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Dengue virus (DENV) is a critical public health concern in tropical and subtropical regions worldwide. Thus, immunocompetent murine models of DENV infection with robust viremia are required for vaccine studies. Diabetes is highly prevalent worldwide, making it frequent comorbidity in patients with dengue fever. Therefore, murine models are needed to understand viral pathogenesis and disease progression. Acquired-induced and inherently diabetic C57BL/6 and db/db mice were inoculated with DENV-3 via the tail vein. After infection, both the diabetic C57BL/6 and db/db mice showed obvious weight loss with clinical manifestations. Quantitative reverse-transcription polymerase chain reaction revealed robust and replicable viremia in the two types of diabetic mice. Immunohistochemical detection showed persistent DENV-3 infection in the liver. Enzyme-linked immunosorbent assay for cytokine detection revealed that diabetic mice showed more severe inflammatory responses than did nondiabetic mice, and significant histological alterations were observed in diabetic mice. Thus, the diabetic mice were more susceptible to DENV infection than the nondiabetic mice. Taken together, we established two types of immunocompetent diabetic mice for DENV infection, which can be used to further study the mechanisms of dengue pathogenesis in diabetes and to develop antiviral pharmaceuticals and treatments.

The construction of integrated energy systems has received widespread attention. In addition to system design and operating optimization, clarifying the internal relationship between the project’s own characteristics and its economic indicators is also important for high-value project selection and implementation. Based on various energy prices and the climatic characteristics of typical cities, 60 integrated energy supply projects in 4 typical cities were used as a case study, and the cold and heat source system solutions with the shortest investment payback period for each project were calculated through a system optimization model. We calculated the correlation coefficient between the initial investment of system equipment, annual energy supply, annual energy sales revenue, annual equivalent full-load energy supply hours, initial equipment investment indicators for annual unit energy supply, and the project’s static investment payback period. The key factors affecting the static investment payback period of the project were identified. The results show that, under the optimal system scheme, even for buildings of the same type in the same area, the economic indicators of different integrated energy projects are still quite different. Under the current design, operation, and operation conditions, load distribution is the decisive factor for the economic feasibility of the project. The static investment payback period of the project can be quickly calculated based on the equivalent full-load energy supply hours of the project throughout the year. Compared with the current numerical and system dynamics model for point-to-point single system optimizing modeling, the proposed statistical regression model can help reveal the main factors of integrated energy system’s economically feasible.

Background: Yarrowia lipolytica, an oleaginous yeast with the GRAS status, has been developed as a platform for the chemical production. Specifically, promoter engineering is an important approach to regulating gene expression at the transcriptional level, which is of great significance in constructing microbial cell factories. Until now, some work on the promoter study has been carried out in Y. lipolytica. However, compared with other microorganisms, such as Saccharomyces cerevisiae, Bacillus subtilis, and etc., obtained achievements still need further replenishment and development for Y. lipolytica. Results: To accurately analyze the promoter strength and avoid background interference, we used the NanoLuc luciferase reporter method. Furthermore, we screened 81 endogenous promoters in Y. lipolytica, mainly involved in carbon metabolism, amino acid metabolism, and lipid metabolism. Among them, the strongest promoter is PMnDH2 (YALI0D18964g), 1.60-fold of the strength of the PTEF promoter, and the weakest promoter is PPHO89 (YALI0E23859g), 0.06% of the PTEF promoter. Conclusions: As a result, we obtained 15 strong promoters, 41 medium strength promoters, and 25 weak promoters, with the strength spanning from 0.06% to 1.60-fold of PTEF promoter. In general, our study provides a unique and available endogenous promoter library for Y. lipolytica.

Acute liver injury caused by overdose usage of acetaminophen (APAP) is an intractable clinical problem. Necrotic hepatocytes release large amounts of intracellular components including damage-associated molecular patterns (DAMPs) which contribute to liver failure and may serve as therapeutic targets. However, the pathogenic mechanisms of DAMPs in APAP-induced liver injury (AILI) are remain largely uncovered. Here, we found that a recently identified DAMP, interferon-induced protein 35 (IFP35), is involved in the early phase of AILI. Our data demonstrated that although the expression level of IFP35 is not significantly increased in either patients or mice with AILI, it is released from necrotic hepatocytes. Within 24 h post APAP injection, mice lacking Ifp35 are resistant to APAP-induced toxicity, and induce less inflammatory response than that of wild-type mice, including reduced AST/ALT level, pro-inflammatory cytokines production and neutrophils infiltration. More importantly, antibody of IFP35 reduces the expression level of inflammatory factors and chemokines. This study brings new knowledge into the pathogenic mechanism of AILI.

