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DNA double-strand breaks (DSBs) are the most severe DNA damage, and defective repair can lead to apoptosis or malignant transformation. DSBs are mainly repaired by nonhomologous end joining (NHEJ) and homologous recombination (HR), while microhomology-mediated end joining (MMEJ) serves as a backup pathway. Since DNA polymerase theta (Polθ) is essential for MMEJ, this pathway is also named Polθ-mediated end joining. Polθ is barely expressed in normal tissues but overexpressed in many cancers, making it a promising therapeutic target. In recent years, Polθ inhibitors and related therapeutic strategies have emerged rapidly, with clinical trials underway. This review summarizes the structure, function and expression of Polθ in tumorigenesis, highlights synthetic lethal strategies, drug development and clinical translation, and discusses current limitations and future directions for cancer research. Polθ-mediated microhomology-mediated end joining (MMEJ) promotes genomic instability and facilitates mutation accumulation, thereby leading to cancer initiation and progression.Polθ expression is significantly upregulated in various cancer types and markedly correlates with cancer prognosis.DNA damage repair pathways and some proteins can regulate Polθ expression and mediated microhomology-mediated end joining (MMEJ) activity in cancer.Polθ inhibitor have appeared sequentially and clinical trials targeting Polθ are being gradually launched.Polθ is a highly attractive therapeutic target and synthetic lethal strategies targeting Polθ in cancer have been continuously explored.

SPO11 forms hundreds of double-strand breaks (DSBs) to initiate meiotic recombination that is normally error-free. However, SPO11 activity can be mutagenic when one chromatid incurs closely spaced DSBs (double cuts), especially when DSBs are dysregulated by loss of the ATM kinase. De novo indels and structural variants can arise via end joining at double cuts within a single hotspot (microdeletions) or at adjacent hotspots separated by at least 30 kb, as we now show, sometimes accompanied by ectopic insertions of double-cut fragments. Here, we investigate how meiotic DSB end processing influences end joining. In MRE11-deficient mouse spermatocytes, which do not resect their DSBs, deletions at double cuts occur readily, with end-joining breakpoint profiles closely matching SPO11 DSB profiles. Microdeletions suggest that two DSBs can be as close as ∼21 bp. The tyrosyl-DNA phosphodiesterase TDP2 contributes to both deletion formation and ectopic insertion of double-cut fragments, presumably by removing SPO11 from DNA ends prior to joining. Finally, observations suggest a cooperative role for MRE11 and ATM in locally regulating DSB distributions. Our findings provide insight into the mechanism of de novo mutation origin, emphasizing the role of meiotic DSBs in shaping genome evolution.

Discontinuation of infertility care without achieving a still-desired pregnancy represents a potential failure to meet patient needs and indicates healthcare system inefficiencies. While specific reasons for premature treatment cessation are documented in various populations, no study has extensively examined its prevalence or drivers within the Military Health System (MHS). This study identifies predictors and reasons for early discontinuation among active-duty servicewomen (ADSW), whose unique sociodemographic circumstances influence how and where fertility care is accessed and sustained. This cross-sectional secondary analysis used data from 3281 ADSW who received infertility services or treatments within the MHS, with a weighted response rate of 17.8%. We evaluated military and demographic characteristics, alongside care-related variables such as clinical setting, payment source, out-of-pocket expenses, care received both within and outside the MHS and unmet need for fertility services since joining the military. The outcome of the study was discontinuation of infertility treatments before achieving a desired pregnancy. A weighted binary logistic regression model calculated adjusted ORs (aORs) with 95% CIs to identify predictors of discontinuation before achieving pregnancy. The prevalence of early discontinuation among ADSW who received infertility services or treatments within the MHS was 28.2% (95% CI 26.2% to 30.2%). Factors that were related to early treatment cessation included: educational attainment of high school or less (aOR: 1.40, 95% CI 1.04 to 1.89), age 35-44 years (aOR: 1.33, 95% CI 1.07 to 1.65), receiving care both within and outside the MHS (aOR: 1.52, 95% CI 1.22 to 1.90), incurring out-of-pocket expenses (aOR: 1.31, 95% CI 1.04 to 1.65) and having an unmet need for fertility services since joining the military (aOR: 1.37, 95% CI 1.12 to 1.67). To minimise early treatment discontinuation, the MHS should expand reproductive services to more facilities, integrate standardised psychological support and conduct qualitative research to explore uncaptured reasons for ADSW to discontinue care.

