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Objective: Effective adjuvant therapeutic strategies are urgently needed to overcome MAPK inhibitor (MAPKi) resistance, which is one of the most common forms of resistance that has emerged in many types of cancers. Here, we aimed to systematically identify the genetic interactions underlying MAPKi resistance, and to further investigate the mechanisms that produce the genetic interactions that generate synergistic MAPKi resistance. Methods: We conducted a comprehensive pair-wise sgRNA-based high-throughput screening assay to identify synergistic interactions that sensitized cancer cells to MAPKi, and validated 3 genetic combinations through competitive growth, cell viability, and spheroid formation assays. We next conducted Kaplan-Meier survival analysis based on The Cancer Genome Atlas database and conducted immunohistochemistry to determine the clinical relevance of these synergistic combinations. We also investigated the MAPKi resistance mechanisms of these validated synergistic combinations by using co-immunoprecipitation, Western blot, qRTPCR, and immunofluorescence assays. Results: We constructed a systematic interaction network of MAPKi resistance and identified 3 novel synergistic combinations that effectively targeted MAPKi resistance (ITGB3 + IGF1R, ITGB3 + JNK, and HDGF + LGR5). We next analyzed their clinical relevance and the mechanisms by which they sensitized cancer cells to MAPKi exposure. Specifically, we discovered a novel protein complex, HDGF-LGR5, that adaptively responded to MAPKi to enhance cancer cell stemness, which was up- or downregulated by the inhibitors of ITGB3 + JNK or ITGB3 + IGF1R. Conclusions: Pair-wise sgRNA library screening provided systematic insights into elucidating MAPKi resistance in cancer cells. ITGB3- + IGF1R-targeting drugs (cilengitide + linsitinib) could be used as an effective therapy for suppressing the adaptive formation of the HDGF-LGR5 protein complex, which enhanced cancer stemness during MAPKi stress.

This study was performed to investigate the effects of dietary trehalose on growth, muscle composition, non-specific immune responses, gene expression and desiccation resistance of juvenile red claw crayfish (Cherax quadricarinatus). A total of 540 (body weight of 0.41 ± 0.05) crayfish were randomly divided into six groups for a feeding experiment. Six diets with trehalose levels at 0 (Diet 1), 1 (Diet 2), 2 (Diet 3), 5 (Diet 4), 10 (Diet 5) and 15 (Diet 6) g kg−1 were prepared to feed juvenile red claw crayfish for 8 weeks. The results showed that the weight gain rate (WGR) and specific growth rate (SGR) of crayfish in Diet 4, Diet 5 and Diet 6 groups were significantly improved compared with the control group (Diet 1). Muscle crude protein contents of crayfish fed Diet 4, Diet 5 and Diet 6 were significantly higher than those of the control group. The activities of superoxide dismutase (SOD) and alkaline phosphatase (AKP) in hepatopancreas and hemolymph of crayfish for Diet 4, Diet 5, and Diet 6 groups were significantly increased while malondialdehyde (MDA) content was significantly reduced when compared with the control. The total antioxidant capacity (T-AOC), catalase (CAT) and glutathione peroxidase (GPx) activities in the hepatopancreas and hemolymph of crayfish fed Diet 5 and Diet 6 were significantly higher than those in the control group. However, acid phosphatase (ACP) activity was not significantly different among all experimental groups. The hepatopancreas and intestine trehalose contents of crayfish showed an upward trend with the increase of dietary trehalose levels. Compared with the control group, supplementation of 5–15 g kg−1 trehalose in the feed up-regulated the expression levels of GPx, C-type lysozyme (C-LZM), antilipolysacchride factor (ALF), facilitated trehalose transporter homolog isoform X2 (Tret1-2) and facilitated trehalose transporter isoform X4 (Tret1-4) mRNA. In addition, supplementation of 5–15 g kg−1 trehalose in the feed could improve the survival rate of red claw crayfish under desiccation stress. These results suggested that supplementation of 5–15 g kg−1 trehalose in feed could significantly improve the growth performance, muscle protein, non-specific immunity and desiccation resistance of juvenile red claw crayfish.

This work aimed to develop an efficient lubricant for physical vapor-deposited TiN coatings on steel by adding cyclopropane-carboxylic acid (CPCa) to PAO4 base oil to enhance boundary lubrication. Results showed that an ultralow coefficient of friction (0.008) and wear rate (7.0 × 10-8 mm3/N∙m) were obtained for the steel/TiN sliding contact using PAO4+2.5 wt % CPCa oil due to the in situ formation of a carbon-based lubricating tribofilm during the sliding process.

