This study aimed to investigate the function of KLF11 in regulating radiosensitivity (RT) in esophageal squamous cell carcinoma (ESCC) and to elucidate the underlying mechanisms. A nude mouse ESCC xenograft model was established by injecting KYSE150 cells into the left dorsal flank. Cell proliferation was assessed using cell counting kit-8 (CCK-8) and colony formation assays, while DNA damage was evaluated via a neutral comet assay. Key gene and protein expression levels were analyzed by reverse transcription-quantitative polymerase chain reaction (RT-qPCR), Western blotting, and immunohistochemistry. Additionally, coimmunoprecipitation and immunofluorescence were employed to validate proteinprotein interactions. KLF11 expression was upregulated in both ESCC and RT-resistant tissues. At the cellular level, KLF11 expression was higher in ESCC cell lines than in the normal esophageal epithelial cell line HET-1A, with the most pronounced upregulation in KYSE150 cells and the least in TE1 cells. Notably, KLF11 knockdown under ionizing radiation exposure suppressed proliferation and colony formation, promoted apoptosis, and increased the expression of the DNA damage marker γ-H2AX as well as overall DNA damage levels in KYSE150 cells. Conversely, KLF11 overexpression in TE1 cells led to the opposite phenotype, suggesting that KLF11 confers RT resistance in ESCC by mitigating DNA damage. Further investigations revealed that KLF11 primarily repairs RT-induced DNA damage through the homologous recombination (HR) pathway rather than through nonhomologous end joining (NHEJ). Additionally, the expression of MDM2, E2F1, and RAD51 was significantly elevated in ESCC and RT-resistant ESCC tissues. Mechanistically, KLF11 promotes MDM2 expression, which inhibits E2F1 ubiquitination, thereby stabilizing E2F1 protein levels and enhancing RAD51-mediated HR repair, ultimately leading to RT resistance in ESCC. This study elucidates the critical role and molecular mechanism through which KLF11 drives radiotherapy resistance in ESCC by regulating the MDM2/E2F1 axis and enhancing HR repair, thereby providing a solid theoretical foundation and potential target for the development of KLF11-targeted radiosensitization therapies for ESCC.

The impact of specific chromatin modifications on meiotic crossover frequency has typically been inferred from correlative studies, leaving the question of causality unresolved. To directly test this, we used a catalytically inactive CRISPR-associated protein 9 (dCas9)-based system to recruit the histone demethylase JMJ14 to defined genomic loci. Recruitment of JMJ14 led to a reduction in local histone H3 lysine 4 trimethylation (H3K4me3) levels and a decrease in crossover frequency within the targeted interval. This was accompanied by reduced expression of a long noncoding RNA (lncRNA) at the hotspot and altered crossover topology. Suppressed recombination was also observed at neighboring, untargeted hotspots. In contrast, targeting the transcriptional activator VP64 to the same region increased lncRNA expression, elevated crossover frequency, and raised H3K4me3 levels. Together, these findings establish a causal link between H3K4me3, transcription, and local crossover activity, demonstrating that H3K4me3 levels are closely associated with both transcriptional output and recombination frequency at specific genomic loci.

