Category: 3. Business

  • Kyndryl announces leadership rotations and appointments

    Kyndryl announces leadership rotations and appointments

    Harsh Chugh will take on an expanded role as Global Head of Practices, Corporate Development and Administration. In this new role, he will lead Kyndryl’s Global Practices, effective immediately, and will lead Corporate Development beginning May 1. Country practices will continue to operate with the same reporting structure as they do today. Chugh will integrate the practices and corporate development agenda for future growth with a focus on leveraging the combined and holistic value the practices provide customers, while maintaining a flat structure. As Kyndryl’s Chief Operating Officer, Chugh has transformed the company through the successful transition services agreement (TSA) exit and solved tough commercial challenges. Chugh will continue to own all aspects of operations for Kyndryl.

    Farhaz Thobani will become Chief Administrative Officer, responsible for Kyndryl’s operations, real estate, quote to cash and procurement, effective immediately. As President of Kyndryl Canada, Thobani transformed Kyndryl’s Canadian business while fostering a highly engaged team. Under his leadership, the team has strengthened customer relationships, elevated Kyndryl’s brand presence and laid a robust foundation for sustained growth in Canada.

    Paul Savill will become, effective immediately, Global Practice Leader, Cyber Security and Resiliency, Network and Edge, which is a newly combined Global Practice that reflects the integrated way customers view and purchase network and security offerings. Previously, as Global Practice Leader for Network and Edge, Paul has been a senior leader at Kyndryl since it became an independent company and has transformed the Network and Edge Practice to focus on growth and innovation while building a strong, experienced team. He will bring together these two teams of experts to provide customers with a unified set of capabilities and support.

    Ivan Dopplé has decided to retire following a distinguished career at Kyndryl. After building and leading Kyndryl operations during its transition to an independent company, Dopplé has led its Digital Workplace Services (DWS) Global Practice. Dopplé has been instrumental in establishing Kyndryl’s eminence in the DWS space, driven by a deep passion for customers and keen industry insights. Dopplé has also been an advocate for the company’s culture, including his leadership as the Executive Sponsor for KIN True Ability. He will remain at Kyndryl until July to transition with his successor and work on projects focused on advancing the company’s growth.

    Michael Przytula will join Kyndryl on January 19 as Global Practice Leader, Digital Workplace. Przytula brings almost 30 years of experience leading and delivering Digital Workplace and Service Desk services for global customers at Accenture, Dell and HP. He has spent his career in this space, working across every role in the practice and brings a global perspective shaped by living and working in Australia, Asia and the United States.

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  • Pursuit, Adoption of State-Level OZ Incentives on a Longer Timeline, Say Experts – Novogradac

    1. Pursuit, Adoption of State-Level OZ Incentives on a Longer Timeline, Say Experts  Novogradac
    2. Why 2026 Is a Pivotal Year for Opportunity Zones  OpportunityZones.com
    3. Opportunity Zones are about to matter again, says GTIS Partners’ head of capital markets  InvestmentNews
    4. Help clients take advantage of new opportunity zone tax advantages  Accounting Today

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  • Whataburger launches new ‘Whatadeal’ menu for 2026

    Whataburger launches new ‘Whatadeal’ menu for 2026

    The menu is available for a limited time only at participating locations

    Whataburger launches new deals menu for 2026 (Copyright Whataburger)

    SAN ANTONIO – Whataburger is giving you more to love in 2026 with a new Whatadeal menu.

    You can enjoy options for as low as $3 for a limited time only at participating locations, according to a press release from the popular chain.

    The new menu includes three options, with the ability to add small fries and a small drink for $2.49.

    “We’ve always believed that good, fresh food should be easy to enjoy and easy on the wallet,” said Whataburger Senior Vice President and CMO Scott Hudler. “The Whatadeal menu is our way of giving fans more of what they love at prices that make it easy to come hungry and leave full.”

    You can get a Big Ranch Wrap for $3. Whataburger said this is its Whatachick’n Strip with fresh veggies, ranch and American cheese wrapped in a tortilla.

    For $4, you can chow down on a five-count Whatachick’n Bites. Just like it sounds, these are bite-sized crispy chicken pieces for dipping and snacking.

    The Bacon and Cheese Whataburger Jr. is available for $5. The chain said this features a 100% beef patty topped with bacon and melty cheese.

    You can learn more on Whataburger’s website.