Na+/K+-ATPase (NKA) is a large transmembrane protein expressed in all cells. It is well studied for its ion exchanging function, which is indispensable for the maintenance of electrochemical gradients across the plasma membrane and herein neuronal excitability. The widely recognized pump function of NKA closely depends on its unique structure features and conformational changes upon binding of specific ions. Various Na+-dependent secondary transport systems are rigorously controlled by the ionic gradients generated by NKA and are essential for multiple physiological processes. In addition, roles of NKA as a signal transducer have also been unveiled nowadays. Plethora of signaling cascades are defined including Src-Ras-MAPK signaling, IP3R-mediated calcium oscillation, inflammation, and autophagy though most underlying mechanisms remain elusive. Ischemic stroke occurs when the blood flow carrying nutrients and oxygen into the brain is disrupted by blood clots, which is manifested by excitotoxicity, oxidative stress, inflammation, etc. The protective effect of NKA against ischemic stress is emerging gradually with the application of specific NKA inhibitor. However, NKA-related research is limited due to the opposite effects caused by NKA inhibitor at lower doses. The present review focuses on the recent progression involving different aspects about NKA in cellular homeostasis to present an in-depth understanding of this unique protein. Moreover, essential roles of NKA in ischemic pathology are discussed to provide a platform and bright future for the improvement in clinical research on ischemic stroke.

Additive manufacturing techniques have revolutionized the field of fabricating micro-supercapacitors (MSCs) with a high degree of pattern and geometry flexibility. However, traditional additive manufacturing processes are based on the functionality of microstructural modulation, which is essential for device performance. Herein, Ti3C2Tx MXene was chosen to report a convenient aerosol jet printing (AJP) process for the in situ curling and alignment of MXene nanosheets. The aerosol droplet provides a microscale regime for curling MXene monolayers while their alignment is performed by the as-generated directional stress derived from the quasi-conical fiber array (CFA)-guided parallel droplet flow. Interdigital microelectrodes were further developed with the curled MXene and a satisfying areal capacitance performance has been demonstrated. Importantly, the AJP technique holds promise for revolutionizing additive manufacturing techniques for fabricating future smart microelectronics and devices not only in the microscale but also in the nanoscale.

Calcium phosphate (CaP) has been widely used for bone defect repair due to good biocompatibility and osteoconductivity. Additive manufacture of calcium phosphate bioceramics with tailored architectures and improved mechanical properties has recently attracted great attention. Herein, calcium phosphate nanoparticles with the size of ∼89−164 nm were synthesized by the hydrothermal treatment of amorphous calcium phosphate (ACP) precursors at 180 °C for 24 h. Biofunctional elements including Mg, Sr and Zn have been doped into these calcium phosphate nanoparticles. Our results revealed that Mg2+ ions played critical roles in formation of whitlockite-type calcium phosphate (not hydroxyapatite) from ACP precursors. Moreover, gyroid scaffolds with bionic triply periodic minimal surface structures were fabricated using stereolithography printing of these calcium phosphate nanoparticles, which are likely used as biofunctional scaffolds for bone repair.

Macrophage polarization in response to environmental cues has emerged as an important event in the development of atherosclerosis. Compelling evidences suggest that P21-activated kinases 1 (PAK1) is involved in a wide variety of diseases. However, the potential role and mechanism of PAK1 in regulation of macrophage polarization remains to be elucidated. Here, we observed that PAK1 showed a dramatically increased expression in M1 macrophages but decreased expression in M2 macrophages by using a well-established in vitro model to study heterogeneity of macrophage polarization. Adenovirus-mediated loss-of-function approach demonstrated that PAK1 silencing induced an M2 macrophage phenotype-associated gene profiles but repressed the phenotypic markers related to M1 macrophage polarization. Additionally, dramatically decreased foam cell formation was found in PAK1 silencing-induced M2 macrophage activation which was accompanied with alternation of marker account for cholesterol efflux or influx from macrophage foam cells. Moderate results in lipid metabolism and foam cell formation were found in M1 macrophage activation mediated by AdshPAK1. Importantly, we presented mechanistic evidence that PAK1 knockdown promoted the expression of PPARγ, and the effect of macrophage activation regulated by PAK1 silencing was largely reversed when a PPARγ antagonist was utilized. Collectively, these findings reveal that PAK1 is an independent effector of macrophage polarization at least partially attributed to regulation of PPARγ expression, which suggested PAK1-PPARγ axis as a novel therapeutic strategy in atherosclerosis management.

