The Circadian Clock Component RORA Increases Immunosurveillance in Melanoma by Inhibiting PD-L1 Expression.

Circadian clock perturbation frequently occurs in cancer and facilitates tumor progression by regulating malignant growth and shaping the immune microenvironment. Emerging evidence has indicated that clock genes are disrupted in melanoma and linked to immune escape. Here, we found that the expression of retinoic acid receptor-related orphan receptor-α (RORA) is downregulated in melanoma patients and that patients with higher RORA expression have a better prognosis after immunotherapy. Additionally, RORA was significantly positively correlated with T-cell infiltration and recruitment. Overexpression or activation of RORA stimulated cytotoxic T-cell-mediated antitumor responses. RORA bound to the CD274 promoter and formed an inhibitory complex with HDAC3 to suppress PD-L1 expression. In contrast, the DEAD-box helicase family member DDX3X competed with HDAC3 for binding to RORA, and DDX3X overexpression promoted RORA release from the suppressive complex and thereby increased PD-L1 expression to generate an inhibitory immune environment. The combination of a RORA agonist with an anti-CTLA4 antibody synergistically increased T-cell antitumor immunity in vivo. A score based on the combined expression of HDAC3, DDX3X and RORA correlated with immunotherapy response in melanoma patients. Together, this study elucidates a mechanism of clock component-regulated antitumor immunity, which will help inform the use of immunotherapy and lead to improved outcomes for melanoma patients receiving combined therapeutic treatments.

Soluble starch-derived porous carbon microspheres with interconnected and hierarchical structure by a low dosage KOH activation for ultrahigh rate supercapacitors.

The developed porous structure and high density are essential to enhance the bulk performance of carbon-based supercapacitors. Nevertheless, it remains a significant challenge to optimize the balance between the porous structure and the density of carbon materials to realize superior gravimetric and areal electrochemical performance. The soluble starch-derived interconnected hierarchical porous carbon microspheres were prepared through a simple hydrothermal treatment succeeded by chemical activation with a low dosage of KOH. Due to the formation of interconnected spherical morphology, hierarchical porous structure, reasonable mesopore volume (0.33 cm3 g-1) and specific surface area (1162 m2 g-1), the prepared carbon microsphere has an ultrahigh capacitance of 394 F g-1 @ 1 A g-1 and a high capacitance retention of 62.7 % @ 80 A g-1. The assembled two-electrode device displays good cycle stability after 20,000 cycles and an ultra-high energy density of 11.6 Wh kg-1 @ 250 W kg-1. Moreover, the sample still exhibits a specific capacitance of 165 F g-1 @ 1 A g-1 at a high mass loading of 10 mg cm-2, resulting in a high areal capacitance of 1.65 F cm-2. The strategy proposed in this study, via a low-dose KOH activation process, provides the way for the synthesis of high-performance porous carbon materials.

High Thermal Conductivity and Radiative Cooling Designed Boron Nitride Nanosheets/Silk Fibroin Films for Personal Thermal Management.

The implementation of passive cooling strategies is crucial for transitioning from the current high-power- and energy-intensive thermal management practices to more environmentally friendly and carbon-neutral alternatives. Among the various approaches, developing thermal management materials with high thermal conductivity and emissivity for effective cooling of personal and wearable devices in both indoor and outdoor settings poses significant challenges. In this study, we successfully fabricated a cooling patch by combining biodegradable silk fibroin with boron nitride nanosheets. This patch exhibits consistent heat dissipation capabilities under different ambient conditions. Leveraging its excellent radiative cooling efficiency (Rsolar = 0.89 and εLWIR = 0.84) and high thermal conductivity (in-plane 27.58 W m-1 K-1 and out-plane 1.77 W m-1 K-1), the cooling patch achieves significant simulated skin temperature reductions of approximately 2.5 and 8.2 °C in outdoor and indoor conditions, respectively. Furthermore, the film demonstrates excellent biosafety and can be recycled and reused for at least three months. This innovative BNNS/SF film holds great potential for advancing the field of personal thermal management materials.

