Cytotoxic T Lymphocyte Antigen-4 Down-Regulates T Helper 1 Cells by Increasing Expression of Signal Transducer and Activator of Transcription 3 in Acute Graft-versus-Host Disease.

Numerous previous studies have suggested that cytotoxic T lymphocyte antigen-4 (CTLA-4) plays an important role in acute graft-versus-host disease (GVHD). How CTLA-4 acts in regulating acute GVHD remains unknown, however. In the present study, we found that, compared with healthy controls, CTLA-4 plasma and relative mRNA levels in patients with acute GVHD were initially decreased and then markedly elevated after 28 days of treatment. CTLA-4 levels were higher in patients with grade I-II acute GVHD compared with those with grade III-IV acute GVHD both before and after treatment. Up-regulation of CTLA-4 significantly increased the luciferase activity and degree of phosphorylation of signal transducer and activator of transcription 3 (STAT3). Meanwhile, T cell activation was significantly inhibited, and levels of IFN-γ, IL-17, and IL-22 decreased. These findings suggest that CTLA-4 might be involved in the pathogenesis of acute GVHD, and may down-regulate T helper 1 cells by increasing STAT3 expression in acute GVHD.

Increased expression of T cell immune response cDNA 7 in patients with acute graft-versus-host disease.

Acute graft-versus-host disease (aGVHD) has become the important complication post-allogeneic hematopoietic stem cell transplantation. Abnormally activated T cells might play an important role in the pathogenesis of aGVHD. But its exact mechanism remains poorly understood. T cell immune response cDNA 7 (TIRC7) has been identified to be essential in T cell activation; however, the role of TIRC7 in aGVHD remains unclear. The purpose of this study was to measure the expression of TIRC7 and T helper (Th) cells in patients with aGVHD before and after treatment. We showed that TIRC7 levels in aGVHD patients were higher than those of healthy controls and markedly declined after treatment. The levels of IFN-γ (Th1), IL-17 (Th17), and IL-22 (Th22) were in accordance with the grade of aGVHD. In addition, TIRC7 levels were also associated with the severity of aGVHD. In conclusion, TIRC7 might be involved in the pathogenesis of aGVHD and TIRC7 level might be an indicator to evaluate the response of patients with aGVHD to treatment.

Direct-coating of cellulose hydrogel on PVDF membranes with superhydrophilic and antifouling properties for high-efficiency oil/water emulsion separation.

As a well-known natural and innocuous plant constituent, cellulose consists of abundant hydroxyl groups and can tightly adsorb onto material surfaces hydrogen bonding, resulting in a superhydrophilic surface. In this work, the hydrophobic polyvinylidene fluoride (PVDF) membranes were modified by immersing them in cellulose hydrogel using a simple one-step process. The modified PVDF membrane exhibited excellent resistance to fouling and oil adhesion, making it highly effective in separating various oil-in-water emulsions. The cellulose-modified PVDF membranes achieved a high oil rejection rate (>99 %) and a maximum separation flux of 2675.2 L·m-2·h-1. Furthermore, even an oil-in-water emulsion containing bovine serum albumin maintained a steady permeation flux after four filtration cycles. Additionally, these cellulose-modified PVDF membranes demonstrated excellent underwater superoleophobicity across a wide range of pH levels and high saline conditions. Overall, these cellulose-modified superhydrophilic PVDF membranes are sustainable, environmentally friendly, easily scalable, and hold great promise for practical applications in oily wastewater treatment.

Rapid solar-driven atmospheric water-harvesting with MAF-4-derived nitrogen-doped nanoporous carbon.

Sorption-based atmospheric water-harvesting (AWH) could help to solve global freshwater scarcity. The search for adsorbents with high water-uptake capacity at low relative humidity, rapid adsorption-desorption kinetics and high thermal conductivity is a critical challenge in AWH. Herein, we report a MAF-4 (aka ZIF-8)-derived nanoporous carbon (NPCMAF-4-800) with multiple N-doped sites, considerable micropore characteristics and inherent photothermal properties, for efficient water production in a relatively arid climate. NPCMAF-4-800 exhibited optimal water-sorption performance of 306 mg g-1 at 40% relative humidity (RH). An excellent sunlight-absorption rate was realized (97%) attributed to its high degree of graphitization. A proof-of-concept device was designed and investigated for the practical harvesting of water from the atmosphere using natural sunlight. NPCMAF-4-800 achieved an unprecedentedly high water production rate of 380 mg g-1 h-1 at 40% RH, and could produce 1.77 L kg-1 freshwater during daylight hours in an outdoor low-humidity climate of ∼25 °C and 40% RH. These findings may shed light on the potential of MOF-derived porous carbons in the AWH field, and inspire the future development of solar-driven water-generation systems.

