Base Editors-Mediated Gene Therapy in Hematopoietic Stem Cells for Hematologic Diseases.

Base editors, developed from the CRISPR/Cas system, consist of components such as deaminase and Cas variants. Since their emergence in 2016, the precision, efficiency, and safety of base editors have been gradually optimized. The feasibility of using base editors in gene therapy has been demonstrated in several disease models. Compared with the CRISPR/Cas system, base editors have shown great potential in hematopoietic stem cells (HSCs) and HSC-based gene therapy, because they do not generate double-stranded breaks (DSBs) while achieving the precise realization of single-base substitutions. This precise editing mechanism allows for the permanent correction of genetic defects directly at their source within HSCs, thus promising a lasting therapeutic effect. Recent advances in base editors are expected to significantly increase the number of clinical trials for HSC-based gene therapies. In this review, we summarize the development and recent progress of DNA base editors, discuss their applications in HSC gene therapy, and highlight the prospects and challenges of future clinical stem cell therapies.

Is Reaction Acceleration of Microdroplet Chemistry Favorable to Controlling the Enantioselectivity?

Microdroplet chemistry has been proven to amazingly accelerate many chemical and biological reactions in the past 2 decades. Current microdroplet accelerated reactions are predominantly symmetric synthetic but minorly asymmetric synthetic reactions, where stereoselectivity is scarcely concerned. This study selected unimolecular and bimolecular reactions, multicomponent Passerini reactions, and enzymatic ketone reduction as the model reactions to illustrate whether reaction acceleration of microdroplet chemistry is favorable to retaining a chiral center and controlling the enantioselectivity or not. The results illustrated that microdroplet chemistry did not disrupt pre-existing stereogenic centers in chiral starting materials during reactions but did harm to stereospecificity in asymmetric catalysis by chiral catalysts and chiral organic ligands with the exclusion of enzymatic reactions. Our preliminary study reminds us of more cautions to the product enantioselectivity when conducting asymmetric catalysis in microdroplets. We also hope this study may promote more valuable further research on the stereoselectivity of microdroplet chemistry.

Microdroplet Chemistry Accelerating a Three-Component Passerini Reaction for α-Acyloxy Carboxamide Synthesis.

α-Acyloxy carboxamides are important multifunctional natural products that show bioactive and pharmacological activities. Traditional three-component Passerini reactions among isocyanates, aldehydes/ketones, and carboxylic acids for affording α-acyloxy carboxamides suffer from several drawbacks such as long reaction time, high reaction temperature, special reaction devices, etc. Herein, we developed a high-efficiency microdroplet method for accelerating the Passerini reactions by 3 orders of magnitude by comparing with the rate constants in bulk, achieving high-yield and gram-scale (scaling up to 1.91 g for 1 h collection) synthesis of α-acyloxy carboxamides at near room temperature. The Passerini microdroplet method shows a wide scope for a variety of benzoic acids, aryl aldehydes, and isocyanates. Moreover, the Passerini reaction was poorly conducted in aqueous microdroplets but well accelerated in acetonitrile microdroplets with at least 230 times efficiency than on-water Passerini reactions. All results proved it an attractive alternative to classic organic synthesis for the construction of α-acyloxy carboxamides and derivatives.

Catalyst-Free Accelerated Three-Component Synthesis of Betti Bases in Microdroplets.

Due to their important roles in medicine and asymmetric metal catalysis, the formation of Betti bases has attracted wide interest in organic chemical community. Traditional multicomponent reaction methods for synthesizing Betti bases normally require long reaction times under harsh conditions (high temperature, microwave or ultrasonic irradiation, etc.) in the presence of various catalysts. In this study, we developed a mild, highly efficient and environmentally friendly method to synthesize Betti bases without the use of any catalysts in microdroplets. The Betti reaction was accelerated by 6.53×103 in microdroplets by comparing the measured rate constant in bulk. Fifteen Betti bases were synthesized by the microdroplet method using a variety of aldehydes, naphthols and amines with 68-98 % yields at a scaled-up amount of 1.9 g h-1 . Overall it is an attractive alternative to classic organic synthesis for the construction of Betti bases and derivatives.

