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This study used aluminum powder as a raw material to fabricate a wick for loop heat pipes by the powder metallurgy method and took advantage of the excellent corrosion resistance, low density and low cost of aluminum. The average pore diameter, porosity and permeability of the aluminum wicks were 9 ?m, 47.65%, and 2.1 ? 10?13 m?2, respectively. Then, to verify the feasibility of the aluminum wick, it was installed into a loop heat pipe to test the heat transfer performance. The experimental results showed that the loop heat pipe could transport a heating load of 130 W with a thermal resistance of 0.04 K/W under horizontal condition. A steady-state loop heat pipe mathematical model was developed, and the numerical results were compared with the experimental data. The results show that the model data are consistent with the experimental data, which means that Al wicks are suitable for use in the case of a high heating load and light weight.

Three carbazole derivatives, AcPTC, PxPTC and PtPTC, consisting of two 9,9-dimethyl-9,10-dihydroacridine, phenoxazine or phenothiazine donor groups and one diphenyltriazine acceptor group fixed at 1,8,9-positions of a single carbazole ring via phenylene, are designed and synthesized. X-ray diffraction analysis of AcPTC reveals that there exist multiple π-π interactions between the donor and acceptor groups to form a sandwich-like structural unit with edge-to-face interaction model. The compounds thus show obvious thermally activated delayed fluorescence with through-space charge transfer character and possess considerable photoluminescence quantum yields of up to 73% in doped films with sky-blue to yellow emissions. The solution-processed electroluminescent devices achieve the highest maximum external quantum efficiencies of 10.0%, 11% and 5.6% for AcPTC, PxPTC and PtPTC, respectively, with small efficiency roll-offs.

The discovery of reldesemtiv, a second-generation fast skeletal muscle troponin activator (FSTA) that increases force production at submaximal stimulation frequencies, is reported. Property-based optimization of high throughput screening hit 1 led to compounds with improved free exposure and in vivo muscle activation potency compared to the first-generation FSTA, tirasemtiv. Reldesemtiv demonstrated increased muscle force generation in a phase 1 clinical trial and is currently being evaluated in clinical trials for the treatment of amyotrophic lateral sclerosis.

The wick is the most crucial element of loop heat pipes (LHPs). At present, wick materials are limited to copper, stainless steel, nickel, and so on. Little research has been carried out on new wick materials. This paper reports the fabrication of aluminum wicks and performance tests of LHPs using aluminum wicks. Experimental data show that this LHP is capable of transferring a heating load of 130 W, while the thermal resistance is only approximately 0.04 K/W. Then, the experimental data were compared with those for LHPs using a polytetrafluoroethylene (PTFE) wick. Based on the SIMPLE algorithm, a 2-D unsteady-state heat transfer model and a 2-D steady-state flow model of the wicks are established to analyze the effects of wick material, pore size and porosity on the performance of the evaporator. The experimental data for LHPs with PTFE wicks are from the literature. The simulation results show that a PTFE wick can effectively reduce heat leakage, while an aluminum wick has better temperature uniformity and a lower casing temperature. However, wicks with large porosities have lower flow resistance.

A series of new cyclic siloxane side-chain liquid crystal oligomers containing chiral (-)-menthyl monomer (M1) and achiral benzene methyl ester monomer (M2), denoted as O1–O4, were successfully syn...

Osteoporosis is a metabolic disorder characterized by low bone mass and deteriorated microarchitecture, with an increased risk of fracture. Some miRNAs have been confirmed as potential modulators of osteoblast differentiation to maintain bone mass. Our miRNA sequencing results showed that miR‐664‐3p was significantly down‐regulated during the osteogenic differentiation of the preosteoblast MC3T3‐E1 cells. However, whether miR‐664‐3p has an impact on bone homeostasis remains unknown. In this study, we identified overexpression of miR‐664‐3p inhibited the osteoblast activity and matrix mineralization in vitro. Osteoblastic miR‐664‐3p transgenic mice exhibited reduced bone mass due to suppressed osteoblast function. Target prediction analysis and experimental validation confirmed Smad4 and Osterix (Osx) are the direct targets of miR‐664‐3p. Furthermore, specific inhibition of miR‐664‐3p by subperiosteal injection with miR‐664‐3p antagomir protected against ovariectomy‐induced bone loss. In addition, miR‐664‐3p expression was markedly higher in the serum from patients with osteoporosis compared to that from normal subjects. Taken together, this study revealed that miR‐664‐3p suppressed osteogenesis and bone formation via targeting Smad4 and Osx. It also highlights the potential of miR‐664‐3p as a novel diagnostic and therapeutic target for osteoporotic patients.

Due to the excellent optical properties and great application prospects in the optical field, both pyrene compounds (PCs) and chiral liquid crystal have attracted extensive attention in theoretical...

Exploiting Ni-based catalysts with excellent catalytic activity and anti-coking ability is significant for dry reforming of CH4 with CO2 (DRM) which is a promising route to CO2 utilization. In this work, the Ni/Al2O3 catalyst with hydrotalcite precursor (NiAl-LDH) was synthesized by a facile in-situ growth method. And the effect of the NiAl-LDH structure on the catalytic activity and anti-coking ability of Ni/Al2O3 catalyst was revealed. The H2-temperature programmed desorption (H2-TPD) revealed that better Ni dispersion and more Ni–Al2O3 interface could be obtained by the NiAl-LDH precursor, which were vital for the activation of CH4 and CO2. Moreover, the NiAl-LDH precursor with non-LDH phase or turbostratic structure was also created by insufficient or extra amount of urea, and the obtained catalysts exhibited a poor catalytic stability, further confirming the importance of the LDH structure. In comparison with the Ni-IMP catalyst prepared by the conventional impregnation method, the CH4 conversion increased by 16% and the carbon deposition decreased by 75% over Ni-6 catalyst with well-organized LDH precursor under the same reaction conditions. Hence, this work represents an important step toward developing Ni-based catalysts with excellent catalytic activity and anti-coking ability for DRM with the LDH precursor.

Biodegradable nanocomposites were prepared by melt blending biodegradable poly(lactic acid) (PLA) and poly(butylene adipate-co-butylene terephthalate) (PBAT) (70/30, w/w) with diatomite or talc (1–7%). From the SEM test, the particles were transported to the interface of two phases, which acted as an interface modifier to strengthen the interfacial adhesion between PLA and PBAT. Talc and diatomite acted as nucleating agents to improve the crystallization of PBAT in the blends by DSC analysis. Moreover, adding the particles improved the tensile and impact toughness of the blends. The elongation at break with 5% talc was 78% (vs ∼21%) and the impact strength was 15 kJ/m2 (vs ∼6.5 kJ/m2). The rheological measurement revealed that the talc and diatomite reduced the viscosity of the blends. The results showed a good possibility of using talc- and diatomite-filled PLA/PBAT blends with high toughness for green-packaging and bio-membranes application.

