rate. When the strain is 0.9, the strain rate sensitivity exponent m is greater than 0.5 when the deformation temperature is 800 °C and the strain rate is 0.001 s−1 and 1 s−1. Under this condition, the SP700 titanium alloy may have superplastic deformed. In addition, the analysis shows that when the deformation temperature is 775–825 °C, the strain rate is 0.3–1 s−1 and 0.001–0.002 s−1, this condition is the best processing parameter range of SP700 titanium alloy.

Ebola virus (EBOV), a member of the Filoviridae family of viruses and a causative agent of Ebola Virus Disease (EVD), is a highly pathogenic virus that has caused over twenty outbreaks in Central and West Africa since its formal discovery in 1976. The only FDA-licensed vaccine against Ebola virus, rVSV-ZEBOV-GP (Ervebo®), is efficacious against infection following just one dose. However, since this vaccine contains a replicating virus, it requires ultra-low temperature storage which imparts considerable logistical challenges for distribution and access. Additional vaccine candidates could provide expanded protection to mitigate current and future outbreaks. Here, we designed and characterized two multimeric protein nanoparticle subunit vaccines displaying 8 or 20 copies of GPΔmucin, a truncated form of the EBOV surface protein GP. Single-dose immunization of mice with GPΔmucin nanoparticles revealed that neutralizing antibody levels were roughly equivalent to those observed in mice immunized with non-multimerized GPΔmucin trimers. These results suggest that some protein subunit antigens do not elicit enhanced antibody responses when displayed on multivalent scaffolds and can inform next-generation design of stable Ebola virus vaccine candidates.

Summary: Enolase is a highly conserved enzyme that presents in all organisms capable of glycolysis or fermentation. Its immediate product phosphoenolpyruvate is essential for other important processes like peptidoglycan synthesis and the phosphotransferase system in bacteria. Therefore, enolase inhibitors are of great interest. Here, we report that Gp60, a phage-encoded enolase inhibitor protein (PEIP) of bacteriophage SPO1 for Bacillus subtilis, is an enolase inhibitor. PEIP-expressing bacteria exhibit growth attenuation, thinner cell walls, and safranin color in Gram staining owing to impaired peptidoglycan synthesis. We solve the structure of PEIP-enolase tetramer and show that PEIP disassembles enolase by disrupting the basic dimer unit. The structure reveals that PEIP does not compete for substrate binding but induces a cascade of conformational changes that limit accessibility to the enolase catalytic site. This phage-inspired disassembly of enolase represents an alternative strategy for the development of anti-microbial drugs.

Ric-8A is guanine nucleotide exchange factor (GEF) that also acts as a folding chaperone for its Gα subunit. Here, the authors present the structure of Ric-8A bound to nucleotide-free Gαi1, revealing the mechanism by which Ric-8A exerts both GEF and chaperone activity.

Although paclitaxel is widely used as a chemotherapy, it suffers from poor solubility and toxicity issues. Here, the authors develop thermostable RNA nanoparticles and report the RNA-paclitaxel complex to display improved stability, drug loading capacity and solubility for improved targeted cancer therapy and reduced immune responses.

The conformational heterogeneity of RNA molecules makes their structure determination by X-ray crystallography and NMR challenging. Here the authors show that RNA structures can be solved by cryo-EM and present the structures of a 40 kDa SAM-IV riboswitch in the apo form and bound to its ligand S-adenosylmethionine.

Background: Pyroptosis, a kind of programmed cell death characterized by the rupture of cell membranes and the release of inflammatory substances, plays an important role in the occurrence and development of cancer. However, few studies focus on the pyroptosis-associated long non-coding RNAs (lncRNAs) in breast cancer (BC). The prognostic value of pyroptosis-associated lncRNAs and their relationship with tumor microenvironment (TME) in BC remain unclear. The purpose of this study was to explore the prognostic role of pyroptosis-associated lncRNAs and their relationship with TME in BC.Methods: The transcriptome data and clinical data of female BC patients were downloaded from The Cancer Genome Atlas (TCGA) database. A total of 937 patients were randomly assigned to either training set or validation set. A pyroptosis-associated lncRNA signature was constructed in the training set and verified in the validation set. Functional analysis and immune microenvironment analysis related to pyroptosis-associated lncRNAs were performed. A nomogram based on the risk score and clinical characteristics was established.Results: A 9-pyroptosis-associated lncRNA signature was constructed to separate BC patients into two risk groups. High-risk patients had poorer prognosis than low-risk patients. The risk score was proven to be an independent prognostic factor by multivariate Cox regression analysis. Function analysis and immune microenvironment analysis showed that low-risk BC tended to be an immunologically “hot” tumor. A nomogram was constructed with risk score and clinical characteristics. Receiver operating characteristic curve (ROC) analysis demonstrated credible predictive power of the nomogram. The area under time-dependent ROC curve (AUC) reached 0.880 at 1 year, 0.804 at 3 years, and 0.769 at 5 years in the training set, and 0.799 at 1 year, 0.794 at 3 years, and 0.728 at 5 years in the validation set.Conclusion: We identified a novel pyroptosis-associated lncRNA signature that was an independent prognostic indicator for BC patients. Pyroptosis-associated lncRNAs had potential relationship with the immune microenvironment and might be therapeutic targets for BC patients.

