Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 69
Filtrar
Más filtros

Intervalo de año de publicación
1.
Brief Bioinform ; 25(1)2023 11 22.
Artículo en Inglés | MEDLINE | ID: mdl-38152979

RESUMEN

The identification and characterization of essential genes are central to our understanding of the core biological functions in eukaryotic organisms, and has important implications for the treatment of diseases caused by, for example, cancers and pathogens. Given the major constraints in testing the functions of genes of many organisms in the laboratory, due to the absence of in vitro cultures and/or gene perturbation assays for most metazoan species, there has been a need to develop in silico tools for the accurate prediction or inference of essential genes to underpin systems biological investigations. Major advances in machine learning approaches provide unprecedented opportunities to overcome these limitations and accelerate the discovery of essential genes on a genome-wide scale. Here, we developed and evaluated a large language model- and graph neural network (LLM-GNN)-based approach, called 'Bingo', to predict essential protein-coding genes in the metazoan model organisms Caenorhabditis elegans and Drosophila melanogaster as well as in Mus musculus and Homo sapiens (a HepG2 cell line) by integrating LLM and GNNs with adversarial training. Bingo predicts essential genes under two 'zero-shot' scenarios with transfer learning, showing promise to compensate for a lack of high-quality genomic and proteomic data for non-model organisms. In addition, the attention mechanisms and GNNExplainer were employed to manifest the functional sites and structural domain with most contribution to essentiality. In conclusion, Bingo provides the prospect of being able to accurately infer the essential genes of little- or under-studied organisms of interest, and provides a biological explanation for gene essentiality.


Asunto(s)
Proteínas de Drosophila , Genes Esenciales , Ratones , Animales , Proteómica , Drosophila melanogaster/genética , Flujo de Trabajo , Redes Neurales de la Computación , Proteínas/genética , Proteínas de Microfilamentos/genética , Proteínas de Drosophila/genética
2.
Int Orthop ; 48(5): 1351-1356, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38302595

RESUMEN

In orthopaedic surgery, as well as other areas in medicine, it is common for a surgical technique to carry the original authors' name describing the procedure. The Judet family represents a unique history, since several orthopaedic procedures are known as "Judet's technique". The aim of this historic review is to outline the genealogy of the orthopaedic arm of the Judet family, while crediting each surgical procedure to the specific family member that described the technique.


Asunto(s)
Procedimientos Ortopédicos , Ortopedia , Humanos , Procedimientos Ortopédicos/efectos adversos , Procedimientos Ortopédicos/métodos
3.
Int J Mol Sci ; 25(13)2024 Jun 27.
Artículo en Inglés | MEDLINE | ID: mdl-39000124

RESUMEN

Over the years, comprehensive explorations of the model organisms Caenorhabditis elegans (elegant worm) and Drosophila melanogaster (vinegar fly) have contributed substantially to our understanding of complex biological processes and pathways in multicellular organisms generally. Extensive functional genomic-phenomic, genomic, transcriptomic, and proteomic data sets have enabled the discovery and characterisation of genes that are crucial for life, called 'essential genes'. Recently, we investigated the feasibility of inferring essential genes from such data sets using advanced bioinformatics and showed that a machine learning (ML)-based workflow could be used to extract or engineer features from DNA, RNA, protein, and/or cellular data/information to underpin the reliable prediction of essential genes both within and between C. elegans and D. melanogaster. As these are two distantly related species within the Ecdysozoa, we proposed that this ML approach would be particularly well suited for species that are within the same phylum or evolutionary clade. In the present study, we cross-predicted essential genes within the phylum Nematoda (evolutionary clade V)-between C. elegans and the pathogenic parasitic nematode H. contortus-and then ranked and prioritised H. contortus proteins encoded by these genes as intervention (e.g., drug) target candidates. Using strong, validated predictors, we inferred essential genes of H. contortus that are involved predominantly in crucial biological processes/pathways including ribosome biogenesis, translation, RNA binding/processing, and signalling and which are highly transcribed in the germline, somatic gonad precursors, sex myoblasts, vulva cell precursors, various nerve cells, glia, or hypodermis. The findings indicate that this in silico workflow provides a promising avenue to identify and prioritise panels/groups of drug target candidates in parasitic nematodes for experimental validation in vitro and/or in vivo.


