Novel Compound Heterogeneous Mutations in CYB5R3 Gene Leading to Methemoglobinemia (Type I) in a Chinese Boy: Case Report and Relevant Comprehensive Analysis.

INTRODUCTION: Recessive congenital methemoglobinemia (RCM) caused by CYB5R3 deficiency due to the mutations in the reduced nicotinamide adenine dinucleotide (NADH) cytochrome b5 reductase (CYB5R) gene is an autosomal recessive inherited disease. Clinically, it can be divided into two types, namely red blood cell affected type (RCM I) and systemically affected type (RCM II). CASE PRESENTATION: A 5-year-old male patient was diagnosed with cyanosis for 5 years. Physical examination showed cyanosis in areas such as the lips, fingers, and toes. Laboratory examination revealed low pulse oxygen saturation (81%) and increased blood methemoglobin (23.6%). Gene testing revealed the compound heterozygous mutations in the CYB5R3 gene, c.149G>A (p.Arg50Gln) and c.331A>G (p.Lys111Glu), respectively originating from his parents. By constructing 3D models of CYB5R3 wild-type and mutant types using SWISS-MODEL software, it was found that the mutation caused significant structural abnormalities in the CYB5R protein. The relationship between CYB5R3 gene mutation sites, amino acid change, enzyme activity, and methemoglobinemia type I and II were listed and analyzed. CONCLUSION: A case of congenital RCM type I caused by compound heterozygous mutations in the CYB5R3 gene was reported, with c.331A>G (p.Lys111Glu) being the newly reported mutation. The homozygosity or heterozygosity of CYB5R3 gene mutations that lead to premature termination, loss of exons, and change in amino acid properties in FAD or NADH binding domains, is positively correlated with the severity (from type I to type II) of methemoglobinemia.

The forkhead box protein P3 gene rs3761548 promoter polymorphism confers a genetic contribution to the risk of preeclampsia: A systematic review and meta-analysis.

Various studies have investigated the risk of preeclampsia with the forkhead box protein P3 (FOXP3) gene rs2232365 and rs3761548 polymorphisms. However, the results remained contradictory. A comprehensive literature search was conducted using the Cochrane Library, PubMed, and Web of Science (up to Oct 11, 2021). Meta-analysis was carried out in the R language environment for statistical computing and graphics. A fixed-effect or random-effects model was used according to the statistical significance of heterogeneity among included studies. The pooled odds ratios and corresponding 95% confidence intervals were calculated to estimate the strength of the effect. For the rs2232365 polymorphism, statistical significance was detected neither in the overall population nor among the East Asian and West Asian subgroups. However, for rs3761548, the summarized statistics revealed a significant association between the C allele carriage and preeclampsia risk in the homozygote, heterozygote, and dominant models. The further stratified analysis found this effect might be specific to West-South Asian ethnic subgroups. To sum up, this meta-analysis showed that the FOXP3 rs3761548 polymorphism was significantly associated with preeclampsia susceptibility, and it had a deleterious effect especially in the West-South Asian population. In contrast, rs2232365 may serve as neither a protective nor a risk factor for preeclampsia onset.

Increasing prevalence of gestational diabetes mellitus when carrying the T variant allele of the MTHFR gene C677T polymorphism: a systematic review and meta-analysis.

PURPOSE: Previous epidemiological data linking the C677T and A1298C MTHFR polymorphisms to gestational diabetes risk have been mixed and controversial. Therefore, we conducted this meta-analysis to derive a more precise estimation of the relationship between MTHFR polymorphisms and this pregnancy disorder. METHODS: A systematic literature search for original epidemiological studies was performed in the CNKI, WanFang, Cochrane Library, PubMed, and Web of Science databases. R language-based programs were employed for all statistical analyses. Odds ratios and corresponding 95% confidence intervals were calculated to estimate the effects of the variant allele on gestational diabetes risk. RESULTS: A summary of the estimates for the C677T polymorphism showed that the exposure cohorts were prone to gestational diabetes by a greater magnitude than the control groups. Further subgroup analysis by ethnicity showed that the Asians carrying the variant T allele were more susceptible to this pregnancy disorder. However, the pathogenic effect was not evident in the non-Asian subgroup. For the A1298C polymorphism, no statistical significance could be detected. CONCLUSION: This meta-analysis suggests that the T allele of the MTHFR gene C677T polymorphism tends to increase gestational diabetes susceptibility, especially for Asians. However, the A1298C polymorphism is not associated with an increased risk of this crippling pregnancy disorder.

