Artificial intelligence for cardiovascular disease risk assessment in personalised framework: a scoping review.

Background: The field of precision medicine endeavors to transform the healthcare industry by advancing individualised strategies for diagnosis, treatment modalities, and predictive assessments. This is achieved by utilizing extensive multidimensional biological datasets encompassing diverse components, such as an individual's genetic makeup, functional attributes, and environmental influences. Artificial intelligence (AI) systems, namely machine learning (ML) and deep learning (DL), have exhibited remarkable efficacy in predicting the potential occurrence of specific cancers and cardiovascular diseases (CVD). Methods: We conducted a comprehensive scoping review guided by the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) framework. Our search strategy involved combining key terms related to CVD and AI using the Boolean operator AND. In August 2023, we conducted an extensive search across reputable scholarly databases including Google Scholar, PubMed, IEEE Xplore, ScienceDirect, Web of Science, and arXiv to gather relevant academic literature on personalised medicine for CVD. Subsequently, in January 2024, we extended our search to include internet search engines such as Google and various CVD websites. These searches were further updated in March 2024. Additionally, we reviewed the reference lists of the final selected research articles to identify any additional relevant literature. Findings: A total of 2307 records were identified during the process of conducting the study, consisting of 564 entries from external sites like arXiv and 1743 records found through database searching. After 430 duplicate articles were eliminated, 1877 items that remained were screened for relevancy. In this stage, 1241 articles remained for additional review after 158 irrelevant articles and 478 articles with insufficient data were removed. 355 articles were eliminated for being inaccessible, 726 for being written in a language other than English, and 281 for not having undergone peer review. Consequently, 121 studies were deemed suitable for inclusion in the qualitative synthesis. At the intersection of CVD, AI, and precision medicine, we found important scientific findings in our scoping review. Intricate pattern extraction from large, complicated genetic datasets is a skill that AI algorithms excel at, allowing for accurate disease diagnosis and CVD risk prediction. Furthermore, these investigations have uncovered unique genetic biomarkers linked to CVD, providing insight into the workings of the disease and possible treatment avenues. The construction of more precise predictive models and personalised treatment plans based on the genetic profiles of individual patients has been made possible by the revolutionary advancement of CVD risk assessment through the integration of AI and genomics. Interpretation: The systematic methodology employed ensured the thorough examination of available literature and the inclusion of relevant studies, contributing to the robustness and reliability of the study's findings. Our analysis stresses a crucial point in terms of the adaptability and versatility of AI solutions. AI algorithms designed in non-CVD domains such as in oncology, often include ideas and tactics that might be modified to address cardiovascular problems. Funding: No funding received.

Intravascular Ultrasound during Endovascular Intervention for Peripheral Artery Disease, By Severity, Location, Device, and Procedure.

There is limited evidence for the role of Intravascular Ultrasound (IVUS) in patients undergoing peripheral vascular intervention (PVI). We conducted retrospective cohort study utilizing the HCUP-AHRQ National Readmission database(NRD) to delineate outcomes in IVUS guided PVI versus non-IVUS guided PVI. The current study utilized NRD between January 1, 2016, and December 31, 2019. We identified patients undergoing endovascular intervention for peripheral artery disease using relevant ICD-10-PCS. The cohort was divided based on the use of IVUS during the procedure. The primary outcome was major amputation at 6 months after index hospitalization. Measured confounders were matched using propensity score inverse probability of treatment weighing method. We further performed a subgroup analysis based on disease severity, location of intervention, device, and procedure.A total of 434901 hospitalizations were included in the present analysis. PVI with IVUS compared with no IVUS had similar risk of amputation at 6 months (195 of 8939[2.17%] versus 10404 of 384003 [2.71%]);Hazard Ratio,0.98;CI, 0.77-1.25. Further, there was no difference in the rates of secondary outcomes. On subgroup analysis, amputation rates were significantly lower among patients with rest pain, in iliac intervention, or patients undergoing drug eluting stent implantation with the use of IVUS compared with no IVUS. This nationwide observational study showed that there was no difference in major amputation rates with the use of IVUS in patients undergoing PVI. However, in subgroup of patients with rest pain, iliac intervention or drug-eluting stent implantation IVUS use was associated with significantly lower major amputation rates.

