Search Results (27)

Background/Objectives: An accurate evaluation of variant actionability is essential in cancer management. In Von Hippel–Lindau Syndrome (VHL), the interpretation of the germline variants is confounded by the presence of non-syndromic component tumors, such as clear cell renal cell carcinoma (ccRCC), hemangioblastoma, pheochromocytoma, and neuroendocrine tumors. These tumors frequently occur sporadically, without any association with VHL syndrome. The presence of these tumors in a patient with a germline VHL variant could lead to inaccurate attribution of these tumors to the germline variant and VHL syndrome. In our previous INT²GRATE (INTegrated INTerpretation of GeRmline And Tumor gEnomes) programs, we demonstrated that integrating tumor-derived and germline evidence offers a comprehensive approach for the accurate assessment of the germline variants in cancer syndromes. Methods/Results: Here, we present a novel INT²GRATE variant evidence framework (VEF) for evaluating the clinical actionability of the germline variants in VHL syndrome, offering an integrated approach that incorporates both constitutional and tumor data. We analyzed 2672 variants in the VHL gene and their associated tumors and clinical evidence to effectively distinguish between constitutional, sporadic, VHL differentials, and VHL allelic genetic conditions. The germline INT²GRATE variants, along with their comprehensive associated evidence, were made accessible in the first open-access INT²GRATE Variant data Portal. Conclusions: This novel and integrated approach to variant assessment and data sharing in hereditary cancer syndromes is essential in the clinical evaluation of genomic variants, advancing precision oncology, and improving patient care. Full article

Designing scaffolds similar to the structure of trabecular bone requires specialised algorithms. Existing scaffold designs for bone tissue engineering have repeated patterns that do not replicate the random stochastic porous structure of the internal architecture of bones. In this research, the Voronoi tessellation method is applied to create random porous biomimetic structures. A volume mesh created from the shape of a Zygoma fracture acts as a boundary for the generation of random seed points by point spacing to create Voronoi cells and Voronoi diagrams. The Voronoi lattices were obtained by adding strut thickness to the Voronoi diagrams. Gradient Voronoi scaffolds of pore sizes (19.8 µm to 923 µm) similar to the structure of the trabecular bone were designed. A Finite Element Method-based computational fluid dynamics (CFD) simulation was performed on all designed Voronoi scaffolds to predict the pressure drops and permeability of non-Newtonian blood flow behaviour using the power law material model. The predicted permeability (0.33 × 10⁻⁹ m² to 2.17 × 10⁻⁹ m²) values of the Voronoi scaffolds from the CFD simulation are comparable with the permeability of scaffolds and bone specimens from other research works. Full article

Falls are a major concern for people with Parkinson’s disease (PwPD), but accurately assessing real-world fall risk beyond the clinic is challenging. Contemporary technologies could enable the capture of objective and high-resolution data to better inform fall risk through measurement of everyday factors (e.g., obstacles) that contribute to falls. Wearable inertial measurement units (IMUs) capture objective high-resolution walking/gait data in all environments but are limited by not providing absolute clarity on contextual information (i.e., obstacles) that could greatly influence how gait is interpreted. Video-based data could compliment IMU-based data for a comprehensive free-living fall risk assessment. The objective of this study was twofold. First, pilot work was conducted to propose a novel artificial intelligence (AI) algorithm for use with wearable video-based eye-tracking glasses to compliment IMU gait data in order to better inform free-living fall risk in PwPD. The suggested approach (based on a fine-tuned You Only Look Once version 8 (YOLOv8) object detection algorithm) can accurately detect and contextualize objects (mAP50 = 0.81) in the environment while also providing insights into where the PwPD is looking, which could better inform fall risk. Second, we investigated the perceptions of PwPD via a focus group discussion regarding the adoption of video technologies and AI during their everyday lives to better inform their own fall risk. This second aspect of the study is important as, traditionally, there may be clinical and patient apprehension due to ethical and privacy concerns on the use of wearable cameras to capture real-world video. Thematic content analysis was used to analyse transcripts and develop core themes and categories. Here, PwPD agreed on ergonomically designed wearable video-based glasses as an optimal mode of video data capture, ensuring discreteness and negating any public stigma on the use of research-style equipment. PwPD also emphasized the need for control in AI-assisted data processing to uphold privacy, which could overcome concerns with the adoption of video to better inform IMU-based gait and free-living fall risk. Contemporary technologies (wearable video glasses and AI) can provide a holistic approach to fall risk that PwPD recognise as helpful and safe to use. Full article