Salvianolic Acid B Protects Cardiomyocytes from Ischemia/Reperfusion Injury by Mediating circTRRAP/miR-214-3p/SOX6 Axis.

Circular RNAs (circRNAs) are a class of powerful regulators of gene expression. This study aimed to determine whether circTRRAP (hsa_circ_0081241) was implicated in the cardioprotective effects of salvianolic acid B (Sal B) against myocardial ischemia/reperfusion (I/R) injury and its associated mechanism.Cell viability was analyzed using Cell Counting Kit-8 (CCK-8), and flow cytometry was conducted to evaluate cell cycle progression and cell apoptosis. The leakage of lactic dehydrogenase (LDH), production of malondialdehyde (MDA), and activity of superoxide dismutase (SOD) were measured using their corresponding commercial kits to analyze cell death and oxidative stress.I/R treatment suppressed viability and cell cycle progression and induced the apoptosis and oxidative stress of AC16 cardiomyocytes, whereas Sal B protected AC16 cardiomyocytes against I/R injury. I/R upregulated circTRRAP expression, whereas Sal B dose-dependently reduced the circTRRAP level in AC16 cardiomyocytes. The protective effects of Sal B in I/R-induced AC16 cardiomyocytes were overturned by the overexpression of circTRRAP. CircTRRAP negatively regulated miR-214-3p expression by binding to it in AC16 cardiomyocytes. The circTRRAP overexpression-mediated effects were reversed by the addition of miR-214-3p mimics in AC16 cardiomyocytes. MiR-214-3p targeted the 3'-untranslated region (3'UTR) of SOX6, and SOX6 was regulated by the circTRRAP/miR-214-3p axis in AC16 cardiomyocytes. SOX6 knockdown overturned the circTRRAP overexpression-induced effects in AC16 cardiomyocytes.In conclusion, the silence of circTRRAP was implicated in Sal B-mediated cardioprotective effects against I/R injury by regulating the miR-214-3p/SOX6 axis.

Risk factors of tumor lysis syndrome in relapsed/refractory multiple myeloma patients undergoing BCMA CAR-T cell therapy.

OBJECTIVE: To investigate the risk factors of tumor lysis syndrome (TLS) in relapsed/refractory multiple myeloma (MM) patients undergoing B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cell therapy. METHOD: The clinical data of 99 relapsed/refractory MM patients receiving BCMA CAR-T cell therapy in the First Affiliated Hospital, Zhejiang University School of Medicine from July 2018 to December 2021 were collected in this study. Univariate analysis and multivariate logistic regression were performed to evaluate the risk factors of TLS following BCMA CAR-T cell therapy. RESULTS: Among the 99 patients, TLS occurred in 17 cases (17.2%) with an onset time of (8.9±3.0) d after BCMA CAR-T cell therapy. All TLS patients developed TLS-related clinical manifestations, including 17 cases with renal dysfunction, 8 cases with arrhythmia. All TLS patients developed cytokine release syndrome (CRS) with an onset of 1.0 (1.0, 6.5) d after CAR-T cell therapy, and 13 cases developed grade 3-4 CRS. The levels of serum uric acid, serum creatinine and the ratio of cases with grade 3-4 CRS were significantly higher in TLS patients than in non-TLS patients (all P<0.05). Multivariate logistic regression revealed that serum creatinine ( OR=1.015, P<0.01) and severe CRS ( OR=9.371, P<0.01) were independent risk factors of TLS. CONCLUSIONS: Relapsed/refractory MM patients undergoing BCMA CAR-T therapy shows high incidence of TLS, which are related to elevated levels of serum creatinine and severe CRS. TLS can be prevented clinically by reducing serum creatinine and controlling CRS severity.