Assessment of tolerance limits of petroleum residues in soil organic matter: sorption of dichlorobenzene by soil.

Soil organic matter can protect plants and microorganisms from toxic substances. Beyond the tolerance limit, the toxicity of petroleum pollution to soil organisms may increase rapidly with the increase of petroleum content. However, the method for evaluating the petroleum tolerance limit of soil organic matter (SOM) is still lacking. In this study, the petroleum saturation limit in SOM was first evaluated by the sorption coefficient (Kd) of 1,2-dichlorobenzene (DCB) from water to soils containing different petroleum levels. The sorption isotherm of dichlorobenzene in several petroleum-contaminated soils with different organic matter content and the microbial toxicity test of several petroleum-contaminated soils were determined. It is found that when the petroleum content is about 5% of the soil organic matter content, the sorption of petroleum to organic matter reached saturation limit. When organic matter reaches petroleum saturation limit, the sorption coefficient of DCB by soil particles increased linearly with the increase of petroleum content (R2 > 0.991). The results provided important insights into the understanding the fate of petroleum pollutants in soil and the analysis of soil toxicity.

Anisotropic Black Phosphorene Structural Modulation for Thermal Storage and Solar-Thermal Conversion.

Exploiting novel strategies for simultaneously harvesting ubiquitous, renewable, and easily accessible solar energy based on the photothermal effect, and efficiently storing the acquired thermal energy plays a vital role in revolutionizing the current fossil fuel-dominating energy structure. Developing black phosphorene-based phase-change composites with optimized photothermal conversion efficiencyand high latent heat is the most promising way to achieve efficient solar energy harvesting and rapid thermal energy storage. However, exfoliating high-quality black phosphorene nanosheets  remains challenging, Furthermore, an efficient strategy that can construct the aligned black phosphorene frameworks to maximize thermal conductivity enhancement is still lacking. Herein, high-quality black phosphorene nanosheets are prepared by an optimized exfoliating strategy. Meanwhile, by regulating the temperature gradient during freeze-casting, the framework consisting of shipshape aligned black phosphorene at long-range is successfully fabricated, improving the thermal conductivity of the poly(ethylene glycol) matrix up to 1.81 W m-1  K-1 at 20 vol% black phosphorene loading. The framework also endows the composite with excellent phase-change material encapsulation capacity and  high latent heat of 103.91 J g-1 . It is envisioned that the work advances the paradigm of contrasting frameworks with nanosheets toward controllable structure thermal enhancement of the composites.

Purinergic receptor P2X7 contributes to abdominal aortic aneurysm development via modulating macrophage pyroptosis and inflammation.

The purinergic receptor P2X7 has been established as an important mediator of inflammation and participates in a variety of cardiovascular diseases including atherosclerosis, however, its role in abdominal aortic aneurysms (AAA) remains unclear. In this study, we demonstrate that P2X7 plays essential roles in AAA development via modulating macrophage pyroptosis and inflammation. P2X7 is highly expressed in human AAA specimen, as well as in experimental murine AAA lesions (both CaCl2- and Angiotensin II-induced AAA models), and it mainly confines in macrophages. Furthermore, P2X7 deficiency or pharmacological inhibition with its antagonist could significantly attenuate aneurysm formation in experimental murine AAA models, while P2X7 agonist could promote AAA development. The caspase-1 activity, matrix metalloproteinase (MMP) activity, reactive oxygen species (ROS) production and pro-inflammatory gene expression were significantly reduced in experimental AAA lesions in mice with P2X7 deficiency or inhibition. Mechanistically, macrophage P2X7 can mediate the activation of NLRP3 inflammasome and activate its downstream caspase-1 to initiate the pyroptosis pathway. After caspase-1 activation, it further cleaves pro-interleukin (IL)-1ß and gasdermin D (GSDMD). Consequently, the N-terminal fragment of GSDMD forms pores on the cell membrane, leading to macrophage pyroptosis and release of the pro-inflammatory factor IL-1ß. The resulting vascular inflammation further leads to the upregulation of MMP and ROS, thereby promoting AAA development. In summary, these data identify P2X7-mediated macrophage pyroptosis signaling pathway as a novel contributory mechanism of AAA formation.