Oxalic acid as a dual C1 surrogate for heterogeneous palladium-catalyzed tandem four-component quinazolinone synthesis.

Herein, a heterogeneous Pd/C-catalyzed direct one-step four-component double carbonylative approach for cascade synthesis of 2-aryl quinazolinones has been reported for the first time starting from 2-iodoaniline derivatives and aryl iodides. The given reaction involves the simultaneous implementation of two different gaseous surrogates i.e., ammonium carbamate as an NH3 precursor and oxalic acid as a bi-functional reagent acting as a CO as well as a C-atom surrogate under ligand-free conditions.

The genetic architecture of dog ownership: large-scale genome-wide association study in 97,552 European-ancestry individuals.

Dog ownership has been associated with several complex traits and there is evidence of genetic influence. We performed a genome-wide association study of dog ownership through meta-analysis of 31,566 Swedish twins in five discovery cohorts and additional 65,986 European-ancestry individuals in three replication cohorts from Sweden, Norway, and the UK. Association test with >7.4 million single-nucleotide polymorphisms were meta-analyzed using a fixed effect model after controlling for population structure and relatedness. We identified two suggestive loci using discovery cohorts, which did not reach genome-wide significance after meta-analysis with replication cohorts. Single-nucleotide polymorphisms-based heritability of dog ownership using linkage disequilibrium score regression was estimated at 0.123 (CI 0.038-0.207) using the discovery cohorts and 0.018 (CI -0.002, 0.039) when adding in replication cohorts. Negative genetic correlation with complex traits including type 2 diabetes, depression, neuroticism and asthma was only found using discovery summary data. Furthermore, we did not identify any genes/gene-sets reaching even suggestive level of significance. This genome-wide association study does not, by itself, provide clear evidence on common genetic variants that influence the dog ownership among European-ancestry individuals.

Nanocarrier mediated entinostat and oxaliplatin combination therapy displayed enhanced efficacy against pancreatic cancer.

Pancreatic cancer is the third leading cause of cancer-related death in the United States, with a 5-year survival rate of only 12%. The poor prognosis of pancreatic cancer is primarily attributed to the lack of early detection, the aggressiveness of the disease, and its resistance to conventional chemotherapeutics. The use of combination chemotherapy targeting different key pathways has emerged as a potential strategy to minimize drug resistance while improving therapeutic outcomes. Here, we evaluated a novel approach to treating pancreatic cancer using entinostat (ENT), a selective class I and IV HDAC inhibitor, and oxaliplatin (OXP) administered at considerably lower dosages. Combination therapy exhibited strong synergistic interaction against human (PANC-1) and murine (KPC) pancreatic cancer cells. As expected, ENT treatment enhanced acetylated histone H3 and H4 expression in treated cells, which was even augmented in the presence of OXP. Similarly, cells treated with a combination therapy showed higher expression of cleaved caspase 3 and increased apoptosis compared to monotherapy. To further improve the efficacy of the combination treatment, we encapsulated OXP and ENT into bovine serum albumin and poly(lactic-co-glycolic) acid nanoparticles. Both nanocarriers showed suitable physicochemical properties with respect to size, charge, polydispersity index, and loading. Besides, the combination of OXP and ENT nanoparticles showed similar or even better synergistic effects compared to free drugs during in vitro cytotoxicity and colony formation assays towards pancreatic cancer cells.

Skeletal muscle transcriptomics of sheep acclimated to cold desert and tropical regions identifies genes and pathways accentuating their diversity.

The current study attempts to investigate the differences in gene expression in longissimus thoracis muscles between sheep breeds acclimated to diverse environments. Changthangi sheep inhabits the cold arid plateau of Ladakh, at an altitude above 3000 m with prevalence of rarefied atmosphere. Muzzafarnagri sheep, on the other hand is found in the sub-tropical hot and humid plains at an altitude of about 250 m. Comparative transcriptomics was used to provide a molecular perspective of the differential adaptation of the two breeds. RNA sequencing data was generated from four biological replicates of the longissimus thoracis muscles from both breeds. The common genes expressed in both breeds were involved in muscle contraction and muscle fibre organization. The most significant pathways enriched in Changthangi muscles were glycogen metabolism, reduction of cytosolic Ca++ levels and NFE2L2 regulating anti-oxidant, while those in Muzzafarnagri were extracellular matrix organization and collagen formation. The hub genes identified in Changthangi were involved in hematopoiesis and HIF signaling pathway, suggesting the molecular acclimatization of Changthangi to the high altitude cold desert of Ladakh. The nodal genes discovered in Muzzafarnagri sheep were associated with the extracellular matrix which accentuates its significance in the development, growth and repair of muscles. The observed transcriptomic differences underscore the morphological and adaptive disparity between the two breeds. The candidate genes and pathways identified in this study will form the basis for future research on adaptation to high altitude and body size in small ruminants.

