The globally increasing annual incidence of chronic obstructive pulmonary disease (COPD), a common chronic disease, poses a serious risk to public health. Although the exact mechanism underlying the ...pathogenesis of COPD remains unclear, a large number of studies have shown that its pathophysiology and disease course are closely related to oxidative stress, inflammation, apoptosis, autophagy, and aging. The key players involved in COPD include the sirtuin family of NAD-dependent deacetylases that comprise seven members (SIRT1-7) in mammals. Sirtuins play an important role in metabolic diseases, cell cycle control, proliferation, apoptosis, and senescence. Owing to differences in subcellular localization, sirtuins exhibit anisotropy. In this narrative review, we discuss the roles and molecular pathways of each member of the sirtuin family involved in COPD to provide novel insights into the prevention and treatment of COPD and how sirtuins may serve as adjuvants for COPD treatment.
The human nervous system senses the physical world in an analogue but efficient way. As a crucial ability of the human brain, sound localization is a representative analogue computing task and often ...employed in virtual auditory systems. Different from well-demonstrated classification applications, all output neurons in localization tasks contribute to the predicted direction, introducing much higher challenges for hardware demonstration with memristor arrays. In this work, with the proposed multi-threshold-update scheme, we experimentally demonstrate the in-situ learning ability of the sound localization function in a 1K analogue memristor array. The experimental and evaluation results reveal that the scheme improves the training accuracy by ∼45.7% compared to the existing method and reduces the energy consumption by ∼184× relative to the previous work. This work represents a significant advance towards memristor-based auditory localization system with low energy consumption and high performance.
The room‐temperature sodium‐sulfur (RT Na‐S) batteries have been seriously hindered in their practical application due to the sluggish redox kinetics and incomplete conversion of polysulfides. In ...this study, a structure‐determined Keggin‐type heteropolyvanadotungstate of H5PW10V2O40·30H2O (PW10V2) is engineered and reveal its catalytic mechanism in RT Na‐S system. With the assistance of precise V sites and highly reversible multi‐electron redox properties, PW10V2 as a bidirectional molecular catalyst expedites the complete conversions between polysulfides and the insoluble sodium sulfide, while undergoing the reversible transformation between its reduced and oxidized states. Furthermore, PW10V2 with multicenter active sites can capture polysulfides efficiently. Consequently, the cell with the constructed PW10V2‐based modified separator achieves the perdurable cyclability up to 4000 loops even at 10 C toward an exceptionally low capacity decay rate of 0.012% per cycle, far surpassing those of current state‐of‐the‐art RT Na‐S batteries that employ the functional materials based on separator. This work first demonstrates the underlying electrochemical reaction processes of polyoxometalate‐based functional materials, which guides solving the challenging issues related to sodium polysulfides in RT Na‐S batteries.
The structure‐determined Keggin‐type heteropolyvanadotungstate of H5PW10V2O40·30H2O (PW10V2) can function as a bidirectional molecular catalyst to unlock the complete conversions of S8 reduction and Na2S oxidation via two‐step 1, 2‐electron transfer behavior. Moreover, the V active center is more conducive to enhancing the adsorption of PW10V2 for NaPSs, which prominently restrains the shuttle effect of polysulfides.
•A 3D porous microsphere based on COL and BC was prepared by the template method combined with reverse-phase suspension regeneration.•The microspheres effectively promoted the adhesion, ...proliferation, and osteogenic differentiation of mice MC3T3-E1 cells.•The study can provide a theoretical basis for the application of COL/BC porous microspheres in the field of bone tissue engineering.
Collagen (COL) and bacterial cellulose (BC) were chemically recombined by Malaprade and Schiff-base reactions. A three-dimensional (3D) porous microsphere of COL/BC/Bone morphogenetic protein 2 (BMP-2) with multistage structure and components were prepared by the template method combined with reverse-phase suspension regeneration. The microspheres were full of pores and had a rough surface. The particle size ranged from 8 to 12 microns, the specific surface area (SBET) was 123.4 m2/g, the pore volume (VPore) was 0.59 cm3/g, and the average pore diameter (DBJH) was 198.5 nm. The adsorption isotherm of the microspheres on the N2 molecule belongs to that of mesoporous materials. The microspheres showed good biocompatibility, and the 3D porous microspheres with multiple structures and components effectively promoted the adhesion, proliferation, and osteogenic differentiation of mice MC3T3-E1 cells. The study can provide a theoretical basis for the application of COL/BC porous microspheres in the field of bone tissue engineering.
