ß-Thalassemia gene editing therapy: Advancements and difficulties.

ß-Thalassemia is the world's number 1 single-gene genetic disorder and is characterized by suppressed or impaired production of ß-pearl protein chains. This results in intramedullary destruction and premature lysis of red blood cells in peripheral blood. Among them, patients with transfusion-dependent ß-thalassemia face the problem of long-term transfusion and iron chelation therapy, which leads to clinical complications and great economic stress. As gene editing technology improves, we are seeing the dawn of a cure for the disease, with its reduction of ineffective erythropoiesis and effective prolongation of survival in critically ill patients. Here, we provide an overview of ß-thalassemia distribution and pathophysiology. In addition, we focus on gene therapy and gene editing advances. Nucleic acid endonuclease tools currently available for gene editing fall into 3 categories: zinc finger nucleases, transcription activator-like effector nucleases, and regularly interspaced short palindromic repeats (CRISPR-Cas9) nucleases. This paper reviews the exploratory applications and exploration of emerging therapeutic tools based on 3 classes of nucleic acid endonucleases in the treatment of ß-thalassemia diseases.

Effects of aeration modes and rates on nitrogen conversion and bacterial community in composting of dehydrated sludge and corn straw.

Aeration is an important factor to regulate composting efficiency and nitrogen loss. This study is aimed to compare the effects of different aeration modes (continuous and intermittent) and aeration rate on nitrogen conversion and bacterial community in composting from dehydrated sludge and corn straw. Results showed that the intermittent aeration mode at same aeration volume was superior to the continuous aeration mode in terms of NH3 emission reduction, nitrogen conversion and germination index (GI) improvement. Intermittent aeration mode with 1200 L/h (aeration 5 min, stop 15 min) [K5T15 (V1200)] and 300 L/h of continuous aeration helped to the conservation of nitrogen fractions and accelerate the composting process. However, it was most advantageous to use 150 L/h of continuous aeration to reduce NH3 emission and ensure the effective composting process. The aeration mode K5T15 (V1200) showed the fastest temperature rise, the longer duration of thermophilic stage and the highest GI (95%) in composting. The cumulative NH3 emission of intermittent aeration mode was higher than continuous aeration mode. The cumulative NH3 emission of V300 was 23.1% lower than that of K5T15 (V1200). The dominant phyla in dehydrated sludge and corn straw composting were Firmicutes, Proteobacteria, Actinobacteria, and Bacteroidetes. The dominant phylum in the thermophilic stage was Firmicutes (49.39%~63.13%), and the dominant genus was Thermobifida (18.62%~30.16%). The relative abundance of Firmicutes was greater in the intermittent aeration mode (63.13%) than that in the continuous aeration mode (57.62%), and Pseudomonas was dominant in composting with lower aeration rate and the lowest NH3 emission. This study suggested that adjustment to the aeration mode and rate could affect core bacteria to reduce the nitrogen loss and accelerate composting process.

Potential of novel iron 1,3,5-benzene tricarboxylate loaded on biochar to reduce ammonia and nitrous oxide emissions and its associated biological mechanism during composting.

In this study, a novel iron 1,3,5-benzene tricarboxylate loaded on biochar (BC-FeBTC) was developed and applied to kitchen waste composting. The results demonstrated that the emissions of NH3 and N2O were significantly reduced by 57.2% and 37.8%, respectively, compared with those in control group (CK). Microbiological analysis indicated that BC-FeBTC addition altered the diversity and abundance of community structure as well as key functional genes. The nitrification genes of ammonia-oxidizing bacteria were enhanced, thereby promoting nitrification and reducing the emission of NH3. The typical denitrifying bacterium, Pseudomonas, and critical functional genes (nirS, nirK, and nosZ) were significantly inhibited, contributing to reduced N2O emissions. Network analysis further revealed the important influence of BC-FeBTC in nitrogen transformation driven by functional microbes. These findings offer crucial scientific foundation and guidance for the application of novel materials aimed at mitigating nitrogen loss and environmental pollution during composting.

