Clinical outcome and intraprocedural characteristics of left atrial appendage occlusion: a comparison between single-occlusive plug-type and dual-occlusive disc-type devices.

Background: Percutaneous interventional left atrial appendage occlusion (LAAO) is a reliable, safe, and effective alternative for stroke prevention in selected patients with atrial fibrillation (AF). Methods: In a retrospective observational study, 149 patients underwent LAAO between 2016 and 2022 at the Department of Cardiology of the Charité-Universitätsmedizin Berlin, Campus Virchow, with AF for prevention of thromboembolic complications. We compared patient characteristics, intraoperative details and postoperative outcomes between single-occlusive plug-type (SOPT) and dual-occlusive disc-type (DODT) devices. Results: In all patients, the device implantation was successful. 60 patients received a SOPT occluder, including Watchman (35%) and Watchman FLX Occluders (65%), while 89 patients received a DODT occluder, including Amplatzer Cardiac Plug (37.1%), the Amplatzer Amulet (25.8%), and the LAmbre occluder (37.1%) systems. Procedure duration was significantly longer for DODT occluder implantation (49 ± 33 vs. 41 ± 25 min, p = 0.018). There were no in-hospital deaths or thromboembolic events reported after LAAO in both groups. Beyond that, a low rate of bleeding or access-side-related complications and pericardial tamponades were observed. Anticoagulation at discharge varied. About 60.8% of patients received dual antiplatelet therapy at hospital discharge, and 33.1% received direct oral anticoagulants. A 6-month follow-up was obtained in 85% of the patients. All implanted devices were in the desired position. However, in 5.7% of the patients, a device-related thrombus formation was detected in the SOPT group, while no thrombus was seen in the DODT group (p = 0.11). Thromboembolic events were noticed in 3.1%, without any difference between the device types. There was a statistically non-significant trend for less residual device leaks after SOPT vs. DODT implantation (no leak in 71.7% vs. 62.2%, p = 0.07; minor leaks <5 mm, 9.4% vs. 20.3%, p = 0.1). In the SOPT group, less bleeding complications were reported after LAAO (11.3% vs. 17.6%, p = 0.1). Conclusion: Our data suggest the safety and efficiency of LAAO with a very high procedural implantation success rate irrespective of the used LAA device. Furthermore, no relevant procedural or device-related complication occurred during the 6-month follow-up in all patients.

Catheter-based ablation to improve outcomes in patients with atrial fibrillation and heart failure with preserved ejection fraction: Rationale and design of the CABA-HFPEF-DZHK27 trial.

AIMS: Atrial fibrillation (AF) is common in heart failure (HF) and negatively impacts outcomes. The role of ablation-based rhythm control in patients with AF and HF with preserved (HFpEF) or mildly reduced ejection fraction (HFmrEF) is not known. The CABA-HFPEF-DZHK27 (CAtheter-Based Ablation of atrial fibrillation compared to conventional treatment in patients with Heart Failure with Preserved Ejection Fraction) trial will determine whether early catheter ablation for AF can prevent adverse cardiovascular outcomes in patients with HFpEF or HFmrEF. METHODS: CABA-HFPEF-DZHK27 (NCT05508256) is an investigator-initiated, prospective, randomized, open, interventional multicentre strategy trial with blinded outcome assessment. Approximately 1548 patients with paroxysmal or persistent AF diagnosed within 24 months prior to enrolment and HFpEF or HFmrEF will be randomized to early catheter ablation within 4 weeks after randomization or to usual care. All patients receive anticoagulation, rate control, and HF management according to current guideline recommendations. Usual care can include rhythm control in symptomatic patients. Patients will be followed until the end of the trial for the primary outcome, a composite of cardiovascular death, stroke, and total unplanned hospitalizations for HF or acute coronary syndrome. The safety outcome comprises complications of catheter ablation and death. The trial is powered for a rate ratio of 0.75 (two-sided alpha = 0.05, 1-beta = 0.8). CONCLUSION: CABA-HFPEF-DZHK27 will define the role of systematic and early catheter ablation in patients with AF and HFpEF or HFmrEF.

