Characterization and application of a lactate and branched chain amino acid metabolism related gene signature in a prognosis risk model for multiple myeloma.

BACKGROUND: About 10% of hematologic malignancies are multiple myeloma (MM), an untreatable cancer. Although lactate and branched-chain amino acids (BCAA) are involved in supporting various tumor growth, it is unknown whether they have any bearing on MM prognosis. METHODS: MM-related datasets (GSE4581, GSE136337, and TCGA-MM) were acquired from the Gene Expression Omnibus (GEO) database and the Cancer Genome Atlas (TCGA) database. Lactate and BCAA metabolism-related subtypes were acquired separately via the R package "ConsensusClusterPlus" in the GSE4281 dataset. The R package "limma" and Venn diagram were both employed to identify lactate-BCAA metabolism-related genes. Subsequently, a lactate-BCAA metabolism-related prognostic risk model for MM patients was constructed by univariate Cox, Least Absolute Shrinkage and Selection Operator (LASSO), and multivariate Cox regression analyses. The gene set enrichment analysis (GSEA) and R package "clusterProfiler"were applied to explore the biological variations between two groups. Moreover, single-sample gene set enrichment analysis (ssGSEA), Microenvironment Cell Populations-counter (MCPcounte), and xCell techniques were applied to assess tumor microenvironment (TME) scores in MM. Finally, the drug's IC50 for treating MM was calculated using the "oncoPredict" package, and further drug identification was performed by molecular docking. RESULTS: Cluster 1 demonstrated a worse prognosis than cluster 2 in both lactate metabolism-related subtypes and BCAA metabolism-related subtypes. 244 genes were determined to be involved in lactate-BCAA metabolism in MM. The prognostic risk model was constructed by CKS2 and LYZ selected from this group of genes for MM, then the prognostic risk model was also stable in external datasets. For the high-risk group, a total of 13 entries were enriched. 16 entries were enriched to the low-risk group. Immune scores, stromal scores, immune infiltrating cells (except Type 17 T helper cells in ssGSEA algorithm), and 168 drugs'IC50 were statistically different between two groups. Alkylating potentially serves as a new agent for MM treatment. CONCLUSIONS: CKS2 and LYZ were identified as lactate-BCAA metabolism-related genes in MM, then a novel prognostic risk model was built by using them. In summary, this research may uncover novel characteristic genes signature for the treatment and prognostic of MM.

A Novel Optimized iBeacon Localization Algorithm Modeling.

The conventional methods for indoor localization rely on technologies such as RADAR, ultrasonic, laser range localization, beacon technology, and others. Developers in the industry have started utilizing these localization techniques in iBeacon systems that use Bluetooth sensors to measure the object's location. The iBeacon-based system is appealing due to its low cost, ease of setup, signaling, and maintenance; however, with current technology, it is challenging to achieve high accuracy in indoor object localization or tracking. Furthermore, iBeacons' accuracy is unsatisfactory, and they are vulnerable to other radio signal interference and environmental noise. In order to address those challenges, our study focuses on the development of error modeling algorithms for signal calibration, uncertainty reduction, and interfered noise elimination. The new error modeling is developed on the Curve Fitted Kalman Filter (CFKF) algorithms. The reliability, accuracy, and feasibility of the CFKF algorithms are tested in the experiments. The results significantly show the improvement of the accuracy and precision with this novel approach for iBeacon localization.

Quantitative proteomic analysis reveals that serine/threonine kinase is involved in Streptococcus suis virulence and adaption to stress conditions.

The eukaryotic-type serine/threonine kinase of Streptococcus suis serotype 2 (SS2) performs critical roles in bacterial pathogenesis. In this study, isobaric tags for relative and absolute quantification (iTRAQ) MS/MS were used to analyze the protein profiles of wild type strain SS2-1 and its isogenic STK deletion mutant (Δstk). A total of 281 significant differential proteins, including 147 up-regulated and 134 down-regulated proteins, were found in Δstk. Moreover, 69 virulence factors (VFs) among these 281 proteins were predicted by the Virulence Factor Database (VFDB), including 38 downregulated and 31 up-regulated proteins in Δstk, among which 15 down regulated VFs were known VFs of SS2. Among the down-regulated proteins, high temperature requirement A (HtrA), glutamine synthase (GlnA), ferrichrome ABC transporter substrate-binding protein FepB, and Zinc-binding protein AdcA are known to be involved in bacterial survival and/or nutrient and energy acquisition under adverse host conditions. Overall, our results indicate that STK regulates the expression of proteins involved in virulence of SS2 and its adaption to stress environments.