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  • Capecchi, M. R. Altering the genome by homologous recombination. Science 244, 1288–1292 (1989).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Gowen, L. C., Johnson, B. L., Latour, A. M., Sulik, K. K. & Koller, B. H. Brca1 deficiency results in early embryonic lethality characterized by neuroepithelial abnormalities. Nat. Genet. 12, 191–194 (1996).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Hakem, R. et al. The tumor suppressor gene Brca1 is required for embryonic cellular proliferation in the mouse. Cell 85, 1009–1023 (1996).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Liu, C. Y., Flesken-Nikitin, A., Li, S., Zeng, Y. & Lee, W. H. Inactivation of the mouse Brca1 gene leads to failure in the morphogenesis of the egg cylinder in early postimplantation development. Genes Dev. 10, 1835–1843 (1996).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Ludwig, T., Chapman, D. L., Papaioannou, V. E. & Efstratiadis, A. Targeted mutations of breast cancer susceptibility gene homologs in mice: lethal phenotypes of Brca1, Brca2, Brca1/Brca2, Brca1/p53, and Brca2/p53 nullizygous embryos. Genes Dev. 11, 1226–1241 (1997).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Sharan, S. K. et al. Embryonic lethality and radiation hypersensitivity mediated by Rad51 in mice lacking Brca2. Nature 386, 804–810 (1997).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Suzuki, A. et al. Brca2 is required for embryonic cellular proliferation in the mouse. Genes Dev. 11, 1242–1252 (1997).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Shen, S. X. et al. A targeted disruption of the murine Brca1 gene causes γ-irradiation hypersensitivity and genetic instability. Oncogene 17, 3115–3124 (1998).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Xu, X. et al. Centrosome amplification and a defective G2–M cell cycle checkpoint induce genetic instability in BRCA1 exon 11 isoform-deficient cells. Mol. Cell 3, 389–395 (1999).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Connor, F. et al. Tumorigenesis and a DNA repair defect in mice with a truncating Brca2 mutation. Nat. Genet. 17, 423–430 (1997).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Patel, K. J. et al. Involvement of Brca2 in DNA repair. Mol. Cell 1, 347–357 (1998).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Tutt, A. et al. Mutation in Brca2 stimulates error-prone homology-directed repair of DNA double-strand breaks occurring between repeated sequences. EMBO J. 20, 4704–4716 (2001).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Lomonosov, M., Anand, S., Sangrithi, M., Davies, R. & Venkitaraman, A. R. Stabilization of stalled DNA replication forks by the BRCA2 breast cancer susceptibility protein. Genes Dev. 17, 3017–3022 (2003).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Schlacher, K. et al. Double-strand break repair-independent role for BRCA2 in blocking stalled replication fork degradation by MRE11. Cell 145, 529–542 (2011).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Schlacher, K., Wu, H. & Jasin, M. A distinct replication fork protection pathway connects Fanconi anemia tumor suppressors to RAD51–BRCA1/2. Cancer Cell 22, 106–116 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Hatchi, E. et al. BRCA1 recruitment to transcriptional pause sites is required for R-loop-driven DNA damage repair. Mol. Cell 57, 636–647 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Shivji, M. K. K., Renaudin, X., Williams, C. H. & Venkitaraman, A. R. BRCA2 regulates transcription elongation by RNA polymerase II to prevent R-loop accumulation. Cell Rep. 22, 1031–1039 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Zhang, X. et al. Attenuation of RNA polymerase II pausing mitigates BRCA1-associated R-loop accumulation and tumorigenesis. Nat. Commun. 8, 15908 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Patel, P. S. et al. RNF168 regulates R-loop resolution and genomic stability in BRCA1/2-deficient tumors. J. Clin. Invest. 131, e140105 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Xu, X., Aprelikova, O., Moens, P., Deng, C.-X. & Furth, P. A. Impaired meiotic DNA-damage repair and lack of crossing-over during spermatogenesis in BRCA1 full-length isoform deficient mice. Development 130, 2001–2012 (2003).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Broering, T. J. et al. BRCA1 establishes DNA damage signaling and pericentric heterochromatin of the X chromosome in male meiosis. J. Cell Biol. 205, 663–675 (2014).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Sharan, S. K. et al. BRCA2 deficiency in mice leads to meiotic impairment and infertility. Development 131, 131–142 (2004).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Hakem, R., de la Pompa, J. L., Elia, A., Potter, J. & Mak, T. W. Partial rescue of Brca15–6 early embryonic lethality by p53 or p21 null mutation. Nat. Genet. 16, 298–302 (1997).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Xu, X. et al. Genetic interactions between tumor suppressors Brca1 and p53 in apoptosis, cell cycle and tumorigenesis. Nat. Genet. 28, 266–271 (2001).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Cao, L. et al. ATM–Chk2–p53 activation prevents tumorigenesis at an expense of organ homeostasis upon Brca1 deficiency. EMBO J. 25, 2167–2177 (2006).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Cao, L. et al. A selective requirement for 53BP1 in the biological response to genomic instability induced by Brca1 deficiency. Mol. Cell 35, 534–541 (2009).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Bouwman, P. et al. 53BP1 loss rescues BRCA1 deficiency and is associated with triple-negative and BRCA-mutated breast cancers. Nat. Struct. Mol. Biol. 17, 688–695 (2010).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Bunting, S. F. et al. 53BP1 inhibits homologous recombination in Brca1-deficient cells by blocking resection of DNA breaks. Cell 141, 243–254 (2010).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Petrucelli, N., Daly, M. B. & Pal, T. In GeneReviews (eds Adam, M. P. et al.) (University of Washington, 1998–2025).