Asunto(s)
Caenorhabditis elegans , Genes Esenciales , Haemonchus , Aprendizaje Automático , Animales , Haemonchus/genética , Caenorhabditis elegans/genética , Proteínas del Helminto/genética , Proteínas del Helminto/metabolismo , Biología Computacional/métodos , Drosophila melanogaster/genética
4.
Artículo en Inglés | MEDLINE | ID: mdl-39249520

RESUMEN

PURPOSE: The optimal duration of antibiotic therapy for fracture-related infection (FRI) has not been well defined. Our aim was to assess the recurrence rate of infection in patients who underwent six, 12, or 24 weeks of antibiotic therapy following surgical treatment for FRI one year after antibiotic discontinuation. Additionally, complications were monitored. METHODS: Patients with FRI underwent surgical treatment, and antibiotic therapy was initiated. The patients were divided into groups at the 6th and 12th weeks of antibiotic therapy. The primary endpoint was the recurrence of deep or superficial infection at 90 days and one year after the end of antimicrobial therapy. RESULTS: There was no difference in the recurrence of infection 90 days or one year after stopping antibiotic therapy among patients treated for six, 12, or 24 weeks (p = 0.98 and p = 0.19, respectively). The overall recurrence rate of infection 90 days after stopping antibiotic therapy was 4.9% (8/163), and one year after discontinuation of antibiotic therapy was 9.8% (16/163). There was a statistically significant difference in the incidence of adverse effects among the three groups (chi-square; p = 0.01). Adverse effects were more common in the group treated for 24 weeks than in the groups treated for 6 weeks (z score, p = 0.017) or 12 weeks (z score, p = 0.005). CONCLUSION: Antibiotic therapy longer than 6 weeks did not reduce the recurrence of FRI after one year of follow-up. Additionally, antibiotic treatment for 24 weeks increases adverse events such as skin reactions and acute renal failure.

6.
Nucleic Acids Res ; 49(D1): D998-D1003, 2021 01 08.
Artículo en Inglés | MEDLINE | ID: mdl-33084874

RESUMEN

OGEE is an Online GEne Essentiality database. Gene essentiality is not a static and binary property, rather a context-dependent and evolvable property in all forms of life. In OGEE we collect not only experimentally tested essential and non-essential genes, but also associated gene properties that contributes to gene essentiality. We tagged conditionally essential genes that show variable essentiality statuses across datasets to highlight complex interplays between gene functions and environmental/experimental perturbations. OGEE v3 contains gene essentiality datasets for 91 species; almost doubled from 48 species in previous version. To accommodate recent advances on human cancer essential genes (as known as tumor dependency genes) that could serve as targets for cancer treatment and/or drug development, we expanded the collection of human essential genes from 16 cell lines in previous to 581. These human cancer cell lines were tested with high-throughput experiments such as CRISPR-Cas9 and RNAi; in total, 150 of which were tested by both techniques. We also included factors known to contribute to gene essentiality for these cell lines, such as genomic mutation, methylation and gene expression, along with extensive graphical visualizations for ease of understanding of these factors. OGEE v3 can be accessible freely at https://v3.ogee.info.