Wheat stem rust, caused by Puccinia graminis f. sp. tritici (Pgt), is a persistent threat to Ethiopian wheat production, posing risks to food security. This study evaluated the virulence and genotypic diversity of the Pgt population following the stem rust epidemic in 2013, and the vulnerability of Ethiopian bread wheat cultivars to the newly identified Pgt races. We analyzed 639 stem rust samples collected between 2014 and 2022 in Ethiopia and identified 21 Pgt races from 722 single-pustule isolates. The Ethiopian Pgt population has undergone significant temporal shifts driven by exotic race introductions and possibly by selection pressure. Race TKTTF (clades IV-A and -B) dominated in 2014-2016 seasons but was largely replaced by races TTRTF (clade III-B) and TKKTF (clade IV-F) from 2017 onward. Since 2020, races TTKTT (clade I) and TTKTF (clade IV-F) were detected with increasing frequencies, emerging alongside TKKTF as the predominant races by 2022. All major races from genetic clades III and IV detected in Ethiopia exhibit a similar, broad geographic distribution with a likely origin in the Caucasus region. All five variants in the Ug99 race group (clade I) observed in Ethiopia were previously detected in Kenya, suggesting a potential incursion from this bordering country. Races BKBJC and BKGKC with distinct avirulence and genotypic profiles were derived from a sample collected near the alternate host Berberis holstii, suggesting that these avirulent isolates likely originated through sexual recombination. Seedling assays of 101 Ethiopian bread wheat cultivars against six prevailing races showed varying resistance, with only 36% and 48% resistant to race TTKTT and TTKSK, respectively. Although resistance genes deployed in Ethiopian cultivars do not appear to have exerted significant selection pressure favoring races TTRTF and TKKTF, the increased deployment of Sr24 in recent years may have contributed to the establishment and dissemination of race TTKTT. Our findings emphasize the need for breeding wheat cultivars with pyramided effective resistance genes and continuous pathogen surveillance to preempt future stem rust epidemics in Ethiopia and beyond.

Uterine serous carcinoma (USC) is an aggressive p53-mutated endometrial carcinoma that exhibits gene mutations in homologous recombination (HR) pathways, similar to high-grade serous ovarian carcinoma (HGSOC). However, the therapeutic effect of PARP inhibitors on USC is limited. This study investigated cyclin-dependent kinase 12 (CDK12), a transcriptional regulator of HR genes, and evaluated the efficacy of a novel CDK12 inhibitor, CTX-439, combined with a PARP inhibitor, olaparib, in patient-derived xenograft (PDX) models of USC. We evaluated the homologous recombination deficiency (HRD) scores, genetic alterations, and HR-related gene abnormalities, including CDK12 in USC, other histopathological types of uterine endometrial carcinoma, and HGSOC using the Cancer Genome Atlas dataset. We also assessed CDK12 function and CTX-439 efficacy in USC utilizing USC cell lines and PDX models. USC exhibited a higher HRD score than other histological subtypes of uterine endometrial carcinoma but lower than HGSOC. CDK12 amplification occurred more frequently in USC than in HGSOC but was not associated with HRD scores. Tumors with CDK12 amplification demonstrated high CDK12 expression, which correlated with poor prognosis in USC. The CDK12 inhibitor CTX-439 suppressed HR-related gene expression, including BRCA1 and BRCA2, induced apoptosis and DNA damage, and inhibited tumor growth in USC PDX models with high CDK12 expression. Furthermore, CDK12 inhibition enhanced tumor sensitivity to the PARP inhibitor, olaparib in USC PDX models. This study indicates that CDK12 is a potential therapeutic target for enhancing the antitumor effects of PARP inhibitors in patients with USC.

Streptococcus pneumoniae (the pneumococcus) is a human bacterial pathogen and the major cause of bacterial pneumonia, which can further develop into sepsis. The pneumococcus has evolved over 107 antigenically-distinct serotypes that are defined by the chemical composition of its capsule; its major virulence factor and the main protective antigen within the vaccine. Owing to its capsule diversification, certain serotypes are known for being more effective at either colonization or invasiveness. It has historically been accepted that these differences are due to the chemical properties of the capsule itself, whose biosynthetic genes are encoded in a single capsular polysaccharide (cps) operon. Here we show that infection outcomes can also be the result of a serotype's subtle, natural variations within the regulatory region which results in unique transcriptional control of the cps locus. We propose that these data explain, in part, how this pathogen might rapidly evolve its capsule expression to accommodate evolutionary pressures introduced from pneumococcal vaccines, without having to rely on genetic recombination.