  • Ludwig, T., Fisher, P., Ganesan, S. & Efstratiadis, A. Tumorigenesis in mice carrying a truncating Brca1 mutation. Genes Dev. 15, 1188–1193 (2001).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Bachelier, R. et al. Normal lymphocyte development and thymic lymphoma formation in Brca1 exon-11-deficient mice. Oncogene 22, 528–537 (2003).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Kim, S. S. et al. Hyperplasia and spontaneous tumor development in the gynecologic system in mice lacking the BRCA1-Δ11 isoform. Mol. Cell. Biol. 26, 6983–6992 (2006).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Friedman, L. S. et al. Thymic lymphomas in mice with a truncating mutation in Brca2. Cancer Res. 58, 1338–1343 (1998).

    CAS 
    PubMed 

    Google Scholar 

  • McAllister, K. A. et al. Cancer susceptibility of mice with a homozygous deletion in the COOH-terminal domain of the Brca2 gene. Cancer Res. 62, 990–994 (2002).

    CAS 
    PubMed 

    Google Scholar 

  • Xu, X. et al. Conditional mutation of Brca1 in mammary epithelial cells results in blunted ductal morphogenesis and tumour formation. Nat. Genet. 22, 37–43 (1999).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Liu, X. et al. Somatic loss of BRCA1 and p53 in mice induces mammary tumors with features of human BRCA1-mutated basal-like breast cancer. Proc. Natl Acad. Sci. USA 104, 12111–12116 (2007).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • McCarthy, A. et al. A mouse model of basal-like breast carcinoma with metaplastic elements. J. Pathol. 211, 389–398 (2007).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Jonkers, J. et al. Synergistic tumor suppressor activity of BRCA2 and p53 in a conditional mouse model for breast cancer. Nat. Genet. 29, 418–425 (2001).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Ludwig, T., Fisher, P., Murty, V. & Efstratiadis, A. Development of mammary adenocarcinomas by tissue-specific knockout of Brca2 in mice. Oncogene 20, 3937–3948 (2001).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Szabova, L. et al. Perturbation of Rb, p53, and Brca1 or Brca2 cooperate in inducing metastatic serous epithelial ovarian cancer. Cancer Res. 72, 4141–4153 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Perets, R. et al. Transformation of the fallopian tube secretory epithelium leads to high-grade serous ovarian cancer in Brca;Tp53;Pten models. Cancer Cell 24, 751–765 (2013).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Levanon, K., Crum, C. & Drapkin, R. New insights into the pathogenesis of serous ovarian cancer and its clinical impact. J. Clin. Oncol. 26, 5284–5293 (2008).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Iyer, S. et al. Genetically defined syngeneic mouse models of ovarian cancer as tools for the discovery of combination immunotherapy. Cancer Discov. 11, 384–407 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Skoulidis, F. et al. Germline Brca2 heterozygosity promotes KrasG12D-driven carcinogenesis in a murine model of familial pancreatic cancer. Cancer Cell 18, 499–509 (2010).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Rowley, M. et al. Inactivation of Brca2 promotes Trp53-associated but inhibits KrasG12D-dependent pancreatic cancer development in mice. Gastroenterology 140, 1303–1313 (2011).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Shakya, R. et al. BRCA1 tumor suppression depends on BRCT phosphoprotein binding, but not its E3 ligase activity. Science 334, 525–528 (2011).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Drost, R. et al. BRCA1 RING function is essential for tumor suppression but dispensable for therapy resistance. Cancer Cell 20, 797–809 (2011).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Drost, R. et al. BRCA1185delAG tumors may acquire therapy resistance through expression of RING-less BRCA1. J. Clin. Invest. 126, 2903–2918 (2016).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Chen, J. et al. 53BP1 loss rescues embryonic lethality but not genomic instability of BRCA1 total knockout mice. Cell Death Differ. 27, 2552–2567 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Nacson, J. et al. BRCA1 mutational complementation induces synthetic viability. Mol. Cell 78, 951–959 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Park, D. et al. Ablation of the Brca1–Palb2 interaction phenocopies Fanconi anemia in mice. Cancer Res. 80, 4172–4184 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Pulver, E. M. et al. A BRCA1 coiled-coil domain variant disrupting PALB2 interaction promotes the development of mammary tumors and confers a targetable defect in homologous recombination repair. Cancer Res. 81, 6171–6182 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Krais, J. J. et al. RNF168-mediated localization of BARD1 recruits the BRCA1–PALB2 complex to DNA damage. Nat. Commun. 12, 5016 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Hartford, S. A. et al. Interaction with PALB2 is essential for maintenance of genomic integrity by BRCA2. PLoS Genet. 12, e1006236 (2016).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Lim, P. X., Zaman, M., Feng, W. & Jasin, M. BRCA2 promotes genomic integrity and therapy resistance primarily through its role in homology-directed repair. Mol. Cell 84, 447–462 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Atanassov, B. S., Barrett, J. C. & Davis, B. J. Homozygous germ line mutation in exon 27 of murine Brca2 disrupts the Fancd2–Brca2 pathway in the homologous recombination-mediated DNA interstrand cross-links’ repair but does not affect meiosis. Genes Chromosomes Cancer 44, 429–437 (2005).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Pathania, S. et al. BRCA1 haploinsufficiency for replication stress suppression in primary cells. Nat. Commun. 5, 5496 (2014).