Civil society organisations (CSOs) can play an important role in crisis management and facilitate effective communication and crisis response. To improve capacity for intercultural health communication in future health crises, it is crucial to learn from CSOs' experiences during the COVID-19 (SARS-CoV-2) pandemic and from their cooperation with healthcare systems. This study aims to gain insights into CSOs' experiences of intercultural health communication during the pandemic in two disadvantaged areas in Stockholm, Sweden. We also wanted to explore healthcare staff's experiences of collaboration with CSOs. We conducted a qualitative thematic analysis of interviews with informants from 15 CSOs with substantial local pandemic activity. Additionally, we conducted a secondary analysis of qualitative interview data from 21 informants involved in delivering intercultural health crisis communication during the pandemic. CSOs emphasised the importance of effective and trusted communication, which requires more than translation. They highlighted the need for a deep understanding of how language, cultural frameworks and lived experiences shape the reception of public health messages. From the perspective of healthcare staff, the collaboration with CSOs was both necessary and transformative. The partnership with CSOs was a process of "joining forces, "in which mutual learning and shared responsibility strengthened the overall intercultural communication strategy. In times of crisis, CSOs have the capacity to act as community-based knowledge brokers by strengthening trusted, understandable intercultural communication and fostering a sense of community. However, CSOs are not just an extension of the public health authorities, but independent actors with a unique ability to communicate and build trust. Collaborative structures between CSOs and healthcare need to be firmly established well ahead of future health crises. Our results emphasise the importance of culturally and linguistically adapted communication as an integral part of inclusive crisis communication. These findings position CSOs as community-engagement actors in inclusive emergency preparedness.

This review article provides a comprehensive analysis of the synthesis, properties, and applications of Ti3SiC2 and Ti2AlC phases. It begins with an overview of the synthesis techniques for these materials, including bulk, thin film, and powder forms. Subsequently, it delves into their polymorphism, phase stability, the electrical, thermal, and elastic properties, as well as hardness, machinability, deformation, fracture, fatigue, creep, oxidation, corrosion, and friction and wear. Additionally, the review covers the advancements in composite materials, surface technologies, joining techniques, and carbide-derived carbon (CDC) based on these phases. Finally, the article suggests future research directions that aimed at guiding and inspiring further studies in the field of material sciences.

We report our experience with Holmium Laser Ablation (HOLA) of posterior urethral valves (PUV) in preterm newborns. After stabilization under anesthesia, in lithotomy position, using a 4.5/6.5 compact cystoscope (Richard Wolf) & 365-micron fibre, laser was applied at 2 J/10 Hz for HOLA. The valve leaflets were divided by short bursts of laser energy (video) joining the dots to provide complete clearance. A repeat VCUG and cystoscopy was performed in all patients after 3-6 months to confirm clearance. All patients were followed up for a median duration of 5 years (range 3-9 years). Biochemical, radiological and bladder parameters were followed up. Between 2015 and 2025, 22 neonates; median gestation 34 weeks; [32,36] underwent HOLA of PUV. Successful clearance of PUV was achieved in 20/22 neonates (90.9%), as confirmed by repeat VCUG/cystoscopy. Renal function improved significantly (p = 0.001), with the median (IQR) creatinine level decreasing from 2.6 (1,3) pre-fulguration to 0.9 (0.7,1.2) at the one-year follow-up. Upper tract dilatation persisted in seven, subsequent urodynamic evaluation identified bladder; all were successfully managed with anticholinergic medication. HOLA of PUV is feasible in preterm neonates with acceptable short-term complication profile, and without apparent excess morbidity in this small cohort.

