Integrated analysis of omics reveals the role of scapular fat in thermogenesis adaptation in sunite sheep.

Inhabiting some of the world's most inhospitable climatic regions, the Sunite Mongolian sheep generates average temperatures as low as 4.3 °C and a minimum temperature of -38.8 °C; in these environments, they make essential cold adaptations. In this regard, scapular fat tissues from Mongolian sheep were collected both in winter and summer for transcriptomic and proteomic analyses to identify genes related to adaptive thermogenesis. In the transcriptome analysis, 588 differentially expressed genes were identified to participate in smooth muscle activity and fat metabolism, as well as in nutrient regulation. There were 343 upregulated and 245 downregulated genes. GO and KEGG pathway analyses on these genes revealed their participation in regulating smooth muscle activity, metabolism of fats, and nutrients. Proteomic analysis showed the differential expression of 925 proteins: among them, there are 432 up- and 493 down-expressed proteins. These proteins are mainly involved in oxidative phosphorylation, respiratory chain complex assembly, and ATP production by electron transport. Furthermore, using both sets at a more detailed level of analysis revealed over-representation in gene ontology categories related to hormone signaling, metabolism of lipids, the pentose phosphate pathway, the TCA cycle, and especially the process of oxidative phosphorylation. The identified essential genes and proteins were further validated by quantitative real-time polymerase chain reaction and Western blotting, respectively; key metabolic network constriction was constructed. The present study emphasized the critical role of lipid turnover in scapular fat for thermogenic adaptation in Sunite sheep.

Research on financing countermeasures of online game SMEs based on the identification of intangible assets information.

As an important part of the cultural industry, small and medium-sized online game enterprises undertake the functions of technological innovation, employment absorption and cultural cultivation. However, the lack of credit ability restricts the financial development of such enterprises. To solve the financing problem of online small and medium-sized game enterprises, this paper firstly uses the information of intangible assets to identify their credit ability, and considers that the information of intangible assets is a problem worthy of attention in evaluating credit risk. Secondly, the intangible assets information disclosure index, the revenue sharing contract of credit synergy and the dynamic game mechanism are constructed to study the importance of the intangible assets index and the evolution of the dynamic game. Finally, the empirical study shows that the intangible assets of delisting and special treated online game small and medium-sized enterprises still have value, this type of enterprise and credit suppliers have the behavior of seeking advantages and avoiding disadvantages. Therefore, credit synergy should be constructed and government regulation should be implemented.

Effects of resveratrol on DLD and NDUFB9 decrease in frozen semen of Mongolian sheep.

Mongolian sheep are a breed of sheep in China known for their excellent cold and drought resistance. Sperm from Mongolian sheep are often cryopreserved to improve breeding outcomes. However, cryopreservation of sperm often results in issues such as reduced vitality and altered morphology. Therefore, the objective of this study was to investigate the impact of the cryoprotectant resveratrol on frozen sperm from Mongolian sheep, specifically examining its effects on key proteins during cryopreservation. In this study, sperm samples were obtained from three adult Mongolian rams and processed through semen centrifugation. The sperm motility parameters of Fresh Sperm Group (FR), Resveratrol added before freezing group (FF-Res), Resveratrol-free frozen sperm group (FT), and Resveratrol added after freeze-thawing group (FA-Res) were determined. The tandem mass tags (TMT) peptide labeling combined with LC-MS/MS was used for proteomic analysis of the total proteins in FR and FT groups. A total of 2651 proteins were identified, among which 41 proteins were upregulated and 48 proteins were downregulated after freezing. In-depth bioinformatics analysis of differentially abundant proteins (DAPs) revealed their close association with the tricarboxylic acid cycle (TCA) and oxidative phosphorylation pathway. The energy-related protein dihydrolipoamide dehydrogenase (DLD) and the reactive oxygen species (ROS)-related protein NADH dehydrogenase 1 beta subcomplex subunit 9 (NDUFB9) exhibited significant decreases, indicating their potential role as key proteins contributing to reduced sperm vitality. The study demonstrated that the addition of resveratrol (RES) to semen could elevate the expression levels of DLD and NDUFB9 proteins. This study represents the pioneering proteomic analysis of Mongolian ram sperm before and after cryopreservation, establishing the significance of DLD and NDUFB9 as key proteins influencing the decline in vitality following cryopreservation of Mongolian ram sperm. These findings clarify that resveratrol can enhance the levels of DLD and NDUFB9 proteins in cryopreserved Mongolian ram sperm, consequently enhancing their vitality.