Octanuclear Cobalt(II) Cluster-Based Metal-Organic Framework with Caged Structure Exhibiting the Selective Adsorption of Ethane over Ethylene.

A novel metal-organic framework (MOF) of [Co8(OH)4(TCA)4(H2O)4]n (abbreviation: JXNU-9) based on the unique octanuclear Co8(µ3-OH)4 clusters linked by 4,4',4″-nitrilotribenzoate (TCA3-) ligands featuring small caged structures and one-dimensional channels was prepared and characterized. JXNU-9 shows a high C2H6 uptake capacity of 3.60 mmol g-1 (4.46 mmol cm-3) at 298 K and 1 atm with a small isosteric heat of adsorption (23.6 kJ mol-1) and a moderate C2H6/C2H4 adsorption selectivity of 1.7, resulting in excellent C2H6/C2H4 separation performance. The pore walls decorated by plenty of aromatic rings provide π-electron-cloud-surrounding environments to accommodate the large polarizable C2H6 molecules. The calculations demonstrate that the rich π-systems in JXNU-9 facilitate an adsorption affinity for large C2H6 molecules through multiple C-H···π interactions. Additionally, the open metal sites located in the concave pores with a close Co···Co separation (4.21 Å) in octanuclear Co8(µ3-OH)4 clusters make the open metal sites inaccessible for the C2H4 molecule with a kinetic diameter of 4.163 Å. Thus, the annihilation of open metal sites in this structure is achieved, which further facilitates the C2H6-selective C2H6/C2H4 separation.

Long non-coding RNA HOTAIR regulates myeloid differentiation through the upregulation of p21 via miR-17-5p in acute myeloid leukaemia.

Long non-coding RNA HOTAIR has been reported to play a key role in regulating various biological processes in various cancers. However, the roles and mechanisms of HOTAIR in acute myeloid leukaemia (AML) are still unclear and need to be investigated. In this study, we induced differentiation of four AML cell lines by all-trans retinoic acid (ATRA) and found HOTAIR was significantly upregulated in the process. Chromatin immunoprecipitation (ChIP) assays indicated that C/EBPß upregulated HOTAIR during ATRA induced differentiation in HL-60 cells. By gain- and loss-of-function analysis, we then observed that HOTAIR expression was positively correlated with ATRA-induced differentiation and negatively regulated G1 phase arrest in HL-60 cells. In addition, we found that HOTAIR promoted ATRA-induced differentiation via the regulation of the cell cycle regulator p21 via miR-17-5p. Moreover, we detected the expression of HOTAIR in 84 de novo AML patients, HOTAIR was found significantly downregulated in the AML patients compared to the iron deficiency anaemia (IDA) control group, negatively correlated with the platelet level in M2 patients. In all, our data suggest that HOTAIR may be subtype-specific in AML-M2 patients, also HOTAIR regulates AML differentiation by C/EBPBß/HOTAIR/miR-17-5p/p21 pathway. The findings of the present study provide a novel insight into the mechanism of lncRNA-mediated differentiation and indicate that HOTAIR may be a promising therapeutic target for leukaemia, especially for AML with M2 type.Abbreviation: AML: acute myeloid leukaemia; APL: acute promyelocytic leukaemia; ATRA: all-trans retinoic acid; CCK8: cell Counting Kit-8; CDKs: cyclin-dependent kinases ; CeRNA: competing endogenous RNAs; ChIP: chromatin immunoprecipitation; CHX: cycloheximide; FAB: French-American-British; FCM: flow cytometry; HOTAIR: HOX transcript antisense RNA; IDA: iron-deficiency anemia; lncRNA: long non-coding RNA; 3'UTR: 3'untranslated region; MT: Mutation type; WT: Wild type; qRT-PCR: Quantitative real-time PCR.

