Methods Enzymol. 2024;706:263-283. doi: 10.1016/bs.mie.2024.07.038. Epub 2024 Aug 17.

ABSTRACT

Mitochondria consist of several hundreds of proteins, the vast majority of which are synthesized in the cytosol as precursor proteins from where they are targeted to and imported into mitochondria. The transport of proteins into mitochondria relies on specific targeting information encoded within the protein sequence, known as mitochondrial targeting sequences (MTSs). These N-terminal extensions are usually between 8 and 80 residues long and form amphipathic helices with one hydrophobic and one positively charged surface. Receptors on the mitochondrial surface recognize the MTSs and direct precursors through protein-conducting channels in the outer and inner membrane to the mitochondrial matrix, where presequences are often removed by proteases. In addition to these MTSs, many mitochondrial proteins contain internal matrix targeting sequences (iMTSs) which share the same structural features with MTSs. These iMTSs are neither necessary nor sufficient for mitochondrial targeting, however, they help to increase the import-competence of precursor proteins as they bind to the TOM receptors and presumably facilitate the unfolding of precursors on the mitochondrial surface. Prediction algorithms allow the identification of iMTSs in protein sequences. In this chapter, we present iMLP, an agnostic algorithm for the prediction of iMTS propensity profiles. This iMTS prediction tool is provided via an iMLP webservice at http://iMLP.bio.uni-kl.de and is also available as a BioFSharp application that can be executed locally. We describe and explain the usage of this prediction algorithm and how to interpret the results of this valuable tool.

PMID:39455219 | DOI:10.1016/bs.mie.2024.07.038

Lancet Digit Health. 2024 Nov;6(11):e791-e802. doi: 10.1016/S2589-7500(24)00172-9.

ABSTRACT

BACKGROUND: Artificial intelligence (AI)-enabled electrocardiography (ECG) can be used to predict risk of future disease and mortality but has not yet been adopted into clinical practice. Existing model predictions do not have actionability at an individual patient level, explainability, or biological plausibi. We sought to address these limitations of previous AI-ECG approaches by developing the AI-ECG risk estimator (AIRE) platform.

METHODS: The AIRE platform was developed in a secondary care dataset (Beth Israel Deaconess Medical Center [BIDMC]) of 1 163 401 ECGs from 189 539 patients with deep learning and a discrete-time survival model to create a patient-specific survival curve with a single ECG. Therefore, AIRE predicts not only risk of mortality, but also time-to-mortality. AIRE was validated in five diverse, transnational cohorts from the USA, Brazil, and the UK (UK Biobank [UKB]), including volunteers, primary care patients, and secondary care patients.

FINDINGS: AIRE accurately predicts risk of all-cause mortality (BIDMC C-index 0·775, 95% CI 0·773-0·776; C-indices on external validation datasets 0·638-0·773), future ventricular arrhythmia (BIDMC C-index 0·760, 95% CI 0·756-0·763; UKB C-index 0·719, 95% CI 0·635-0·803), future atherosclerotic cardiovascular disease (0·696, 0·694-0·698; 0·643, 0·624-0·662), and future heart failure (0·787, 0·785-0·789; 0·768, 0·733-0·802). Through phenome-wide and genome-wide association studies, we identified candidate biological pathways for the prediction of increased risk, including changes in cardiac structure and function, and genes associated with cardiac structure, biological ageing, and metabolic syndrome.

INTERPRETATION: AIRE is an actionable, explainable, and biologically plausible AI-ECG risk estimation platform that has the potential for use worldwide across a wide range of clinical contexts for short-term and long-term risk estimation.

FUNDING: British Heart Foundation, National Institute for Health and Care Research, and Medical Research Council.

PMID:39455192 | DOI:10.1016/S2589-7500(24)00172-9

Biochim Biophys Acta Gene Regul Mech. 2024 Oct 23:195065. doi: 10.1016/j.bbagrm.2024.195065. Online ahead of print.