A Comparative In Vitro Physicochemical Analysis of Resin Infiltrants Doped With Bioactive Glasses.

Objective This study aimed to investigate the longevity and effectiveness of bioactive glass (BAG)-based dental resin infiltrants. Materials and methods The three types of BAG - 45S5 bioglass (RIS), boron-substituted (RIB), and fluoride-substituted (RIF) - were incorporated with photoinitiated dimethacrylate monomers to create experimental resin infiltrants. ICON® (CN; DMG-America, Ridgefield Park, NJ) and pure resin (PR) were used as control groups in this study. Disc-shaped samples were prepared for the experimental and control groups. The samples were challenged with the pH cycle and immersed in the artificial saliva for 30 days. On Day 0 and Day 30, the pH cycle and artificial saliva immersion, Vicker's microhardness, surface roughness, and surface morphology were investigated. Results The RIF group's disc samples showed the highest Vicker's microhardness values (78.20 ±0.06) on Day 30 of artificial saliva immersion, whereas the CN group's values were the lowest (55.99 ±0.24). Following the pH cycling, the RIF displayed the highest hardness (64.15 ±1.89) whereas the CN group's values were the lowest (33.47 ±1.28). Regarding surface roughness, on Day 30, the RIB resin group exhibited the highest (1.14 ±0.001 µm). In contrast, the CN resin showed the lowest (1.07 ±0.06 µm) values, while immersed in the artificial saliva solution. In the same duration of time, in the pH cycling solution, PR showed the least (0.85 ±0.89 µm), while RIF showed the highest roughness value (0.94 ±0.54 µm). Morphological analysis revealed that following the artificial saliva immersion, the RIB, CN, and PR exhibited smoother surfaces compared to the RIS and RIF groups. However, when immersed in the pH cycling solution, RIB and RIF showed more resistance against acid attack. Conclusions Our results revealed that the experimental resin groups performed much better than the commercial resin infiltrants following artificial saliva and pH cycling challenges.

MolDy: molecular dynamics simulation made easy.

MOTIVATION: Molecular dynamics (MD) is a computational experiment that is crucial for understanding the structure of biological macro and micro molecules, their folding, and the inter-molecular interactions. Accurate knowledge of these structural features is the cornerstone in drug development and elucidating macromolecules functions. The open-source GROMACS biomolecular MD simulation program is recognized as a reliable and frequently used simulation program for its precision. However, the user requires expertise, and scripting skills to carrying out MD simulations. RESULTS: We have developed an end-to-end interactive MD simulation application, MolDy for Gromacs. This front-end application provides a customizable user interface integrated with the Python and Perl-based logical backend connecting the Linux shell and Gromacs software. The tool performs analysis and provides the user with simulation trajectories and graphical representations of relevant biophysical parameters. The advantages of MolDy are (i) user-friendly, does not requiring the researcher to have prior knowledge of Linux; (ii) easy installation by a single command; (iii) freely available for academic research; (iv) can run with minimum configuration of operating systems; (v) has valid default prefilled parameters for beginners, and at the same time provides scope for modifications for expert users. AVAILABILITY AND IMPLEMENTATION: MolDy is available freely as compressed source code files with user manual for installation and operation on GitHub: https://github.com/AIBResearchMolDy/Moldyv01.git and on https://aibresearch.com/innovations.

Nano-Assembled Polyphosphazene Delivery System Enables Effective Intranasal Immunization with Nipah Virus Subunit Vaccine.

