c-Myc inhibits LAPTM5 expression in B-cell lymphomas.

Myc is a pivotal protooncogenic transcription factor that contributes to the development of almost all Burkitt's lymphomas and about one-third of diffuse large B-cell lymphomas. How B-cells sustain their uncontrolled proliferation due to high Myc is not yet well defined. Here, we found that Myc trans-represses the expression of murine LAPTM5, a gene coding a lysosome-associated protein, by binding to two E-boxes in the LAPTM5 promoter. While the product of intact mRNA (CDS+3'UTR) of LAPTM5 failed to suppress the growth of B-lymphomas, either the protein coded by coding sequence (CDS) itself or the non-coding 3'-untranslated region (3'UTR) mRNA was able to inhibit the growth of B-lymphomas. Moreover, Myc trans-activated miR-17-3p, which promoted tumor growth. Strikingly, LAPTM5 3'UTR contains 11 miR-17-3p-binding sites through which the LAPTM5 protein synthesis was inhibited. The functional interplay between low LAPTM5 mRNA and high miR-17-3p due to high Myc in B-lymphomas leads to further dampening of tumor-suppressive LAPTM5 protein, which promotes tumor progression. Our results indicate that Myc inhibits LAPTM5 expression in B-lymphoma cells by transcriptional and post-transcriptional modifications.

Mollugin ameliorates murine allergic airway inflammation by inhibiting Th2 response and M2 macrophage activation.

Mollugin, isolated from Rubia cordifolia L, is a pharmacological compound with anti-inflammatory activity. This study aimed to investigate whether mollugin protects mice against shrimp tropomyosin (ST)-induced allergic airway inflammation. Mice were sensitized with ST combined with Al(OH)3 administered intraperitoneally (i.p.) once weekly for 3 wk followed by ST challenge for 5 d. Mice were i.p.-administered daily with mollugin for 7 d. Results showed that mollugin attenuated ST-induced infiltration of eosinophils and epithelial mucus secretion in the lung tissues and suppressed lung eosinophil peroxidase activity. Additionally, mollugin lowered the Th2 cytokine, IL-4 and IL-5, production and downregulated the mRNA levels of Il-4, Il-5, Il-13, eotaxin, Ccl-17, Muc5ac, arginase-1, Ym-1, and Fizz-1 in the lung tissues. Network pharmacology was employed to predict core targets, and the molecular docking approach was used to verify the compound targets. The results of the molecular docking study of mollugin into p38 MAPK or poly(ADP-ribose) polymerase 1 (PARP1) binding sites revealed that its mechanism was possibly similar to that of SB203580 (a p38 MAPK inhibitor) or olaparib (a PARP1 inhibitor). Immunohistochemistry analysis revealed that mollugin mitigated ST-induced elevation of arginase-1 expression and macrophage levels in the lungs and bronchoalveolar lavage fluid, respectively. Furthermore, arginase-1 mRNA level and phosphorylation of p38 MAPK were inhibited in IL-4-stimulated peritoneal macrophages. In ST-stimulated mouse primary splenocytes, mollugin notably inhibited IL-4 and IL-5 production and downregulated PARP1 and PAR protein expression. According to our findings, mollugin ameliorated allergic airway inflammation by inhibiting Th2 response and macrophage polarization.

Powder Metallurgy Route to Ultrafine-Grained Refractory Metals.

Ultrafine-grained (UFG) refractory metals are promising materials for applications in aerospace, microelectronics, nuclear energy, and many others under extreme environments. Powder metallurgy (PM) allows to produce such materials with well-controlled chemistry and microstructure at multiple length scales and near-net shape manufacturing. However, sintering refractory metals to full density while maintaining a fine microstructure is still challenging due to the high sintering temperature and the difficulty to separate the kinetics of densification versus grain growth. Here an overview of the sintering issues, microstructural design rules, and PM practices towards UFG and nanocrystalline refractory metals are sought to be provided. The previous efforts shall be reviewed to address the processing challenges, including the use of fine/nanopowders, second-phase grain growth inhibitors, and field-assisted sintering techniques. Recently, pressureless two-step sintering has been successfully demonstrated in producing dense UFG refractory metals down to ≈300 nm average grain size with a uniform microstructure and this technological breakthrough shall be reviewed. PM progresses in specific materials systems shall be next reviewed, including elementary metals (W and Mo), refractory alloys (W-Re), refractory high-entropy alloys, and their composites. Last, future developments and the endeavor towards UFG and nanocrystalline refractory metals with exceptionally uniform microstructure and improved properties are outlined.