Molecular basis of JAK2 H608Y and H608N mutations in the pathology of acute myeloid leukemia.

Risk-stratification of acute myeloid leukemia (AML) based on (cyto)genetic aberrations, including hotspot mutations, deletions and point mutations have evolved substantially in recent years. With the development of next-generation sequence technology, more and more novel mutations in the AML were identified. Thus, to unravel roles and mechanism of novel mutations would improve prognostic and predictive abilities. In this study, two novel germline JAK2 His608Tyr (H608Y) and His608Asn (H608N) mutations were identified and the molecular basis of these mutations in the leukemiagenesis of AML was elucidated. Our results indicated that JAK2 H608Y and H608N mutations disrupted the hydrogen bond between Q656 and H608 which reduced the JH2 domain's activity and abolished interactions between JH1 and JH2 domains, forced JAK2 into the active conformation, facilitated the entrance of substrates and thus caused JAK2 hyperactivation. Further studies suggested that JAK2 H608Y and H608N mutations enhanced the cell proliferation and inhibited the differentiation of Ba/F3 and MV4-11 cells via activating the JAK2-STAT5 signaling pathway. Moreover, rescue experiments demonstrated that mutations repaired the hydrogen bond between Q656 and H608 displayed opposite results. Thus, this study revealed the molecular basis of JAK2 H608Y and H608N mutations in the pathology of AML.

The ameliorative effects and mechanisms of abscisic acid on learning and memory.

Abscisic acid (ABA), a conserved hormone existing in plants and animals, not only regulates blood glucose and inflammation but also has good therapeutic effects on obesity, diabetes, atherosclerosis and inflammatory diseases in animals. Studies have shown that exogenous ABA can pass the blood-brain barrier and inhibit neuroinflammation, promote neurogenesis, enhance synaptic plasticity, improve learning, memory and cognitive ability in the central nervous system. At the same time, ABA plays a crucial role in significant improvement of Alzheimer's disease, depression, and anxiety. Here we review the previous research progress of ABA on the physiological effects and clinical application in the related diseases. By summarizing the biological functions of ABA, we aim to reveal the possible mechanisms of ameliorative function of ABA on learning and memory, to provide a theoretical basis that ABA as a novel and safe drug improves learning memory and cognitive impairment in central system diseases such as aging, neurodegenerative diseases and traumatic brain injury.

The latest role of nerve-specific splicing factor PTBP1 in the transdifferentiation of glial cells into neurons.

Central nervous system injury diseases can cause the loss of many neurons, and it is difficult to regenerate. The field of regenerative medicine believes that supplementing the missing neurons may be an ideal method for nerve injury repair. Recent studies have found that down-regulation of polypyrimidine tract binding protein 1 (PTBP1) expression can make glial cells transdifferentiate into different types of neurons, which is expected to be an alternative therapy to restore neuronal function. This article summarized the research progress on the structure and biological function of the PTBP family, the mutual regulation of PTBP1 and PTBP2, their role in neurogenesis, and the latest research progress in targeting PTBP1 to mediate the transdifferentiation of glial cells into neurons, which may provide some new strategies and new ideas for the future treatment of central nervous system injury and neurodegenerative diseases. This article is categorized under: RNA Processing > Splicing Regulation/Alternative Splicing.

Syntaphilin mediates axonal growth and synaptic changes through regulation of mitochondrial transport: a potential pharmacological target for neurodegenerative diseases.