The intermittent heating mode of Kang plays an important role in the heat storage and release in cave dwellings. However, research on the effect of Kang heating on the thermal process of traditional buildings is rare. Therefore, based on long-term monitoring of cave dwellings, regular conclusions about the influence of Kang heating on the thermal environment were obtained. Furthermore, an unsteady heat transfer model of the envelope was proposed for the first time. Then, based on this model, the thermal storage performance of cave dwellings during the period of Kang intermittent heating was explored. The results showed that, due to Kang heating, the indoor air temperature of cave dwellings could be increased by an average of 3.1 °C. Furthermore, the inner walls had a large thermal mass and the maximum heat storage in a single day was 487.75 kJ/m2, while the maximum heat release was 419.02 kJ/m2. The heat release at night could reach 87%. In this paper, the law of thermal storage and release characteristics of earthen building envelopes under intermittent heating was firstly obtained. Results can enrich the thermal process theory of earthen buildings and provide a theoretical basis and technical support for building thermal environmental construction.

Climate responsive strategies contained in traditional native dwellings can provide theoretical basis for the development of sustainable buildings. This study focused on a quantitative analysis of cliff-side cave dwellings located in cold region of China. Field measurements in summer and winter were carried out. Based on the monitoring data, thermal environment of the cave dwelling and thermal characteristics of the adobe massive building envelope were evaluated. Results showed that the cliff-side cave dwelling was well adapted to local environment for its good ability of thermal insulation under the natural conditions. Furthermore, in order to assess the whole annual thermal performance and thermal comfort level, numerical simulations on the cliff-side cave dwelling models was also performed using the software Energyplus. Results showed that 52.50% time of the year was comfortable of the living room. Meanwhile, some technical strategies of making full use of solar energy and natural ventilation was proposed in the end of this paper, which can provide technical support for the regeneration design of traditional residential buildings.

Lys deacylases are essential regulators of cell biology in many contexts. Here, we have identified CddA (cyanobacterial deacetylase/depropionylase), a Lys deacylase enzyme expressed in the cyanobacterium Synechococcus sp. PCC 7002 that has both deacetylase and depropionylase activity. Loss of the gene cddA led to slower growth and impaired linear and cyclic photosynthetic electron transfer. We determined the crystal structure of this depropionylase/deacetylase at 2.1 A resolution and established that it has a unique and characteristically folded α/β structure. We detected an acyl binding site within CddA via site-directed mutagenesis and demonstrated that this site is essential for the deproprionylase activity of this enzyme. Through a proteomic approach, we identified a total of 598 Lys residues across 382 proteins that were capable of undergoing propionylation. These propionylated proteins were highly enriched for photosynthetic and metabolic functionality. We additionally demonstrated that CddA was capable of catalyzing in vivo and in vitro Lys depropionylation and deacetylation of Fru-1,6-bisphosphatase, thereby regulating its enzymatic activity. Our identification of a Lys deacylase provides insight into the mechanisms globally regulating photosynthesis and carbon metabolism in cyanobacteria and potentially in other photosynthetic organisms as well.

SUMMARYInfluenza polymerase (FluPol) transcripts viral mRNA and switches to replicate viral genome after transcription. However, it remains unknown how FluPol switches between transcription and replication cycles, especially when considering that the structural basis of these two functions is fundamentally different. Here, we proposed a mechanism that FluPol achieves the functional switching between these two cycles through an unreported intermediate conformation, termed as resident state. We obtained a resident state structure of H5N1 FluPol at 3.7 Å using cryo-EM, which is characterized by a blocked Cap-binding domain and a contracted core region, distinct from the structures of either transcription or replication states. Structural analysis results suggest that the resident state structure is feasible to smoothly transit into structures of both transcription and replication states. Furthermore, we show that formation of the resident state is required for both transcription and replication activities of FluPol. Together, the transcription and replication cycles of FluPol are connected via a resident state.