The ultimate vaccine against infections caused by Nipah virus should be capable of providing protection at the respiratory tract─the most probable port of entry for this pathogen. Intranasally delivered vaccines, which target nasal-associated lymphoid tissue and induce both systemic and mucosal immunity, are attractive candidates for enabling effective vaccination against this lethal disease. Herein, the water-soluble polyphosphazene delivery vehicle assembles into nanoscale supramolecular constructs with the soluble extracellular portion of the Hendra virus attachment glycoprotein─a promising subunit vaccine antigen against both Nipah and Hendra viruses. These supramolecular constructs signal through Toll-like receptor 7/8 and promote binding interactions with mucin─an important feature of effective mucosal adjuvants. High mass contrast of phosphorus-nitrogen backbone of the polymer enables a successful visualization of nanoconstructs in their vitrified state by cryogenic electron microscopy. Here, we characterize the self-assembly of polyphosphazene macromolecule with biologically relevant ligands by asymmetric flow field flow fractionation, dynamic light scattering, fluorescence spectrophotometry, and turbidimetric titration methods. Furthermore, a polyphosphazene-enabled intranasal Nipah vaccine candidate demonstrates the ability to induce immune responses in hamsters and shows superiority in inducing total IgG and neutralizing antibodies when benchmarked against the respective clinical stage alum adjuvanted vaccine. The results highlight the potential of polyphosphazene-enabled nanoassemblies in the development of intranasal vaccines.

A novel induced pluripotent stem cell model of Schwann cell differentiation reveals NF2 - related gene regulatory networks of the extracellular matrix.

Schwann cells are vital to development and maintenance of the peripheral nervous system and their dysfunction has been implicated in a range of neurological and neoplastic disorders, including NF2 -related schwannomatosis. We developed a novel human induced pluripotent stem cell (hiPSC) model to study Schwann cell differentiation in health and disease. We performed transcriptomic, immunofluorescence, and morphological analysis of hiPSC derived Schwann cell precursors (SPCs) and terminally differentiated Schwann cells (SCs) representing distinct stages of development. To validate our findings, we performed integrated, cross-species analyses across multiple external datasets at bulk and single cell resolution. Our hiPSC model of Schwann cell development shared overlapping gene expression signatures with human amniotic mesenchymal stem cell (hAMSCs) derived SCs and in vivo mouse models, but also revealed unique features that may reflect species-specific aspects of Schwann cell biology. Moreover, we identified gene co-expression modules that are dynamically regulated during hiPSC to SC differentiation associated with ear and neural development, cell fate determination, the NF2 gene, and extracellular matrix (ECM) organization. By cross-referencing results between multiple datasets, we identified new genes potentially associated with NF2 expression. Our hiPSC model further provides a tractable platform for studying Schwann cell development in the context of human disease.

ECEL1 related distal arthrogryposis 5D in an Indian cohort-Report of recognizable musculoskeletal phenotype and a possible founder variant.

Distal arthrogryposis type 5D (DA5D) is clinically characterized by knee extension contractures, distal joint contractures, clubfoot, micrognathia, ptosis, and scoliosis. We report nine affected individuals from eight unrelated Indian families with DA5D. Although the overall musculoskeletal phenotype is not very distinct from other distal arthrogryposis, the presence of fixed knee extension contractures with or without scoliosis could be an important early pointer to DA5D. We also report a possible founder variant in ECEL1 along with four novel variants and further expand the genotypic spectrum of DA5D.

Hesitancy Over the COVID-19 Vaccine Among Various Healthcare Workers: An International Narrative Review.