Effect of noise on hearing loss among workers in a fastener manufacturing enterprise / 预防医学

Objective @#To investigate the current status of hearing loss in a fastener manufacturing enterprise, and to analyze its influencing factors, so as to provide insights into occupational disease prevention and control. @*Methods@#The occupational health examination data of noise exposed workers and the workplace occupational disease hazard factors detection data in a fastener manufacturing enterprise in Jiaxing City in 2022 were collected through the Occupational Disease and Occupational Health Hazard Factors Detection System of China Disease Prevention and Control Information System, and factors affecting the development of high-frequency noise-induced hearing loss (HFNIHL) and speech-frequency noise-induced hearing loss (SFNIHL) were analyzed. @*Results@#Totally 625 workers were investigated, with a median age of 44.00 (interquartile range, 13.00) years and a median length of service of 8.00 (interquartile range, 9.00) years, and including 519 men (83.04%) and 106 women (16.96%). There were 309 workers with single noise exposure (49.44%) and 316 workers with joint noise exposure (50.56%), and 518 workers exposed to noise with the normalized continuous A-weighted sound pressure level equivalent to a 40 h working week (LEX,40 h) that exceeded the national standard (82.88%). The detection rates of HFNIHL and SFNIHL were 49.12% and 35.04%, respectively. Multivariable logistic regression analysis indicated that males (OR=10.528, 95%CI: 5.271-21.025), length of service of 10 years and longer (OR=2.451, 95%CI: 1.599-3.759), LEX,40 h of >85 dB (A) (OR=2.227, 95%CI: 1.318-3.764) and joint noise exposure (OR=3.002, 95%CI: 2.080-4.334) were associated with an increased risk of HFNIHL, and male (OR=9.400, 95%CI: 4.211-20.985), LEX,40 h of >85 dB (A) (OR=2.305, 95%CI: 1.345-3.951), and joint noise exposure (OR=3.880, 95%CI: 2.677-5.623) were associated with an increased risk of SFNIHL.@*Conclusion@#Gender, length of service, noise intensity and exposure mode are factors affecting the risk of HFNIHL, while gender, noise intensity and exposure mode are factors affecting the risk of SFNIHL.

Enantioselective Total Synthesis of 10-Desoxy Analogue of a Previously Reported Natural Peroxyguaidiol.

Described herein is an enantioselective synthesis of an analogue of a previously reported guaiane endoperoxide isolated from aerial parts of Croton arboreous. The polycyclic framework of the target structure was constructed with the C-7 stereogenic center derived from L-(-)-carvone and other stereogenic centers installed via substrate chirality-induced asymmetric reactions, starting with the synthesis of the seven-membered ring through regioselective enolization of carvone, ring-expansion, and installation of a conjugated C═C bond. Further functionalization was then achieved through regioselective enolization, triflation, and installation of an isopropenyl group. During the synthesis, some exceptions to the well-known rules of "thermodynamic control" and "kinetic control" in enolization of asymmetric cyclic ketones were observed. In construction of the bridged five-membered and endoperoxy rings, a peroxycarbenium [3 + 2] cycloaddition reaction with alkenes was carried out with several alkenes-silyl-gem-dihydroperoxides of different relative configurations. However, no expected [3 + 2] products were observed. Finally, the five-membered ring was smoothly installed through an intramolecular Darzens reaction, and the peroxy functionality was introduced via a carbon-centered radical-mediated reaction with triplet oxygen, followed by an intramolecular etherification under acidic conditions. Comparison of the 1H and 13C NMR spectra of the synthetic analogue and the natural product revealed that the latter was definitely not an endoperoxide.

A Low-Cost and Scalable Synthesis of a Cyclohexanone-Related Bifunctional Building Block.

A practical route to 2-(2-(2-methyl-1,3-dioxolan-2-yl)ethyl)cyclohexan-1-one was developed, featuring the use of inexpensive starting materials/reagents and readily attainable reaction conditions. The overall transformation was achieved in 53% yield with one chromatographic purification via NaOH-mediated aldol condensation, ethylene glycol protection of the ketone group in the presence of HC(OEt)3/concd HCl, saturation of the C=C bond and the benzene ring with Al-Ni alloy in aqueous KOH, and oxidation of the intermediate cyclohexanol with aqueous NaClO/TEMPO/KBr.

Synthesis of (+)-Panamonon B, 7-epi-Panamonon B, and Their (Z)-Isomers.