Asunto(s)
Biología Computacional/métodos , Bases de Datos Genéticas , Genes Esenciales/genética , Genómica/métodos , Neoplasias/genética , Oncogenes/genética , Animales , Sistemas CRISPR-Cas , Línea Celular Tumoral , Minería de Datos/métodos , Predisposición Genética a la Enfermedad/genética , Humanos , Internet , Neoplasias/patología , Interferencia de ARN
7.
Int Orthop ; 47(10): 2429-2437, 2023 10.
Artículo en Inglés | MEDLINE | ID: mdl-37099167

RESUMEN

PURPOSE: To evaluate the chondrotoxic effects of intra-articular use of TXA 20 mg/kg and/or 0.35% PVPI on knee joint cartilage in an experimental model of rabbits. METHODS: Forty-four male New Zealand adult rabbits were randomly assigned to four groups (control, tranexamic acid (TXA), povidone-iodine (PVPI), and PVPI + TXA). The knee joint cartilage was accessed through an arthrotomy and exposed to physiological saline SF 0.9% (control group), TXA, PVPI, and PVPI followed by TXA. Sixty days after surgical procedure, the animals were sacrificed and osteochondral specimens of the distal femur were obtained. Histological sections of cartilage from this area were stained with hematoxylin/eosin and toluidine blue. The following cartilage parameters were evaluated by the Mankin histological/histochemical grading system: structure, cellularity, glycosaminoglycan content in the extracellular matrix, and integrity of the tidemark. RESULTS: The isolated use of PVPI causes statistically significant changes in cartilage cellularity (p-value = 0.005) and decrease glycosaminoglycan content (p = 0.001), whereas the isolated use of TXA decreased significantly the glycosaminoglycan content (p = 0.031). The sequential use of PVPI + TXA causes more pronounced alterations in the structure (p = 0.039) and cellularity (p = 0.002) and decreased content of glycosaminoglycans (p < 0.001) all with statistical significance. CONCLUSION: Data suggest that intra-articular use of tranexamic acid 20 mg/kg and intraoperative lavage with 0.35% povidone-iodine solution for three min are toxic to the articular cartilage of the knee in an experimental in vivo study in rabbits.


Asunto(s)
Antifibrinolíticos , Cartílago Articular , Ácido Tranexámico , Masculino , Conejos , Animales , Povidona Yodada/toxicidad , Ácido Tranexámico/farmacología , Articulación de la Rodilla/cirugía , Inyecciones Intraarticulares , Glicosaminoglicanos , Antifibrinolíticos/farmacología , Antifibrinolíticos/uso terapéutico
8.
Eur J Orthop Surg Traumatol ; 32(1): 107-112, 2022 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33740127

RESUMEN

BACKGROUND: We established a method in which patients are instructed before total knee arthroplasty (TKA) in a differentiated way without the necessity of reading any self-orientation, which can be applied even for illiterate patients METHODS: We developed a multidisciplinary approach to improve patient education in TKA comprising of a differentiated orientation conducted by an orthopedic surgeon, a nurse and a physiotherapist. It consists of standardized lectures regarding on pre-, intra- and postoperative issues in a randomized controlled trial of 79 consecutive patients undergoing primary TKA. Thirty-four patients received the standard education (control group), and 45 patients received the differentiated education (intervention group). The patients were evaluated during at least 6 months. RESULTS: After a 6-month follow-up period, the Short Form Health Survey (SF-36), the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), the visual analogue pain scale (VAS) and knee range of motion (ROM) improved significantly in both groups. Range of motion was better in the intervention group (mean and SD-106.9 ± 5.7 versus 92.5 ± 12.1 degrees, p = 0.02). Moreover, walk ability (more than 400 m) was better in the intervention group compared with the control group (97.4% versus 72.4%, p = 0.003). In the intervention and control groups, respectively, 10.5% and 31% of patients reported the need for some walking devices (p = 0.03). CONCLUSIONS: A differentiated educational program with a multidisciplinary team had a positive impact on functional outcomes, improving ROM and walk ability of patients undergoing TKA in a short-term evaluation.


