The Drosophila NPY-like system protects against chronic stress-induced learning deficit by preventing the disruption of autophagic flux.

Chronic stress may induce learning and memory deficits that are associated with a depression-like state in Drosophila melanogaster. The molecular and neural mechanisms underlying the etiology of chronic stress-induced learning deficit (CSLD) remain elusive. Here, we show that the autophagy-lysosomal pathway, a conserved cellular signaling mechanism, is associated with chronic stress in Drosophila, as indicated by time-series transcriptome profiling. Our findings demonstrate that chronic stress induces the disruption of autophagic flux, and chronic disruption of autophagic flux could lead to a learning deficit. Remarkably, preventing the disruption of autophagic flux by up-regulating the basal autophagy level is sufficient to protect against CSLD. Consistent with the essential role of the dopaminergic system in modulating susceptibility to CSLD, dopamine neuronal activity is also indispensable for chronic stress to induce the disruption of autophagic flux. By screening knockout mutants, we found that neuropeptide F, the Drosophila homolog of neuropeptide Y, is necessary for normal autophagic flux and promotes resilience to CSLD. Moreover, neuropeptide F signaling during chronic stress treatment promotes resilience to CSLD by preventing the disruption of autophagic flux. Importantly, neuropeptide F receptor activity in dopamine neurons also promotes resilience to CSLD. Together, our data elucidate a mechanism by which stress-induced excessive dopaminergic activity precipitates the disruption of autophagic flux, and chronic disruption of autophagic flux leads to CSLD, while inhibitory neuropeptide F signaling to dopamine neurons promotes resilience to CSLD by preventing the disruption of autophagic flux.

Superconductivity above 105 K in Nonclathrate Ternary Lanthanum Borohydride below Megabar Pressure.

Hydrides are promising candidates for achieving room-temperature superconductivity, but a formidable challenge remains in reducing the stabilization pressure below a megabar. In this study, we successfully synthesized a ternary lanthanum borohydride by introducing the nonmetallic element B into the La-H system, forming robust B-H covalent bonds that lower the pressure required to stabilize the superconducting phase. Electrical transport measurements confirm the presence of superconductivity with a critical temperature (Tc) of up to 106 K at 90 GPa, as evidenced by zero resistance and Tc shift under an external magnetic field. X-ray diffraction and transport measurements identify the superconducting compound as LaB2H8, a nonclathrate hydride, whose crystal structure remains stable at pressures as low as ∼ half megabar (59 GPa). Stabilizing superconductive stoichiometric LaB2H8 in a submegabar pressure regime marks a substantial advancement in the quest for high-Tc superconductivity in polynary hydrides, bringing us closer to the ambient pressure conditions.

A pair of dopamine neurons mediate chronic stress signals to induce learning deficit in Drosophila melanogaster.

Chronic stress could induce severe cognitive impairments. Despite extensive investigations in mammalian models, the underlying mechanisms remain obscure. Here, we show that chronic stress could induce dramatic learning and memory deficits in Drosophila melanogaster The chronic stress-induced learning deficit (CSLD) is long lasting and associated with other depression-like behaviors. We demonstrated that excessive dopaminergic activity provokes susceptibility to CSLD. Remarkably, a pair of PPL1-γ1pedc dopaminergic neurons that project to the mushroom body (MB) γ1pedc compartment play a key role in regulating susceptibility to CSLD so that stress-induced PPL1-γ1pedc hyperactivity facilitates the development of CSLD. Consistently, the mushroom body output neurons (MBON) of the γ1pedc compartment, MBON-γ1pedc>α/ß neurons, are important for modulating susceptibility to CSLD. Imaging studies showed that dopaminergic activity is necessary to provoke the development of chronic stress-induced maladaptations in the MB network. Together, our data support that PPL1-γ1pedc mediates chronic stress signals to drive allostatic maladaptations in the MB network that lead to CSLD.

