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1.
EMBO J ; 42(1): e111251, 2023 01 04.
Article in English | MEDLINE | ID: mdl-36326833

ABSTRACT

Maintenance of stemness is tightly linked to cell cycle regulation through protein phosphorylation by cyclin-dependent kinases (CDKs). However, how this process is reversed during differentiation is unknown. We report here that exit from stemness and differentiation of pluripotent cells along the neural lineage are controlled by CDC14, a CDK-counteracting phosphatase whose function in mammals remains obscure. Lack of the two CDC14 family members, CDC14A and CDC14B, results in deficient development of the neural system in the mouse and impairs neural differentiation from embryonic stem cells (ESCs). Mechanistically, CDC14 directly dephosphorylates specific proline-directed Ser/Thr residues of undifferentiated embryonic transcription Factor 1 (UTF1) during the exit from stemness, triggering its proteasome-dependent degradation. Multiomic single-cell analysis of transcription and chromatin accessibility in differentiating ESCs suggests that increased UTF1 levels in the absence of CDC14 prevent the proper firing of bivalent promoters required for differentiation. CDC14 phosphatases are dispensable for mitotic exit, suggesting that CDC14 phosphatases have evolved to control stemness rather than cell cycle exit and establish the CDK-CDC14 axis as a critical molecular switch for linking cell cycle regulation and self-renewal.


Subject(s)
Cell Cycle Proteins , Saccharomyces cerevisiae Proteins , Animals , Mice , Cell Cycle Proteins/genetics , Cell Cycle Proteins/metabolism , Protein Tyrosine Phosphatases/genetics , Protein Tyrosine Phosphatases/metabolism , Cyclin-Dependent Kinases/metabolism , Cell Cycle , Phosphorylation/physiology , Mitosis , Saccharomyces cerevisiae Proteins/metabolism , Mammals
2.
Proc Natl Acad Sci U S A ; 120(30): e2306088120, 2023 Jul 25.
Article in English | MEDLINE | ID: mdl-37463215

ABSTRACT

The Rayleigh-Plateau instability occurs when surface tension makes a fluid column become unstable to small perturbations. At nanometer scales, thermal fluctuations are comparable to interfacial energy densities. Consequently, at these scales, thermal fluctuations play a significant role in the dynamics of the instability. These microscopic effects have previously been investigated numerically using particle-based simulations, such as molecular dynamics (MD), and stochastic partial differential equation-based hydrodynamic models, such as stochastic lubrication theory. In this paper, we present an incompressible fluctuating hydrodynamics model with a diffuse-interface formulation for binary fluid mixtures designed for the study of stochastic interfacial phenomena. An efficient numerical algorithm is outlined and validated in numerical simulations of stable equilibrium interfaces. We present results from simulations of the Rayleigh-Plateau instability for long cylinders pinching into droplets for Ohnesorge numbers of Oh = 0.5 and 5.0. Both stochastic and perturbed deterministic simulations are analyzed and ensemble results show significant differences in the temporal evolution of the minimum radius near pinching. Short cylinders, with lengths less than their circumference, were also investigated. As previously observed in MD simulations, we find that thermal fluctuations cause these to pinch in cases where a perturbed cylinder would be stable deterministically. Finally, we show that the fluctuating hydrodynamics model can be applied to study a broader range of surface tension-driven phenomena.

3.
J Biol Chem ; 299(10): 105222, 2023 Oct.
Article in English | MEDLINE | ID: mdl-37673337

ABSTRACT

Many microorganisms use both biological and nonbiological molecules as sources of carbon and energy. This resourcefulness means that some microorganisms have mechanisms to assimilate pollutants found in the environment. One such organism is Comamonas testosteroni, which metabolizes 4-methylbenzenesulfonate and 4-methylbenzoate using the TsaMBCD pathway. TsaM is a Rieske oxygenase, which in concert with the reductase TsaB consumes a molar equivalent of NADH. Following this step, the annotated short-chain dehydrogenase/reductase and aldehyde dehydrogenase enzymes TsaC and TsaD each regenerate a molar equivalent of NADH. This co-occurrence ameliorates the need for stoichiometric addition of reducing equivalents and thus represents an attractive strategy for integration of Rieske oxygenase chemistry into biocatalytic applications. Therefore, in this work, to overcome the lack of information regarding NADH recycling enzymes that function in partnership with Rieske non-heme iron oxygenases (Rieske oxygenases), we solved the X-ray crystal structure of TsaC to a resolution of 2.18 Å. Using this structure, a series of substrate analog and protein variant combination reactions, and differential scanning fluorimetry experiments, we identified active site features involved in binding NAD+ and controlling substrate specificity. Further in vitro enzyme cascade experiments demonstrated the efficient TsaC- and TsaD-mediated regeneration of NADH to support Rieske oxygenase chemistry. Finally, through in-depth bioinformatic analyses, we illustrate the widespread co-occurrence of Rieske oxygenases with TsaC-like enzymes. This work thus demonstrates the utility of these NADH recycling enzymes and identifies a library of short-chain dehydrogenase/reductase enzyme prospects that can be used in Rieske oxygenase pathways for in situ regeneration of NADH.