Integrative analysis of hub genes and key pathway in two subtypes of diffuse large B-cell lymphoma by bioinformatics and basic experiments.

BACKGROUND: The germinal center B-cell (GCB) and activated B-cell (ABC) subtypes of diffuse large B-cell lymphoma (DLBCL) have a significant difference in prognosis. This study aimed to identify potential hub genes, and key pathways involved in them. METHODS: Databases including Gene Expression Omnibus (GEO), Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and STRING were accessed to obtain potential crucial genes and key pathways associated with the GCB and ABC. Then qRT-PCR and Western blot experiments were performed to verify the most clinically significant gene and pathway. RESULTS: Three cohort datasets from the GEO database were analyzed, including 195 GCB and 169 ABC samples. We identified 1113 differentially expressed genes (DEGs) between the GCB and ABC subtypes. The DEGs were mainly enriched in biological processes (BP). The KEGG analysis showed enrichment in cell cycle and Wnt signaling pathways. We selected the top 10 genes using the STRING database and Cytoscape software. We used 5 calculation methods of the cytoHubba plugin, and found 3 central genes (IL-10, CD44, CCND2). CCND2 was significantly related to the prognosis of DLBCL patients. Besides, our experimental results demonstrated a significantly higher expression of CCND2 in the ABC-type cell line than in the GCB-type; it was proportional to the expression of key proteins in the Wnt signaling pathway. CONCLUSION: CCND2 overexpression and Wnt pathway activation might be the main reasons for the poor prognosis of ABC-DLBCL.

Lanthanide 5,7-Disulfonate-1,4-naphthalenedicarboxylate Frameworks Constructed from Trinuclear and Tetranuclear Lanthanide Carboxylate Clusters: Proton Conduction and Selective Fluorescent Sensing of Fe3.

The novel sulfonate-carboxylate ligand of 5,7-disulfonate-1,4-naphthalenedicarboxylic acid (H4-DSNPDC) was synthesized, and its series of lanthanide compounds {[Ln3(µ2-OH)(DSNPDC)2(H2O)x]·yH2O}n (JXNU-7; Ln = La3+, x = 10. y = 4; Ln = Nd3+, Sm3+ Eu3+, x = 9, y = 2) and {[Ln4(µ3-OH)4(DSNPDC)2(H2O)11]·28H2O}n (JXNU-8; Ln = Eu3+, Gd3+) are presented. JXNU-7 is a three-dimensional structure based on linear trinuclear Ln3 building units, while JXNU-8 has a two-dimensional layer constructed from tetranuclear Ln4(µ3-OH)4 building units. The representative Eu compounds of JXNU-7 and -8 show good proton conductive properties under high humidity. The hydrophilic sulfonate groups pointing to the pores and the water molecules included in the pores mainly contribute to the high proton conductivity for the materials. The presence of one-dimensional infinite hydrogen-bonded networks in channels of JXNU-7(Eu) facilitates a fast and efficient proton transfer, resulting in higher proton conductivity in comparison to that of JXNU-8(Eu). Additionally, JXNU-7(Eu) with a characteristic red emission exhibits a promising potential for selective sensing of Fe3+ ions in aqueous solution. Our work demonstrates the integration of functional organic components (sulfonate groups) and inorganic components (lanthanide centers) in MOFs for the successful preparation of multifunctional MOF materials.

Nerve injury elevates functional Cav3.2 channels in superficial spinal dorsal horn.

Cav3 channels play an important role in modulating chronic pain. However, less is known about the functional changes of Cav3 channels in superficial spinal dorsal horn in neuropathic pain states. Here, we examined the effect of partial sciatic nerve ligation (PSNL) on either expression or electrophysiological properties of Cav3 channels in superficial spinal dorsal horn. Our in vivo studies showed that the blockers of Cav3 channels robustly alleviated PSNL-induced mechanical allodynia and thermal hyperalgesia, which lasted at least 14 days following PSNL. Meanwhile, PSNL triggered an increase in both mRNA and protein levels of Cav3.2 but not Cav3.1 or Cav3.3 in rats. However, in Cav3.2 knockout mice, PSNL predominantly attenuated mechanical allodynia but not thermal hyperalgesia. In addition, the results of whole-cell patch-clamp recordings showed that both the overall proportion of Cav3 current-expressing neurons and the Cav3 current density in individual neurons were elevated in spinal lamina II neurons from PSNL rats, which could not be recapitulated in Cav3.2 knockout mice. Altogether, our findings reveal that the elevated functional Cav3.2 channels in superficial spinal dorsal horn may contribute to the mechanical allodynia in PSNL-induced neuropathic pain model.