The extracellular space between the cell wall and plasma membrane is a battlefield in plant-pathogen interactions. Within this space, the pathogen employs its secretome to attack the host in a ...variety of ways, including immunity manipulation. However, the role of the plant secretome is rarely studied for its role in disease resistance.
Here, we examined the secretome of Verticillium wilt-resistant Gossypium hirsutum cultivar Zhongzhimian No.2 (ZZM2, encoding 95,327 predicted coding sequences) to determine its role in disease resistance against the wilt causal agent, Verticillium dahliae. Bioinformatics-driven analyses showed that the ZZM2 genome encodes 2085 secreted proteins and that these display disequilibrium in their distribution among the chromosomes. The cotton secretome displayed differences in the abundance of certain amino acid residues as compared to the remaining encoded proteins due to the localization of these putative proteins in the extracellular space. The secretome analysis revealed conservation for an allotetraploid genome, which nevertheless exhibited variation among orthologs and comparable unique genes between the two sub-genomes. Secretome annotation strongly suggested its involvement in extracellular stress responses (hydrolase activity, oxidoreductase activity, and extracellular region, etc.), thus contributing to resistance against the V. dahliae infection. Furthermore, the defense response genes (immunity marker NbHIN1, salicylic acid marker NbPR1, and jasmonic acid marker NbLOX4) were activated to varying degrees when Nicotina benthamiana leaves were agro-infiltrated with 28 randomly selected members, suggesting that the secretome plays an important role in the immunity response. Finally, gene silencing assays of 11 members from 13 selected candidates in ZZM2 displayed higher susceptibility to V. dahliae, suggesting that the secretome members confer the Verticillium wilt resistance in cotton.
Our data demonstrate that the cotton secretome plays an important role in Verticillium wilt resistance, facilitating the development of the resistance gene markers and increasing the understanding of the mechanisms regulating disease resistance.
Despite the substantial burden caused by childhood cancer globally, childhood cancer incidence obtained in a nationwide childhood cancer registry and the accessibility of relevant health services are ...still unknown in China. We comprehensively assessed the most up-to-date cancer incidence in Chinese children and adolescents, nationally, regionally, and in specific population subgroups, and also examined the association between cancer incidence and socioeconomic inequality in access to health services.
In this national cross-sectional study, we used data from the National Center for Pediatric Cancer Surveillance, the nationwide Hospital Quality Monitoring System, and public databases to cover 31 provinces, autonomous regions, and municipalities in mainland China. We estimated the incidence of cancer among children (aged 0–14 years) and adolescents (aged 15–19 years) in China through stratified proportional estimation. We classified regions by socioeconomic status using the human development index (HDI). Incidence rates of 12 main groups, 47 subgroups, and 81 subtypes of cancer were reported and compared by sex, age, and socioeconomic status, according to the third edition of the International Classification of Childhood Cancer. We also quantified the geographical and population density of paediatric oncologists, pathology workforce, diagnoses and treatment institutions of paediatric cancer, and paediatric beds. We used the Gini coefficient to assess equality in access to these four health service indicators. We also calculated the proportions of cross-regional patients among new cases in our surveillance system.
We estimated the incidence of cancer among children (aged 0–14 years) and adolescents (aged 15–19 years) in China from Jan 1, 2018, to Dec 31, 2020. An estimated 121 145 cancer cases were diagnosed among children and adolescents in China between 2018 and 2020, with world standard age-standardised incidence rates of 122·86 (95% CI 121·70–124·02) per million for children and 137·64 (136·08–139·20) per million for adolescents. Boys had a higher incidence rate of childhood cancer (133·18 for boys vs 111·21 for girls per million) but a lower incidence of adolescent cancer (133·92 for boys vs 141·79 for girls per million) than girls. Leukaemias (42·33 per million) were the most common cancer group in children, whereas malignant epithelial tumours and melanomas (30·39 per million) surpassed leukaemias (30·08 per million) in adolescents as the cancer with the highest incidence. The overall incidence rates ranged from 101·60 (100·67–102·51) per million in very low HDI regions to 138·21 (137·14–139·29) per million in high HDI regions, indicating a significant positive association between the incidence of childhood and adolescent cancer and regional socioeconomic status (p<0·0001). The incidence in girls showed larger variation (48·45% from the lowest to the highest) than boys (36·71% from lowest to highest) in different socioeconomic regions. The population and geographical densities of most health services also showed a significant positive correlation with HDI levels. In particular, the geographical density distribution (Gini coefficients of 0·32–0·47) had higher inequalities than population density distribution (Gini coefficients of 0·05–0·19). The overall proportion of cross-regional patients of childhood and adolescent cancer was 22·16%, and the highest proportion occurred in retinoblastoma (56·54%) and in low HDI regions (35·14%).