Ceratonia siliqua is a nutritionally and economically important Mediterranean tree species whose natural stands in Morocco are increasingly threatened by habitat degradation and genetic erosion. However, the spatial organisation of genetic diversity across its natural range in Morocco remains insufficiently resolved. To support conservation and germplasm management initiatives, interpopulation genetic differentiation among Moroccan carobs populations was assessed using a pooled DNA sample and SSR markers analysed through three genotyping workflows: high-resolution melting (HRM), conventional PCR, and capillary electrophoresis. Genetic relationships among populations were evaluated using Neighbour-Joining (NJ) analysis, principal component analysis (PCA), and K-means clustering. Among the evaluated approaches, HRM provided the highest discriminatory resolution and generated the most informative polymorphism profiles across loci. All analytical frameworks consistently revealed substantial interpopulation differentiation and broad geographic grouping patterns. Southern populations formed genetically cohesive groups, whereas northern and central populations displayed more complex patterns of genetic similarity. K-means clustering supported the presence of four major population groups, while PCA identified a subset of highly discriminative SSR loci contributing to regional differentiation. Overall, the results reveal a genetically diverse and spatially differentiated Moroccan carob germplasm and demonstrate that SSR-HRM is a robust and cost-effective approach for population-level genetic screening. These findings provide useful genetic resources for future conservation, germplasm management, and breeding programmes in Moroccan carob.

Understanding Human papillomavirus (HPV) oncogenic mechanisms is essential for developing preventive and therapeutic strategies and overcoming therapy resistance in HPV-related cancers. These challenges may arise from the ability of high-risk HPV to subvert host tumor suppressors such as p53 and Rb, and to drive oncogenesis through homologous recombination deficiency (HRD) and multi-network dysregulation. Mechanistically, HPV exerts context-dependent effects on the host DNA damage response (DDR). During episomal replication, E6/E7 activate DDR and recruit BRCA1/RAD51 to replication foci to support viral replication without significantly compromising host HR repair. Upon viral integration, however, sustained E6/E7 expression drives HRD and shifts DNA repair toward error-prone end joining, generating genomic instability that fuels malignant transformation. These alterations are most clearly established in cervical cancer, whereas evidence in HPV-positive non-cervical cancer is more variable and requires further context-specific validation. In parallel, HPV E6/E7 antagonize transforming growth factor-β (TGF-β)-mediated tumor suppression and, potentially through FAT Atypical Cadherin 4 (FAT4) down-regulation, engage Wnt/β-catenin signaling. The resultant elevation of nuclear β-catenin induces programmed death-ligand 1 (PD-L1) expression promotes immune evasion, stemness, and invasiveness. Of note, while the DDR-TGF-β-β-catenin-PD-L1 axis is backed by substantial evidence in HPV-related cancers, certain connections within this pathway are extrapolated from non-HPV models or general pathway biology and are explicitly denoted as such in the main text. With residual p53 activity, HRD may confer initial sensitivity to DNA-damaging agents, but resistance frequently develops-a pattern reminiscent of the initial response followed by acquired resistance observed with immunotherapies in HPV-related cancers. Integrating these mechanistic insights, we propose ablative therapies (e.g., ablation, photodynamic therapy, surgery) for cervical intraepithelial neoplasia (CIN), and for advanced or resistant disease, a synthetic-lethality framework combining genotoxic therapies with DDR inhibitors, targeting DDR-TGF-β-β-catenin-PD-L1 axis, and antiviral approaches. The proposed therapeutic strategies, however, should be interpreted with caution, as their evidence base varies across tumor types and warrants further investigation.

Cas12a is widely used in plant genome editing, but its targeting scope is constrained by stringent protospacer adjacent motif (PAM) requirements and variable activity across species, limiting its application at diverse genomic loci. LbCas12a-RRV-based editing system was established in nonheading Chinese cabbage, and T5exo-PF-LbCas12a was generated by introducing a triple mutation (D535G/S551F/D665N) and fusing with T5 exonuclease. This engineered system recognizes an expanded PAM sequence from 5'-VTTV-3' to 5'-NYHV-3'. The system exhibited efficient editing at noncanonical PAM sites in cabbage, tomato, and rice. Additionally, it successfully mediated large-fragment deletions via microhomology-mediated end joining (MMEJ) in plants. This study expands Cas12a targeting scope in plants and provides the first evidence for Cas12-mediated MMEJ-based large-fragment deletion. The toolkit facilitates functional genomics and crop improvement, and the methodology is readily adaptable to other plant species.

