'Bingo'-a large language model- and graph neural network-based workflow for the prediction of essential genes from protein data.

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.

Standing on shoulder of giants: the incredible legacy of the Judet family in orthopaedic surgery.

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.

Reemergence of Dengue Virus Serotype 3, Brazil, 2023.

We characterized 3 autochthonous dengue virus serotype 3 cases and 1 imported case from 2 states in the North and South Regions of Brazil, 15 years after Brazil's last outbreak involving this serotype. We also identified a new Asian lineage recently introduced into the Americas, raising concerns about future outbreaks.

OGEE v3: Online GEne Essentiality database with increased coverage of organisms and human cell lines.

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.

Chondrotoxic effects of tranexamic acid and povidone-iodine on the articular cartilage of rabbits.

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.

A new methodology for patient education in total knee arthroplasty: a randomized controlled trial.

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.

Cross-Predicting Essential Genes between Two Model Eukaryotic Species Using Machine Learning.

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.

Expanding the indications for calcaneal plates beyond foot fractures: a technical trick and case series.

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.

Building protein-protein interaction networks for Leishmania species through protein structural information.

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.

The trochlear isometric point is different in patients with recurrent patellar instability compared to controls: a radiographical study.

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.

High Frequency of OXA-253-Producing Acinetobacter baumannii in Different Hospitals in Recife, Brazil.

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.

Supplementary methods in the nonsurgical treatment of osteoarthritis.

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.

Critical Assessment of Novel Developments in HPGR Technology Using DEM.

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.

Analysis of Haemonchus embryos at single cell resolution identifies two eukaryotic elongation factors as intervention target candidates.

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.

Evolutionary Profile of Mayaro Virus in the Americas: An Update into Genome Variability.

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.

ViralFlow v1.0-a computational workflow for streamlining viral genomic surveillance.

ViralFlow v1.0 is a computational workflow developed for viral genomic surveillance. Several key changes turned ViralFlow into a general-purpose reference-based genome assembler for all viruses with an available reference genome. New virus-agnostic modules were implemented to further study nucleotide and amino acid mutations. ViralFlow v1.0 runs on a broad range of computational infrastructures, from laptop computers to high-performance computing (HPC) environments, and generates standard and well-formatted outputs suited for both public health reporting and scientific problem-solving. ViralFlow v1.0 is available at: https://viralflow.github.io/index-en.html.

Spatiotemporal transmission of SARS-CoV-2 lineages during 2020-2021 in Pernambuco-Brazil.

SARS-CoV-2 virus emerged as a new threat to humans and spread around the world, leaving a large death toll. As of January 2023, Brazil is among the countries with the highest number of registered deaths. Nonpharmacological and pharmacological interventions have been heterogeneously implemented in the country, which, associated with large socioeconomic differences between the country regions, has led to distinct virus spread dynamics. Here, we investigate the spatiotemporal dispersion of SARS-CoV-2 lineages in the Pernambuco state (Northeast Brazil) throughout the distinct epidemiological scenarios that unfolded in the first 2 years of the pandemic. We generated a total of 1,389 new SARS-CoV-2 genomes from June 2020 to August 2021. This sampling captured the arrival, communitary transmission, and the circulation of the B1.1, B.1.1.28, and B.1.1.33 lineages; the emergence of the former variant of interest P.2; and the emergence and fast replacement of all previous variants by the more transmissible variant of concern P.1 (Gamma). Based on the incidence and lineage spread pattern, we observed an East-to-West to inner state pattern of transmission, which is in agreement with the transmission of more populous metropolitan areas to medium- and small-size country-side cities in the state. Such transmission patterns may be partially explained by the main routes of traffic across municipalities in the state. Our results highlight that the fine-grained intrastate analysis of lineages and incidence spread can provide actionable insights for planning future nonpharmacological intervention for air-borne transmissible human pathogens.IMPORTANCEDuring the COVID-19 pandemic, Brazil was one of the most affected countries, mainly due its continental-size, socioeconomic differences among regions, and heterogeneous implementation of intervention methods. In order to investigate SARS-CoV-2 dynamics in the state of Pernambuco, we conducted a spatiotemporal dispersion study, covering the period from June 2020 to August 2021, to comprehend the dynamics of viral transmission during the first 2 years of the pandemic. Throughout this study, we were able to track three significant epidemiological waves of transmission caused by B1.1, B.1.1.28, B.1.1.33, P.2, and P.1 lineages. These analyses provided valuable insights into the evolution of the epidemiological landscape, contributing to a deeper understanding of the dynamics of virus transmission during the early years of the pandemic in the state of Pernambuco.