Seeing Is Not Necessarily Believing: Is the Surface-Enhanced Raman Spectroscopy Signal Really from the Target?

Reagent purity is crucial to experimental research, considering that the ignorance of ultratrace impurities may induce wrong conclusions in either revealing the reaction nature or qualifying the target. Specifically, in the field of surface science, the strong interaction between the impurity and the surface will bring a non-negligible negative effect. Surface-enhanced Raman spectroscopy (SERS) is a highly surface-sensitive technique, providing fingerprint identification and near-single molecule sensitivity. In the SERS analysis of trace chloromethyl diethyl phosphate (DECMP), we figured out that the SERS performance of DECMP is significantly distorted by the trace impurities from DECMP. With the aid of gas chromatography-based techniques, one strongly interfering impurity (2,2-dichloro-N,N-dimethylacetamide), the byproduct during the synthesis of DECMP, was confirmed. Furthermore, the nonignorable interference of impurities on the SERS measurement of NaBr, NaI, or sulfadiazine was also observed. The generality ignited us to refresh and consolidate the guideline for the reliable SERS qualitative analysis, by which the potential misleading brought by ultratrace impurities, especially those strongly adsorbed on Au or Ag surfaces, could be well excluded.

Alterations in factors associated with diabetic retinopathy combined with thrombosis: A review.

Diabetic retinopathy (DR) is one of the most common and serious microvascular complications of diabetes mellitus, the incidence of which has been increasing annually, and it is the main cause of vision loss in diabetic patients and a common cause of blindness. It is now found that thrombosis plays a crucial role in the disease progression in DR patients, and the final vision loss in DR may be related to the occurrence of thrombosis in the retinal vessels, which is dominated by abnormal endothelial cell function, together with platelet dysfunction, imbalance of coagulation and fibrinolytic function, and related alterations of inflammatory factors leading to the main cause of thrombotic disease in DR patients. In this review, we examine the role between DR and thrombosis and the association of each factor, including endothelial dysfunction; platelet dysfunction; coagulation-fibrinolytic imbalance; and alterations in inflammatory factors.

Ticlopidine induces embryonic development toxicity and hepatotoxicity in zebrafish by upregulating the oxidative stress signaling pathway.

Ticlopidine exerts its anti-platelet effects mainly by antagonizing platelet p2y12 receptors. Previously, a few studies have shown that ticlopidine can induce liver injury, but the exact mechanism of hepatotoxicity remains unclear. Oxidative stress, metabolic disorders, hepatocyte apoptosis, lipid peroxidation, and inflammatory responses can all lead to hepatic liver damage, which can cause hepatotoxicity. In this study, in order to deeply explore the potential molecular mechanisms of ticlopidine -induced hepatotoxicity, we used zebrafish as a model organism to comprehensively evaluate the hepatotoxicity of ticlopidine and its associated mechanism. Three days post-fertilization, zebrafish larvae were exposed to varying concentrations (1.5, 1.75 and 2 µg/mL) of ticlopidine for 72 h, in contrast, adult zebrafish were exposed exposure to 4 µg/mL of ticlopidine for 28 days. Ticlopidine-exposed zebrafish larvae showed changes in liver morphology, shortened body length, and delayed development of the swim bladder development. Liver tissues of ticlopidine-exposed zebrafish larvae and adults stained with Hematoxylin & Eosin revealed vacuolization and increased cellular interstitial spaces in liver tissues. Furthermore, using Oil Red O and periodic acid-Schiff staining methods and evaluating different metabolic enzymes of ticlopidine-exposed zebrafish larvae and adults suggested abnormal liver metabolism and liver injury in both ticlopidine-exposed zebrafish larvae and adults. Ticlopidine also significantly elevated inflammation and oxidative stress and reduced hepatocyte proliferation. During the rescue intervention using N-acetylcysteine, we observed significant improvement in ticlopidine-induced morphological changes in the liver, shortened body length, delayed swim bladder development, and proliferation of liver tissues showed significant improvement. In conclusion, ticlopidine might inhibit normal development and liver proliferation in zebrafish by upregulation of oxidative stress levels, thus leading to embryonic developmental toxicity and hepatotoxicity. In this study, we used zebrafish as a model organism to elucidate the developmental toxicity and hepatotoxicity induced by ticlopidine upregulation of oxidative stress signaling pathway in zebrafish, providing a theoretical basis for clinical application.