Healthcare workers (HCWs) are role models in their communities. If they receive the COVID-19 vaccine, many people are likely to follow and have the vaccine. If HCWs are hesitant or resistant to taking the vaccine, this may impede the efforts to implement the vaccine, reach herd immunity, and eliminate the pandemic. In this narrative review, we reviewed previous studies on hesitancy over COVID-19 vaccination among different healthcare professions and people in the medical field, such as primary HCWs, dentists, nurses, and medical students. We reviewed the common reasons and associated factors for hesitancy toward the COVID-19 vaccine among different healthcare professions. The following keywords were used in the database search: COVID-19 AND vaccine AND hesitancy AND healthcare workers. We searched for articles using the PubMed, Scopus, and Google Scholar databases. We found HCW professions with various rates of hesitancy, including primary healthcare center (PHC) workers (50%), medical students (45%), nurses (21%), and dentists (18%). Hesitancy toward booster doses was also found in HCWs who had taken primary doses (2.8% to 26%). Race and ethnicity also influenced hesitancy rates, with Black individuals being the most hesitant group. The most common reasons were concerns about the safety and adverse effects of the vaccine, insufficient information, and a lack of confidence in healthcare policies. Despite varying rates of HCW hesitancy after the vaccine's release, this hesitancy is expected to negatively affect efforts to achieve widespread vaccination. The recommendations to policymakers to address these concerns are raising the awareness of PHC doctors because they are the easiest to reach and are the first line for patient information, improving communication with the HCWs through all channels (e.g., webinars, e-mails, and social media), and inviting HCWs to online meetings or workshops with the healthcare policymakers so the policymakers can listen to their concerns and recommendations. Correctly addressing the issue of HCWs' vaccination hesitancy can support efforts to contain the pandemic.

The acidic C-terminal tail of DNA Gyrase of Salmonella enterica serovar Typhi controls DNA relaxation in an acidic environment.

The intracellular bacteria, Salmonella Typhi adapts to acidic conditions in the host cell by resetting the chromosomal DNA topology majorly controlled by DNA Gyrase, a Type II topoisomerase. DNA Gyrase forms a heterodimer A2B2 complex, which manages the DNA supercoiling and relaxation in the cell. DNA relaxation forms a part of the regulatory mechanism to activate the transcription of genes required to survive under hostile conditions. Acid-induced stress attenuates the supercoiling activity of the DNA Gyrase, resulting in DNA relaxation. Salmonella DNA becomes relaxed as the bacteria adapt to the acidified intracellular environment. Despite comprehensive studies on DNA Gyrase, the mechanism to control supercoiling activity needs to be better understood. A loss in supercoiling activity in E. coli was observed upon deletion of the non-conserved acidic C-tail of Gyrase A subunit. Salmonella Gyrase also contains an acidic tail at the C-terminus of Gyrase A, where its deletion resulted in reduced supercoiling activity compared to wild-type Gyrase. Interestingly, we also found that wild-type Gyrase compromises supercoiling activity at acidic pH 2-3, thereby causing DNA relaxation. The absence of a C-tail displayed DNA supercoiling to some extent between pH 2-9. Hence, the C-tail of Gyrase A might be one of the controlling factors that cause DNA relaxation in Salmonella at acidic pH conditions. We propose that the presence of the C-tail of GyraseA causes acid-mediated inhibition of the negative supercoiling activity of Gyrase, resulting in relaxed DNA that attracts DNA-binding proteins for controlling the transcriptional response.

Structure-based identification of potential natural compound inhibitors targeting bacterial cytoskeleton protein FtsZ from Acinetobacter baumannii by computational studies.

Acinetobacter baumannii is one of the multi-drug-resistant pathogens responsible for hospital-acquired infections reported worldwide. Clinically it is challenging to treat these pathogens as they have developed resistance against the existing class of antibiotics. Hence, there is an urgent need to develop a new class of antibiotics against these pathogens to prevent the spread of infections and mortality. In Acinetobacter baumannii, the filamentous temperature-sensitive mutant Z protein polymerizes at the imminent division site to form a Z-ring at the mid-point of the cell and act as a scaffold to recruit other cell division proteins involved in orchestrating septum synthesis in bacteria. Perturbation in the assembly of FtsZ affects bacterial cell dynamics and survival. Hence, FtsZ has emerged as a new drug target in antibiotic discovery to identify compounds that inhibit bacterial cell division. In this study, we have performed a virtual screening of 30,000 compounds from the ZINC Biogenic natural compound library targeting the nucleotide-binding site of FtsZ from Acinetobacter baumannii. We have identified 8 new natural compounds with binding energy in the range of -8.66 to -6.953 kcal/mol and analyzed them by 200 ns molecular dynamics simulations. Out of these eight compounds, ZINC14708526 showed the best binding with relatively optimal drug-likeness and medicinal chemistry as a potent inhibitor of abFtsZ. Thus, the identified FtsZ inhibitor ZINC14708526 is a promising lead compound to develop potent antimicrobial agents against Acinetobacter baumannii infections.Communicated by Ramaswamy H. Sarma.