Asunto(s)
Artroplastia de Reemplazo de Rodilla , Osteoartritis de la Rodilla , Humanos , Articulación de la Rodilla/cirugía , Osteoartritis de la Rodilla/cirugía , Educación del Paciente como Asunto , Rango del Movimiento Articular , Resultado del Tratamiento
9.
Int J Mol Sci ; 22(10)2021 May 11.
Artículo en Inglés | MEDLINE | ID: mdl-34064595

RESUMEN

Experimental studies of Caenorhabditis elegans and Drosophila melanogaster have contributed substantially to our understanding of molecular and cellular processes in metazoans at large. Since the publication of their genomes, functional genomic investigations have identified genes that are essential or non-essential for survival in each species. Recently, a range of features linked to gene essentiality have been inferred using a machine learning (ML)-based approach, allowing essentiality predictions within a species. Nevertheless, predictions between species are still elusive. Here, we undertake a comprehensive study using ML to discover and validate features of essential genes common to both C. elegans and D. melanogaster. We demonstrate that the cross-species prediction of gene essentiality is possible using a subset of features linked to nucleotide/protein sequences, protein orthology and subcellular localisation, single-cell RNA-seq, and histone methylation markers. Complementary analyses showed that essential genes are enriched for transcription and translation functions and are preferentially located away from heterochromatin regions of C. elegans and D. melanogaster chromosomes. The present work should enable the cross-prediction of essential genes between model and non-model metazoans.


Asunto(s)
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Evolución Molecular , Genes Esenciales , Aprendizaje Automático , Animales , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/genética , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Ontología de Genes , Genómica
10.
Eur J Orthop Surg Traumatol ; 31(2): 275-282, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-32809148

RESUMEN

Although non-locking calcaneal plates are designed to treat calcaneal fractures, they present some interesting characteristics that justify using them beyond their current application in fractures of the foot. Calcaneal plates are malleable, have an increased footprint area for fracture containment or buttressing, and present several hole options for screw placement in different trajectories, thereby providing proper fixation even in comminuted fracture patterns. The aim of this study is to describe the unconventional use of calcaneal plates in the orthopaedic trauma scenario.


Asunto(s)
Calcáneo , Fracturas Óseas , Placas Óseas , Tornillos Óseos , Calcáneo/diagnóstico por imagen , Calcáneo/cirugía , Fijación Interna de Fracturas , Fracturas Óseas/diagnóstico por imagen , Fracturas Óseas/cirugía , Humanos
11.
BMC Bioinformatics ; 19(1): 85, 2018 03 06.
Artículo en Inglés | MEDLINE | ID: mdl-29510668

RESUMEN

BACKGROUND: Systematic analysis of a parasite interactome is a key approach to understand different biological processes. It makes possible to elucidate disease mechanisms, to predict protein functions and to select promising targets for drug development. Currently, several approaches for protein interaction prediction for non-model species incorporate only small fractions of the entire proteomes and their interactions. Based on this perspective, this study presents an integration of computational methodologies, protein network predictions and comparative analysis of the protozoan species Leishmania braziliensis and Leishmania infantum. These parasites cause Leishmaniasis, a worldwide distributed and neglected disease, with limited treatment options using currently available drugs. RESULTS: The predicted interactions were obtained from a meta-approach, applying rigid body docking tests and template-based docking on protein structures predicted by different comparative modeling techniques. In addition, we trained a machine-learning algorithm (Gradient Boosting) using docking information performed on a curated set of positive and negative protein interaction data. Our final model obtained an AUC = 0.88, with recall = 0.69, specificity = 0.88 and precision = 0.83. Using this approach, it was possible to confidently predict 681 protein structures and 6198 protein interactions for L. braziliensis, and 708 protein structures and 7391 protein interactions for L. infantum. The predicted networks were integrated to protein interaction data already available, analyzed using several topological features and used to classify proteins as essential for network stability. CONCLUSIONS: The present study allowed to demonstrate the importance of integrating different methodologies of interaction prediction to increase the coverage of the protein interaction of the studied protocols, besides it made available protein structures and interactions not previously reported.