Physical and social environments influence immune homeostasis within adipose tissue, yet the mechanisms remain poorly defined. We report that an enriched environment (EE) housing modulates the immune cell population in white adipose tissue of mice including an increase in the abundance of natural killer (NK) cells. EE upregulates the expression of IL-15 and its receptor IL-15Rα specifically within mature adipocytes. Mechanistically, we show that hypothalamic brain-derived neurotrophic factor (BDNF) upregulates IL-15 production in adipocytes via sympathetic β-adrenergic signaling. Overexpressing BDNF mediated by recombinant adeno-associated virus (rAAV) vector in the hypothalamus expands adipose NK cells. Conversely, inhibition of hypothalamic BDNF signaling via gene transfer of a dominant negative TrkB receptor suppresses adipose NK cells. In white adipose tissue, overexpression of IL-15 using an adipocyte-specific rAAV vector stimulates adipose NK cells and inhibits the progression of subcutaneous melanoma, whereas local IL-15 knockdown blocks the EE effect. These results suggest that bio-behavioral factors regulate adipose NK cells via a hypothalamic BDNF-sympathoneural-adipocyte IL-15 axis. Targeting this pathway may have therapeutic significance for cancer.

The low abundance of circulating tumour DNA (ctDNA) in plasma samples makes the analysis of ctDNA biomarkers for the detection or monitoring of early-stage cancers challenging. Here we show that deep methylation sequencing aided by a machine-learning classifier of methylation patterns enables the detection of tumour-derived signals at dilution factors as low as 1 in 10,000. For a total of 308 patients with surgery-resectable lung cancer and 261 age- and sex-matched non-cancer control individuals recruited from two hospitals, the assay detected 52-81% of the patients at disease stages IA to III with a specificity of 96% (95% confidence interval (CI) 93-98%). In a subgroup of 115 individuals, the assay identified, at 100% specificity (95% CI 91-100%), nearly twice as many patients with cancer as those identified by ultradeep mutation sequencing analysis. The low amounts of ctDNA permitted by machine-learning-aided deep methylation sequencing could provide advantages in cancer screening and the assessment of treatment efficacy.

We report on the acquisition and modeling of the transient response of a commercial silicon (Si) solar cell using a benchtop pulsed X-ray source. The solar-cell transient output to the X-ray pulses was acquired under the dark and steady-state light illumination to mimic the practical operation of a solar cell under different light illumination levels. A solar-cell circuit model was created to develop a fundamental understanding of the transient current/voltage response of solar cell at read-out circuit level. The model was validated by a good agreement between the simulation and experimental results. It was found that the solar-cell resistance ( $R$ ) and capacitance ( $C$ ) depend on the light illumination, and the resulting variation in $RC$ time constant significantly affects the solar-cell transient response. Thus, the solar cell produced different transient signals under different illumination intensities in response to the same X-ray pulse. The experimental data acquired in this work proves the feasibility of using solar panels for prompt detection of nuclear detonations, which also builds a practical mode of X-ray detection using a low-cost self-powered detector.

The mesoionic carbene-stabilized PS+ cation 6 has been synthesized and first characterized by single-crystal X-ray diffraction analysis. Computational investigations reveal the typical multiple-bon...

Aim Activin receptor-like kinase 7 (ALK7) acts as a key receptor for TGF-β family members, which play important roles in regulating cardiovascular activity. However, ALK7's potential role, and underlying mechanism, in the macrophage activation involved in atherogenesis remain unexplored. Methods ALK7 expression in macrophages was tested by RT-PCR, western blot, and immunofluorescence co-staining. The loss-of-function strategy using AdshALK7 was performed for functional study. Oil Red O staining was used to observe the foam cell formation, while inflammatory mediators and genes related to cholesterol efflux and influx were determined by RT-PCR and western blot. A PPARγ inhibitor (G3335) was used to reveal whether PPARγ was required for ALK7 to affect macrophage activation. Results The results exhibited upregulated ALK7 expression in oxidized low-density lipoprotein (Ox-LDL) induced bone marrow derived macrophages (BMDMs) and mouse peritoneal macrophages (MPMs), isolated from ApoE-deficient mice, while ALK7's strong immunoreactivity in BMDMs was observed. ALK7 knockdown significantly attenuated pro-inflammatory, but promoted anti-inflammatory, macrophage markers expression. Additionally, ALK7 silencing decreased foam cell formation, accompanied by the up-regulation of ABCA1 and ABCG1 involved in cholesterol efflux but the down-regulation of CD36 and SR-A implicated in cholesterol influx. Mechanistically, ALK7 knockdown upregulated PPARγ expression, which was required for the ameliorated effect of ALK7 silencing macrophage activation. Conclusions Our study demonstrated that ALK7 was a positive regulator for macrophage activation, partially through down-regulation of PPARγ expression, which suggested that neutralizing ALK7 might be promising therapeutic strategy for treating atherosclerosis.