Background: Ferroptosis, a regulated cell death which is driven by the iron-dependent peroxidation of lipids, plays an important role in cancer. However, studies about ferroptosis-related Long non-coding RNAs (lncRNAs) in breast cancer (BC) are limited. Besides, the prognostic role of ferroptosis-related lncRNAs and their relationship to immune microenvironment in breast cancer remain unclear. This study aimed to explore the potential prognostic value of ferroptosis-related lncRNAs and their relationship to immune microenvironment in breast cancer.Methods: RNA-sequencing data of female breast cancer patients were downloaded from TCGA database. 937 patients were randomly separated into training or validation cohort in 2:1 ratio. Ferroptosis-related lncRNAs were screened by Pearson correlation analysis with 239 reported ferroptosis-related genes. A ferroptosis-related lncRNAs signature was constructed with univariate and multivariate Cox regression analyses in the training cohort, and its prognostic value was further tested in the validation cohort.Results: An 8-ferroptosis-related-lncRNAs signature was developed by multivariate Cox regression analysis to divide patients into two risk groups. Patients in the high-risk group had worse prognosis than patients in the low-risk group. Multivariate Cox regression analysis showed the risk score was an independent prognostic indicator. Receiver operating characteristic curve (ROC) analysis proved the predictive accuracy of the signature. The area under time-dependent ROC curve (AUC) reached 0.853 at 1 year, 0.802 at 2 years, 0.740 at 5 years in the training cohort and 0.791 at 1 year, 0.778 at 2 years, 0.722 at 5 years in the validation cohort. Further analysis demonstrated that immune-related pathways were significantly enriched in the high-risk group. Analysis of the immune cell infiltration landscape showed that breast cancer in the high-risk group tended be immunologically “cold”.Conclusion: We identified a novel ferroptosis-related lncRNA signature which could precisely predict the prognosis of breast cancer patients. Ferroptosis-related lncRNAs may have a potential role in the process of anti-tumor immunity and serve as therapeutic targets for breast cancer.

Abstract Background Psoriasis is a chronic and systemic, immune-mediated, inflammatory disease. Mesenchymal stem cells have effects on the inflammatory microenvironment, including regulating the proliferation, differentiation, recruitment, and migration of immunocytes. Methods To investigate whether dermal mesenchymal stem cells (DMSCs) may act on migration of immunocytes in psoriasis patients, 22 patients with psoriasis and 22 matching healthy controls (age and sex in this study) were recruited. Seven migration-associated genes including chemokine like receptor-1 (CMKLR-1), collagen type VIII alpha1 (COL8A-1), neuropilin and tolloid-like 2 (NETO-2), nik-related kinase (NRK), secreted frizzled-related protein (SFRP), sulfate 6-O-endosulfatase 2 (SULF-2), and synaptotagmin-like protein 2 (SYTL-2) were analyzed by quantitative real-time reverse transcription PCR and western blot. Peripheral blood-derived mononuclear cells (PBMCs) migration to MSCs was measured using a Thanswell chamber system. Results We observed the upregulation of CMKLR-1, COL8A-1, NETO-2, NRK, SYTL-2, and SULF-2 in dermal mesenchymal stem cells derived from patients with psoriasis at both mRNA and protein level, however, a significant downregulation of SFRP-2 between two groups. By contrast, there were no significant between-group differences at the mRNA and protein expression level of NETO-2 and SULF-2. The migration assay showed that in vitro the normal PBMC migration to psoriatic DMSC group was a 6.3 ± 0.7-fold increase compared with the control group. Conclusions The results may suggest a potential pathogenetic involvement of DMSCs on migration of monocytes in psoriasis. Immune responses are regulated at the level of DMSCs, which probably represent the cells primarily involved in the “psoriatic march.”