Asunto(s)
Leishmania/metabolismo , Mapas de Interacción de Proteínas , Proteínas Protozoarias/química , Área Bajo la Curva , Leishmaniasis/metabolismo , Leishmaniasis/parasitología , Aprendizaje Automático , Proteoma/metabolismo , Termodinámica
12.
Knee Surg Sports Traumatol Arthrosc ; 26(9): 2797-2803, 2018 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-29204862

RESUMEN

PURPOSE: The purpose of the study was to investigate the theoretical isometric point based of the curve of the femoral groove and relating it to the origin of the MPFL femoral tunnel on lateral radiograph by comparing a patellar instability cohort with a control cohort. METHODS: From a Patellar Instability database the radiographs of 40 consecutive patients were analysed to define Schöttle's point, and the arc of the circle of the trochlear groove. A comparison population of 20 radiographs from comparable patients with tibiofemoral joint disorders was used as a control. The distance from Schöttle's point to the most anterior part of the groove (extension) was also compared to the distance to the distal end of the roof of the notch (flexion). RESULTS: The trochlea was circular in the controls but not the Patellofemoral Instability cohort where trochlear dysplasia is usually present. The difference between the extension and flexion length was a mean of - 2.0 ± 0.5 mm in the controls and + 6.0 ± 0.5 mm in the patellofemoral cohort. In neither cohort did the centre of the circle correspond to Schöttle's point. The extension distance correlated with the boss height. CONCLUSIONS: The dysplastic trochlea is not circular and the centre of the best matched circle was different to the control trochleae which were circular. The circle centres did not correlate with Schöttle's point for either cohort, and was more proximal in the Patellofemoral Instability cohort. CLINICAL RELEVANCE: For the MPFL to have equal tension throughout flexion within the groove, the length should not change. In normal knees the MPFL does not behave isometrically. The change in length, as measured from Schöttle's point to the trochlea, was greater for patellofemoral instability patients explaining why an isolated MPFL reconstruction in the presence of severe trochlear dysplasia risks poor outcomes. Level of evidence III.


Asunto(s)
Fémur/diagnóstico por imagen , Inestabilidad de la Articulación/diagnóstico por imagen , Articulación Patelofemoral/diagnóstico por imagen , Adolescente , Adulto , Estudios de Casos y Controles , Estudios de Cohortes , Femenino , Humanos , Ligamentos Articulares/diagnóstico por imagen , Masculino , Persona de Mediana Edad , Luxación de la Rótula/diagnóstico por imagen , Radiografía , Rango del Movimiento Articular , Adulto Joven
13.
Artículo en Inglés | MEDLINE | ID: mdl-27855080

RESUMEN

Here, we report the isolation of 31 Acinetobacter baumannii strains producing OXA-253 in a single large Brazilian city. These strains belonged to five different sequence types (STs), including 4 STs not previously associated with blaOXA-253 In all strains, the blaOXA-253 gene was located in a plasmid within a genetic environment similar to what was found previously in Brazil and Italy. The reported data emphasize the successful transmission of the blaOXA-253 gene through a large area and the tendency for this resistance determinant to remain in the A. baumannii population.


Asunto(s)
Acinetobacter baumannii/efectos de los fármacos , Antibacterianos/farmacología , beta-Lactamasas/metabolismo , Acinetobacter baumannii/enzimología , Acinetobacter baumannii/genética , Brasil , Hospitales , Italia , Pruebas de Sensibilidad Microbiana , Plásmidos/genética , beta-Lactamasas/genética
14.
Arthroscopy ; 31(4): 785-92, 2015 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-25633815

RESUMEN

PURPOSE: This article discusses current evidence in nutraceuticals and viscosupplementation uses in osteoarthritis (OA) treatment. METHODS: A search was carried out to identify systematic reviews, randomized controlled trials, review articles, and original articles (PubMed and Cochrane Database) about nutraceuticals and viscosupplementation. The keywords used were nutraceuticals, glucosamine, chondroitin, diacerein, avocado, soybean unsaponifiables, nutraceuticals, and viscosupplementation, independently or combined with the terms "review" and "randomized." RESULTS: Glucosamine hydrochloride has no effect on pain management, although the sulfate formulation has a moderate effect. Diacerein leads to pain relief, with a superior carryover effect when compared with placebo. Avocado and soybean unsaponifiables may have positive effects on knee and hip OA, but long-term results could not be confirmed. Despite the American Academy of Orthopaedic Surgeons' recommendation against the use of hyaluronic acid in OA, some systematic reviews found some benefits in the knee. CONCLUSIONS: There is no evidence that nutraceuticals or viscosupplementation influences OA's natural progression. However, some of these agents seem to reduce pain and improve function. LEVEL OF EVIDENCE: Level IV, systematic review of studies with Level I through Level IV evidence.