Subject(s)
Bacterial Proteins , Comamonas testosteroni , Oxygenases , Aldehyde Dehydrogenase/metabolism , NAD/metabolism , Oxygenases/metabolism , Substrate Specificity , Comamonas testosteroni/enzymology , Comamonas testosteroni/genetics , Bacterial Proteins/chemistry , Bacterial Proteins/genetics , Bacterial Proteins/metabolism , Nonheme Iron Proteins/chemistry , Nonheme Iron Proteins/genetics , Nonheme Iron Proteins/metabolism , Recombinant Proteins/chemistry , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , Protein Structure, Tertiary , Models, Molecular , Protein Stability , Computational Biology
4.
Bioinformatics ; 39(9)2023 09 02.
Article in English | MEDLINE | ID: mdl-37682115

ABSTRACT

MOTIVATION: The maturation of systems immunology methodologies requires novel and transparent computational frameworks capable of integrating diverse data modalities in a reproducible manner. RESULTS: Here, we present the ePlatypus computational immunology ecosystem for immunogenomics data analysis, with a focus on adaptive immune repertoires and single-cell sequencing. ePlatypus is an open-source web-based platform and provides programming tutorials and an integrative database that helps elucidate signatures of B and T cell clonal selection. Furthermore, the ecosystem links novel and established bioinformatics pipelines relevant for single-cell immune repertoires and other aspects of computational immunology such as predicting ligand-receptor interactions, structural modeling, simulations, machine learning, graph theory, pseudotime, spatial transcriptomics, and phylogenetics. The ePlatypus ecosystem helps extract deeper insight in computational immunology and immunogenomics and promote open science. AVAILABILITY AND IMPLEMENTATION: Platypus code used in this manuscript can be found at github.com/alexyermanos/Platypus.


Subject(s)
Ecosystem , Platypus , Animals , Computational Biology/methods , Phylogeny , Machine Learning , Software
5.
Ophthalmology ; 2024 Mar 06.
Article in English | MEDLINE | ID: mdl-38452874

ABSTRACT

PURPOSE: Analyze the influence of risk factors at presentation in the long-term immunosuppressive therapy (IMT) outcomes of ocular mucous membrane pemphigoid (OMMP). DESIGN: Retrospective multicenter study. PARTICIPANTS: Patients with OMMP seen at the Duke Eye Center, Tecnologico de Monterrey, and Hospital Clinic of Barcelona from 1990 to 2022. METHODS: Data at presentation on demographics, direct immunofluorescence, ocular findings, sites of extraocular manifestations (EOMs), and previous treatments in patients with a clinical or laboratory diagnosis of OMMP, were analyzed with multivariable analysis and Kaplan-Meier plots to identify factors associated with adverse outcomes. MAIN OUTCOME MEASURES: (1) Inflammatory control (no conjunctival inflammation in both eyes at 3 months on IMT); (2) relapse (new-onset inflammation after absolute control in either eye); (3) progression (≥ 1 cicatrizing stage progression in either eye); and (4) vision loss (≥ 2 Snellen lines). RESULTS: A total of 117 patients (234 eyes), 61% (71/117) of whom were women, with a mean age of 66.6 (SD: 12.4) years (range: 37-97 years) and median follow-up of 34 months (interquartile range: 16-66 months; range: 3-265 months), were enrolled. Inflammatory control was achieved in 57% of patients (67/117), with high-risk EOM (HR-EOM), including esophageal, nasopharyngeal, and/or genital involvement (adjusted odds ratio [aOR]: 12.51; 95% confidence interval [CI]: 2.61-59.99; P = 0.002) and corneal scarring (aOR: 3.06; 95% CI, 1.15-8.14; P = 0.025), as significant risk factors for persistent inflammation. Disease relapse, progression, and vision loss occurred in 20% of patients (23/117), 12% of patients (14/117), and 27% of patients (32/117), respectively. Baseline corneal scarring was a risk factor for relapse (adjusted hazard ratio: 4.14; 95% CI: 1.61-10.62; P = 0.003), progression (aOR: 11.46; 95% CI: 1.78-73.75; P = 0.010), and vision loss (aOR: 3.51; 95% CI: 1.35-9.10; P = 0.010). HR-EOM was associated with stage progression (aOR, 34.57; 95% CI, 6.57-181.89; P<0.001) and vision loss (aOR, 8.42; 95% CI, 2.50-28.42; P = 0.001). No significant differences were found between IMT regimes and relapse (P = 0.169). CONCLUSIONS: Ocular mucous membrane pemphigoid presenting with HR-EOMs and corneal scarring has an increased risk of stage progression and vision loss. Corneal scarring and severe inflammation at baseline were associated with an increased risk of relapse. A disease progression staging system incorporating both the HR-EOMs and corneal involvement is required to predict the visual outcome of OMMP better. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