ABSTRACT

BCL11b is a transcription regulator and a tumor suppressor involved in lymphomagenesis, central nervous system (CNS) and immune system developments. BCL11b favors persistence of HIV latency and contributes to control cell cycle, differentiation and apoptosis in multiple organisms and cell models. Although BCL11b recruits the non-coding RNA 7SK and epigenetic enzymes to regulate gene expression, BCL11b-associated ribonucleoprotein complexes are unknown. Thanks to CLIP-seq and quantitative LC-MS/MS mass spectrometry approaches complemented with systems biology validations, we show that BCL11b interacts with RNA splicing and non-sense-mediated decay proteins, including FUS, SMN1, UPF1 and Drosha, which may contribute in isoform selection of protein-coding RNA isoforms from noncoding-RNAs isoforms (retained introns or nonsense mediated RNA). Interestingly, BCL11b binds to RNA transcripts and proteins encoded by the same genes (FUS, ESWR1, CHD and Tubulin). Our study highlights that BCL11b targets RNA processing and splicing proteins, and RNAs that implicate cell cycle, development, neurodegenerative, and cancer pathways. These findings will help future mechanistic understanding of developmental disorders. IMPORTANCE: BCL11b-protein and RNA interactomes reveal BLC11b association with specific nucleoprotein complexes involved in the regulation of genes expression. BCL11b interacts with RNA processing and splicing proteins.

PMID:39455000 | DOI:10.1016/j.bbagrm.2024.195065

J Thromb Haemost. 2024 Oct 23:S1538-7836(24)00621-4. doi: 10.1016/j.jtha.2024.09.033. Online ahead of print.

ABSTRACT

BACKGROUND: Acute large vessel occlusion (LVO) stroke is highly prevalent and severe. Despite thrombolytic therapy, many patients experience substantial complications. Understanding the origins, constituents, and pathological processes involved in thrombus formation in acute intracranial large artery occlusion is crucial.

OBJECTIVES: To identify the characteristics of insoluble proteins from different sources of cerebral thrombus.

METHODS: This study included 13 patients with cardiogenic embolic thrombus (CE) and 15 with large artery atherosclerosis thrombus (LAA). High-performance liquid chromatography and liquid chromatography-tandem mass spectrometry were used to analyze insoluble proteins in thrombi. Bioinformatics analyses explored differential proteins and associated functional pathways. Least Absolute Shrinkage and Selection Operator and Random Forest identified biomarkers for diagnosing thrombus sources, validated by parallel reaction monitoring.

RESULTS: We constructed an insoluble protein atlas of cerebral thrombi, identifying 6975 insoluble proteins, including 143 extracellular matrix (ECM)-related proteins. The enrichment pathways considerably varied between thrombi from different sources. Inflammation-related pathways, such as "acute inflammatory response," along with ECM-related pathways such as "laminin interactions," were notably upregulated in LAA compared to CE. Additionally, two biomarkers (IDH2, HSPG2) exhibited strong diagnostic performance (AUC = 1) and robustness.

CONCLUSIONS: In the insoluble Proteomics of thrombus, we highlighted the crucial roles of immune responses and ECM proteins in thrombus formation, providing new insights into its mechanisms and potential drug development. Additionally, we identified two biomarkers that offer new methods for determining thrombus sources in patients with LVO.

PMID:39454879 | DOI:10.1016/j.jtha.2024.09.033

Clin Microbiol Infect. 2024 Oct 23:S1198-743X(24)00498-1. doi: 10.1016/j.cmi.2024.10.016. Online ahead of print.

ABSTRACT

OBJECTIVES: To determine the agreement of Mycobacterium tuberculosis (MTB) antigen-based skin test (TBST) with interferon-gamma release assay (IGRA) in elderly individuals aged ≥ 65 years beyond instruction for use in China.

METHODS: Based on the baseline survey of randomized controlled trial with objective to explore suitable regimen for tuberculosis (TB) preventive treatment, MTB infection was tested using TBST and IGRA in parallel in rural residents aged 50-70 years by means of a cross-sectional study design.

RESULTS: A total of 21219 participants with both TBST and IGRA results were included in this analysis. The concordance between TBST and IGRA was 89.4% (95%CI: 89.0 - 89.8%) with a kappa coefficient of 0.61 (95%CI: 0.60 - 0.62). In those aged ≥ 65 years, the concordance was 86.5% (95%CI: 85.6 - 87.4%) with a kappa coefficient of 0.55 (95%CI: 0.52 - 0.58). 21.2% (35/165) of the participants with indeterminate IGRA results were TBST positive, and 9 of them aged ≥ 65 years.

CONCLUSIONS: The consistent agreement between TBST and IGRA in individuals aged ≥ 65 years suggests that TBST has potential to be used in the elderly with age beyond instruction for use in China. The respective diagnostic performance of each test will be analyzed when the longitudinal data on incident TB be obtained in the future.