Bassaricyon (Carnivora, Procyonidae) is a little-known group of small Neotropical carnivores from central and northern South America. Despite their charismatic nature, they are difficult to spot in the field, and they are confused with another procyonid, the kinkajou. This poorly studied genus comprises four species: B. gabbii, B. alleni, B. medius, and B. neblina, the latter with two subspecies. In this study, the genetic diversity of Bassaricyon from eastern Amazonia was explored based on the mitochondrial gene cytochrome b. A maximum-likelihood analysis confirms the taxa recognized at the species and subspecies levels and shows that populations from the Guiana Shield (GS) are well structured relative to the lineage from western Amazonia (WA), with genetic distances among them comparable to those of other Bassaricyon subspecies. A median-joining network showed five median vectors between B. alleni lineages, more than between B. medius and B. neblina subspecies (n = 1); additionally, there are at least 10 nucleotide substitutions between them, suggesting a considerable difference between these lineages. In the last review of the genus, the estimated divergence time between B. alleni from western Amazonia and Guiana Shield was slightly less than that between B. neblina and B. medius subspecies, suggesting less time to differentiate. We collected Potos flavus in the two municipalities sampled; however, in different localities, suggesting different habitat specificities. These results, together with morphological differences among B. alleni lineages, suggest a subspecies taxonomic status for the Guiana Shield population, B. alleni beddardi.

In 2024, there was an increase from the previous year in the number of births in South Dakota with 11,434 new babies joining the state's population. Among this birth cohort, 71% were White, 12% American Indian, 9% Hispanic, 3% Black, and 5% other races. Over recent years, a declining percent of this annual cohort is White or American Indian with other racial groups increasingly contributing to the births in the state. South Dakota's 2023 birth and fertility rates were the highest of the nation. These state rates also showed that compared to all other races, Whites also had the lowest rates of fertility in South Dakota. The state's infant mortality rate (IMR) is increased in 2024 (7.35) from the previous year (5.36) with increases in both the neonatal and post neonatal rates that occurred in only the White/Hispanic population. Five-year (2020-24) data, however, show that 71% of births are White yet they contribute to 51% of infant deaths; dissimilar to American Indians who comprise 13% of births yet contribute to 30% of all infant deaths. Almost a quarter (23%) of all infant deaths in the state are caused by sudden unexpected infant death (SUID) with a rate that is statistically significantly higher (p<.01) than what is observed nationally. Further, data show that the state's rate of SUID is not decreasing and there also has been an increasing percent of these deaths having potentially preventable risks associated with them. Overall, the state's 2020-24 total IMR (7.03) and post neonatal mortality rate (2.03) were significantly higher (p<.01) than the 2023 rates (5.6; 1.96) for the nation.

Polymeric (p) immunoglobulins (Igs) and their secretory (S) forms are critical to vertebrate immunity. The pIgs and SIgs comprise a molecularly diverse family of antibodies that contain multiple Ig monomers, up to one joining chain (JC), and up to one secretory component. A subset of pIgs function in circulation whereas SIgs populate mucosal barriers. The pIgs and SIgs exhibit unique functions compared to monomeric Igs, yet their underlying molecular structures remained largely elusive until 2020 when cryo-electron microscopy revealed SIgA and SIgM to be remarkably asymmetric antibody assemblies. More recent reports have uncovered IgM and IgA complexes with host receptors and pathogenic virulence factors, species-specific structural differences, and conformational relationships between pIgs' structural cores and antigen binding fragments. Together, these findings highlight pIg and SIg conformational asymmetry as a key feature and establish a foundation to advance our understanding of pIg and SIg structure-function relationships critical for understanding immunity.

Genetic profiling of a new HPV-negative cervical cancer model identified pathogenic variants in genes implicated in oncogenic signaling, cell cycle regulation, and DNA damage repair pathways, including homologous recombination, non-homologous end-joining, and mismatch repair. Deficiencies in BRCA2, RAD51 and MLH1 were among these actionable targets. The newly described cervical cancer model revealed sensitivity towards the PARP inhibitor olaparib, which was further augmented upon combination with platinum-based chemotherapeutics. In contrast, BRCA1/2-proficient cervical cancer cells exhibited greater resistance to these strategies. This study highlights the potential of in-depth genetic analysis to identify genetic susceptibilities to guide personalized medicine approaches.