Cardiac papillary fibroelastoma: a rare cause of ST-segment elevation myocardial infarction: a case report.

Introduction and importance: Primary tumors of the heart are extremely rare occurrences. Among them, cardiac papillary fibroelastoma (CPF) is the second most common type. Although these tumors are usually benign, they can pose a risk of embolization, which may lead to severe complications like sudden death or embolization affecting the neurological, systemic, or coronary vasculature. Such complications can be life-threatening. Case presentation: In this report, the authors present the case of a 68-year-old woman who experienced ST-segment elevation myocardial infarction due to embolization from a large papillary fibroelastoma. To address the issue, the authors performed a minimally invasive surgical removal and resection of the aortic valve, followed by a histological examination to confirm the diagnosis. Clinical discussion: This case report discusses a rare occurrence of myocardial infarction caused by tumor embolization from a CPF. The patient presented with complete blockage of a coronary artery in the absence of atherosclerotic disease. Through a comprehensive workup, including transesophageal echocardiography, the CPF was identified as the source of embolization. Surgical resection of CPFs is curative, and recurrence has not been documented. Clinicians should consider CPFs in cases of coronary artery occlusion without atherosclerotic disease and employ transesophageal echocardiography for diagnosis. Prompt surgical intervention leads to an excellent prognosis and prevents recurrent embolization. Conclusion: This report emphasizes the importance of recognizing the potential complications associated with papillary fibroelastoma-induced embolization to the coronary arteries and highlights the need to mitigate the risk of such complications occurring.

Quadratus lumborum block and transversus abdominis plane block in laparoscopic nephrectomy: a meta-analysis.

Aim: To study the efficacy of quadratus lumborum block (QLB) and transversus abdominis plane (TAP) in laparoscopic nephrectomy patients. Materials & methods: We conducted a meta-analysis of randomized controlled trials for QLB and/or TAP technique compared with each other or a control. Results: Direct analysis of 24 h post-op pain score at rest for each compared with control showed significant reduction, QLB (mean differences [MD] [95% CI]: -1.12 [-1.87,-0.36]; p = 0.004) and TAP (MD [95% CI]: -0.36 [-0.59, -0.12]; p = 0.003). With movement both were respectively lower than control QLB (MD [95% CI]: -1.12 [-1.51, -0.72]; p = <0.0001) and TAP (MD [95% CI]: -0.50 [-0.95, -0.05]; p = 0.03). Moreover, QLB demonstrated less risk 24 h of post-op nausea vomiting (PONV) versus control (PONV; risk ratios [RR] [95% CI]: 0.64 [0.45,0.90]; p = 0.01). Conclusion: TAP and QLB reduce pain scores compared with control, whereas only QLB reduces PONV compared with control.

Fluorine-Functionalized Polyphosphazene Immunoadjuvant: Synthesis, Solution Behavior and In Vivo Potency.

The inclusion of fluorine motifs in drugs and drug delivery systems is an established tool for modulating their biological potency. Fluorination can improve drug specificity or boost the vehicle's ability to cross cellular membranes. However, the approach has yet to be applied to vaccine adjuvants. Herein, the synthesis of fluorinated bioisostere of a clinical stage immunoadjuvant-poly[di(carboxylatophenoxy)phosphazene], PCPP-is reported. The structure of water-soluble fluoropolymer-PCPP-F, which contains two fluorine atoms per repeat unit-was confirmed using 1H, 31P and 19F NMR, and its molecular mass and molecular dimensions were determined using size-exclusion chromatography and dynamic light scattering. Insertion of fluorine atoms in the polymer side group resulted in an improved solubility in acidic solutions and faster hydrolytic degradation rate, while the ability to self-assemble with an antigenic protein, lysozyme-an important feature of polyphosphazene vaccine adjuvants-was preserved. In vivo assessment of PCPP-F demonstrated its greater ability to induce antibody responses to Hepatitis C virus antigen when compared to its non-fluorinated counterpart. Taken together, the superior immunoadjuvant activity of PCPP-F, along with its improved formulation characteristics, demonstrate advantages of the fluorination approach for the development of this family of macromolecular vaccine adjuvants.