PMID:39454755 | DOI:10.1016/j.cmi.2024.10.016

J Biomed Inform. 2024 Oct 23:104740. doi: 10.1016/j.jbi.2024.104740. Online ahead of print.

ABSTRACT

OBJECTIVE: We propose a way to enhance the evaluation of minimal cut sets (MCSs) in biological systems modeled by Petri nets, by providing criteria and methodology for determining their optimality in disabling specific processes without affecting critical system components.

METHODS: This study concerns Petri nets to model biological systems and utilizes two primary approaches for MCS evaluation. First is the analyzing impact on t-invariants to identify structural dependencies. Second is assessing the impact on potentially starved transitions caused by the inactivity of specific MCSs. This approach deal with net dynamics. These methodologies aim to offer practical tools for assessing the quality and effectiveness of MCSs.

RESULTS: The proposed methodologies were applied to two case studies. In the first case, a cholesterol metabolism network was analyzed to investigate how local inflammation and oxidative stress, in conjunction with cholesterol imbalances, influence the progression of atherosclerosis. The MCSs were ranked, with the top sets presented, focusing on those that disabled the fewest number of t-invariants. In the second case, a carbohydrate metabolism disorder model was examined to understand its impact on atherosclerosis progression. The analysis aimed to identify MCSs that could inhibit the atherosclerosis process by targeting specific transitions. Both studies utilized the Holmes software for calculations, demonstrating the effectiveness of the proposed evaluation methodologies in ranking MCSs for practical biological applications.

CONCLUSION: The algorithms proposed in this paper offer an analytical approach for evaluating the quality of MCSs in biological systems. By providing criteria for MCS optimality, these approaches have potential to enhance the utility of MCS analysis in systems biology, aiding in the understanding and manipulation of complex biological networks. Algorithm are implemented within Holmes software, an open-source project available at https://github.com/bszawulak/HolmesPN.

PMID:39454703 | DOI:10.1016/j.jbi.2024.104740

Lancet Rheumatol. 2024 Oct 22:S2665-9913(24)00237-6. doi: 10.1016/S2665-9913(24)00237-6. Online ahead of print.

NO ABSTRACT

PMID:39454618 | DOI:10.1016/S2665-9913(24)00237-6

J Am Chem Soc. 2024 Oct 25. doi: 10.1021/jacs.4c09531. Online ahead of print.

ABSTRACT

Owing to their synthetic accessibility and protein-mimetic features, peptides represent an attractive biomolecular building block for the fabrication of artificial biomimetic materials with emergent properties and functions. Here, we expand the peptide building block design space through unveiling the design, synthesis, and characterization of novel, multivalent peptide macrocycles (96mers), termed coiled coil peptide tiles (CCPTs). CCPTs comprise multiple orthogonal coiled coil peptide domains that are separated by flexible linkers. The constraints, imposed by cyclization, confer CCPTs with the ability to direct programmable, multidirectional interactions between coiled coil-forming "edge" domains of CCPTs and their free peptide binding partners. These fully synthetic constructs are assembled using a convergent synthetic strategy via a combination of native chemical ligation and Sortase A-mediated cyclization. Circular dichroism (CD) studies reveal the increased helical stability associated with cyclization and subsequent coiled coil formation along the CCPT edges. Size-exclusion chromatography (SEC), analytical high-performance liquid chromatography (HPLC), and fluorescence quenching assays provide a comprehensive biophysical characterization of various assembled CCPT complexes and confirm the orthogonal colocalization between coiled coil domains within CCPTs and their designed on-target free peptide partners. Lastly, we employ molecular dynamics (MD) simulations, which provide molecular-level insights into experimental results, as a supporting method for understanding the structural dynamics of CCPTs and their complexes. MD analysis of the simulated CCPT architectures reveals the rigidification and expansion of CCPTs upon complexation, i.e., coiled coil formation with their designed binding partners, and provides insights for guiding the designs of future generations of CCPTs. The addition of CCPTs into the repertoire of coiled coil-based building blocks has the potential for expanding the coiled coil assembly landscape by unlocking new topologies having designable intermolecular interfaces.

PMID:39454098 | DOI:10.1021/jacs.4c09531

Sci Adv. 2024 Oct 25;10(43):eadp2229. doi: 10.1126/sciadv.adp2229. Epub 2024 Oct 25.