Isobaric Stable Isotope N-Phosphorylation Labeling (iSIPL) for Ultrasensitive Proteome Quantification.

Stable isotope chemical labeling methods have been widely used for high-throughput mass spectrometry (MS)-based quantitative proteomics in biological and clinical applications. However, the existing methods are far from meeting the requirements for high sensitivity detection. In the present study, a novel isobaric stable isotope N-phosphorylation labeling (iSIPL) strategy was developed for quantitative proteome analysis. The tryptic peptides were selectively labeled with iSIPL tag to generate the novel reporter ions containing phosphoramidate P-N bond with high intensities under lower collision energies. iSIPL strategy are suitable for peptide sequencing and quantitative analysis with high sensitivity and accuracy even for samples of limited quantity. Furthermore, iSIPL coupled with affinity purification and mass spectrometry was applied to measure the dynamics of cyclin dependent kinase 9 (CDK9) interactomes during transactivation of the HIV-1 provirus. The interaction of CDK9 with PARP13 was found to significantly decrease during Tat-induced activation of HIV-1 gene transcription, suggesting the effectiveness of iSIPL strategy in dynamic analysis of protein-protein interaction in vivo. More than that, the proposed iSIPL strategy would facilitate large-scale accurate quantitative proteomics by increasing multiplexing capability.

High oil content inhibits humification in food waste composting by affecting microbial community succession and organic matter degradation.

Composting is an effective technology to realize resource utilization of food waste in rural China. However, high oil content in food waste limits composting humification. This study investigated the effects of blended plant oil addition at different proportions (0, 10, 20, and 30%) on the humification of food waste composting. Oil addition at 10%-20% enhanced lignocellulose degradation by 16.6%-20.8% and promoted humus formation. In contrast, the high proportion of oil (30%) decreased the pH, increased the electrical conductivity, and reduced the seed germination index to 64.9%. High-throughput sequencing showed that high oil inhibited the growth and reproduction of bacteria (Bacillus, Fodinicurvataceae, and Methylococcaceae) and fungi (Aspergillus), attenuated their interaction, thus, reducing the conversion of organic matter, such as lignocellulose, fat, and total sugar, to humus, consequently leading to negative impacts on composting humification. The results can guide composting parameter optimization and improve effective management of rural food waste.

Nickel-Catalyzed Radical Ring-Opening Phosphorylation of Cycloalkyl Hydroperoxides Leading to Distal Acylphosphine Oxides.

A facile and efficient nickel-catalyzed C-C bond cleavage/phosphorylation of various cycloalkyl hydroperoxides was developed. This radical ring-opening strategy provided practical access to structurally diverse distal ketophosphine oxides in one pot through concurrent C═O/C-P bond formation with high atom economy under mild room temperature and base-free conditions.

An Efficient Fisher Matrix Approximation Method for Large-Scale Neural Network Optimization.

Although the shapes of the parameters are not crucial for designing first-order optimization methods in large scale empirical risk minimization problems, they have important impact on the size of the matrix to be inverted when developing second-order type methods. In this article, we propose an efficient and novel second-order method based on the parameters in the real matrix space [Formula: see text] and a matrix-product approximate Fisher matrix (MatFisher) by using the products of gradients. The size of the matrix to be inverted is much smaller than that of the Fisher information matrix in the real vector space [Formula: see text]. Moreover, by utilizing the matrix delayed update and the block diagonal approximation techniques, the computational cost can be controlled and is comparable with first-order methods. A global convergence and a superlinear local convergence analysis are established under mild conditions. Numerical results on image classification with ResNet50, quantum chemistry modeling with SchNet, and data-driven partial differential equations solution with PINN illustrate that our method is quite competitive to the state-of-the-art methods.