Complete genome sequences of porcine circovirus-like virus P1 mutants with 163 amino acids in the capsid protein.

Porcine circovirus-like virus P1 is a novel circovirus that was originally detected in China in 2005. Here, we report the genome sequences of P1 isolates JS02, JS03, and HuN06, each with 163 amino acids in its capsid protein. The complete genome of each of these isolates contains 649 nucleotides and has a T insertion at position 207. Phylogenetic analysis based on complete genome sequences of 18 P1 reference strains grouped 16 P1 sequences from this study into one cluster, with the JS02, JS03, and HuN06 isolates forming an independent clade. However, phylogenetic analysis based on amino acid sequences of the capsid protein showed that the JS02, JS03, and HuN06 strains were on the same large branch with PCV2, distinct from other P1 isolates. These results help us to understand the origin and evolution of P1.

A flagellin-adjuvanted inactivated porcine epidemic diarrhea virus (PEDV) vaccine provides enhanced immune protection against PEDV challenge in piglets.

Since late 2010, outbreaks of porcine epidemic diarrhea (PED) have been reported in the swine industry in China. A variant PEDV strain that differs from strain CV777 causes prevalent PEDV infections which commercial vaccines based on CV777 cannot provide complete protection. In this study, we designed a new vaccine based on the epidemic PEDV strain AH2012/12, adjuvanted with flagellin, a mucosal adjuvant that induces mucosal and systemic production of IgA. Three groups of pregnant sows were immunized twice, with a 14-day interval, with PEDV adjuvanted with flagellin, PEDV alone, or PBS before farrowing, and newborn piglets from each group were selected and challenged with PEDV. Immunization with this vaccine elicited high levels of IgG, IgA, and neutralizing antibodies in the serum and colostrum of sows, and newborn piglets were protected against PEDV while suckling. This study should guide the prevention and control strategies for PEDV infection, thereby reducing the losses associated with this virus.

The efficacy of topical gentamycin application on prophylaxis and treatment of wound infection: A systematic review and meta-analysis.

OBJECTIVES: The purpose of this study was to conduct a systematic review and meta-analysis in patients with local wound infection or infective risk, evaluating effects of topical gentamycin application on prophylaxis and treatment of wound infection. METHODS: Embase, the Cochrane Library, Pubmed, Medline (from Ovid) and three Chinese literature databases (CNKI, VIP and WANFANG) were searched. Randomised controlled studies (RCTs) and observational studies (OSs) that assessed the efficacy of topical gentamycin application on prophylaxis and treatment of local wound infection were included. The primary outcome was clinical efficacy. Secondary outcomes included duration of recovery time and length of hospital stay. RESULTS: Fifteen studies (1781 patients) met inclusion criteria. Twelve studies were RCTs and other three studies were OSs. Compared with non-gentamycin group, topical gentamycin application had significantly higher rates of clinical efficacy (OR = 3.57, 95% CI 2.52-5.07). In terms of duration of wound healing, it's taken shorter time in gentamycin group than non-gentamycin group (OR = -4.94, 95% CI -8.37 to -1.51). However, the length of hospital stay had no significantly difference between the two groups (OR = -3.40, 95% CI -8.42 to 1.63). Subgroup analyses were conducted according to study design (RCTs or OSs), purpose and administration type. And the results showed that there were no significant difference of clinical efficacy in study design (P = 0.21, I2  = 35.4%), purpose (P = 0.32, I2  = 0%) and administration type subgroup (P = 0.74, I2  = 0%). However, topical gentamycin application had significantly shorter duration of wound healing in randomly controlled trials compared with observational studies, but had no difference in terms of administration type(P = 0.20, I2  = 38.6%). CONCLUSIONS: Studies to date show that topical gentamycin application significantly increases the rate of clinical efficacy and decreases the duration of wound healing in patients with local wound infection or infective risk.

MicroRNA-30a-5p promotes replication of porcine circovirus type 2 through enhancing autophagy by targeting 14-3-3.