Excessive activation of T cells and microglia represents a hallmark of the pathogenesis of human multiple sclerosis (MS). However, the regulatory molecules overactivating these immune cells remain to be identified. Previously, we reported that extracellular IFP35 family proteins, including IFP35 and NMI, activated macrophages as proinflammatory molecules in the periphery. Here, we investigated their functions in the process of neuroinflammation both in the central nervous system (CNS) and the periphery. Our analysis of clinical transcriptomic data showed that expression of IFP35 family proteins was up-regulated in patients with MS. Additional in vitro studies demonstrated that IFP35 and NMI were released by multiple cells. IFP35 and NMI subsequently triggered nuclear factor kappa B–dependent activation of microglia via the TLR4 pathway. Importantly, we showed that both IFP35 and NMI activated dendritic cells and promoted naïve T cell differentiation into Th1 and Th17 cells. Nmi(−/−), Ifp35(−/−), or administration of neutralizing antibodies against IFP35 alleviated the immune cells’ infiltration and demyelination in the CNS, thus reducing the severity of experimental autoimmune encephalomyelitis. Together, our findings reveal a hitherto unknown mechanism by which IFP35 family proteins facilitate overactivation of both T cells and microglia and propose avenues to study the pathogenesis of MS.

Chromosome translocation is a major cause of the onset and progression of diverse types of cancers. However, the mechanisms underlying this process remain poorly understood. Here, we identified a non-homologous end-joining protein, IFFO1, which structurally forms a heterotetramer with XRCC4. IFFO1 is recruited to the sites of DNA damage by XRCC4 and promotes the repair of DNA double-strand breaks in a parallel pathway with XLF. Interestingly, IFFO1 interacts with lamin A/C, forming an interior nucleoskeleton. Inactivating IFFO1 or its interaction with XRCC4 or lamin A/C leads to increases in both the mobility of broken ends and the frequency of chromosome translocation. Importantly, the destruction of this nucleoskeleton accounts for the elevated frequency of chromosome translocation in many types of cancer cells. Our results reveal that the lamin A/C-IFFO1-constituted nucleoskeleton prevents chromosome translocation by immobilizing broken DNA ends during tumorigenesis.

The Isw1b chromatin-remodelling complex is specifically recruited to gene bodies to help retain pre-existing histones during transcription by RNA polymerase II. Recruitment is dependent on H3K36 methylation and the Isw1b subunit Ioc4, which contains an N-terminal PWWP domain. Here, we present the crystal structure of the Ioc4-PWWP domain, including a detailed functional characterization of the domain on its own as well as in the context of full-length Ioc4 and the Isw1b remodeller. The Ioc4-PWWP domain preferentially binds H3K36me3-containing nucleosomes. Its ability to bind DNA is required for nucleosome binding. It is also furthered by the unique insertion motif present in Ioc4-PWWP. The ability to bind H3K36me3 and DNA promote the interaction of full-length Ioc4 with nucleosomes in vitro and they are necessary for its recruitment to gene bodies in vivo. Furthermore, a fully functional Ioc4-PWWP domain promotes efficient remodelling by Isw1b and the maintenance of ordered chromatin in vivo, thereby preventing the production of non-coding RNAs.

Nuclear factor κB (NF-κB)–mediated signaling pathway plays a crucial role in the regulation of inflammatory process, innate and adaptive immune responses. The hyperactivation of inflammatory response causes host cell death, tissue damage, and autoinflammatory disorders, such as sepsis and inflammatory bowel disease. However, how these processes are precisely controlled is still poorly understood. In this study, we demonstrated that ankyrin repeat and suppressor of cytokine signaling box containing 1 (ASB1) is involved in the positive regulation of inflammatory responses by enhancing the stability of TAB2 and its downstream signaling pathways, including NF-κB and mitogen-activated protein kinase pathways. Mechanistically, unlike other members of the ASB family that induce ubiquitination-mediated degradation of their target proteins, ASB1 associates with TAB2 to inhibit K48-linked polyubiquitination and thereby promote the stability of TAB2 upon stimulation of cytokines and lipopolysaccharide (LPS), which indicates that ASB1 plays a noncanonical role to further stabilize the target protein rather than induce its degradation. The deficiency of Asb1 protects mice from Salmonella typhimurium– or LPS-induced septic shock and increases the survival of mice. Moreover, Asb1-deficient mice exhibited less severe colitis and intestinal inflammation induced by dextran sodium sulfate. Given the crucial role of ASB proteins in inflammatory signaling pathways, our study offers insights into the immune regulation in pathogen infection and inflammatory disorders with therapeutic implications.

