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Ataxia telangiectasia mutated and Rad3-related (ATR), a vital member of the phosphatidylinositol 3-kinase-related kinase (PIKK) family, plays a critical role in the DNA damage response (DDR). Tumor cells with a loss of DDR function or defects in the ataxia telangiectasia mutated (ATM) gene are generally more dependent on ATR for survival, suggesting that ATR is an attractive anticancer drug target based on its synthetic lethality. Herein, we present a potent and highly selective ATR inhibitor, ZH-12 (IC50 = 0.0068 μM). It showed potent antitumor activity as a single agent or in combination with cisplatin in the human colorectal adenocarcinoma LoVo tumor xenograft mouse model. Overall, ZH-12 may be a promising ATR inhibitor based on the principle of synthetic lethality and deserves further in-depth study.

The DNA damage response (DDR) system is a complicated network of signaling pathways that detects and repairs DNA damage or induces apoptosis. Critical regulators of the DDR network include the DNA damage kinases ataxia telangiectasia mutated Rad3-related kinase (ATR) and ataxia-telangiectasia mutated (ATM). The ATR pathway coordinates processes such as replication stress response, stabilization of replication forks, cell cycle arrest, and DNA repair. ATR inhibition disrupts these functions, causing a reduction of DNA repair, accumulation of DNA damage, replication fork collapse, inappropriate mitotic entry, and mitotic catastrophe. Recent data have shown that the inhibition of ATR can lead to synthetic lethality in ATM-deficient malignancies. In addition, ATR inhibition plays a significant role in the activation of the immune system by increasing the tumor mutational burden and neoantigen load as well as by triggering the accumulation of cytosolic DNA and subsequently inducing the cGAS-STING pathway and the type I IFN response. Taken together, we review stimulating data showing that ATR kinase inhibition can alter the DDR network, the immune system, and their interplay and, therefore, potentially provide a novel strategy to improve the efficacy of antitumor therapy, using ATR inhibitors as monotherapy or in combination with genotoxic drugs and/or immunomodulators.

DNA replication stress (RS) causes genomic instability and vulnerability in cancer cells. To counteract RS, cells have evolved various mechanisms involving the ATR kinase signaling pathway, which regulates origin firing, cell cycle checkpoints, and fork stabilization to secure the fidelity of replication. However, ATR signaling also alleviates RS to support cell survival by driving RS tolerance, thereby contributing to therapeutic resistance. Cancer cells harboring genetic mutations and other changes that disrupt normal DNA replication increase the risk of DNA damage and the levels of RS, conferring addiction to ATR activity for sustainable replication and susceptibility to therapeutic approaches using ATR inhibitors (ATRis). Therefore, clinical trials are currently being conducted to evaluate the efficacy of ATRis as monotherapies or in combination with other drugs and biomarkers. In this review, we discuss recent advances in the elucidation of the mechanisms by which ATR functions in the RS response and its therapeutic relevance when utilizing ATRis. Potential models of action of ataxia telangiectasia and Rad3‐related inhibitors (ATRis) depending on DNA replication stress (RS) levels. Cancer cells often harbor increased RS because of oncogene activation and/or DNA damage response defects and become RS tolerant by acquiring ATR‐mediated RS tolerance mechanisms, thereby conferring susceptibility to therapeutic approaches using ATRis. RS at levels over the threshold, induced by ATRis as monotherapies or in combination with other drugs, can lead to cell death through replication catastrophe and mitotic catastrophe.

In this paper, a spectral collection of over 150 ATR-FT-IR spectra of materials related to cultural heritage and conservation science has been presented that have been measured in the extended region of 4000-80 cm(-1) (mid-IR and far-IR region). The applicability of the spectra and, in particular, the extended spectral range, for investigation of art-related materials is demonstrated on a case study. This collection of ATRFT-IR reference spectra is freely available online (http://tera.chem.ut.ee/IR_spectra/) and is meant to be a useful tool for researchers in the field of conservation and materials science.

The hydrogen evolution reaction (HER) is a critical process in the electrolysis of water. Recently, much effort has been dedicated to developing low‐cost, highly efficient, and stable electrocatalysts. Transition metal phosphides are investigated intensively due to their high electronic conductivity and optimized absorption energy of intermediates in acid electrolytes. However, the low stability of metal phosphide materials in air and during electrocatalytic processes causes a decay of performance and hinders the discovery of specific active sites. The HER in alkaline media is more intricate, which requires further delicate design due to the Volmer steps. In this work, phosphorus‐modified monoclinic β‐CoMoO4 is developed as a low‐cost, efficient, and stable HER electrocatalyst for the electrolysis of water in alkaline media. The optimized catalyst shows a small overpotential of 94 mV to reach a current density of 10 mA cm−2 for the HER with high stability in KOH electrolyte, and an overpotential of 197 mV to reach a current density of 100 mA cm−2. Combined computational and in situ spectroscopic techniques show P is present as a surface phosphate ion; that electron holes localize on the surface ions and both (PO1−) and Co3+OH− are prospective surface active sites for the HER. A P‐doped Ni foam/CoMoO4 electrocatalyst is successfully prepared by a facile hydrothermal‐annealing method. Optimized P‐doped Ni foam/CoMoO4 shows excellent hydrogen evolution reaction (HER) activity (94 mV@10 mA cm−2) and remarkable stability in 1 M KOH. A combined in situ spectroscopic and computational study shows the mechanism of P doping and active sites for the catalyst.