Investigating the adsorption processes of polymer resins for the removal of micropollutants: A comprehensive review in the field of environmental remediation.

The growing worry for human health stems from the fact that micropollutants (MPs), particularly dyes, are more common in aquatic settings. These particles pose a serious risk to both humans and animals since they have been found in a variety of bodily fluids and waste products from both humans and animals. MPs pose significant dangers to human health and other living things due to their extended half-lives, high fragmentation propensity, and capacity to absorb organic pollutants as well (MB, MR, MO and CV dyes) and heavy metals as well (Pb(II), Cd(II) Co(II) Cr(III) and Ag(I) ….). They also contribute to the degradation of terrestrial and aquatic habitats. Sustainable and effective methods for removing MPs from wastewater and treating organic micropollutants in an environmentally friendly manner are being developed in order to address this problem. This work offers a thorough review of adsorption technology as a productive and environmentally friendly means of eliminating MPs from aqueous environments, with an emphasis on developments in the application of polymeric resin in MP removal. The review examines the adsorption process and the variables that affect adsorption efficiency, including the characteristics of the micropollutant, the resin, and the solution. To improve understanding, a number of adsorption mechanisms and models are explored. The study also addresses the difficulties and future possibilities of adsorption technology, emphasising the need to optimize resin characteristics, create sustainable and affordable regeneration techniques, and take into account the environmental effects of adsorbent materials.

The Salmonella typhi Cell Division Activator Protein StCAP Impacts Pathogenesis by Influencing Critical Molecular Events.

Conserved molecular signatures in multidrug-resistant Salmonella typhi can serve as novel therapeutic targets for mitigation of infection. In this regard, we present the S. typhi cell division activator protein (StCAP) as a conserved target across S. typhi variants. From in silico and fluorimetric assessments, we found that StCAP is a DNA-binding protein. Replacement of the identified DNA-interacting residue Arg34 of StCAP with Ala34 showed a dramatic (15-fold) increase in Kd value compared to the wild type (Kd 546 nm) as well as a decrease in thermal stability (10 °C shift). Out of the two screened molecules against the DNA-binding pocket of StCAP, eltrombopag, and nilotinib, the former displayed better binding. Eltrombopag inhibited the stand-alone S. typhi culture with an IC50 of 38 µM. The effect was much more pronounced on THP-1-derived macrophages (T1Mac) infected with S. typhi where colony formation was severely hindered with IC50 reduced further to 10 µM. Apoptotic protease activating factor1 (Apaf1), a key molecule for intrinsic apoptosis, was identified as an StCAP-interacting partner by pull-down assay against T1Mac. Further, StCAP-transfected T1Mac showed a significant increase in LC3 II (autophagy marker) expression and downregulation of caspase 3 protein. From these experiments, we conclude that StCAP provides a crucial survival advantage to S. typhi during infection, thereby making it a potent alternative therapeutic target.

Utilization of Point-of-Care Ultrasound as an Imaging Modality in the Emergency Department: A Systematic Review and Meta-Analysis.