A novel variant of COL6A3 c.6817-2(IVS27)A>G causing Bethlem myopathy: A case report.

Bethlem myopathy (BM) is a disease that is caused by mutations in the collagen VI genes. It is a mildly progressive disease characterized by proximal muscle weakness and contracture of the fingers, the wrist, the elbow, and the ankle. BM is an autosomal dominant inheritance that is mainly caused by dominant COL6A1, COL6A2, or COL6A3 mutations. However, a few cases of collagen VI mutations with bilateral facial weakness and Beevor's sign have also been reported. This study presents a 50-year-old female patient with symptoms of facial weakness beginning in childhood and with the slow progression of the disease with age. At the age of 30 years, the patient presented with asymmetrical proximal muscle weakness, and the neurological examination revealed bilateral facial weakness and a positive Beevor's sign. Phosphocreatine kinase was slightly elevated with electromyography showing myopathic changes and magnetic resonance imaging (MRI) of the lower limb muscles showing the muscle MRI associated with collagen VI (COL6)-related myopathy (COL6-RM). The whole-genome sequencing technology identified the heterozygous mutation c.6817-2(IVS27)A>G in the COL6A3 gene, which was in itself a novel mutation. The present study reports yet another case of BM, which is caused by the recessive COL6A3 intron variation, widening the clinical spectrum and genetic heterogeneity of BM.

An Overview of Antitumour Activity of Polysaccharides.

Cancer incidence and mortality are rapidly increasing worldwide; therefore, effective therapies are required in the current scenario of increasing cancer cases. Polysaccharides are a family of natural polymers that hold unique physicochemical and biological properties, and they have become the focus of current antitumour drug research owing to their significant antitumour effects. In addition to the direct antitumour activity of some natural polysaccharides, their structures offer versatility in synthesizing multifunctional nanocomposites, which could be chemically modified to achieve high stability and bioavailability for delivering therapeutics into tumor tissues. This review aims to highlight recent advances in natural polysaccharides and polysaccharide-based nanomedicines for cancer therapy.

[Retracted] Upregulation of microRNA­25­3p inhibits proliferation, migration and invasion of osteosarcoma cells in vitro by directly targeting SOX4.

Following the publication of this paper, it was drawn to the Editors' attention by a concerned reader that certain of the cell migration assay data shown in Figs. 3B and 5C were strikingly similar to data that had appeared in different form in other articles by different authors. Owing to the fact that the contentious data in the above article had already been published elsewhere, or were already under consideration for publication, prior to its submission to Molecular Medicine Reports, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a satisfactory reply. The Editor apologizes to the readership for any inconvenience caused. [Molecular Medicine Reports 16: 4293­4300, 2017; DOI: 10.3892/mmr.2017.7103].

Enhanced thermal transportation across an electrostatic self-assembly of black phosphorene and boron nitride nanosheets in flexible composite films.

For effective heat dissipation in portable electronics, there is a great demand for lightweight and flexible films with superior thermal transport properties. Despite extensive efforts, enhancing the intrinsic low thermal conductivity of polymers while simultaneously maintaining their flexibility is difficult to achieve due to the dilemma of quarrying appropriate filler loading. Herein, a cellulose nanofiber-based film with high in-plane thermal conductivity up to 72.53 W m-1 K-1 was obtained by harnessing the advantage of functionalized boron nitride nanosheets (f-BNNS) and black phosphorene (BP) via the vacuum filtration process. Besides, our unique design based on the electrostatic coupling of black phosphorene and functionalized boron nitride nanosheets significantly reduced the interfacial thermal resistance of the composite films. This work offers new insights into establishing a facile, yet efficient approach to preparing high thermal conductive heat spreaders.