Our study showed that the burden of cancer in children and adolescents in China is much higher than previously nationally reported from 2000 to 2015. The distribution of the accessibility of health services, as a social determinant of health, might have a notable role in the socioeconomic inequalities in cancer incidence among Chinese children and adolescents. With regards to achieving the Sustainable Development Goals, policy approaches should prioritise increasing the accessibility of health services for early diagnosis to improve outcomes and subsequently reduce disease burdens, as well as narrowing the socioeconomic inequalities of childhood and adolescent cancer.
National Major Science and Technology Projects of China, National Natural Science Foundation of China, Chinese Academy of Engineering Consulting Research Project, Wu Jieping Medical Foundation, Beijing Municipal Administration of Hospitals Incubating Program.
Background Internal tandem duplication (ITD) mutations in the juxtamembrane domain–coding sequence of the Fms-like tyrosine kinase 3 (FLT3) gene have been identified in 30% of acute myeloid leukemia ...(AML) patients and are associated with a poor prognosis. The kinase inhibitor sorafenib induces growth arrest and apoptosis at much lower concentrations in AML cell lines that harbor FLT3-ITD mutations than in AML cell lines with wild-type FLT3. Methods The antileukemic activity of sorafenib was investigated in isogenic murine Ba/F3 AML cell lines that expressed mutant (ITD, D835G, and D835Y) or wild-type human FLT3, in primary human AML cells, and in a mouse leukemia xenograft model. Effects of sorafenib on apoptosis and signaling in AML cell lines were investigated by flow cytometry and immunoblot analysis, respectively, and the in vivo effects were determined by monitoring the survival of leukemia xenograft–bearing mice treated with sorafenib (groups of 15 mice). In a phase 1 clinical trial, 16 patients with refractory or relapsed AML were treated with sorafenib on different dose schedules. We determined their FLT3 mutation status by a polymerase chain reaction assay and analyzed clinical responses by standard criteria. All statistical tests were two-sided. Results Sorafenib was 1000- to 3000-fold more effective in inducing growth arrest and apoptosis in Ba/F3 cells with FLT3-ITD or D835G mutations than in Ba/F3 cells with FLT3-D835Y mutant or wild-type FLT3 and inhibited the phosphorylation of tyrosine residues in ITD mutant but not wild-type FLT3 protein. In a mouse model, sorafenib decreased the leukemia burden and prolonged survival (median survival in the sorafenib-treated group vs the vehicle-treated group = 36.5 vs 16 days, difference = 20.5 days, 95% confidence interval = 20.3 to 21.3 days; P = .0018). Sorafenib reduced the percentage of leukemia blasts in the peripheral blood and the bone marrow of AML patients with FLT3-ITD (median percentages before and after sorafenib: 81% vs 7.5% P = .016 and 75.5% vs 34% P = .05, respectively) but not in patients without this mutation. Conclusion Sorafenib may have therapeutic efficacy in AML patients whose cells harbor FLT3-ITD mutations.
Adhesion G-protein-coupled receptors (aGPCRs) are important for organogenesis, neurodevelopment, reproduction and other processes
. Many aGPCRs are activated by a conserved internal (tethered) ...agonist sequence known as the Stachel sequence
. Here, we report the cryogenic electron microscopy (cryo-EM) structures of two aGPCRs in complex with G
: GPR133 and GPR114. The structures indicate that the Stachel sequences of both receptors assume an α-helical-bulge-β-sheet structure and insert into a binding site formed by the transmembrane domain (TMD). A hydrophobic interaction motif (HIM) within the Stachel sequence mediates most of the intramolecular interactions with the TMD. Combined with the cryo-EM structures, biochemical characterization of the HIM motif provides insight into the cross-reactivity and selectivity of the Stachel sequences. Two interconnected mechanisms, the sensing of Stachel sequences by the conserved 'toggle switch' W
and the constitution of a hydrogen-bond network formed by Q
/Y
and the P
/V
φφG
motif (φ indicates a hydrophobic residue), are important in Stachel sequence-mediated receptor activation and G
coupling. Notably, this network stabilizes kink formation in TM helices 6 and 7 (TM6 and TM7, respectively). A common G
-binding interface is observed between the two aGPCRs, and GPR114 has an extended TM7 that forms unique interactions with G
. Our structures reveal the detailed mechanisms of aGPCR activation by Stachel sequences and their G
coupling.