A novel antagonist of the CCL5/CCR5 axis suppresses the tumor growth and metastasis of triple-negative breast cancer by CCR5-YAP1 regulation.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer (BC) with a high mortality rate, and few effective therapeutic strategies are available. CCL5/CCR5 is an appealing immunotherapeutic target for TNBC. However, its signaling mechanism is poorly understood and its direct antagonists have not been reported. Here, we developed a high-throughput screening (HTS) assay for discovering its antagonists. Verteporfin was identified as a more selective and potent antagonist than the known CCR5 antagonist maraviroc. Without photodynamic therapy, verteporfin demonstrated significant inhibition on TNBC tumor growth through immune regulation, remarkable suppression of lung metastasis by cell-intrinsic mechanism, and a significant extension of overall survival in vivo. Mechanistically, CCR5 was found to be essential for expression of the key hippo effector YAP1. It promoted YAP1 transcription via HIF-1α and exerted further control over the migration of CD8+ T, NK, and MDSC immune cells through chemokines CXCL16 and CXCL8 which were identified from RNA-seq. Moreover, the CCR5-YAP1 axis played a vital role in promoting metastasis by modulating ß-catenin and core epithelial-mesenchymal transition transcription factors ZEB1 and ZEB2. It is noteworthy that the regulatory relationship between CCR5 and YAP1 was observed across various BC subtypes, TNBC patients, and showed potential relevance in fifteen additional cancer types. Overall, this study introduced an easy-to-use HTS assay that streamlines the discovery of CCL5/CCR5 axis antagonists. Verteporfin was identified as a specific molecular probe of this axis with great potentials as a therapeutic agent for treating sixteen malignant diseases characterized by heightened CCR5 and YAP1 levels.

Novel Boron-rich Phosphides with High Hardness, Large Strain, and Magnetism.

Boron-rich compounds have attracted much attention due to their interesting structures and excellent properties. Here, we performed an extensive study on the different B-P stoichiometries under pressure by combining a particle swarm optimization method with first-principles calculations. At 1 atm, BP and B6P are thermodynamically stable, while other stoichiometries are metastable. Under pressure, BP and B6P remain stable relative to constituent pure solids up to 80 GPa, while other stoichiometries become unstable at relatively low pressures. A new Cmca B6P is predicted with the lowest energy at 1 atm and shows higher shear strain than the R3̅m structure, which is known to be more resistant to brittle fracture than B4C. Moreover, the predicted Pm B8P is a magnetic semiconductor with a magnetic moment of 1 µB. All these boron-rich phosphides are hard materials. The present results enrich the B-P phase diagram and promote extensive research on their excellent properties.

Biofuel manufacturing from woody biomass: effects of sieve size used in biomass size reduction.

Size reduction is the first step for manufacturing biofuels from woody biomass. It is usually performed using milling machines and the particle size is controlled by the size of the sieve installed on a milling machine. There are reported studies about the effects of sieve size on energy consumption in milling of woody biomass. These studies show that energy consumption increased dramatically as sieve size became smaller. However, in these studies, the sugar yield (proportional to biofuel yield) in hydrolysis of the milled woody biomass was not measured. The lack of comprehensive studies about the effects of sieve size on energy consumption in biomass milling and sugar yield in hydrolysis process makes it difficult to decide which sieve size should be selected in order to minimize the energy consumption in size reduction and maximize the sugar yield in hydrolysis. The purpose of this paper is to fill this gap in the literature. In this paper, knife milling of poplar wood was conducted using sieves of three sizes (1, 2, and 4 mm). Results show that, as sieve size increased, energy consumption in knife milling decreased and sugar yield in hydrolysis increased in the tested range of particle sizes.

UBR5 targets tumor suppressor CDC73 proteolytically to promote aggressive breast cancer.

UBR5, a HECT-domain E3 ubiquitin ligase, is an attractive therapeutic target for aggressive breast cancers. Defining the substrates of UBR5 is crucial for scientific understanding and clinical intervention. Here, we demonstrate that CDC73, a component of the RNA polymerase II-associated factor 1 complex, is a key substrate that impedes UBR5's profound tumorigenic and metastatic activities in triple-negative breast cancer (TNBC) via mechanisms of regulating the expression of ß-catenin and E-cadherin, tumor cell apoptosis and CD8+ T cell infiltration. Expression of CDC73 is also negatively associated with the progression of breast cancer patients. Moreover, we show that UBR5 destabilizes CDC73 by polyubiquitination at Lys243, Lys247, and Lys257 in a non-canonical manner that is dependent on the non-phosphorylation state of CDC73 at Ser465. CDC73 could serve as a molecular switch to modulate UBR5's pro-tumor activities and may provide a potential approach to developing breast cancer therapeutic interventions.