X-ray nanotomography is a powerful tool for the characterization of nanoscale materials and structures, but it is difficult to implement due to the competing requirements of X-ray flux and spot size. Due to this constraint, state-of-the-art nanotomography is predominantly performed at large synchrotron facilities. We present a laboratory-scale nanotomography instrument that achieves nanoscale spatial resolution while addressing the limitations of conventional tomography tools. The instrument combines the electron beam of a scanning electron microscope (SEM) with the precise, broadband X-ray detection of a superconducting transition-edge sensor (TES) microcalorimeter. The electron beam generates a highly focused X-ray spot on a metal target held micrometers away from the sample of interest, while the TES spectrometer isolates target photons with a high signal-to-noise ratio. This combination of a focused X-ray spot, energy-resolved X-ray detection, and unique system geometry enables nanoscale, element-specific X-ray imaging in a compact footprint. The proof of concept for this approach to X-ray nanotomography is demonstrated by imaging 160 nm features in three dimensions in six layers of a Cu-SiO₂ integrated circuit, and a path toward finer resolution and enhanced imaging capabilities is discussed. Full article

Three-dimensional porous scaffolds are substitutes for traditional bone grafts in bone tissue engineering (BTE) applications to restore and treat bone injuries and defects. The use of computational modelling is gaining momentum to predict the parameters involved in tissue healing and cell seeding procedures in perfusion bioreactors to reach the final goal of optimal bone tissue growth. Computational modelling based on finite element method (FEM) and computational fluid dynamics (CFD) are two standard methodologies utilised to investigate the equivalent mechanical properties of tissue scaffolds, as well as the flow characteristics inside the scaffolds, respectively. The success of a computational modelling simulation hinges on the selection of a relevant mathematical model with proper initial and boundary conditions. This review paper aims to provide insights to researchers regarding the selection of appropriate finite element (FE) models for different materials and CFD models for different flow regimes inside perfusion bioreactors. Thus, these FEM/CFD computational models may help to create efficient designs of scaffolds by predicting their structural properties and their haemodynamic responses prior to in vitro and in vivo tissue engineering (TE) applications. Full article

Vaccine development against group A Streptococcus (GAS) has gained traction in the last decade, fuelled by recognition of the significant worldwide burden of the disease. Several vaccine candidates are currently being evaluated in preclinical and early clinical studies. Here, we investigate two conjugate vaccine candidates that have shown promise in mouse models of infection. Two antigens, the J8 peptide from the conserved C-terminal end of the M protein, and the group A carbohydrate lacking N-acetylglucosamine side chain (ΔGAC) were each conjugated to arginine deiminase (ADI), an anchorless surface protein from GAS. Both conjugate vaccine candidates combined with alum adjuvant were tested in a non-human primate (NHP) model of pharyngeal infection. High antibody titres were detected against J8 and ADI antigens, while high background antibody titres in NHP sera hindered accurate quantification of ΔGAC-specific antibodies. The severity of pharyngitis and tonsillitis signs, as well as the level of GAS colonisation, showed no significant differences in NHPs immunised with either conjugate vaccine candidate compared to NHPs in the negative control group. Full article

Standard methods of variant assessment in hereditary cancer susceptibility genes are limited by the lack of availability of key supporting evidence. In cancer, information derived from tumors can serve as a useful source in delineating the tumor behavior and the role of germline variants in tumor progression. We have previously demonstrated the value of integrating tumor and germline findings to comprehensively assess germline variants in hereditary cancer syndromes. Building on this work, herein, we present the development and application of the INT²GRATE|HPPGL platform. INT²GRATE (INTegrated INTerpretation of GeRmline And Tumor gEnomes) is a multi-institution oncology consortium that aims to advance the integrated application of constitutional and tumor data and share the integrated variant information in publicly accessible repositories. The INT²GRATE|HPPGL platform enables automated parsing and integrated assessment of germline, tumor, and genetic findings in hereditary paraganglioma–pheochromocytoma syndromes (HPPGLs). Using INT²GRATE|HPPGL, we analyzed 8600 variants in succinate dehydrogenase (SDHx) genes and their associated clinical evidence. The integrated evidence includes germline variants in SDHx genes; clinical genetics evidence: personal and family history of HPPGL-related tumors; tumor-derived evidence: somatic inactivation of SDHx alleles, KIT and PDGFRA status in gastrointestinal stromal tumors (GISTs), multifocal or extra-adrenal tumors, and metastasis status; and immunohistochemistry staining status for SDHA and SDHB genes. After processing, 8600 variants were submitted programmatically from the INT²GRATE|HPPGL platform to ClinVar via a custom-made INT²GRATE|HPPGL variant submission schema and an application programming interface (API). This novel integrated variant assessment and data sharing in hereditary cancers aims to improve the clinical assessment of genomic variants and advance precision oncology. Full article