6.
J Surg Res ; 296: 265-272, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38295714

ABSTRACT

INTRODUCTION: Disparate access to laparoscopic surgery may contribute to poorer health outcomes among racial and ethnic minorities, especially among children. We investigated whether racial and ethnic disparities in laparoscopic procedures existed among four common surgical operations in the pediatric population in the United States. METHODS: Using the American College of Surgeons National Surgical Quality Improvement Program-Pediatrics, we conducted a retrospective review of pediatric patients, aged less than 18 y old, undergoing appendectomy, fundoplication, cholecystectomy, and colectomy from 2012 to 2021. To compare the surgical approach (laparoscopy or open), a propensity score matching algorithm was used to compare laparoscopic and open procedures between non-Hispanic Black with non-Hispanic White children and Hispanic with non-Hispanic White children. RESULTS: 143,205, 9,907, 4,581, and 26,064 children underwent appendectomy, fundoplication, colectomy, and cholecystectomy, respectively. After propensity score matching, non-Hispanic Black children undergoing appendectomy were found to be treated laparoscopically less than non-Hispanic White children (93.5% versus 94.4%, P = 0.007). With fundoplication, Hispanic children were more likely to be treated laparoscopically than White ones (86.7% versus 80.9%, P < 0.0001). There were no statistically significant differences between Black or Hispanic children and White children in rates of laparoscopy for other procedures. CONCLUSIONS: Though some racial and ethnic disparities exist with appendectomies and fundoplications, there is limited evidence to indicate that widespread inequities among common laparoscopic procedures exist in the pediatric population.


Subject(s)
Ethnicity , Laparoscopy , Child , Humans , Black People , Healthcare Disparities , Hispanic or Latino , Racial Groups , United States/epidemiology , Black or African American , White
7.
J Surg Res ; 296: 704-710, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38364698

ABSTRACT

INTRODUCTION: Intraoperative cryoablation of intercostal thoracic nerves is gaining popularity as a technique that decreases postoperative pain in thoracic surgery. Our study evaluates the efficacy and safety of cryoablation in pain management of pediatric cancer patients undergoing thoracotomy. METHODS: We reviewed cancer patients undergoing thoracotomies for pulmonary metastasis resection at our children's hospital from 2017 to 2023. Patients who received cryoablation were compared to those who did not. Our primary outcomes were self-reported postoperative pain scores (from 0 to 10) and opioid consumption, measured as oral morphine equivalent per kilogram. RESULTS: Thirty eight procedures were performed in 17 patients, of which 11 (64.7%) were males. Cryoablation was used in 14 (32.4%) procedures, while it was not in 24 (67.6%). Median age (17 y in both groups, P = 0.84) and length of surgery (300 cryoablation versus 282 no cryoablation, P = 0.65) were similar between the groups. Patients treated with cryoablation had a shorter hospital stay compared to those who did not (3.0 versus 4.5 d, respectively, P = 0.04) and received a lower total dose of opioids (2.2 oral morphine equivalent per kilogram versus 14.4, P = 0.004). No significant difference was noted in daily pain scores between the two groups (3.8 cryoablation versus 3.9 no cryoablation, P = 0.93). There was no difference in rates of readmissions between the cryoablation and no-cryoablation groups (14.3% versus 8.3%, P = 0.55). CONCLUSIONS: Our study suggests that cryoablation of the thoracic nerves during a thoracotomy is associated with reduced opiate consumption and shorter hospital stay. Cryoablation appears to be a promising technique for pain management in this patient population.


Subject(s)
Cryosurgery , Lung Neoplasms , Metastasectomy , Male , Child , Humans , Female , Analgesics, Opioid/therapeutic use , Cryosurgery/adverse effects , Length of Stay , Retrospective Studies , Pain, Postoperative/etiology , Pain, Postoperative/prevention & control , Pain, Postoperative/drug therapy , Morphine/therapeutic use , Lung Neoplasms/surgery , Lung Neoplasms/drug therapy
8.
Curr Opin Pediatr ; 36(1): 105-111, 2024 Feb 01.
Article in English | MEDLINE | ID: mdl-37991009

ABSTRACT

PURPOSE OF REVIEW: The aim of this review is to provide the reader with the most updated available information so that it can be helpful in the approach of patients with early-onset scoliosis (EOS). RECENT FINDINGS: While confirming the efficacy and safety of classic techniques for the treatment of EOS such as traditional growing rods or Mehta casting, recent research suggests that there is room for improvement with less invasive techniques. SUMMARY: The most important goal when treating patients with EOS should be to promote rib cage expansion and lung development. Different techniques have been described and may be used depending on the specific patient's characteristics.


