Meiotic transcriptional reprogramming mediated by cell-cell communications in humans and mice revealed by scATACseq and scRNA-seq

Meiosis is a highly complex process significantly influenced by transcriptional regulation.However,studies on the mechanisms that govern transcriptomic changes during meiosis,especially in prophase I,are limited.Here,we performed single-cell ATAC-seq of human testis tissues and observed reprogramming during the transition from zygotene to pachytene spermatocytes.This event,conserved in mice,involved the deactivation of genes associated with meiosis after reprogramming and the activation of those related to spermatogenesis before their functional onset.Furthermore,we identified 282 transcriptional regulators(TRs)that underwent activation or deactivation subsequent to this process.Evidence suggested that physical contact signals from Sertoli cells may regulate these TRs in spermatocytes,while secreted ENHO signals may alter metabolic patterns in these cells.Our results further indicated that defective transcriptional reprogramming may be associated with non-obstructive azoospermia(NOA).This study revealed the importance of both physical contact and secreted signals between Sertoli cells and germ cells in meiotic progression.

Calmodulin regulates the post-anaphase reposition of centrioles during cytokinesis

A transient postanaphase repositioning of the centriole is found to control the completion of cytokinesis. Using agreen fluorescent protein-calmodulin fusion protein as a living cell probe, we have previously found that calmodulin isassociated with the initiation and progression of cytokinesis. In this study, we further studied the effect of calmodulinon the repositioning of the centriole and subsequent cell cycle progression. When activity of calmodulin is inhibited, theregression of the centriole from the intercellular bridge to the cell center is blocked, and thus the completion of celldivision is repressed and two daughter cells are linked by longer cell bridge in perturbed cells. W7 treatment duringcytokinesis also results in unfinished cytokinesis and stopped G1 phase. These results suggest that calmodulin activity isrequired for centriole repositioning and can affect the completion of cytokinesis and cell cycle progression.

Photocatalytic Decarboxylative Minisci Reaction Catalyzed by Palladium-Loaded Gallium Nitride

The decarboxylative Minisci reaction is a versatile tool for the direct C-H alkylation of heteroarenes,where stoichiometric amounts of oxidants or expensive,precious metal reagents are commonly used.Herein,we reported a photodriven decarboxylative Minisci reaction enabled by a gallium nitride-based heterogeneous photocatalyst under mild conditions.This method can be effectively applied to a broad substrate scope of acids,including primary,secondary,and tertiary carboxylic acids and N-heteroarenes effectively.The practicability and robustness of the approach are demonstrated for the functionalization of biologically active compounds.

On Inventing Cross-Dehydrogenative Coupling(CDC):Forming C-C Bond from Two Different C-H Bonds

Constructing C-C bonds is central to the synthesis of all chemical products.While conventional C-C bond formation methods always require one or two functional groups,20 years ago,our establishment of the concept of Cross-Dehydrogenative Coupling(CDC),wherein C-C bonds are directly formed from two different C-H bonds via the"formal"removal of two H atoms,has revolutionized chemical synthesis and has become one of the most active research subjects in chemistry.This perspective article will provide an insight of the origin of this concept and its early development in our laboratory.

The neonatal ketone body is important for primordial follicle pool formation and regulates ovarian ageing in mice

Adverse nutritional conditions during the perinatal stage are related to early menopause in adulthood;however,the underlying mechanism is still unclear.Herein,we revealed that colostrum-activated ketone body elevation during the postnatal stage regulated primordial follicle reservoir size and then affected ovarian ageing.We found that the expression of the ketogenesis rate-limiting enzyme 3-hydroxy-3-methylglutaryl-CoA synthase 2(Hmgcs2)was largely enhanced during primordial follicle pool formation after birth and might be activated in the ovaries by colostrum.Reactive oxygen species(ROS)elevation in the ovaries leads to follicle apoptosis to deplete damaged follicles,while Hmgcs2 deficiency enhances follicle apoptosis and thus decreases the size of the primordial follicle pool and leads to premature ovarian ageing(POA),which might be related to the activation of cellular endogenous antioxidant system.All these defects could be rescued by ketone body administration,which suppressed ROS-activated follicle apoptosis.Our results suggest that the internal metabolic homeostasis of newborn mice is critical for the primordial reservoir and that any intrauterine and perinatal undernutrition could result in POA.

Cleavage/cross-coupling strategy for converting β-O-4 linkage lignin model compounds into high valued benzyl amines via dual C–O bond cleavage

Lignin is the most recalcitrant of the three components of lignocellulosic biomass. The strength and stability of the linkages have long been a great challenge for the degradation and valorization of lignin biomass to obtain bio-fuels and commercial chemicals. Up to now, the selective cleavage of C–O linkages of lignin to afford chemicals contains only C, H and O atoms. Our group has developed a cleavage/crosscoupling strategy for converting 4-O-5 linkage lignin model compounds into high value-added compounds. Herein, we present a palladium-catalyzed cleavage/cross-coupling of the β-O-4 lignin model compounds with amines via dual C–O bond cleavage for the preparation of benzyl amine compounds and phenols.

