Hydrogen peroxide is produced upon radiolysis of water and has been shown to be the main oxidant driving oxidative dissolution of UO2-based nuclear fuel under geological repository conditions. While ...the overall mechanism and speciation are well known for granitic groundwaters, considerably less is known for saline waters of relevance in rock salt or during emergency cooling of reactors using seawater. In this work, the ternary uranyl–peroxo–chloro and uranyl–peroxo–bromo complexes were identified using IR, Raman, and nuclear magnetic resonance (NMR) spectroscopy. Based on Raman spectra, the estimated stability constants for the identified uranyl–peroxo–chloro ((UO2)(O2)(Cl)(H2O)2 –) and uranyl–peroxo–bromo ((UO2)(O2)(Br)(H2O)2 –) complexes are 0.17 and 0.04, respectively, at ionic strength ≈5 mol/L. It was found that the uranyl–peroxo–chloro complex is more stable than the uranyl–peroxo–bromo complex, which transforms into studtite at high uranyl and H2O2 concentrations. Studtite is also found to be dissolved at a high ionic strength, implying that this may not be a stable solid phase under very saline conditions. The uranyl–peroxo–bromo complex was shown to facilitate H2O2 decomposition via a mechanism involving reactive intermediates.
A high-performance liquid chromatographic method was developed for the simultaneous determination of the related substances-three potential synthesis-related chemical impurities and the distomer-of ...escitalopram. The separation capacity of seven different polysaccharide-type chiral columns, including three amylose-based (Lux Amylose-1, Lux i-Amylose-1, Lux Amylose-2) and four cellulose-based columns (Lux Cellulose-1, Lux Cellulose-2, Lux Cellulose-3, and Lux Cellulose-4) were screened in the polar organic and reversed-phase modes. Lux Cellulose-1, based on cellulose tris(3,5-dimethylphenylcarbamate) as the chiral selector with an acetonitrile-water mixture containing 0.1% diethylamine was identified as the most promising separation system. Using the "one factor at a time" optimization approach, the effect of column temperature, flow rate, and mobile phase constituents on separation performance was evaluated, and the critical resolution values were determined. A U-shaped retention pattern was obtained when plotting the retention factors of the citalopram enantiomers versus the water content of the binary mobile phases on the Lux Cellulose-1 column. A thermodynamic analysis revealed enthalpy-driven enantioseparation in both the polar organic and reversed-phase modes. For further method optimizations, an L9 orthogonal array table was employed. Using the optimized parameters (Lux Cellulose-1 column with 0.1% (
/
) diethylamine in water/acetonitrile 55/45 (
/
); 0.8 mL/min flow rate at 25 °C), baseline separations were achieved between all compounds. Our newly developed HPLC method was validated according to the ICH guidelines and its application was tested with a commercially available pharmaceutical formulation. The method proved to be suitable for routine quality control of related substances and the enantiomeric purity of escitalopram.
We modify the construction of knot Floer homology to produce a one-parameter family of homologies tHFK for knots in S3. These invariants can be used to give homomorphisms from the smooth concordance ...group C to Z, giving bounds on the four-ball genus and the concordance genus of knots. We give some applications of these homomorphisms.
A new, reversed-phase HPLC (RP-HPLC) method was developed for the simultaneous determination of the dipeptidyl-peptidase-IV-inhibitor antidiabetic drug vildagliptin (VIL) enantiomeric impurity and ...four other achiral related impurities. An initial screening was performed on five polysaccharide-type chiral stationary phases (Lux Amylose-1, Lux Amylose-2, Lux-Cellulose-1, Lux-Cellulose-2, Lux-Cellulose-3) in polar organic mode with methanol, ethanol, 2-propanol, or acetonitrile containing 0,1% diethylamine as mobile phase to identify the best conditions for the separation of VIL enantiomers. Lux-Cellulose-2 column was found to provide the best chiral resolution for VIL enantiomers. Further experiments were conducted using different aqueous-organic mobile phases to achieve the simultaneous chiral-achiral separation of the selected compounds. Experimental design-based optimization was performed by using a face-centered central composite design. The optimal separation conditions (Lux Cellulose-2 stationary phase, 45 °C, mobile phase consisting of methanol/water/diethylamine 80:20:0.2 (v/v/v), and 0.45 mL/min flow rate) provided baseline separation for all 6 compounds. The optimized method was validated according to the ICH guideline and proved to be reliable, specific, linear, precise, and accurate for the determination of at least 0.1% for all impurities in VIL samples. The validated method was applied for determinations from a commercially available drug formulation and proved to be suitable for routine quality control of both enantiomeric and organic impurities of VIL.