Subject(s)
Orthopedic Procedures , Scoliosis , Humans , Scoliosis/therapy , Scoliosis/surgery , Orthopedic Procedures/methods , Retrospective Studies , Treatment Outcome
9.
Brain ; 146(7): 2869-2884, 2023 07 03.
Article in English | MEDLINE | ID: mdl-36624280

ABSTRACT

Improvements in functional genomic annotation have led to a critical mass of neurogenetic discoveries. This is exemplified in hereditary ataxia, a heterogeneous group of disorders characterised by incoordination from cerebellar dysfunction. Associated pathogenic variants in more than 300 genes have been described, leading to a detailed genetic classification partitioned by age-of-onset. Despite these advances, up to 75% of patients with ataxia remain molecularly undiagnosed even following whole genome sequencing, as exemplified in the 100 000 Genomes Project. This study aimed to understand whether we can improve our knowledge of the genetic architecture of hereditary ataxia by leveraging functional genomic annotations, and as a result, generate insights and strategies that raise the diagnostic yield. To achieve these aims, we used publicly-available multi-omics data to generate 294 genic features, capturing information relating to a gene's structure, genetic variation, tissue-specific, cell-type-specific and temporal expression, as well as protein products of a gene. We studied these features across genes typically causing childhood-onset, adult-onset or both types of disease first individually, then collectively. This led to the generation of testable hypotheses which we investigated using whole genome sequencing data from up to 2182 individuals presenting with ataxia and 6658 non-neurological probands recruited in the 100 000 Genomes Project. Using this approach, we demonstrated a high short tandem repeat (STR) density within childhood-onset genes suggesting that we may be missing pathogenic repeat expansions within this cohort. This was verified in both childhood- and adult-onset ataxia patients from the 100 000 Genomes Project who were unexpectedly found to have a trend for higher repeat sizes even at naturally-occurring STRs within known ataxia genes, implying a role for STRs in pathogenesis. Using unsupervised analysis, we found significant similarities in genomic annotation across the gene panels, which suggested adult- and childhood-onset patients should be screened using a common diagnostic gene set. We tested this within the 100 000 Genomes Project by assessing the burden of pathogenic variants among childhood-onset genes in adult-onset patients and vice versa. This demonstrated a significantly higher burden of rare, potentially pathogenic variants in conventional childhood-onset genes among individuals with adult-onset ataxia. Our analysis has implications for the current clinical practice in genetic testing for hereditary ataxia. We suggest that the diagnostic rate for hereditary ataxia could be increased by removing the age-of-onset partition, and through a modified screening for repeat expansions in naturally-occurring STRs within known ataxia-associated genes, in effect treating these regions as candidate pathogenic loci.


Subject(s)
Cerebellar Ataxia , Spinocerebellar Degenerations , Adult , Humans , Spinocerebellar Degenerations/genetics , Cerebellar Ataxia/diagnosis , Cerebellar Ataxia/genetics , Ataxia/diagnosis , Ataxia/genetics , Genomics , Genetic Testing
10.
Int J Colorectal Dis ; 39(1): 29, 2024 Feb 22.
Article in English | MEDLINE | ID: mdl-38386177

ABSTRACT

PURPOSE: Our study investigates ethnic disparities in pediatric appendicitis, focusing on the impact of Hispanic ethnicity on presentation, complications, and postoperative outcomes. METHODS: We conducted a retrospective analysis of pediatric patients undergoing appendectomy for acute appendicitis from 2015 to 2020 using the National Surgical Quality Improvement Program-Pediatric database. We compared 30-day postoperative complications, postoperative length of stay, and postoperative interventions between Hispanic and non-Hispanic White patients. RESULTS: 65,976 patients were included, of which 23,462 (35.56%) were Hispanic and 42,514 (64.44%) non-Hispanic White. Hispanic children were more likely to present to the hospital with complicated appendicitis (31.75% vs. 25.15%, P < 0.0001) and sepsis (25.22% vs. 19.02%, P < 0.0001) compared to non-Hispanic White. Hispanics had higher rates of serious complications (4.06% vs. 3.55%, P = 0.001) but not overall complications (5.37% vs. 5.09%, P = 0.12). However, after multivariate analysis, Hispanic ethnicity was not associated with an increased rate of serious postoperative complications (OR 0.93, CI 0.85-1.01, P = 0.088); it was associated with less overall complications (OR 0.88, CI 0.81-0.96, P = 0.003) but a longer postoperative length of stay (OR 1.09, CI 1.04-1.14, P < 0.0001). CONCLUSION: Hispanic children are more likely to present with complicated appendicitis, contributing to increased postoperative complications. Notably, upon adjustment for the impact of complicated appendicitis, our findings suggest potentially favorable outcomes for Hispanic ethnicity. This emphasizes the need to understand delays in presentation to improve outcomes in the Hispanic population.