    Article 
    PubMed 

    Google Scholar 

  • Konishi, H. et al. Mutation of a single allele of the cancer susceptibility gene BRCA1 leads to genomic instability in human breast epithelial cells. Proc. Natl Acad. Sci. USA 108, 17773–17778 (2011).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Sedic, M. et al. Haploinsufficiency for BRCA1 leads to cell-type-specific genomic instability and premature senescence. Nat. Commun. 6, 7505 (2015).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Zong, D. et al. BRCA1 haploinsufficiency is masked by RNF168-mediated chromatin ubiquitylation. Mol. Cell 73, 1267–1281 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Li, C. M. et al. Brca1 haploinsufficiency promotes early tumor onset and epigenetic alterations in a mouse model of hereditary breast cancer. Nat. Genet. 56, 2763–2775 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Kumar, P. et al. Cooperativity of Rb, Brca1, and p53 in malignant breast cancer evolution. PLoS Genet. 8, e1003027 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Annunziato, S. et al. Comparative oncogenomics identifies combinations of driver genes and drug targets in BRCA1-mutated breast cancer. Nat. Commun. 10, 397 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Liu, H. et al. Identifying and targeting sporadic oncogenic genetic aberrations in mouse models of triple-negative breast cancer. Cancer Discov. 8, 354–369 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Menghi, F. et al. The tandem duplicator phenotype is a prevalent genome-wide cancer configuration driven by distinct gene mutations. Cancer Cell 34, 197–210 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Molyneux, G. et al. BRCA1 basal-like breast cancers originate from luminal epithelial progenitors and not from basal stem cells. Cell Stem Cell 7, 403–417 (2010).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Sau, A. et al. Persistent activation of NF-κB in BRCA1-deficient mammary progenitors drives aberrant proliferation and accumulation of DNA damage. Cell Stem Cell 19, 52–65 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Bach, K. et al. Time-resolved single-cell analysis of Brca1 associated mammary tumourigenesis reveals aberrant differentiation of luminal progenitors. Nat. Commun. 12, 1502 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Ciwinska, M. et al. Mechanisms that clear mutations drive field cancerization in mammary tissue. Nature 633, 198–206 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Rottenberg, S. et al. Selective induction of chemotherapy resistance of mammary tumors in a conditional mouse model for hereditary breast cancer. Proc. Natl Acad. Sci. USA 104, 12117–12122 (2007).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Zander, S. A. et al. Sensitivity and acquired resistance of BRCA1;p53-deficient mouse mammary tumors to the topoisomerase I inhibitor topotecan. Cancer Res. 70, 1700–1710 (2010).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Pajic, M. et al. Tumor-initiating cells are not enriched in cisplatin-surviving BRCA1;p53-deficient mammary tumor cells in vivo. Cell Cycle 9, 3780–3791 (2010).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Pajic, M. et al. Selected alkylating agents can overcome drug tolerance of G0-like tumor cells and eradicate BRCA1-deficient mammary tumors in mice. Clin. Cancer Res. 23, 7020–7033 (2017).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Evers, B. et al. A high-throughput pharmaceutical screen identifies compounds with specific toxicity against BRCA2-deficient tumors. Clin. Cancer Res. 16, 99–108 (2010).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Planells-Cases, R. et al. Subunit composition of VRAC channels determines substrate specificity and cellular resistance to Pt-based anti-cancer drugs. EMBO J. 34, 2993–3008 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Widmer, C. A. et al. Loss of the volume-regulated anion channel components LRRC8A and LRRC8D limits platinum drug efficacy. Cancer Res. Commun. 2, 1266–1281 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Rottenberg, S. et al. High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs. Proc. Natl Acad. Sci. USA 105, 17079–17084 (2008).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Hay, T. et al. Poly(ADP-ribose) polymerase-1 inhibitor treatment regresses autochthonous Brca2/p53-mutant mammary tumors in vivo and delays tumor relapse in combination with carboplatin. Cancer Res. 69, 3850–3855 (2009).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Jaspers, J. E. et al. Loss of 53BP1 causes PARP inhibitor resistance in Brca1-mutated mouse mammary tumors. Cancer Discov. 3, 68–81 (2013).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Xu, G. et al. REV7 counteracts DNA double-strand break resection and affects PARP inhibition. Nature 521, 541–544 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Barazas, M. et al. The CST complex mediates end protection at double-strand breaks and promotes PARP inhibitor sensitivity in BRCA1-deficient cells. Cell Rep. 23, 2107–2118 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Ter Brugge, P. et al. Mechanisms of therapy resistance in patient-derived xenograft models of BRCA1-deficient breast cancer. J. Natl Cancer Inst. 108, djw148 (2016).