Oncolytic viruses engineered to enforce cholesterol efflux restore tumor-associated macrophage phagocytosis and anti-tumor immunity in glioblastoma.

The codependency of cholesterol metabolism sustains the malignant progression of glioblastoma (GBM) and effective therapeutics remain scarce. In orthotopic GBM models in male mice, we identify that codependent cholesterol metabolism in tumors induces phagocytic dysfunction in monocyte-derived tumor-associated macrophages (TAMs), resulting in disease progression. Manipulating cholesterol efflux with apolipoprotein A1 (ApoA1), a cholesterol reverse transporter, restores TAM phagocytosis and reactivates TAM-T cell antitumor immunity. Cholesterol metabolomics analysis of in vivo-sorted TAMs further reveals that ApoA1 mediates lipid-related metabolic remodeling and lowers 7-ketocholesterol levels, which directly inhibits tumor necrosis factor signaling in TAMs through mitochondrial translation inhibition. An ApoA1-armed oncolytic adenovirus is also developed, which restores antitumor immunity and elicits long-term tumor-specific immune surveillance. Our findings provide insight into the mechanisms by which cholesterol metabolism impairs antitumor immunity in GBM and offer an immunometabolic approach to target cholesterol disturbances in GBM.

Intelligent interior atmosphere lamp system based on quantum dot LEDs for safe driving assistance.

A driver safety assisting system is essential to reduce the probability of traffic accidents. But most of the existing driver safety assisting systems are simple reminders that cannot improve the driver's driving status. This paper proposes a driver safety assisting system to reduce the driver's fatigue degree by the light with different wavelengths that affect people's moods. The system consists of a camera, an image processing chip, an algorithm processing chip, and an adjustment module based on quantum dot LEDs (QLEDs). Through this intelligent atmosphere lamp system, the experimental results show that blue light reduced the driver's fatigue degree when just turned on; but as time went on, the driver's fatigue degree rebounded rapidly. Meanwhile, red light prolonged the driver's awake time. Different from blue light alone, this effect can remain stable for a long time. Based on these observations, an algorith was designed to quantify the degree of fatigue and detect its rising trend. In the early stage, the red light is used to prolong the awake time and the blue light to suppress when the fatigue value increases, so as to maximize the awake driving time. The result showed that our device prolonged the awake driving time of the drivers by 1.95 times and reduced fatigue during driving: the quantitative value of fatigue degree generally decreased by about 0.2 times. In most experiments, the subjects were able to complete four hours of safe driving, which reached the maximum length of continuous driving at night allowed by China laws. In conclusion, our system changes the assisting system from a reminder to a helper, thus effectively reducing the driving risk.

Targeting KRAS mutant cancers: from druggable therapy to drug resistance.

Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) is the most frequently mutated oncogene, occurring in a variety of tumor types. Targeting KRAS mutations with drugs is challenging because KRAS is considered undruggable due to the lack of classic drug binding sites. Over the past 40 years, great efforts have been made to explore routes for indirect targeting of KRAS mutant cancers, including KRAS expression, processing, upstream regulators, or downstream effectors. With the advent of KRAS (G12C) inhibitors, KRAS mutations are now druggable. Despite such inhibitors showing remarkable clinical responses, resistance to monotherapy of KRAS inhibitors is eventually developed. Significant progress has been made in understanding the mechanisms of drug resistance to KRAS-mutant inhibitors. Here we review the most recent advances in therapeutic approaches and resistance mechanisms targeting KRAS mutations and discuss opportunities for combination therapy.

Semisolid Extrusion 3D Printing of Propranolol Hydrochloride Gummy Chewable Tablets: an Innovative Approach to Prepare Personalized Medicine for Pediatrics.