ABSTRACT

The master regulator of the DNA damage response, the transcription factor p53, orchestrates multiple downstream responses and coordinates repair processes. In response to double-strand DNA breaks, p53 exhibits pulses of expression, but how it achieves temporal coordination of downstream responses remains unclear. Here, we show that p53's posttranslational modification state is altered between its first and second pulses of expression. We show that acetylations at two sites, K373 and K382, were reduced in the second pulse, and these acetylations differentially affected p53 target genes, resulting in changes in gene expression programs over time. This interplay between dynamics and modification may offer a strategy for cellular hubs like p53 to temporally organize multiple processes in individual cells.

PMID:39454005 | DOI:10.1126/sciadv.adp2229

Sci Adv. 2024 Oct 25;10(43):eadp8783. doi: 10.1126/sciadv.adp8783. Epub 2024 Oct 25.

ABSTRACT

Cells that lack p53 signaling frequently occur in ulcerative colitis (UC) and are considered early drivers in UC-associated colorectal cancer (CRC). Epithelial injury during colitis is associated with transient stem cell reprogramming from the adult, homeostatic to a "fetal-like" regenerative state. Here, we use murine and organoid-based models to study the role of Trp53 during epithelial reprogramming. We find that p53 signaling is silent and dispensable during homeostasis but strongly up-regulated in the epithelium upon DSS-induced colitis. While in WT cells this causes termination of the regenerative state, crypts that lack Trp53 remain locked in the highly proliferative, regenerative state long-term. The regenerative state in WT cells requires high Wnt signaling to maintain elevated levels of glycolysis. Instead, Trp53 deficiency enables Wnt-independent glycolysis due to overexpression of rate-limiting enzyme PKM2. Our study reveals the context-dependent relevance of p53 signaling specifically in the injury-induced regenerative state, explaining the high abundance of clones lacking p53 signaling in UC and UC-associated CRC.

PMID:39453996 | DOI:10.1126/sciadv.adp8783

United European Gastroenterol J. 2024 Oct 25. doi: 10.1002/ueg2.12676. Online ahead of print.

ABSTRACT

BACKGROUND AND AIMS: Timely and accurate detection of tumor recurrence in pancreatic ductal adenocarcinoma (PDAC) patients is an urgent and unmet medical need. This study aimed to develop a noninvasive molecular diagnostic procedure for the detection of recurrence after PDAC resection based on quantification of circulating mRNA and miRNA biomarkers in serum samples.

METHODS: In a multicentric study, serum samples from a total of 146 patients were prospectively collected after resection. Samples were classified into a "No Evidence of Disease" and a "Recurrence" group based on clinical follow-up data. A multianalyte biomarker panel was composed of mRNAs and miRNA markers and simultaneously analyzed in serum samples using custom microfluidic qPCR arrays (TaqMan array cards). A diagnostic algorithm was developed combining a 7-gene marker signature with CA19-9 data.

RESULTS: The best-performing marker combination achieved 90% diagnostic accuracy in predicting the presence of tumor recurrence (98% sensitivity; 84% specificity), clearly outperforming the singular CA 19-9 analysis. Moreover, time series data obtained by analyzing successively collected samples from 5 patients during extended follow-up suggested that molecular diagnosis has the potential to detect recurrence earlier than routine clinical procedures.

CONCLUSIONS: TaqMan array card measurements were found to be biologically valid and technically reproducible. The BioPac multianalyte marker panel is capable of sensitive and accurate detection of recurrence in patients resected for PDAC using a simple blood test. This could allow a closer follow-up using shorter time intervals than currently used for imaging, thus potentially prompting an earlier work-up with additional modalities to allow for earlier therapeutic intervention. This study provides a promising approach for improved postoperative monitoring of resected PDAC patients, which is an urgent and unmet clinical need.

PMID:39453683 | DOI:10.1002/ueg2.12676

Metabolomics. 2024 Oct 25;20(6):120. doi: 10.1007/s11306-024-02187-y.