In an environment of high salinity, low temperature, and the presence of a few bacteria in seawater, improving the non-enzymatic hydrolysis of polyesters is one of the effective methods for developing seawater degradable materials. In this research, poly(butylene furandicarboxylate-co-glycolate) (PBFGA) copolyesters were synthesized via melt polycondensation. The PBFGA copolymer possessed excellent mechanical properties and thermal stability. Its tensile strength was 15–50 MPa and the elongation at break was more than 120% from the tensile tests. GA units improved the flexibility of PBF segments, and the PBFGA copolymer exhibited an amorphous structure. The PBFGA copolymer possessed good hydrolysis properties and the weight loss of PBFGA50 was more than 30% after 84 days of degradation in deionized water. Lipase catalyzed, and the salt inhibited the hydrolysis of the ester bond. PBFGA exhibited a bulk degradation mechanism, and sponge pores were formed on the surface due to preferential degradation of the PGA component, which was conducive to the further degradation of the internal groups. Some butanediol and glycolic acid terminated oligomers were produced during the degradation process, and rearrangement crystallization occurred in the chain segment. Thus, PBFGA copolyesters have the potential to serve as promising seawater degradable materials with excellent tensile and non-enzymatic degradable properties.

Fluorescent liquid crystals in luminescent materials have attracted considerable interest owing to their unique feature of fluorescence in response to external stimuli and their applicability in information security and anti-counterfeiting. Herein, fluorescent nematic liquid crystalline oligomers (FNLCO) containing pyrene chromogenic segments with tunable fluorescence properties and dynamic reversible striped textures were dexterously designed and prepared by poly(methylhydrogeno)siloxane (PMHS), liquid crystalline monomer M1, monomer M2, and fluorescent pyrene compound M3. The discrete pyrene chromophore in the FNLCO matrix can enable tunable photoluminescence. Therefore, FNLCO can emit blue fluorescence by irradiating with ultraviolet light, and the fluorescence intensity can be reversibly and precisely controlled by applying thermal stimuli. The as-prepared FNLCO display reversible striped textures during the heating and cooling process, and surprisingly, the striped textures and fluorescence can be simultaneously and precisely adjusted by temperature. Temperature-driven dynamic fluorescence patterns with FNLCO can be made with fast and reversible response. The reversible thermal driven dynamic reversible striped textures and fluorescence properties can make smart materials promising candidates in the field of high-level anti-counterfeiting.

Hydrogen sulfide (H2S), a gaseous intracellular signal transducer, participates in multiple physiological and pathological conditions, including reproductive conditions, and disrupts spermatogenesis. The blood-testis barrier (BTB) plays a vital role in spermatogenesis. However, the effect of H2S on the BTB and the underlying mechanism remain unclear. Herein, we examined the effect of H2S and omega-3 polyunsaturated fatty acids (ω-3 PUFAs) on the BTB and testicular functions. ICR male mice were randomly divided into the following groups: control, H2S exposure, and H2S exposure with ω-3 PUFAs intervention. The sperm parameters (sperm concentration and sperm motility) declined in the H2S group and improved in the ω-3 intervention group. BTB integrity was severely disrupted by H2S, and the BTB-related gene levels (ZO-1, Occludin, Claudin 11) decreased; ω-3 supplementation could alleviate BTB disruption by upregulating BTB-related genes, and TM4 Sertoli cells had a similar trend in vitro. p38 MAPK phosphorylation was upregulated in the Na2S treatment group and downregulated after ω-3 cotreatment. These findings suggest that H2S can impair the BTB and that ω-3 PUFAs supplementation can attenuate H2S toxicity in the male reproductive system. Our study elucidated the relationship between a gasotransmitter (H2S) and the BTB and identified the potential therapeutic effect of ω-3 PUFAs.

Leg problems often result from the rapid weight gain and poor bone quality in modern ducks, leading to a high risk of fractures and continuous pain. We hypothesized that improving bone quality in combination with delaying weight gain via a low nutrient density (LND) diet probably reverses these skeletal abnormalities. Studies indicated that 25-hydroxycholecalciferol (25-OH-D3), a vitamin D3 metabolite, is effective in treating bone-related disorders. Therefore, Exp. 1 evaluated the effects of 25-OH-D3 on tibial mass of meat ducks. Male meat ducklings were fed a standard nutrient density diet (containing a regular vitamin regimen) without or with 25-OH-D3 at 0.069 mg/kg for 35 d. The results showed that 25-OH-D3 supplementation improved the mineral content, microarchitecture and mechanical properties of tibias, and this companied by a decreased serum bone resorption marker and a concomitant decrement in osteoclast-specific marker genes expression. Subsequently, Exp. 2 was conducted to examine the impacts of 25-OH-D3 incorporating an LND diet on tibial quality of ducks under 2 different vitamin regimens (regular and high). Ducklings were allocated to a 2 × 2 factorial arrangement with 2 kinds of vitamin premixes and without or with 25-OH-D3 at 0.069 mg/kg in LND diets. The high premix had higher levels of all vitamins except biotin than the regular premix. The results demonstrated that high vitamin diets exhibited more significant effects than regular vitamin diets on inhibiting bone turnover and increasing minerals deposition. Tibial mineral content, microarchitecture, and strength of birds under the regular vitamin regimen were increased by 25-OH-D3 supplementation; However, these positive effects were not observed in ducks under the high vitamin regimen. To conclude, 25-OH-D3 supplementation improves tibial mass by suppressing osteoclast-mediated bone resorption in meat ducks, and this positive impact only was observed in regular but not high vitamin regimen when birds fed an LND diet.

The mechanism underlying the association between age and depletion of the human ovarian follicle reserves remains uncertain. Many identified that impaired DNA polymerase β (Pol β)-mediated DNA base-excision repair (BER) drives to mouse oocyte aging. With aging, DNA lesions accumulate in primordial follicles. However, the expression of most DNA BER genes, including APE1, OGG1, XRCC1, Ligase I, Ligase α, PCNA and FEN1, remains unchanged during aging in mouse oocytes. Also, the reproductive capacity of Pol β+/- heterozygote mice was impaired, and the primordial follicle counts were lower than that of wild type (wt) mice. The DNA lesions of heterozygous mice increased. Moreover, the Pol β knockdown leads to increased DNA damage in oocytes and decreased survival rate of oocytes. Oocytes over-expressing Pol β showed that the vitality of senescent cells enhances significantly. Furthermore, serum concentrations of anti-Müllerian hormone (AMH) indicated that the ovarian reserves of young mice with Pol β germline mutations were lower than those in wt. These data show that Pol β-related DNA BER efficiency is a major factor governing oocyte aging in mice.

Previous studies have revealed the critical roles of the N6-methyladenosine (m6A) modification of long non-coding RNAs (lncRNAs) in cancers, but the relationship between the oncogenic role of the lncRNA THOR (a representative of cancer/testis lncRNAs) and m6A modification remains unclear. Here, we show that the internal m6A modification of the lncRNA THOR via an m6A-reader-dependent modality regulates the proliferation of cancer cells. Our findings demonstrated that the loss of the lncRNA THOR inhibits the proliferation, migration, and invasion of cancer cells in vitro and in vivo. In addition, m6A is highly enriched on lncRNA THOR transcripts, which contain GA (m6A) CA, GG (m6A) CU, and UG (m6A) CU sequence motifs. RIP-qRT-PCR and RNA pull-down assay results revealed that the specific m6A readers YTHDF1 and YTHDF2 can read the m6A motifs and regulate the stability of the lncRNA THOR (stabilization and decay). These m6A-dependent RNA-protein interactions can maintain the oncogenic role of the lncRNA THOR. Collectively, these findings highlight the critical role of the m6A modification in oncogenic lncRNA THOR and reveal a novel long non-coding RNA regulatory mechanism, providing a new way to explore RNA epigenetic regulatory patterns in the future.