Due to their excellent properties, triply periodic minimal surfaces (TPMS) have been applied to design scaffolds for bone tissue engineering applications. Predicting the mechanical response of bone scaffolds in different loading conditions is vital to designing scaffolds. The optimal mechanical properties can be achieved by tuning their geometrical parameters to mimic the mechanical properties of natural bone. In this study, we designed gyroid scaffolds of different user-specific pore and strut sizes using a combined TPMS and signed distance field (SDF) method to obtain varying architecture and porosities. The designed scaffolds were converted to various meshes such as surface, volume, and finite element (FE) volume meshes to create FE models with different boundary and loading conditions. The designed scaffolds under compressive loading were numerically evaluated using a finite element method (FEM) to predict and compare effective elastic moduli. The effective elastic moduli range from 0.05 GPa to 1.93 GPa was predicted for scaffolds of different architectures comparable to human trabecular bone. The results assert that the optimal mechanical properties of the scaffolds can be achieved by tuning their design and morphological parameters to match the mechanical properties of human bone. Full article

Estimates of global population growth are often cited as a significant challenge for global food production. It is estimated that by 2050 there will be approximately two- billion additional people on earth, with the greatest proportion of that growth occurring in central Africa. To meet recommended future protein needs (60 g/d), approximately 120 million kg of protein must be produced daily. The production of ruminant meat (particularly beef cattle) offers the potential to aid in reaching increased global protein needs. However, advancements in beef cattle production are necessary to secure the industry’s future sustainability. This article draws attention to a subset of sustainable beef cattle production challenges, including the role of ruminant livestock in meeting global human protein needs, the environmental relationships of advanced beef cattle production, and big data and machine learning in beef cattle production. Considering the significant quantities of resources necessary to produce this form of protein, such advancements are not just a moral imperative but critical to developing advanced beef cattle production practices and predictive models that will reduce costs and liabilities and advance industry sustainability. Full article

Fall risk assessment needs contemporary approaches based on habitual data. Currently, inertial measurement unit (IMU)-based wearables are used to inform free-living spatio-temporal gait characteristics to inform mobility assessment. Typically, a fluctuation of those characteristics will infer an increased fall risk. However, current approaches with IMUs alone remain limited, as there are no contextual data to comprehensively determine if underlying mechanistic (intrinsic) or environmental (extrinsic) factors impact mobility and, therefore, fall risk. Here, a case study is used to explore and discuss how contemporary video-based wearables could be used to supplement arising mobility-based IMU gait data to better inform habitual fall risk assessment. A single stroke survivor was recruited, and he conducted a series of mobility tasks in a lab and beyond while wearing video-based glasses and a single IMU. The latter generated topical gait characteristics that were discussed according to current research practices. Although current IMU-based approaches are beginning to provide habitual data, they remain limited. Given the plethora of extrinsic factors that may influence mobility-based gait, there is a need to corroborate IMUs with video data to comprehensively inform fall risk assessment. Use of artificial intelligence (AI)-based computer vision approaches could drastically aid the processing of video data in a timely and ethical manner. Many off-the-shelf AI tools exist to aid this current need and provide a means to automate contextual analysis to better inform mobility from IMU gait data for an individualized and contemporary approach to habitual fall risk assessment. Full article

Escherichia coli is a versatile commensal and pathogenic member of the human microflora. As the primary causative pathogen in urosepsis, E. coli places an immense burden on healthcare systems worldwide. To further exacerbate the issue, multi drug resistance (MDR) has spread rapidly through E. coli populations, making infections more troublesome and costlier to treat. This paper aimed to review the literature concerning the development of MDR in uropathogenic E. coli (UPEC) and explore the existing evidence of current and emerging treatment strategies. While some MDR strains maybe treated with β-lactam-β-lactamase inhibitor combinations as well as cephalosporins, cephamycin, temocillin and fosfomycin, current treatment strategies for many MDR UPEC strains are reliant on carbapenems. Carbapenem overreliance may contribute to the alarming dissemination of carbapenem-resistance amongst some UPEC communities, which has ushered in a new age of difficult to treat infections. Alternative treatment options for carbapenem resistant UPEC may include novel β-lactam-β-lactamase or carbapenemase inhibitor combinations, cefiderocol, polymyxins, tigecycline, aminoglycosides or fosfomycin. For metallo-β-lactamase producing strains (e.g., NDM, IMP-4), combinations of cefazidime-avibacam with aztreonam have been used. Additionally, the emergence of new antimicrobials brings new hope to the treatment of such infections. However, continued research is required to successfully bring these into the clinic for the treatment of MDR E. coli urosepsis. Full article