Patients with triple-negative breast cancer (ER-, PR-, and HER2-) are routinely treated with chemotherapies that induce DNA damage. However, around 30% of patients display resistance, owing largely to increased DNA repair mechanisms, upregulated to allow cancer cells to escape such therapies. PRMT1 and PRMT5, the two main protein arginine methyltransferases, are involved in several biological pathways, including DNA repair signaling, where they contribute to ensuring DNA integrity. We then speculated that targeting their enzymatic activity may sensitize TNBC cells to chemotherapeutic agents inducing DNA double-strand breaks. Here, we showed that PRMT1 and PRMT5 are recruited to DNA double-strand breaks upon doxorubicin or carboplatin treatment, two chemotherapies currently used to treat TNBC patients, and are preferentially involved in the homologous recombination pathway. By combining PRMT inhibitors with doxorubicin or carboplatin, we increased DNA double-strand breaks and impaired TNBC cell proliferation and clonogenicity invitro and sensitized patient-derived models of TNBC to carboplatin treatment. These preclinical data provide a rationale for the clinical evaluation of PRMT inhibitors as combinatorial agents to improve chemotherapy efficacy for TNBC patients.

Complex chromosomal rearrangements (CCRs) are structural variants involving multiple breakpoints. Among these, intrachromosomal balanced CCRs containing inversions pose significant diagnostic and interpretative challenges, as conventional cytogenetic methods including G-banded karyotype, FISH, and chromosomal microarray lack the resolution needed to determine their structural complexity. Paracentric inversions are traditionally associated with a negligible risk of a viable unbalanced offspring. Here, we describe a familial intrachromosomal rearrangement comprising a complex paracentric inversion of chromosome 6q, transmitted across multiple generations, that resulted in five affected children with recombinant chromosomes harboring reciprocal interstitial gains and losses on 6q. High-resolution optical genome mapping revealed a ~75 Mb parental balanced CCR, formed by multiple sequential paracentric inversions that contain a single ~13 Mb correctly oriented segment. Bias meiotic recombination between homologous chromosomes 6 within this segment is responsible for recurrent unbalanced products resembling recombinant chromosomes typically associated with pericentric inversions. These findings challenge the prevailing assumption that paracentric inversions rarely result in viable recombinant chromosomes and demonstrate how complex chromosomal architecture can directly influence meiotic behavior and reproductive outcomes. Our study underscores the importance of high-resolution genomic technologies for accurate diagnosis, interpretation of a molecular mechanism, and reproductive risk assessment in carriers of CCR.

Threonine and tyrosine kinase (TTK) is a crucial element of the spindle assembly checkpoint. This study aimed to investigate the prognostic value of TTK in LUAD and its correlation with immunity. Data from The Cancer Genome Atlas was used in the study to examine TTK expression in both lung adenocarcinoma (LUAD) and normal tissue samples. To investigate the correlation between TTK expression and overall survival, multivariable analysis and Kaplan-Meier survival curves were utilized in this study. The biological function of TTK in LUAD was investigated using LinkedOmics and the STRING database for interacting genes/proteins. Furthermore, examine the relationship between TTK expression and its DNA methylation. Evaluated the correlation between the expression of the TTK gene and the infiltrating levels of 24 different types of immune cells. Additionally, cell culture validation was conducted in A549 cells and BEAS-2B cells. Expression levels of TTK were significantly increased in LUAD samples from the The Cancer Genome Atlas compared to normal tissue samples. TTK plays a role in cell cycle checkpoints, meiotic recombination, and DNA replication. TTK demonstrates a strong functional correlation with 10 partner genes. Furthermore, there is an inverse relationship between TTK DNA methylation and both TTK expression and overall survival rates among LUAD patients. TTK expression has also been found to be associated with immune cell presence, potentially impacting immune cell infiltration and serving as a predictive factor for patient prognosis. Cell culture investigations revealed significantly elevated levels of TTK mRNA and protein expression in A549 cells compared to BEAS-2B cells. TTK expression in LUAD is correlated with disease advancement, unfavorable prognosis, and alterations in the immune cell composition. TTK levels could offer valuable insights into the progression and prognosis of LUAD, as well as potential implications for immunotherapy strategies.