Enhanced Thermal Conductivity of Polymer Composite by Adding Fishbone-like Silicon Carbide.

The rapid development of chip technology has all put forward higher requirements for highly thermally conductive materials. In this work, a new type of material of Fishbone-like silicon carbide (SiC) material was used as the filler in a polyvinylidene fluoride (PVDF) matrix. The silicon carbide/polyvinylidene fluoride (SiC/PVDF) composites were successfully prepared with different loading by a simple mixing method. The thermal conductivity of SiC/PVDF composite reached 0.92 W m-1 K-1, which is 470% higher than that of pure polymer. The results show that using the filler with a new structure to construct thermal conductivity networks is an effective way to improve the thermal conductivity of PVDF. This work provides a new idea for the further application in the field of electronic packaging.

Constructing a three-dimensional nano-crystalline diamond network within polymer composites for enhanced thermal conductivity.

In order to meet the requirement of thermal performance with the rapid development of high-performance electronic devices, constructing a three-dimensional thermal transport skeleton is an effective method for enhancing the thermal conductivity of polymer composites. In this work, a three-dimensional porous diamond framework was prepared by depositing nano-crystalline diamond on alumina foam which was impregnated with epoxy to obtain a nano-crystalline diamond@alumina foam/epoxy composite. The epoxy composite with nano-crystalline diamond@alumina foam demonstrated a thermal conductivity of 2.21 W m-1 K-1, which was increased by 1063% in comparison with pure epoxy. The thermal conductivity of the epoxy composite measured under various conditions and heat transport applications demonstrates that it possesses excellent thermal transportation and stability properties. This work provides a new idea to significantly enhance the thermal transportation properties of epoxy composites in the application of advanced packaging materials.

THAP9-AS1 Promotes Tumorigenesis and Reduces ROS Generation through the JAK2/STAT3 Signaling Pathway by Increasing SOCS3 Promoter Methylation in Osteosarcoma.

Increasing studies have demonstrated that dysfunction of long noncoding RNAs (lncRNAs) plays critical roles in the development of human cancers. THAP9-AS1 has been reported to be dysregulated and associated with tumor progression in some cancers. However, the function and mechanism of THAP9-AS1 in osteosarcoma (OS) remain unclear. In the present study, we found that the expression of THAP9-AS1 was significantly upregulated in OS tissues and associated with the advanced stage of tumors and poor prognosis of patients. Blast comparison results showed that the SOCS3 promoter region and THAP9-AS1 had base complementary pairing binding sites. The interactions between THAP9-AS1, DNA methyltransferases (DNMTs), and SOCS3 were assessed by RIP and ChIP assays. The results of methylation-specific PCR (MSP) and bisulfite sequencing PCR (BSP) validated that THAP9-AS1 enhanced the methylation level of the SOCS3 promoter. The mRNA levels of SOCS3 in OS cells could be reversed by the demethylation agent 5-aza-2'-deoxycytidine. The mRNA expression of SOCS3 was downregulated in OS tissues and negatively correlated with THAP9-AS1 expression in tumors. Moreover, the western blot and immunofluorescence (IF) assay data showed that THAP9-AS1 activated the JAK2/STAT3 signaling pathway by upregulating p-JAK2 and p-STAT3 and the nuclear translocation of p-STAT3. Functionally, ectopic expression of THAP9-AS1 promoted cell proliferation, migration, and invasion and inhibited apoptosis, and this phenomenon could be reversed by SOCS3. Introduction of the JAK/STAT inhibitor AG490 partially abolished the stimulative effect of THAP9-AS1 on cellular processes. In addition, THAP9-AS1 decreased oxidative stress by reducing reactive oxygen species (ROS) and enhancing the mitochondrial membrane potential of OS cells via the SOCS3/JAK2/STAT3 pathway. Stable overexpression of THAP9-AS1 contributed to tumor growth and metastasis in vivo. In total, our findings suggested that upregulation of THAP9-AS1 might recruit DNMTs to epigenetically inhibit SOCS3, thereby activating the JAK2/STAT3 signaling pathway and oncogenesis of OS. These results provide novel insights for the understanding of OS progression.