Lys deacylases are essential regulators of cell biology in many contexts. Here, we have identified CddA (cyanobacterial deacetylase/depropionylase), a Lys deacylase enzyme expressed in the cyanobacterium Synechococcus sp. PCC 7002 that has both deacetylase and depropionylase activity. Loss of the gene cddA led to slower growth and impaired linear and cyclic photosynthetic electron transfer. We determined the crystal structure of this depropionylase/deacetylase at 2.1 Å resolution and established that it has a unique and characteristically folded α/β structure. We detected an acyl binding site within CddA via site-directed mutagenesis and demonstrated that this site is essential for the deproprionylase activity of this enzyme. Through a proteomic approach, we identified a total of 598 Lys residues across 382 proteins that were capable of undergoing propionylation. These propionylated proteins were highly enriched for photosynthetic and metabolic functionality. We additionally demonstrated that CddA was capable of catalyzing in vivo and in vitro Lys depropionylation and deacetylation of Fru-1,6-bisphosphatase, thereby regulating its enzymatic activity. Our identification of a Lys deacylase provides insight into the mechanisms globally regulating photosynthesis and carbon metabolism in cyanobacteria and potentially in other photosynthetic organisms as well.

Minichromosome maintenance 8 (MCM8) is a recently identified member of the minichromosome maintenance family, which possesses helicase and ATPase activity. It interacts with MCM9 and participates in homologous recombination repair. The structure of MCM8 is unclear now. Here, we report the crystal structure of the winged-helix domain of human MCM8 (MCM8-WHD) at 1.21 A resolution. MCM8-WHD adopts a conserved winged-helix architecture. Structure analysis and biochemical study results showed the DNA binding ability and crucial residues of MCM8-WHD. Our results are helpful to understand the function of MCM8.

Autophagy is a conserved process that delivers cytosolic substances to the lysosome for degradation, but its direct role in the regulation of antiviral innate immunity remains poorly understood. Here, through high-throughput screening, we discovered that CCDC50 functions as a previously unknown autophagy receptor that negatively regulates the type I interferon (IFN) signaling pathway initiated by RIG-I-like receptors (RLRs), the sensors for RNA viruses. The expression of CCDC50 is enhanced by viral infection, and CCDC50 specifically recognizes K63-polyubiquitinated RLRs, thus delivering the activated RIG-I/MDA5 for autophagic degradation. The association of CCDC50 with phagophore membrane protein LC3 is confirmed by crystal structure analysis. In contrast to other known autophagic cargo receptors that associate with either the LIR-docking site (LDS) or the UIM-docking site (UDS) of LC3, CCDC50 can bind to both LDS and UDS, representing a new type of cargo receptor. In mouse models with RNA virus infection, CCDC50 deficiency reduces the autophagic degradation of RIG-I/MDA5 and promotes type I IFN responses, resulting in enhanced viral resistance and improved survival rates. These results reveal a new link between autophagy and antiviral innate immune responses and provide additional insights into the regulatory mechanisms of RLR-mediated antiviral signaling.

Previous studies showed that the high mortality caused by viruses such as SARS-CoV-2 and influenza virus, primarily results from the complications of a cytokine storm. Therefore, it is critical to identify the key factors participating in the cytokine storm. Here, we demonstrate that the interferon-induced protein 35 (IFP35), plays an important role in the cytokine storm induced by SARS-CoV-2 and influenza virus infection. We find that the levels of serum IFP35 in SARS-CoV-2 patients correlates with the severity of the syndrome. Using mouse model and cell assays, we show that IFP35 is released by lung epithelial cells and macrophage after SARS-CoV-2 or influenza virus infection. In addition, we show that administration of neutralizing antibody against IFP35 considerably reduce lung injuries, and thus the mortality rate of mice exposed to viral infection. In conclusion, our findings suggest that IFP35 serves both as a biomarker and a therapeutic target in virus-induced syndromes., Graphical Abstract, Yu et al. identify IFP35 both as a biomarker and a therapeutic target in SARS-CoV-2 or influenza virus induced syndromes. Neutralizing antibody against IFP35 considerably reduces lung injury and the mortality of infected mice.