Point-of-care ultrasound (POCUS) is an imaging modality that has become a fundamental part of clinical care provided in the emergency department (ED). The applications of this tool in the ED have ranged from resuscitation, diagnosis, and therapeutic to procedure guidance. This review aims to summarize the evidence on the use of POCUS for diagnosis and procedure guidance. To achieve this, CrossRef, PubMed, Cochrane Library, Web of Science, and Google Scholar databases were extensively searched for studies published between January 2000 and November 2023. Additionally, the risk of bias assessment was performed using the Quality Assessment of Diagnostic Accuracy Studies 2 (for studies on the diagnostic role of POCUS) and Cochrane Risk of Bias tool (for studies on the use of POCUS for procedure guidance). Furthermore, diagnostic accuracy outcomes were pooled using STATA 16 software (StatCorp., College Station, TX, USA), while outcomes related to procedure guidance were pooled using the Review Manager software. The study included 81 articles (74 evaluating the diagnostic application of POCUS and seven evaluating the use of POCUS in guiding clinical procedures). In our findings sensitivities and specificities for various conditions were as follows: appendicitis, 65% and 89%; hydronephrosis, 82% and 74%; small bowel obstruction, 93% and 82%; cholecystitis, 75% and 96%; retinal detachment, 94% and 91%; abscess, 95% and 85%; foreign bodies, 67% and 97%; clavicle fractures, 93% and 94%; distal forearm fractures, 97% and 94%; metacarpal fractures, 94% and 92%; skull fractures, 91% and 97%; and pleural effusion, 91% and 97%. A subgroup analysis of data from 11 studies also showed that the two-point POCUS has a sensitivity and specificity of 89% and 96%, while the three-point POCUS is 87% sensitive and 92% specific in the diagnosis of deep vein thrombosis. In addition, the analyses showed that ultrasound guidance significantly increases the overall success rate of peripheral venous access (p = 0.02) and significantly reduces the number of skin punctures (p = 0.01) compared to conventional methods. In conclusion, POCUS can be used in the ED to diagnose a wide range of clinical conditions accurately. Furthermore, it can be used to guide peripheral venous access and central venous catheter insertion.

Analysing district-level climate vulnerability pattern in Madhya Pradesh, India, based on agricultural and socio-economic indicators.

Indian agriculture transitioned from a food deficit sector to a food surplus following the Green Revolution. However, the continued progress of Indian agriculture has been hampered by climate change. This research explores the district-wise vulnerability in Madhya Pradesh, India, to climate change by assessing the composite vulnerability index using the agricultural vulnerability index (AVI) and socio-economic vulnerability index (SEVI). The study seeks to understand how agricultural and socio-economic factors lead to variations in vulnerability across districts and influence targeted adaptation and mitigation strategies. The trend analysis results present declining rainfall and inclining temperature from 1951 to 2021 in Madhya Pradesh, directly affecting the agricultural sector and human livelihood. The composite vulnerability index (CVI) results revealed that districts with low values (< 0.394), such as Burhanpur and Balaghat, demonstrate reduced susceptibility due to limited cultivation, low reliance on rainfall, lower drought susceptibility, and decreased population density. Districts such as Panna and Bhopal show moderate vulnerability (0.394-0.423), with lower fallow land, reduced rainfed agriculture, and socio-economic vulnerability. Extensive agriculture and marginalised workers' presence influence high vulnerability (0.423 to 0.456) in districts such as Tikamgarh and Indore. Districts like Barwani and Jhabua have the highest CVI values (> 0.456), indicating substantial susceptibility to climate impacts. The cluster analysis validates the results of the vulnerability index. The findings highlight the urgent need for tailored adaptation strategies to address the diverse agricultural and socio-economic indicators creating vulnerability in Madhya Pradesh. The study helps understand regional vulnerability patterns and provides evidence-based policy approaches for resilience to climate change effects.

Langerhans cell histiocytosis: NACHO update on progress, chaos, and opportunity on the path to rational cures.

Langerhans cell histiocytosis (LCH) is a myeloid neoplastic disorder characterized by lesions with CD1a-positive/Langerin (CD207)-positive histiocytes and inflammatory infiltrate that can cause local tissue damage and systemic inflammation. Clinical presentations range from single lesions with minimal impact to life-threatening disseminated disease. Therapy for systemic LCH has been established through serial trials empirically testing different chemotherapy agents and durations of therapy. However, fewer than 50% of patients who have disseminated disease are cured with the current standard-of-care vinblastine/prednisone/(mercaptopurine), and treatment failure is associated with long-term morbidity, including the risk of LCH-associated neurodegeneration. Historically, the nature of LCH-whether a reactive condition versus a neoplastic/malignant condition-was uncertain. Over the past 15 years, seminal discoveries have broadly defined LCH pathogenesis; specifically, activating mitogen-activated protein kinase pathway mutations (most frequently, BRAFV600E) in myeloid precursors drive lesion formation. LCH therefore is a clonal neoplastic disorder, although secondary inflammatory features contribute to the disease. These paradigm-changing insights offer a promise of rational cures for patients based on individual mutations, clonal reservoirs, and extent of disease. However, the pace of clinical trial development behind lags the kinetics of translational discovery. In this review, the authors discuss the current understanding of LCH biology, clinical characteristics, therapeutic strategies, and opportunities to improve outcomes for every patient through coordinated agent prioritization and clinical trial efforts.

