Automated annotation of protein function is challenging. As the number of sequenced genomes rapidly grows, the overwhelming majority of protein products can only be annotated computationally. If computational predictions are to be relied upon, it is crucial that the accuracy of these methods be high. Here we report the results from the first large-scale community-based critical assessment of protein function annotation (CAFA) experiment. Fifty-four methods representing the state of the art for protein function prediction were evaluated on a target set of 866 proteins from 11 organisms. Two findings stand out: (i) today's best protein function prediction algorithms substantially outperform widely used first-generation methods, with large gains on all types of targets; and (ii) although the top methods perform well enough to guide experiments, there is considerable need for improvement of currently available tools.

Long noncoding RNAs (LncRNAs) show dysregulation in a variety of cancers. However, the function and specific mechanism of LncRNA GSEC in the progression of osteosarcoma remain mostly unknown. In this study, we sought to elucidate the role and mechanism of LncRNA GSEC in the occurrence and progression of osteosarcoma.

Neuroinflammation plays hypertensive roles in the uninjured autonomic nuclei of the central nervous system, while its mechanisms remain unclear. The present study is to investigate the effect of neuroinflammation on autophagy in the neurons of the rostral ventrolateral medulla (RVLM), where sympathetic premotor neurons for the maintenance of vasomotor tone reside.

The fragile X mental retardation protein (FMRP), an RNA-binding protein that mediates the transport, stability, and translation of hundreds of brain RNAs, is critically involved in regulating synaptic function. Loss of FMRP, as in fragile X syndrome (FXS), is a leading monogenic cause of autism and results in altered structural and functional synaptic plasticity, widely described in the hippocampus and cortex. Though FXS is associated with hyperactivity, impaired social interaction, and the development of repetitive or stereotyped behaviors, all of which are influenced by striatal activity, few studies have investigated the function of FMRP here. Utilizing a cortical-striatal co-culture model, we find that striatal medium spiny neurons (MSNs) lacking FMRP fail to make normal increases in PSD95 expression over a short time period and have significant deficits in dendritic spine density and colocalized synaptic puncta at the later measured time point compared to wildtype (WT) MSNs. Acute expression of wtFMRP plasmid in Fmr1 KO co-cultures results in contrasting outcomes for these measures on MSNs at the more mature time point, reducing spine density across multiple spine types but making no significant changes in colocalized puncta. FMRP's KH2 and RGG RNA-binding domains are required for normal elimination of PSD95, and interruption of these domains slightly favors elimination of immature spine types. Further, KH2 is required for normal levels of colocalized puncta. Our data are largely consistent with a basal role for FMRP and its RNA-binding domains in striatal synapse stabilization on developing MSNs, and in light of previous findings, suggest distinct regional and/or cell type-specific roles for FMRP in regulating synapse structure.

Aedes aegypti, the vector of dengue fever, was first reported in Yunnan in 2002. Now, this species is found in nine counties in border areas of south-west Yunnan. Related dengue fever outbreaks have been reported since 2013. The population genetics of Ae. aegypti in these areas were studied to explain the expansion history of this species.

Characterizing the breeding sites of Culex pipiens complex is of major importance for the control of West Nile disease and other related diseases. However, little information is available about the characteristics and associated factors of the breeding sites of the Cx. pipiens complex in Lhasa, a representative high-altitude region in Southwestern China. In this study, a cross-sectional study concerning the breeding site characteristics and associated factors of the Cx. pipiens complex was carried out in Lhasa, Tibet from 2013-2016. Chi-square analysis and binary logistic regression analysis were applied to identify the key factors associated with the presence of Cx. pipiens complex larvae. Using a standard dipping method, 184 water bodies were examined and Cx. pipiens complex larvae were observed in 36 (19.57%) of them. There were significant differences in the composition of Cx. pipiens complex larvae among the breeding site stability (χ2 = 19.08, p = 0.00) and presence or absence of predators (χ2 = 6.986, p = 0.008). Binary logistic regression analysis indicated that breeding site stability and presence or absence of predators were significantly associated with the presence of Cx. pipiens complex larvae in Chengguan District, Lhasa. Relatively permanent water bodies such as water bodies along river fringes, ponds and puddles, and water bodies with no predators should be paid more attention for future Cx. pipiens complex larvae abatement campaigns in Lhasa, China.