Integrated transcriptomics, proteomics, and functional analysis to characterize the tissue-specific small extracellular vesicle network of breast cancer.

Small extracellular vesicles (sEVs) are essential mediators of intercellular communication within the tumor microenvironment (TME). Although the biological features of sEVs have been characterized based on in vitro culture models, recent evidence indicates significant differences between sEVs derived from tissue and those derived from in vitro models in terms of both content and biological function. However, comprehensive comparisons and functional analyses are still limited. Here, we collected sEVs from breast cancer tissues (T-sEVs), paired normal tissues (N-sEVs), corresponding plasma (B-sEVs), and tumor organoids (O-sEVs) to characterize their transcriptomic and proteomic profiles. We identified the actual cancer-specific sEV signatures characterized by enriched cell adhesion and immunomodulatory molecules. Furthermore, we revealed the significant contribution of cancer-associated fibroblasts in the sEV network within the TME. In vitro model-derived sEVs did not entirely inherit the extracellular matrix- and immunity regulation-related features of T-sEVs. Also, we demonstrated the greater immunostimulatory ability of T-sEVs on macrophages and CD8+ T cells compared to O-sEVs. Moreover, certain sEV biomarkers derived from noncancer cells in the circulation exhibited promising diagnostic potential. This study provides valuable insights into the functional characteristics of tumor tissue-derived sEVs, highlighting their potential as diagnostic markers and therapeutic agents for breast cancer.

Optimizing Room-Temperature Thermoelectric Performance of n-Type Bi2Te2.7Se0.3.

Bi2Te3-based compounds are exclusive commercial thermoelectric materials around room temperature. For n-type compounds, optimal thermoelectric properties are normally obtained at temperatures higher than room temperature to suppress the bipolar effect through increased carrier concentration. We find that doping with trace amounts of Cd and the addition of excess Bi are effective ways to optimize carrier concentration and achieve enhanced room-temperature thermoelectric performance for the Bi2Te2.7Se0.3 alloy in this work. For the Cd-doped samples, the replacement of Cd with Bi leads to not only a significant decrease in electron concentration but also apparently reduces the total thermal conductivity. The addition of excess Bi in the samples creates a Bi-rich synthetic atmosphere during the synthesis process, leading to increased BiTe antisite defects, decreased electron concentration, and reduced total thermal conductivity. Doping a small amount of Cd or adding excess Bi causes optimal thermoelectric performance of the n-type Bi2Te2.7Se0.3 sample shifts obviously toward low temperatures, and the samples with 0.4 atom % Cd and 0.8 atom % excess Bi achieve maximum zT of ∼0.97 at 448 K and ∼0.88 at 348 K, respectively.

VEGF receptor 2 (KDR) protects airways from mucus metaplasia through a Sox9-dependent pathway.

Mucus-secreting goblet cells are the dominant cell type in pulmonary diseases, e.g., asthma and cystic fibrosis (CF), leading to pathologic mucus metaplasia and airway obstruction. Cytokines including IL-13 are the major players in the transdifferentiation of club cells into goblet cells. Unexpectedly, we have uncovered a previously undescribed pathway promoting mucous metaplasia that involves VEGFa and its receptor KDR. Single-cell RNA sequencing analysis coupled with genetic mouse modeling demonstrates that loss of epithelial VEGFa, KDR, or MEK/ERK kinase promotes excessive club-to-goblet transdifferentiation during development and regeneration. Sox9 is required for goblet cell differentiation following Kdr inhibition in both mouse and human club cells. Significantly, airway mucous metaplasia in asthmatic and CF patients is also associated with reduced KDR signaling and increased SOX9 expression. Together, these findings reveal an unexpected role for VEGFa/KDR signaling in the defense against mucous metaplasia, offering a potential therapeutic target for this common airway pathology.

Precise Regulation of Carrier Concentration in Thermoelectric BiSbTe Alloys via Magnetic Doping.