Actual Self-Image Versus Ideal Self-Image: An Exploratory Study of Self-Congruity Effects on Gambling Tourism.

This study aims to apply self-congruity theory to examine the relationship between self-congruity of tourists and their perceived image of a gambling destination. This study employs the Euclidean distance model and extends Malhotra's pars of adjectives with five new items about gambling motives. A face-to-face questionnaire survey was used, and a total of 152 samples were collected from tourists in Macau. The results show that the actual self-image of tourists is more related to their perception of Macau image. For actual congruence, tourists exhibit a greater tendency to match the informal, liberal, and emotional image of Macau. For ideal congruence, they have a tendency to match the contemporary, organized, and pleasant image of Macau. This study makes up for the deficiency of self-congruity theory in tourism research. This study helps tourism departments to develop appropriate strategies to promote gambling tourism and disseminate relevant information that can bring gambling destinations closer to tourists.

Next generation of anti-PD-L1 Atezolizumab with enhanced anti-tumor efficacy in vivo.

FDA-approved anti-PD-L1 antibody drug Atezolizumab is a human IgG1 without glycosylation by an N297A mutation. Aglycosylation of IgG1 has been used to completely remove the unwanted Fc-mediated functions such as antibody-dependent cytotoxicity (ADCC). However, aglycosylated Atezolizumab is very unstable and easy to form aggregation, which causes quick development of anti-drug antibody (ADA) in 41% of Atezolizumab-treated cancer patients, eventually leading to loss of efficacy. Here, we report the development of the anti-PD-L1 antibody drug Maxatezo, a glycosylated version of Atezolizumab, with no ADCC activity, better thermo-stability, and significantly improved anti-tumor activity in vivo. Using Atezolizumab as the starting template, we back-mutated A297N to re-install the glycosylation, and inserted a short, flexible amino acid sequence (GGGS) between G237 and G238 in the hinge region of the IgG1 heavy chain. Our data shows that insertion of GGGS, does not alter the anti-PD-L1's affinity and inhibitory activity, while completely abolishing ADCC activity. Maxatezo has a similar glycosylation profile and expression level (up to 5.4 g/L) as any normal human IgG1. Most importantly, Maxatezo's thermal stability is much better than Atezolizumab, as evidenced by dramatic increases of Tm1 from 63.55 °C to 71.01 °C and Tagg from 60.7 °C to 71.2 °C. Furthermore, the levels of ADA in mice treated with Maxatezo were significantly lower compared with animals treated with Atezolizumab. Most importantly, at the same dose (10 mg/kg), the tumor growth inhibition rate of Maxatezo was 98%, compared to 68% for Atezolizumab.

Effect of Zr content on microstructure and mechanical properties of lightweight Al2NbTi3V2Zrx high entropy alloy.

Lightweight Al2NbTi3V2Zrx (x = 1.0, 0.8, 0.6, 0.4, 0.2, 0) high entropy alloys are produced by mechanical milling and vacuum hot pressing. The microstructure, phase evolution and mechanical properties of the alloys are analyzed. The microstructure of the alloys with x = 1.0, 0.8, 0.6 consists of BCC solid solution matrix and two intermetallics (i.e., α and ß), and then ß phase disappears in Al2NbTi3V2Zr0.4 alloy. Further decreasing Zr content to below 0.2, α phase vanishes and γ and δ intermetallics emerge in Al2NbTi3V2Zr0.2 and Al2NbTi3V2 alloys. The Al2NbTi3V2Zrx alloys cannot obtain a single phase structure by decreasing Zr content with current fabrication process, which is likely because that the mixing entropy of the HEA system is not large enough to prohibit the formation of the secondary phases at hot pressing temperature of 1250 °C. All the bulks possess low density ranging from 4.93 to 5.21 g/cm3. Hardness of the Al2NbTi3V2Zrx alloys decreases from 781 HV to 697 HV and then increases to 814 HV with the decrease of Zr from x = 1 to 0. This varying tendency is closely related with the content of secondary intermetallic phases. The compressive test shows the Al2NbTi3V2Zr0.4 alloy has a yield strength of 1742 MPa, fracture strength of 2420 MPa, compressive strain of 38.2 %, which is probably related to its simplest microstructure. The comprehensive mechanical property of Al2NbTi3V2Zr0.4 alloy is superior to the majority of other HEAs and Ti64 alloy.

