A sparse approach for high-dimensional data with heavy-tailed noise

High-dimensional data have commonly emerged in diverse fields, such as economics, finance, genetics, medicine, machine learning, and so on. In this paper, we consider the sparse quantile regression problem of high-dimensional data with heavy-tailed noise, especially when the number of regressors is much larger than the sample size. We bring the spirit of Lp-norm support vector regression into quantile regression and propose a robust Lp-norm support vector quantile regression for high-dimensional data with heavy-tailed noise. The proposed method achieves robustness against heavy-tailed noise due to its use of the pinball loss function. Furthermore, Lp-norm support vector quantile regression ensures that the most representative variables are selected automatically by using a sparse parameter. We use a simulation study to test the variable selection performance of Lp-norm support vector quantile regression, where the number of explanatory variables greatly exceeds the sample size. The simulation study confirms that Lp-norm support vector quantile regression is not only robust against heavy-tailed noise but also selects representative variables. We further apply the proposed method to solve the variable selection problem of index construction, which also confirms the robustness and sparseness of Lp-norm support vector quantile regression

Potential drug-drug interaction of olverembatinib (HQP1351) using physiologically based pharmacokinetic models

Olverembatinib (HQP1351) is a third-generation BCR-ABL tyrosine kinase inhibitor for the treatment of chronic myeloid leukemia (CML) (including T315I-mutant disease), exhibits drug-drug interaction (DDI) potential through cytochrome P450 (CYP) enzymes CYP3A4, CYP2C9, CYP2C19, CYP1A2, and CYP2B6. A physiologically-based pharmacokinetic (PBPK) model was constructed based on physicochemical and in vitro parameters, as well as clinical data to predict 1) potential DDIs between olverembatinib and CYP3A4 and CYP2C9 inhibitors or inducers 2), effects of olverembatinib on the exposure of CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP3A4 substrates, and 3) pharmacokinetics in patients with liver function injury. The PBPK model successfully described observed plasma concentrations of olverembatinib from healthy subjects and patients with CML after a single administration, and predicted olverembatinib exposure increases when co-administered with itraconazole (strong CYP3A4 inhibitor) and decreases with rifampicin (strong CYP3A4 inducer), which were validated by observed data. The predicted results suggest that 1) strong, moderate, and mild CYP3A4 inhibitors (which have some overlap with CYP2C9 inhibitors) may increase olverembatinib exposure by approximately 2.39-, 1.80- to 2.39-, and 1.08-fold, respectively; strong, and moderate CYP3A4 inducers may decrease olverembatinib exposure by approximately 0.29-, and 0.35- to 0.56-fold, respectively 2); olverembatinib, as a “perpetrator,” would have no or limited impact on CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP3A4 enzyme activity 3); systemic exposure of olverembatinib in liver function injury with Child-Pugh A, B, C may increase by 1.22-, 1.79-, and 2.13-fold, respectively. These simulations inform DDI risk for olverembatinib as either a “victim” or “perpetrator”

PB2 segment promotes high-pathogenicity of H5N1 avian influenza viruses in mice

H5N1 influenza viruses with high lethality are a continuing threat to humans and poultry. Recently, H5N1 high-pathogenicity avian influenza virus (HPAIV) has been shown to transmit through aerosols between ferrets in lab experiments by acquiring some mutation. This is another deeply aggravated threat of H5N1 HPAIV to humans. To further explore the molecular determinant of H5N1 HPAIV virulence in a mammalian model, we compared the virulence of A/Duck/Guangdong/212/2004 (DK212) and A/Quail/Guangdong/90/2004 (QL90). Though they were genetically similar, they had different pathogenicity in mice, as well as their 16 reassortants. The results indicated that a swap of the PB2 gene could dramatically decrease the virulence of rgDK212 in mice (1896-fold) but increase the virulence of rgQL90 in mice (60-fold). Furthermore, the polymerase activity assays showed that swapping PB2 genes between these two viruses significantly changed the activity of polymerase complexes in 293T cells. The mutation Ser715Asn in PB2 sharply attenuated the virulence of rgDK212 in mice (2710-fold). PB2 segment promotes high-pathogenicity of H5N1 avian influenza viruses in mice and 715 Ser in PB2 plays an important role in determing high virulence of DK212 in mice

Targeting Myocardial Equilibrative Nucleoside Transporter ENT1 Provides Cardioprotection by Enhancing Myeloid Adora2b Signaling.