Mitochondria are a crucial energy source for maintaining neuronal growth and synaptic function. Neurons possess unique morphological characteristics, which make the proper regulation of mitochondrial transport essential for meeting their energy demands. Syntaphilin (SNPH) is capable of specifically targeting the outer membrane of axonal mitochondria, anchoring them to microtubules, and thereby preventing their transport. SNPH also interacts with other mitochondrial proteins to regulate mitochondrial transport. The regulation of mitochondrial transport and anchoring mediated by SNPH is indispensable for axonal growth during neuronal development, maintenance of ATP levels during neuronal synaptic activity, and regeneration of mature neurons following damage. Precise blocking of SNPH may be an effective therapeutic strategy for neurodegenerative diseases and related mental disorders.

Effects and mechanisms of tanshinone IIA on PTSD-like symptoms.

BACKGROUND: In recent years, Salvia miltiorrhiza and its active substances have remarkably progressed in treating central neurological disorders. Tanshinone IIA (TSA) is an active ingredient derived from the rhizome of Salvia miltiorrhiza that has been found to alleviate the symptoms of several psychiatric illnesses. Post-traumatic stress disorder (PTSD) is a mental disorder that results after experiencing a serious physical or psychological injury. The currently used drugs are not satisfactory for the treatment of PTSD. However, it has been reported that TSA can improve PTSD-like symptoms like learning and memory, cognitive disorder, and depression through multi-target regulation. PURPOSE: This paper discusses the ameliorative effects of TSA on PTSD-like symptoms and the possible mechanisms of action in terms of inhibition of neuronal apoptosis, anti-neuroinflammation, and anti-oxidative stress. Based on the pathological changes and clinical observations of PTSD, we hope to provide some reference for the clinical transformation of Chinese medicine in treating PTSD. METHODS: A large number of literatures on tanshinone in the treatment of neurological diseases and PTSD were retrieved from online electronic PubMed and Web of Science databases. CONCLUSION: TSA is a widely studied natural active ingredient against mental illness. This review will contribute to the future development of TSA as a new clinical candidate drug for improving PTSD-like symptoms.

The role of RNA splicing factor PTBP1 in neuronal development.

Alternative pre-mRNA splicing, which produces various mRNA isoforms with distinct structures and functions from a single gene, is regulated by specific RNA-binding proteins and is an essential method for regulating gene expression in mammals. Recent studies have shown that abnormal change during neuronal development triggered by splicing mis-regulation is an important feature of various neurological diseases. Polypyrimidine tract binding protein 1 (PTBP1) is a kind of RNA-binding proteins with extensive biological functions. As a well-known splicing regulator, it affects the neuronal development process through its involvement in axon formation, synaptogenesis, and neuronal apoptosis, according to the most recent studies. Here, we summarized the mechanism of alternative splicing, structure and function of PTBP1, and the latest research progress on the role of alternative splicing events regulated by PTBP1 in axon formation, synaptogenesis and neuronal apoptosis, to reveal the mechanism of PTBP1-regulated changes in neuronal development process.

Amino acid residue E543 in JAK2 C618R is a potential therapeutic target for myeloproliferative disorders caused by JAK2 C618R mutation.

Janus kinase 2 (JAK2) is an important mediator of cytokine receptor signaling and plays a key role in the hematopoietic and immune responses. The acquired JAK2 C618R somatic mutation is detected in a subset of myeloproliferative disorders (MPDs) patients and presumed to be a biomarker for MPDs. However, how JAK2 C618R mutation causes MPDs is still unclear. Our results indicate that the amino acid residue E543 in JAK2 C618R is indispensable for its constitutive activation. When the glutamic acid at this position was mutated to alanine (E543A) in the JAK2 C618R, its activity significantly decreased. However when the glutamic acid was mutated to the acidic amino acid, aspartic acid, JAK2 C618R activity changed little. These results suggest that there is an interaction between the amino acid residue R618 and E543, and that this interaction is crucial to sustain the constitutive activation of JAK2 C618R. More importantly, the E543 single mutation had no effects on the function of wild type JAK2 (WT JAK2). This study suggests that the amino acid residue E543 might be a potential target for specific inhibitors to treat MPDs caused by the JAK2 C618R mutation.

Non-covalent functionalization of graphene sheets by pyrene-endcapped tetraphenylethene: Enhanced aggregation-induced emission effect and application in explosive detection.