The hydrogenation of CO2 to CH4 can realize the utilization of CO2, which has an important implications to both the energy and environment. As a result of the low catalytic activity of the supported Ni/SiO2 catalyst, the ZrO2 is added to improve its catalytic performance by the impregnation method. The experimental results show that ZrO2 is an effective promoter to enhance the low-temperature catalytic activity of Ni/SiO2 catalyst.

Platelets are implicated in the pathophysiology of breast and other cancers through their role in exchanging biomolecules with tumor cells in the tumor microenvironment. Such exchange results in tumor‐educated platelets with altered RNA expression profiles. Multiple lines of evidence indicate that platelet RNA profiles may be suitable as diagnostic biomarkers for cancer‐related biological processes. In this study, we characterized the gene expression signatures of platelets in breast cancer (BC) by high‐throughput sequencing and quantitative real‐time RT‐PCR. Our results indicate that the expression of TPM3 (tropomyosin 3) mRNA is significantly elevated in platelets from patients with BC compared with age‐matched healthy control subjects. Furthermore, up‐regulation of TPM3 mRNA in platelets was found to be significantly correlated with metastasis in patients with BC. Finally, we report that platelet TPM3 mRNA is delivered into BC cells through microvesicles and leads to enhanced migrative phenotype of BC cells. In summary, our findings suggest that the transfer of platelet TPM3 mRNA into cancer cells via microvesicles promotes cancer cell migration, and thus platelet‐derived TPM3 mRNA may be a suitable biomarker for early diagnosis of metastatic BC., Platelets are implicated in the pathophysiology of breast and other cancers through their role in exchanging biomolecules with tumor cells in the tumor microenvironment. In this study, we found that platelet TPM3 (tropomyosin 3) mRNA can be delivered into cancer cells via microvesicles to promote cancer cell migration. Platelet‐derived TPM3 mRNA may be a suitable biomarker for early diagnosis of metastatic breast cancer.

A series of conjugated donor–acceptor (D–A) block copolymers (BCPs) were synthesised using a one-pot Stille coupling polycondensation reaction. This involved reaction between a series of mono-bromo-functionalised Poly3-hexylthiophene (P3HT) polymers (P3HT-Br, Mn : 17, 21 and 43 kg/mol) and [N, N′-bis(2-decyl-tetradecyl)-1,7-dibromo-3,4,9,10-perylene diimide (PBI) and [2,5-bis(trimethylstannyl)-thiophene] (T) monomers. Purification using preparative gel permeation chromatography (GPC) removed any excess P3HT and resulted in BCPs with low polydispersity index values. The P3HT-b-PBIT BCPs were characterised using 1H-NMR and Fourier-transform infrared spectroscopy. When compared to a P3HT/PBIT polymer blend, the D–A BCP films exhibited a remarkably fine structure with a nanoscale morphology. These results indicated that these D–A BCPs have the potential for use as nanostructured active layers in polymer solar cells.

All-conjugated donor-acceptor block copolymers (BCP) were synthesized in a one-pot reaction by a Stille coupling polycondensation through a terminal functional polymer copolymerization process. Mono bromo end-functionalized P3HT samples with various molecular weights (P3HT-Br, Mn: 5, 9, and 26 kg/mol) were copolymerized with AA (N,Nʹ-Bis(2-decyl-1-tetradecyl)-2,6-dibromonaphthalene-1,4,5,8-tetracarboxylic acid bisimide, NDI) and BB (5,5′-bis(trimethylstannyl)-2,2′-bithiophene) type monomers. Further purification by preparative GPC removed excess P3HT to yield block copolymers of low polydispersities with different donor and acceptor block chain lengths. The block copolymers were characterized by 1H-NMR and UV–vis absorption and FTIR spectroscopy. The optical properties, film morphologies, and optoelectronic properties of the block copolymer were strongly influenced by the donor and acceptor block chain lengths. Furthermore, the fully conjugated D-A block copolymer films exhibited fine structures, smooth film morphologies, and better OPV performance than those features of P3HT/PNDIT2 polymer blends. In polymer solar cells based on the various block copolymer as active layers, the device power convention efficiency was improved by maintaining the acceptor block content at 40–50 kg/mol and increasing the P3HT chain from 5 to 26 kg/mol.

Three sets of polyfluorenes grafting one/two orange emissive groups on central or terminal fluorene unit have been synthesized successfully through the catalyst-transfer polymerization. The molecular weights linearly increase with increase in the feed ratios of [monomer]/[catalyst] in a certain molecular weight range. The initiators with bis(2,6-diisopropylphenyl)imidazolin-2-ylidene) (IPr) as the ancillary ligand show better catalytic activity, leading to higher molecular weight of up to 126.3 kDa. All polymers in toluene have the similar absorption spectra to polyfluorene homopolymer, while the weak absorption bands of 420–500 nm are observed only in the polymers with low molecular weight. Photoluminescence spectra display a dominant blue emission from the polyfluorene backbone and a weak orange emission (508–661 nm) from the orange group. The clearly enhanced orange emission in the polymers with low molecular weight is mainly ascribed to the intramolecular Forster energy transfer from the polyfluorene segment to the orange group, which is further confirmed by the electroluminescent behavior of the polymers.

Dietary lipid oxidation is a lasting concern to aquafeed manufacturers and aquaculture farmers. Here, we determined if there was an association between oxidized fish oil (OFO) and hepatopancreatic injury in Chinese mitten crab, and evaluated the alleviating effects of a combination of vitamins C and E on hepatopancreatic injury. There were significant reductions in the body weight gain, hepatopancreatic index, and feed efficiency in crabs that received OFO. Diets with OFO also resulted in reduced crude fat contents in the hepatopancreas and muscle tissues, and alternations in the hepatopancreatic fatty acid compositions, especially a reduction in polyunsaturated fatty acids. Moreover, dietary OFO exposure reduced the antioxidant defense and non‐specific immune response, caused hepatopancreatic injury, and even apparent whitening. An ultrastructural examination of the whitened hepatopancreas revealed that hepatopancreatic cells were injured at varying degrees following OFO exposure. The combination of vitamins C and E could efficiently maintain a constant fatty acid profile in the hepatopancreas exposed to OFO, thus alleviating OFO‐induced hepatopancreatic injury. In addition, a biochemical analysis indicated that a combination of vitamins C and E not only improved the antioxidant status by mitigating the harmful effects of oxidized oil, but also modulated non‐specific immune responses in the crab that received OFO. Overall, OFO‐induced hepatopancreatic injury may be alleviated by a dietary combination of vitamins C and E, and the feeding of rancid forage fish or diets that contain highly oxidized oil is likely a cause of hepatopancreatic necrosis that is frequently observed in farmed crabs.