The Brigade Nurse Counselor (BNC) is a critical asset in shaping and sustaining the Army Nurse Corps (ANC). This article examines the historical development, strategic relevance, and operational responsibilities of BNCs, particularly within the Reserve Officer Training Corps (ROTC) environment. The BNC serves as a mentor and subject matter expert, influencing nurse cadet retention, readiness, and transition to active duty. From academic advising and policy implementation to career coaching and partnership development with civilian nursing institutions, the role is expansive and uniquely impactful. The paper also highlights how the BNC position contributes to the Army's long-term nurse production and mission success. There are multiple commissioning sources for nurses in the Army Nurse Corps (ANC);however, the highest per-centage of nurses join through the United States Army Cadet Command (USACC) Reserve Officer Training Corps (ROTC). Subsequently, most nurses have interacted with a Brigade Nurse Counselor (BNC) during their undergraduate endeavors. To say nursing school is difficult is an under-statement; adding the ROTC leadership and tactical training adds further stressors requiring time management and per-severance. The BNC position was created to provide nursing Cadets with mentorship to support them while earning their Bachelor of Science in Nursing and taking the National Council Licensure Examination (NCLEX) necessary to become an Army Nurse. Cadet Command consists of eight brigades across the United States and is the largest officer-producing organization for the United States military. Each brigade is typically assigned two BNCs who mentor around 250 nursing Cadets every semester. The BNCs are the Brigade Commander's primary advisors on all topics related to marketing, recruiting, re-tention, incentives, academic requirements, certification, internships, and training for nurses. Their expertise and oversight are invaluable as they are traditionally the only nurses assigned to the brigade. Brigade Nurse Counselors provide direct interface and engagement with the leaders of Schools and Colleges of Nursing, admission offices, and high school counselors to promote ANC educational and professional opportunities and the benefits of joining ROTC. While the responsibilities of BNCs are extensive, their most critical role is to provide nursing cadets with guidance on Fig. 1 Brigadier General James Burk visits with Brigade Nurse Counselors (BNCs) during their 2024 BNC Conference at Fort Knox, KY their future careers and support in balancing the strenuous demands of the nursing academic and ROTC curriculum and commissioning requirements.

To evaluate a support structure for women victims of violence from the perspective of the survivors themselves. We conducted semi-structured interviews with 17 women attending a Maison des Femmes (MdF), a hospital-based multiprofessional structure providing medical, psychological, social, and legal support to women victims of violence, within a model currently being scaled up nationally in France. When enrolling in the MdF, participants reported seeking safety and support and expecting a therapeutic relationship tailored to their individual needs. They valued access to a wide range of professionals, coordinated by a single trusted interlocutor responsible for their care pathway. Overall, participants reported improved well-being since initiating MdF care. Experiences of group therapy were mixed: some participants described it as fostering supportive social interactions (n&#x2009;=&#x2009;12), whereas others felt outperformed by other group members (n&#x2009;=&#x2009;5), leading to feelings of discouragement. Frustration arose from unmet needs related to housing and income support, the slow pace of legal proceedings, and long waiting times for appointments within the structure. When considering the planned end of care, typically after 6-12&#x2009;months, participants expressed uncertainty and fear of losing a vital source of support. Although women survivors of violence reported improved well-being after joining the MdF, persistent unmet social and legal needs and anxiety surrounding the end of care were identified. These findings highlight the importance of early information and anticipatory planning regarding care duration and post-discharge support.