Previous studies implicate extracellular adenosine signaling in attenuating myocardial ischemia and reperfusion injury (IRI). This extracellular adenosine signaling is terminated by its uptake into cells by equilibrative nucleoside transporters (ENTs). Thus, we hypothesized that targeting ENTs would function to increase cardiac adenosine signaling and concomitant cardioprotection against IRI. Mice were exposed to myocardial ischemia and reperfusion injury. Myocardial injury was attenuated in mice treated with the nonspecific ENT inhibitor dipyridamole. A comparison of mice with global Ent1 or Ent2 deletion showed cardioprotection only in Ent1-/- mice. Moreover, studies with tissue-specific Ent deletion revealed that mice with myocyte-specific Ent1 deletion (Ent1loxP/loxP Myosin Cre+ mice) experienced smaller infarct sizes. Measurements of cardiac adenosine levels demonstrated that postischemic elevations of adenosine persisted during reperfusion after targeting ENTs. Finally, studies in mice with global or myeloid-specific deletion of the Adora2b adenosine receptor (Adora2bloxP/loxP LysM Cre+ mice) implied that Adora2b signaling on myeloid-inflammatory cells in cardioprotection provided by ENT inhibition. These studies reveal a previously unrecognized role for myocyte-specific ENT1 in cardioprotection by enhancing myeloid-dependent Adora2b signaling during reperfusion. Extension of these findings implicates adenosine transporter inhibitors in cardioprotection against ischemia and reperfusion injury

Systemic Infection and Limited Replication of SHIV Vaccine Virus in Brains of Macaques Inoculated Intracerebrally with Infectious Viral DNA

AbstractSHIV deleted in two accessory genes, ΔvpuΔnef SHIVPPC, functioned well as a vaccine against later challenge with highly pathogenic SHIVKU, and it was able to reach the brain after oral inoculation of live virus. In this study, the proviral genome cloned into a plasmid was inoculated as DNA intracerebrally and spread systemically. Few regions of the brain had detectable proviral DNA by real-time PCR. Two measures of virus replication, detection of viral mRNA expression and circular proviral DNA, were negative for those brain regions, with the exception of the infection site in the right parietal lobe, whereas lymphoid tissues were positive by both measures. Histopathological analyses of all the sampled brain and spinal cord regions did not reveal any abnormalities. Despite intracerebral inoculation of the viral DNA, the brain was not targeted for high levels of virus replication

Untargeted metabolomics reveal rhizosphere metabolites mechanisms on continuous ramie cropping

Ramie is an important fiber feed dual-purpose crop in China and plays an important role in the national economy. However, ramie yield and quality can be reduced after many years of continuous cultivation. Currently, relatively little research has been conducted on rhizosphere metabolites and their pathways in continuous ramie cropping. Therefore, a healthy group (CK) and obstacle groups (XZQG, JZ, DJY, and GXD) with 8 years of continuous cultivation were selected for the study. LC-MS and GC-MS untargeted metabolomics were used to explore and analyze ramie rhizosphere metabolites and pathways. The results revealed that significant differences in the agronomic traits of ramie occurred after 8 years of continuous cultivation, with dwarfed plants and decreased yields in the obstacle groups. Metabolomic analysis identified 49 and 19 rhizosphere metabolites, including lipids, organic acids, phenols, and amino acids. In addition, four differential metabolic pathways (phenylpropanoid biosynthesis, fatty acid metabolism, amino acid metabolism, and ascorbate and aldarate metabolism) were elucidated. It was also clarified that sinapic acid, jasmonic acid, glutamine, and inositol might be the main metabolites affecting ramie continuous-cropping obstacle groups, and they were significantly correlated with ramie agronomic traits and physiological indicators. This provided important insights into the mechanisms affecting continuous ramie cropping. Accordingly, it is expected that the increase or decrease of sinapic acid, jasmonic acid, glutamine, and inositol in the soil will alleviate obstacles to continuous ramie cropping and promote the healthy development of the ramie industry in the future