Asunto(s)
Suplementos Dietéticos , Osteoartritis de la Cadera/terapia , Osteoartritis de la Rodilla/terapia , Viscosuplementación , Artralgia/terapia , Humanos
15.
Comput Struct Biotechnol J ; 23: 3081-3089, 2024 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-39185442

RESUMEN

Detailed explorations of the model organisms Caenorhabditis elegans (elegant worm) and Drosophila melanogaster (vinegar fly) have substantially improved our knowledge and understanding of biological processes and pathways in metazoan organisms. Extensive functional genomic and multi-omic data sets have enabled the discovery and characterisation of 'essential' genes that are critical for the survival of these organisms. Recently, we showed that a machine learning (ML)-based pipeline could be utilised to predict essential genes in both C. elegans and D. melanogaster using features from DNA, RNA, protein and/or cellular data or associated information. As these distantly-related species are within the Ecdysozoa, we hypothesised that this approach could be suited for non-model organisms within the same group (phylum) of protostome animals. In the present investigation, we cross-predicted essential genes within the phylum Nematoda - between C. elegans and the parasitic filarial nematodes Brugia malayi and Onchocerca volvulus, and then ranked and prioritised these genes. Highly ranked genes were linked to key biological pathways or processes, such as ribosome biogenesis, translation and RNA processing, and were expressed at relatively high levels in the germline, gonad, hypodermis and/or nerves. The present in silico workflow is hoped to expedite the identification of drug targets in parasitic organisms for subsequent experimental validation in the laboratory.

16.
Materials (Basel) ; 17(7)2024 Apr 04.
Artículo en Inglés | MEDLINE | ID: mdl-38612178

RESUMEN

Advances in high-pressure grinding roll (HGPR) technology since its first commercial application in the cement industry include new roll wear protection techniques and new confinement systems. The latter contribute to reductions in the edge effects in an attempt to reach a more homogenous product size along the rolls. Additional advances in this technology have been made in recent years, while modeling and simulation tools are also reaching maturity and can now be used to subject such novel developments to detailed scrutiny. This work applies a hybrid approach combining advanced simulations using the discrete element method, the particle replacement model and multibody dynamics to a phenomenological population balance model to critically assess two recent advances in HPGR technology: spring-loaded cheek plates and the offset roller press. Force and torque controllers, included in the EDEM 2022.1 software, were used to describe the responses of the geometries in contact with the granular material processed. Simulations showed that while the former successfully reduced the lateral bypass of the material by as much as 65% when cheek plates became severely worn, the latter demonstrated lower throughput and higher potential wear but an ability to generate a finer product than the traditional design.

17.
Viruses ; 16(5)2024 05 20.
Artículo en Inglés | MEDLINE | ID: mdl-38793690

RESUMEN

The Mayaro virus (MAYV) is an arbovirus with emerging potential, though with a limited understanding of its epidemiology and evolution due to the lack of studies and surveillance. Here, we investigated 71 MAYV genome sequences from the Americas available at GenBank and characterized the phylogenetic relationship among virus strains. A phylogenetic analysis showed that sequences were grouped according to the genotypes L, D, and N. Genotype D sequences were closely related to sequences collected in adjacent years and from their respective countries, suggesting that isolates may have originated from circulating lineages. The coalescent analysis demonstrated similar results, indicating the continuous circulation of the virus between countries as well. An unidentified sequence from the USA was grouped with genotype D, suggesting the insertion of this genotype in the country. Furthermore, the recombination analysis detected homologous and three heterologous hybrids which presented an insertion into the nsP3 protein. Amino acid substitutions among sequences indicated selective pressure sites, suggesting viral adaptability. This also impacted the binding affinity between the E1-E2 protein complex and the Mxra8 receptor, associated with MAYV entry into human cells. These results provide information for a better understanding of genotypes circulating in the Americas.