DNA replication in eukaryotic cells is performed by a multiprotein complex called the replisome, which consists of helicases, polymerases, and adaptor molecules. Human acidic nucleoplasmic DNA-binding protein 1 (AND-1), also known as WD repeat and high mobility group (HMG)-box DNA-binding protein 1 (WDHD1), is an adaptor molecule crucial for DNA replication. Although structural information for the AND-1 yeast ortholog is available, the mechanistic details for how human AND-1 protein anchors the lagging-strand DNA polymerase α (pol α) to the DNA helicase complex (Cdc45-MCM2–7-GINS, CMG) await elucidation. Here, we report the structures of the N-terminal WD40 and SepB domains of human AND-1, as well as a biochemical analysis of the C-terminal HMG domain. We show that AND-1 exists as a homotrimer mediated by the SepB domain. Mutant study results suggested that a positively charged groove within the SepB domain provides binding sites for pol α. Different from its ortholog protein in budding yeast, human AND-1 is recruited to the CMG complex, mediated by unknown participants other than Go Ichi Ni San. In addition, we show that AND-1 binds to DNA in vitro, using its C-terminal HMG domain. In conclusion, our findings provide important insights into the mechanistic details of human AND-1 function, advancing our understanding of replisome formation during eukaryotic replication.

Purpose Our aim was to characterize the newly established new drug conditional approval process in China and discuss the challenges and opportunities with respect to new drug research and development and registration. Methods We examined the new approval program through literature review, law analysis, and data analysis. Data were derived from published materials, such as journal articles, government publications, press releases, and news articles, along with statistical data from INSIGHT-China Pharma Databases, the China Food and Drug Administration website, the Center for Drug Evaluation website, the US Food and Drug Administration website, and search results published by Google. Findings Currently, there is a large backlog of New Drug Applications in China, mainly because of the prolonged review time at the China Food and Drug Administration, resulting in a lag in drug approvals. In 2015, the Chinese government implemented the drug review and registration system reform and tackled this issue through various approaches, such as setting up a drug review fee system, adjusting the drug registration classification, and establishing innovative review pathways, including the conditional approval process. Implications In Europe and the United States, programs comparable to the conditional approval program in China have been well developed. The conditional approval program recently established in China is an expedited new drug approval process that is expected to affect new drug development at home and abroad and profoundly influence the public health and the pharmaceutical industry in China. Like any program in its initial stage, the conditional approval program is facing several challenges, including setting up a robust system, formatting new drug clinical research requirements, and improving the regulatory agency’s function for drug review and approval. The program is expected to evolve and improve as part of the government mandate of the drug registration system reform.

AlpK is an essential monooxygenase involved in the biosynthesis of kinamycin. It catalyzes the C5-hyfroxylattion of the crucial benzo[b]-fluorence intermediate in kinamycin synthesis. However, the structure and mechanism of AlpK is unclear. Here, we report the first structure of AlpK in complex with FAD. Our structure sheds light on the catalytic mechanism of AlpK.

Chromatin assembly factor 1 (CAF-1) is a histone H3–H4 chaperone that deposits newly synthesized histone (H3–H4)2 tetramers during replication-coupled nucleosome assembly. However, how CAF-1 functions in this process is not yet well understood. Here, we report the crystal structure of C terminus of Cac1 (Cac1C), a subunit of yeast CAF-1, and the function of this domain in stabilizing CAF-1 at replication forks. We show that Cac1C forms a winged helix domain (WHD) and binds DNA in a sequence-independent manner. Mutations in Cac1C that abolish DNA binding result in defects in transcriptional silencing and increased sensitivity to DNA damaging agents, and these defects are exacerbated when combined with Cac1 mutations deficient in PCNA binding. Similar phenotypes are observed for corresponding mutations in mouse CAF-1. These results reveal a mechanism conserved in eukaryotic cells whereby the ability of CAF-1 to bind DNA is important for its association with the DNA replication forks and subsequent nucleosome assembly.

NS1-binding protein (NS1-BP), which belongs to the Kelch protein superfamily, was first identified as a novel human 70 kDa protein that interacts with NS1 ofInfluenza A virus. It is involved in many cell functions, including pre-mRNA splicing, the ERK signalling pathway, the aryl hydrocarbon receptor (AHR) pathway, F-actin organization and protein ubiquitylation. However, the structure of NS1-BP is still unknown, which may impede functional studies. Here, the structure of the C-terminal Kelch domain of NS1-BP (NS1-BP-C; residues 330–642) was determined at 1.98 Å resolution. The Kelch domain adopts a highly symmetric six-bladed β-propeller fold structure. Each blade of the β-propeller is composed of four antiparallel β-strands. Comparison of the Kelch-domain structures of NS1-BP and its homologues showed that the Gly–Gly pair in β-strandBand the hydrophobic Trp residue in β-strandDare highly conserved, while theB–Cloops in blades 2 and 6 are variable. This structure of the Kelch domain of NS1-BP extends the understanding of NS1-BP.