Siderophore-mediated iron acquisition by Klebsiella pneumoniae.

Microbes synthesize and secrete siderophores, that bind and solubilize precipitated or otherwise unavailable iron in their microenvironments. Gram (-) bacterial TonB-dependent outer membrane receptors capture the resulting ferric siderophores to begin the uptake process. From their similarity to fepA, the structural gene for the Escherichia coli ferric enterobactin (FeEnt) receptor, we identified four homologous genes in the human and animal ESKAPE pathogen Klebsiella pneumoniae (strain Kp52.145). One locus encodes IroN (locus 0027 on plasmid pII), and three other loci encode other FepA orthologs/paralogs (chromosomal loci 1658, 2380, and 4984). Based on the crystal structure of E. coli FepA (1FEP), we modeled the tertiary structures of the K. pneumoniae FepA homologs and genetically engineered individual Cys substitutions in their predicted surface loops. We subjected bacteria expressing the Cys mutant proteins to modification with extrinsic fluorescein maleimide (FM) and used the resulting fluorescently labeled cells to spectroscopically monitor the binding and transport of catecholate ferric siderophores by the four different receptors. The FM-modified FepA homologs were nanosensors that defined the ferric catecholate uptake pathways in pathogenic strains of K. pneumoniae. In Kp52.145, loci 1658 and 4984 encoded receptors that primarily recognized and transported FeEnt; locus 0027 produced a receptor that principally bound and transported FeEnt and glucosylated FeEnt (FeGEnt); locus 2380 encoded a protein that bound ferric catecholate compounds but did not detectably transport them. The sensors also characterized the uptake of iron complexes, including FeGEnt, by the hypervirulent, hypermucoviscous K. pneumoniae strain hvKp1. IMPORTANCE: Both commensal and pathogenic bacteria produce small organic chelators, called siderophores, that avidly bind iron and increase its bioavailability. Klebsiella pneumoniae variably produces four siderophores that antagonize host iron sequestration: enterobactin, glucosylated enterobactin (also termed salmochelin), aerobactin, and yersiniabactin, which promote colonization of different host tissues. Abundant evidence links bacterial iron acquisition to virulence and infectious diseases. The data we report explain the recognition and transport of ferric catecholates and other siderophores, which are crucial to iron acquisition by K. pneumoniae.

Computational Analysis of Lenalidomide and Pomalidomide Enantiomers' Binding Interactions With Prostaglandin (PG)-Protein: Implications for Inflammatory Activity in Cancer.

BACKGROUND: Lenalidomide and Pomalidomide are chiral immunomodulatory drugs (IMiDs) and have antiangiogenic and anti-immunomodulatory activity. Each enantiomer may have distinct binding and biological activity. This study aimed to explore the in-silico binding of both enantiomers of Lenalidomide and Pomalidomide with Prostaglandin and its potential impact on persisting inflammatory activity in cancer. This can further provide insight into the transport of pro-inflammatory mediators and their potential implications for the inflammatory microenvironment within tumors. MATERIALS AND METHODS: Molecular docking studies were performed to explore the binding potential of both enantiomers of Lenalidomide and Pomalidomide with Pg protein. The crystal structure of Pg-protein (PDB ID: 1IW7) was obtained from the Protein Data Bank. RESULTS: The binding energies for (-)-Lenalidomide and (+)-Lenalidomide were -6.7 and -7.2 kcal/mol, respectively, while the binding energies for (-)-Pomalidomide and (+)-Pomalidomide were -7.8 and -8.1 kcal/mol, respectively. The binding mode analysis revealed that all four compounds formed hydrogen bonds with key amino acid residues of Pg-protein. The hydrogen bond distances for (-)-Lenalidomide, (+)-Lenalidomide, (-)-Pomalidomide, and (+)-Pomalidomide were 2.1 Å, 2.0 Å, 2.2 Å, and 2.1 Å, respectively. CONCLUSIONS: The present study suggests that both enantiomers of Lenalidomide and Pomalidomide have a high affinity for Pg-protein and can effectively target the Pg-protein pathway to persist inflammatory activity in cancer. By targeting inflammation-mediated processes, these drugs may offer a novel strategy to combat tumor progression.