Combined reconstruction of medial collateral ligament and posterior cruciate ligament using one femoral tunnel: a technical note and case report applicable to limited-resource settings.

Knee dislocations are severe injuries difficult to treat. Specially in low-resources scenarios, reconstruction of multiple ligaments can be challenging. We describe a technical note that can be reconstruct multi ligaments using ipsilateral hamstrings autograft. A posteromedial knee incision is made to visualise the medial corner of the knee and to reconstruct medial collateral ligament (MCL) and posterior cruciate ligament (PCL) with semitendinosus and gracilis tendon graft, using one femoral tunnel from the anatomic femoral insertion of the MCL to the anatomic femoral insertion of the PCL. After 1-year follow-up, the patient returned to his previous function with a Lysholm score of 86. This technique can reconstruct more than one ligament anatomically with limited graft resource.

High prevalence of GR2 and GR4 plasmids in Acinetobacter baumannii strains from Brazil.

Acinetobacter baumannii is Gram-negative pathogen with extensive role in healthcare-associated infections (HAIs). Plasmids in this species are important carriers of antimicrobial resistance genes. In this work, we investigated the plasmids of 227 Brazilian A. baumannii genomes. A total of 389 plasmid sequences with 424 Rep proteins typed to 22 different homology groups (GRs) were identified. The GR2 plasmid group was the most predominant (40.6%), followed by the GR4 group (16.7%), representing ∼57% of all plasmids. There is a wide distribution of plasmids among the isolates and most strains carry more than one plasmid. Our analyses revealed a significant prevalence of GR4 plasmids in Brazilian A. baumannii genomes carrying several antimicrobial resistance genes, notably to carbapenem (39.43%). These plasmids harbor a MOBQ relaxase that might confer increased spreading potential in the environment. Most plasmids of the predominant groups belong to the same plasmid taxonomic unit (PTU-Pse7) and have a AbkA/AbkB toxin-antitoxin system that has a role in plasmid stability and dissemination of carbapenem resistance genes. The results of this work should contribute to our understanding of the molecular content of plasmids in a large and populous country, highlighting the importance of genomics for enhanced epidemiological surveillance.

Ankle fractures malreduction rate and its causes in two Brazilian tertiary training hospitals.

INTRODUCTION: Ankle fractures are one of the most frequent injuries managed by any trauma surgeon. Literature has shown that adequate reduction is of utmost importance to achieve satisfactory functional outcomes. However, malreduction rates remain high worldwide. The objective of the present study is to evaluate the quality of ankle fracture reduction in two major trauma centers in a large Brazilian city and to analyze the factors associated with malreduction METHODS: Epidemiologic data of 382 patients (189 men; 193 women) aged between 7 and 87 years who underwent osteosynthesis of the ankle in two trauma centers in a large Brazilian city. Electronic clinical records, preoperative and immediate postoperative radiographs in anteroposterior (AP), lateral and mortise views were evaluated. Pettrone's criteria were used to evaluate the quality of ankle fractures reduction. All radiographs were independently evaluated by two foot and ankle senior surgeons RESULTS: Overall, malreduction rate was 22.2%. Forty-seven (55.2%) fractures classified as malreduced had medial malleolar displacement The results showed three factors that significantly affected the quality of reduction (p<0.05), patients over 60 years, open fractures and fracture-dislocations. Patients aged over 60 years were twice more likely to have poor reduction of ankle fractures than younger ones. The risk of poor fracture reduction among those individuals with open fractures is 2.15 times greater than among patients with closed injuries. Fracture-dislocation imposed a 2.7 higher risk for malreduction DISCUSSION: We found a malreduction rate below most series previously published. Further results agree with the literature. Elderly people aged over 60 years, fracture dislocations and open fractures are associated with worse results, influencing the quality of the reduction, clinical outcomes, and the development of post-traumatic arthrosis CONCLUSION: Ankle fractures malreduction are associated with higher age, open fractures, and fracture-dislocations.