Subject(s)
Appendicitis , Healthcare Disparities , Hispanic or Latino , Child , Humans , Appendicitis/surgery , Ethnicity , Postoperative Complications/etiology , Retrospective Studies
11.
Pediatr Crit Care Med ; 25(7 Suppl 1): e53-e65, 2024 Jul 01.
Article in English | MEDLINE | ID: mdl-38959360

ABSTRACT

OBJECTIVES: To derive systematic review-informed, modified Delphi consensus regarding the management of children on extracorporeal membrane oxygenation (ECMO) undergoing invasive procedures or interventions developed by the Pediatric Anticoagulation on ECMO CollaborativE (PEACE) Consensus Conference. DATA SOURCES: A structured literature search was performed using PubMed, EMBASE, and Cochrane Library (CENTRAL) databases from January 1988 to May 2021. STUDY SELECTION: ECMO anticoagulation and hemostasis management in the perioperative period and during procedures. DATA EXTRACTION: Two authors reviewed all citations independently, with a third independent reviewer resolving any conflicts. Seventeen references were used for data extraction and informed recommendations. Evidence tables were constructed using a standardized data extraction form. DATA SYNTHESIS: Risk of bias was assessed using the Quality in Prognosis Studies tool. The evidence was evaluated using the Grading of Recommendations Assessment, Development, and Evaluation system. Forty-eight experts met over 2 years to develop evidence-based recommendations and, when evidence was lacking, expert-based consensus statements for the management of bleeding and thrombotic complications in pediatric ECMO patients. A web-based modified Delphi process was used to build consensus via the Research And Development/University of California Appropriateness Method. Consensus was defined as greater than 80% agreement. Four good practice statements, 7 recommendations, and 18 consensus statements are presented. CONCLUSIONS: Although agreement among experts was strong, important future research is required in this population for evidence-informed recommendations.


Subject(s)
Anticoagulants , Delphi Technique , Extracorporeal Membrane Oxygenation , Humans , Extracorporeal Membrane Oxygenation/methods , Extracorporeal Membrane Oxygenation/adverse effects , Anticoagulants/administration & dosage , Anticoagulants/adverse effects , Anticoagulants/therapeutic use , Child , Perioperative Period , Consensus , Perioperative Care/methods , Perioperative Care/standards , Hemorrhage/chemically induced , Thrombosis/prevention & control , Thrombosis/etiology
12.
Pediatr Crit Care Med ; 25(7): 643-675, 2024 Jul 01.
Article in English | MEDLINE | ID: mdl-38959353

ABSTRACT

OBJECTIVES: To present recommendations and consensus statements with supporting literature for the clinical management of neonates and children supported with extracorporeal membrane oxygenation (ECMO) from the Pediatric ECMO Anticoagulation CollaborativE (PEACE) consensus conference. DATA SOURCES: Systematic review was performed using PubMed, Embase, and Cochrane Library (CENTRAL) databases from January 1988 to May 2021, followed by serial meetings of international, interprofessional experts in the management ECMO for critically ill children. STUDY SELECTION: The management of ECMO anticoagulation for critically ill children. DATA EXTRACTION: Within each of eight subgroup, two authors reviewed all citations independently, with a third independent reviewer resolving any conflicts. DATA SYNTHESIS: A systematic review was conducted using MEDLINE, Embase, and Cochrane Library databases, from January 1988 to May 2021. Each panel developed evidence-based and, when evidence was insufficient, expert-based statements for the clinical management of anticoagulation for children supported with ECMO. These statements were reviewed and ratified by 48 PEACE experts. Consensus was obtained using the Research and Development/UCLA Appropriateness Method. Results were summarized using the Grading of Recommendations Assessment, Development, and Evaluation method. We developed 23 recommendations, 52 expert consensus statements, and 16 good practice statements covering the management of ECMO anticoagulation in three broad categories: general care and monitoring; perioperative care; and nonprocedural bleeding or thrombosis. Gaps in knowledge and research priorities were identified, along with three research focused good practice statements. CONCLUSIONS: The 91 statements focused on clinical care will form the basis for standardization and future clinical trials.