ABSTRACT

INTRODUCTION AND OBJECTIVES: The application of untargeted metabolomics assays using ultra high performance liquid chromatography-mass spectrometry (UHPLC-MS) to study metabolism in biological systems including humans is rapidly increasing. In some of these studies there is a requirement to collect and analyse low sample volumes of biofluids (e.g. tear fluid) or low cell and tissue mass samples (e.g. tissue needle biopsies). The application of microflow, capillary or nano liquid chromatography (≤ 1.0 mm column internal diameter (i.d.)) theoretically should accomplish a higher assay sensitivity compared to analytical liquid chromatography (2.1-5.0 mm column internal diameter). To date, there has been limited research into microflow UHPLC-MS assays that can be applied to study samples of low volume or mass.

METHODS: This paper presents three complementary UHPLC-MS assays (aqueous C18 reversed-phase, lipidomics C18 reversed-phase and Hydrophilic Interaction Liquid Chromatography (HILIC)) applying 1.0 mm internal diameter columns for untargeted metabolomics. Human plasma and urine samples were applied for the method development, with porcine plasma, urine and tear fluid used for method assessment. Data were collected and compared for columns of the same length, stationary phase and stationary phase particle size but with two different column internal diameters (2.1 mm and 1.0 mm).

RESULTS AND CONCLUSIONS: All three assays showed an increase in peak areas and peak widths when applying the 1.0 mm i.d. assays. HILIC assays provide an advantage at lower sample dilutions whereas for reversed phase (RP) assays there was no benefit added. This can be seen in the validation study where a much higher number of compounds were detected in the HILIC assay. RP assays were still appropriate for small volume samples with hundreds of compounds being detected. In summary, the 1.0 mm i.d. column assays are applicable for small volume samples where dilution is required during sample preparation.

PMID:39453548 | DOI:10.1007/s11306-024-02187-y

Aging Cell. 2024 Oct 25:e14393. doi: 10.1111/acel.14393. Online ahead of print.

ABSTRACT

Aging is an intricate process involving interactions among multiple factors, which is one of the main risks for chronic diseases, including Alzheimer's disease (AD). As a member of cysteine protease, cathepsin S (CTSS) has been implicated in inflammation across various diseases. Here, we investigated the role of neuronal CTSS in aging and AD started by examining CTSS expression in hippocampus neurons of aging mice and identified a significant increase, which was negatively correlated with recognition abilities. Concurrently, we observed an elevation of CTSS concentration in the serum of elderly people. Transcriptome and fluorescence-activated cell sorting (FACS) results revealed that CTSS overexpression in neurons aggravated brain inflammatory milieu with microglia activation to M1 pro-inflammatory phenotype, activation of chemokine C-X3-C-motif ligand 1 (CX3CL1)-chemokine C-X3-C-motif receptor 1 (CX3CR1) axis and janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 (STAT3) pathway. As CX3CL1 is secreted by neurons and acts on the CX3CR1 in microglia, our results revealed for the first time the role of neuron CTSS in neuron-microglia "crosstalk." Besides, we observed elevated CTSS expression in multiple brain regions of AD patients, including the hippocampus. Utilizing CTSS selective inhibitor, LY3000328, rescued AD-related pathological features in APP/PS1 mice. We further noticed that neuronal CTSS overexpression increased cathepsin B (CTSB) activity, but decreased cathepsin L (CTSL) activity in microglia. Overall, we provide evidence that CTSS can be used as an aging biomarker and plays regulatory roles through modulating neuroinflammation and recognition in aging and AD process.

PMID:39453382 | DOI:10.1111/acel.14393

Metabolites. 2024 Oct 20;14(10):562. doi: 10.3390/metabo14100562.

ABSTRACT

BACKGROUND: Specialised anti-herbivory metabolites are abundant in the solanaceous genus Nicotiana. These metabolites include the large family of 17-hydroxygeranyllinalool diterpene glycosides (HGL-DTGs). Many HGL-DTGs occur exclusively within the Nicotiana genus, but information from the molecular model species N. tabacum, N. benthamiana, and the tree tobacco N. glauca is limited.

OBJECTIVES: We studied HGL-DTG occurrence and complexity in these species with the aim of providing in-depth reference annotations and comprehensive HGL-DTG inventories.

METHODS: We analysed polar metabolite extracts in comparison to the previously investigated wild reference species N. attenuata using positive ESI(+) and negative ESI(-) mode electrospray ionisation LC-MS and MS/MS.