Monocytes and their downstream effectors are critical components of the innate immune system. Monocytes are equipped with chemokine receptors, allowing them to migrate to various tissues, where they can differentiate into macrophage and dendritic cell subsets and participate in tissue homeostasis, infection, autoimmune disease, and cancer. Enabling genome engineering in monocytes and their effector cells will facilitate a myriad of applications for basic and translational research. Here, we demonstrate that CRISPR-Cas9 RNPs can be used for efficient gene knockout in primary human monocytes. In addition, we demonstrate that intracellular RNases are likely responsible for poor and heterogenous mRNA expression as incorporation of pan-RNase inhibitor allows efficient genome engineering following mRNA-based delivery of Cas9 and base editor enzymes. Moreover, we demonstrate that CRISPR-Cas9 combined with an rAAV vector DNA donor template mediates site-specific insertion and expression of a transgene in primary human monocytes. Finally, we demonstrate that SIRPa knock-out monocyte-derived macrophages have enhanced activity against cancer cells, highlighting the potential for application in cellular immunotherapies. Full article

Introducing ionospheric information into a precise point positioning (PPP) solution enables faster ambiguity resolution and significantly improves positioning accuracy. To compute such corrections over wide areas, sparse networks with potentially irregular station distributions are often used. This aspect brings a new level of complexity as ionospheric corrections should be weighted appropriately in the PPP filter. This paper presents a possible implementation of grid-based wide-area slant ionospheric delay corrections, with a focus on the reported uncertainties. A balance is obtained between obtaining corrections with formal errors small enough to enable fast convergence, while large enough to overbound most errors. Based on least-squares collocation, the method uses satellite-specific variograms based on the 99th percentile values in each distance bin. Tested in southern Canada over a 53-week period in 2020, ionospheric grids allowed dual-frequency receivers to obtain around 5 cm accuracy in each horizontal component within 5 min of static data collection. For single-frequency solutions using data from geodetic receivers, positioning errors were reduced by over 60% for both static and kinematic processing. Full article

Modulation of the endocannabinoid system (ECS) is of great interest for its therapeutic relevance in several pathophysiological processes. The CB2 subtype is largely localized to immune effectors, including microglia within the central nervous system, where it promotes anti-inflammation. Recently, a rational drug design toward precise modulation of the CB2 active site revealed the novelty of Pyrrolo[2,1-c][1,4]benzodiazepines tricyclic chemotype with a high conformational similarity in comparison to the existing leads. These compounds are structurally unique, confirming their chemotype novelty. In our continuing search for new chemotypes as selective CB2 regulatory molecules, following SAR approaches, a total of 17 selected (S,E)-11-[2-(arylmethylene)hydrazono]-PBD analogs were synthesized and tested for their ability to bind to the CB1 and CB2 receptor orthosteric sites. A competitive [³H]CP-55,940 binding screen revealed five compounds that exhibited >60% displacement at 10 μM concentration. Further concentration-response analysis revealed two compounds, 4k and 4q, as potent and selective CB2 ligands with sub-micromolar activities (K_i = 146 nM and 137 nM, respectively). In order to support the potential efficacy and safety of the analogs, the oral and intravenous pharmacokinetic properties of compound 4k were sought. Compound 4k was orally bioavailable, reaching maximum brain concentrations of 602 ± 162 ng/g (p.o.) with an elimination half-life of 22.9 ± 3.73 h. Whether administered via the oral or intravenous route, the elimination half-lives ranged between 9.3 and 16.7 h in the liver and kidneys. These compounds represent novel chemotypes, which can be further optimized for improved affinity and selectivity toward the CB2 receptor. Full article

Nitrogen (N) response studies in rice (Oryza sativa L.) are conducted to provide grower recommendations with economically optimum N rates (EONRs). This study was conducted to determine if experimental design alters the predicted EONR for rice. The effects of experimental design and soil texture on predicted EONR were investigated near Arcola, Greenville, Minter City, and Shaw, MS on soil textures ranging from sandy loam to clay. The response of rice grain yield to seven N fertilizer rates was fitted with a quadratic equation, and the quadratic trend was compared between the randomized complete block (RCB) and split-plot (SP) designs. No differences were detected between RCB and SP designs for rice grain yield response to N rate; therefore, either design, RCB or SP, would be appropriate for use in N response studies for rice. Full article