The immunoscore, which is used to quantify immune infiltrates, has greater relative prognostic value than tumor, node, and metastasis (TNM) stage and might serve as a new system for classification of colorectal cancer. However, a comparable immunoscore for predicting lung adenocarcinoma (LUAD) prognosis is currently lacking.

Osteosarcoma, a highly aggressive malignant tumor of the bone, usually occurs in children and young adults. However, although the considerable achievement in the clinical treatment of osteosarcoma recent years, the overall survival of osteosarcoma patients has not been obviously improved. Cancer cells preferentially use glycolysis instead of oxidative phosphorylation to meet their increased energetic and biosynthetic demands, a phenomenon known as the Warburg effect. Glycolysis is a driving factor in multiple cancers and is emerging as a new cancer target treatment. In the present study, we established a model to screen for glycolysis-associated genes in osteosarcoma. This risk score of the model were correlated with clinical characteristics osteosarcoma patients. Besides, a functional assay identified that STC2 enhanced the glycolysis of osteosarcoma cells. Modulation of STC2 changes glucose consumption and lactate production as well as GLUT1 expression in osteosarcoma. Furthermore, we identified that change in the expression levels of STC2 affected the proliferation, invasion, and migration of osteosarcoma cells. Our findings showed STC2 as a new tumor-promoting factor of osteosarcoma cells through enhancing glycolysis.

Hypoxia is a significant feature of solid tumors, including pancreatic ductal adenocarcinoma (PDAC). It is associated with tumor invasion, metastasis, and drug resistance. However, the spatial distribution of hypoxia-related heterogeneity in PDAC remains unclear.

Background: Malaria is endemic in Sierra Leone, with stable and perennial transmission in all parts of the country. At present, the main prevention and control measures for mosquito vectors here involve insecticide treated nets (ITN) and indoor residual spraying (IRS). The most recent entomological surveillance was conducted prior to the civil war, between 1990 and 1994. Therefore, a new entomological surveillance required to support targeted malaria control strategies. Methods:Anopheles mosquitoes were collected between June and December 2019 using the light trap method. On these, we conducted species identification, analyzed seasonal fluctuation and Plasmodium infection rate, and monitored insecticide resistance. Results: Surveillance of seasonal fluctuation showed that there were two peak of Anopheles density in July (mean 13.67 mosquitoes/trap/night) and October (mean 13.00 mosquitoes/trap/night). Meanwhile, the lowest Anopheles density was seen in early September. Ninety-one representatives of Anopheles gambiae s.l. were selected and identified as An. coluzzii (n = 35) and An. gambiae s.s. (n = 56) using PCR. An. coluzzii and An. gambiae s.s. were found to be heterozygous resistant to the knockdown resistance (kdr) L1014F mutation (100%). Meanwhile, the East African mutation (kdr L1014S) was absent in the tested mosquitoes. Three mosquitoes that tested positive for the parasite, had an individual Plasmodium falciparum infection rate of 12.50, 16.67, and 14.29%. The sampling dates of positive mosquitoes were distributed in the two periods of peak Anopheles mosquito density. Conclusion: This study identified the dominant Anopheles species in Freetown as An. gambiae while the predominant species within the An. gambiae complex was An. gambiae sensu stricto. Surveillance of seasonal fluctuations and high P. falciparum infection rates in Anopheles indicate that the alternation of drought and rainy seasons from June to July, and from October to November, are the key periods for malaria control and prevention in Freetown, Sierra Leone. The high frequency of kdr allele mutations in An. gambiae calls for close monitoring of vector susceptibility to insecticides and tracing of resistance mechanisms in order to develop more effective vector control measures and strategies.

Osteosarcoma (OS) is a common disease in the world, and its pathogenesis is still unclear. This study aims to identify the key genes that promote the proliferation, invasion, and metastasis of osteosarcoma cells.

Cao Huang Gui Xiang (CHGX) formula, a Chinese herbal medicine, has been empirically used for the treatment of Candida infections. In the present study, we discovered that the CHGX showed potent antifungal activities against the major human fungal pathogen Candida albicans and other clinical Candida species. Besides, we indicated that CHGX had in vivo efficacy on treating C. albicans infection in mice without noticeable toxicity at the clinical therapeutic concentration. We then set out to investigate the antifungal mechanisms of CHGX against C. albicans. We found that CHGX played an important role in inhibiting biofilm formation and filament development, two critical virulence factors of C. albicans. We further demonstrated that CHGX disrupted cell membrane integrity, triggered the accumulation of reactive oxygen species (ROS) and consumption of adenosine triphosphate (ATP), followed by a rapid fungal cell death in C. albicans. Multiple pathways, including the conserved Ras1-cAMP pathway and mitochondrial protein Mcu1 are involved in CHGX-induced cell death. Our finding expands the understanding of antifungal mechanism of CHGX against C. albicans, and provides new insights in treating patients with Candida infections in clinical practice.