Neutrophils: As a Key Bridge between Inflammation and Thrombosis.

Immunothrombosis is a mechanism of defense of the organism against pathogenic microorganisms that increases their recognition, limitation, and clearance and is part of the innate immune defense. Physiological immunothrombosis is beneficial to the body against the invasion of pathogenic microorganisms, but when immunothrombosis is out of control, it is easy to cause thrombotic diseases, thus, causing unpredictable consequences to the body. Neutrophils play a pivotal role in this process. Understanding the mechanism of neutrophils in immune thrombosis and out-of-control is particularly important for the treatment of related thrombotic diseases. In this review, we studied the role of neutrophils in immune thrombosis and each link out of control (including endothelial cell dysfunction; activation of platelets; activation of coagulation factor; inhibition of the anticoagulation system; and inhibition of the fibrinolysis system).

A Combined Experimental and Computational Study on the Adsorption Sites of Zinc-Based MOFs for Efficient Ammonia Capture.

Ammonia (NH3) is a common pollutant mostly derived from pig manure composting under humid conditions, and it is absolutely necessary to develop materials for ammonia removal with high stability and efficiency. To this end, metal-organic frameworks (MOFs) have received special attention because of their high selectivity of harmful gases in the air, resulting from their large surface area and high density of active sites, which can be tailored by appropriate modifications. Herein, two synthetic metal-organic frameworks (MOFs), 2-methylimidazole zinc salt (ZIF-8) and zinc-trimesic acid (ZnBTC), were selected for ammonia removal under humid conditions during composting. The two MOFs, with different organic linkers, exhibit fairly distinctive ammonia absorption behaviors under the same conditions. For the ZnBTC framework, the ammonia intake is 11.37 mmol/g at 298 K, nine times higher than that of the ZIF-8 framework (1.26 mmol/g). In combination with theoretical calculations, powder XRD patterns, FTIR, and BET surface area tests were conducted to reveal the absorption mechanisms of ammonia for the two materials. The adsorption of ammonia on the ZnBTC framework can be attributed to both physical and chemical adsorption. A strong coordination interaction exists between the nitrogen atom from the ammonia molecule and the zinc atom in the ZnBTC framework. In contrast, the absorption of ammonia in the ZIF-8 framework is mainly physical. The weak interaction between the ammonia molecule and the ZIF-8 framework mainly results from the inherent severely steric hindrance, which is related to the coordination mode of the imidazole ligands and the zinc atom of this framework. Therefore, this study provides a method for designing promising MOFs with appropriate organic linkers for the selective capture of ammonia during manure composting.

Effect of Ca2+ cross-linking on the properties and structure of lutein-loaded sodium alginate hydrogels.

In order to construct nano-lutein hydrogels with sustained release properties, the basic properties and structure of nano-lutein hydrogels cross-linked with different concentrations of Ca2+ were investigated. The results showed that the highest loading capacity for lutein reached 770.88 µg/g, while the encapsulation efficiency was as high as 99.39%. When Ca2+ concentration was lower than 7.5 mM, the filling of lutein nanoparticles reduced the hardness and gumminess of the hydrogel. The resilience and cohesiveness of the hydrogel decreased as the concentration of Ca2+ increased. Filling with lutein nanoparticles and increasing Ca2+ concentration both increased the G' and G″. The hydrogel loaded with lutein showed different swelling properties in different pH environments, the filling of lutein nanoparticles inhibited the swelling of the hydrogel. When Ca2+ concentration was greater than 7.5 mM, the cut-off amount of lutein on the surface of the Ca2+ cross-linked hydrogel was larger. The digestive enzymes quickly degraded the hydrogel structure, resulting in a high initial release of lutein. DSC and FTIR results showed that lutein nanoparticles were mainly physically trapped in the hydrogel network structure. Lutein nanoparticles and excessive Ca2+ affected the stability of cross-linked ionic bonds in the hydrogel, thereby reducing its thermodynamic stability.