Estrogen stimulates SREBP2 expression in hepatic cell lines via an estrogen response element in the SREBP2 promoter.

OBJECTIVE: Hypoestrogenism in women is strongly associated with menopause and it can lead to lipid disorder, which predisposes people to premature cardiovascular disease. However, the mechanism of lipid disorder remains unclear. Sterol regulatory element-binding protein 2 (SREBP2) is the key transcription factor regulating cholesterol metabolism. We hypothesize that estrogen regulates SREBP2 transcription through an estrogen response element (ERE) in the SREBP2 promoter region. METHODS: Human hepatoblastoma cells (HepG2) were treated with dose-dependent concentrations of estradiol (E2) for 24 h. Then, SREBP2 expression was determined via real-time PCR and immunofluorescence. The expressions of the SREBP2 downstream target genes HMGCR and LDLR were determined via real-time PCR. Lipid secretion in the culture media of HepG2 cells was measured using ELISA. Through bioinformatics analysis, we identified high-scoring ERE-like sequences in the SREBP2 gene promoter. Chromatin immunoprecipitation analysis was used to confirm the ERE. DNA fragments of the putative or mutated ERE-like sequence were synthesized and ligated into pGL3-basic plasmid to construct the SREBP2 promoter luciferase reporter systems. SREBP2-Luciferase (SREBP2-Luc), SREBP2-Mutation (SREBP2-Mut) and the blank control were transfected into hepatic cell lines. Luciferase activities were measured using the dual-luciferase reporter assay system. Chromatin immunoprecipitation analysis and the luciferase reporter assay were repeated in human hepatoma cells (HuH-7). RESULTS: We found that E2 dose-dependently increased the expression of SREBP2 in HepG2 cells and that the increased levels were blocked when treated with an estrogen receptor-alpha antagonist. Additionally, E2 increased both HMGCR and LDLR expression and lipid secretion in HepG2 cells. Notably, we identified a functional ERE in the SREBP2 gene promoter, to which E2 could specifically bind and induce transcription. CONCLUSIONS: An ERE was identified in the SREBP2 gene promoter. It mediates the regulation of SREBP2 expression by estrogen in hepatocytes. This study provides a mechanism to link cardiovascular disease with estrogen.

A bibliometric analysis of the global research in ankylosing spondyloarthritis (2008-2017).

The current study was to investigate the quantity and quality of researches in the field of ankylosing spondylitis, and to reveal the characteristics of worldwide productivity on this disease. This was a bibliometric study on ankylosing spondylitis using Web of Science. The numbers of papers, citations, research output normalized by population and gross domestic product, and the main active countries were analyzed. A total number of 7239 papers were published between 2008 and 2017. The yearly number of papers published during this period showed a significant increase (p < 0.001). North America, West Europe and East Asia were the main regions for AS papers. High-income countries contributed the greatest proportion of papers (70.49%). The research productivity from middle- and low-income countries was low (29.45%; 0.06%). The United States was the country with the greatest contributions between 2008 and 2017 (12.47%), followed by China (12.17%), Turkey (8.34%), Germany (7.82%), and the United Kingdom (5.97%). Significantly positive correlations were proved between the number of papers and population/gross domestic product (p < 0.05). From 2013, the number of AS publications by the authors from China exceeded those from the United States. However, China had far less total citations (7219 vs. 22,043) and average citations (8.19 vs. 24.41) than the United States. Denmark had the greatest productivity when normalized by population, followed by Norway, and Netherlands. When normalized by gross domestic product, Denmark led the top list, followed by Netherlands, and Greece. Papers from Australia showed the highest average citation (32.64), followed by Netherlands (31.63), and Germany (26.88). The current study showed a noticeable growth in global research output on ankylosing spondylitis between 2008 and 2017. High-income countries especially the United States had the greatest contributions. The contributions from middle- and low-income countries were considerably small. The number of papers published by countries was positively associated with their population and gross domestic product. Although China had exceeded the United States in the quantity of yearly AS publications, the quality of papers from China was lower compared to the United States. European countries may have better performance relative to their population and economic size.