Multiple omics revealed the growth-promoting mechanism of Bacillus velezensis strains on ramie

Beneficial bacteria that promote plant growth can shield plants from negative effects. Yet, the specific biological processes that drive the relationships between soil microbes and plant metabolism are still not fully understood. To investigate this further, we utilized a combination of microbiology and non-targeted metabolomics techniques to analyze the impact of plant growth-promoting bacteria on both the soil microbial communities and the metabolic functions within ramie (Boehmeria nivea) tissues. The findings indicated that the yield and traits of ramie plants are enhanced after treatment with Bacillus velezensis (B. velezensis). These B. velezensis strains exhibit a range of plant growth-promoting properties, including phosphate solubilization and ammonia production. Furthermore, strain YS1 also demonstrates characteristics of IAA production. The presence of B. velezensis resulted in a decrease in soil bacteria diversity, resulting in significant changes in the overall structure and composition of soil bacteria communities. Metabolomics showed that B. velezensis significantly altered the ramie metabolite spectrum, and the differential metabolites were notably enriched (P < 0.05) in five main metabolic pathways: lipid metabolism, nucleotide metabolism, amino acid metabolism, plant secondary metabolites biosynthesis, and plant hormones biosynthesis. Seven common differential metabolites were identified. Correlation analysis showed that the microorganisms were closely related to metabolite accumulation and yield index. In the B. velezensis YS1 and B. velezensis Y4-6-1 treatment groups, the relative abundances of BIrii41 and Bauldia were significantly positively correlated with sphingosine, 9,10,13-TriHOME, fresh weight, and root weight, indicating that these microorganisms regulate the formation of various metabolites, promoting the growth and development of ramie. Conclusively, B. velezensis (particularly YS1) played an important role in regulating soil microbial structure and promoting plant metabolism, growth, and development. The application of the four types of bacteria in promoting ramie growth provides a good basis for future application of biological fertilizers and bio-accelerators

Impact of clinicopathological factors on extended endocrine therapy decision making in estrogen receptor–positive breast cancer

PurposeIn our study, we aim to analyze the impact of clinicopathological factors on the recommendation of extended endocrine therapy (EET) in patients with ER+ breast cancer and to retrospectively validate the value of CTS5 in EET decision making.Patients and methodsThe retrospective analysis was performed in patients with ER+ breast cancer who have finished 4.5–5 years of adjuvant endocrine therapy and undergone MDT discussion from October 2017 to November 2019. Multivariate logistic regression was used to identify the independent factors for treatment recommendation. CTS5 was calculated for retrospective validation of the EET decision making.ResultsTwo hundred thirty-five patients were received; 4.5–5 years of adjuvant endocrine therapy were included in the study. Multivariate analysis suggested that age (OR 0.460, 95% CI 0.219–0.965, p = 0.04), pN (OR 39.350, 95% CI 9.831–157.341, P < 0.001), and receipt of chemotherapy (OR 3.478, 95% CI 1.336–9.055, p = 0.011) were independent predictors for the recommendation of EET. In the previously selective estrogen receptor modulator (SERM)–treated subgroup, pN and receipt of chemotherapy were independent predictors for the recommendation of EET. In the previously AI-treated subgroup, age, pN, and receipt of chemotherapy were independent predictors. Adverse events did not affect the recommendation in patients previously treated with adjuvant endocrine treatment nor in the previously SERM or AI-treated subgroups. CTS5 (OR 21.887, 95% CI 2.846–168.309, p = 0.003) remained an independent predictor for the recommendation of EET.ConclusionsOur study indicated that age, lymph nodal status, and receipt of chemotherapy were independent predictors for the recommendation of EET. The application of the CTS5 on EET decision making might be valuable among ER+ breast cancer patients