Subject(s)
Anticoagulants , Critical Illness , Extracorporeal Membrane Oxygenation , Extracorporeal Membrane Oxygenation/methods , Humans , Anticoagulants/therapeutic use , Anticoagulants/administration & dosage , Child , Critical Illness/therapy , Infant, Newborn , Infant , Child, Preschool
13.
Nucleic Acids Res ; 50(D1): D858-D866, 2022 01 07.
Article in English | MEDLINE | ID: mdl-34761257

ABSTRACT

SCoV2-MD (www.scov2-md.org) is a new online resource that systematically organizes atomistic simulations of the SARS-CoV-2 proteome. The database includes simulations produced by leading groups using molecular dynamics (MD) methods to investigate the structure-dynamics-function relationships of viral proteins. SCoV2-MD cross-references the molecular data with the pandemic evolution by tracking all available variants sequenced during the pandemic and deposited in the GISAID resource. SCoV2-MD enables the interactive analysis of the deposited trajectories through a web interface, which enables users to search by viral protein, isolate, phylogenetic attributes, or specific point mutation. Each mutation can then be analyzed interactively combining static (e.g. a variety of amino acid substitution penalties) and dynamic (time-dependent data derived from the dynamics of the local geometry) scores. Dynamic scores can be computed on the basis of nine non-covalent interaction types, including steric properties, solvent accessibility, hydrogen bonding, and other types of chemical interactions. Where available, experimental data such as antibody escape and change in binding affinities from deep mutational scanning experiments are also made available. All metrics can be combined to build predefined or custom scores to interrogate the impact of evolving variants on protein structure and function.


Subject(s)
COVID-19/virology , Databases, Genetic , Molecular Dynamics Simulation , SARS-CoV-2/genetics , Software , Viral Proteins/genetics , Evolution, Molecular , Gene Expression Regulation, Viral , Genome, Viral , Humans , Hydrogen Bonding , Internet , Models, Molecular , Phylogeny , Point Mutation , Protein Binding , Protein Interaction Mapping , SARS-CoV-2/growth & development , SARS-CoV-2/metabolism , SARS-CoV-2/pathogenicity , Structure-Activity Relationship , Viral Proteins/chemistry , Viral Proteins/metabolism
14.
J Enzyme Inhib Med Chem ; 39(1): 2330907, 2024 Dec.
Article in English | MEDLINE | ID: mdl-38651823

ABSTRACT

Antimicrobial resistance (AMR) is a pressing global issue exacerbated by the abuse of antibiotics and the formation of bacterial biofilms, which cause up to 80% of human bacterial infections. This study presents a computational strategy to address AMR by developing three novel quantitative structure-activity relationship (QSAR) models based on molecular topology to identify potential anti-biofilm and antibacterial agents. The models aim to determine the chemo-topological pattern of Gram (+) antibacterial, Gram (-) antibacterial, and biofilm formation inhibition activity. The models were applied to the virtual screening of a commercial chemical database, resulting in the selection of 58 compounds. Subsequent in vitro assays showed that three of these compounds exhibited the most promising antibacterial activity, with potential applications in enhancing food and medical device safety.


Subject(s)
Anti-Bacterial Agents , Biofilms , Drug Design , Microbial Sensitivity Tests , Quantitative Structure-Activity Relationship , Biofilms/drug effects , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/chemical synthesis , Molecular Structure , Humans , Food Contamination/prevention & control , Dose-Response Relationship, Drug
15.
Biochem Genet ; 62(1): 352-370, 2024 Feb.
Article in English | MEDLINE | ID: mdl-37347449

ABSTRACT

Malignant pleural mesothelioma (MPM) is a rare and aggressive neoplasm of the pleural tissue that lines the lungs and is mainly associated with long latency from asbestos exposure. This tumor has no effective therapeutic opportunities nowadays and has a very low five-year survival rate. In this sense, identifying molecular events that trigger the development and progression of this tumor is highly important to establish new and potentially effective treatments. We conducted a meta-analysis of genome-wide expression studies publicly available at the Gene Expression Omnibus (GEO) and ArrayExpress databases. The differentially expressed genes (DEGs) were identified, and we performed functional enrichment analysis and protein-protein interaction networks (PPINs) to gain insight into the biological mechanisms underlying these genes. Additionally, we constructed survival prediction models for selected DEGs and predicted the minimum drug inhibition concentration of anticancer drugs for MPM. In total, 115 MPM tumor transcriptomes and 26 pleural tissue controls were analyzed. We identified 1046 upregulated DEGs in the MPM samples. Cellular signaling categories in tumor samples were associated with the TNF, PI3K-Akt, and AMPK pathways. The inflammatory response, regulation of cell migration, and regulation of angiogenesis were overrepresented biological processes. Expression of SOX17 and TACC1 were associated with reduced survival rates. This meta-analysis identified a list of DEGs in MPM tumors, cancer-related signaling pathways, and biological processes that were overrepresented in MPM samples. Some therapeutic targets to treat MPM are suggested, and the prognostic potential of key genes is shown.


