Crossover Pathway Research Articles

The kinase ATR controls meiotic crossover distribution at the genome scale in Arabidopsis

Abstract Meiotic crossover, i.e. the reciprocal exchange of chromosome fragments during meiosis, is a key driver of genetic diversity. Crossover is initiated by the formation of programmed DNA double-strand breaks (DSBs). While the role of ATAXIA-TELANGIECTASIA AND RAD3-RELATED (ATR) kinase in DNA damage signaling is well-known, its impact on crossover formation remains understudied. Here, using measurements of recombination at chromosomal intervals and genome-wide crossover mapping, we showed that ATR inactivation in Arabidopsis (Arabidopsis thaliana) leads to dramatic crossover redistribution, with an increase in crossover frequency in chromosome arms and a decrease in pericentromeres. These global changes in crossover placement were not caused by alterations in DSB numbers, which we demonstrated by analyzing phosphorylated H2A.X foci in zygonema. Using the seed-typing technique, we found that hotspot usage remains mainly unchanged in atr mutants compared with wild-type individuals. Moreover, atr showed no change in the number of crossovers caused by two independent pathways, which implies no effect on crossover pathway choice. Analyses of genetic interaction indicate that while the effects of atr are independent of MMS AND UV SENSITIVE81 (MUS81), ZIPPER1 (ZYP1), FANCONI ANEMIA COMPLEMENTATION GROUP M (FANCM), and D2 (FANCD2), the underlying mechanism may be similar between ATR and FANCD2. This study extends our understanding of ATR's role in meiosis, uncovering functions in regulating crossover distribution.

Zinc Promoted Cross-Electrophile Sulfonylation to Access Alkyl-Alkyl Sulfones.

The transition metal-catalyzed multi-component cross-electrophile sulfonylation, which incorporates SO2 as a linker within organic frameworks, has proven to be a powerful, efficient, and cost-effective means of synthesizing challenging alkyl-alkyl sulfones. Transition metal catalysts play a crucial role in this method by transferring electrons from reductants to electrophilic organohalides, thereby causing undesirable side reactions such as homocoupling, protodehalogenation, β-hydride elimination, etc. It is worth noting that tertiary alkyl halides have rarely been demonstrated to be compatible with current methods owing to various undesired side reactions. In this work, a zinc-promoted cross-electrophile sulfonylation is developed through a radical-polar crossover pathway. This approach enables the synthesis of various alkyl-alkyl sulfones, including 1°-1°, 2°-1°, 3°-1°, 2°-2°, and 3°-2° types, from inexpensive and readily available alkyl halides. Various functional groups are well tolerated in the work, resulting in yields of up to 93%. Additionally, this protocol has been successfully applied to intramolecular sulfonylation and homo-sulfonylation reactions. The insights gained from this work shall be useful for the further development of cross-electrophile sulfonylation to access alkyl-alkyl sulfones.

Adolescent Developmental Pathways Among Depression, Conduct Problems, and Rejection: Integrative Data Analysis Across Three Samples

ABSTRACT Objective The current study investigated sex differences in longitudinal associations among youth depression, conduct problems, and peer rejection from ages 11 to 16. We hypothesized that girls would follow the irritable depression model, which posits that depression leads to conduct problems, and that peer rejection would mediate this relationship. We hypothesized that boys would follow the cumulative failure model, which suggests that conduct problems predict future depression, mediated by peer rejection. Method We used integrative data analysis to combine three datasets, creating an aggregate sample of 2,322 adolescents, 58.4% of an ethnic minority group, and 51.3% boys. Using random-intercept cross-lagged panel modeling with data from ages 11–16, we conducted a nested model comparison. Results Results indicated that a model which allowed paths to differ by sex demonstrated better model fit than a constrained model. While depression, conduct problems, and peer rejection were relatively stable over time and had correlated random intercepts, there were few crossover paths between these domains for either sex. When the strengths of individual crossover pathways were compared based on sex, only the path from conduct problems at age 13 to depression at age 14 was significantly different, with this path being stronger for girls. Conclusions These results suggest that stable, between-person effects largely drive relationships between depression, conduct problems, and peer rejection during adolescence, whereas there are few transactional, within-person pathways between these domains. This pattern of findings demonstrates the utility of random intercept cross-lagged panel modeling for disentangling between- and within-person effects.