In a new vanadium extracting process, the effective separation of Na3VO4 from the aqueous NaOH solution containing impurities of Na2CO3, NaAlO2, or Na2SiO3 plays a significant role. The solubility ...

The effects of 0.01–0.11 wt.% Zr on the inclusions, microstructure, tensile properties, and impact toughness of the China low activation martensitic steel were investigated. Results showed that Zr exhibits good deoxidation and desulfurization abilities. The scanning electron microscope was used to examine the inclusions in the ingots. The main inclusions in the alloys were Zr–Ta–O, Zr–O, and Zr–O–S. However, some blocky Zr-rich inclusions appeared in Zr-2 and Zr-3 alloys. Typical martensitic structures were observed in the alloys, and average prior austenite grain sizes of 21.1, 15.7, and 14.8 µm were obtained for Zr-1, Zr-2, and Zr-3 steels, respectively. However, increasing Zr content of the steels deteriorated their mechanical property, owing to the blocky inclusions. The alloy with 0.01% Zr resulted in excellent mechanical properties due to the fine inclusions and the precipitation of Zr3V3C carbides. Values of 576 and 682 MPa were obtained for the yield strength and ultimate tensile strength of Zr-1 alloy, respectively. Furthermore, the ductile–brittle transition temperature of the alloy decreased to − 85 °C.

Bimetallic metal organic framework (MOF) as a precursor to prepare catalysts with bifunctional catalytic activity of oxygen evolution reaction (OER) and hydrogen evolution reaction (HER) attracts more and more attention. Herein, hollow oxygen deficiency-enriched NiFe2O4 is synthesized by pyrolytic FeNi bimetallic MOF. The defects of rGO during carbonization can act as nucleation sites for FeNi particles. After nucleation and N doping, the FeNi particles were served as catalysts for the deposition of dissolved carbon in the defects of the N/rGO. These deposited carbon, like a bridge, connect N/rGO and hollow oxygen deficiency-enriched NiFe2O4 together, which giving full play to the advantages of N/rGO in fast electron transfer, thereby improving its catalytic activity. The resultant NiFe2O4@N/rGO-800 exhibits a low overpotential of 252 mV at 20 mA cm−2 for OER and 157 mV at 10 mA cm−2 for HER in 1 M KOH, respectively. When used as bifunctional electrodes for overall water splitting, it also shows low cell voltage of 1.60 V and 1.67 V at 10 and 20 mA cm−2, respectively.

Gefitinib, the first approved inhibitor for oral epidermal growth factor receptor (EGFR), has been proved to be effective in non-small cell lung cancer with EGFR mutation. However, there are many m...

Iron, nitrogen-co-doped carbon quantum dots (Fe,N-CDs) were prepared via a simple one-step hydrothermal method. The quantum yield of fluorescence reached about 27.6% and the blue-emissive Fe,N-CDs had a mean size of 3.76 nm. The as-prepared carbon quantum dots showed good solubility, a high quantum yield, good biocompatibility, low cytotoxicity, and high photostability. Interestingly, the as-prepared Fe,N-CDs exhibited good selectivity and sensitivity toward both hematin and ferric ions, and the limit of detection for hematin and ferric ions was calculated to be about 0.024 μM and 0.64 μM, respectively. At the same time, Fe,N-CDs were used for imaging HeLa cells and showed that most Fe,N-CDs were detained in the lysosome. Thus, this fluorescent probe has potential application in the quantitative detection of hematin or Fe3+ in a complex environment and for determining Fe3+ at the cellular level.