Accumulating evidence demonstrates that autophagy and microRNAs (miRNAs) play key roles in regulating virus-host interactions and can restrict or facilitate viral replication. In the present study we examined whether a functional relationship exists between autophagy, miRNA and porcine circovirus type 2 (PCV2) infection, using several approaches. We demonstrated that there was a positive correlation between PCV2 infection and autophagy in 3D4/21 cells and autophagy induced by PCV2 infection triggered PCV2 replication. Four miRNA were selected by real-time PCR and further studied, but only miR-30a-5p mimic had a significant effect on PCV2 replication. Overexpression of miR-30a-5p significantly enhanced PCV2 infection and autophagy in a dose-dependent manner. Blockage of miR-30a-5p significantly decreased PCV2 replication. We provided further evidence that miR-30a-5p regulate the link between PCV2 infection and host immune system. Furthermore, miR-30a-5p targeted and regulated 14-3-3 gene, which is a regulator of autophagy. Flow cytometry data demonstrated that miR-30a-5p promotes cell cycle arrest at the G2 phase to regulate PCV2 replication and autophagy by interacting directly with 14-3-3, but not with the PCV2 genome. These data not only provide new insights into virus-host interactions during PCV2 infection but also suggest a potential new antiviral therapeutic strategy against PCV2 infection.

Anti-endotoxin and anti-inflammatory effects of Chinese herbal medicinal alkaloid ingredients in vivo.

The aim of the research was to investigate the anti-endotoxin and anti-inflammatory effects of sinomenine, fangchinoline, stachydrine, chuanxionggzine, oxymartrine, and evodiamine alkaloids commonly found in Chinese herbal medicines. In an endotoxin (LPS) control group, each mouse was challenged with 1 mg LPS/kg by intraperitoneal (IP) injection. In high-, middle- and low-dose alkaloid groups, mice were initially challenged with 1 mg LPS/kg by IP injection and, 3 h later, dosed intramuscularly (IM) with one of the six alkaloids at one of three levels (1, 5, or 10 mg/kg body weight). In the drug control group, mice were dosed IM with 10 mg/kg body weight of a given alkaloid; mice in a naïve control group were administered the same volume of normal saline. The results revealed the six alkaloids could reduce the incidence/severity of LPS- induced toxicities, e.g., body temperature elevation, weight loss, systemic inflammation, multiple organ dysfunction. Taken together, the data suggested to us that these alkaloids might effectively regulate inflammatory responses and have a potential to be used in anti-endotoxin therapies.

Characterization and proteome analysis of inosine 5-monophosphate dehydrogenase in epidemic Streptococcus suis serotype 2.

Streptococcus suis serotype 2 (SS2) is an important zoonotic pathogen that causes severe disease symptoms in pigs and humans. In the present study, we found one isogenic mutant lacking inosine 5-monophosphate dehydrogenase (IMPDH) ΔZY05719 was attenuated in pigs compared with the wild-type SS2 strain ZY05719. Comparative proteome analysis of the secreted proteins expression profiles between ZY05719 and ΔZY05719 allowed us to identify Triosephosphate isomerase (TPI) and glyceraldehyde phosphate dehydrogenase (GAPDH), which were down expressed in the absence of the IMPDH. Both of them are glycolytic enzymes participating in the glycolytic pathway. Compared with ZY05719, ΔZY05719 lost the ability of utilize mannose, which might relate to down expression of TPI and GAPDH. In addition, GAPDH is a well-known factor that involved in adhesion to host cells, and we demonstrated ability of adhesion to HEp-2 and PK15 by ΔZY05719 was significantly weakened, in contrast to ZY05719. The adhesion to host cells is the crucial step to cause infection for pathogen, and the reduction adhesion of ΔZY05719, to some extent illustrates the attenuated virulence of ΔZY05719.

Fc receptor-like 5 (FCRL5)-directed CAR-T cells exhibit antitumor activity against multiple myeloma.

Multiple myeloma (MM) remains a challenging hematologic malignancy despite advancements in chimeric antigen receptor T-cell (CAR-T) therapy. Current targets of CAR-T cells used in MM immunotherapy have limitations, with a subset of patients experiencing antigen loss resulting in relapse. Therefore, novel targets for enhancing CAR-T cell therapy in MM remain needed. Fc receptor-like 5 (FCRL5) is a protein marker with considerably upregulated expression in MM and has emerged as a promising target for CAR-T cell therapeutic interventions, offering an alternative treatment for MM. To further explore this option, we designed FCRL5-directed CAR-T cells and assessed their cytotoxicity in vitro using a co-culture system and in vivo using MM cell-derived xenograft models, specifically focusing on MM with gain of chromosome 1q21. Given the challenges in CAR-T therapies arising from limited T cell persistence, our approach incorporates interleukin-15 (IL-15), which enhances the functionality of central memory T (TCM) cells, into the design of FCRL5-directed CAR-T cells, to improve cytotoxicity and reduce T-cell dysfunction, thereby promoting greater CAR-T cell survival and efficacy. Both in vitro and xenograft models displayed that FCRL5 CAR-T cells incorporating IL-15 exhibited potent antitumor efficacy, effectively inhibiting the proliferation of MM cells and leading to remarkable tumor suppression. Our results highlight the capacity of FCRL5-specific CAR-T cells with the integration of IL-15 to improve the therapeutic potency, suggesting a potential novel immunotherapeutic strategy for MM treatment.