Subject(s)
Lung Neoplasms , Mesothelioma, Malignant , Mesothelioma , Pleural Neoplasms , Humans , Mesothelioma/genetics , Mesothelioma/metabolism , Phosphatidylinositol 3-Kinases , Pleural Neoplasms/genetics , Pleural Neoplasms/metabolism , Lung Neoplasms/pathology
16.
Int J Mol Sci ; 25(7)2024 Mar 27.
Article in English | MEDLINE | ID: mdl-38612532

ABSTRACT

Cherry stems, prized in traditional medicine for their potent antioxidant and anti-inflammatory properties, derive their efficacy from abundant polyphenols and anthocyanins. This makes them an ideal option for addressing skin aging and diseases. This study aimed to assess the antioxidant and anti-inflammatory effects of cherry stem extract for potential skincare use. To this end, the extract was first comprehensively characterized by HPLC-ESI-qTOF-MS. The extract's total phenolic content (TPC), antioxidant capacity, radical scavenging efficiency, and its ability to inhibit enzymes related to skin aging were determined. A total of 146 compounds were annotated in the cherry stem extract. The extract effectively fought against NO· and HOCl radicals with IC50 values of 2.32 and 5.4 mg/L. Additionally, it inhibited HYALase, collagenase, and XOD enzymes with IC50 values of 7.39, 111.92, and 10 mg/L, respectively. Based on the promising results that were obtained, the extract was subsequently gently integrated into a cosmetic gel at different concentrations and subjected to further stability evaluations. The accelerated stability was assessed through temperature ramping, heating-cooling cycles, and centrifugation, while the long-term stability was evaluated by storing the formulations under light and dark conditions for three months. The gel formulation enriched with cherry stem extract exhibited good stability and compatibility for topical application. Cherry stem extract may be a valuable ingredient for creating beneficial skincare cosmeceuticals.


Subject(s)
Anthocyanins , Cosmetics , Antioxidants/pharmacology , Anti-Inflammatory Agents/pharmacology , Plant Extracts/pharmacology
17.
Aten Primaria ; 56(3): 102854, 2024 Mar.
Article in Spanish | MEDLINE | ID: mdl-38219392

ABSTRACT

Cybercrime in the health sector is a growing threat in the digital age. With computerization of medical records and telemedicine on the rise, cyberattacks can have devastating consequences. Leaking sensitive data or hijacking systems can compromise patient's privacy and jeopardize healthcare. To counter this threat, robust cybersecurity measures are required as a protective measure. This article aims to expose the main dangers and threats faced by ICT, as well as present cybersecurity with its bioethical implications and, finally, the ideal scheme for it in the health sector in order to create a safer and more efficient environment. This article aims to address these issues and provide a comprehensive view of how cybersecurity and ICT can coexist safely and effectively in the healthcare field.


Subject(s)
Computer Security , Telemedicine , Humans , Health Facilities , Medical Records
18.
Int Ophthalmol ; 44(1): 60, 2024 Feb 12.
Article in English | MEDLINE | ID: mdl-38345707

ABSTRACT

PURPOSE: To analyze higher-order aberrations (HOAs) and their visual impact in a pediatric blepharokeratoconjunctivitis (PBKC) cohort compared with healthy controls. METHODS: Prospective case-control study of pediatric patients (≤ 16 years old). Subjects underwent wavefront aberrometry analysis to compare HOAs and their impact on visual quality. RESULTS: A total of 150 eyes from 76 patients were included in the analysis. The PBKC group consisted of 50 eyes and the control group of 100 healthy eyes. Mean age was 10.39 ± 3.81 years for the PBKC group and 10.80 ± 3.61 years for the controls. Mean corrected-distance visual acuity (CDVA) was 0.24 ± 0.21 logMAR in the PBKC group and 0.07 ± 0.1 in the controls (P < 0.001). Mean astigmatism was 1.6 ± 1.98D in the PBKC group vs. 0.67 ± 0.76D in the control group (P = 0.01). Mean RMS of HOAs was 1.05 ± 1.7mm in the PBKC group and 0.41 ± 0.18mm in the controls (P < 0.001). The mean modulation transfer function (MTF) in the PBKC group was significantly lower (16.37 ± 16.32) than controls (30.3 ± 23.57) (P < 0.001). Corneal leukomas, stromal vascularization, peripheral nummular subepithelial scars, and pannus formation are associated with increased HOAs. CONCLUSIONS: There was a significant increase in total HOAs of eyes with PBKC compared to healthy controls. Corneal opacity, vascularization, and scarring are associated with increased HOAs. The PBKC eye aberration profile: coma, secondary astigmatism, quadrafoil, and pentafoil, were associated with decreased CDVA and visual quality (PSF and MTF).