Highlights • SHC014748M was proved to be more selective for PI3Kδ inhibition relative to other class i PI3K enzymes. • SHC014748M showed in vitro activity in most of 23 B lymphoma cell lines and primary CLL cells and also inhibited phosphorylation of AKT, targets downstream of PI3Kδ. • In vivo study revealed that SHC014748M significantly reduced lymphoma cell growth in the treatment group compared with control mice. • SHC014748M seemed to be a novel promising compound in the treatment of B cell lymphomas and CLL., PI3Kδ (phosphatidylinositol 3-kinase-δ), one of the class I PI3Ks, is found expressed primarily in leukocytes and plays an essential role in B-cell development and function. This provides a rationale for the development of small molecule inhibitors that selectively target p110δ for patients with indolent non-Hodgkin lymphomas. Here in this paper, we comprehensively evaluated the in vitro and in vivo antitumor activity of SHC014748M, an oral selective inhibitor of PI3Kδ under Phase I clinical evaluation. Biochemical and cell-based assays were used to measure compound potency and selectivity in lymphoma cell lines as well as primary chronic lymphocytic leukemia (CLL) cells. Scid mice were subcutaneously inoculated with the SU-DHL-6 cell line. SHC014748M was more selective for PI3Kδ inhibition relative to other class I PI3K enzymes and showed in vitro activity in most of 23 B lymphoma cell lines and primary CLL cells. SHC014748M also inhibited phosphorylation of AKT, targets downstream of PI3Kδ, in both lymphoma cells and primary CLL cells. In vivo study revealed that SHC014748M significantly reduced lymphoma cell growth in the treatment group compared with control mice. CCL4, CCL17, CCL22 and CXCL13 in patient serum decreased sharply after SHC014748M treatment. According to the results, SHC014748M appeared to be a novel promising compound in the treatment of B cell lymphomas and CLL.

Background/Objectives Environmental enrichment (EE) is a physiological model to investigate brain-fat interactions. We previously discovered that EE activates the hypothalamic-sympathoneural adipocyte (HSA) axis via induction of brain-derived neurotrophic factor (BDNF), thus leading to sympathetic stimulation of white adipose tissue (WAT) and an anti-obesity phenotype. Here, we investigate whether PTEN acts as a downstream mediator of the HSA axis in the EE. Methods Mice were housed in EE for 4- and 16-week periods to determine how EE regulates adipose PTEN. Hypothalamic injections of adeno-associated viral (AAV) vectors expressing BDNF and a dominant negative form of its receptor were performed to assess the role of the HSA axis in adipose PTEN upregulation. A β-blocker, propranolol, and a denervation agent, 6-hydroydopamine, were administered to assess sympathetic signaling in the observed EE-PTEN phenotype. To determine whether inducing PTEN is sufficient to reproduce certain EE adipose remodeling, we overexpressed PTEN in WAT using an AAV vector. To determine whether adipose PTEN is necessary for the EE-mediated reduction in adipocyte size, we injected a rAAV vector expressing Cre recombinase to the WAT of adult PTENflox mice and placed the mice in EE. Results EE upregulated adipose PTEN expression, which was associated with suppression of AKT and ERK phosphorylation, increased hormone-sensitive lipase (HSL) phosphorylation, and reduced adiposity. PTEN regulation was found to be controlled by the HSA axis—with the hypothalamic BDNF acting as the upstream mediator—and dependent on sympathetic innervation. AAV-mediated adipose PTEN overexpression recapitulated EE-mediated adipose changes including suppression of AKT and ERK phosphorylation, increased HSL phosphorylation, and reduced adipose mass, whereas PTEN knockdown blocked the EE-induced reduction of adipocyte size. Conclusions These data suggest that adipose PTEN responds to environmental stimuli and serves as downstream mediator of WAT remodeling in the EE paradigm, resulting in decreased adipose mass and decreased adipocyte size.

A series of two-coordinate AuI and CuI complexes (3 a, 3 b and 5 a, 5 b) are reported as new organometallic thermally activated delayed fluorescence (TADF) emitters, which are based on the carbene-metal-carbazole model with a pyridine-fused 1,2,3-triazolylidene (PyTz) ligand. PyTz features low steric hindrance and a low-energy LUMO (LUMO=-1.47 eV) located over the π* orbitals of the whole ligand, which facilitates intermolecular charge transfer between a donor (carbazole) and an accepter (PyTz). These compounds exhibit efficient TADF with microsecond lifetimes. Temperature-dependent photoluminescence kinetics of 3 a supports a rather small energy gap between S1 and T1 (ΔE S1-T1 =60 meV). Further experiments reveal that there are dual-emission properties from a monomer-dimer equilibrium in solution, exhibiting single-component multicolor emission from blue to orange, including white-light emission.