Cholesterol metabolic enzyme Ggpps regulates epicardium development and ventricular wall architecture integrity in mice

During embryonic heart development,the progenitor cells in the epicardium would migrate and differentiate into noncardiomyocytes in myocardium and affect the integrity of ventricular wall,but the underlying mechanism has not been well studied.We have found that myocardium geranylgeranyl diphosphate synthase(Ggpps),a metabolic enzyme for cholesterol biosynthesis,is critical for cardiac cytoarchitecture remodelling during heart development.Here,we further reveal that epicardial Ggpps could also regulate ventricular wall architecture integrity.Epicardium-specific deletion of Ggpps before embryonic day 10.5(E10.5)is embryonic lethal,whereas after E13.5 is survival but with defects in the epicardium and ventricular wall structure.Ggpps deficiency in the epicardium enhances the proliferation of epicardial cells and disrupts cell‒cell contact,which makes epicardial cells easier to invade into ventricular wall.Thus,the fibroblast proliferation and coronary formation in myocardium were found enhanced that might disturb the coronary vasculature remodelling and ventricular wall integrity.These processes might be associated with the activation of YAP signalling,whose nuclear distribution is blocked by Ggpps deletion.In conclusion,our findings reveal a potential link between the cholesterol metabolism and heart epicardium and myocardium development in mammals,which might provide a new view of the cause for congenital heart diseases and potential therapeutic target in pathological cardiac conditions.

A Cu/Cinchona P,N-ligand system enabled general asymmetric C(sp^3)–C(sp) coupling

Due to the special structural feature and versatile reactivity towards various types of transformations,alkynes have inspired continuous research interest for their generation,incorporation and application in organic synthesis,chemical biology and material science[1].Notably,since its invention in 1975,the Sonogashira reaction,which efficiently couples aryl halides with aryl or vinyl terminal alkynes via Pd(0)/Cu(I)synergistic catalysis.

Demetallation of organometallic and metal-mediated reactions

The use of stoichiometric organometallic reagents and stoichiometric metals formed the basis of vast majority of classical reactions for constructing carbon–carbon bonds.The indispensable requirement of stoichiometric metals for such reactions constitutes significant challenges in terms of resource sustainability,operational safety,and chemical-waste management.The recent developments in C–H functionalizations,hydrogenative alkene/alkyne addition to electrophiles,the hydrazone umpolung chemistry,and other emerging fields such as the electrosynthesis and photoredox chemistry provide potential solutions to overcome these inherent challenges.

One-pot synthesis of toluene from methane and methanol catalyzed by GaN nanowire

The generation of aromatic benzene,toluene,xylene(BTX)compounds from non-petroleum feedstocks is of particular interest for chemists in the eyes of sustainability.Herein,a novel synthesis of toluene catalyzed by GaN semiconductor nanowire arrays is reported.Using methane and methanol as starting materials,the GaN nanowire arrays can synergistically facilitate the facile generation of toluene under either photo-irradiation or thermal-conditions.The detailed computational studies unveiled different mechanisms involved for the photo-and thermal-toluene synthesis.

Iodomethane as an organocatalyst for the aerobic ortho-selective trifluoromethylation of pyridines

Iodomethane is usually used as an electrophilic methylation reagent.Herein,we report its use as a C1 organocatalyst for the aerobic ortho-selective trifluoromethylation of pyridines in the absence of a transition metal.Trifluoroacetic acid(TFA)was employed as an inexpensive,readily available trifluoromethyl source.The reaction efficiently produced a variety of trifluoromethylation products,with good functional group compatibility.Pyridine-containing drug molecules could also be selectively trifluoromethylated for late-stage functionalizations.Mechanistic studies showed that iodomethane selectively reacted with the pyridine starting material,rather than the pyridine product,to generate the corresponding N-methylpyridinium iodide.The decarboxylation of trifluoroacetic acid produced a trifluoromethyl anion,which added to the methylpyridinium iodide,and the subsequent aerobic rearomatization led to the generation of the ortho-trifluoromethylated product.

Ru(Ⅱ)-catalyzed ortho-amidation and decarboxylation of aromatic acids: a versatile route to meta-substituted N-aryl benzamides

Carboxylate as a promising and valuable directing group has attracted a great deal of attention.However,employing it as a traceless direction group has rarely been reported.We developed the ruthenium-catalyzed amidation of substituted benzoic acids with isocyanates via directed C–H functionalization followed by decarboxylation to afford the corresponding metasubstituted N-aryl benzamides,in which the carboxylate serves as a unique,removable directing group.Notably,this protocol can provide an efficient alternative to access meta-substituted N-aryl benzamides,which are much more difficult to prepare than ortho-substituted analogues.