CB-0821, a novel CC chemokine receptor 5 (CCR5) inhibitor with improved binding efficacy proposed as anti-HIV candidate: Computational and in vitro approach.

The CC chemokine receptor 5 (CCR5) serves a pivotal role in human immunodeficiency virus 1 (HIV-1) infection by acting as a co-receptor and facilitating the binding of the viral envelope glycoprotein (env). Maraviroc (MVC), a Food and Drug Administration-approved monocarboxylic acid amide, is one of the CCR5 inhibitors employed in HIV treatment. Despite the existence of approved drugs, the emergence of drug resistance underscores the necessity for novel compounds to combat resistance and enhance therapeutic efficacy. In this study, CB-0821, identified from the ChemBridge library, emerged as a promising CCR5 inhibitor. Molecular dynamics simulations indicate comparable dynamic properties for CB-0821 and MVC. In silico comparisons with other CCR5 inhibitors emphasize CB-0821's superior binding affinity, positioning it as a potential lead compound. Evaluations of the dissociation constant (Ki) and absorption, distribution, metabolism, and excretion predictions suggest CB-0821 as a well-tolerated drug. Furthermore, the dose-dependent inhibition of CCR5 by CB-0821 in Peripheral blood mononuclear cells (PBMCs) (ranging from 10 to 200 nM) demonstrates efficacy, coupled with nontoxicity to Vero cells at concentrations up to 500 nM. These results underscore the potential of CB-0821 in HIV antiviral therapy, calling for additional preclinical validations before advancing to clinical considerations.

Uncovering the diversity of pathogenic invaders: insights into protozoa, fungi, and worm infections.

Post COVID-19, there has been renewed interest in understanding the pathogens challenging the human health and evaluate our preparedness towards dealing with health challenges in future. In this endeavour, it is not only the bacteria and the viruses, but a greater community of pathogens. Such pathogenic microorganisms, include protozoa, fungi and worms, which establish a distinct variety of disease-causing agents with the capability to impact the host's well-being as well as the equity of ecosystem. This review summarises the peculiar characteristics and pathogenic mechanisms utilized by these disease-causing organisms. It features their role in causing infection in the concerned host and emphasizes the need for further research. Understanding the layers of pathogenesis encompassing the concerned infectious microbes will help expand targeted inferences with relation to the cause of the infection. This would strengthen and augment benefit to the host's health along with the maintenance of ecosystem network, exhibiting host-pathogen interaction cycle. This would be key to discover the layers underlying differential disease severities in response to similar/same pathogen infection.

Specificity and mechanism of TonB-dependent ferric catecholate uptake by Fiu.