    Article 

    Google Scholar 

  • Gogola, E. et al. Selective Loss of PARG restores PARylation and counteracts PARP inhibitor-mediated synthetic lethality. Cancer Cell 33, 1078–1093 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Paes Dias, M. et al. Loss of nuclear DNA ligase III reverts PARP inhibitor resistance in BRCA1/53BP1 double-deficient cells by exposing ssDNA gaps. Mol. Cell 81, 4692–4708 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Barazas, M. et al. Radiosensitivity is an acquired vulnerability of PARPi-resistant BRCA1-deficient tumors. Cancer Res. 79, 452–460 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Juvekar, A. et al. Combining a PI3K inhibitor with a PARP inhibitor provides an effective therapy for BRCA1-related breast cancer. Cancer Discov. 2, 1048–1063 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Ding, L. et al. PARP inhibition elicits STING-dependent antitumor immunity in Brca1-deficient ovarian cancer. Cell Rep. 25, 2972–2980 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Pantelidou, C. et al. PARP inhibitor efficacy depends on CD8+ T-cell recruitment via intratumoral STING pathway activation in BRCA-deficient models of triple-negative breast cancer. Cancer Discov. 9, 722–737 (2019).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Wang, Q. et al. STING agonism reprograms tumor-associated macrophages and overcomes resistance to PARP inhibition in BRCA1-deficient models of breast cancer. Nat. Commun. 13, 3022 (2022).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Zatreanu, D. et al. Polθ inhibitors elicit BRCA-gene synthetic lethality and target PARP inhibitor resistance. Nat. Commun. 12, 3636 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Zhou, J. et al. A first-in-class polymerase θ inhibitor selectively targets homologous-recombination-deficient tumors. Nat. Cancer 2, 598–610 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Mateos-Gomez, P. A. et al. Mammalian polymerase θ promotes alternative NHEJ and suppresses recombination. Nature 518, 254–257 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Ceccaldi, R. et al. Homologous-recombination-deficient tumours are dependent on Polθ-mediated repair. Nature 518, 258–262 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Krais, J. J. et al. Genetic separation of Brca1 functions reveal mutation-dependent Polθ vulnerabilities. Nat. Commun. 14, 7714 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • DuPage, M. & Jacks, T. Genetically engineered mouse models of cancer reveal new insights about the antitumor immune response. Curr. Opin. Immunol. 25, 192–199 (2013).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Nolan, E. et al. Combined immune checkpoint blockade as a therapeutic strategy for BRCA1-mutated breast cancer. Sci. Transl. Med. 9, eaal4922 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Rebbeck, T. R. et al. Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations. N. Engl. J. Med. 346, 1616–1622 (2002).

    Article 
    PubMed 

    Google Scholar 

  • Poole, A. J. et al. Prevention of Brca1-mediated mammary tumorigenesis in mice by a progesterone antagonist. Science 314, 1467–1470 (2006).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Nolan, E. et al. RANK ligand as a potential target for breast cancer prevention in BRCA1-mutation carriers. Nat. Med. 22, 933–939 (2016).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Sigl, V. et al. RANKL/RANK control Brca1 mutation-driven mammary tumors. Cell Res. 26, 761–774 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • van de Ven, M. et al. BRCA1-associated mammary tumorigenesis is dependent on estrogen rather than progesterone signaling. J. Pathol. 246, 41–53 (2018).

    Article 
    PubMed 

    Google Scholar 

  • Gorrini, C. et al. Estrogen controls the survival of BRCA1-deficient cells via a PI3K–NRF2-regulated pathway. Proc. Natl Acad. Sci. USA 111, 4472–4477 (2014).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Vinayak, S. & Ford, J. M. PARP inhibitors for the treatment and prevention of breast cancer. Curr. Breast Cancer Rep. 2, 190–197 (2010).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • To, C. et al. The PARP inhibitors, veliparib and olaparib, are effective chemopreventive agents for delaying mammary tumor development in BRCA1-deficient mice. Cancer Prev. Res. 7, 698–707 (2014).

    Article 
    CAS 

    Google Scholar 

  • van de Ven, M. et al. Prophylactic window therapy with the clinical poly(ADP-ribose) polymerase inhibitor olaparib delays BRCA1-deficient mammary tumour formation in mice. J. Pathol. 241, 511–521 (2017).