Glioma is the most common malignant tumor of the central nervous system, and it is characterized by high relapse and fatality rates and poor prognosis. Bufalin is one of the main ingredients of Chan-su, a traditional Chinese medicine (TCM) extracted from toad venom. Previous studies revealed that bufalin exerted inhibitory effects on a variety of tumor cells. To demonstrate the inhibitory effect of bufalin on glioma cells and glioma stem-like cells (GSCs) and discuss the underlying mechanism, the proliferation of glioma cells was detected by MTT and colony formation assays following treatment with bufalin. In addition, we investigated whether bufalin inhibits or kills GSCs using flow cytometry, Western blotting, and reverse transcription polymerase chain reaction analysis (RT-PCR). Finally, we investigated whether bufalin could improve the therapeutic effect of temozolomide (TMZ) and discussed the underlying mechanism. Taken together, our data demonstrated that bufalin inhibits glioma cell growth and proliferation, inhibits GSC proliferation, and kills GSCs. Bufalin was found to induce the apoptosis of GSCs by upregulating the expression of the apoptotic proteins cleaved caspase 3 and poly(ADP-ribose) polymerase (PARP) and by downregulating the expression of human telomerase reverse transcriptase, which is a marker of telomerase activity. Bufalin also improved the inhibitory effect of TMZ on GSCs by activating the mitochondrial apoptotic pathway. These results suggest that bufalin damages GSCs, induces apoptosis, and enhances the sensitivity of GSCs to TMZ.

SUMMARY 5-hydroxymethylcytosine (5hmC) is enriched in brain and has been recognized as an important DNA modification. However, the roles of 5hmC and its writers, ten-eleven translocation (Tet) proteins, in stress-induced response have yet to be elucidated. Here, we show that chronic restraint stress (CRS) induced depression-like behavior in mice and resulted in a 5hmC reduction in prefrontal cortex (PFC). We found that loss of Tet1 (Tet1 KO) led to resistance to CRS, whereas loss of Tet2 (Tet2 KO) increased the susceptibility of mice to CRS. Genome-wide 5hmC profiling identified the phenotype-associated stress-induced dynamically hydroxymethylated loci (PA-SI-DhMLs), which are strongly enriched with hypoxia-induced factor (HIF) binding motifs. We demonstrated the physical interaction between TET1 and HIF1α induced by CRS and revealed that the increased HIF1α binding under CRS is associated with SI-DhMLs. These results suggest that TET1 could regulate stress-induced response by interacting with HIFIα., Graphical Abstract, In Brief The roles of 5-hydroxymethylcytosine (5hmC) and its writers, Tet proteins, in stress-induced response remain unclear. Cheng et al. show that Tet1 knockout mice exhibit resistance, whereas Tet2 knockout mice have increased susceptibility to stress. Biochemical and genome-wide analyses suggest that Tet1 could regulate stress-induced response by interacting with Hif1α.

The Sertoli cell is the only somatic cell within the seminiferous tubules, and is vital for testis development and spermatogenesis. Rosiglitazone (RSG) is a member of the thiazolidinedione family and is a peroxisome proliferator-activated receptor-γ (PPARγ) agonist. It has been reported that RSG protects various types of cells from fatty acid-induced damage. However, whether RSG serves a protective role in Sertoli cells against palmitic acid (PA)-induced toxicity remains to be elucidated. Therefore, the aim of the present study was to investigate the effect of RSG on PA-induced cytotoxicity in Sertoli cells. MTT assay and Oil Red O staining revealed that RSG ameliorated the PA-induced decrease in TM4 cell viability, which was accompanied by an alleviation of PA-induced lipid accumulation in cells. In primary mouse Sertoli cells, RSG also showed similar protective effects against PA-induced lipotoxicity. Knockdown of PPARγ verified that RSG exerted its protective role in TM4 cells through a PPARγ-dependent pathway. To evaluate the mechanism underlying the protective role of RSG on PA-induced lipotoxicity, the present study analyzed the effects of RSG on PA uptake, and the expression of genes associated with both fatty acid oxidation and triglyceride synthesis. The results demonstrated that although RSG did not affect the endocytosis of PA, it significantly elevated the expression of carnitine palmitoyltransferase (CPT)-1A, a key enzyme involved in fatty acid oxidation, which indicated that the protective effect of RSG may have an important role in fatty acid oxidation. On the other hand, the expression of CPT1B was not affected by RSG. Moreover, the expression levels of diacylglycerol O-acyltransferase (DGAT)-1 and DGAT2, both of which encode enzymes catalyzing the synthesis of triglycerides, were not suppressed by RSG. The results indicated that RSG reduced PA-induced lipid accumulation by promoting fatty acid oxidation mediated by CPT1A. The effect of RSG in protecting cells from lipotoxicity was also found to be specific to Sertoli cells and hepatocytes, and not to other cell types that do not store excess lipid in large quantities, such as human umbilical vein endothelial cells. These findings provide insights into the cytoprotective effects of RSG on Sertoli cells and suggest that PPARγ activation may be a useful therapeutic method for the treatment of Sertoli cell dysfunction caused by dyslipidemia. Electronic supplementary material The online version of this article (10.1186/s12958-018-0416-0) contains supplementary material, which is available to authorized users.

Forkhead box O (FoxO) protein, a major downstream transcription factor of insulin/insulin-like growth factor signaling/target of rapamycin pathway (IIS/TOR), is involved in the regulation of larval growth and the determination of organ size. FoxO also interacts with 20-hydroxyecdysone (20E) and juvenile hormone (JH) signal transduction pathways, and hence is critical for larval development in holometabolans. However, whether FoxO plays a critical role during larval metamorphosis needs to be further determined in Leptinotarsa decemlineata. We found that 20E stimulated the expression of LdFoxO. RNA interference (RNAi)-aided knockdown of LdFoxO at the third-instar stage repressed 20E signaling and reduced larval weight. Although the resultant larvae survived through the third-fourth instar ecdysis, around 70% of the LdFoxO depleted moribund beetles developmentally arrested at prepupae stage. These LdFoxO depleted beetles were completely wrapped in the larval exuviae, gradually darkened and finally died. Moreover, approximately 12% of the LdFoxO RNAi beetles died as pharate adults. Ingestion of either 20E or JH by the LdFoxO depletion beetles excessively rescued the corresponding hormonal signals, but could not alleviate larval performance and restore defective phenotypes. Therefore, FoxO plays an important role in regulation of larval-pupal-adult transformation in L. decemlineata, in addition to mediation of IIS/TOR pathway and stimulation of ecdysteroidogenesis.

BackgroundN6-methyladenosine (m6A) modification is known to impact many aspects of RNA metabolism, including mRNA stability and translation, and is highly prevalent in the brain.ResultsWe show that m6A modification displays temporal and spatial dynamics during neurodevelopment and aging. Genes that are temporally differentially methylated are more prone to have mRNA expression changes and affect many pathways associated with nervous system development. Furthermore, m6A shows a distinct tissue-specific methylation profile, which is most pronounced in the hypothalamus. Tissue-specific methylation is associated with an increase in mRNA expression and is associated with tissue-specific developmental processes. During the aging process, we observe significantly more m6A sites as age increases, in both mouse and human. We show a high level of overlap between mouse and human; however, humans at both young and old ages consistently show more m6A sites compared to mice. Differential m6A sites are found to be enriched in alternative untranslated regions of genes that affect aging-related pathways. These m6A sites are associated with a strong negative effect on mRNA expression. We also show that many Alzheimer-related transcripts exhibit decreased m6A methylation in a mouse model of Alzheimer’s disease, which is correlated with reduced protein levels.ConclusionsOur results suggest that m6A exerts a critical function in both early and late brain development in a spatio-temporal fashion. Furthermore, m6A controls protein levels of key genes involved in Alzheimer’s disease-associated pathways, suggesting that m6A plays an important role in aging and neurodegenerative disease.