Postoperative bisphosphonate do not significantly alter the fusion rate after lumbar spinal fusion: a meta-analysis.

BACKGROUND: To evaluate the effect of postoperative BP treatment on improving the fusion rate after lumbar spinal fusion surgery by performing a meta-analysis of randomized controlled trials (RCTs) and other comparative cohort studies. METHODS: A comprehensive search of PubMed, EMBASE, the Web of Science, and the Cochrane Central Register of Controlled Trials was performed for RCTs and other comparative cohort studies on the effect of BP treatment on improving the fusion rate after lumbar spinal fusion surgery. The primary outcome measures were the number of patients with bone formation grades A, B, and C at 12 months of follow-up; fusion rates at 12 and 24 months of follow-up; vertebral compression fracture (VCF) at 12 and 24 months of follow-up; pedicle screw loosening at 24 months of follow-up; and cage subsidence, the Oswestry disability index (ODI), and the visual analogue score (VAS) at 12 months of follow-up. The final search was performed in July 2020. RESULTS: Seven studies with 401 patients were included. Compared with the placebo, BP treatment did not significantly alter the number of patients with bone formation grades A, B, and C, or the VAS at the 12-month follow-up or the fusion rates at the 12- and 24-month follow-ups. In addition, compared with the placebo, BPs significantly reduced the risks of VCF at the 12- and 24-month follow-ups, pedicle screw loosening at the 24-month follow-up, and cage subsidence and the ODI at the 12-month follow-up. CONCLUSIONS: Postoperative BPs do not clearly improve bone formation and the fusion rate, but they reduce VCF, cage subsidence, and loosening of pedicle screws after lumbar fusion surgery compared with the control treatment.

miR-19 Is a Potential Clinical Biomarker for Gastrointestinal Malignancy: A Systematic Review and Meta-analysis.

OBJECTIVES: To assess the expression and clinical value of miR-19 in gastrointestinal malignancy. Setting. Embase, Web of Science, PubMed, and other databases were retrieved to screen out relevant studies until December 31, 2019. Participants. Gastrointestinal cancer patients with the description of miR-19 expression, as well as the correlation between miR-19 and clinicopathological characteristics or prognosis. Main Outcome Measures. Pooled odds ratio (OR) or hazard ratio (HR) with 95% confidence interval (CI) was obtained to determine miR-19 expression in gastrointestinal malignancy and the association between miR-19 and patients' clinical characteristics and survival. RESULTS: Thirty-seven studies were included in this study. miR-19 levels in gastrointestinal malignancy, especially in hepatocellular (OR = 4.88, 95% CI = 2.38-9.99), colorectal (OR = 4.81, 95% CI = 2.38-9.72), and pancreatic (OR = 5.12, 95% CI = 2.43-10.78) cancers, were significantly overexpressed, and miR-19 was tightly related to some clinicopathological characteristics, such as lymph node metastasis (OR = 1.74, 95% CI = 1.05-2.86). Although gastrointestinal cancer patients with low and high miR-19 expression had comparable OS (overall survival) and DFS (disease-free survival), subgroup analyses showed that patients with high miR-19 presented better DFS than those with low miR-19 in liver cancer (HR = 0.46, 95% CI = 0.30-0.71). CONCLUSIONS: miR-19 might be a potential progression and prognostic biomarker for gastrointestinal malignancy.

Immune checkpoint inhibitor combination therapy for gastric cancer: Research progress.

Gastric cancer is one of the most common types of cancer; notably, gastric cancer is one of the top five malignancies with regards to incidence and mortality rates. The symptoms of early gastric cancer are not typical, exhibiting only slight upper abdominal discomfort. When the symptoms become more obvious, the lesion has usually progressed to an advanced stage. Notably, >90% of inpatients already have locally advanced or metastatic gastric cancer at the time of initial diagnosis, with limited treatment options for advanced gastric cancer. These options include chemotherapy, targeted therapy and immune checkpoint inhibitors (ICIs). With regards to ICIs, the clinical benefit of monotherapy for advanced gastric cancer is limited; however, combinations of ICIs and other therapies may have clinical benefit. Relevant clinical studies have demonstrated that combinations of ICIs with chemotherapy, anti-vascular targeted therapy or other molecular targeted therapies, and the use of two ICIs, improve outcomes for patients with advanced gastric cancer. This article is a review of progress in the use of ICIs in combination with other therapies for the treatment of gastric cancer. The purpose of this article was to advance gastric cancer immunotherapy and to improve the overall therapeutic benefit for patients with advanced gastric cancer.