With the development of deep learning, image super-resolution has made great breakthroughs. However, compared with a color image, the performance of depth map super-resolution is still poor. To address this problem, multilevel recursive guidance and progressive supervised network (MRG-PS) is proposed in this paper. First, a multilevel recursive guidance architecture is presented to extract features of a color stream and depth stream, in which the depth stream is guided by the color features at each level. Second, a progressive supervision module is developed to supervise the multilevel recursion to obtain depth residual information on different levels. Finally, a residual fusion and construction strategy is designed to fuse all residual information and reconstruct the high-resolution depth map. The experimental results demonstrate that the proposed method outperforms the state-of-the-art methods.

Plenoptic imaging has emerged as a representative approach for recording richer visual information from the real world. With the insertion of a microlens array, plenoptic cameras can record both angular and spatial information of a scene on a plenoptic image. However, the large amount of data calls for efficient coding techniques for both transmission and storage. In this paper, we propose a convolutional neural network (CNN)-based macropixel-level up-sampling method for plenoptic image coding. First, a macropixel-based down-sampling method, which performs the down-sampling in the units of macropixels, is developed for reducing the block resolution. Then, an up-sampling CNN is carefully designed to achieve resolution recovery and quality enhancement for down-sampled blocks. The experimental results show that the proposed method achieves considerable bitrate reduction compared with the HEVC/H.265 format SCC extension profile.

Isothermal and constant-strain-rate compression experiments for S280 ultra-high-strength stainless steel were carried out under deformation temperatures of 1000–1150 °C and strain rates of 0.001–10 s−1 with a Thermecmaster-Z thermal simulator. The flow–stress behavior of the alloy was studied and the hot deformation activation energy was calculated. A critical strain model of the dynamic recrystallization (DRX) of the alloy was established using the work hardening rate for the first time. The results show that S280 ultra-high-strength stainless steel was positively sensitive to the strain rate and negatively sensitive to temperature, and its flow–stress curve showed characteristics of flow softening. The hot deformation activation energy corresponding to the peak strain was 519.064 kJ/mol. The DRX critical strain of the steel was determined from the minimum value of the −∂(lnθ)/∂ε − ε curve. The relationship between the DRX critical strain and peak strain could be characterized as εc=0.599εp and the relationship between the DRX critical stress and peak stress could be characterized as σc= 0.959σp The critical strain model of DRX could be expressed as εc=0.010Z0.062. The research results can provide theoretical support for avoiding the generation of actual thermal processing microstructure defects such as coarse grains and for obtaining products with excellent microstructure and properties.

Bacterial resistance to antibiotics reduced the demand for antibiotics in the field of medical devices. Polymer antibacterial materials have shown great potential in the medical field. However, the treatment of materials after use is not environmentally friendly. Therefore, the development of dissoluble polymer antibacterial materials has become an urgent challenge. In this paper, an antibacterial polymer material with high self-healing ability and rapid dissolution is reported. The new material was formed by the Schiff base reaction and cross-linking of aldehyde group and amino in terephthalaldehyd (TA), 3,4-diaminofurazan (DAF) and α,ω-aminopropyl terminated polydimethylsiloxane (PDMS, Mn = 3000). The properties of the material were further enhanced by the coordination of zinc ion with nitrogen and oxygen atoms of 3,4-diaminofurazan. The antibacterial polymer material designed by us can be effectively repaired at 100 °C. The first repair efficiency was 89.5%. After repeated repair, its mechanical properties were not significantly reduced. E. coli and S.aureus were used to evaluate the antibacterial ability of the material. The antibacterial efficiency of the material was 99.9993% and 99.9997% respectively. This new idea solved the urgent problems in the current application, and provided guidance for the research of flexible antibacterial materials.