Transition-metal-catalyst-free electroreductive alkene hydroarylation with aryl halides under visible-light irradiation.

The radical hydroarylation of alkenes is an efficient strategy for accessing linear alkylarenes with high regioselectivity. Herein, we report the electroreductive hydroarylation of electron-deficient alkenes and styrene derivatives using (hetero)aryl halides under mild reaction conditions. Notably, the present hydroarylation proceeded with high efficiency under transition-metal-catalyst-free conditions. The key to success is the use of 1,3-dicyanobenzene as a redox mediator and visible-light irradiation, which effectively suppresses the formation of simple reduction, i.e., hydrodehalogenation, products to afford the desired products in good to high yields. Mechanistic investigations proposed that a reductive radical-polar crossover pathway is likely to be involved in this transformation.

Hybrid Palladium-Catalyzed Intramolecular Carboamination of Conjugated Dienes: Synthesis of Functionalized Pyrrolidines via Selective Trifluoromethylarene Defluorination.

The incorporation of difluoromethylene groups into aza-heterocycles represents a compelling yet underexplored avenue in contemporary chemical research. In this study, we unveil a hybrid palladium-catalyzed intramolecular gem-difluoroalkylamination of conjugated dienes, providing a versatile approach to the synthesis of diverse functionalized pyrrolidines. Noteworthy features include mild reaction conditions and a remarkable tolerance toward various functional groups. Additionally, the use of alkyl iodides as electrophiles facilitates the generation of the corresponding alkylamination products. Control experiments support a proposed hybrid palladium-catalyzed radical-polar crossover pathway, offering insights into the underlying chemical processes governing this transformation.

Electroreductive Arylcarboxylation of Styrenes with CO2 and Aryl Halides via a Radical-Polar Crossover Mechanism.

2,3-Diaryl propanoic acids are important structures as a result of their widespread presence in numerous bioactive compounds. However, the limitations of existing synthetic techniques include the requirement for costly catalysts and limited substrates. Here, we developed a novel electroreductive arylcarboxylation of alkenes with CO2 based on a radical-polar crossover pathway assisted by easily accessible dimethyl terephthalate as a reductive mediator. This method will provide an efficient strategy for the synthesis of 2,3-diarylpropanoic acids.

Investigating chiral morphogenesis of gold using generative cellular automata.

Homochirality is an important feature in biological systems and occurs even in inorganic nanoparticles. However, the mechanism of chirality formation and the key steps during growth are not fully understood. Here we identify two distinguishable pathways from achiral to chiral morphologies in gold nanoparticles by training an artificial neural network of cellular automata according to experimental results. We find that the chirality is initially determined by the nature of the asymmetric growth along the boundaries of enantiomeric high-index planes. The deep learning-based interpretation of chiral morphogenesis provides a theoretical understanding but also allows us to predict an unprecedented crossover pathway and the resulting morphology.

Proteomic study on nintedanib in gastric cancer cells.

Gastric cancer is a very common gastrointestinal tumor with a high mortality rate. Nintedanib has been shown to significantly reduce tumor cell proliferation and increase apoptosis in gastric cancer cells in vitro. However, its systemic action mechanism on gastric cancer cells remains unclear. A high-throughput proteomic approach should help identify the potential mechanisms and targets of nintedanib on gastric cancer cells. The effects of nintedanib on the biological behavior of gastric cancer cells were evaluated. A cytotoxic proliferation assay was performed to estimate the half maximal inhibitory concentration (IC50). AGS cells were divided into control, and nintedanib-treated groups (5 µM, 48 h), and differential protein expression was investigated using tandem mass tags (TMT) proteomics. The molecular mechanisms of these differentially expressed proteins and their network interactions were then analyzed using bioinformatics, and potential nintedanib targets were identified. This study identified 845 differentially expressed proteins in the nintedanib-treated group (compared to the control group), comprising 526 up-regulated and 319 down-regulated proteins. Bioinformatics analysis revealed that the differentially expressed proteins were primarily enriched in biological pathways for branched-chain amino acid metabolism, steroid biosynthesis, propionate metabolism, fatty acid metabolism, lysosome, peroxisome, and ferroptosis. Key driver analysis revealed that proteins, such as enoyl-CoA hydratase and 3-hydroxyacyl CoA dehydrogenase (EHHADH), isocitrate dehydrogenase 1 (IDH1), acyl-CoA oxidase 1 (ACOX1), acyl-CoA oxidase 2 (ACOX2), acyl-CoA oxidase 3 (ACOX3), and acetyl-CoA acyltransferase 1 (ACAA1) could be linked with nintedanib action. Nintedanib inhibits the proliferation, invasion, and metastasis of gastric cancer cells. The crossover pathways and protein networks predicted by proteomics should provide more detailed molecular information enabling the use of nintedanib against gastric cancer.