Among the different antibiotics, tetracycline hydrochloride (TCH) is one of the most commonly used. In this study, the activated sodium persulfate (SPS) process induced by microwave (MW) energy was used to treat TCH. The effect of different operational parameters of MW/SPS-treated TCH, such as SPS concentration, TCH concentration, initial pH, and MW power, was investigated. The concentration changes of TCH were determined using a spectrophotometer. The results of radical scavenger experiments indicated that the sulfate radical () was stronger than the hydroxyl radical (·OH). On the basis of high performance liquid chromatography–mass spectrometry (HPLC–MS) analysis, a possible degradation pathway of TCH was proposed. This research indicates that the MW/SPS system is a promising prospect for the treatment of TCH.

Thermal properties and orientation in optical textures of liquid crystal (LC) are two crucial factors for LC application. Here, a series of achiral and chiral LC compounds (Cn) with different end groups were prepared. The chemical structures were investigated by Fourier transform infrared (FT-IR) and proton nuclear magnetic resonance (1H NMR). The thermal properties and optical textures were studied by differential scanning calorimetry (DSC), polarizing optical microscopy (POM) and X-ray diffraction (XRD). The results showed that all the compounds possessed good thermal properties and enantiotropic mesomorphism. For achiral compounds C1 C4, droplets and schlieren textures of nematic phase (N) and broken fan-shape textures and dull grayish/cloudy textures of smectic phase (Sc) were seen. Oily streak and focal conic textures of chiral nematic phase (N*), fan-shape textures and dull grayish/cloudy textures of chiral smectic phase (Sc*) were observed for chiral compounds C5 C7. For C1, C2, C3 and C5 with aliphatic chain in the end groups, it was found that lateral substitution in the end groups had a greater effect on the clearing point than that of the increase in the length of end groups. Moreover, due to the increasing free volume for the increase of branch chain on six-membered ring structure, the clearing point (Ti) of C4 was higher than those of C6 and C7.

MicroRNAs (miRNAs) regulate protein expression by antagonizing the translation of mRNAs and are effective regulators of normal nervous system development, function, and disease. MicroRNA-29b (miR-29b) plays a broad and critical role in brain homeostasis. In this study, we tested the function of miR-29b in animal and cell models by inhibiting miR-29b expression. Mouse models of middle cerebral artery occlusion were established using the modified Zea-Longa suture method. Prior to modeling, 50 nmol/kg miR-29b antagomir was injected via the tail vein. MiR-29b expression was found to be abnormally increased in ischemic brain tissue. The inhibition of miR-29b expression decreased the neurological function score and reduced the cerebral infarction volume and cell apoptosis. In addition, the inhibition of miR-29b significantly decreased the malondialdehyde level, increased superoxide dismutase activity, and Bcl-2 expression, and inhibited Bax and Caspase3 expression. PC12 cells were treated with glutamate for 12 hours to establish in vitro cell models of ischemic stroke and then treated with the miR-29 antagomir for 48 hours. The results revealed that miR-29b inhibition in PC12 cells increased Bcl-2 expression and inhibited cell apoptosis and oxidative damage. These findings suggest that the inhibition of miR-29b inhibits oxidative stress and cell apoptosis in ischemic stroke, producing therapeutic effects in ischemic stroke. This study was approved by the Laboratory Animal Care and Use Committee of the First Affiliated Hospital of Zhengzhou University (approval No. 201709276S) on September 27, 2017.

Although blockade of programmed death-ligand 1 (PD-L1) to enhance T cell immune responses shows great promise in tumor immunotherapy, the efficacy of such immune-checkpoint inhibition strategy is limited for patients with solid tumors. The mechanism underlying the limited efficacy of PD-L1 inhibitors remains unclear. Here, we show that human lung adenocarcinoma, regardless of PD-L1 protein positive or negative, all produce a long non-coding RNA isoform of PD-L1 (PD-L1-lnc) via alternative splicing, which promotes lung adenocarcinoma proliferation and metastasis. PD-L1-lnc in various lung adenocarcinoma cells is significantly upregulated by IFNγ in a manner similar to PD-L1 mRNA. Both in vitro and in vivo studies demonstrate that PD-L1-lnc increases proliferation and invasion but decreases apoptosis of lung adenocarcinoma cells. Mechanistically, PD-L1-lnc directly binds to c-Myc and enhances c-Myc transcriptional activity downstream in lung adenocarcinoma cells. Our results provide targeting PD-L1-lnc−c-Myc axis as a novel strategy for lung cancer therapy.

Abnormal lipid/lipoprotein metabolism induced by obesity may affect spermatogenesis by inhibiting testosterone synthesis in Leydig cells. It is crucial to determine which components of lipoproteins inhibit testosterone synthesis. Circulating oxidized low-density lipoprotein (oxLDL), the oxidized form of LDL, has been reported to be an independent risk factor for decreased serum testosterone levels. However, whether oxLDL has a damaging effect on Leydig cell function and the detailed mechanisms have been rarely studied. This study first showed the specific localization of oxLDL and mitochondrial structural damage in testicular Leydig cells of high-fat diet-fed mice in vivo. We also found that oxLDL reduced the mitochondrial membrane potential (MMP) by disrupting electron transport chain and inhibited testosterone synthesis-related proteins and enzymes (StAR, P450scc, and 3β‑HSD), which ultimately led to mitochondrial dysfunction and decreased testosterone synthesis in Leydig cells. Further experiments demonstrated that oxLDL promoted lipid uptake and mitochondrial dysfunction by inducing CD36 transcription. Meanwhile, oxLDL facilitated COX2 expression through the p38 MAPK signaling pathway in Leydig cells. Blockade of COX-2 attenuated the oxLDL-induced decrease in StAR and P450scc. Our clinical results clarified that the increased serum oxLDL level was associated with a decline in circulating testosterone levels. Our findings amplify the damaging effects of oxLDL and provide the first evidence that oxLDL is a novel metabolic biomarker of male-acquired hypogonadism caused by abnormal lipid metabolism.