Solution‐printed organic single‐crystalline films hold great potential for achieving low‐cost manufacturing of large‐area and flexible electronics. For practical applications, organic field‐effect ...transistor arrays must exhibit high performance and small device‐to‐device variation. However, scalable fabrication of highly aligned organic crystalline arrays is rather difficult due to the lack of control over the crystallographic orientation, crystal uniformity, and thickness. Here, a facile solution‐printing method to fabricate centimeter‐sized highly aligned organic crystalline arrays with a thickness of a few molecular layers is reported. In this study, the solution shearing technique is used to produce large‐area, organic highly crystalline thin films. Water‐soluble ink is printed on the hydrophobic surface of organic crystalline films, to selectively protect it, followed by etching. It is shown that the addition of a surfactant dramatically changes the fluid drying dynamics and increases the contact line friction of the aqueous solution to the underlying nonwetting organic crystalline film. As a result, centimeter‐scale highly aligned organic crystalline arrays are successfully prepared on different substrates. The devices based on organic crystalline arrays show good performance and uniformity. This study demonstrates that solution printing is close to industrial application and also expands its applicability to various printed flexible electronics.
A facile method of fabricating centimeter‐scale highly aligned organic semiconductors (OSCs) arrays is developed. The wetting of a water‐soluble resist on the hydrophobic surface of the OSCs is also studied, which is critical to maintain high‐quality printing. The highly aligned OSCs arrays exhibit excellent electrical characteristics, which is promising for industrial applications and expands its applicability to various printed flexible electronics.
Scope
High‐fat‐diet (HFD) is an important factor in obesity. Extracellular matrix (ECM) regulates white adipose tissue (WAT), but its mechanism is unknown.
Methods and Results
This study uses three ...models—HFD‐fed mice, human with obesity, and 3T3‐L1 adipocytes with oleic acid (OA)/macromolecular crowders (MMC) treatment. Glucose and lipids metabolic disorders, increased collagen I/IV and laminin α2/4 (LAMA2/4), and upregulated integrins (ITGA1/ITGA7) – focal adhesion kinase (FAK) – c‐Jun N‐terminal kinase (JNK)/extracellular regulated protein kinase 1/2 (ERK1/2) signals in obese WAT from mice and human are observed. The upregulation of ECM – integrin – FAK signals is stronger in subcutaneous WAT than that in visceral WAT of mice, but these results are reversed in human. In vitro, oleic acid (OA) promotes lipid accumulation and upregulates collagen IV, LAMA4, and p‐JNK. MMC is used to induce ECM deposition in adipocytes. MMC promotes adipocyte differentiation and integrins – FAK – JNK/ERK1/2 signals. When FAK phosphorylation is inhibited, downstream p‐JNK is decreased. Inhibition of FAK phosphorylation reduces adipocyte differentiation, but MMC partially reverses this effect.
Conclusion
HFD‐induced ECM deposition, whose signals are transmitted into adipocytes through upregulating ITGA1/ITGA7, activates the phosphorylation of intracellular FAK – JNK/ERK1/2 signals, and promotes adipogenesis in WAT. This mechanism provides novel therapeutic targets to treat obesity.
High‐fat‐diet‐induced extracellular matrix (ECM, e.g., collagen I/IV, and LAMA2/4) deposition upregulate integrin (ITGA1/ITGA7) expression in adipocytes. Integrins activate the downstream phosphorylation of intracellular FAK – JNK/ERK1/2 signals to promote white adipose tissue (WAT) adipogenesis when obesity occurs. These signals are stronger in subcutaneous WAT than that in visceral WAT of mice, but the results are reversed in human WAT.
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