Radiation-resistant microorganisms that survive high doses of ionising radiation serve as valuable models for understanding stress adaptation; however, the genomic determinants underlying extreme radiation tolerance in bacteria from natural environments with high background radiation remain insufficiently characterised. Bacterial isolates from the Chavara-Neendakara HBRA (Kerala, India) were evaluated for desiccation tolerance, and the desiccation-resistant isolates were subsequently exposed to gamma irradiation (1-10&#xa0;kGy) using a 60Co source. Isolates were identified through 16S rRNA sequencing, morphologically characterised by FE-SEM, and screened for antibiotic susceptibility. The highly radiation-resistant strain underwent whole-genome sequencing via Oxford Nanopore Technology, with De novo assembly, polishing, and genome annotation. Four bacterial isolates (Micrococcaceae and Paenibacillaceae) exhibited D10 values of 1-7&#xa0;kGy, including one multidrug-resistant strain; no endospores were observed in the Paenibacillus isolate under the tested conditions. Paenibacillus sp. HBRA004 survived 10&#xa0;kGy gamma radiation, exceeding all previously reported HBRA isolates by over fourfold. Its 5.0 Mbp genome (GC&#x2009;=&#x2009;48.27%,&#x2009;&#x2265;&#x2009;99% completeness) encodes five mechanistically independent DNA repair pathways; homologous recombination (recA, recN, radA), base excision repair (mutM, mutY, mutT), mismatch repair (mutL, mutS), nucleotide excision repair (uvrA, uvrB, uvrD), and non-homologous end joining (ku, ligD), alongside a redundant antioxidant network comprising triple-copy Fe/Mn-family superoxide dismutases and ahpC peroxiredoxin. A thioredoxin system (trxA, trxB, msrA) and manganese uptake via mntH may contribute to further layers of ROS defence. Their specific contribution to the HBRA004 phenotype remains to be experimentally and comparatively validated. These findings represent the first genomically characterised 10&#xa0;kGy-resistant bacterial isolate from the Chavara-Neendakara HBRA, establishing a new benchmark for radiation tolerance within this ecologically significant environment. Pathway depth, gene copy amplification, and Mn/Fe homeostasis appear to be candidate mechanisms contributing to high-level radiation tolerance, consistent with patterns in other radiation-resistant taxa, though their contribution requires functional validation.

DNA double-strand breaks (DSBs) that occur during mitosis are primarily repaired by Pol&#x3b8;-mediated microhomology-mediated end joining (MMEJ). The CIP2A-TOPBP1 complex has been shown to tether broken chromatin at mitotic DSBs, but whether it coordinates with or functions independently of Pol&#x3b8; remains unknown. Here, we show that the CIP2A-TOPBP1 complex is recruited to mitotic DSB sites, where it directly interacts with Pol&#x3b8; and corecruits Pol&#x3b8; to chromatin. CIP2A sustains Pol&#x3b8; phosphorylation by inhibiting PP2A, thereby prolonging Pol&#x3b8; chromatin retention and enabling efficient repair. Upon repair completion, the CIP2A-TOPBP1 complex dissociates, PP2A dephosphorylates Pol&#x3b8;, and Pol&#x3b8; is released from chromatin. Loss of CIP2A impairs tumor growth, while disruption of CIP2A-Pol&#x3b8; binding leads to persistent DNA damage, micronucleus formation, and synthetic lethality in BRCA1/2-deficient cells. These findings uncover a cooperative mechanism by which CIP2A-TOPBP1 dynamically regulates Pol&#x3b8; in mitotic DSB repair and provide insights into the synthetic lethal interaction of CIP2A with BRCA1/2 under radiotherapy.

Burnout and occupational stress among mental health providers within the U.S. Veterans Health Administration are of critical concern, particularly for clinicians providing trauma-focused evidence-based psychotherapies. Burnout has been defined and measured in different ways across studies. In this article, burnout is conceptualized as a work-related syndrome involving emotional exhaustion, cynicism, and reduced professional efficacy, while recognizing that other constructs such as secondary traumatic stress and moral distress may also affect provider well-being. This article describes the Intensive Virtual Evidence-Based Psychotherapy Team at the Veterans Affairs Pacific Islands Health Care System, a fully virtual 2- to 4-week program that delivers massed prolonged exposure therapy or the Unified Protocol with Whole Health integration. Although the Intensive Virtual Evidence-Based Psychotherapy Team was developed as a clinical care model for Veterans, it was also intentionally structured in ways that support provider well-being at the service-delivery, team, and individual levels. Preliminary local program evaluation findings are presented. In a small retrospective pre-post evaluation, staff reported greater perceived support and lower burnout, secondary traumatic stress, and moral distress after joining the Intensive Virtual Evidence-Based Psychotherapy Team. A second 8-week Employee Whole Health initiative showed favorable descriptive trends and positive qualitative feedback regarding job satisfaction, collegial support, and accountability for personal wellness goals. Findings should be interpreted as preliminary given the nature of the small program evaluation. This article highlights one approach to promote provider well-being and embed sustainable practices into clinical program design in Veterans Health Administration mental health settings. (PsycInfo Database Record (c) 2026 APA, all rights reserved).