Complete genome sequence of a novel porcine circovirus-like agent.

We report here the genome sequence of a porcine circovirus-like agent. The sequenced genome of this porcine circovirus-like agent is composed of a 648-nucleotide circular DNA that includes three predicted protein-coding genes, which means the agent should be a novel member of the family Circoviridae.

In vitro and in vivo isolation of a novel rearranged porcine circovirus type 2.

Here, we present the first report of a novel rearranged porcine circovirus type 2 (PCV2) strain named BIV, isolated from both in vitro and in vivo sources. The complete circular genome of BIV is 896 nucleotides in length. The data will help us to update current knowledge of the replication of PCV2 viruses in cell culture and of their molecular evolution, as well as their diagnosis.

Complete genome sequence of a novel species of Porcine Bocavirus, PBoV5.

Porcine bocavirus 5 is a novel porcine bocavirus species found in a pig with clinical diarrhea from a farm in China. Here, we report the complete genome sequence of strain PBoV5/JS677, which will help toward understanding the molecular and evolutionary characteristics of the porcine bocavirus.

Complete genome sequence of the rearranged porcine circovirus type 2.

We first report here the genome sequences of 4 rearranged porcine circovirus type 2 strains, JSTZ, ZJQDH1, ZJQDH2, and JSHM, isolated from porcine sera in China. The complete circular genomes of these isolates are 578, 483, 574, and 772 nucleotides in length, respectively. They are predicted to be defective interfering particles of porcine circovirus type 2. The findings will help us to understand molecular evolution of porcine circovirus type 2 and the relationship between porcine circovirus type 2 and diseases.

Complete genome sequence of a highly prevalent porcine circovirus 2 isolated from piglet stool samples in China.

Porcine circovirus type 2 (PCV2) is the etiologic agent of porcine circovirus-associated disease. Here, we first report the complete genome sequence of PCV2 strain JSTZ, which was isolated from piglet stool samples and is highly prevalent in China. It will help in understanding the epidemiology and molecular characteristics of PCV2.

In vitro intragenomic rearrangement of porcine circovirus type 2.

We report here for the first time the genome sequence of a rearranged porcine circovirus type 2 (PCV2) strain, CH-IVT1, isolated from PCV2-infected PK-15 cells. The complete circular genome of the CH-IVT1 is 605 nucleotides (nt) in length. The finding will help us to understand the molecular evolution of PCV2 and the relationship between PCV2 and PCV-associated diseases.

Nutritional Status Indices and Monoclonal Gammopathy of Undetermined Significance Risk in the Elderly Population: Findings from the National Health and Nutrition Examination Survey.

OBJECTIVE: Although several studies have found dietary intake is related to multiple myeloma (MM) and its precursor status risks, the role of one's nutritional status has been ignored and its role in plasma cell neoplasm development is still unclear. This study aimed to explore the relationship between various clinical indices of nutritional status and the risk of monoclonal gammopathy of undetermined significance (MGUS) in the population. METHODS: We selected 9520 participants from the NHANES III and NHANES 1999-2004 studies. Controlling nutritional status index (CONUT), prognostic nutritional index (PNI), geriatric nutritional risk index (GNRI) and body mass index (BMI) were calculated as indices of nutritional status of the participants. Associations between nutritional indices and MGUS were investigated using multiple logistic regression, subgroup analysis, and an RCS model. RESULTS: In our study, 266 participants had MGUS, with a prevalence of 2.79%. This study found that CONUT and PNI identified populations with poor nutritional status and had a significant positive correlation with the risk of MGUS. In multivariate logistic regression, compared with the lower CONUT score (<3) group, the OR for the group with higher scores (≥3) was 1.805 (95%CI: 1.271, 2.564). Compared with the lowest quartile group, the highest quartile PNI score group had an OR of 0.509 (95%CI: 0.290, 0.896). GNRI had no significant correlation with the risk of MGUS, with an OR of 0.737 (95%CI: 0.443, 1.227). CONCLUSION: This study found that older adults with CONUT and PNI scores indicating poorer nutrition had a higher risk of MGUS.

Low cholesterol levels are associated with increasing risk of plasma cell neoplasm: A UK biobank cohort study.