(+)-Panamonon B was synthesized with the key quaternary center (of a predefined absolute configuration) installed using Stoltz asymmetric allylation. The C-5 ketone functionality and the cross-conjugated enone moiety in the side chain were introduced via a photosensitized [2+4] cycloaddition of singlet oxygen to diene silyl enol ether and an aldol condensation under the conditions of Sugiura, respectively. The 1H and 13C NMR of the synthetic and natural samples were fully consistent with each other. However, because two samples showed opposite signs for optical rotations, they must be antipodes to one another. The synthesis also provided valuable chances to observe unexpected, yet rather intriguing, phenomena such as a bulky substituent in an axial position of a cyclohexane ring and (E)-and (Z)-isomers with opposite signs for optical rotations despite their identical stereogenic centers. The rare occurrence of a bulky substituent in an axial position of a cyclohexane ring is rationalized as a consequence of the presence of a quaternary center and formation of the five-membered lactone fused to the six-membered ring, while the so far unnoticed influence of C═C geometry on optical rotation is shown to be consistent with the information encapsulated in several discrete pairs of similar compounds retrieved from the literature.

Enantioselective Synthesis Muqubilin and Negombatoperoxides B and C/D.

Muqubilin, negombatoperoxide B, and negombatoperoxide C/D were synthesized through enantioselective routes, with the quaternary center derived from a peroxy chiral building block of known absolute configuration. The C-2/C-3 stereogenic centers were introduced by asymmetric aldol condensation, and the 1,2-dioxane ring was constructed via an intramolecular alkylation of a hydroperoxide with a mesylate. The synthetic samples showed physical and spectroscopic data consistent with those reported in the literature and thus verified the configurations of the natural products. A potentially more expeditious enantioselective entry to the 1,2-dioxane-aldol moiety (C-1 to C-6) of such cyclic peroxides was also briefly explored, where the C-2/C-3 stereogenic centers were installed through a [2+2] cycloaddition and the 1,2-dioxane ring was closed via an intramolecular alkylation coupled with an alkyl-oxygen cleavage of a ß-lactone.

Synthesis of Primary gem-Dihydroperoxides and Their Peroxycarbenium [3 + 2] Cycloaddition Reactions with Alkenes.

It is long known that dihydroperoxidation of aliphatic aldehydes is extremely difficult and normally stops halfway at the hydroxyhydroperoxide stage. This strange phenomenon now has been explored, and a highly effective protocol for conversion of aliphatic aldehydes into gem-dihydroperoxides has been developed. Silyl protection of primary gem-dihydroperoxides, which is also a challenge due to unexpected based-induced decomposition, was achieved using 2,6-lutidine as the base. The silyl-protected gem-dihydroperoxides were then examined in a peroxycarbenium [3 + 2] cycloaddition reaction with alkenes for the first time. Aromatic substrates normally reacted smoothly, affording the expected 1,2-dioxolanes smoothly. Aliphatic aldehydes generally failed to yield 1,2-dioxolane. In all cases, unexpected formation of either a chlorohydrin or a 1,2-dichloride (with Cl atoms derived from TiCl4) depending on the alkene employed was observed, which displays some so far unknown facets of the cycloaddition and helped to gain many mechanistic insights.

Regio- and Stereoselective Addition of HO/OOH to Allylic Alcohols.

A range of allylic alcohols are shown to readily react with ethereal H2O2 in the presence of catalytic amounts of Na2MoO4-gly or MoO2(acac)2, affording the C═C trans hydroxylation-hydroperoxylation products in good yields with high regio- and stereoselectivity. Use of enantiomers of cyclic substrates resulted in corresponding enantiopure diol-tert-hydroperoxides. The possibility of further conversion of the diol-tert-hydroperoxides into triols or linear building blocks with an isolated tert-peroxy group containing a quaternary center is also exemplified.

Perhydrolysis in Ethereal H2O2 Mediated by MoO2(acac)2: Distinct Chemoselectivity between Ketones, Ketals, and Epoxides.

Ketones, ketals, and epoxides were converted into corresponding hydroperoxides in high yields by reaction with ethereal H2O2 in the presence of a catalytic amount of MoO2(acac)2 with distinct (to date unattainable) chemoselectivity.

Synthesis and Configuration of Natural Dracaenones.

Several dracaenones were synthesized in enantiopure forms for the first time. The key chiral center at C-7 was installed with well-defined stereochemistry using either an Evans aldol condensation or a chiral oxidant-mediated asymmetric epoxidation, while and the critical oxidative coupling was achieved under the PIFA/PTA conditions. Comparison of optical rotations for the synthetic and natural samples allowed for unequivocal assignment of the absolute configurations of the natural dracaenones.