Regulated pyroptosis is critical for pathogen elimination by inducing infected cell rupture and pro-inflammatory cytokines secretion, while overwhelmed pyroptosis contributes to organ dysfunction and pathological inflammatory response. Caffeic acid (CA) and ferulic acid (FA) are both well-known antioxidant and anti-inflammatory phenolic acids, which resemble in chemical structure. Here we found that CA, but not FA, protects macrophages from both Nigericin-induced canonical and cytosolic lipopolysaccharide (LPS)-induced non-canonical pyroptosis and alleviates LPS-induced mice sepsis. It significantly improved the survival of pyroptotic cells and LPS-challenged mice and blocked proinflammatory cytokine secretion. The anti-pyroptotic effect of CA is independent of its regulations in cellular lipid peroxidation, mitochondrial function, or pyroptosis-associated gene transcription. Instead, CA arrests pyroptosis by directly associating with gasdermin D (GSDMD) and blocking its processing, resulting in reduced N-GSDMD pore construction and less cellular content release. In LPS-induced septic mice, CA inhibits GSDMD activation in peritoneal macrophages and reduces the serum levels of interleukin-1β and tumor necrosis factor-α as the known pyroptosis inhibitors, disulfiram and dimethyl fumarate. Collectively, these findings suggest that CA inhibits pyroptosis by targeting GSDMD and is a potential candidate for curbing the pyroptosis-associated disease.

Melioidosis is an emerging infectious disease caused by Burkholderia pseudomallei and is associated with high morbidity and mortality rates in endemic areas. Antibiotic treatment is protracted and not always successful; even with appropriate therapy, up to 40% of individuals presenting with melioidosis in Thailand succumb to infection. In these circumstances, an effective vaccine has the potential to have a dramatic impact on both the scale and the severity of disease. Currently, no vaccines are licensed for human use. A leading vaccine candidate is the capsular polysaccharide consisting of a homopolymer of unbranched 1→3 linked 2-O-acetyl-6-deoxy-β-d-manno-heptopyranose. Here, we present the chemical synthesis of this challenging antigen using a novel modular disaccharide assembly approach. The resulting hexasaccharide was coupled to the nontoxic Hc domain of tetanus toxin as a carrier protein to promote recruitment of T-cell help and provide a scaffold for antigen display. Mice immunized with the glycoconjugate developed IgM and IgG responses capable of recognizing native capsule, and were protected against infection with over 120 × LD50 of B. pseudomallei strain K96243. This is the first report of the chemical synthesis of an immunologically relevant and protective hexasaccharide fragment of the capsular polysaccharide of B. pseudomallei and serves as the rational starting point for the development of an effective licensed vaccine for this emerging infectious disease.

Hydroxysafflor yellow A (HSYA) is an effective therapeutic agent for inflammatory diseases and autoimmune disorders; however, its regulatory effect on NLRP3 inflammasome activation in macrophages has not been investigated. In this study, we predicted the potential interaction between HSYA and xanthine oxidase (XO) via PharmMapper inverse docking and confirmed the binding inhibition via inhibitory test (IC50 = 40.04 μM). Computation docking illustrated that, in this HSYA-XO complex, HSYA was surrounded by Leu 648, Leu 712, His 875, Leu 873, Ser 876, Glu 879, Phe 649, and Asn 650 with a binding energy of -5.77 kcal/M and formed hydrogen bonds with the hydroxyl groups of HSYA at Glu 879, Asn 650, and His 875. We then found that HSYA significantly decreased the activity of XO in RAW264.7 macrophages and suppressed LPS-induced ROS generation. Moreover, we proved that HSYA markedly inhibited LPS-induced cleaved caspase-1 activation via suppressing the sensitization of NLRP3 inflammasome and prevented the mature IL-1β formation from pro-IL-1β form. These findings suggest that XO may be a potential target of HSYA via direct binding inhibition and the combination of HSYA-XO suppresses LPS-induced ROS generation, contributing to the depression of NLRP3 inflammasome and inhibition of IL-1β secretion in macrophages.