Novisyntrophococcus fermenticellae gen. nov., sp. nov., isolated from an anaerobic fermentation cellar of Chinese strong-flavour baijiu.

A Gram-stain-negative, coccus-shaped, obligately anaerobic, non-motile and non-spore-forming bacterium, designated strain JN500902T, was isolated from the mud in a fermentation cellar used continuously over 30 years for Chinese strong-flavour baijiu production. Colonies were white, circular, convex and smooth-edged. Growth was observed at 20-40 °C (optimum, 37 °C), at pH 5.0-10 (optimum, pH 7.5), with 0-2 % (w/v) NaCl and with 0-4 % (v/v) ethanol. The Biolog assay demonstrated positive reactions of strain JN500902T in the metabolism of l-fucose and pyruvate. The predominant cellular fatty acids (>10 %) consisted of C16 : 0 and C14 : 0. The major end metabolites of strain JN500902T were acetic acid and ethanol when incubated anaerobically in liquid reinforced clostridial medium. Acetate was the major organic acid end product. The complete genome size of strain JN500902T was 3 420 321 bp with 3327 identified genes. The G+C content was 43.5 mol%. Phylogenetic analysis based on 16S rRNA gene sequences affiliated strain JN500902T with the family Lachnospiraceae, having low sequence similarity (92.8 %) to the nearest type strain, Syntrophococcus sucromutans DSM 3224T and forming a clearly distinct branch. Core genome phylogenetic analysis of the isolate and 134 strains belonging to the family Lachnospiraceae also revealed that strain JN500902T was well-separated from other genera of this family as a monophyletic clade. The average nucleotide identity and amino acid identity values between strain JN500902T and 134 Lachnospiraceae strains were less than 74 and 65 %, respectively. Considering its polyphasic characteristics, strain JN500902T represents a novel genus and species within the family Lachnospiraceae, for which the name Novisyntrophococcus fermenticellae gen. nov., sp. nov. is proposed. The type strain is JN500902T (=CICC 24502T=JCM 33939T).

Palladium-catalyzed C-P cross-coupling of allenic alcohols with H-phosphonates leading to 2-phosphinoyl-1,3-butadienes.

The first facile, efficient, atom-economical and regioselective palladium-catalyzed direct C-P cross-coupling of unprotected allenic alcohols with H-phosphonates for the one-pot synthesis of structurally diverse multisubstituted 2-phosphinoyl-1,3-butadienes was developed. This strategy would enrich the allene chemistry and afford new scaffolds to construct complex molecular skeletons.

Genetic variants in MIR17HG affect the susceptibility and prognosis of glioma in a Chinese Han population.

BACKGROUND: lncRNA MIR17HG was upregulated in glioma, and participated in promoting proliferation, migration and invasion of glioma. However, the role of MIR17HG polymorphisms in the occurrence and prognosis of glioma is still unclear. METHODS: In the study, 592 glioma patients and 502 control subjects were recruited. Agena MassARRAY platform was used to detect the genotype of MIR17HG polymorphisms. Logistic regression analysis was used to evaluate the relationship between MIR17HG single nucleotide polymorphisms (SNPs) and glioma risk by odds ratio (OR) and 95% confidence intervals (CIs). Kaplan-Meier curves, Cox hazards models were performed for assessing the role of these SNPs in glioma prognosis by hazard ratios (HR) and 95% CIs. RESULTS: We found that rs7318578 (OR = 2.25, p = 3.18 × 10- 5) was significantly associated with glioma susceptibility in the overall participants. In the subgroup with age <  40 years, rs17735387 (OR = 1.53, p = 9.05 × 10- 3) and rs7336610 (OR = 1.35, p = 0.016) were related to the higher glioma susceptibility. More importantly, rs17735387 (HR = 0.82, log-rank p = 0.026) were associated with the longer survival of glioma patients. The GA genotype of rs17735387 had a better overall survival (HR = 0.75, log-rank p = 0.013) and progression free survival (HR = 0.73, log-rank p = 0.032) in patients with I-II glioma. We also found that rs72640334 was related to the poor prognosis (HR = 1.49, Log-rank p = 0.035) in female patients. In the subgroup of patients with age ≥ 40 years, rs17735387 was associated with a better prognosis (HR = 0.036, Log-rank p = 0.002). CONCLUSION: Our study firstly reported that MIR17HG rs7318578 was a risk factor for glioma susceptibility and rs17735387 was associated with the longer survival of glioma among Chinese Han population, which might help to enhance the understanding of MIR17HG gene in gliomagenesis. In subsequent studies, we will continue to collect samples and follow up to further validate our findings and further explore the function of these MIR17HG SNPs in glioma in a larger sample size.

