Pseudoprolines as stereoelectronically tunable proline isosteres.

The cyclic structure of proline (Pro) confers unique conformational properties on this natural amino acid that influences polypeptide structure and function. Pseudoprolines are a family of Pro isosteres that incorporate a heteroatom, most prominently oxygen or sulfur but also silicon and selenium, to replace the Cß or Cγ carbon atom of the pyrrolidine ring. These readily synthetically accessible structural motifs can facilitate facile molecular editing in a fashion that allows modulation of the amide bond topology of dipeptide elements and influence over ring pucker. While the properties of pseudoprolines have been exploited most prominently in the design of oligopeptide analogues, they have potential application in the design and optimization of small molecules. In this Digest, we summarize the physicochemical properties of pseudoprolines and illustrate their potential in drug discovery by surveying examples of applications in the design of bioactive molecules.

Factors effecting recurrence and progression of high grade non invasive bladder cancer treated by intravesical BCG.

OBJECTIVE: The rate of recurrence in high grade non muscle invasive bladder cancer (NMIBC) is 70% with progression rate of 15-40% at 5 years. The treatment of high grade NMIBC is intravesical BCG therapy, however for high risk cases radical cystectomy is recommended. In this study we determined the response of high grade NMIBC to BCG therapy and the factors affecting it in south Asian population. METHODS: This retrospective cohort study was conducted on 64 patients treated with intravesical BCG for high grade NMIBC from Dec 2008 to July 2012. Smoking, tumor size, location and multiplicity were taken as prognostic factors. Recurrence and progression were determined by cystoscopy and upper tract imaging according to European Association of Urology guidelines. The association of prognostic factors with recurrence and progression was determined. RESULTS: The rate of recurrence and progression was found to 45.8% and 27.1% respectively after a mean follow up 28.36 months. Smokers had 4 times greater odds of progression of tumor as compared to non-smokers. Patients with large tumors had 6.7 times greater odds of progression as compared to patients with small tumors. CONCLUSION: Smokers with large and multiple high grade NMIBC constitute the high risk group. These patients may be offered early radical cystectomy and advised to stop smoking.

Mechanistic insights into C-C coupling in electrocatalytic CO2 reduction reaction.

The utilization of CO2 has become an emerging area of research in response to climate change and global warming. The electrochemical CO2 reduction reaction (CO2RR) holds significant promise as a technology to address this issue by converting CO2 molecules into various commercially valuable chemicals. While CO2RR to C1 hydrocarbons has achieved high activity and selectivity, the C-C coupling to produce higher hydrocarbons remains challenging due to low energy efficiency and the prevalent hydrogen evolution reaction (HER) on the same catalyst, leading to high hydrogenation rates. In this review, we aim to elucidate the fundamental challenges of C-C coupling and explore potential strategies to enhance the selectivity for higher hydrocarbon products. We discuss the mechanisms underlying the formation of C2 and C3 products, focusing on molecular catalysts that facilitate C-C coupling by positioning CO2 molecules in close proximity. Additionally, we provide a comprehensive overview of different approaches to improve higher hydrocarbon selectivity, along with future suggestions and recommendations for new researchers in the field. This review serves as a valuable resource for both academic researchers and industrial stakeholders aiming for the commercialization of CO2RR technologies.

Diabetes Mellitus and Coronary Revascularization: Comparing Outcomes Between Coronary Artery Bypass Grafting and Percutaneous Coronary Intervention.

Background Coronary artery disease (CAD) significantly contributes to morbidity and mortality globally, particularly in individuals with diabetes mellitus, who are at a heightened risk for cardiovascular complications. The complexity of coronary lesions and diffuse atherosclerosis in diabetic patients presents challenges in their treatment and prognosis. Coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) are primary revascularization strategies for managing multi-vessel CAD in diabetic patients. Despite advancements in both techniques, their relative efficacy and safety remain debated, especially in the diabetic population. Objective This multicenter study aims to compare the long-term outcomes of CABG and PCI in diabetic patients with multi-vessel CAD. The primary endpoints include overall survival and the incidence of major adverse cardiac events (MACE). Secondary endpoints encompass revascularization success and procedural complication rates. Methods This retrospective cohort study was conducted across multiple centers, and the research spanned from January 2020 to December 2021. A total of 500 diabetic patients with multi-vessel CAD were included: 250 underwent CABG and 250 received PCI. Data were collected from electronic health records, capturing demographic details, clinical characteristics, procedural specifics, and follow-up outcomes over 24 months. Statistical analyses were performed using SPSS version 25 (IBM Corp., Armonk, NY), including Kaplan-Meier survival curves and Cox proportional hazards regression. Results The mean age of participants was 60.3 ± 10.5 years, with males constituting 52% of each group. Both groups achieved a high revascularization success rate of 90%. The CABG group treated more vessels on average (2.3 ± 0.7) compared to the PCI group (1.9 ± 0.8) (p < 0.001). Survival rates were higher in the CABG group (88%) compared to the PCI group (82%) (p = 0.08). MACE incidence was lower in the CABG group (22%) compared to the PCI group (28%) (p = 0.10). Procedural complications were marginally higher in the CABG group (16%) than in the PCI group (14%) (p = 0.60). Conclusion Both CABG and PCI are effective revascularization options for diabetic patients with multi-vessel CAD. CABG may offer a slight advantage in long-term survival and reduction in MACE, although the differences were not statistically significant. These findings suggest that individualized treatment strategies should be considered to optimize patient outcomes.