Endosomal transport represents the primary mode for intracellular trafficking and signaling transduction and thus has to be tightly controlled. The molecular processes controlling the endosomal positioning utilize several large protein complexes, one of which contains the small GTPase Rab7, Rab-interacting lysosomal protein (RILP), and oxysterol-binding protein–related protein 1 (ORP1L). Rab7 is known to interact with RILP through a canonical binding site termed the effector-interacting switch region, but it is not clear how Rab7 interacts with ORP1L, limiting our understanding of the overall process. Here, we report structural and biochemical investigation of the Rab7-ORP1L interaction. We found that, contrary to prior studies, the interaction between Rab7 and the N-terminal ankyrin repeat domain (ARD(N)) of ORP1L is independent of Rab7's GTP- or GDP-binding state. Moreover, we show that Rab7 interacts with ORP1L ARD(N) via a unique region consisting of helix3 (α3) and 3(10)-helix 2 (η2). This architecture leaves the canonical effector-interacting switch regions available for RILP binding and thus allows formation of the ORP1L-Rab7-RILP tripartite complex. Mutational disruption of the interacting interface between ORP1L and Rab7 compromised the ability of ORP1L-Rab7-RILP to regulate the late endosome positioning. Collectively, our results again manifested the versatility in the interaction between GTPase and its effector.

Replication and transcription of influenza virus genome mainly depend on its RNA-dependent RNA polymerase (RdRP), composed of the PA, PB1, and PB2 subunits. Although extensively studied, the underlying mechanism of the RdRP complex is still unclear. Here we report the biochemical characterization of influenza RdRP subcomplex comprising PA, PB1, and N terminus of PB2, which exist as dimer in solution and can assemble into a tetramer state, regulated by vRNA promoter. Using single-particle cryo-electron microscopy, we have reconstructed the RdRP tetramer complex at 4.3 Å, highlighting the assembly and interfaces between monomers within the tetrameric structure. The individual RdRP subcomplex contains all the characterized motifs and appears as a cage-like structure. High-throughput mutagenesis profiling revealed that residues involved in the oligomer state formation are critical for viral life cycle. Our results lay a solid base for understanding the mechanism of replication of influenza and other negative-stranded RNA viruses.

Damage-associated molecular patterns (DAMP) trigger innate immune response and exacerbate inflammation to combat infection and cellular damage. Identifying DAMPs and revealing their functions are thus of crucial importance. Here we report that two molecules, N-myc and STAT interactor (NMI) and interferon-induced protein 35 (IFP35) act as DAMPs and are released by activated macrophages during lipopolysaccharide-induced septic shock or acetaminophen-induced liver injury. We show that extracellular NMI and IFP35 activate macrophages to release proinflammatory cytokines by activating nuclear factor-κB through the Toll-like receptor 4 pathway. In addition, the serum levels of NMI are increased in patients who succumbed to severe inflammation. NMI deficiency reduces inflammatory responses and mortality in mouse models of sepsis and liver injury. We therefore propose that extracellular NMI and IFP35 exacerbate inflammation as DAMPs, making them potential therapeutic targets for clinical intervention., Damage-associated molecular patterns (DAMP) are important mediators of innate immunity. Here the authors show that N-myc and STAT interactor (NMI) and interferon-induced protein 35 (IFP35) act as DAMPs to promote inflammation by activating macrophages via the Toll-like receptor 4 and NF-κB pathways.

Protein-disulfide isomerase-like protein of the testis (PDILT), a member of the protein-disulfide isomerase family, is a chaperone essential for the folding of spermatogenesis-specific proteins in male postmeiotic germ cells. However, the structural mechanisms that regulate the chaperone function of PDILTs are unknown. Here, we report the structures of human PDILT (hPDILT) determined by X-ray crystallography to 2.4 A resolution and small-angle X-ray scattering (SAXS). Distinct from previously reported U-like structures of related PDI family proteins, our structures revealed that hPDILT folds into a compact L-like structure in crystals and into an extended chain-like structure in solution. The hydrophobic regions and the hydrophobic pockets in hPDILT, which are important for substrate recognition, were clearly delineated in the crystal structure. Moreover, our results of the SAXS analysis and of structure-based substitutions and truncations indicated that the C-terminal tail in hPDILT is required for suppression of aggregation of denatured proteins, suggesting that the tail is crucial for the chaperone activity of PDILT. Taken together, our findings have identified the critical regions and conformational changes of PDILT that enable and control its activity. These results advance our understanding of the structural mechanisms involved in the chaperone activity of PDILT.