Effects of cadmium exposure on expression of glutathione synthetase system genes in Acidithiobacillus ferrooxidans.

The glutathione synthetase system (GSS) is an important pathway of glutathione synthesis and plays a key role in heavy metal resistance. In this work, the response of Acidithiobacillus ferrooxidans to extracellular Cd2+ was investigated, and the interplay between Cd2+ resistance and the expression of GSS related-genes was analyzed by reverse-transcription quantitative PCR (RT-PCR). During growth in the presence of 5, 15 and 30 mM Cd2+, the transcript levels of eight GSS pathway genes were affected between 0.81- and 7.12-fold. Increased transcription was also reflected in increased enzyme activities: with those of glutathione reductase (GR) increased by 1.10-, 2.26- and 1.54-fold in the presence of 5, 15 and 30 mM Cd2+, respectively. In contrast, the activities of catalase (CAT) and superoxide dismutase (SOD) were decreased in the presence of Cd2+. At the metabolite level, intracellular methane dicarboxylic aldehyde (MDA) content was increased 1.97-, 3.31- and 1.92-fold in the presence of 5, 15 and 30 mM Cd2+, respectively. These results suggest that Cd2+ directly inhibits the activities of CAT and SOD, breaks the redox balance of the cells, which leads to the activation of the other antioxidant pathway of GSS. Resistance of A. ferrooxidans to Cd2+ may involve modulation of expression levels of glutathione S-transferase (GST), GR, and glutathione synthetase, which may protect against oxidative damage.

A Type of Low-Latency Data Gathering Method with Multi-Sink for Sensor Networks.

To balance energy consumption and reduce latency on data transmission in Wireless Sensor Networks (WSNs), a type of low-latency data gathering method with multi-Sink (LDGM for short) is proposed in this paper. The network is divided into several virtual regions consisting of three or less data gathering units and the leader of each region is selected according to its residual energy as well as distance to all of the other nodes. Only the leaders in each region need to communicate with the mobile Sinks which have effectively reduced energy consumption and the end-to-end delay. Moreover, with the help of the sleep scheduling and the sensing radius adjustment strategies, redundancy in network coverage could also be effectively reduced. Simulation results show that LDGM is energy efficient in comparison with MST as well as MWST and its time efficiency on data collection is higher than one Sink based data gathering methods.

Altered thyroid hormone profile in offspring after exposure to high estradiol environment during the first trimester of pregnancy: a cross-sectional study.