•Enantiomeric separation of vildagliptin using Lux-Cellulose-2 column.•First published method for the simultaneous quantification of vildagliptin chiral and achiral impurities.•Method optimization based on response surface methodology.•Applicability in routine quality control of drug products.
Due to the proliferation of large language models (LLMs) and their widespread use in applications such as ChatGPT, there has been a significant increase in interest in AI over the past year. Multiple ...researchers have raised the question: how will AI be applied and in what areas? Programming, including the generation, interpretation, analysis, and documentation of static program code based on promptsis one of the most promising fields. With the GPT API, we have explored a new aspect of this: static analysis of the source code of front-end applications at the endpoints of the data path. Our focus was the detection of the CWE-653 vulnerability—inadequately isolated sensitive code segments that could lead to unauthorized access or data leakage. This type of vulnerability detection consists of the detection of code segments dealing with sensitive data and the categorization of the isolation and protection levels of those segments that were previously not feasible without human intervention. However, we believed that the interpretive capabilities of GPT models could be explored to create a set of prompts to detect these cases on a file-by-file basis for the applications under study, and the efficiency of the method could pave the way for additional analysis tasks that were previously unavailable for automation. In the introduction to our paper, we characterize in detail the problem space of vulnerability and weakness detection, the challenges of the domain, and the advances that have been achieved in similarly complex areas using GPT or other LLMs. Then, we present our methodology, which includes our classification of sensitive data and protection levels. This is followed by the process of preprocessing, analyzing, and evaluating static code. This was achieved through a series of GPT prompts containing parts of static source code, utilizing few-shot examples and chain-of-thought techniques that detected sensitive code segments and mapped the complex code base into manageable JSON structures.Finally, we present our findings and evaluation of the open source project analysis, comparing the results of the GPT-based pipelines with manual evaluations, highlighting that the field yields a high research value. The results show a vulnerability detection rate for this particular type of model of 88.76%, among others.
Tumors are composed of abnormally transformed cell types and tissues that differ from normal tissues in their genetic and epigenetic makeup, metabolism, and immunology. Molecular compounds that ...modulate the immune response against neoplasms offer promising new strategies to combat cancer. Inhibitors targeting the indoleamine-2,3-dioxygenase 1 enzyme (IDO1) represent one of the most potent therapeutic opportunities to inhibit tumor growth. Herein, we assess the biochemical role of IDO1 in tumor metabolism and immune surveillance, and review current diagnostic and therapeutic approaches that are intended to increase the effectiveness of immunotherapies against highly aggressive and difficult-to-treat IDO-expressing cancers.
Myeloid cell leukemia 1 (Mcl-1), an antiapoptotic member of the Bcl-2 family of proteins, whose upregulation when observed in human cancers is associated with high tumor grade, poor survival, and ...resistance to chemotherapy, has emerged as an attractive target for cancer therapy. Here, we report the discovery of selective small molecule inhibitors of Mcl-1 that inhibit cellular activity. Fragment screening identified thienopyrimidine amino acids as promising but nonselective hits that were optimized using nuclear magnetic resonance and X-ray-derived structural information. The introduction of hindered rotation along a biaryl axis has conferred high selectivity to the compounds, and cellular activity was brought on scale by offsetting the negative charge of the anchoring carboxylate group. The obtained compounds described here exhibit nanomolar binding affinity and mechanism-based cellular efficacy, caspase induction, and growth inhibition. These early research efforts illustrate drug discovery optimization from thienopyrimidine hits to a lead compound, the chemical series leading to the identification of our more advanced compounds S63845 and S64315.
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