Synthesis and Configuration of Neomaclafungin A.

The relative and absolute configuration of neomaclafungins were impossible to establish by spectroscopic analyses alone because of the lack of exploitable 1 H-1 H couplings and nOes between the upper and the lower subunits. This very difficult task now is finally completed by an enantioselective total synthesis of neomaclafungin A (revised) and its diastereomer (reported). The results also provided a key reference for the complete structures for other neomaclafungins and the long-known closely related natural product maclafungin.

Efficient Synthetic Routes to (±)-Hippolachnin†A, (±)-Gracilioethers†E and F and the Alleged Structure of (±)-Gracilioether†I.

Two monocyclic members in the gracilioether family were synthesized in only three steps. The monocyclic products were further elaborated into advanced precursors to hippolachnin A and gracilioether E, respectively. Gracilioether F and the alleged structure for gracilioether I were also synthesized using a late-stage C(sp3 )-H thermo-oxidation.

Probing the Peroxycarbenium [3+2] Cycloaddition Reactions with 1,2-Disubstituted Ethylenes: Results and Insights.

The causes for the title reaction to be limited to only the alkenes with an unsubstituted terminal alkenic carbon were explored. In some "failed" cases the cycloaddition products actually formed but rearranged concurrently. An oxygen atom or a N-Boc (Boc=tert-butyloxycarbonyl) group at the double bond was proven essential for acquisition of intact [3+2] cycloaddition products from 1,2-disubstituted ethylenes.

Greatly Accelerated Condensation of d-Mannose Diacetonide with Aqueous Formaldehyde (Formalin).

Condensation of d-mannose diacetate with aqueous formaldehyde, a long known quaternary center-generating transformation, was reinvestigated to solve the hidden problem of incomplete conversion, a lasting challenge since 1979 despite many previous efforts. The mysterious cause for the retarded transformation was found to be generation of formic acid by a Cannizzaro reaction. By using additional amounts of base, the reaction time was shortened from 48 h to 100 min and the product was readily isolated in 81% yield.

Synthesis and Structural Reassignment of Plakinidone.

In connection with its first synthesis, plakinidone was structurally revised to a five-membered lactone. The key evidence for the previous assignment of this natural product as a perlactone was proven to be a misinterpretation of the MS data because of unawareness of a facile air oxidation. The synthetic samples also allowed for detection of differences in (13)C NMR for diastereomers of remote stereogenic centers, along with the influence of the air oxidation on the optical rotation.

A Novel Allyl Transfer Coupled with a Grob Fragmentation.

A novel acid-promoted rearrangement is disclosed. In the previously unknown transformation, an allyl group migrated to an in situ formed carbocation stabilized by an electron-rich aryl or heteroaryl group, resulting in a stereoselective intramolecular Grob fragmentation. The outcome of the rearrangement observed with an array of substrates can be satisfactorily rationalized using a working hypothesis with the aid of a six-membered transition state similar to those proposed for the anionic oxy-Cope or oxonia-Cope rearrangements, but involving only one instead of two double bonds.

Socioeconomic Status and Physical Activity in Chinese Adults: A Report from a Community-Based Survey in Jiaxing, China.

OBJECTIVES: This study examines the associations of socioeconomic status (SES) with intensity of different types of physical activity (PA) in Chinese adults, aimed at outlining and projecting socioeconomic disparities in PA among the population undergoing a rapid nutrition transition. METHODS: A community-based survey was conducted among 3,567 residents aged 30-65 years old in Jiaxing, China, in 2010. SES and PA were assessed by a structured questionnaire. SES was assessed as socioeconomic index (SEI) score based on self-reported educational attainment, household income and occupation. Metabolic equivalents (METs) were calculated for each subject to quantify the total amount of PA from occupation, exercise, transportation and housework. RESULTS: Intensity of overall PA in this population was 165 MET-hours/week, in which energy expenditure in occupational PA accounted for 82%. Both types and intensity of PA were significantly different by SES: middle SES groups had higher intensity of occupational activities; lower SES subjects engaged in more household work; whereas higher SES subjects were more likely to exercise, more active during commuting and had longer sedentary time. All the three components of SES, education attainment, income and occupation, contributed to socioeconomic disparities in PA in this population. CONCLUSIONS: Our results suggest an overall insufficiency and socioeconomic inequalities in PA among Chinese adults in Jiaxing, a typical city experiencing a rapid urbanization in China. There is an urgent need to promote leisure-time activities in this population.