Targeting glutamine metabolic reprogramming of SLC7A5 enhances the efficacy of anti-PD-1 in triple-negative breast cancer

BackgroundTriple-negative breast cancer (TNBC) is a heterogeneous disease that is characterized by metabolic disruption. Metabolic reprogramming and tumor cell immune escape play indispensable roles in the tumorigenesis that leads to TNBC.MethodsIn this study, we constructed and validated two prognostic glutamine metabolic gene models, Clusters A and B, to better discriminate between groups of TNBC patients based on risk. Compared with the risk Cluster A patients, the Cluster B patients tended to exhibit better survival outcomes and higher immune cell infiltration. In addition, we established a scoring system, the glutamine metabolism score (GMS), to assess the pattern of glutamine metabolic modification.ResultsWe found that solute carrier family 7 member 5 (SLC7A5), an amino acid transporter, was the most important gene and plays a vital role in glutamine metabolism reprogramming in TNBC cells. Knocking down SLC7A5 significantly inhibited human and mouse TNBC cell proliferation, migration, and invasion. In addition, downregulation of SLC7A5 increased CD8+ T-cell infiltration. The combination of a SLC7A5 blockade mediated via JPH203 treatment and an anti-programmed cell death 1 (PD-1) antibody synergistically increased the immune cell infiltration rate and inhibited tumor progression.ConclusionsHence, our results highlight the molecular mechanisms underlying SLC7A5 effects and lead to a better understanding of the potential benefit of targeting glutamine metabolism in combination with immunotherapy as a new therapy for TNBC

Response of fermentation quality and microbial community of oat silage to homofermentative lactic acid bacteria inoculation

Oat (Avena sativa L.) is one of the important forage crops in the world. However, oat grown in Southwest China has higher moisture content and their preservation face significant challenges. In addition, existing commercial lactic acid bacteria (LAB) have poor fermentation effects in hot and humid regions. Consequently, the current study investigated the response of oat fermentation quality and microbial community to self-selected LAB inoculation. The treatments were: CK, sterilized water; LP694, Lactobacillus plantarum 694; LR753, Lactobacillus rhamnosus 753; and LPLR, LP694 combined with LR753, followed by 1, 3, 7, 14, and 60 days (d) of fermentation. The results showed that LAB inoculation significantly raised the lactic acid content, and decreased the level of pH value, acetic acid, and ammonia-N in oat silage. The LR753 group had a significantly higher (p < 0.05) lactic acid content (60.95 g kg–1 DM), and lower pH value (3.95) and ammonia-N content (10.1 g kg–1 DM) followed by the LPLR group. The LR753 showed lower NDF (54.60% DM) and ADF (39.73% DM) contents than other groups. The Lactobacillus was a prevalent genus in LAB-treated groups, and its relative abundance reached maximum in LP694 (69%) on day 3, while in the LR753 group (72%) on 60 days. The Lactobacillus rhamnosus, Lactobacillus plantarum, and Lactobacillus fermentum became the dominant species in LAB-treated groups with fermentation time. The Lactobacillus genus was positively correlated with WSC (R = 0.6, p < 0.05), while negatively correlated with pH (R = −0.5, p < 0.05), and BA (R = −0.5, p < 0.01). Overall, the LR753 group had better fermentation quality and preservation of nutritional components providing theoretical support and guidance for future oat silage production in Southwest China