Synergy between ion motion and nonradiative recombination constitutes an instability pathway that undermines the optoelectronic performance of metal halide perovskites, with prior studies largely centered on rapidly diffusing halide ions. However, the interplay between rotational and torsional motions of organic cations, such as methylammonium (MA = CH3NH3+), and hydrogen defects in hybrid organic-inorganic perovskites has remained unexplored. Here, we employed machine learning force-field-assisted nonadiabatic molecular dynamics to investigate, on the nanosecond time scale, the coupling between MA rotation and nonradiative recombination mediated by carbon-site hydrogen vacancies (VH-C). The results reveal that fluctuations of VH-C defect state levels are strongly modulated by MA rotation and torsion, primarily governed by the φ(H-C-N-H) dihedral angle defined by the two residual hydrogens at the C site and the C-N bond. At low φ(H-C-N-H) values, the VH-C defect state resides near the conduction band minimum, whereas increasing φ(H-C-N-H) drives it toward the valence band maximum. On the nanosecond time scale, MA motion places the defect state in the midgap region. The coupling between MA rotation and VH-C defect state enhances electron-vibrational interactions and accelerates charge losses. The demonstrated synergy between the organic cation motions and hydrogen defects represents a previously unrecognized pathway for nonradiative charge recombination, highlighting a critical challenge to the optoelectronic performance of hybrid organic-inorganic perovskites.

In conventional low-viscosity solvents, magnetic field effects (MFEs) in photoredox catalysis are often negligible because photogenerated radical ion pairs (RIPs) diffuse apart before significant spin evolution occurs. This study reports using ionic liquids (ILs) as a tunable homogeneous "solvent cage" to observe distinct low-field MFEs in the phenothiazine-mediated photoinduced reductive dechlorination of aryl chlorides. Experimental results demonstrate that MFEs increase significantly with bulk viscosity, reaching saturation at approximately 1000 Gs with a maximum enhancement of about 15%, consistent with the hyperfine coupling mechanism (HFCM). Femtosecond transient absorption spectroscopy (fs-TA) reveals that the ionic liquid environment effectively reduces the radical cage escape rate, matching it with the spin evolution rate. This allows the external magnetic field to intervene in the back electron transfer (BET) process. However, unlike strongly confined micellar systems, the contribution of the triplet charge recombination (TCR) pathway here is moderate, intrinsically limiting the magnetic enhancement amplitude. These findings establish that MFE magnitude is determined by both viscosity-controlled cage dynamics and the efficiency of the TCR channel, providing a mechanistic basis for designing spin-modulated homogeneous photoredox systems.

Graphene quantum dots (GQDs) exhibit complex photoluminescence (PL) originating from intrinsic sp2 carbon domains, surface functional groups, and structural defects. Yet the spectral overlap among these emissive channels hinders clear identification of their recombination pathways. Here, we investigate multichannel PL dynamics of commercial GQDs using time-resolved and cryogenic PL spectroscopy. PL spectra reveal three distinct peaks: Peak I (443nm) from π-π* transitions, Peak II (520nm) from surface-dominated contribution functional states, and Peak III (583nm) from pyrrolic N-related defects. Time-correlated single-photon counting detects only a 460nm emission linked to graphitic N traps, indicating that Peaks I-III decay faster than the nanosecond window. Ultrafast optical Kerr-gate measurements further resolve distinct lifetimes for hydroxyl (<5ps), carboxyl (5-10ps), amine (20-30ps), and carbonyl (40-80ps) groups. The transient evolution displays cascade relaxation from deep to shallow traps, evidenced by a progressive blue-shift of Peak II. Cryogenic PL shows stable emission of Peak I, whereas Peak III red-shifts and broadens with temperature, revealing strong electron-phonon coupling and deep-level trapping. These results clarify the multichannel emission mechanisms of GQDs and provide design principles for tuning their optical properties.