A series of lead- and bismuth-free tetragonal tungsten bronze ceramics with chemical formula given as Sr2–xMxNaNb5–xTixO15 (M = La3+ and Ho3+) were prepared. Through codoping of A- and B-sites, swi...

The high-temperature (HT) and low-temperature (LT) hydrothermal stabilities of molecular-sieve-based catalysts are important for the selective catalytic reduction of NOx with ammonia (NH3-SCR). In this paper, we report a catalyst, Cu2+ loading SAPO-17, synthesized using cyclohexylamine (CHA), which is commercially available and inexpensive and is utilized in NH3-SCR reduction for the first time. After systematic investigations on the optimization of Si and Cu2+ contents, it was concluded that Cu-SAPO-17-8.0%-0.22 displays favorable catalytic performance, even after being heated at 353 K for 24 h and at 973 K for 16 h. Moreover, the locations of CHAs, host–guest interaction and the Bronsted acid sites were explored by Rietveld refinement against powder X-ray diffraction data of as-made SAPO-17-8.0%. The refinement results showed that two CHAs exist within one eri cage and that the protonated CHA forms a hydrogen bond with O4, which indicates that the proton bonding with O4 will form the Bronsted acid site after the calcination.

SAPO-34s with varying Si content templated by bulky tetraethylammonium hydroxide (TEAOH) were prepared to investigate the effect of Si environments on the selective catalytic reduction (SCR) of NOx and the moisture stability of Cu-SAPO-34 catalysts. These Cu-SAPO-34s have similar Cu loadings, isolated Cu2+ content, and Bronsted acid sites (BAS). Both the ratio of Si islands and the acid strength of Cu-SAPO-34s increase with increasing Si content. In situ diffused reflection infrared Fourier transform spectroscopy (DRIFTS) studies reveal that the NH3 adsorbed on mild BAS (associated with Si(4Al) species) is more active for NOx conversion than NH3 adsorbed on strong ones (associated with Si islands). This agrees well with the high turnover frequency (TOF) and the low activation energy on Cu-SAPO-34 with low Si content and abundant Si(4Al) species (sample Si-7.7). Upon hydration treatment, the textural properties, strong acid sites, and reducibility of isolated Cu2+ ions show a decrease. This deterioration intensifies with the increasing Si islands in the catalysts due to the easier occurrence of Si migration and the formation of larger Si islands. Sample Si-7.7 exhibits the best moisture stability and thus well-preserved denitration performance. These results imply that a practical Cu-SAPO-34 catalyst with superior activity and moisture stability may be achieved by controlling the Si environments of SAPO-34 templated by bulky amines.

C36H32ClN3O7, orthorhombic, P212121 (no. 19), a = 11.4608(5) Å, b = 12.1489(5) Å, c = 23.1684(7) Å, V = 3225.9(2) Å3, Z = 4, R gt (F) = 0.0588, wR ref (F 2) = 0.1546, T = 293 K.

We report a performance comparison of Zr, Bi, Ti, and Ga as metal contacts on solution-grown CsPbBr3 single-crystal gamma-ray detectors. The same CsPbBr3 single crystal was repeatedly deposited with different metal contacts for the evaluation of gamma spectral performance to eliminate crystal-to-crystal variation. Leakage current as low as 2–3 nA at −200 V with detector thickness 2–3 mm was consistently achieved with Zr, Bi, Ti, and Ga as Schottky contact metal, which is comparable to the leakage current level of a commercial cadmium zinc telluride (CZT) detector. Gamma energy spectra with a prominent photopeak at 662 keV were consistently acquired with all studied metal contacts. The best resolution at 662 keV is 11% with a peak-to-Compton valley ratio of 2, indicating an improved spectrum shape than previous results. Through Americium-241 (241Am) alpha spectra acquisition, the hole mobility of the CsPbBr3 single crystal is evaluated to be 1.78 cm2 V−1 s−1. We also discussed issues related with the CsPbBr3 gamma detector architecture and interface layers, commonly encountered during CsPbBr3 gamma detector fabrication, that is, impact of electron/hole transport layer and surface oxide layer on gamma detector spectral performance, comparison of different metal–perovskite–metal structures. The persistent CsPbBr3 gamma spectral performance marks the good reproducibility of CsPbBr3 gamma detectors, further enabling CsPbBr3 detector field applications.