[Differences of the structure, succession and function of Clostridial communities between jiupei and pit mud during Luzhou-flavour baijiu fermentation].

Clostridia inhabiting in jiupei and pit mud plays key roles in the formation of flavour during the fermentation process of Luzhou-flavour baijiu. However, the differences of Clostridial communities between jiupei and pit mud remains unclear. Here, the species assembly, succession, and metabolic capacity of Clostridial communities between jiupei and pit mud were analysed by high-throughput sequencing and pure culture approaches. The ratio of Clostridial biomass to bacterial biomass in the pit mud was relatively stable (71.5%-91.2%) throughout the fermentation process. However, it varied widely in jiupei (0.9%-36.5%). The dominant Clostridial bacteria in jiupei were Clostridium (19.9%), Sedimentibacter (8.8%), and Hydrogenispora (7.2%), while Hydrogenispora (57.2%), Sedimentibacter (5.4%), and Caproiciproducens (4.9%) dominated in the Clostridial communities in pit mud. The structures of Clostridial community in pit mud and jiupei were significantly different (P=0.001) throughout fermentation. Isolated Clostridial strains showed different metabolic capacities of volatile fatty acids in pure culture. Spatial and temporal heterogeneity of Clostridial communities existed in the baijiu fermentation pit, which was closely related to the main flavour components of Luzhou-flavour baijiu.

TfOH-Catalyzed Phosphinylation of 2,3-Allenols into γ-Ketophosphine Oxides.

The first facile and efficient acid-catalyzed direct coupling of a wide range of unprotected 2,3-allenols with arylphosphine oxides was developed, offering a general, one-step approach for the synthesis of structurally diverse γ-ketophosphine oxides accompanied by concurrent C-P/C═O bond formation with remarkable functional group tolerance and complete atom-economy under metal- and additive-free conditions. Mechanistic studies showed that this transformation involved a rearrangement and a phospha-Michael reaction.

Insights into bacterial diversity in compost: Core microbiome and prevalence of potential pathogenic bacteria.

Fertilizer-replacement programs by the ministry of agriculture and rural affairs are extraordinary actions for environment protection and sustainable agriculture in China. A national-level survey was performed to acquire consensuses of bio-physiochemical properties for composts. A total of 116 compost samples collected from 16 provinces in China were analyzed by high throughput sequencing of bacterial 16S rRNA gene amplicons. The germination index and bacterial alpha-diversity were lower in composts from poultry manure than others. This large-scale survey revealed that bacterial communities were distinct among different composts and slightly explained by pH, moisture and total nitrogen, but not by raw material or composting process. Nevertheless, 26 OTUs affiliated with Firmicutes (Cerasibacillus, Atopostipes and Bacillus) and Actinobacteria (Thermobifida, Actinomadura and Nocardiopsis) were present in most (>90%) composts and majority of these bacterial species were possibly associated with the biodegradation of organic materials. Surprisingly, 629 potential human or animal bacterial pathogens accounting an average of 1.21% of total 16S rRNA gene were detected and these bacteria were mainly affiliated with Helicobacter, Staphylococcus, Acinotobacter, Streptococcus, Mycobacterium and Enterococcus. In summary, this study provides baseline data for the diversity and abundance of core microbiome and potential pathogens in composts.