Extending excited-state of sensitizer that absorbs visible photon and produces charge separation is of importance for a photoelectrochemical biofuel cell (PEBFC). In the present work, the dependence of series of porphyrins functionalized at β-positions as sensitizers' structures on their excited-state are analyzed with the density functional theory and time-dependent density functional theory. The calculated results expect that the radiative lifetime decreases in the order of haematoporphyrin > protoporphyrin IX > H2-mesoporphyrin IX. The designed PEBFCs with the above porphyrins as sensitizers are assembled, in which the photocurrent action spectra testifies that the order of the radiative lifetime is consistent with that of the incident photon-to-collected electron conversion efficiency (IPCE) value based on the series of porphyrins. All the experimental characteristics show that the porphyrin with ethanol group (–CHOH–CH3) at β-positions can enhance the photovoltaic performance of the PEBFC as expected.

Weibo is a popular social medium nowadays, and they have a large number of users. The release of information about enterprise development and products on official weibo is an important way for businesses to carry out online marketing. Improved business income depends largely on the result of information dissemination, which can be measured by readers forwarding behavior. In this paper, based on a BA scale-free network and SIRS propagation model, a dissemination model of weibo information in a scale-free network is constructed. The influence of each parameter on information transmission is analyzed by numerical simulation. The research results provide a reference for businesses using weibo for marketing and the management of rumors in social media.

Orthomyxoviruses are a family of ssRNA virus, including influenza virus, infectious salmon anaemia virus and Thogoto virus. The matrix proteins of orthomyxoviruses play crucial roles in some essential processes of the viral life cycle. However, the mechanisms of the matrix proteins involved in these processes remain incompletely understood. Currently, only the structure and function of the matrix protein from influenza virus have been studied. Here, we present the crystal structures of the N-terminal domain of matrix protein from Thogoto virus at pH 7.0 and 4.5. By analysing the structures, we identified the conformational changes of monomers and dimers in different pH conditions, mainly caused by two flexible loops, L3 and L5. These structural deviations would reflect the basis of viral capsid assembly or disassembly.

Interferon-stimulated gene 56 (ISG56) family members play important roles in blocking viral replication and regulating cellular functions, however, their underlying molecular mechanisms are largely unclear. Here, we present the crystal structure of ISG54, an ISG56 family protein with a novel RNA-binding structure. The structure shows that ISG54 monomers have 9 tetratricopeptide repeat-like motifs and associate to form domain-swapped dimers. The C-terminal part folds into a super-helical structure and has an extensively positively-charged nucleotide-binding channel on its inner surface. EMSA results show that ISG54 binds specifically to some RNAs, such as adenylate uridylate (AU)-rich RNAs, with or without 5' triphosphorylation. Mutagenesis and functional studies show that this RNA-binding ability is important to its antiviral activity. Our results suggest a new mechanism underlying the antiviral activity of this interferon-inducible gene 56 family member.

During apoptosis, apoptotic cells are removed by professional phagocytes or neighboring engulfing cells either directly through phagocytic receptors or indirectly through bridging molecules that cross-link dying cells to phagocytes. However, how bridging molecules recognize “eat me” signals and phagocytic receptors to mediate engulfment remains unclear. Here, we report the structural and functional studies of Caenorhabditis elegans TTR-52, a recently identified bridging molecule that cross-links surface-exposed phosphatidylserine (PtdSer) on apoptotic cells to the CED-1 receptor on phagocytes. Crystal structure studies show that TTR-52 has an open β-barrel-like structure with some similarities to the PKCα-C2 domain. TTR-52 is proposed to bind PtdSer via an “ion-mediating” PtdSer-binding mode. Intensive functional studies show that CED-1 binds TTR-52 through its N-terminal EMI domain and that the hydrophobic region of the TTR-52 C terminus is involved in this interaction. In addition, unlike other PtdSer-binding domains, TTR-52 forms dimers, and its dimerization is important for its function in vivo. Our results reveal the first full-length structure of a bridging molecule and the mechanism underlying bridging molecule-mediated apoptotic cell recognition.