BACKGROUND: The increasing number of babies conceived by in vitro fertilization and embryo transfer (IVF-ET) shifts concern from pregnancy outcomes to long-time health of offspring. Maternal high estradiol (E2) is a major characteristic of IVF-ET and lasts throughout the first trimester of pregnancy. The fetal thyroid develops during this period and may thus be affected by exposure to the supra-physiological E2. The aim of this study is to investigate whether the high E2 maternal environment in the first trimester increases the risk of thyroid dysfunction in children born following IVF-ET. METHODS: A cross-sectional survey design was used to carry out face-to-face interviews with consecutive children attending the hospital. A total of 949 singletons born after fresh embryo transfer (ET) (n=357), frozen ET (n=212), and natural conception (NC) (n=380), aged 3 to 10 years old, were included. All children were thoroughly examined. Meanwhile, another 183 newborns, including 55 fresh ET, 48 frozen ET, and 80 NC were studied. Levels of serum T3, FT3, T4, FT4, and TSH and levels of maternal E2 at different stages of the first trimester were examined. RESULTS: The mean serum E2 levels of women undergoing fresh ET during the first trimester of pregnancy were significantly higher than those of the women undergoing frozen ET or following NC. The thyroid hormone profile, especially the levels of T4, FT4, and TSH, were significantly increased in 3- to 10-year-old children conceived by fresh ET compared to NC. The same tendency was confirmed in newborns. However, levels of T4 and TSH in the frozen ET group were nearer to that of the NC group. Furthermore, levels of T4 and FT4 in fresh ET were positively correlated with maternal serum levels of E2 during early pregnancy. CONCLUSIONS: The maternal high E2 environment in the first trimester is correlated with increased risk of thyroid dysfunction. Frozen ET could reduce risks of thyroid damage in children conceived by IVF. Further studies are needed to confirm these findings and to better determine the underlying molecular mechanisms and clinical significance. TRIAL REGISTRATION: ChicCTR-OCC-14004682 (22-05-2014).

Visible-light-mediated metal-free regioselective oxidative C-C bond cleavage of lignin dimers to aromatic acids.

The upgrading of lignin is a sustainable and promising pathway for fossil-based aromatic compounds but always faces low selectivity. Herein, a metal-free photocatalyst, 2,4,6-triphenylpyrylium tetrafluoroborate (TPP), was illustrated to remarkably facilitate the regioselective oxidative Cα-Cß bond cleavage of ß-1 and ß-O-4 lignin alcohol/ketone models into aromatic acids (92-99% yields) under visible-light irradiation at room temperature without any additive/co-catalyst, which was enabled by the synergistic effect of Cß-H⋯C(TPP) interaction and·Ë™O2-/1O2 species. The synergy of the catalyst-substrate interaction and active species offers a reference for the enhancive and selective transformation of polymeric biomass and complex molecules.

Alleviation of behavioral deficits, amyloid-ß deposition, and mitochondrial structure damage associated with mitophagy upregulation in AD animal models via AAV9-IGF-1 treatment.

By safeguarding the neurological system, insulin-like growth factor 1 (IGF-1) may have a role in the etiology of Alzheimer's disease (AD). The mechanism and signaling route, however, remain unclear. This research aimed to investigate the impact of IGF-1 on AD as well as its possible mechanism and signaling route. In this work, intracerebroventricular AAV9-IGF-1 was delivered to APP/PS1 transgenic mice. Following therapy, the Morris water maze and passive avoidance tests were administered to evaluate spatial learning and memory. The elevated plus maze, the open field test, and the sucrose preference test were used to evaluate anxious-depressive-like behavior. Thioflavin S staining was employed to visualize Aß deposition, and ELISA was used to determine the quantities of soluble Aß1-40 and Aß1-42. Transmission electron microscopy was used to view the mitochondrial structure and mitophagy vesicles. The protein expression levels of PINK1, Parkin, and LC3-II/LC3-I were finally determined by Western blotting. AAV9-IGF-1 therapy enhanced spatial learning and memory, relieved anxious-depressive-like behavior impairments, lowered amyloid-ß deposition, and decreased levels of soluble Aß1-40 and Aß1-42. In addition, AAV9-IGF-1 therapy restored mitochondrial integrity and increased the number of mitophagy in transgenic mice expressing APP/PS1. These results indicate that IGF-1 is protective for APP/PS1 mice. The mechanism of the favorable benefits mediated by IGF-1 was connected to an increase in mitophagy, which might give a novel therapy target in the future.

Biomimetic Hydrogel Containing Copper Sulfide Nanoparticles and Deferoxamine for Photothermal Therapy of Infected Diabetic Wounds.