    Article 
    PubMed 

    Google Scholar 

  • Zeng, J. et al. A genetic mosaic mouse model illuminates the pre-malignant progression of basal-like breast cancer. Dis. Model. Mech. 16, dmm050219 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Singh, A. K. & Yu, X. Tissue-specific carcinogens as soil to seed BRCA1/2-mutant hereditary cancers. Trends Cancer 6, 559–568 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Kass, E. M., Lim, P. X., Helgadottir, H. R., Moynahan, M. E. & Jasin, M. Robust homology-directed repair within mouse mammary tissue is not specifically affected by Brca2 mutation. Nat. Commun. 7, 13241 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Uijttewaal, E. C. H. et al. CRISPR-StAR enables high-resolution genetic screening in complex in vivo models. Nat. Biotechnol. 43, 1848–1860 (2024).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Yamashita, M. et al. Cell-type specific, inducible and acute degradation of targeted protein in mice by two degron systems. Nat. Commun. 15, 10129 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Pettitt, S. J. et al. Clinical BRCA1/2 reversion analysis identifies hotspot mutations and predicted neoantigens associated with therapy resistance. Cancer Discov. 10, 1475–1488 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Billing, D. et al. The BRCT domains of the BRCA1 and BARD1 tumor suppressors differentially regulate homology-directed repair and stalled fork protection. Mol. Cell 72, 127–139 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Stratton, M. R. Pathology of familial breast cancer: differences between breast cancers in carriers of BRCA1 or BRCA2 mutations and sporadic cases. Lancet 349, 1505–1510 (1997).

    Article 

    Google Scholar 

  • Lakhani, S. R. et al. Multifactorial analysis of differences between sporadic breast cancers and cancers involving BRCA1 and BRCA2 mutations. J. Natl Cancer Inst. 90, 1138–1145 (1998).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Bhin, J. et al. Multi-omics analysis reveals distinct non-reversion mechanisms of PARPi resistance in BRCA1- versus BRCA2-deficient mammary tumors. Cell Rep. 42, 112538 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Holstege, H. et al. Cross-species comparison of aCGH data from mouse and human BRCA1– and BRCA2-mutated breast cancers. BMC Cancer 10, 455 (2010).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

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  • Rice stripe virus utilizes a Laodelphax striatellus salivary carbonic anhydrase to facilitate plant infection by direct molecular interaction

    Rice stripe virus utilizes a Laodelphax striatellus salivary carbonic anhydrase to facilitate plant infection by direct molecular interaction

    During plant virus transmission by piercing-sucking insects, most viruses are inoculated into the plant phloem via the insect’s secreted saliva (Arcà and Ribeiro, 2018; Conway et al., 2016; Wu et al., 2022). Thus, insect saliva acts as an interface for the virus–insect–host tripartite interaction and can directly promote viral transmission to, and infection of, the host plants (Sun et al., 2020; Wu et al., 2022). However, despite the importance of insect salivary proteins in this tripartite interaction, there is still much to learn about how these proteins enable successful viral infection.

    Previous studies have revealed that there are two ways in which insect saliva facilitates viral infection. One is an indirect approach whereby the saliva modulates the host microenvironment at the feeding site, and saliva effectors work together to allow the arthropod to go unnoticed while it feeds on the host plant (Acevedo et al., 2019; Arcà and Ribeiro, 2018; Sun et al., 2020). For example, our work indicated that a Laodelphax striatellus mucin protein, LssaMP, enables the formation of the salivary sheath and facilitates the transmission of rice stripe virus (RSV) into the rice phloem (Huo et al., 2022). The study on leafhoppers revealed that the expression of a saliva calcium-binding protein is inhibited by rice gall dwarf virus (RGDV), thus causing an increase of cytosolic Ca2+ levels in rice and triggering callose deposition and H2O2 production. This increases the frequency of insect probing, thereby enhancing viral horizontal transmission into the rice phloem (Wu et al., 2022). The other mechanism by insect saliva to facilitate virus infection is direct regulation, whereby saliva proteins promote virus transmission through specific molecular interactions (Wen et al., 2019). Direct saliva protein–pathogen interactions have been reported in animal pathogens. For example, during transmission of Borrelia burgdorferi by Ixodes scapularis, the saliva protein Salp15 of I. scapularis binds to the bacterial outer surface protein C, which prevents the bacterium from being recognized by the animal immune system. In this way, the saliva protein enables the pathogen to infect the animal host (Ramamoorthi et al., 2005; Schuijt et al., 2008). Although most plant viruses are heavily dependent on insect vectors for plant-to-plant transmission (Gray, 2008), the direct function of insect saliva proteins in mediating virus transmission remains largely uninvestigated.

    During sap-feeding, arthropods produce two distinct types of saliva at different stages of the feeding process: gel saliva and watery saliva (Bonaventure, 2012; Lou et al., 2019). The former forms a salivary sheath to provide a smooth path for the stylet penetration (Lou et al., 2019). The latter is mainly secreted into the phloem sieve elements to prevent them from plugging up and suppress plant defense responses. Some salivary components may act as herbivore-associated molecular patterns that can trigger pattern-triggered immunity, and certain salivary effectors may be recognized by plant resistance proteins to induce effector-triggered immunity, etc. (Huang et al., 2017; Ji et al., 2017; Yi et al., 2021).