Asunto(s)
Evolución Molecular , Variación Genética , Genoma Viral , Genotipo , Filogenia , Américas/epidemiología , Humanos , Alphavirus/genética , Alphavirus/clasificación , Alphavirus/aislamiento & purificación , Animales , Recombinación Genética , Infecciones por Alphavirus/virología , Infecciones por Alphavirus/epidemiología
18.
Comput Struct Biotechnol J ; 23: 1026-1035, 2024 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-38435301

RESUMEN

Advances in single cell technologies are allowing investigations of a wide range of biological processes and pathways in animals, such as the multicellular model organism Caenorhabditis elegans - a free-living nematode. However, there has been limited application of such technology to related parasitic nematodes which cause major diseases of humans and animals worldwide. With no vaccines against the vast majority of parasitic nematodes and treatment failures due to drug resistance or inefficacy, new intervention targets are urgently needed, preferably informed by a deep understanding of these nematodes' cellular and molecular biology - which is presently lacking for most worms. Here, we created the first single cell atlas for an early developmental stage of Haemonchus contortus - a highly pathogenic, C. elegans-related parasitic nematode. We obtained and curated RNA sequence (snRNA-seq) data from single nuclei from embryonating eggs of H. contortus (150,000 droplets), and selected high-quality transcriptomic data for > 14,000 single nuclei for analysis, and identified 19 distinct clusters of cells. Guided by comparative analyses with C. elegans, we were able to reproducibly assign seven cell clusters to body wall muscle, hypodermis, neuronal, intestinal or seam cells, and identified eight genes that were transcribed in all cell clusters/types, three of which were inferred to be essential in H. contortus. Two of these genes (i.e. Hc-eef-1A and Hc-eef1G), coding for eukaryotic elongation factors (called Hc-eEF1A and Hc-eEF1G), were also demonstrated to be transcribed and expressed in all key developmental stages of H. contortus. Together with these findings, sequence- and structure-based comparative analyses indicated the potential of Hc-eEF1A and/or Hc-eEF1G as intervention targets within the protein biosynthesis machinery of H. contortus. Future work will focus on single cell studies of all key developmental stages and tissues of H. contortus, and on evaluating the suitability of the two elongation factor proteins as drug targets in H. contortus and related nematodes, with a view to finding new nematocidal drug candidates.

19.
Int J Parasitol ; 2024 Aug 20.
Artículo en Inglés | MEDLINE | ID: mdl-39168434

RESUMEN

Millions of livestock animals worldwide are infected with the haematophagous barber's pole worm, Haemonchus contortus, the aetiological agent of haemonchosis. Despite the major significance of this parasite worldwide and its widespread resistance to current treatments, the lack of a high-quality genome for the well-defined strain of this parasite from Australia, called Haecon-5, has constrained research in a number of areas including host-parasite interactions, drug discovery and population genetics. To enable research in these areas, we report here a chromosome-contiguous genome (∼280 Mb) for Haecon-5 with high-quality models for 19,234 protein-coding genes. Comparative genomic analyses show significant genomic similarity (synteny) with a UK strain of H. contortus, called MHco3(ISE).N1 (abbreviated as "ISE"), but we also discover marked differences in genomic structure/gene arrangements, distribution of nucleotide variability (single nucleotide polymorphisms (SNPs) and indels) and orthology between Haecon-5 and ISE. We used the genome and extensive transcriptomic resources for Haecon-5 to predict a subset of essential single-copy genes employing a "cross-species" machine learning (ML) approach using a range of features from nucleotide/protein sequences, protein orthology, subcellular localisation, single-cell RNA-seq and/or histone methylation data available for the model organisms Caenorhabditis elegans and Drosophila melanogaster. From a set of 1,464 conserved single copy genes, transcribed in key life-cycle stages of H. contortus, we identified 232 genes whose homologs have critical functions in C. elegans and/or D. melanogaster, and prioritised 10 of them for further characterisation; nine of the 10 genes likely play roles in neurophysiological processes, germline, hypodermis and/or respiration, and one is an unknown (orphan) gene for which no detailed functional information exists. Future studies of these genes/gene products are warranted to elucidate their roles in parasite biology, host-parasite interplay and/or disease. Clearly, the present Haecon-5 reference genome and associated resources now underpin a broad range of fundamental investigations of H. contortus and could assist in accelerating the discovery of novel intervention targets and drug candidates to combat haemonchosis.