Recently, glycerol has raised great interest among researchers as an environmentally-friendly lubricant. Low friction, even super-lubricity, can be achieved when glycerol is used with diamond-like carbon coatings. Though TiN coatings are currently widely used in improving the tribological performance of forming tools, cutting tools, and machine elements, no literature exists on the tribological performance of a PVD TiN coating under glycerol lubrication. This paper investigates the combination of TiN coatings with glycerol. The results show that glycerol exhibits excellent lubrication performance, which is stronger in the steel/TiN than in the steel/steel tribopair. The action mechanism of glycerol in steel/TiN tribopair is also proposed.

Paraneoplastic pemphigus (PNP) is a severe autoimmune syndrome commonly triggered by neoplasms. The prognosis of CLL-associated PNP is dismal due to its refractory course and secondary infection and no standard treatment was recommended. We retrospectively reported six CLL with PNP cases from 842 cases of CLL including diagnosis, treatment and prognosis. The median time between the initial of CLL to PNP was 36 months while the median overall survival from the diagnosis of PNP was 26 months. And three cases died of lung infection while 5 developed pulmonary symptoms. And 5 cases received fludarabine-based chemotherapy before developing PNP, which suggesting fludarabine was one of potential causes of PNP. For the treatment, five patients were rescued by combined regimens including rituximab, methylprednisolone, immunoglobulin, fresh frozen plasma and the last received ibrutinib combined with short-term prednisone. Fludarabine-based regimen may be one of the potential causes of PNP. The combined regimen might shed a new light, while ibrutinib is a promising drug for CLL with PNP, but needs much more evidence. PNP should be carefully treated to guide early diagnosis and intervention for a better prognosis.

Marine sediment is the primary sink of microplastics and is an indicator of pollution levels. However, although there are well-developed detection methods, detection is rarely focused on low-micrometer-sized particles, mainly due to technique limitations. In this study, a simplified process omitting digestion procedures was developed to pretreat microplastics obtained from marine sediment and was coupled with micro-Raman spectroscopy to identify microplastics. Based on the overall analysis of the characteristic peak assignments, a Raman spectral reference library was constructed for 18 types of plastic. In addition, the effects of the measurement parameters were systematically described. Field research was then conducted to validate the developed process and investigate microplastic contamination in Huiquan Bay, Qingdao, China. This simplified process could retain the original appearance of microparticles and accomplish the detection of

Social and environmental factors impact cancer and energy balance profoundly. Years ago, our lab established the existence of a novel brain-fat interaction we termed the "hypothalamic-sympathoneural-adipocyte (HSA) axis", through which complex environmental stimuli provided by an enriched environment regulate body composition, energy balance, and development of cancer. We have spent a significant portion of the past decade to further characterize the broad health benefits of an enriched environment (for example, leanness, enhanced immune function, and cancer resistance), and to identify mediators in the brain and periphery along the HSA axis. This review summarizes our recent work regarding the interface between endocrinology, immunology, cancer biology, aging, and neuroscience. We will discuss the interplay between these systemic phenomena and how the HSA axis can be targeted for regulation of cancer and aging.

As a receptor for transforming growth factor-β, nodal and activin, activin receptor-like kinase 7 (ALK7) previously acts as a suppressor of tumorigenesis and metastasis, which has emerged to play a key role in cardiovascular diseases. However, the potential effect and molecular mechanism of ALK7 on vascular smooth muscle cells' (VSMCs) phenotypic modulation have not been investigated. Using cultured mouse VSMCs with platelet-derived growth factor-BB administration, we observed that ALK7 showed a significantly increased expression in VSMCs accompanied by decreased VSMCs differentiation marker genes. Loss-of-function study demonstrated that ALK7 knockdown inhibited platelet-derived growth factor-BB-induced VSMCs phenotypic modulation characterized by increased VSMCs differentiation markers, reduced proliferation, and migration of VSMCs. Such above effects were reversed by ALK7 overexpression. Notably, we noticed that ALK7 silencing dramatically enhanced PPARγ expression, which was required for the attenuated effect of ALK7 knockdown on VSMCs phenotypic modulation. Collected, we identified that ALK7 acted as a novel and positive regulator for VSMCs phenotypic modulation partially through inactivation of PPARγ, which suggested that neutralization of ALK7 might act as a promising therapeutic strategy of intimal hyperplasia.