Breast-conserving therapy was once a contraindication in young breast cancer patients (aged ≤40 years). Emerging studies suggest that breast-conserving therapy and mastectomy could achieve similar prognosis in this population. However, the effect of molecular subtype disparity on surgical strategy in these patients remains unclear. Data from 8656 young patients (aged ≤40 years) diagnosed with invasive breast cancer between in 2010 and 2014 were retrospectively reviewed from the Surveillance, Epidemiology, and End Results database. The Cox proportional hazards model was used to evaluate subtype-dependent relationships between the surgical method and survival. Of the 8656 patients, 4132 (47.7%) underwent breast-conserving therapy and 4524 (52.3%) underwent mastectomy. The median follow-up period was 30.0 months. Patients in the breast-conserving therapy group demonstrated better overall survival and breast cancer-specific survival than those in the mastectomy group (both p < 0.05). Patients with different molecular subtypes exhibited significant differences in overall survival and breast cancer-specific survival ( p < 0.001). Patients with luminal subtypes experienced better overall survival and breast cancer-specific survival than those with the triple-negative subtype. Multivariate analysis revealed that overall mortality risk of the breast-conserving therapy group was lower than that of the mastectomy group among HR(+)HER-2(-) and HR(-)HER-2(-) patients (overall mortality risk of 36.3% [adjusted hazard ratio = 0.637 {95% confidence interval = 0.448–0.905}, p = 0.012] and 36.0% [adjusted hazard ratio = 0.640 {95% confidence interval = 0.455–0.901}, p = 0.010] respectively.) The breast cancer-specific mortality risk was also lower by a percentage similar to that of the overall mortality risk. In the HR(+)HER-2(+) group, the surgical method was an independent prognostic factor for breast cancer-specific survival (adjusted hazard ratio = 0.275 [95% confidence interval = 0.089–0.849], p = 0.025), while there was a trend that patients with breast-conserving therapy had better overall survival than those with mastectomy ( p = 0.056). In the HR(-)HER-2(+) group, no significant difference was observed in overall survival and breast cancer-specific survival ( p = 0.791 and p = 0.262, respectively). Breast-conserving therapy resulted in significantly better prognosis in patients with luminal and triple-negative subtypes, while no significant difference was observed in patients with the HER-2 enriched subtype. These results may be helpful in informing clinically precise decision-making for surgery in this population.

Although it is known that psoriatic dermal-derived mesenchymal stem cells (DMSCs) dysregulate keratinocyte proliferation, the biological activity profile of keratinocytes influenced by psoriatic DMSCs remain unknown. In the present study, we assessed the impact of psoriatic DMSCs on keratinocyte proliferation, differentiation, and glucose metabolism in normal human epidermal keratinocytes co-cultured with or without psoriatic DMSCs. Co-culture of normal human epidermal keratinocytes with psoriatic DMSCs downregulated expression levels of proteins associated with cell junction assembly (alpha-actinin-1, catenin beta-1, poliovirus receptor-related protein 4 and procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2), while upregulating proteins associated with keratinocyte proliferation and differentiation (involucrin, isoform 2 of Histone-binding protein, isoform 3 of Telomeric repeat-binding factor 2 and keratin 13). Moreover, co-culture of normal human epidermal keratinocytes with psoriatic DMSCs stimulated keratinocyte proliferation and glycolysis, but reduced keratinocyte junctions. Taken together, these results demonstrate that psoriatic DMSCs increase keratinocyte proliferation and glycolysis, and reduce cell junctions, suggesting a pathogenic role of psoriatic DMSCs in epidermal hyperplasia, aberrant differentiation, and reduction in turnover time of keratinocytes in psoriasis.

Abstract Background Psoriasis is a chronic inflammatory disorder of the skin, and genetic factors are reported to be involved in the disease pathogenesis. Many studies have named psoriasis candidate genes. Objective In this study, we determined the mutation frequency of 7 variable genes in 1,027 psoriatic patients and investigated its possible mechanism associated with psoriasis. Method A total of 7 variable genes from 1,027 psoriatic patients were amplified and sequenced using the Sanger method. The mutation frequency was compared to that of non‐psoriatic individuals in Asia using information from databases. Results Among the 7 investigated genes, the mutation frequency of ACOT12 (c.80A>G, 9.98% vs. 5.85%, p T,15.8% vs. 9.93%, p G), SPRED1(c.155A>G), and ACOT12 (c.80A>G) differed significantly between the groups organized by medical history, PASI, and family history. SPRED1 gene variants (17.25% vs. 7.78%, p