BACKGROUND: Plasma cell neoplasms are a group of hematologic neoplasms that often develop in the elderly population. The relationship between cholesterol levels and hematologic malignancy has been identified in population studies. However, it is still unclear if there is a relationship between cholesterol levels and plasma cell neoplasm in European ancestry. METHODS: Prospective cohorts included 502,507 individuals from the UK Biobank who were followed up to 2019 and assessed total cholesterol(TC) levels, low-density lipoprotein (LDL) levels, high-density lipoprotein (HDL) levels, apolipoprotein A (ApoA) and apolipoprotein B (ApoB) as risk factors for plasma cell neoplasms with Cox proportional hazard regression and restricted cubic spline model. We also used two-sample Mendelian randomization to determine if the cholesterol level has a causal effect on developing plasma cell neoplasms. RESULTS: We observed 1819 plasma cell neoplasm cases during 14.2 years of follow-up in the UK Biobank. We found higher blood serum cholesterol levels at baseline were associated with a lower risk of plasma cell neoplasm in our study. All lipid profiles we analyzed in this study were inversely associated with plasma cell neoplasm risk (all ptrend <0.005) but triglycerides did not have such association. However, there was no suggestive association of genetically predicted serum LDL, HDL, and total cholesterol levels with multiple myeloma. CONCLUSION: Low serum total cholesterol, LDL, HDL, ApoA, and ApoB levels were all associated with increasing the risk of plasma cell neoplasm.

Impacts of Random Atomic Defects on Critical Buckling Stress of Graphene under Different Boundary Conditions.

Buckled graphene has potential applications in energy harvest, storage, conversion, and hydrogen storage. The investigation and quantification analysis of the random porosity in buckled graphene not only contributes to the performance reliability evaluation, but it also provides important references for artificial functionalization. This paper proposes a stochastic finite element model to quantify the randomly distributed porosities in pristine graphene. The Monte Carlo stochastic sampling process is combined with finite element computation to simulate the mechanical property of buckled graphene. Different boundary conditions are considered, and the corresponding results are compared. The impacts of random porosities on the buckling patterns are recorded and analyzed. Based on the large sampling space provided by the stochastic finite element model, the discrepancies caused by the number of random porosities are discussed. The possibility of strengthening effects in critical buckling stress is tracked in the large sampling space. The distinguishable interval ranges of probability density distribution for the relative variation of the critical buckling stress prove the promising potential of artificial control by the atomic vacancy amounts. In addition, the approximated Gaussian density distribution of critical buckling stress demonstrates the stochastic sampling efficiency by the Monte Carlo method and the artificial controllability of porous graphene. The results of this work provide new ideas for understanding the random porosities in buckled graphene and provide a basis for artificial functionalization through porosity controlling.

The evolution of minimal residual disease: key insights based on a bibliometric visualization analysis from 2002 to 2022.

Background: The topic of minimal residual disease (MRD) has emerged as a crucial subject matter in the domain of oncology in recent years. The detection and monitoring of MRD have become essential for the diagnosis, treatment, and prognosis of various types of malignancy. Aims: The purpose of this study is to explore the research trends, hotspots, and frontiers of MRD in the last two decades through bibliometric analysis. Methods: We employed Web of Science databases to carry out a bibliometric visualization analysis of research on 8,913 academic papers about MRD research from 2002 to 2022. VOSviewer, CiteSpace, RStudio, and a bibliometric online analysis platform were mainly used to conduct co-occurrence analysis and cooperative relationship analysis of countries/regions, institutions, journals, and authors in the literature. Furthermore, co-occurrence, co-citation, and burst analyses of keyword and reference were also conducted to generate relevant knowledge maps. Results: In the past 20 years, the number of MRD research papers has presented an overall rising trend, going through three stages: a plateau, development, and an explosion. The output of articles in the United States was notably superior and plays a dominant role in this field, and the Netherlands had the highest average citation per article. The most productive and influential institution was the University of Texas MD Anderson Cancer Center. Blood published the most papers and was the most cited journal. A collection of leading academics has come to the fore in the research field, the most prolific of which is Kantarjian HM. It was found that the application of MRD in "acute myeloid leukemia", "acute lymphoblastic leukemia", "multiple myeloma", as well as the detection technology of MRD, are the research hotspots and frontiers in this domain. Furthermore, we analyzed the co-citation network of references and found that the top 10 co-cited references were all associated with MRD in hematological malignancies. Conclusion: This bibliometric visualization analysis conducted a thorough exploration into the research hotspots and trends in MRD from 2002 to 2022. Our findings can aid researchers in recognizing possible collaborations, guiding future research directions, and fostering the growth of MRD detection and monitoring technologies.