Perspectives on green synthesis and catalysis

Despite their impressive capacity to access diverse functional groups and to synthesize structurally complex molecules,the majority of the organic reactions suffers from harsh conditions,low atom economy,and hazardous waste production.The goal of our research is geared towards developing efficient methods to minimize the adverse environmental impact and contributing to chemical sustainability.Herein,we illustrate three distinct green approaches,studying the novel reactivities with environmentally innocuous reagents to improve the synthetic efficiency,utilization of natural feedstocks,and employment of green energy to facilitate various important chemical transformations.From this perspective article,we hope to provide an overview of green synthetic chemistry and inspire the expansion of the field in the future.

The role of tyrosine phosphatase Shp2 in spermatogonial differentiation and spermatocyte meiosis

The transition from spermatogonia to spermatocytes and the initiation of meiosis are key steps in spermatogenesis and are precisely regulated by a plethora of proteins.However,the underlying molecular mechanism remains largely unknown.Here,we report that Src homology domain tyrosine phosphatase 2(Shp2;encoded by the protein tyrosine phosphatase,nonreceptor type 11[Ptpn11]gene)is abundant in spermatogonia but markedly decreases in meiotic spermatocytes.Conditional knockout of Shp2 in spermatogonia in mice using stimulated by retinoic acid gene 8(Stra8)-cre enhanced spermatogonial differentiation and disturbed the meiotic process.Depletion of Shp2 in spermatogonia caused many meiotic spermatocytes to die;moreover,the surviving spermatocytes reached the leptotene stage early at postnatal day 9(PN9)and the pachytene stage at PN11-13.In preleptotene spermatocytes,Shp2 deletion disrupted the expression of meiotic genes,such as disrupted meiotic cDNA 1(Dmc1),DNA repair recombinase rad51(Rad51),and structural maintenance of chromosome 3(Smc3),and these deficiencies interrupted spermatocyte meiosis.In GC-1 cells cultured in vitro,Shp2 knockdown suppressed the retinoic acid(RA)-induced phosphorylation of extracellular-regulated protein kinase(Erk)and protein kinase B(Akt/PKB)and the expression of target genes such as synaptonemal complex protein 3(Sycp3)and Dmc1.Together,these data suggest that Shp2 plays a crucial role in spermatogenesis by governing the transition from spermatogonia to spermatocytes and by mediating meiotic progression through regulating gene transcription,thus providing a potential treatment target for male infertility.

Ggps1 deficiency in the uterus results in dystocia by disrupting uterine contraction

Dystocia is a serious problem for pregnant women, and it increases the cesarean section rate. Although uterine dysfunction has an unknown etiology, it is responsible for cesarean delivery and clinical dystocia, resulting in neonatal morbidity and mortality;thus, there is an urgent need for novel therapeutic agents. Previous studies indicated that statins, which inhibit the mevalonate (MVA) pathway of cholesterol synthesis, can reduce the incidence of preterm birth, but the safety of statins for pregnant women has not been thoroughly evaluated. Therefore, to unambiguously examine the function of the MVA pathway in pregnancy and delivery, we employed a genetic approach by using myometrial cell-specific deletion of geranylgeranyl pyrophosphate synthase (Ggps1) mice. We found that Ggps1 deficiency in myometrial cells caused impaired uterine contractions, resulting in disrupted embryonic placing and dystocia. Studies of the underlying mechanism suggested that Ggps1 is required for uterine contractions to ensure successful parturition by regulating RhoA prenylation to activate the RhoA/Rock2/p-MLC pathway. Our work indicates that perturbing the MVA pathway might result in problems during delivery for pregnant females, but modifying protein prenylation with supplementary farnesyl pyrophosphate or geranylgeranyl pyrophosphate might be a strategy to avoid side effects.

Photoinduced transition-metal and external photosensitizer free phosphonation of unactivated C(sp^(2))-F bond via SET process under mild conditions

Transition-metal catalyzed cross-couplings of aryl halides(ArI,ArBr and ArCl)with a broad range of nucleophiles have been developed as powerful methods for carbon-carbon and carbon-heteroatom bonds formation.However,due to the high bond dissociation energy of unactivated C(sp^(2))-F,cross-couplings of mono-fluoroarenes are the most challenging,especially without using transition-metal catalysts.Herein,a photo-induced transition-metal and external photosensitizer free defluorophosphonation of monofluoroarenes via unactivated C(sp^(2))-F bond cleavage is reported.Different mono-fluoroarenes have been successfully cross-coupled with dialkyl phosphites in moderate to excellent yields under mild conditions.Mechanistic studies have revealed the possible involvement of a photo-induced SET process and aryl free radical intermediates.

Base-Promoted Catalyst-Free Regioselective Hydroacylation of Styrenes with Hydrazones via Carbanion Addition

Wereport a base-promoted catalyst-free protocol for the highly regioselective hydroacylation of styrenes with hydrazones derived from naturally abundant aldehydes.This protocolgeneratedlinearketoneswith goodfunctional grouptolerance anda broadsubstrate scope under mild conditions.Mechanistic studies showed that the addition of hydrazone anion to a styrene double bond was the key step,different from previoushydroacylationpathways(viaorganometallic complexes or radical intermediates).