The Bi2Te3-based alloy is the best commercial thermoelectric material around room temperature, although it is extremely difficult to further improve its thermoelectric performance. In this work, we demonstrate that magnetic doping is an effective strategy to regulate the thermoelectric performance of p-type Bi0.5Sb1.5Te3. According to our experiments, it is much more difficult for ferromagnetic Fe/Co to enter the Bi0.5Sb1.5Te3 lattice in comparison with diamagnetic Pb, which can be understood by the "like dissolves like" rule. At the same doping content, Fe and Co provide much lower hole carriers than Pb due to their larger carrier thermal activation energies, indicating that Fe and Co as dopants are very applicable for the fine regulation of the carrier concentration. The Fe/Co-doped samples have higher Seebeck coefficients but less carrier mobilities than the Pb-doped sample since the doped magnetic atoms induce additional carrier scattering. Beyond the solid solubility limit, excess Fe/Co represents as the impurity, which can maintain a high carrier concentration due to the metal-semiconductor contact. Finally, the zT values of ∼1.05 and 1.15 near room temperature have been achieved for the samples with 1.71 at. % Co and 1.80 at. % Fe, respectively.

Enhanced room-temperature thermoelectric performance of p-type BiSbTe by reducing carrier concentration.

Improving room-temperature thermoelectric performance of p-type (Bi,Sb)2Te3 is essential for its practical application. However, the usual doping or alloying methods increase the carrier concentration and result in enhanced thermoelectric properties at high temperatures but not room temperature. In this work, we find that Ti is a promising dopant to shift the optimum thermoelectric properties of p-type (Bi,Sb)2Te3 to room temperature by reducing its carrier concentration. p-type Bi0.5Sb1.5-x Ti x Te3 samples with various Ti contents have been prepared using a simple melting method. The carrier concentration of Bi0.5Sb1.5-x Ti x Te3 is reduced by partially replacing Sb with Ti, leading to not only a significantly increased Seebeck coefficient but also an improved power factor near room temperature. Moreover, the total thermal conductivity near room temperature also decreases owing to the combined effect of decreased electrical conductivity and an anisotropic microstructure. An optimal zT value of ∼1.2 is achieved near room temperature for the sample containing 6 at% Ti, and its average zT value below 150 °C increases to ∼1.1, demonstrating the great potential of this material for room-temperature thermoelectric devices.

Apolipoprotein E epsilon 2 allele and low serum cholesterol as risk factors for gastric cancer in a Chinese Han population.

Apolipoprotein E (apoE) mediates lipid metabolism both in peripheral and in the brain. The human APOE gene has three polymorphic alleles that influence the risk for various types of cancer and neurodegenerative diseases. A potential association between APOE allele and the risk for gastric cancer has been implicated, but the specific allele involved and potential associations with the subtype and the grade of cancer malignancy need further clarification. We screened the APOE genotype in 550 gastric cancer patients and 550 non-cancer control individuals and found that the presence of the APOE ε2 and lower serum total cholesterol are associated with an increased risk for gastric cancer (all P ≤ 0.0005). Interestingly, APOE ε2 is also correlated with increased risk for both intestinal and diffuse histotypes but not with TN classification or stage in gastric cancer patients, suggesting that APOE polymorphic alleles are associated with the risk of development but unlikely the progression of gastric cancer. Since ε2 carriers have lower levels of serum total cholesterol than non-ε2 carriers, our findings suggest that the increased risk for gastric cancer by APOE ε2 allele might be mediated through lowered serum total cholesterol levels.

Demographic and Lifestyle Characteristics, but Not Apolipoprotein E Genotype, Are Associated with Intelligence among Young Chinese College Students.

BACKGROUND: Intelligence is an important human feature that strongly affects many life outcomes, including health, life-span, income, educational and occupational attainments. People at all ages differ in their intelligence but the origins of these differences are much debated. A variety of environmental and genetic factors have been reported to be associated with individual intelligence, yet their nature and contribution to intelligence differences have been controversial. OBJECTIVE: To investigate the contribution of apolipoprotein E (APOE) genotype, which is associated with the risk for Alzheimer's disease, as well as demographic and lifestyle characteristics, to the variation in intelligence. METHODS: A total of 607 Chinese college students aged 18 to 25 years old were included in this prospective observational study. The Chinese revision of Wechsler Adult Intelligence Scale (the fourth edition, short version) was used to determine the intelligence level of participants. Demographic and lifestyle characteristics data were obtained from self-administered questionnaires. RESULTS: No significant association was found between APOE polymorphic alleles and different intelligence quotient (IQ) measures. Interestingly, a portion of demographic and lifestyle characteristics, including age, smoking and sleep quality were significantly associated with different IQ measures. CONCLUSIONS: Our findings indicate that demographic features and lifestyle characteristics, but not APOE genotype, are associated with intelligence measures among young Chinese college students. Thus, although APOE ε4 allele is a strong genetic risk factor for Alzheimer's disease, it does not seem to impact intelligence at young ages.