We investigate the defect-dependent electronic structure and gas-sensing potential of cubic α-CsPbI3 using first-principles density functional theory and nonadiabatic molecular dynamics. Among the intrinsic defects, interstitials, vacancies, antisites, and switches studied, the IPb and PbI antisite defects exhibit transition energy levels near the middle of the band gap, thus functioning as deep traps. Short-term adsorption of ammonia selectively modifies the electronic structure, coordinating with Pb at PbI sites and Cs at IPb sites, significantly altering recombination pathways. Detailed analysis reveals that NH3 reduces anharmonicity at IPb defects, enabling enhanced recombination at elevated temperatures, while trap-assisted recombination dominates at room temperature. Other analytes, including CH3NH2 and NO2, show negligible impact on the band gap or recombination dynamics, highlighting the potential selectivity of NH3 interactions. Ab initio nonadiabatic molecular dynamics simulations at 300 K and 600 K further demonstrate temperature-dependent modulation of carrier lifetimes, with NH3 accelerating recombination at ambient conditions and suppressing certain pathways at higher temperatures. These findings suggest that α-CsPbI3 can serve as a selective and sensitive ammonia sensor over a broad temperature range and offer insights for ammonia detection under industrially relevant conditions.

Mechanism of PP2A affecting ubiquitination pathway in spermatogenesis.

Phenotypic POLE Variant Classification Identifies Patients Who May Have Favorable Prognosis and Benefit from Immunotherapy.

The Cryptosporidium spp. are protozoan parasites of significance in the world and the major cause of the diarrheal disease (cryptosporidiosis) in humans, which presents a significant risk to young children, immunocompromised people, and livestock. The introduction of molecular methods has completely transformed the view on the taxonomy, genetic diversity, and the mode of transmission of the parasite that was not initially evident due to the morphological homogeneity of the oocysts. This review summarizes the existing information and knowledge regarding the molecular characterization of species of Cryptosporidium that infect human beings based on genetic diversity. We touch upon the development of diagnostic and typing methods, starting with the classical microscopy and all the way to the current state of multilocus sequence typing (MLST) and whole-genome sequencing (WGS). The review addresses the two most common human-pathogenic species, C. hominis and C. parvum, includes the description of the population structure, genetic recombination role and the public health importance of different subtype families. We look at the specific epidemiological trends where anthroponotic is more likely in low- and middle-income nations than is zoonotic in the high-income nations. In addition, the clinical consequences of this genetic diversity, especially in the vulnerable groups like the HIV/AIDS patients are discussed. This review brings together the results of the most important molecular epidemiological research and points out how advancing knowledge about the genetic landscape of Cryptosporidium can be very essential in crafting an effective disease management approach, outbreak surveillance and population health interventions.

Persistence of unrepaired DNA damage in oocytes is detrimental and may cause genetic aberrations, miscarriage, and infertility. RPA, a single-stranded DNA (ssDNA)-binding complex, is essential for various DNA-related processes. Here we report that RPA plays a novel role in DNA damage repair during postnatal oocyte development after meiotic recombination. To investigate the role of RPA during oogenesis, we inactivated RPA1 (replication protein A1), the largest subunit of the heterotrimeric RPA complex, specifically in oocytes using two germline-specific Cre drivers (Ddx4-Cre and Zp3-Cre). We find that depletion of RPA1 leads to the disassembly of the RPA complex, as evidenced by the absence of RPA2 and RPA3 in RPA1-deficient oocytes. Strikingly, severe DNA damage occurs in RPA1-deficient GV-stage oocytes. Loss of RPA in oocytes triggered the canonical DNA damage response mechanisms and pathways, such as activation of ATM, ATR, DNA-PK, and p53. In addition, the RPA deficiency causes chromosome misalignment at metaphase I and metaphase II stages of oocytes, which is consistent with altered transcript levels of genes involved in cytoskeleton organization in RPA1-deficient oocytes. Absence of the RPA complex in oocytes severely impairs folliculogenesis and leads to a significant reduction in oocyte number and female infertility. Our results demonstrate that RPA plays a previously unrecognized role in DNA damage repair during mammalian folliculogenesis.