Subspecific rodent taxa as the relevant host taxonomic level for mammarenavirus host specificity.

Mastomys natalensis-borne mammarenaviruses appear specific to subspecific M. natalensis taxa rather than to the whole species. Yet mammarenaviruses carried by M. natalensis are known to spill over and jump hosts in northern sub-Saharan Africa. Phylogeographic studies increasingly show that, like M. natalensis, small mammals in sub-Saharan Africa are often genetically structured into several subspecific taxa. Other mammarenaviruses may thus also form virus-subspecific host taxon associations. To investigate this, and if mammarenaviruses carried by M. natalensis in southern Africa are less prone to spill-over, we screened 1225 non-M. natalensis samples from Tanzania where many small mammal taxa meet. We found mammarenavirus RNA in 6 samples. Genetic/genomic characterisation confirmed they were not spill-over from M. natalensis. We detected host jumps among rodent tribe members and an association between mammarenaviruses and subspecific taxa of Mus minutoides and Grammomys surdaster, indicating host genetic structure may be crucial to understand virus distribution and host specificity.

Phase Transition of High-Surface-Area Glycol-Thermal Synthesized Lanthanum Manganite.

Cubic and rhombohedral phases of lanthanum manganite were synthesized in a high-pressure reactor. A mixture of La and Mn nitrates with ethylene glycol at a synthesis temperature of 200 °C and a calcination temperature of up to 1000 °C, resulted in a single-phase perovskite, LaMnO3 validated using X-ray diffraction. Significant changes in unit cell volumes from 58 to 353 Å3 were observed associated with structural transformation from the cubic to the rhombohedral phase. This was confirmed using structure calculations and resistivity measurements. Transmission electron microscopy analyses showed small particle sizes of approximately 19, 39, 45, and 90 nm (depending on calcination temperature), no agglomeration, and good crystallinity. The particle characteristics, high purity, and high surface area (up to 33.1 m2/g) of the material owed to the inherent PAAR reactor pressure, are suitable for important technological applications, that include the synthesis of perovskite oxides. Characteristics of the synthesized LaMnO3 at different calcination temperatures are compared, and first-principles calculations suggest a geometric optimization of the cubic and rhombohedral perovskite structures.

Comprehensive omics studies of p53 mutants in human cancer.

The p53 is the master regulator of the cell known for regulating a large array of cellular processes. Inactivation of p53 by missense mutations is one of the leading causes of cancer. Some of these mutations endow p53 with selective oncogenic functions to promote tumor progression. Due to the vast array of mutations found in p53, the experimental studies showing the role of different mutant p53 as an oncogene are also expanding. In this review, we discuss the oncogenic roles of different p53 mutants at the cellular level identified by multi-omics tools. We discuss some of the therapeutic studies to tackle p53 mutants and their downstream targets identified by omics. We also highlight the future prospective and scope of further studies of downstream p53 targets by omics.

Evidence of reduced academic performance among schoolchildren with helminth infection.