    For phloem-feeding insects, callose deposited on phloem sieve plate and plasmodesmata of sieve elements functions as a defense mechanism by reducing insect feeding and preventing viral movement (Hao et al., 2008; Hipper et al., 2013; Will and Vilcinskas, 2015; Zavaliev et al., 2011; Yue et al., 2022). Callose is a β-(1,3)-D-glucan polysaccharide that is synthesized by callose synthases and degraded by β-(1,3)-glucanases. Plants defend themselves by depositing callose at the sieve plates and plasmodesmata in response to virus infection, whereas viruses counter this defense by activating β-(1,3)-glucanases to degrade callose (Bucher et al., 2001; Hao et al., 2008; Wu et al., 2022; Zavaliev et al., 2011).

    RSV is the causative agent of rice stripe disease, a serious disease of rice crops that has occurred repeatedly in China, Japan, and Korea (Xu et al., 2021). RSV is completely dependent on insect vectors for transmission among its host plants, and L. striatellus is the main vector (Xu et al., 2021; Zhao et al., 2017). L. striatellus transmits RSV in a persistent-propagative manner. The virus initially infects the midgut, then disperses from the hemolymph into the salivary glands and is inoculated into the plant host during L. striatellus feeding (Huo et al., 2022). L. striatellus belongs to the order Hemiptera, whose members mainly feed from sieve tubes through their mouthparts (stylets) that penetrate plant tissues and reach sieve tubes to ingest the phloem sap (Tjallingii, 2006; van Bel and Will, 2016). RSV is mainly secreted into the rice phloem via the watery saliva (Huo et al., 2022; Wang and Blanc, 2021).

    In this study, we identified a molecular interaction among RSV, an L. striatellus saliva protein, and a plant β-1,3-glucanase. The insect saliva protein directly binds to the RSV nucleocapsid protein (NP) and then binds to a rice thaumatin-like protein to activate its β-1,3-glucanase activity. The activation of β-1,3-glucanase helps RSV infection by inhibiting callose deposition in response to viral infection.

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  • the golden thread through textile recycling? – CEPS

    the golden thread through textile recycling? – CEPS


    The European textile sector continues to operate on largely linear production models, with around 73 % of post-consumer textiles in the EU incinerated or landfilled. Transitioning to a system of durable, reusable, repairable, and recyclable textiles is therefore essential to reducing waste, emissions, and virgin resource dependency. This transition relies on high-quality product and material data. Traceability enables the tracking of fibres, processes, and actors across the supply chain, while transparency ensures that information is accessible to the relevant stakeholders. Reliable data underpin circular business models, support verification of environmental claims, and improve sorting, reuse, and recycling efficiency.

    This PESCO-UP policy brief aims to contribute timely evidence to the ongoing debate on traceability and transparency in the textiles sector. This comes at a critical moment when the Delegated Act for Textiles under the Ecodesign for Sustainable Products Regulation (ESPR) is still under preparation. Once adopted, it will define compulsory data to be collected and shared, governance rules, and implementation timelines for the Digital Product Passport (DPP) in the textiles sector. As such, it is essential that the requirements reflect real needs and capacities of actors involved in textile sorting and recycling, while also taking potential challenges for these and other actors in the supply chain (including brands, software providers, manufacturers etc.) into account. Ensuring that the DPP is practical, relevant, and scalable will be crucial to unlocking circular business models in the sector and ultimately achieving the environmental and social outcomes the EU has set for the textile industry.

     

    This policy brief was written in the context of the PESCO-UP project, funded by the European Union under grand agreement No. 101138367. This policy brief was first published on .

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  • EBRD promotes domestic production of pharmaceuticals in Uzbekistan

    EBRD promotes domestic production of pharmaceuticals in Uzbekistan

    • EBRD provides US$ 20 million to Nika Pharm
    • Company to increase its production capacity, achieve GMP certification
    • Project will stimulate local production of medicines

    The European Bank for Reconstruction and Development (EBRD) is promoting further growth in domestic production of pharmaceutical products in Uzbekistan by supporting the operations of leading local manufacturer Nika Pharm. 

    Nika Pharm will use the EBRD loan of up to US$ 20 million to restructure its balance sheet and upgrade equipment and facilities in order to increase production capacity, improve product quality and bring the entire manufacturing process into compliance with the Good Manufacturing Practice (GMP) standards of the World Health Organisation’s certification scheme.

    The company has been an EBRD client since 2021 and is a well-established producer of tablets, capsules, sachets and nasal sprays for use in the treatment of common colds, as well as in gastroenterology, paediatrics and urology. During this time, Nika Pharm has become a leader in several key segments, including decongestants, and has shown strong and sustainable growth by replacing imports with high-quality local production.

    The project will help to expand Nika Pharm’s manufacturing base, improve its sustainability and efficiency, and lead to an average 140 per cent increase in the company’s production of generic pharmaceuticals and prescription drugs. Together with GMP certification, this will allow Nika Pharm to strengthen its position both domestically and regionally.