RESULTS: We provide annotations of 66 HGL-DTGs with in-source and MS/MS fragmentation spectra for selected HGL-DTGs with exemplary fragment interpretations of ESI(+) as well as less studied ESI(-) spectra. We assemble a potential biosynthesis pathway comparing the presence of HGL-DTGs in N. tabacum, N. glauca, and N. benthamiana to N. attenuata. Approximately one-third of HGL-DTGs are chromatographically resolved isomers of hexose, deoxyhexose, or malonate conjugates. The number of isomers is especially high for conjugates with low numbers of deoxyhexose moieties.

CONCLUSIONS: We extend the number of known HGL-DTGs with a focus on Nicotiana model species and demonstrate that the HGL-DTG family of N. tabacum plants can be surprisingly complex. Our study provides an improved basis with detailed references to previous studies of wild Nicotiana species and enables inference of HGL-DTG pathways with required enzymes for the biosynthesis of this important family of specialised defence metabolites.

PMID:39452943 | DOI:10.3390/metabo14100562

J Funct Biomater. 2024 Oct 12;15(10):303. doi: 10.3390/jfb15100303.

ABSTRACT

Titanium and titanium alloys are the prevailing dental implant materials owing to their favorable mechanical properties and biocompatibility, but how roughness dictates the biological response is still a matter of debate. In this study, laser texturing was used to generate eight paradigmatic roughened surfaces, with the aim of studying the early biological response elicited on MC3T3-E1 pre-osteoblasts. Prior to cell tests, the samples underwent SEM analysis, optical profilometry, protein adsorption assay, and optical contact angle measurement with water and diiodomethane to determine surface free energy. While all the specimens proved to be biocompatible, supporting similar cell viability at 1, 2, and 3 days, surface roughness could impact significantly on cell adhesion. Factorial analysis and linear regression showed, in a robust and unprecedented way, that an isotropic distribution of deep and closely spaced valleys provides the best condition for cell adhesion, to which both protein adsorption and surface free energy were highly correlated. Overall, here the authors provide, for the first time, a thorough investigation of the relationship between roughness parameters and osteoblast adhesion that may be applied to design and produce new tailored interfaces for implant materials.

PMID:39452601 | DOI:10.3390/jfb15100303

Insects. 2024 Sep 26;15(10):744. doi: 10.3390/insects15100744.

ABSTRACT

The bird cherry-oat aphid, Rhopalosiphum padi (L.), is an economically significant pest of pasture grasses, the latter being capable of hosting several fungal endophyte-perennial ryegrass symbiota rich in alkaloids and toxic to vertebrates and invertebrates. Measuring aphid feeding behaviour can provide insights into the effectiveness and mode of action of different fungal endophytes. This study investigated the effects of different Epichloë-perennial ryegrass symbiota on the feeding behaviour of R. padi using the electrical penetration graph technique while also assessing the aphid life history. In most cases, endophytes had significant feeding deterrence and paired fecundity and mortality effects. But, in some instances, endophytes with the highest aphid mortality did not significantly deter feeding, suggesting a more complicated scenario of interactions between the relative concentration of metabolites, e.g., host plant defence response metabolites and alkaloids, and/or physical changes to leaf morphology. Overall, this study sheds light on the mode of action of Epichloë endophytes against aphids and highlights the importance of Epichloë-perennial ryegrass symbiota in the management of insect pests such as aphids in pasture-based grazing systems.

PMID:39452320 | DOI:10.3390/insects15100744

Antibiotics (Basel). 2024 Oct 14;13(10):971. doi: 10.3390/antibiotics13100971.

ABSTRACT

The Unani Tibb is a medical system of Greek descent that has undergone substantial dissemination since the 11th century and is currently prevalent in modern South and Central Asia, particularly in primary health care. The ingredients of Unani herbal medicines are primarily derived from plants. Our research aimed to address the pressing issues of antibiotic resistance, multi-drug resistance, and the emergence of superbugs by examining the molecular-level effects of Unani ingredients as potential new natural antibiotic candidates. We utilized a machine learning approach to tackle these challenges, employing decision trees, kernels, neural networks, and probability-based methods. We used 12 machine learning algorithms and several techniques for preprocessing data, such as Synthetic Minority Over-sampling Technique (SMOTE), Feature Selection, and Principal Component Analysis (PCA). To ensure that our model was optimal, we conducted grid-search tuning to tune all the hyperparameters of the machine learning models. The application of Multi-Layer Perceptron (MLP) with SMOTE pre-processing techniques resulted in an impressive accuracy precision and recall values. This analysis identified 20 important metabolites as essential components of the formula, which we predicted as natural antibiotics. In the final stage of our investigation, we verified our prediction by conducting a literature search for journal validation or by analyzing the structural similarity with known antibiotics using asymmetric similarity.