The demand for personalized medicine has received extensive attention, especially in pediatric preparations. An emerging technology, extrusion-based 3D printing, is highly attractive in the field of personalized medicine. In this study, we prepared propranolol hydrochloride (PR) gummy chewable tablets tailored for children by semisolid extrusion (SSE) 3D printing technology to meet personalized medicine needs in pediatrics. In this study, the effects of critical formulation variables on the rheological properties and printability of gum materials were investigated by constructing a full-factorial design. In addition, the masticatory properties, thermal stability, and disintegration time of the preparations were evaluated. Bitterness inhibitors were used to mask the bitterness of the preparations. The results of the full-factorial design showed that the amount of gelatin and carrageenan were the key factors in the formulation. Gelatin can improve printability and masticatory properties, carrageenan can improve thermal stability, and accelerate the disintegration of preparations; therefore, a reasonable combination of both could satisfactorily meet the demand for high-quality 3D printing. γ-Aminobutyric acid can reduce the bitterness of gummy chewable tablets to improve medication compliance and the determined formulation (F7) met the quality requirements. In conclusion, the gum material has excellent potential as an extrusion material for 3D printing. The dosage can be adjusted flexibly by the model shape and size. 3D printing has broad prospects in pediatric preparations.

Multifunctional thermo-sensitive hydrogel for modulating the microenvironment in Osteoarthritis by polarizing macrophages and scavenging RONS.

Osteoarthritis (OA) is a common degenerative joint disease that can lead to disability. Blocking the complex malignant feedback loop system dominated by oxidative stress and pro-inflammatory factors is the key to treating OA. Here, we develop a multifunctional composite thermo-sensitive hydrogel (HPP@Cu gel), which is utilized by Poloxamer 407 (P407) and hyaluronic acid (HA) mixture as the gel matrix, then physically mixed with copper nanodots (Cu NDs) and platelet-rich plasma (PRP). Cu NDs is a novel nano-scavenger of reactive oxygen and nitrogen species (RONS) with efficient free radical scavenging activity. HPP@Cu gel is injected into the articular cavity, where it form an in situ gel that slowly released Cu NDs, HA, and PRP, prolonging the duration of drug action. Our results indicate that HPP@Cu gel could efficiently remove RONS from inflammatory sites and promote repolarization of macrophages to an anti-inflammatory phenotype. The HPP@Cu gel therapy dramatically reduces cartilage degradation and inflammatory factor production in OA rats. This study provides a reliable reference for the application of injectable hydrogels in inflammatory diseases associated with oxidative stress.

Cyclophilin acts as a ribosome biogenesis factor by chaperoning the ribosomal protein (PlRPS15) in filamentous fungi.

The rapid transport of ribosomal proteins (RPs) into the nucleus and their efficient assembly into pre-ribosomal particles are prerequisites for ribosome biogenesis. Proteins that act as dedicated chaperones for RPs to maintain their stability and facilitate their assembly have not been identified in filamentous fungi. PlCYP5 is a nuclear cyclophilin in the nematophagous fungus Purpureocillium lilacinum, whose expression is up-regulated during abiotic stress and nematode egg-parasitism. Here, we found that PlCYP5 co-translationally interacted with the unassembled small ribosomal subunit protein, PlRPS15 (uS19). PlRPS15 contained an eukaryote-specific N-terminal extension that mediated the interaction with PlCYP5. PlCYP5 increased the solubility of PlRPS15 independent of its catalytic peptide-prolyl isomerase function and supported the integration of PlRPS15 into pre-ribosomes. Consistently, the phenotypes of the PlCYP5 loss-of-function mutant were similar to those of the PlRPS15 knockdown mutant (e.g. growth and ribosome biogenesis defects). PlCYP5 homologs in Arabidopsis thaliana, Homo sapiens, Schizosaccharomyces pombe, Sclerotinia sclerotiorum, Botrytis cinerea and Metarhizium anisopliae were identified. Notably, PlCYP5-PlRPS15 homologs from three filamentous fungi interacted with each other but not those from other species. In summary, our data disclosed a unique dedicated chaperone system for RPs by cyclophilin in filamentous fungi.