Prognostic significance of the neutrophil-to-lymphocyte and platelet-to-lymphocyte ratio in patients with metastatic gastric cancer.

Advanced gastric cancer has a poor prognosis because of advanced gastric cancer is prone to metastasis. It is urgent for us to find an indicator to predict the prognosis of gastric cancer in a timely fashion. Research has revealed that inflammation has an important role in predicting survival in some cancers. The purpose of this study was to evaluate the significance of neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) on the prognosis of metastatic gastric cancer (GC).This was a retrospective review of 110 patients were at presentation diagnosed with stage IV metastatic GC and all patients received palliative chemotherapy between January 2012 and January 2016 at the Affiliated Hospital of Qingdao University. Pretreatment NLR and PLR, as well as clinicopathological characteristics were collected. Patients were divided into high and low groups according to the cutoff values for NLR and PLR. The Kaplan-Meier method was applied to estimate the overall survival (OS) and the Cox proportional hazards model to evaluate the related risk factors for OS. All tests were 2-tailed and a P < .05 was considered to indicate a statistically significant difference.One hundred ten patients were enrolled. Eighty-four patients were men, 24 patients were women, 61 patients were ≥65 years of age, and 49 patients were <65 years of age. The Eastern Cooperative Oncology Group (ECOG) score of most patients (n = 107) ranged from 0 to 1. Ten patients were human epidermal growth factor receptor 2 (HER2)-positive. Seventy-one patients presented with an elevated carcinoembryonic antigen (CEA) level and 49 patients had an elevated Carcinoembryonic 199 (CA-199) level. Fifty-two patients received first-line chemotherapy only. Nineteen patients received third-line or greater chemotherapy. One hundred patients chose dual drug chemotherapy. The median duration of follow-up was 11.6 months. Based on the receiver operating characteristic (ROC) curve, the optimal cut-off value for NLR and PLR was 2.48 and 143.39. Patients with high NLR and high PLR had poor overall survival compared with those who had low NLR and low PLR (P < .001 and P = .013, respectively). In univariate analysis, old age (P = .013), liver metastasis (P = .001), >1 metastatic sites (P = .028), higher NLR (P = .000), and higher PLR (P = .014) were identified as poor prognostic factors associated with OS. Our multivariate analysis had indicated that high NLR (hazard ratio [HR]: 1.617, 95% CI: 1.032-2.525, P = .036) and peritoneal metastasis (HR: 1.547, 95% CI:1.009-2.454, P = .045) was independent prognostic factors for overall survival; however, the PLR was not shown to be an independent prognostic factor.Our study suggested that the pretreatment NLR can be used as significant prognosis biomarker in metastatic gastric cancer patients receiving palliative chemotherapy.

The selectively fluorescent sensing detection and adsorptive removal of Pb2+ with a stable [δ-Mo8O26]-based hybrid.

A polyoxomolybdate based hybrid, [δ-Mo8O26](L)2·2H2O (BUC-77), was synthesized via hydrothermal method, which exhibited selectively fluorescent detection and efficient adsorptive removal toward Pb2+ in aqueous environment. A good linearity was observed between the fluorescence quenching percentage of BUC-77 and the Pb2+ concentration, along with the detection limit being 6.91 ppb. BUC-77 was stable in common solvents and wide pH range, which could be regenerated by being washed with dilute inorganic acids like HNO3 after adsorption of Pb2+. The results revealed that BUC-77 could be potentially used to achieve both detection and removal of Pb2+ in wastewater.

Histone deacetylase HDAC1 expression correlates with the progression and prognosis of lung cancer: A meta-analysis.