Transition-Metal-Free Anti-Markovnikov Hydroarylation of Alkenes with Aryl Chlorides through Consecutive Photoinduced Electron Transfer.

The hydroarylation of alkenes has emerged as a powerful strategy for arene functionalization. However, aryl chlorides remain a large challenge in this type of reaction due to the chemical inertness of the C(sp2)-Cl bond and high negative reduction potential. Herein, we report an anti-Markovnikov radical hydroarylation of alkenes with aryl chlorides via visible-light photoredox catalysis. The key reactive aryl radicals can be efficiently achieved from aryl chlorides by consecutive photoinduced electron transfer. This transition-metal-free protocol features mild conditions, a wide substrate scope, and functional group tolerance, producing a diverse range of linear alkylarenes in moderate to good yields. The reaction is proposed to proceed through a radical-polar crossover pathway.

Crossover shortage in potato is caused by StMSH4 mutant alleles and leads to either highly uniform unreduced pollen or sterility.

The balanced segregation of homologous chromosomes during meiosis is essential for fertility and is mediated by crossovers (COs). A strong reduction of CO number leads to the unpairing of homologous chromosomes after the withdrawal of the synaptonemal complex. This results in the random segregation of univalents during meiosis I and ultimately to the production of unbalanced and sterile gametes. However, if CO shortage is combined with another meiotic alteration that restitutes the first meiotic division, then uniform and balanced unreduced male gametes, essentially composed of nonrecombinant homologs, are produced. This mitosis-like division is of interest to breeders because it transmits most of the parental heterozygosity to the gametes. In potato, CO shortage, a recessive trait previously referred to as desynapsis, was tentatively mapped to chromosome 8. In this article, we have fine-mapped the position of the CO shortage locus and identified StMSH4, an essential component of the class I CO pathway, as the most likely candidate gene. A 7 base-pair insertion in the second exon of StMSH4 was found to be associated with CO shortage in our mapping population. We also identified a second allele with a 3,820 base-pair insertion and confirmed that both alleles cannot complement each other. Such nonfunctional alleles appear to be common in potato cultivars. More than half of the varieties we tested are carriers of mutational load at the StMSH4 locus. With this new information, breeders can choose to remove alleles associated with CO shortage from their germplasm to improve fertility or to use them to produce highly uniform unreduced male gametes in alternative breeding schemes.

MP-453085-11 ALLIED PROFESSIONALS DISPOSITION PATHWAY WITH CONDITIONAL DISCHARGE REDUCES BED UTILIZATION AND HOSPITAL RESOURCES

Increasing demands of inpatient level of care continue to pose challenges to hospital resources and available capacity. Alternative disposition pathways overseen by allied professionals (AP) that utilize extended recovery unit (ERU) hours and conditional discharge (CD) can reduce inpatient bed use, total time spent at the hospital and overall resource utilization. To demonstrate that implementation of disposition pathways utilizing CD and same day discharge (SDD) with an ERU reduces hospital resources without compromising patient safety. An ERU was created to reduce inpatient hospital bed utilization and optimize disposition pathways. This unit included 6 patient beds, 2 registered nurses and overnight coverage. Patients (pts) presenting for elective electrophysiology procedures were classified into three different disposition pathways including SDD, CD and admission to EP allied professional (EP AP) service. All 3 pathways were overseen by EP APs. Pts in the SDD and CD group were required to meet specific criteria noted by the AP to be considered safe for discharge. We compared these new pathways with prior disposition orders in relation to efficiency, safety and resource utilization. From 8/28/2022 to 11/13/2022, 918 pts presented for an EP procedure including cardiac device implantation and ablation. Of these, 200/918(21.8%) were eligible for our disposition pathway. There were 74(8.1%) pts who were SDD, 51(5.6%) pts in the CD pathway, 61(6.6%) pts admitted to the EP AP service, and 14(1.5%) pts were cross-over pathways (failed CD transitioned to EP AP service). The remainder were either already inpatient or felt pre-procedure to require inpatient level of care. Pts evaluated on the EP AP service in the ERU had an average discharge time of 10:04AM vs 12:53PM for pts on the EP AP service admitted to an inpatient unit. Patients in the CD group located in the ERU had an average discharge time of 7:49AM. Discharge time with these pathways improved over time (Figure 1). The total number of pts admitted to the ERU and/or discharged the same day was 186 pts, indicating 186 total hospital beds saved. There were no differences in overall complications between disposition groups compared to prior to implementation of this strategy. The implementation of a disposition pathway strategy utilizing SDD, CD and an ERU overseen by APs is associated with reduced resource utilization without compromising pt safety.