Background The ataxia telangiectasia and Rad3-related (ATR) checkpoint kinase 1 (CHK1) pathway plays an essential role in suppressing replication stress from DNA damage and oncogene activation. Main body Preclinical studies have shown that cancer cells with defective DNA repair mechanisms or cell cycle checkpoints may be particularly sensitive to ATR inhibitors. Preclinical and clinical data from early-phase trials on three ATR inhibitors (M6620, AZD6738, and BAY1895344), either as monotherapy or in combination, were reviewed. Conclusion Data from ATR inhibitor-based combinational trials might lead to future expansion of this therapy to homologous recombination repair pathway-proficient cancers and potentially serve as a rescue therapy for patients who have progressed through poly ADP-ribose polymerase inhibitors.

Schlafen-11 (SLFN11) inactivation in ∼50% of cancer cells confers broad chemoresistance. To identify therapeutic targets and underlying molecular mechanisms for overcoming chemoresistance, we performed an unbiased genome-wide RNAi screen in SLFN11-WT and -knockout (KO) cells. We found that inactivation of Ataxia Telangiectasia- and Rad3-related (ATR), CHK1, BRCA2, and RPA1 overcome chemoresistance to camptothecin (CPT) in SLFN11-KO cells. Accordingly, we validate that clinical inhibitors of ATR (M4344 and M6620) and CHK1 (SRA737) resensitize SLFN11-KO cells to topotecan, indotecan, etoposide, cisplatin, and talazoparib. We uncover that ATR inhibition significantly increases mitotic defects along with increased CDT1 phosphorylation, which destabilizes kinetochore-microtubule attachments in SLFN11-KO cells. We also reveal a chemoresistance mechanism by which CDT1 degradation is retarded, eventually inducing replication reactivation under DNA damage in SLFN11-KO cells. In contrast, in SLFN11-expressing cells, SLFN11 promotes the degradation of CDT1 in response to CPT by binding to DDB1 of CUL4CDT2 E3 ubiquitin ligase associated with replication forks. We show that the C terminus and ATPase domain of SLFN11 are required for DDB1 binding and CDT1 degradation. Furthermore, we identify a therapyrelevant ATPase mutant (E669K) of the SLFN11 gene in human TCGA and show that the mutant contributes to chemoresistance and retarded CDT1 degradation. Taken together, our study reveals new chemotherapeutic insights on how targeting the ATR pathway overcomes chemoresistance of SLFN11-deficient cancers. It also demonstrates that SLFN11 irreversibly arrests replication by degrading CDT1 through the DDB1–CUL4CDT2 ubiquitin ligase.

The current measurement techniques described in the literature for the determination of the carbonyl index (CI) for polyolefins such as polyethylene and polypropylene were compared and contrasted. These were all found to be inconsistent or inaccurate and were not capable of differentiating significant changes in carbonyl peak evolution throughout accelerated ageing. As a consequence of these findings, a methodology, specified area under band (SAUB) is presented here to more accurately represent the CI as a general means of reporting. The increased precision in the methodology is explained and compared to other methodologies for determining CI. The SAUB method is also shown to be capable of elucidating the differences in relative extent and rates of CI for different polyolefins, exposed to the same conditions over the same time period.

This study investigated the relationship between the parameters of the DLP manufacturing process and the structure of photopolymerizable acrylic resins. Four different process parameters were established to produce different thin-walled acrylic sample series: exposure time, layer thickness, area offset, and number of transition layers. The structure and the surface of the obtained samples were examined with the use of the FTIR–ATR method and an optical microscope, respectively. It was proved that extension of the exposure time increases the density of crosslinking and sample thickness. A decreasing crosslinking density due to rising layer thickness is observed. The area offset affects only the dimensions of the sample, predictably reducing the dimensions of the sample as the compensation increases. The absence of transition layers proved unfavorable in many respects, both structurally and geometrically.

Edible Bird’s Nest (EBN) is a highly prized food product, making it a frequent target for economic adulteration. Consequently, robust quality assurance is paramount to protect consumers and ensure market integrity. A significant barrier to effective quality control, however, is an incomplete understanding of the natural chemical variability within authentic EBN. This variability, influenced by factors such as geographical origin, bird species, and post-harvest processing, can confound analytical measurements and complicate the definition of a standard reference. This study provides an existence proof in a defined cohort, characterizing microscale chemical heterogeneity in authentic A. fuciphagus EBN. We employed a multi-modal Fourier Transform Infrared (FTIR) spectroscopy approach, integrating transmission, macro-attenuated total reflectance (ATR), and high-resolution micro-ATR chemical imaging. A diverse set of validated, authentic EBN samples was analyzed using unsupervised Principal Component Analysis (PCA) to explore the data structure. Our results reveal significant and previously unquantified spectral heterogeneity, particularly in protein and glycoprotein-related regions. In our cohort, the chemical signatures of authentic EBN do not collapse to a single, uniform profile but span a broad, multi-dimensional continuum. This inherent variability presents a critical challenge for conventional quality control methods that rely on simplistic, single-spectrum standards, which may lead to the misclassification of genuine products. By establishing a robust chemical baseline for the authentic class, this work provides the foundational data essential for developing next-generation authentication models capable of reliably distinguishing this natural variance from deliberate adulteration.