BACKGROUND: Histone deacetylase 1 (HDAC1) is an important epigenetic factor, and is thought to be associated with the progression and prognosis of some types of cancer. HDAC1 has been reported to be overexpressed in lung cancer, but the correlation between HDAC1 overexpression and the clinical features or prognosis of lung cancer is controversial. In this study, we investigated the potential association between HDAC1 and lung cancer. MATERIALS AND METHODS: Embase, Web of Science, PubMed, and other sources were searched for relevant studies. Pooled odds ratios (ORs) or hazard ratios (HRs) with 95% confidence interval (CI) were calculated to evaluate the association of HDAC1 with lung cancer risk. RESULTS: Eight eligible studies were included in the final meta-analysis. We found that HDAC1 mRNA or protein expression was closely associated with the differentiation grade of lung cancer (OR = 2.36, 95% CI = 1.14-4.87, P = .02). In addition, the protein expression level of HDAC1 in squamous cell carcinoma was higher than that in adenocarcinoma (OR = 1.81, 95% CI = 1.13-2.90, P = .01). Finally, HDAC1 mRNA or protein expression was negatively correlated with the overall survival rate of patients with lung cancer (HR = 2.40, 95% CI = 1.48-3.88, P = .0004). CONCLUSION: In this meta-analysis, our results suggest that HDAC1 may serve as a good diagnostic and prognostic marker for lung cancer.

Ultrasonic vibration-assisted (UV-A) pelleting of wheat straw: a constitutive model for pellet density.

Ultrasonic vibration-assisted (UV-A) pelleting can increase cellulosic biomass density and reduce biomass handling and transportation costs in cellulosic biofuel manufacturing. Effects of input variables on pellet density in UV-A pelleting have been studied experimentally. However, there are no reports on modeling of pellet density in UV-A pelleting. Furthermore, in the literature, most reported density models in other pelleting methods of biomass are empirical. This paper presents a constitutive model to predict pellet density in UV-A pelleting. With the predictive model, relations between input variables (ultrasonic power and pelleting pressure) and pellet density are predicted. The predicted relations are compared with those determined experimentally in the literature. Model predictions agree well with reported experimental results.

Effects of cutting orientation in poplar wood biomass size reduction on enzymatic hydrolysis sugar yield.

The aim of this study was to understand how cutting orientation in poplar wood biomass size reduction affects enzymatic hydrolysis sugar yield of wood particles. A metal cutting (milling) machine was used to produce poplar wood particles from three cutting orientations. Results showed that cutting orientation significantly affected enzymatic hydrolysis sugar yield of wood particles. In this study, size reduction from the optimum cutting orientation produced 50% more sugars than the other two cutting orientations. Particles from the cutting orientation with the highest sugar yield had a large enzyme accessible area (125 mg orange dye/g biomass, as evaluated by Simons' stain procedure) and low crystallinity (50% crystallinity index, as calculated by the Segal method). Furthermore, small particle size did not necessarily lead to improvement in enzymatic digestibility.

Ultrasonic vibration-assisted pelleting of wheat straw: a predictive model for energy consumption using response surface methodology.

Cellulosic biomass can be used as a feedstock for biofuel manufacturing. Pelleting of cellulosic biomass can increase its bulk density and thus improve its storability and reduce the feedstock transportation costs. Ultrasonic vibration-assisted (UV-A) pelleting can produce biomass pellets whose density is comparable to that processed by traditional pelleting methods (e.g. extruding, briquetting, and rolling). This study applied response surface methodology to the development of a predictive model for the energy consumption in UV-A pelleting of wheat straw. Effects of pelleting pressure, ultrasonic power, sieve size, and pellet weight were investigated. This study also optimized the process parameters to minimize the energy consumption in UV-A pelleting using response surface methodology. Optimal conditions to minimize the energy consumption were the following: ultrasonic power at 20%, sieve size at 4 mm, and pellet weight at 1g, and the minimum energy consumption was 2.54 Wh.

A physics-based temperature model for ultrasonic vibration-assisted pelleting of cellulosic biomass.

Temperature in ultrasonic vibration-assisted (UV-A) pelleting of cellulosic biomass has a significant impact on pellet quality. However, there are no reports on temperature models for UV-A pelleting of cellulosic biomass. The development of a physics-based temperature model can help to explain experimentally determined relations between UV-A pelleting process variables and temperature, and provide guidelines to optimize these process variables in order to produce pellets of good quality. This paper presents such a model for UV-A pelleting of cellulosic biomass. Development of the model is described first. Then temperature distribution is investigated using the model, and temperature difference between the top and the bottom surfaces of a pellet is explained. Based on this model, relations between process variables (ultrasonic power and pelleting duration) and temperature are predicted. Experiments were conducted for model verification, and the results agreed well with model predictions.