In this work, a dispersible graphene-based material with a characteristic of aggregation-induced emission (AIE) was prepared by wet chemical reduction of graphene oxide (GO). During the GO reduction process, a conjugated molecule TPEP containing tetraphenylethylene (TPE) and pyrene was employed as a stabilizer because of the π-π interactions and the wrapping effect. The as-prepared rGO-TPEP not only has good dispersion in solution but also processes the AIE feature. Its fluorescence intensity is 2.23 times higher than that of TPEP at the same condition. The unique optical properties and AIE effect enable the rGO-TPEP as a chemical sensor for highly sensitive explosive detection in aggregated state and solid state. In the aggregated state, trace 2,4-dinitrotoluene (DNT) can be detected by the rGO-TPEP even when the concentration is as low as 0.91 ppm, and the quenching constant is as high as 2.47 × 104 M-1.

Preparation and Properties of Thin-Film Composite Forward Osmosis Membranes Supported by Cellulose Triacetate Porous Substrate via a Nonsolvent-Thermally Induced Phase Separation Process.

A porous substrate plays an important role in constructing a thin-film composite forward osmosis (TFC-FO) membrane. To date, the morphology and performance of TFC-FO membranes are greatly limited by porous substrates, which are commonly fabricated by non-solvent induced phase separation (NIPS) or thermally induced phase separation (TIPS) processes. Herein, a novel TFC-FO membrane has been successfully fabricated by using cellulose triacetate (CTA) porous substrates, which are prepared using a nonsolvent-thermally induced phase separation (N-TIPS) process. The pore structure, permeability, and mechanical properties of CTA porous substrate are carefully investigated via N-TIPS process (CTAN-TIPS). As compared with those via NIPS and TIPS processes, the CTAN-TIPS substrate shows a smooth surface and a cross section combining interconnected pores and finger-like macropores, resulting in the largest water flux and best mechanical property. After interfacial polymerization, the obtained TFC-FO membranes are characterized in terms of their morphology and intrinsic transport properties. It is found that the TFC-FO membrane supported by CTAN-TIPS substrate presents a thin polyamide film full of nodular and worm-like structure, which endows the FO membrane with high water permeability and selectivity. Moreover, the TFC-FO membrane supported by CTAN-TIPS substrate displays a low internal concentration polarization effect. This work proposes a new insight into preparing TFC-FO membrane with good overall performance.

A case of 5-aminolevulinic acid photodynamic therapy(ALA-PDT)combined with surgery for the treatment of acne conglobata.

We report the case of a 20-year-old man with acne conglobata (AC) who was treated with 5-aminolevulinic acid photodynamic therapy (ALA-PDT) sequentially to deroofing, and finally used fractional carbon dioxide laser for esthetic requirements, achieving satisfying results. AC is a severe form of acne vulgaris that can lead to significant scarring and has serious negative effects on a patient's psychological well-being and quality of life. Some cases are likely resistant to currently available treatments. This report describes a promising, and effective method for the treatment of AC.

[Relationship between surface dead fuel loadings and environmental factors in southern Jiangxi, China]. / èµ£å—åœ°åŒºæ£®æž—åœ°è¡¨æ­»å¯ç‡ƒç‰©è½½é‡ä¸ŽçŽ¯å¢ƒå› å­çš„å ³ç³».

The distribution pattern of forest fuel loading is driven by the interaction of environmental factors, such as terrain and vegetation. Based on field sampling data of surface dead fuels of seven main forest types in southern Jiangxi Province, and according to the classification standard of different time-lags, we constructed structural equation models to explore the relationship between surface fuel loadings and environmental factors such as terrain and vegetation etc. We analyzed the influence path of each factor and its direct, indirect, and total influence. The results showed that the coniferous and broad-leaved mixed forest had the highest loadings and the Phyllostachys heterocycla pure forest had the lowest loadings for all the 1, 10, and 100 h time-lag fuels. The influencing coefficient of environmental factors for 1 h time-lag fuels were ranked as: slope (0.40) > crown height (0.07) > tree species (-0.03) > canopy closure (0.01). For the 10 h time-lag fuels, the environmental factors were ranked as: diameter at breast height (0.15) >tree species (-0.09) > aspect (-0.08) > canopy closure (-0.06). For the 100 h time-lag fuels, the environmental factors were ranked as: aspect (0.25) > diameter at breast height (0.19) > canopy closure (-0.08) > tree species (0.02). The influencing coefficient of environmental factors for the total fuels were ranked as: slope (0.22) > tree species (-0.04), canopy closure (-0.04) > crown height (-0.01).