Given that per- and polyfluoroalkyl substances (PFASs) exhibit different distribution in the serum and semen of adult men, improving our understanding of the predictors of PFAS concentrations in paired serum and semen samples from an individual is essential. Here, we investigated and compared the effects of emerging and legacy PFAS concentrations in serum and semen on reproductive hormone levels in serum within a Chinese adult male population. We explored the relationships among perfluorooctanoate (PFOA), perfluorononanoate (PFNA), perfluorooctane sulfonate (PFOS), and chlorinated polyfluorinated ether sulfonate (6:2 Cl-PFESA) in serum and semen with reproductive hormones in serum among 651 adult men from Nanjing, China. Significant relationships among all analyzed serum and semen PFASs and decreased total testosterone (total T) were found. Serum and semen PFOA levels were associated with significant decreases in free T. Furthermore, the levels of sex hormone-binding globulin (SHBG) were significantly decreased in association with PFNA, PFOS, and 6:2 Cl-PFESA exposure. Negative relationships between the total T/luteinizing hormone (LH) ratio and semen concentrations of selected PFASs were also observed. After adjustment of PFAS concentrations (in both semen and serum), stronger associations of PFASs with total T, free T, estradiol (E2), SHBG, and total T/LH were observed in semen than in serum. We found that 84.8% of the associations between serum PFOA with total T were mediated by semen PFOA. Thus, elevated PFAS exposure may have negative effects on male reproductive health, and semen PFAS may be a better exposure indicator for the male reproductive system than serum PFAS.

Background: During disc degeneration, inflammatory cytokine tumor necrosis factor (TNF)-α is correlated with nucleus pulposus (NP) cell apoptosis. Transforming growth factor (TGF)-β1 has the potential to regenerate degenerative disc. Objective: To investigate the protective role of TGF-β1 against TNF-α-mediated NP cell apoptosis and the underlying mechanism. Methods: Rat NP cells were treated with TNF-α (100 ng/ml) for 48 h. TGF-β1 was added into the culture medium to investigate its protective effects against TNF-α-induced NP cell apoptosis. Exogenous FasL was used to investigate the potential role of the Fas/FasL pathway in this process. Flow cytometry assay was used to analyze NP cell apoptosis. Real-time PCR and Western blotting were used to analyze gene and protein expression of apoptosis-related molecules. Results: In TNF-α-treated NP cells, TGF-β1 significantly decreased NP cell apoptosis, declined caspase-3 and -8 activity, and decreased expression of Bax and caspase-3 (cleaved-caspase-3) but increased expression of Bcl-2. However, exogenous FasL partly reversed these effects of TGF-β1 in NP cells treated with TNF-α. Additionally, expression of Fas and FasL in TNF-α-treated NP cells partly decreased by TGF-β1, whereas exogenous FasL increased expression of Fas and FasL in NP cells treated with TGF-β1 and TNF-α. Conclusion: TGF-β1 helps to inhibit TNF-α-induced NP cell apoptosis and the Fas/FasL pathway may be involved in this process. The present study suggests that TGF-β1 may be effective to retard inflammation-mediated disc degeneration.

Fluorescent nematic terbium-containing liquid crystalline oligomers in the main chain (Tb-LCOs) are prepared using 4,4-dihydroxybiphenyl, 2,5-dihydroxybenzoic acid, bis(4-(chlorocarbonyl)phenyl) decanedioate and anhydrous terbium chloride. The chemical structures, liquid crystalline behaviours and fluorescence properties of Tb-LCOs are characterised by various experimental techniques. The introduction of terbium ions endows oligomers with excellent luminescence properties. Tb-LCOs shows reversible mesomorphic phase transitions, wide mesophase temperature ranges and high thermal stability. The thermogravimetric analysis results shows that decomposition temperatures (5% weight loss) are greater than 308°C in all Tb-LCOs. Tb-LCOs can emit green light when excited. The luminescence intensity of Tb- LCOs gradually enhances with increase in terbium ions from 0.3 to 1.5 mol%.

Background Hypoxic conditions area key feature of allergic rhinitis (AR), however, the role of hypoxia in AR remains to be fully understood. The aim of this study was to survey the effect of hypoxia on the Th17 response in AR patients by investigating the action of hypoxia-influenced signaling pathways on Th17 differentiation. Methods 23 AR patients and 15 healthy controls were recruited for this study. Under normoxia and hypoxic conditions, the expression of HIF-1α, AhR, CYP1A1 and CYP1B1 and the presence of Th17 cells in CD4+T cells were measured. Furthermore, the amount of ARNT combined with either HIF-1α or AhR was determined after the exposure of 2-(1H-Indol-3-ylcarbonyl)-4-thiazolecarboxylic acid methyl easter (ITE) with normoxia and hypoxia. Results HIF-1α and AhR expression were higher in CD4+T cells from AR patients than in those from healthy controls. In a hypoxic environment, the expression of HIF-1α was elevated in CD4+T cells of both AR patients and healthy controls. Meanwhile, the suppressive effects of a non-toxic AhR ligand (ITE) on the Th17 response and its positive effects on IL-10 production were suppressed in the cells of AR patients and healthy controls under hypoxia. These effects were arisen from HIF-1α out-competing AhR for ARNT binding which limited the activity of the AhR pathway. Conclusions The present results suggest that hypoxia is capable of promoting the Th17 response by reducing AhR activity via HIF-1α activity. Thus hypoxia may be intimately involved in the pathogenesis of AR.

3-Phosphoinositide-dependent protein kinase-1 (PDK1) plays a critical role in the development of mammalian brain. Here, we investigated the role of PDK1 in Purkinje cells (PCs) by generating the PDK1-conditional knock-out mice (cKO) through crossing PV-cre or Pcp2-cre mice with Pdk1(fl/fl) mice. The male mice were used in the behavioral testing, and the other experiments were performed on mice of both sexes. These PDK1-cKO mice displayed decreased cerebellar size and impaired motor balance and coordination. By the electrophysiological recording, we observed the reduced spontaneous firing of PCs from the cerebellar slices of the PDK1-cKO mice. Moreover, the cell body size of PCs in the PDK1-cKO mice was time dependently reduced compared with that in the control mice. And the morphologic complexity of PCs was also decreased after PDK1 deletion. These effects may have contributed to the reduction of the rpS6 (reduced ribosomal protein S6) phosphorylation and the PKCγ expression in PDK1-cKO mice since the upregulation of pS6 by treatment of 3-benzyl-5-((2-nitrophenoxy) methyl)-dihydrofuran-2(3H)-1, the agonist of mTOR1, partly rescued the reduction in the cell body size of the PCs, and the delivery of recombinant adeno-associated virus-PKCγ through cerebellar injection rescued the reduced complexity of the dendritic arbor in PDK1-cKO mice. Together, our data suggest that PDK1, by regulating rpS6 phosphorylation and PKCγ expression, controls the cell body maintenance and the dendritic development in PCs and is critical for cerebellar motor coordination. SIGNIFICANCE STATEMENT Here, we show the role of 3-phosphoinositide-dependent protein kinase-1 (PDK1) in Purkinje cells (PCs). The ablation of PDK1 in PCs resulted in a reduction of cell body size, and dendritic complexity and abnormal spontaneous firing, which attributes to the motor defects in PDK1-conditional knock-out (cKO) mice. Moreover, the ribosomal protein S6 (rpS6) phosphorylation and the expression of PKCγ are downregulated after the ablation of PDK1. Additionally, upregulation of rpS6 phosphorylation by3-benzyl-5-((2-nitrophenoxy) methyl)-dihydrofuran-2(3H)-1 partly rescued the reduction in cell body size of PCs, and the overexpression of PKCγ in PDK1-KO PCs rescued the reduction in the dendritic complexity. These findings indicate that PDK1 contributes to the maintenance of the cell body and the dendritic development of PCs by regulating rpS6 phosphorylation and PKCγ expression.