We studied the Escherichia coli outer membrane protein Fiu, a presumed transporter of monomeric ferric catecholates, by introducing Cys residues in its surface loops and modifying them with fluorescein maleimide (FM). Fiu-FM bound iron complexes of the tricatecholate siderophore enterobactin (FeEnt) and glucosylated enterobactin (FeGEnt), their dicatecholate degradation product Fe(DHBS)2 (FeEnt*), the monocatecholates dihydroxybenzoic acid (FeDHBA) and dihydroxybenzoyl serine (FeDHBS), and the siderophore antibiotics cefiderocol (FDC) and MB-1. Unlike high-affinity ligand-gated porins (LGPs), Fiu-FM had only micromolar affinity for iron complexes. Its apparent KD values for FeDHBS, FeDHBA, FeEnt*, FeEnt, FeGEnt, FeFDC, and FeMB-1 were 0.1, 0.7, 0.7, 1.0, 0.3, 0.4, and 4 µM, respectively. Despite its broad binding abilities, the transport repertoires of E. coli Fiu, as well as those of Cir and FepA, were less broad. Fiu only transported FeEnt*. Cir transported FeEnt* and FeDHBS (weakly); FepA transported FeEnt, FeEnt*, and FeDHBA. Both Cir and FepA bound FeGEnt, albeit with lower affinity. Related transporters of Acinetobacter baumannii (PiuA, PirA, BauA) had similarly moderate affinity and broad specificity for di- or monomeric ferric catecholates. Both microbiological and radioisotopic experiments showed Fiu's exclusive transport of FeEnt*, rather than ferric monocatecholate compounds. Molecular docking and molecular dynamics simulations predicted three binding sites for FeEnt*in the external vestibule of Fiu, and a fourth site deeper in its interior. Alanine scanning mutagenesis in the outermost sites (1a, 1b, and 2) decreased FeEnt* binding affinity as much as 20-fold and reduced or eliminated FeEnt* uptake. Finally, the molecular dynamics simulations suggested a pathway of FeEnt* movement through Fiu that may generally describe the process of metal transport by TonB-dependent receptors.

A Bayesian meta-analysis of double kissing (DK) crush or provisional stenting for coronary artery bifurcation lesions.

OBJECTIVE: Despite the development of dedicated, two-stent strategies, including the double kissing (DK) crush technique, the ideal technique for coronary artery bifurcation stenting has not been identified. We aimed to compare and determine the absolute risk difference (ARD) of the DK crush technique alone versus provisional stenting approaches for coronary bifurcation lesions, using the Bayesian technique. METHOD: We queried PubMed/MEDLINE to identify randomized controlled trials (RCTs) that compared DK crush technique with provisional stenting for bifurcation lesions, published till January 2023. We used Bayesian methods to calculate the ARD and 95% credible interval (CrI). RESULTS: We included three RCTs, with 916 patients, in the final analysis. The ARD of cardiac death was centered at -0.01 (95% CrI: -0.04 to 0.02; Tau: 0.02, 85% probability of ARD of DK crush vs. provisional stenting <0). ARD for myocardial infarction was centered at -0.03 (95%CrI: -0.9 to 0.03; Tau: 0.05, 87% probability of ARD of DK crush vs. provisional stenting <0). ARD for stent thrombosis was centered at 0.00 (95% CrI: -0.04 to 0.03, Tau: 0.03, 51% probability of ARD for DK crush vs. provisional stenting <0). Finally, ARD for target lesion revascularization was centered at -0.05 (95% CrI: -0.08 to -0.03, Tau: 0.02, 99.97% probability of ARD for DK crush vs. provisional stenting <0). CONCLUSIONS: Bayesian analysis demonstrated a lower probability of cardiac death, myocardial infarction and target lesion revascularization, with DK crush compared with provisional stenting techniques, and a minimal probability of difference in stent thrombosis.

Kisspeptin/KISS1R Signaling Modulates Human Airway Smooth Muscle Cell Migration.

Airway remodeling is a cardinal feature of asthma, associated with increased airway smooth muscle (ASM) cell mass and upregulation of extracellular matrix deposition. Exaggerated ASM cell migration contributes to excessive ASM mass. Previously, we demonstrated the alleviating role of Kp (kisspeptin) receptor (KISS1R) activation by Kp-10 in mitogen (PDGF [platelet-derived growth factor])-induced human ASM cell proliferation in vitro and airway remodeling in vivo in a mouse model of asthma. Here, we examined the mechanisms by which KISS1R activation regulates mitogen-induced ASM cell migration. KISS1R activation using Kp-10 significantly inhibited PDGF-induced ASM cell migration, further confirmed using KISS1R shRNA. Furthermore, KISS1R activation modulated F/G actin dynamics and the expression of promigration proteins like CDC42 (cell division control protein 42) and cofilin. Mechanistically, we observed reduced ASM RhoA-GTPAse with KISS1R activation. The antimigratory effect of KISS1R was abolished by PKA (protein kinase A)-inhibitory peptide. Conversely, KISS1R activation significantly increased cAMP and phosphorylation of CREB (cAMP-response element binding protein) in PDGF-exposed ASM cells. Overall, these results highlight the alleviating properties of Kp-10 in the context of airway remodeling.