ABSTRACT This study investigates the impact of cerium doping on the structural, optical, and magnetic properties of Ni 0.5 Cu 0.2 Co 0.3 Ce x Fe 2 −x O 4 ( x = 0.000, 0.025, 0.050, and 0.075) spinel ferrites synthesized by sol–gel via auto‐combustion method. Characterization results confirm the formation of cubic spinel structures with reduced crystallite sizes and modified lattice parameters upon cerium incorporation. Increased cerium content correlates with enhanced porosity, increased bandgap energies, and a rise in structural disorder. Optical studies reveal peak shifts, broadening, and intensity variations, indicative of modified metal‐oxygen bonds and nonradiative recombination pathways. Magnetic characterization reveals a non‐monotonic evolution of saturation magnetization, magnetic moment with cerium incorporation, reflecting the intricate interplay of cation redistribution, spin–orbit coupling, and lattice strain effects. These trends underscore the sensitive dependence of magnetic behavior on subtle structural modifications induced by rare‐earth doping.

Meiotic recombination ensures genetic diversity and accurate chromosome segregation by mediating reciprocal DNA exchange between homologous chromosomes. In this process, the meiosis-specific recombinase DMC1 plays a pivotal role in homology search and pairing, but the molecular mechanisms underlying its function remain unclear. Using single-molecule imaging, we demonstrate that the human DMC1-ssDNA presynaptic complex employs a diffusion-based mechanism to search for homologous DNA. Although this diffusing complex generates a migrating DNA "bubble," it cannot align with the homologous sequence in the absence of free DMC1 protein. Strikingly, the meiosis-specific cofactor complex HOP2-MND1 compensates for the lack of free DMC1 and enables homology recognition. Notably, HOP2-MND1 achieves this by codiffusing with the presynaptic complex, acting to clamp the ssDNA-dsDNA junctions and maintain an expanded DNA bubble conducive to sequence alignment. Our findings identify DMC1 together with HOP2-MND1 as a functional homology search unit and provide mechanistic insights into how auxiliary factors regulate DMC1-driven strand exchange during meiotic recombination.

Meiotic recombination plays a crucial role in the correct separation of homologous chromosomes. The DNA mismatch repair protein Msh4 is a meiosis specific protein and msh4 defects were reported to associate with azoospermia and ovarian dysfunction in mammal. However, its role has not been elucidated in an important model animal, zebrafish. Here, we examined the role of Msh4 in meiosis and gametogenesis by knocking out msh4 using CRISPR/Cas9 technology. The resultant msh4-/- mutants showed male predominance (98.5%) and brought asynaptic meiosis to form unpaired univalents evidenced by the immunofluorescence detection of the synaptonemal complex protein Sycp3 and Sycp1, and the recombination protein Rad51. Such unusual meiotic configurations led to meiotic arrest and subsequent abortive spermatogenesis. In contrast, msh4 deficiency induced infrequent msh4-/- female (1.5%) that laid eggs which developed to normal (40-80%) or abnormal (20-60%) progeny by fertilizing with sperm of wild type. Thus, Msh4 is essential for the meiosis in males, but is not strictly required in females.

In 2023, a total of 450 fecal samples were collected from healthy cats and those suspected of being infected with Feline Panleukopenia Virus (FPV) in Harbin, China. The FPV VP2 gene was detected using polymerase chain reaction (PCR). Positive samples were then subjected to VP2 sequence analysis, phylogenetic analysis, recombination analysis, and selective pressure analysis. VP2 sequence analysis showed that the nucleotide similarity of the full-length VP2 gene ranged from 98.7 to 100%, with 19 amino acid mutations observed compared to the 2008 Felocell vaccine strain (GenBank: EU49868.1). Phylogenetic analysis demonstrated that all 42 detected FPV strains clustered with recent domestic isolates. Recombination analysis identified two strains (HRB2312 and HRB2324) as recombinants between FPV and Canine Parvovirus type 2c (CPV-2c). Selective pressure analysis did not detect any positively selected sites. The findings suggest that the FPV lineages circulating in China have remained relatively stable in recent years, with evolution influenced by both random genetic drift and gene recombination. This study provides insights into the genetic diversity of FPV in Harbin, highlighting point mutations and recombination events. Further investigation is warranted to determine the antigenic compatibility of circulating recombinant strains with traditional vaccine strains.