Combination of RSK inhibitor LJH-685 and FLT3 inhibitor FF-10101 promoted apoptosis and proliferation inhibition of AML cell lines.

PURPOSE: FLT3 mutations occurred in approximately one third of patients with acute myeloid leukemia (AML). FLT3-ITD mutations caused the constitutive activation of the RAS/MAPK signaling pathway. Ribosomal S6 Kinases (RSKs) were serine/threonine kinases that function downstream of the Ras/Raf/MEK/ERK signaling pathway. However, roles and mechanisms of RSKs inhibitor LJH-685, and combinational effects of LJH-685 and FLT3 inhibitor FF-10101 on AML cells were till unclear. METHODS: Cell viability assay, CFSE assay, RT-qPCR, Colony formation assay, PI stain, Annexin-V/7-AAD double stain, Western blot, and Xenogeneic transplantation methods were used to used to investigate roles and mechanisms of LJH-685 in the leukemogenesis of AML. RESULTS: LJH-685 inhibited the proliferation and clone formation of AML cells, caused cell cycle arrest and induced the apoptosis of AML cells via inhibiting the RSK-YB-1 signaling pathway. MV4-11 and MOLM-13 cells carrying FLT3-ITD mutations were more sensitive to LJH-685 than that of other AML cell lines. Further studies suggested that LJH-685 combined with Daunorubicin or FF- 10101 synergistically inhibited the cell viability, promoted the apoptosis and caused cycle arrest of AML cells carrying FLT3-ITD mutations. Moreover, in vivo experiments also indicated that LJH-685 combined with FF-10101 or Daunorubicin prolonged the survival time of NSG mice and reduced the leukemogenesis of AML. CONCLUSION: Thus, these observations demonstrated combination of RSK inhibitor LJH-685 and FLT3 inhibitor FF-10101 showed synergism anti-leukemia effects in AML cell lines with FLT3-ITD mutations via inhibiting MAPK-RSKs-YB-1 pathway and provided new targets for therapeutic intervention especially for AML with FLT3-ITD mutations and Daunorubicin-resistant AML.

Effects of the PLK4 inhibitor Centrinone on the biological behaviors of acute myeloid leukemia cell lines.

Polo-like kinase 4 (PLK4), a key regulator of centriole biogenesis, is frequently overexpressed in cancer cells. However, roles and the mechanism of PLK4 in the leukemiagenesis of acute myeloid leukemia (AML) remain unclear. In this study, the PLK4 inhibitor Centrinone and the shRNA knockdown were used to investigate roles and the mechanism of PLK4 in the leukemiagenesis of AML. Our results indicated that Centrinone inhibited the proliferation of AML cells in a dose- and time-dependent manner via reduced the expression of PLK4 both in the protein and mRNA levels. Moreover, colony formation assay revealed that Centrinone reduced the number and the size of the AML colonies. Centrinone induced AML cell apoptosis by increasing the activation of Caspase-3/poly ADP-ribose polymerase (PARP). Notably, Centrinone caused the G2/M phase cell cycle arrest by decreasing the expression of cell cycle-related proteins such as Cyclin A2, Cyclin B1, and Cyclin-dependent kinase 1 (CDK1). Consistent with above results, knockdown the expression of PLK4 also inhibited cell proliferation and colony formation, induced cell apoptosis, and caused G2/M phase cell cycle arrest without affecting cell differentiation. All in all, this study suggested that PLK4 inhibited the progression of AML in vitro, and these results herein may provide clues in roles of PLK4 in the leukemiagenesis of AML.

Impact of inter-subunit interactions on the dimeric arginine kinase activity and structural stability.