MnBr2‐Catalyzed Aerobic Oxyazidation of Fluoroolefins: Access to Fluoroalkylated β‐Hydroxy Aliphatic Azides

AbstractMnBr2‐catalyzed oxyazidation of fluoroolefins with molecular oxygen and TMSN3 is reported. This method gives rise to various useful fluoroalkylated β‐hydroxy aliphatic azides in 36%–97% yields. Importantly, this protocol features mild conditions, operationally simple, and gram‐scalable, it tolerates various functional groups and has been applied in the synthesis of diverse attractive bioactive compounds and analogous. Mechanism studies enable the detection of the intermediate and indicate that a radical reaction process is involved. The β‐fluoride elimination of α‐fluoroalkylated radicals via radical‐polar crossover pathway was completely inhibited in this reaction.magnified image

Isocyanide-Based Multicomponent Reactions Promoted by Visible Light Photoredox Catalysis.

Isocyanide-based multicomponent reactions claim a one century-old history of flourishing developments. On the other hand, the enormous impact of recent progresses in visible light photocatalysis has boosted the identification of new straightforward and green approaches to both new and known chemical entities. In this context, the application of visible light photocatalytic conditions to multicomponent processes has been promoting key stimulating advancements. Spanning from radical-polar crossover pathways, to photoinduced and self-catalyzed transformations, to reactions involving the generation of imidoyl radical species, the present literature analysis would provide a general and critical overview about the potentialities and challenges of exploiting isocyanides in visible light photocatalytic multicomponent reactions.

Lessons from the meiotic recombination landscape of the ZMM deficient budding yeast Lachancea waltii.

Meiotic recombination is a driving force for genome evolution, deeply characterized in a few model species, notably in the budding yeast Saccharomyces cerevisiae. Interestingly, Zip2, Zip3, Zip4, Spo16, Msh4, and Msh5, members of the so-called ZMM pathway that implements the interfering meiotic crossover pathway in S. cerevisiae, have been lost in Lachancea yeast species after the divergence of Lachancea kluyveri from the rest of the clade. In this context, after investigating meiosis in L. kluyveri, we determined the meiotic recombination landscape of Lachancea waltii. Attempts to generate diploid strains with fully hybrid genomes invariably resulted in strains with frequent whole-chromosome aneuploidy and multiple extended regions of loss of heterozygosity (LOH), which mechanistic origin is so far unclear. Despite the lack of multiple ZMM pro-crossover factors in L. waltii, numbers of crossovers and noncrossovers per meiosis were higher than in L. kluyveri but lower than in S. cerevisiae, for comparable genome sizes. Similar to L. kluyveri but opposite to S. cerevisiae, L. waltii exhibits an elevated frequency of zero-crossover bivalents. Lengths of gene conversion tracts for both crossovers and non-crossovers in L. waltii were comparable to those observed in S. cerevisiae and shorter than in L. kluyveri despite the lack of Mlh2, a factor limiting conversion tract size in S. cerevisiae. L. waltii recombination hotspots were not shared with either S. cerevisiae or L. kluyveri, showing that meiotic recombination hotspots can evolve at a rather limited evolutionary scale within budding yeasts. Finally, L. waltii crossover interference was reduced relative to S. cerevisiae, with interference being detected only in the 25 kb distance range. Detection of positive inference only at short distance scales in the absence of multiple ZMM factors required for interference-sensitive crossovers in other systems likely reflects interference between early recombination precursors such as DSBs.