Efficient solution-processible yellow/orange emissive phosphors are highly required in solution-processed phosphorescent organic light-emitting diodes (s-PhOLEDs). With respect to phenyl pyridine (ppy)-type Ir(III) complexes, 2-(9,9-diethylfluoren-2-yl)pyridine (Flpy)-type Ir(III) complexes have huge potential in yellow/orange s-PhOLEDs due to their extended conjugation and excellent solubility in common organic solvents. Herein, a new series of phosphorescent Ir(III) complexes, i.e. Ir(Flpy)2pic-N O, Ir(Flpy-CF3)2pic-N O, Ir(Flpy-CF3)2dbm and Ir(Flpy-CF3)2acac, based on Flpy main ligand and picolinic N-oxide (pic-N O), acetylacetone (acac), and dibenzoyl methane (dbm) ancillary ligands are synthesized. The photophysical, electrochemical, and electroluminescent (EL) properties of these phosphorescent Ir(III) complexes are investigated in details. By introducing the CF3 group in Flpy ligand and varying the ancillary ligands, the emission spectra of these phosphorescent complexes are tuned in a large range with EL emission peaks from 544 nm to 588 nm. The s-PhOLEDs employing these phosphors show promising EL performance with maximum external quantum efficiency (EQE) from 15.4% to 23.7% and high power efficiency from 61.9 l m W−1 to 80.4 l m W−1. These highly efficient phosphorescent Ir(III) complexes may serve as ideal chromaticity components in solution-processed full-color displays and lighting devices.

The roles of the γ-aminobutyric acid (GABA) shunt and polyamine (PA) degradation pathway on GABA accumulation were investigated in fresh tea leaves under anaerobic and aerobic sequential incubations. The GABA accumulation was mainly completed in the first anaerobic incubation through the interaction of the GABA shunt with the PA degradation pathway. When treated with aminoguanidine, the diamine oxidase and polyamine oxidase activities were almost completely inhibited, and the GABA contents decreased by 40.7%, 46.4%, 41.0% and 37.5% in the tea leaves of the four cultivars 'Fuyun No. 6', 'Fudingdabai', 'Longjing No. 43' and 'Pingyangtezao', respectively. The glutamate decarboxylase activity decreased significantly, and the accumulation of GABA may increase or decrease because of varietal differences, which occurred mainly relying on the PA degradation pathway during the second anaerobic incubation. Thus, approximately 37%-47% of the GABA formed in fresh tea leaves under hypoxia was supplied by the PA pathway.

Methylation of histone H4 lysine 20 (H4K20) has been associated with cancer. However, the functions of the histone methyltransferases that trigger histone H4K20 methylation in cancers, including suppressor of variegation 4-20 homolog 1 (Suv4-20h1), remain elusive. In the present study, it was demonstrated that the knockdown of the histone H4K20 methyltransferase Suv4-20h1 resulted in growth inhibition in chronic myeloid leukemia K562 cells. Disruption of Suv4-20h1 expression induced G1 arrest in the cell cycle and increased expression levels of cyclin dependent kinase inhibitor 1A (p21WAF1/CIP1), an essential cell cycle protein involved in checkpoint regulation. Chromatin immunoprecipitation analysis demonstrated that Suv4-20h1 directly binds to the promoter of the p21 gene and that methylation of histone H4K20 correlates with repression of p21 expression. Thus, these data suggest that Suv4-20h1 is important for the regulation of the cell cycle in K562 cells and may be a potential therapeutic target for leukemia.

The photophysics and charge transport properties of polymer host materials largely determine the resultant electroluminescent (EL) performance of solution-processed phosphorescent organic light-emitting diodes (s-PhOLEDs). Herein, these characteristics of the state-of-the-art polymer host material, i.e. poly(N-vinylcarbazole) (PVK), are manipulated via the choice of the processing solvent by means ofdifferent boiling points. Compared to the control PVK film (toluene as solvent), the PVK film with a high packing density processed with o-dichlorobenzene (ODCB) solvent displays a higher excitonic energy, i.e. the more the “p-PVK” contribution, the lower the content of low energy PVK electromers under EL driving, and also a different hole transport capability. For the PVK:FIrpic doped film, it is confirmed that the host-to-guest energy transfer efficiency is the best for the ODCB based film among these samples. PVK:FIpric doped s-PhOLEDs are comparatively fabricated by using these solvents, and the ODCB based device achieves a high luminous efficiency of 29.0 cd A−1, corresponding to 16% enhancement with respect to 25 cd A−1 of the control TOL device. Such performance promotion is attributed to the satisfied energy transfer process from PVK to FIrpic and also the enhanced charge balance conditions achieved in the ODCB device.

An efficient and practical method for chemoselective “on-water” reduction of α-keto amide by Hantzsch ester without using any catalysts and additives was developed. Control experiments indicated that the intramolecular hydrogen bond of α-keto amide was crucial for this transformation. A variety of α-hydroxy amides were prepared in high yields in an environmentally friendly way.

A dynamic surface pattern with tunable liquid crystalline texture and fluorescence in response to external stimulus can enable information recording and reading. Therefore, such patterns are widely used in the field of information security and anti-counterfeiting. A higher level of security in anti-counterfeiting is extremely desirable but challenging, herein, the chiral liquid crystalline networks (CLCN) used for anti-counterfeiting displaying both dynamic reversible Grandjean textures and fluorescence were dexterously designed and prepared by graft copolymerization of polymethylhydrosiloxane (PMHS), nematic liquid crystal M1, chiral crosslinker M2 and organic fluorescent pyrene compounds M3. The CLCN can emit blue-fluorescence when irradiating with ultraviolet light. More importantly, the Grandjean textures and fluorescence can be simultaneously and precisely adjusted by temperature. The as-prepared CLCN display reversible Grandjean textures during the heating and cooling process from the intrinsic chiral arrangement of CLCN. The discrete pyrene chromogenic segments in CLCN matrix enable the tunable photoluminescence by temperature, furthermore, the CLCN present highly sensitive photoluminescence evolution. The dynamic reversible Grandjean textures and fluorescence make the smart materials promising candidates in anticounterfeiting, providing a versatile strategy to fabricate intelligent optical anti-counterfeiting materials.

Cancer cells frequently exhibit aerobic glycolysis, known as the Warburg effect. An et al. identify a novel RNA regulatory activity of BAG3, a protein implicated in various cancers. BAG3 enhances posttranscriptionally the expression of Hexokinase 2, the first enzyme involved in glycolysis, and it reprograms glucose metabolism by pancreatic cancer cells., Aerobic glycolysis, a phenomenon known historically as the Warburg effect, is one of the hallmarks of cancer cells. In this study, we characterized the role of BAG3 in aerobic glycolysis of pancreatic ductal adenocarcinoma (PDAC) and its molecular mechanisms. Our data show that aberrant expression of BAG3 significantly contributes to the reprogramming of glucose metabolism in PDAC cells. Mechanistically, BAG3 increased Hexokinase 2 (HK2) expression, the first key enzyme involved in glycolysis, at the posttranscriptional level. BAG3 interacted with HK2 mRNA, and the degree of BAG3 expression altered recruitment of the RNA-binding proteins Roquin and IMP3 to the HK2 mRNA. BAG3 knockdown destabilized HK2 mRNA via promotion of Roquin recruitment, whereas BAG3 overexpression stabilized HK2 mRNA via promotion of IMP3 recruitment. Collectively, our results show that BAG3 promotes reprogramming of glucose metabolism via interaction with HK2 mRNA in PDAC cells, suggesting that BAG3 may be a potential target in the aerobic glycolysis pathway for developing novel anticancer agents.