Human coronavirus NL63 (HCoV-NL63) is an enveloped pathogen of the family Coronaviridae that spreads worldwide and causes up to 10% of all annual respiratory diseases. HCoV-NL63 is typically associated with mild upper respiratory symptoms in children, elderly and immunocompromised individuals. It has also been shown to cause severe lower respiratory illness. NL63 shares ACE2 as a receptor for viral entry with SARS-CoV-1 and SARS-CoV-2. Here, we present the in situ structure of HCoV-NL63 spike (S) trimer at 3.4-Å resolution by single-particle cryo-EM imaging of vitrified virions without chemical fixative. It is structurally homologous to that obtained previously from the biochemically purified ectodomain of HCoV-NL63 S trimer, which displays a three-fold symmetric trimer in a single conformation. In addition to previously proposed and observed glycosylation sites, our map shows density at other sites, as well as different glycan structures. The domain arrangement within a protomer is strikingly different from that of the SARS-CoV-2 S and may explain their different requirements for activating binding to the receptor. This structure provides the basis for future studies of spike proteins with receptors, antibodies or drugs, in the native state of the coronavirus particles.

Immunoproteasome selective inhibitors might lead to less toxic drugs for treatment of multiple myeloma and graft rejection. Here, the authors develop immunoproteasome specific asparagine-ethylenediamine (AsnEDA)-based inhibitory compounds, demonstrate their efficacy and present the AsnEDA bound immunoproteasome cryo-EM structure.

We propose a novel and simple scheme for photonic frequency eightfold millimeter wave (mm-wave) generation with optical carrier suppression based on only one single-drive Mach–Zehnder modulator (MZM). According to our theoretical analysis and experimental demonstration, by adopting designed direct current bias voltage of MZM and the amplitude voltage of the radio frequency (RF) drive signal, two fourth-order optical subcarriers are generated via a single-drive MZM. Furthermore, the corresponding optical central carrier and undesired sidebands are suppressed simultaneously. Based on our proposed scheme, the generation of 72-GHz optical mm-wave by an RF signal of 9 GHz without any optical filtering is experimentally demonstrated. The radio-over-fiber system with 3.5-Gb/s OOK downstream link based on this generated 72-GHz mm-wave is also experimentally demonstrated. As we know, it is the first time to realize frequency eightfold mm-wave signal generation with simultaneous carrier suppression by using only one single-drive MZM in experiment.

Long non-coding RNA (LncRNA) actin filament-associated protein1-antisense RNA 1 (AFAP1-AS1) is overexpressed in various types of cancers and plays an important role in tumor progression and prognosis. This study investigates the role of AFAP1-AS1 in tumor progression in triple-negative breast cancer (TNBC). We found that AFAP1-AS1 was overexpressed in TNBC tissues and cells. Overexpression of LncRNA AFAP1-AS1 was associated with poor prognosis in TNBC patients. Moreover, we demonstrated that upregulation of AFAP1-AS1 promoted cell proliferation and invasion, and inhibited cell apoptosis in vitro, while overexpression of AFAP1-AS1 promoted tumor growth in vivo. Our results also revealed that upregulation of AFAP1-AS1 activated Wnt/β-catenin pathway to promote tumorigenesis and cell invasion by increasing the expression of C-myc and epithelial-mesenchymal transition-related molecules in TNBC. Collectively, AFAP1-AS1 can be an independent prognostic marker and an effective therapeutic target of triple- negative breast cancer.

Mesenchymal stem cells (MSCs) exhibit high proliferation and self-renewal capabilities and are critical for tissue repair and regeneration during ontogenesis. They also play a role in immunomodulation. MSCs can be isolated from a variety of tissues and have many potential applications in the clinical setting. However, MSCs of different origins may possess different biological characteristics. In this study, we performed a comprehensive comparison of MSCs isolated from bone marrow and skin (BMMSCs and SMSCs, resp.), including analysis of the skin sampling area, separation method, culture conditions, primary and passage culture times, cell surface markers, multipotency, cytokine secretion, gene expression, and fibroblast-like features. The results showed that the MSCs from both sources had similar cell morphologies, surface markers, and differentiation capacities. However, the two cell types exhibited major differences in growth characteristics; the primary culture time of BMMSCs was significantly shorter than that of SMSCs, whereas the growth rate of BMMSCs was lower than that of SMSCs after passaging. Moreover, differences in gene expression and cytokine secretion profiles were observed. For example, secretion of proliferative cytokines was significantly higher for SMSCs than for BMMSCs. Our findings provide insights into the different biological functions of both cell types.