Protein function determination is a key challenge in the post-genomic era. Experimental determination of protein functions is accurate, but time-consuming and resource-intensive. A cost-effective alternative is to use the known information about sequence, structure, and functional properties of genes and proteins to predict functions using statistical methods. In this paper, we describe the Multi-Source k-Nearest Neighbor (MS-kNN) algorithm for function prediction, which finds k-nearest neighbors of a query protein based on different types of similarity measures and predicts its function by weighted averaging of its neighbors' functions. Specifically, we used 3 data sources to calculate the similarity scores: sequence similarity, protein-protein interactions, and gene expressions.

Purpose: The meta-analysis aims to evaluate the efficacy and safety of terlipressin compared with norepinephrine for septic shock. Materials and Methods: The relevant studies from MEDLINE, Cochrane Library, Embase were searched by two independent investigators. A variety of keywords were used to search the studies. Stata software (version 11.0, Stata Corp LP, College Station, TX, USA) was used for statistical analysis. Results: A total of six studies were identified and incorporated into the meta-analysis. The results showed that there was no difference for 28-day mortality (RR = 0.99, 95% CI = [0.85,1.15], P = 0.849), AE (RR = 2.54, 95% CI = [0.58,11.08], P = 0.214), and MAP (SMD = -0.10, 95% CI = [-0.35,0.14], P = 0.405), OI, urinary output, Scr, total bilirubin, ALT, and AST between TP group and NE group. While TP could decrease HR at 24 and 48 h compared with NE. Conclusions: Current results suggest that terlipressin showed no added survival benefit for septic shock when compared with norepinephrine, while terlipressin could decrease heart rate in the late phase of septic shock compared with norepinephrine without further liver and kidney injury. Systematic Review Registration: PROSPERO (ID: CRD42019128743). Available online at: http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42019128743.

Accurate prediction of individuals' brain age is critical to establish a baseline for normal brain development. This study proposes to model brain development with a novel non-negative projective dictionary learning (NPDL) approach, which learns a discriminative representation of multi-modal neuroimaging data for predicting brain age. Our approach encodes the variability of subjects in different age groups using separate dictionaries, projecting features into a low-dimensional manifold such that information is preserved only for the corresponding age group. The proposed framework improves upon previous discriminative dictionary learning methods by incorporating orthogonality and non-negativity constraints, which remove representation redundancy and perform implicit feature selection. We study brain development on multi-modal brain imaging data from the PING dataset (N = 841, age = 3-21 years). The proposed analysis uses our NDPL framework to predict the age of subjects based on cortical measures from T1-weighted MRI and connectome from diffusion weighted imaging (DWI). We also investigate the association between age prediction and cognition, and study the influence of gender on prediction accuracy. Experimental results demonstrate the usefulness of NDPL for modeling brain development.

Zong Qi depression is a disease recorded in the literature of Chinese traditional medicine for a long time. In recent years, the theory of Zong Qi depression has been more and more applied to the diagnosis and treatment of a variety of diseases. Astragalus is the most important drug used to treat the depression of Zong Qi. Meanwhile, Astragalus injection is also widely used in a variety of diseases in accordance with the manifestations of Zong Qi subsidence. However, there is a lack of systematic review or meta-analysis of the clinical effect of Astragalus injection in the treatment of Zong Qi subsidence. Therefore, we searched for diseases characterized by symptoms of Zong Qi subsidence (including heart failure, respiratory failure, acute respiratory distress syndrome, and acute lung injury) and evaluated the effect of Astragalus injection in these diseases with mortality and distance of a 6-minute walking test. The results showed that the mortality of patients with subsidence of Zong Qi decreased in 1 month (OR, 0.26 [0.12, 0.61], 95% CI, P=0.002) and 1 year (OR, 0.38 [0.20, 0.69], 95% CI, P=0.002) after using Astragalus injection. The distance of 6-minute walking test after 7 (MD, 91.60 [6.89, 176.31], 95% CI, P=0.03), 14 (MD, 22.62 [13.80, 31.43], 95% CI, P < 0.00001), and 28 days (MD, 108.31 [30.02, 186.59], 95% CI, P=0.007) of using Astragalus injection also increased. Therefore, we believe that Astragalus injection has a certain therapeutic effect on the depression of Zong Qi.

Hypoxia is an important feature of pancreatic ductal adenocarcinoma (PDAC). Previously, we found that hypoxia promotes ENO1 expression and PDAC invasion. However, the underlying molecular mechanism was remains unclear.