The LIM protein Ajuba recruits DBC1 and CBP/p300 to acetylate ERα and enhances ERα target gene expression in breast cancer cells.

Estrogen/ERα signaling is critical for breast cancer progression and therapeutic treatments. Thus, identifying new regulators of this pathway will help to develop new therapeutics to overcome chemotherapy resistance of the breast cancer cells. Here, we report Ajuba directly interacts with ERα to potentiate ERα target gene expression, and biologically Ajuba promotes breast cancer cell growth and contributes to tamoxifen resistance of these cells. Ajuba constitutively binds the DBD and AF2 regions of ERα, and these interactions can be markedly enhanced by estrogen treatment. Mechanistically, Ajuba recruits DBC1 and CBP/p300 and forms a ternary complex to co-activate ERα transcriptional activity and concomitantly enhances ERα acetylation. Moreover, components of this complex can be found at endogenous promoters containing functional ERα responsive elements. Taken together, these data demonstrate that Ajuba functions as a novel co-activator of ERα and that Ajuba/DBC1/CBP/p300 ternary complex may be a new target for developing therapeutics to treat breast cancer.

Effect on absorption and electron transfer by using Cd(ii) or Cu(ii) complexes with phenanthroline as auxiliary electron acceptors (A) in D-A-π-A motif sensitizers for dye-sensitized solar cells.

To broaden the absorption spectrum, improve intramolecular electronic push-pull balance capability, enhance electron transfer and promote the photovoltaic performances of dye sensitizers, four new polymeric metal complex dyes (PBDTT-PhenCd, PBDTT-PhenCu, PPV-PhenCd and PPV-PhenCu) with donor-acceptor-π-bridge-acceptor (D-A-π-A) structure were designed and synthesized. These dyes, for the first time, used the complexes of Cd(ii) or Cu(ii) with phenanthroline as auxiliary electron acceptors (A) instead of organic electron withdrawing groups and adopted thienylbenzo [1,2-b:4,5-b'] dithiophene (BDTT) or hydroquinone (PV) derivatives as electron donors (D) and 8-quinolinol derivatives as π bridge and acceptors (A). The impacts of different auxiliary electron acceptors (A) of metal complexes due to their thermal, optical, electrochemical properties and photovoltaic performance were also investigated. The best power conversion efficiency of 6.68% was achieved in PBDTT-PhenCd DSSC device. In addition, all dyes showed outstanding thermal stability (Td > 300 °C). The results revealed that these novel polymeric metal complex dyes are potential materials for constructing new sensitizers of high performance.

Meta-analysis of possible role of cadherin gene methylation in evolution and prognosis of hepatocellular carcinoma with a PRISMA guideline.

BACKGROUND: Cadherins (CDHs) have been reported to be associated with cancer. However, the clinical significance of CDH gene methylation in hepatocellular carcinoma (HCC) remains unclear. METHODS: Based on the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement criteria, available studies were identified from online electronic database. The overall odds ratio (OR) and the corresponding 95% confidence interval (95% CI) were calculated and analyzed. RESULTS: A total of 29 eligible studies with 2562 HCC samples and 1685 controls were included. E-cadherin (CDH1) hypermethylation was observed to be significantly higher in HCC than in benign, adjacent, or normal samples. Moreover, CDH1 hypermethylation was not associated with gender, tumor grade, clinical stage, hepatitis B virus (HBV), or hepatitis C virus (HCV) infection in HCC patients. H-cadherin (CDH13), protocadherin-10 (PCDH10), P-cadherin (CDH3), and M-cadherin (CDH15) methylation may have an increased risk of HCC in fewer than 4 studies, and methylated cadherin 8, type 2 (CDH8) and OB-cadherin (CDH11) had a similar OR in HCC and adjacent samples. When HCC samples were compared with normal samples, the analysis of sample type revealed a significantly higher OR in normal blood samples than in normal tissues for hypermethylated CDH1 (50.82 vs 4.44). CONCLUSION: CDH1 hypermethylation may play a key role in the carcinogenesis of HCC. However, CDH1 hypermethylation was not correlated with clinicopathological features. Methylated CDH13, PCDH10, CDH3, and CDH15, but not methylated CDH8 or CDH11, may lead to an increased risk of HCC. Hypermethylated CDH1 may become a noninvasive blood biomarker. Further studies with more data are necessary.