PMID:39452237 | DOI:10.3390/antibiotics13100971

Antibiotics (Basel). 2024 Sep 27;13(10):925. doi: 10.3390/antibiotics13100925.

ABSTRACT

Background/Objectives: Urinary tract infection (UTI) is a prevalent microbial infection in medical practise, leading to significant patient morbidity and increased treatment costs, particularly in developing countries. This retrospective study, conducted at a tertiary care hospital in Dhaka, Bangladesh, aims to examine the antimicrobial resistance (AMR) patterns of uropathogens and evaluate whether these patterns are influenced by demographic factors such as gender, age, or patient status. Methods: Standard microbiological techniques were used to identify uropathogens, and AMR patterns were determined using the Kirby-Bauer disc diffusion method. Results: Out of 6549 urine samples, 1001 cultures were positive. The infection was more prevalent in females compared to males. The incidence of UTIs in children aged 0-10 years accounted for 12.59% of the total cases, with this age group also exhibiting the highest rate of polymicrobial infections. Among the bacterial uropathogens, 71.19% of isolates were multidrug resistant (MDR) and 84.27% were resistant to at least one antibiotic. Escherichia coli (n = 544, 73.90% MDR) and Klebsiella species (n = 143, 48.95% MDR) were the most common Gram-negative uropathogens, while Enterococcus species (n = 78, 94.87% MDR) was the predominant Gram-positive isolate in this study. Our results indicate that most uropathogens showed resistance against ceftazidime, followed by cefuroxime, trimethoprim-sulfamethoxazole, amoxicillin-clavulanate, and netilmicin. Moderate levels of resistance were observed against ciprofloxacin, levofloxacin, aztreonam, and cefpodoxime. Conclusions: Amikacin was observed to be effective against Gram-negative uropathogens, whereas cefixime was more active against Gram-positive microorganisms, such as Enterococcus species. Moreover, a principal coordinate analysis (PCoA) depicted no significant influence of gender, patient status, or age on AMR patterns. For the continued usefulness of most antibiotics, periodic analysis of the AMR patterns of uropathogens can help assess the rise of MDR bacteria, and therefore guide the selection of appropriate antibiotic treatment strategies.

PMID:39452192 | DOI:10.3390/antibiotics13100925

Pediatr Pulmonol. 2024 Oct 25. doi: 10.1002/ppul.27366. Online ahead of print.

NO ABSTRACT

PMID:39451012 | DOI:10.1002/ppul.27366

Kidney360. 2024 Oct 16. doi: 10.34067/KID.0000000602. Online ahead of print.

ABSTRACT

BACKGROUND: Currently there are limited methods to link disease severity and risk of disease progression in Chronic Kidney Disease (CKD). To better understand this potential relationship, we interrogated the renal transcriptomic profile of individuals with CKD with measures of CKD severity and identified FERM-domain containing protein 3 (FRMD3) as a candidate gene for follow-up study.

METHODS: RNA-seq was used to profile the transcriptome of CKD biopsies from the North Dublin Renal BioBank the results of which were correlated with clinical parameters. The potential function of FRMD3 was explored by interrogating the FRMD3 interactome and assessing the impact of lentiviral mediated FRMD3 knock down on human renal proximal tubule epithelial cells by assessing cell viability, metabolic activity, and structural markers.

RESULTS: We identified a subset of 93 genes which are significantly correlated with estimated glomerular filtration rate and percentage tubulointerstitial fibrosis at time of biopsy and with CKD progression 5 years post-biopsy. These results were validated against transcriptomic data from an external cohort of 432 nephrectomy samples. One of the top-ranking genes from this subset, FRMD3, has previously been associated with the risk of developing diabetic kidney disease. Interrogating the interactome of FRMD3 in tubule epithelial cells revealed interactions with cytoskeletal components of cell-cell junctions. Knockdown of FRMD3 expression in tubule epithelial cells resulted in increased pro-apoptotic activity within the cells as well as dysregulation of E-Cadherin.

CONCLUSIONS: We have identified a panel of kidney-specific transcripts correlated with severity and progression of kidney disease, and from this have identified a possible role for FRMD3 in tubule cell structure and health.

PMID:39450948 | DOI:10.34067/KID.0000000602