Visible-light-mediated β-acylative divergent alkene difunctionalization with Katritzky salt/CO2

Photoredox-catalyzed, divergent acylative-benzylation and acylative-carboxylation of alkenes are achievedviathe radical–radical/radical–polar crossover pathway respectively with benzyl radicals and CO2following decarboxylation from ketocarboxylic acids.

Unique spin crossover pathways differentiated by scan rate in a new dinuclear Fe(ii) triple helicate: mechanistic deductions enabled by synchrotron radiation studies

Scan rate dependent spin crossover behaviour is investigated in a new Fe(ii) dinuclear triple helicate. Slow cooling allows relaxation to a densely packed state, while fast cooling traps the structure in a sparsely packed state.

Late‐Stage Modification of Drugs via Alkene Formal Insertion into Benzylic C−F Bond

AbstractC−F insertion of carbon‐atom units is underdeveloped although it poses significant potential applications in both drug discovery and development. Herein, we report a photocatalytic protocol for late‐stage modification of trifluoromethyl aromatic drugs involving formal insertion of abundant alkene feedstocks into a benzylic C−F bond selectively. This redox‐neutral transformation features mild conditions and extraordinary functional group tolerance. Preliminary studies are consistent with this transformation involving a radical‐polar crossover pathway. Additionally, it offers an alternative strategy for difunctionalization of alkenes via quenching of the carbocation intermediate with nucleophiles other than external fluoride.

Late-Stage Modification of Drugs via Alkene Formal Insertion into Benzylic C-F Bond.

C-F insertion of carbon-atom units is underdeveloped although it poses significant potential applications in both drug discovery and development. Herein, we report a photocatalytic protocol for late-stage modification of trifluoromethyl aromatic drugs involving formal insertion of abundant alkene feedstocks into a benzylic C-F bond selectively. This redox-neutral transformation features mild conditions and extraordinary functional group tolerance. Preliminary studies are consistent with this transformation involving a radical-polar crossover pathway. Additionally, it offers an alternative strategy for difunctionalization of alkenes via quenching of the carbocation intermediate with nucleophiles other than external fluoride.

Why do plants need the ZMM crossover pathway? A snapshot of meiotic recombination from the perspective of interhomolog polymorphism

At the heart of meiosis is crossover recombination, i.e., reciprocal exchange of chromosome fragments between parental genomes. Surprisingly, in most eukaryotes, including plants, several recombination pathways that can result in crossover event operate in parallel during meiosis. These pathways emerged independently in the course of evolution and perform separate functions, which directly translate into their roles in meiosis. The formation of one crossover per chromosome pair is required for proper chromosome segregation. This “obligate” crossover is ensured by the major crossover pathway in plants, and in many other eukaryotes, known as the ZMM pathway. The secondary pathways play important roles also in somatic cells and function mainly as repair mechanisms for DNA double-strand breaks (DSBs) not used for crossover formation. One of the consequences of the functional differences between ZMM and other DSB repair pathways is their distinct sensitivities to polymorphisms between homologous chromosomes. From a population genetics perspective, these differences may affect the maintenance of genetic variability. This might be of special importance when considering that a significant portion of plants uses inbreeding as a predominant reproductive strategy, which results in loss of interhomolog polymorphism. While we are still far from fully understanding the relationship between meiotic recombination pathways and genetic variation in populations, recent studies of crossovers in plants offer a new perspective.

Nanoscale insights into the damage tolerance of Cantor alloys at cryogenic temperatures

High-entropy alloys deform plastically and may also be at risk to fracture in extreme environments. In this paper, the damage tolerance of nanocrystalline Cantor alloys under mode I loading at cryogenic temperatures is investigated via molecular dynamics. We find that the damage tolerance is improved significantly with the decrease of temperature, in contrast to conventional metals. Deformation mechanism maps are constructed to assess the plasticity based on the grain size and temperature. Results show that the plastic deformation is governed by a synergy of face-centered-cubic to hexagonal closed-packed martensite transformation, twinning, stacking fault formation, grain boundary (GB) plasticity, and especially dynamic recovery. Specifically, a crossover from shear localization to solid-state amorphization is identified with the decrease of temperature and grain size. The amorphization at GBs dissipates larger strain energy, leading to precursor retardation and hence a high damage tolerance. A final deformation mechanism map is constructed to combine the deformation mechanisms and the crossover pathway from localization to amorphization. This map has great implications on improving the damage tolerance of Cantor alloy at cryogenic temperatures.