Novel dye sensitizers of polymeric metal complexes with benzodithiophene derivatives as donor and their photovoltaic performance.

Four novel donor-acceptor (D-A) type conjugated polymeric metal complexes (P1-P4) bearing benzodithiophene or carbazole derivative as donors were synthesized, characterized and applied as dye sensitizers in dye-sensitized solar cells (DSSCs). Salicylaldehyde derivative complexes acted as electron acceptors, Zn(II) or Cd(II) was chosen as the coordinated metal ion, and diaminomaleonitrile was ancillary ligand in these structures. The thermal, photophysical, electrochemical and photovoltaic properties of these polymeric metal complexes were investigated by FT-IR, GPC, TGA, DSC, UV-Vis absorption spectroscopy, elemental analysis, cyclic voltammetry (CV), J-V curves and IPCE plots. These polymer dyes exhibit good thermal stability for their application in DSSCs. The DSSC device based on P2 which contains benzodithiophene derivative as donor and Cd(II) as coordination ion, exhibited the highest power conversion efficiency of 2.43% (J(sc)=4.95 mA/cm(2), V(oc) =0.71 V, FF=69.3%) under AM 1.5 G solar irradiation. It indicates a new way to design dye sensitizers for DSSCs.

Risk Factors Associated With Abscess Formation in Children 5 Years of Age and Younger.

From 1997 to 2009, hospitalization rates have doubled for pediatric patients with soft tissue abscesses requiring incision and drainage. Despite this increasing national burden, few studies have been conducted to identify the risk factors associated with abscess formation. Our study evaluates a collection of physiological and lifestyle parameters that may serve as risk factors for abscess formation among pediatric patients 5 years of age or younger. Our results indicate family history and age 2 years and younger are associated with higher risk of abscess formation. Furthermore, methicillin-resistant Staphylococcus aureus and methicillin-susceptible Staphylococcus aureus were prevalent pathogens associated with abscess in our study group. Pediatricians may employ these novel parameters to educate parents and/or guardians of high-risk groups on preventing abscess formation to alleviate the burden of incision & dragining requiring abscess on health care costs.

ß-cypermethrin-induced acute neurotoxicity in the cerebral cortex of mice.

A Type II pyrethroid pesticide ß-cypermethrin is widely used in agriculture and domestic applications for pest control. However, the effect of ß-cypermethrin on the glutamate neurotransmitter has not been well-documented. In the current study, mice were treated with 20, 40, or 80 mg/kg ß-cypermethrin by a single oral gavage, with corn oil as a vehicle control. Four hours after treatment, we investigated glutamate levels and glutamate-metabolizing enzyme (phosphate-activated glutaminase, PAG; glutamine synthetase, GS) activities in the cerebral cortex of mice, using a HPLC system with ultraviolet detectors and a colorimetric assay. Glutamate uptake levels in the synaptosomes of cerebral cortex and mRNA expression levels of PAG, GS, and glutamate transporter-1 (GLT-1) in the cerebral cortex were detected by a radioactive labeling method and qRT-PCR, respectively. Toxic symptoms were observed in mice treated with 40 or 80 mg/kg ß-cypermethrin. Compared with the control, significant decreases in glutamate level and GS activity, and an obvious increase in synaptosomal glutamate uptake, were found in the cerebral cortex of mice treated with 80 mg/kg ß-cypermethrin. No significant changes were found among groups in PAG activity or PAG, GS, and GLT-1 mRNA expression levels. These results suggest that ß-cypermethrin treatment may reduce the glutamate level in the mouse cerebral cortex, which is associated with decreased GS activity and increased synaptosomal glutamate uptake. Our findings provide a partial explanation for the neurotoxic effects of synthetic ß-cypermethrin insecticides.