    Uzbekistan’s rapidly growing pharmaceuticals market, which is set to expand by a further 10 per cent by 2029, is dominated (around 75 per cent) by imported medicines. The project will help contribute to the government’s plan of eventually bringing the share of locally produced pharmaceuticals to 80 per cent.

    The EBRD has invested over US$ 6.6 billion in Uzbekistan to date through 196 projects, with the majority of those funds supporting private entrepreneurship, contributing to the country’s economic development.

     

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  • Invitation to the 2025 full year results

    Invitation to the 2025 full year results

    Givaudan will announce its 2025 full year results on 29 January 2026.

    A media release, the integrated and financial reports and the full year results presentation will be published on our website at 07:00 CET. Our live webcast for analysts and investors will be broadcasted at 11:00 CET.

     
    The conference call will be hosted by Gilles Andrier, Chief Executive Officer and Stewart Harris, Chief Financial Officer.

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  • Tomorrowland to hold its first-ever Asia festival in Thailand

    Tomorrowland to hold its first-ever Asia festival in Thailand

    Pre-registration for tickets begins on 8 January. A “full madness pass” covering all three days of the festival will cost 12,500 baht ($400; £300) while a single-day pass is going at 5,100 baht.

    More details on the festival’s theme and line-up will follow soon, organisers said.

    Although the Tomorrowland group has held events in some Asian cities, this is the first time it will be holding an entire festival in the continent, and one that is similar to the scale of what it does in Belgium.

    Thailand finalised an agreement with Tomorrowland to host the event for five years and expects it to generate 21bn baht ($673m; £497m) over the period, Thai media reported.

    “Expanding Tomorrowland to a new continent is a milestone we approach with great respect and excitement… This is the beginning of a long-term story,” said Tomorrowland’s chief executive officer Bruno Vanwelsenaers.

    In recent years, Thailand has become a strong contender in the live music scene. Last year, it played host to international music festivals like Electric Daisy Carnival and Creamfields. Bangkok was also a stop on K-pop band Blackpink’s world tour last October.

    And the country’s homegrown music and arts festival Wonderfruit is emerging as a hot destination on the festival circuit, drawing tens of thousands of people each year.

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  • Türkiye: Preliminary Project Preparation Study for Floating Solar PV Plants

    The European Bank for Reconstruction and Development (the “EBRD” or the “Bank”), within its Green Economy Transition (“GET”) approach, is committed to scale up financing of projects that advance the transition to environmentally sustainable, low-carbon economies in its Countries of Operation (“CoO”), including advanced and innovative renewable energy solutions.

    Besides mature ground-mounted applications, floating solar PV power plants are becoming increasingly popular as costs continue to fall and the interest of reducing land use starts to grow. Quite a few floating applications have become operational or are under construction around the world, ranging in size from a few MW to hundreds of MW each (the biggest currently in operation is the 1 GW Dongying Offshore Floating Solar Farm in China). The total cumulative capacity will likely exceed 10 GW by the end of 2025, driven heavily by large projects in the Asia-Pacific region (China, India, Indonesia). The project pipeline exceeds 60 GW, indicating significant planned growth.

    Floating PV has the advantage of performing better in hot and humid ambient conditions in comparison with ground-mounted plants due to the combined effect of water and wind cooling on panels and cables. Additionally, floating PV has been found to contribute to water conservation due to the ability to reduce water evaporation and algae growth.

    The present study specifically focuses on the viability of developing a cumulative floating PV capacity of up to 3,000 MW over the surface of [3] lakes (the “Projects”).

    The ability to rely on the related existing high-voltage grid infrastructure for the Projects would be an obvious technical and economic advantage. The lakes have a vast theoretical potential for floating PV – in this sense, the choice of the location and design capacity of the Projects is expected to be driven by technical, economic, environmental and considerations on other existing uses of the reservoirs, while still being large enough to be potentially meaningful in terms of electricity production and replicability of the concept.

    As an important side benefit, the Projects might help increasing the water available downstream of the lakes for irrigation and civil uses, thanks to its possible contribution to reducing water evaporation losses. At the same time, the study will carefully consider the possible environmental and social risk and impacts associated with of the Projects including impacts to biodiversity and the local ecosystem, as well as lakes users including irrigation, fishing and recreational activities, energy production, etc., and how these can be addressed and mitigated in line with good international practice.

    The Consultant will be guided by the environmental and social issues considered in EBRD’s Environmental and Social Policy and its associated Performance Requirements.

    The main objective of the assignment is to study and identify the main technical characteristics of the Projects to ensure they meet best international practice, minimise technical, environmental and social risks.

    The main tasks of the study are to support the EBRD and the relevant stakeholders in Türkiye in defining the main features of the Projects, including the overall size and potential locations in each lake, the anticipated investment costs and electricity production estimates, the identification of the main preliminary technical specifications as well as any regulatory or market issues that need to be addressed for the implementation of the Projects.

    The main Counterparts for the assignment will be the Ministry of Energy and Natural Resources, the Electricity Generation Company (EUAS) and the Turkish Electricity Transmission Company (TEIAS).

     

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