Melting lithium alloying to improve the affinity of Cu foil for ultra-thin lithium metal anode.

Before lithium (Li) metal can be formally used as the anode material of Li-ion battery, the key technical defects of Li metal electrode, such as low active Li metal proportion and low mechanical strength, must be solved. Herein, the surface affinity of molten lithium-copper (LiCu) alloy with Cu foil is improved by alloying Cu and Li in a molten state. The surface of Cu foil naturally adsorbs an ultra-thin (∼30 µm) composite Li metal layer. The ultra-thin composite Li metal layer can greatly reduce the amount of inactive Li, and the Cu foil improves the mechanical strength and engineering workability of Li metal anode. In addition, the enhanced Young's modulus facilitates the uniform Li plating/stripping process. As a result, the stable cycle stability of up to 600 h and the average overpotential of 13 mV (area specific capacity is 1 mAh cm-2 and current density is 1 mA cm-2) are achieved. The cycle life is higher than 150 h even though the maximum utilization rate of Li is greater than 50%. The Li metal full battery assembled with the commercial NCM811 cathode shows more stable cycle performance and Coulombic efficiency. Such strategy can effectively pave the way for the practical application of Li metal anode.

A Multimodal Approach towards Genomic Identification of Protein Inhibitors of Uracil-DNA Glycosylase.

DNA-mimicking proteins encoded by viruses can modulate processes such as innate cellular immunity. An example is Ung-family uracil-DNA glycosylase inhibition, which prevents Ung-mediated degradation via the stoichiometric protein blockade of the Ung DNA-binding cleft. This is significant where uracil-DNA is a key determinant in the replication and distribution of virus genomes. Unrelated protein folds support a common physicochemical spatial strategy for Ung inhibition, characterised by pronounced sequence plasticity within the diverse fold families. That, and the fact that relatively few template sequences are biochemically verified to encode Ung inhibitor proteins, presents a barrier to the straightforward identification of Ung inhibitors in genomic sequences. In this study, distant homologs of known Ung inhibitors were characterised via structural biology and structure prediction methods. A recombinant cellular survival assay and in vitro biochemical assay were used to screen distant variants and mutants to further explore tolerated sequence plasticity in motifs supporting Ung inhibition. The resulting validated sequence repertoire defines an expanded set of heuristic sequence and biophysical signatures shared by known Ung inhibitor proteins. A computational search of genome database sequences and the results of recombinant tests of selected output sequences obtained are presented here.

Predictive Potential Of Il28b Gene In Hcv Patients, Resistant To Daclatasvir And Sofosbuvir In KPK Population.

Background: Recently various combinations of direct acting antivirals (DAAs) have been tried successfully. The Sofosbuvir + Daclatasvir combination has been used with promising results. Recently, resistance has been noticed against DAAs. Therefore, polymorphism at particular sites in the interleukin 28B gene are under study to find possible association with resistance. This study was aimed at finding out any association of SNPs rs8099917 and rs12979860 (IL28B gene) with response and resistance to treatment in HCV genotype 3 patients in Khyber Pakhtunkhwa. Methods: This cross sectional, Analytical study was conducted at Gastroenterology/hepatology OPD of Prime Teaching Hospital, Peshawar Medical College. Collected Samples were stored at -20o C in PCR Lab of the College. DNA extraction and genotyping was carried out at BJ Molecular Biology Lab in Rawalpindi. Data was analyzed by using SPSS version 21. Chi-Square Test was used to see the statistically significant differences between rs8099917 T/G and rs12979860 T/C model. Results: In the IL28-B gene, single nucleotide polymorphism at rs12979860 T/C model, we observed that there are 37.5% CC homozygous, 12.5% TT homozygous and 50% CT heterozygous genotypes in resistant patients and 42.85% CC homozygous, 28.57% TT and 28.57% CT genotype in responder group. In rs12979860 T/C model, genotype of IL28-B in the responder and resistant group significantly varies at p-value =0.00572. Conclusion: We conclude that in SNP at rs12979860, CC genotype is associated with clearance of HCV, while CT genotype was more prevalent in the resistant group and associated with chronicity.

Influence of Welded Pores on Very Long-Life Fatigue Failure of the Electron Beam Welding Joint of TC17 Titanium Alloy.

The electron beam welding process is widely used in the connection among titanium alloy material parts of aero-engines. Its mechanical properties need to meet the requirements of long life and high reliability. In this paper, the static strength and the fatigue failure behavior of the electron beam weldments of TC17 titanium alloy were investigated experimentally under low amplitude high frequency (20 kHz), and the mechanical response and failure mechanism under different external loading conditions were analyzed. In summary, the samples were found to have anisotropic microstructure. The tensile strength of the PWHT of TC17 EBW joint was ~4.5% lower than that of the base metal. Meanwhile, compared with the base metal, the fatigue strength was reduced by 45.5% at 109 cycles of fatigue life. The fracture analysis showed that the fatigue failure of the welded joint of TC17 alloy was caused by the welded pores and the fatigue cracks initiated from the welded pores. A fine granular area (FGA) was observed around the crack initiation region. The existence of pores caused the stress intensity factor of the fine granular area (KFGA) to be inversely proportional to the fatigue life. The KFGA calculation formula was modified and the fatigue crack propagation threshold of the welded joint of TC17 alloy was calculated (3.62 MPa·m1/2). Moreover, the influences of the effective size and the relative depth of the pores on the very long fatigue life of the electron beam welded joint of TC17 titanium alloy were discussed.