Sulforaphane ameliorates neurobehavioral deficits and protects the brain from amyloid ß deposits and peroxidation in mice with Alzheimer-like lesions.

Alzheimer's disease (AD) is a common neurodegenerative disease in the elderly individuals and its effective therapies are still unavailable. This study was designed to investigate the neuroprotection of sulforaphane (SFN) in AD-lesion mice induced by combined administration of d-galactose and aluminium. Results showed that SFN ameliorated spatial cognitive impairment and locomotor activity decrease in Morris water maze and open field test, respectively. And attenuated numbers of amyloid ß (Aß) plaques in both hippocampus and cerebral cortex of AD-lesion mice were detected by immunohistochemistry. According to spectrophotometry and quantitative reverse-transcriptase polymerase chain reaction results, a significant increase in carbonyl group level and obvious decreases in both activity and messenger RNA expression of glutathione peroxidase were found in brain of AD-lesion mice compared with control, but not in SFN-treated AD-lesion mice. In conclusion, SFN ameliorates neurobehavioral deficits and protects the brain from Aß deposits and peroxidation in mice with Alzheimer-like lesions, suggesting SFN is likely a potential phytochemical to be used in AD therapeutics.

Huperzine a in the treatment of Alzheimer's disease and vascular dementia: a meta-analysis.

The objective of our study was to perform an updated meta-analysis of placebo-controlled RCTs of Huperzine A (Hup A) on patients with Alzheimer's disease (AD) and vascular dementia (VD), in order to provide the basis and reference for clinical rational drug use. The primary outcome measures assessed were minimental state examination (MMSE) and activities of daily living scale (ADL). Eight AD trials with 733 participants and two VD trials with 92 participants that met our inclusion criteria were identified. The results showed that Hup A could significantly improve the MMSE and ADL score of AD and VD patients, and longer durations would result in better efficacy for the patients with AD. It seemed that there was significant improvement of cognitive function measured by memory quotient (MQ) in patients with AD. Most adverse effects in AD were generally of mild to moderate severity and transient. Compared to the patients with AD, Hup A may offer fewer side effects for participants with VD in this study. Therefore, Hup A is a well-tolerated drug that could significantly improve cognitive performance in patients with AD or VD, but we need to use it with caution in the clinical treatment.

[The effects of endothelin blockade on renal expression of angiotensin II type 1 receptor in diabetic hypertensive rats].

OBJECTIVE: To investigate the changes of angiotensin II type 1 (AT1) receptor in the kidney of spontaneously hypertensive rats (SHR) with diabetes and the influence of endothelin receptor antagonist bosentan. METHODS: Streptozotocin-induced diabetic SHR were divided into four groups: groups treated by cilazapril, bosentan + amlodipine, and amlodipine rsspectively, and untreated group, 6 rats in each group. Six SHR rats and six WKY rats were used as hypertensive and normotensive controls respectively. By the end of the 4th week, all rats were anasthetized and catheteization was conducted to their right common carotis arteries to measure the mean arterial blood pressure and collect blood samples to determine the blood sugar and creatinine by biochemical analyzer, and plasma angiotensin II level by radioimmunoassay. Then the rats were killed and their kidneys were taken. The renal angiotensin II (Ang II) receptor and expression of AT1 receptor was determined by RT-PCR and Western blotting. One day before the rats were killed, 24-hour urine was collected to determine the urinary protein and creatinine. RESULTS: In untreated diabetic SHR, enhanced blood pressure and urinary protein excretion, reduced creatinine clearance, as well as significantly increased plasma and renal Ang II levels were observed compared with those in WKY rats. Immunohistochemistry, Western blotting and semi-quantitatively RT-PCR methods showed that the protein and mRNA levels of AT1 receptor in kidney were significantly reduced in untreated diabetic SHR compared to those in WKY rats. All these abnormalities were attenuated by bosentan + amlodipine and cilazapril therapies. CONCLUSION: Bosentan prevents the down-regulation of AT1 receptor in the kidneys of diabetic hypertensive rats.