BACKGROUND: Soil-transmitted helminths (STHs) pose a formidable health risk to school-age children in resource-limited settings. Unfortunately, mass deworming campaigns have been derailed since the onset of the coronavirus disease 2019 pandemic. The present study assessed the cross-sectional associations between STHs, nutritional status and academic performance of schoolchildren in the Banda District of Ghana. METHODS: Schoolchildren (5-16 y of age; n=275) were recruited through both school and household visits by community health workers using a multistage cluster sampling technique. In addition to school microscopy, anthropometric records were also taken. RESULTS: The prevalence of geohelminthiasis was 40.4% (95% confidence interval 34.6 to 46.2). STHs targeted for elimination by the World Health Organization and national programmes were detected among schoolchildren. Children with intestinal parasite infection (53.7 [standard deviation {SD} 11.5]) had lower mean academic scores compared with uninfected children (59.6 [SD 16.9]) (p=0.034). In multiple regression analysis, intestinal parasite infection status and z-scores for weight-for-age showed a collective significant effect on the academic score (F1117=8.169, p<0.001, R2=0.125). CONCLUSIONS: Schoolchildren with STHs had poorer academic performance compared with uninfected children, despite their nutritional status. In addition to school feeding programmes, school-based mass drug administration campaigns may be critical for improving learning outcomes in young schoolchildren.

Morphology, oxygen vacancies, and other factors affecting the performance of supported bimetallic ceria catalysts.

Here in we report the development of a Pt-V/CeO2 catalyst performing under mild conditions in amide hydrogenation. Ceria with different morphologies was employed as support in this study. We further developed a glycol-thermal technique that yields thermally stable quantum dot ceria, which can be applied as a support. A systematic investigation revealed the importance of proximity between the small crystalline hydrogenating sites (Pt) and oxophilic sites (V). The study showed that oxygen vacancies on the ceria surface oxidize both Pt and V, poisoning the hydrogenation reaction. In contrast, the absence of oxygen vacancies promoted the hydrogenating ability of Pt sites and also improved their ability to participate in the H2 spillover mechanism and in situ formation of oxophilic V3+. This study demonstrates how the engineering of the oxygen vacancies on the surface of the redox support can manipulate the nature of active sites toward specific reactions.

Mechanism of apoptosis activation by Curcumin rescued mutant p53Y220C in human pancreatic cancer.

The mutant p53Y220C (mutp53Y220C) is frequently observed in numerous tumors, including pancreatic cancer. The mutation creates a crevice in the DNA binding core domain and makes p53 a thermally unstable non-functional protein that assists tumor progression and confers resistance to chemotherapeutic drugs. Restoring mutp53 function to its wild type by selectively targeting this crevice with small molecules is a pivotal strategy to promote apoptosis. In this study, we have shown through different biophysical and cell-based studies that curcumin binds and rescues mutp53Y220C to an active wild-type conformation and restores its apoptotic transcription function in BxPC-3-pancreatic cancer cells. In addition, the curcumin-rescued-p53Y220C (CRp53) showed significant hyperphosphorylation at Ser15, Ser20, and acetylation at Lys382 with an 8-fold increase in transcription activity in the BxPC-3 cell lines. We also observed that the active CRp53 escapes Mdm2-mediated proteasomal degradation and the majority of the proteins were localized inside the nucleus with an increased half-life and transcription restoration compared to untreated BxPC-3 cells. By label-free proteomics analysis, we observed that upon curcumin treatment almost 227 proteins were dysregulated with the majority of them being transcriptional targets of p53. Based on our studies, it reflects that apoptosis in pancreatic cancer cells is mediated by curcumin-rescued mutant p53Y220C.

A Rare Case of Third Generation Cephalosporin-Resistant Klebsiella Meningitis.

Acute bacterial meningitis is one of the very common and severe forms of central nervous system (CNS) infection worldwide in almost all age groups. It remains a common cause of mortality, especially in underdeveloped countries, if not treated timely. Detecting an organism from the CSF culture is crucial in the management of acute bacterial meningitis. Selection of antibiotics according to the culture are a very important part of the management. Most commonly involved organisms include Streptococcus pneumoniae, Neisseria meningitides, and Listeria monocytogenes, while other organisms are very uncommon. Here, we report a rare case of Klebsiella pneumoniae meningitis in a young female, which was found resistant to multiple antibiotics including third generation of cephalosporin.