Arginine kinase (AK) is a key enzyme for cellular energy metabolism, catalyzing the reversible phosphoryl transfer from phosphoarginine to ADP in invertebrates. In this study, the inter-subunit hydrogen bonds between the Q53 and D200 and between D57 and D200 were disrupted to explore their roles in the activity and structural stability of Stichopus japonicus (S. japonicus) AK. Mutating Q53 and/or D57 to alanine (A) can cause pronounced loss of activity and substrate synergism, and cause distinct conformational changes. Spectroscopic experiments indicated that mutations destroying the inter-subunit hydrogen bonds impaired the structure of dimer AK, and resulted in a partially unfolded state. The inability to fold to the functional compact state made the mutants prone to be inactivated and aggregate under environmental stresses. Restoring hydrogen bonds in Q53E and D57E mutants could rescue the loss of activity and substrate synergism, and conformational changes. All those results suggested that the inter-subunit interactions played a key role in keeping the activity, substrate synergism and structural stability of dimer AK. The result herein may provide a clue in understanding the folding and self-assembly processes of oligomeric proteins.

[Analysis of Related Early Warning Indexes of Cytokine Release Syndrome in Multiple Myeloma Patients after CAR-T Treatment].

OBJECTIVE: To investigate the relationship between the levels of ferritin, C-reactive protein (CRP), lactate dehydrogenase (LDH) and interleukin-6 (IL-6) in peripheral serum and cytokine release syndrome (CRS) in patients with relapse and/or refractory multiple myeloma (R/R MM) after receiving chimeric antigen receptor T cells (CAR-T) immunotherapy. METHODS: Twenty-eight patients with R/R MM were treated with 1×106/kg humanized CD19 CAR-T and mouse B cell maturation antigen CAR-T cells after pretreatment chemotherapy based on fludarabine and cyclophosphamide. The concentrations of ferritin, CRP, LDH, and IL-6 in peripheral blood were measured regularly within 30 days after infusion, and the correlation between severity of CRS and above indexes was analyzed. RESULTS: Among the 28 patients, 27 cases (96.4%) developed CRS, 24 cases (85.7%) in 1-2 grade CRS and 3 cases (10.7%) in 3-5 grade. The severity grade of CRS of 27 patients was positively correlated with the peak values of ferritin, CRP, LDH, and IL-6 in peripheral blood (r1=0.511, r2=0.375, r3=0.480, r4=0.632). The median peak values of ferritin, CRP, LDH and IL-6 in peripheral serum of patients with grade 3-5 CRS were significantly higher than those in patients with grade 0-2 CRS. CONCLUSION: After receiving CAR-T cellular immunotherapy, the incidence of CRS in patients with R/R MM is higher, but most of them are in grade 1 or 2. The severity of CRS is positively correlated with the levels of ferritin, CRP, LDH and IL-6 in peripheral blood.

Overexpression of chloroplastic monodehydroascorbate reductase enhanced tolerance to temperature and methyl viologen-mediated oxidative stresses.

A tomato (Lycopersicon esculentum Mill.) monodehydroascorbate reductase gene (LeMDAR) was isolated. The LeMDAR-green fluorescence protein (GFP) fusion protein was targeted to chloroplast in Arabidopsis mesophyll protoplast. RNA and protein gel blot analyses confirmed that the sense- and antisense- LeMDAR were integrated into the tomato genome. The MDAR activities and the levels of reduced ascorbate (AsA) were markedly increased in sense transgenic lines and decreased in antisense transgenic lines compared with wild-type (WT) plants. Under low and high temperature stresses, the sense transgenic plants showed lower level of hydrogen peroxide (H(2)O(2)), lower thiobarbituric acid reactive substance (TBARS) content, higher net photosynthetic rate (P(n)), higher maximal photochemical efficiency of PSII (F(v)/F(m)) and fresh weight compared with WT plants. The oxidizable P700 decreased more obviously in WT and antisense plants than that in sense plants at chilling temperature under low irradiance. Furthermore, the sense transgenic plants exhibited significantly lower H(2)O(2) level, higher ascorbate peroxidase (APX) activity, greater P(n) and F(v)/F(m) under methyl viologen (MV)-mediated oxidative stresses. These results indicated that overexpression of chloroplastic MDAR played an important role in alleviating photoinhibition of PSI and PSII and enhancing the tolerance to various abiotic stresses by elevating AsA level.