Pituitary adenoma (PA) is one of the most common intracranial tumors, and approximately 40% of all PAs are prolactinomas. Dopamine agonists (DAs), such as cabergoline (CAB), have been successfully used in the treatment of prolactinomas. The expression of dopamine type 2 receptor (DRD2) determines the therapeutic effect of DAs, but the molecular mechanisms of DRD2 regulation are not fully understood. In this study, we first demonstrated that DRD2 underwent proteasome-mediated degradation. We further employed the yeast two-hybrid system and identified kelch repeat and BTB (POZ) domain containing 7 (KBTBD7), a substrate adaptor for the CUL3-RING ubiquitin (Ub) ligase complex, as a DRD2-interacting protein. KBTBD6/7 directly interacted with, and ubiquitinated DRD2 at five ubiquitination sites (K221, K226, K241, K251, and K258). CAB, a high-affinity DRD2 agonist, induced DRD2 internalization, and cytoplasmic DRD2 was degraded via ubiquitination under the control of KBTBD6/7, the activity of which attenuated CAB-mediated inhibition of the AKT/mTOR pathway. KBTBD7 knockout (KO) mice were generated using the CRISPR-Cas9 technique, in which the static level of DRD2 protein was elevated in the pituitary gland, thalamus, and heart, compared to that of WT mice. Consistently, the expression of KBTBD6/7 was negatively correlated with that of DRD2 in human pituitary tumors. Moreover, KBTBD7 was highly expressed in dopamine-resistant prolactinomas, but at low levels in dopamine-sensitive prolactinomas. Knockdown of KBTBD6/7 sensitized MMQ cells and primary pituitary tumor cells to CAB treatment. Conversely, KBTBD7 overexpression increased CAB resistance of estrogen-induced in situ rat prolactinoma model. Together, our findings have uncovered the novel mechanism of DRD2 protein degradation and shown that the KBTBD6/7-DRD2 axis regulates PA sensitivity to DA treatment. KBTBD6/7 may thus become a promising therapeutic target for pituitary tumors.

To study the effects of omega-3 fatty acid parenteral nutrition on the nutrition, inflammatory responses, immunity and prognoses of critically ill cancer patients. A total of 80 critically ill cancer patients were randomly divided into an observation group and a control group, 40 cases in each group. Both groups of patients received equal-nitrogen and equal-calorie enteral and parenteral nutrition. The observation group, on this basis, was added with omega-3 fatty acid parenteral nutrition. The weekly nutritional status measures, inflammatory response measures, immune function measures and prognosis measures (ICU mortality, ICU stay, infectious complications) of the two groups were observed. The nutrition, inflammatory response and immune measures of the observation group were improved compared with the control group. The ICU stay in the observation group was shorter than the control group. Compared with the control group, the ICU mortality rate and infectious complication rate were lower in the observation group, but the differences were not significant (P mortality = 0.13, P infection rate = 0.165). Omega-3 fatty acid parenteral nutrition could improve patients' nutritional status and immune function, reduce the body's inflammatory responses and shorten the length of hospital stay, but couldn't significantly improve ICU mortality and reduce the incidence of infectious complications.

A series of (1-x)(Sr0.7Ba0.3)5LaNb7Ti3O30–x(Bi0.5Na0.5)TiO3 (x = 0.1–0.4) ceramics with tungsten bronze structure were prepared by solid state reaction. Phase composition, microstructure and energy storage properties were studied. When x = 0.3, excellent thermal stability satisfying the X7R specification was obtained and its energy storage as well as charge-discharge performances were further evaluated. Release energy density (Wre) of 0.77 J/cm3 and an energy storage efficiency of 97.3 % were detected at a low electric field of 20 kV/mm. Under the electric field of 10 kV/mm, the change of Wre in the temperature range of −55 °C to 125 °C is less than 15 % compared to room temperature. Short discharge period (∼0.17 μs), high power density (61.2 MW/cm3) and high discharge energy density (2.45 J/cm3) were evaluated by charge-discharge tests. Excellent thermal stability, high energy storage efficiency and high power density indicate that 0.7(Sr0.7Ba0.3)5LaNb7Ti3O30–0.3(Bi0.5Na0.5)TiO3 ceramic is a promising pulse capacitor for working over a wide temperature range.