Inducing cell migration from the edges to the center of a wound, promoting angiogenesis, and controlling bacterial infection are very important for diabetic wound healing. Incorporating growth factors and antibiotics into hydrogels for wound dressing is considered a potential strategy to meet these requirements. However, some present drawbacks greatly slow down their development toward application, such as the short half-life and high price of growth factors, low antibiotic efficiency against drug-resistant bacteria, insufficient ability of hydrogels to promote cell migration, etc. Deferoxamine (DFO) can upregulate the expression of HIF-1α, thus stimulating the secretion of angiogenesis-related endogenous growth factors. Copper sulfide (CuS) nanoparticles possess excellent antibacterial performance combined with photothermal therapy (PTT). Herein, DFO and CuS nanoparticles are incorporated into a biomimetic hydrogel, which mimics the structure and function of the extracellular matrix (ECM), abbreviated as DFO/CuS-ECMgel. This biomimetic hydrogel is expected to be able to promote cell adhesion and migration, be degraded by cell-secreted matrix metalloproteinases (MMPs), and then release DFO and CuS nanoparticles at the wound site to exert their therapeutic effects. As a result, the three crucial requirements for diabetic wound healing, "beneficial for cell adhesion and migration, promoting angiogenesis, effectively killing drug-resistant bacteria," can be achieved simultaneously.

A novel machine learning-derived four-gene signature predicts STEMI and post-STEMI heart failure.

High mortality and morbidity rates associated with ST-elevation myocardial infarction (STEMI) and post-STEMI heart failure (HF) necessitate proper risk stratification for coronary artery disease (CAD). A prediction model that combines specificity and convenience is highly required. This study aimed to design a monocyte-based gene assay for predicting STEMI and post-STEMI HF. A total of 1,956 monocyte expression profiles and corresponding clinical data were integrated from multiple sources. Meta-results were obtained through the weighted gene co-expression network analysis (WGCNA) and differential analysis to identify characteristic genes for STEMI. Machine learning models based on the decision tree (DT), support vector machine (SVM), and random forest (RF) algorithms were trained and validated. Five genes overlapped and were subjected to the model proposal. The discriminative performance of the DT model outperformed the other two methods. The established four-gene panel (HLA-J, CFP, STX11, and NFYC) could discriminate STEMI and HF with an area under the curve (AUC) of 0.86 or above. In the gene set enrichment analysis (GSEA), several cardiac pathogenesis pathways and cardiovascular disorder signatures showed statistically significant, concordant differences between subjects with high and low expression levels of the four-gene panel, affirming the validity of the established model. In conclusion, we have developed and validated a model that offers the hope for accurately predicting the risk of STEMI and HF, leading to optimal risk stratification and personalized management of CAD, thereby improving individual outcomes.

Impaired Detoxification of Trans, Trans-2,4-Decadienal, an Oxidation Product from Omega-6 Fatty Acids, Alters Insulin Signaling, Gluconeogenesis and Promotes Microvascular Disease.

Omega-6 fatty acids are the primary polyunsaturated fatty acids in most Western diets, while their role in diabetes remains controversial. Exposure of omega-6 fatty acids to an oxidative environment results in the generation of a highly reactive carbonyl species known as trans, trans-2,4-decadienal (tt-DDE). The timely and efficient detoxification of this metabolite, which has actions comparable to other reactive carbonyl species, such as 4-hydroxynonenal, acrolein, acetaldehyde, and methylglyoxal, is essential for disease prevention. However, the detoxification mechanism for tt-DDE remains elusive. In this study, the enzyme Aldh9a1b is identified as having a key role in the detoxification of tt-DDE. Loss of Aldh9a1b increased tt-DDE levels and resulted in an abnormal retinal vasculature and glucose intolerance in aldh9a1b-/- zebrafish. Transcriptomic and metabolomic analyses revealed that tt-DDE and aldh9a1b deficiency in larval and adult zebrafish induced insulin resistance and impaired glucose homeostasis. Moreover, alterations in hyaloid vasculature is induced by aldh9a1b knockout or by tt-DDE treatment can be rescued by the insulin receptor sensitizers metformin and rosiglitazone. Collectively, these results demonstrated that tt-DDE is the substrate of Aldh9a1b which causes microvascular damage and impaired glucose metabolism through insulin resistance.