Chemical modifications on DNA molecules, such as 5-methylcytosine and 5-hydroxymethylcytosine, play important roles in the mammalian brain. A novel DNA adenine modification, N(6)-methyladenine (6mA), has recently been found in mammalian cells. However, the presence and function(s) of 6mA in the mammalian brain remain unclear. Here we demonstrate 6mA dynamics in the mouse brain in response to environmental stress. We find that overall 6mA levels are significantly elevated upon stress. Genome-wide 6mA and transcriptome profiling reveal an inverse association between 6mA dynamic changes and a set of upregulated neuronal genes or downregulated LINE transposon expression. Genes bearing stress-induced 6mA changes significantly overlap with loci associated with neuropsychiatric disorders. These results suggest an epigenetic role for 6mA in the mammalian brain as well as its potential involvement in neuropsychiatric disorders., N6-methyladenine is a covalent epigenetic modification of the genome. Here, Yao and colleagues show that N6-methyladenine level in the mouse brain is dynamic following environmental stress, and the subsequent differential gene expression is correlated with LINE transposon expression.

Background: Approximately 15% of all solid tumors harbor deletions in methylthioadenosine phosphorylase (MTAP) (1). MTAP deficiencies have been reported to sensitize tumor cells to methionine adenosyltransferase 2A (MAT2A) modulation (2). MAT2A synthesizes the universal methyl donor and PRMT5 substrate S-adenosylmethionine (SAM) from methionine. PRMT5 symmetrically di-methylates arginine (SDMA) residues on proteins that are key to genomic integrity and proteostasis. We evaluated the anti-tumor activity of the small molecule MAT2A inhibitor IDE397 in multiple CDX models and in an ongoing study of 45 MTAP-deleted PDX models to inform clinical strategy for a First-in-Human clinical trial evaluating IDE397. Methods: CDX models utilized included the HCT116 isogenic pair and endogenous MTAP-deleted models. A series of dose response and time-course studies were performed to inform the efficacy-PD relationship. SAM was quantified by LC-MS and SDMA was visualized by western blot (WB) and further quantified by immunohistochemistry (IHC). PDX models with MTAP homozygous deletions were selected from bladder, esophageal, gastric, head and neck, NSCLC and pancreatic cancers. MTAP deletion was determined by WES and/or SNP 6.0 microarray and verified by absence of significant mRNA. Tumors were subcutaneously implanted into immunocompromised mice by serial transplantation of tumor fragments. Each PDX model included a vehicle control and an IDE397-treated group (n=5/group). IDE397 was administered orally once per day (QD). Tumor growth inhibition (TGI) was calculated using the formula TGI = (TV controlfinal - TV treatedfinal)/(TV controlfinal - TV controlinitial) x 100. Results: Administration of IDE397 resulted in TGI and/or tumor regression in MTAP-deleted CDX and PDX models. The HCT116 MTAP-deleted CDX model was more sensitive to IDE397 compared to the HCT116 MTAP-WT model. IDE397 produced a dose- and time-dependent modulation of the proximal and distal PD biomarkers SAM and SDMA. SAM was decreased in plasma and tumors irrespective of MTAP status. In contrast, SDMA was selectively modulated in MTAP-null models only. In a NSCLC CDX model, a dose dependent TGI was observed, with the higher doses leading to tumor regression. Anti-tumor activity is observed in MTAP-deleted PDX models, where IDE397 administration has resulted in TGI and tumor regressions. Conclusion: Xenograft studies indicate that IDE397 exhibits anti-tumor activity as a single agent in MTAP-deleted CDX models and in MTAP-deleted PDX models of NSCLC, pancreatic, bladder, head and neck, esophageal and gastric cancer. This data supports the clinical evaluation of IDE397 across a wide range of solid tumor types with MTAP-deletion. References: (1) Beroukhim, R. et al. Nature 2010 Feb 18;463(7283):899-905. (2) Marjon, K. et al. Cell Rep 2016 Apr 19;15(3):574-587. Citation Format: Marcus M. Fischer, Neil Bhola, John Faulhaber, Yevgeniy Freyman, Bing Yao, Zineb Mounir, Mark R. Lackner, Claire Neilan. MAT2A inhibitor, IDE397, displays broad anti-tumor activity across a panel of MTAP-deleted patient-derived xenografts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1278.

S-doped porous carbon (S/C) has been successfully fabricated from biomass waste (drug residue). The S/C not only has a unique porous structure and channel, but porous structures are interconnected to form a sponge-like structures. The unique structure not only increases the specific surface area and energy storage sites, but also shortens the path of ion transmission and charge transfer. When S/C-1 is used as lithium ion batteries (LIBs) anode, the capacity of 710 mAh g−1 can be achieved after 50 cycles at 0.1 A g−1. The capacity still has 364 mAh g−1 at 5 A g−1 for long-life-cycle. For sodium ion batteries (SIBs), a capacity of 518 mAh g−1 can be delivered at 0.1 A g−1 for 50 cycles, and a capacity of long-life-cycle at 5 A g−1 still maintains 230 mAh g−1. The improving rate capacities of S/C-1 can be attributed to the short diffusion lengths of Li+ and Na+ ions for uniform sponge-like structure, large specific surface area (SSA) and additional active sites. This work has an important opportunity to change the current energy situation.

SUMMARY 5-hydroxymethylcytosine (5hmC) undergoes dynamic changes during mammalian brain development, and its dysregulation is associated with Alzheimer’s disease (AD). The dynamics of 5hmC during early human brain development and how they contribute to AD pathologies remain largely unexplored. We generate 5hmC and transcriptome profiles encompassing several developmental time points of healthy forebrain organoids and organoids derived from several familial AD patients. Stage-specific differentially hydroxymethylated regions demonstrate an acquisition or depletion of 5hmC modifications across developmental stages. Additionally, genes concomitantly increasing or decreasing in 5hmC and gene expression are enriched in neurobiological or early developmental processes, respectively. Importantly, our AD organoids corroborate cellular and molecular phenotypes previously observed in human AD brains. 5hmC is significantly altered in developmentally programmed 5hmC intragenic regions in defined fetal histone marks and enhancers in AD organoids. These data suggest a highly coordinated molecular system that may be dysregulated in these early developing AD organoids., Graphical Abstract, In brief Kuehner et al. use forebrain organoids derived from healthy controls to study the dynamics of 5hmC across early brain development. In addition, organoids derived from several AD patients reveal aberrant 5hmC patterns that could disrupt early neuronal networks and contribute to the onset of AD later in life.