Subject(s)
Astigmatism , Corneal Opacity , Corneal Wavefront Aberration , Humans , Child , Adolescent , Case-Control Studies , Visual Acuity , Cornea , Refraction, Ocular
19.
Int Ophthalmol ; 44(1): 4, 2024 Feb 05.
Article in English | MEDLINE | ID: mdl-38315255

ABSTRACT

PURPOSE: Actinic conjunctivitis (AC), along with cheilitis (AChe), is part of the clinical spectrum of actinic prurigo (AP), a rare photo dermatosis that affects high-risk populations. We analyzed the clinical manifestations and onset of actinic conjunctivitis (AC), and its relationship with prurigo (AP) in a susceptible population. METHODS: This prospective observational cohort study was performed on Indigenous populations from the highlands of Chiapas, Mexico. Thorough dermatological and ophthalmological examinations were performed in patients attending a primary health care center. The clinical features, labor and environmental factors, onset timing, and clinical staging of AC and AP were analyzed. RESULTS: Of the 2913 patients studied, 54 patients (108 eyes) (1.8%) had AC, and 14 patients (25.9%) had AP. The mean age at diagnosis was 36.18 ± 18.52 years (6-70 years). The mean residential altitude was 1884 ± 434.2 m above sea level. Mean self-reported sun exposure was 5.14 ± 3.1 h a day (0.5-12 h). A total of 90.7% reported exposure to biomass fuels during cooking, and 50% to farm animals. AC was the sole manifestation in 70% of the cases. All patients had nasal and temporal photo-exposed conjunctiva. Among the eyes, 12.9% were classified as stage-1, 64.8% as stage-2, and 22.2% stage-3. A total of 83.3% of the patients had hyperpigmented lesions, and 35.1% had evaporative dry eye disease. CONCLUSIONS: AC may be the initial or sole manifestation of AP. Most AC cases (87%) were initially observed at the advanced stages of the disease. Although solar exposure was not associated with late AC stages, a positive association was found with farm animal exposure. Evaporative dry eye associated with meibomian gland dysfunction has not been previously reported in patients with AC.


Subject(s)
Conjunctivitis , Photosensitivity Disorders , Prurigo , Skin Diseases, Genetic , Animals , Humans , Adolescent , Young Adult , Adult , Middle Aged , Mexico/epidemiology , Prurigo/complications , Prurigo/epidemiology , Prurigo/pathology , Prospective Studies , Indigenous Peoples
20.
Int Ophthalmol ; 44(1): 145, 2024 Mar 18.
Article in English | MEDLINE | ID: mdl-38498219

ABSTRACT

PURPOSE: To compare the visual, refractive, and topographic outcomes of a high irradiance accelerated corneal crosslinking (ACXL) protocol after a 12-month follow-up between pediatric and adult patients with progressive keratoconus (KC). METHODS: Retrospective, comparative, cohort study. Patients with KC were divided into two groups: pediatric (≤ 18 years) and adult (> 18 years). All of them were managed with epi-OFF ACXL (30 mW/cm2, 8 min, pulsed 1:1 on and off = 7.2 J/cm2). Visual, refractive, and topographic values were measured preoperatively and at 1, 3, 6, and 12 months postoperative. KC progression, defined as a Kmax increase of ≥ 1D during follow-up, was recorded. RESULTS: Eighty-nine eyes (53 patients) were included for analysis; 45 (50.6%) eyes were from pediatric patients and 44 (49.4%) from adults. At one-year follow-up, pediatric patients experienced significantly higher rates of progression (22.2% vs. 4.5%, p = .014). Contrariwise, female gender (Beta = - 3.62, p = .018), a baseline uncorrected visual acuity of Snellen ≥ 20/60 (Beta = - 5.96, p = .007), and being ≥ 15 years at ACXL treatment (Beta = - 0.31, p = .021) were associated with non-progressive disease. A significant improvement in best-corrected visual acuity, Kmin, Km, and Kmax was recorded in both groups. Overall, 86.5% of eyes from both groups showed Kmax stabilization or improvement. CONCLUSIONS: Despite the similarity in visual, refractive, and topographic outcomes in both groups, younger age was associated with KC progression after ACXL at one year of follow-up.


Subject(s)
Keratoconus , Photochemotherapy , Adult , Humans , Female , Child , Keratoconus/diagnosis , Keratoconus/drug therapy , Photosensitizing Agents/therapeutic use , Photochemotherapy/methods , Corneal Cross-Linking , Retrospective Studies , Cohort Studies , Riboflavin/therapeutic use , Ultraviolet Rays , Corneal Topography/methods , Follow-Up Studies , Cross-Linking Reagents/therapeutic use , Collagen/therapeutic use
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