Preparation, Properties and Mechanisms of Carbon Fiber/Polymer Composites for Thermal Management Applications.

With the increasing integration and miniaturization of electronic devices, heat dissipation has become a major challenge. The traditional printed polymer circuit board can no longer meet the heat dissipation demands of microelectronic equipment. If the heat cannot be removed quickly and effectively, the efficiency of the devices will be decreased and their lifetime will be shortened. In addition, the development of the aerospace, automobiles, light emitting diode (LED{ TA \1 "LED; lightemitting diode" \s "LED" \c 1 }) and energy harvesting and conversion has gradually increased the demand for low-density and high thermal conductive materials. In recent years, carbon fiber (CF{ TA \1 "CF; carbon fiber" \c 1 }) has been widely used for the preparation of polymer composites due to its good mechanical property and ultra-high thermal conductivity. CF materials easily form thermal conduction paths through polymer composites to improve the thermal conductivity. This paper describes the research progress, thermal conductivity mechanisms, preparation methods, factors influencing thermal conductivity and provides relevant suggestions for the development of CF composites for thermal management.

Streptococcus gordonii infectious endocarditis presenting as a neurocysticercosis mimic - A rare manifestation.

Infective endocarditis (IE) usually presents with nonspecific signs and symptoms, which delay diagnosis and proper treatment. Here, we describe a patient with initial clinical and radiological features compatible with neurocysticercosis who was later found to have IE. Furthermore, the patient course was complicated by multiple neurological complications (brain abscess, meningitis, infected intracranial aneurysm, subarachnoid hemorrhage and hemorrhage), and patient ultimately deceased. To our knowledge, an IE case mimicking neurocysticercosis and progressing with prominent and complicated neurological manifestations has not been previously reported. We therefore describe the challenges of neurocysticercosis diagnosis based on serum ELISA and radiological findings. For patient diagnosed as neurocysticercosis, clinical follow-up is recommended and presence of systemic symptoms should be red flags for another underlying disease.

Atomic Force Microscopy Based Top-Illumination Electrochemical Tip-Enhanced Raman Spectroscopy.

Electrochemical tip-enhanced Raman spectroscopy (EC-TERS) is a powerful technique for the in situ study of the physiochemical properties of the electrochemical solid/liquid interface at the nanoscale and molecular level. To further broaden the potential window of EC-TERS while extending its application to opaque samples, here, we develop a top-illumination atomic force microscopy (AFM) based EC-TERStechnique by using a water-immersion objective of a high numerical aperture to introduce the excitation laser and collect the signal. This technique not only extends the application of EC-TERS but also has a high detection sensitivity and experimental efficiency. We coat a SiO2 protection layer over the AFM-TERS tip to improve both the mechanical and chemical stability of the tip in a liquid TERS experiment. We investigate the influence of liquid on the tip-sample distance to obtain the highest TERS enhancement. We further evaluate the reliability of the as-developed EC-AFM-TERS technique by studying the electrochemical redox reaction of polyaniline. The top-illumination EC-AFM-TERS is promising for broadening the application of EC-TERS to more practical systems, including energy storage and (photo)electrocatalysis.