20.
Artículo en Inglés | MEDLINE | ID: mdl-39193040

RESUMEN

Background: High-energy traumatic fractures represent a challenge for orthopaedic surgeons because there are a great variety of morphologic patterns and associated injuries1. Although the incidence is higher in developing countries, these fractures pose a major financial burden all over the world because of their considerable hospital length of stay, time away from work, rate of failure to return to work, complications, and cost of treatment2-4. Since the fracture patterns are so variable, some cases may have a lack of available specific osteosynthesis implants, despite recent advancements in implant engineering5. However, experienced surgeons are capable of using their knowledge and creativity to treat challenging lesions with use of preexisting plates while following the principles of fracture fixation and without compromising outcomes. In 2012, Hohman et al. described for the first time the use of a calcaneal plate to treat distal femoral fractures6. In 2020, Pires et al. further expanded the indications for use of a calcaneal plate5. This technical trick is widely utilized in our trauma center, especially in comminuted fractures around the knee. The present video article provides a stepwise description of the off-label use of a calcaneal plate in a medial distal femoral fracture. Description: The key principles of this procedure involve following common fundamentals during open reduction and internal fixation, approaching the fracture, preserving soft-tissue attachments of the comminution, and reducing the main fragments. Afterwards, the off-label use of a calcaneal plate adds the special feature of being able to contain fracture fragments with plate contouring. If necessary and if osseous morphology allows, bone grafting through the plate may also be performed. Alternatives: Multiple fixation implants can be utilized in medial distal femoral fractures. Surgeon-contoured plates (i.e., locking compression plates or low-contact dynamic compression plates), multiple mini-fragment plates, cortical screws alone, cannulated cancellous screws alone, or proximal humeral plates are among the alternatives5-9. However, the lack of specific implants for fixation of fractures involving the medial femoral condyle is notable, even in developed countries10. Rationale: The small-fragment calcaneal plate is a widely available and cheaper implant compared with locking compression plates, which is especially important in developing countries. Additionally, this plate has a lower profile, covers a greater surface area, and allows multiple screws in different planes and directions. The use of this plate represents a great technical trick for surgeons to contain comminution. Expected Outcomes: Patient education regarding fracture severity is mandatory, and it is important to highlight that there is no current gold standard to treat these fractures because of the wide variability of morphological patterns. To our knowledge, all studies reporting the use of a calcaneal plate to treat these fractures have shown promising results, including good functional outcomes and 100% fracture healing with no cases of nonunion, infection, or implant failure5,6,10-14. In the largest case series to date, Shekar et al. performed an interventional prospective study of 30 patients undergoing calcaneal plating for distal femoral unicondylar fractures14. They reported a mean range of motion of 108° ± 28.27° at 6 months, with excellent or satisfactory results in 80% of patients as measured with use of the Neer scoring system14. Important Tips: Preserve the blood supply by performing minimal soft-tissue dissection.Do not detach comminuted fragments from the soft tissues, which will help fracture reduction.Reduce the main fragments anatomically and fix as necessary.Contain the comminution using the spanning property and large covering area of the calcaneal plate.Perform bone grafting through the plate as necessary.

SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA