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The Effects of Muscle Starting Length on Work Loop Power Output of Isolated Mouse Soleus and Extensor Digitorum Longus Muscle
No full textYesForce–length relationships derived from isometric activations may not directly apply to muscle force production during dynamic contractions. As such, different muscle starting lengths between isometric and dynamic conditions could be required to achieve maximal force and power. Therefore, this study examined the effects of starting length [±5–10% of length corresponding to maximal twitch force (L0)] on work loop (WL) power output (PO), across a range of cycle frequencies, of the soleus (SOL) and extensor digitorum longus muscle (EDL; N=8–10) isolated from ∼8 week old C57 mice. Furthermore, passive work was examined at a fixed cycle frequency to determine the association of passive work and active net work. Starting length affected maximal WL PO of the SOL and EDL across evaluated cycle frequencies (P0.494). For the SOL, PO produced at −5% L0 was greater than that at most starting lengths (P0.6), except −10% L0 (P=0.135, d1.08), except versus −5% L0 (P=0.124, d0.163, d<1.04). For the SOL, higher passive work was associated with reduced PO (Spearman's r=0.709, P<0.001), but no relationship was observed between passive work and PO of the EDL (Pearson's r=0.191, r2=0.04, P=0.184). This study suggests that starting length should be optimised for both static and dynamic contractions and confirms that the force–length curve during dynamic contractions is muscle specific.The full-text of this article will be released for public view at the end of the publisher embargo on 30 Apr 2025
Investigate In Vitro Genotoxic and Cytotoxic Effects of Taxifolin and Taxifolin- PCL Electrospun Scaffold on Triple Negative Breast Cancer
No full textTriple-negative breast cancer (TNBC) is characterised by its aggressive nature and poor prognosis. This study examines the anticancer properties of the flavonoid taxifolin and its cytotoxic and genotoxic effects on triple-negative breast cancer (TNBC) and blood cells from healthy individuals and breast cancer patients. Central to this work is the development of a novel taxifolin delivery system via electrospun PCL scaffolds to enhance anticancer and therapeutic efficacy of the drug post-operatively. The Comet assay was utilised to analyse DNA damage and repair in lymphocytes from breast cancer patients versus healthy controls. CCK-8, qPCR and Western Blot were employed to study viability, gene, and protein expression regulation during taxifolin treatment. The process and formulation of the drug-PCL scaffolds were optimised to produce scaffolds with no beadings and optimal fibre structures. Thermal and microscopy analysis indicates no detectable crystals in the scaffold. The results from the experiment using Comet assay indicate that taxifolin significantly protects DNA in both healthy and breast cancer samples, effectively decreasing DNA damage in breast cancer blood samples and showing genotoxicity against TNBC cells. Taxifolin regulates essential molecular pathways, as evidenced by changes in genes (p53, p21, p27,and Bcl-2) using qPCR and protein levels (p53, p27, and Bcl-2) using Western Blot, suggesting its potential in targeted therapy. The optimised taxifolin-PCL electrospun scaffold enhances cell adhesion, reducing cell viability and proliferation of TNBC, underscoring the efficacy of localised taxifolin delivery. This thesis emphasizes the therapeutic potential of a new drug delivery system for more effective treatment of TNBC
Artificial Intelligence and Big Data Analytics for the detection of fake news on social media
No full textNoThe advent of social media has facilitated the rapid dissemination of information, prompting news broadcasting organisations to utilise these platforms for wider audience outreach. While this shift has brought substantial benefits to both organisations and individuals, the proliferation of generative Artificial Intelligence has given rise to an increase in false news and deceptive content, often driven by financial incentives. Such misleading information, widely disseminated on social media, presents opportunities for cybercriminals to engage in activities such as extortion, cyberbullying, and the strategic enhancement of social engineering tactics. These activities are integral components of the footprinting and reconnaissance stages in the lifecycle of cyberattacks. The spread of fake and deceptive content necessitates intensified research into the identification and mitigation of fake and deceptive content. This study evaluates the efficacy of Artificial Intelligence (AI) and Big Data Analytics (BDA) for the detection of fake news on social media using Naíve Bayes (NB), Random Forest (RF), Logistic Regression (LR), and Support Vector Machine (SVM) models. In society at large, it is pertinent to spot fake news to prevent disastrous outcomes when certain information is shared. Out of the four machine learning (ML) techniques applied, the SVM model outperformed others with accuracy and precision of 0.81 and 0.82, respectively. The LR model showed similar precision and the highest recall. These methods provide a foundation for reliable automated fake news detection tools
Docetaxel-tethered di-Carboxylic Acid Derivatised Fullerenes: A Promising Drug Delivery Approach for Breast Cancer
No full textNoDocetaxel (DTX) has become widely accepted as a first-line treatment for metastatic breast cancer; however, the frequent development of resistance provides challenges in treating the disease.C60 fullerene introduces a unique molecular form of carbon, exhibiting attractive chemical and physical properties. Our study aimed to develop dicarboxylic acid-derivatized C60 fullerenes as a novel DTX delivery carrier. This study investigated the potential of water-soluble fullerenes to deliver the anti-cancer drug DTX through a hydrophilic linker. The synthesis was carried out using the Prato reaction. The spectroscopic analysis confirmed the successful conjugation of DTX molecules over fullerenes. The particle size of nanoconjugate was reported to be 122.13 ± 1.63 nm with a conjugation efficiency of 76.7 ± 0.14%. The designed conjugate offers pH-dependent release with significantly less plasma pH, ensuring maximum release at the target site. In-vitro cell viability studies demonstrated the enhanced cytotoxic nature of the developed nanoconjugate compared to DTX. These synthesized nanoscaffolds were highly compatible with erythrocytes, indicating the safer intravenous route administration. Pharmacokinetic studies confirmed the higher bioavailability (~ 6 times) and decreased drug clearance from the system vis-à-vis plain drug. The histological studies reveal that nanoconjugate-treated tumour cells exhibit similar morphology to normal cells. Therefore, it was concluded that this developed formulation would be a valuable option for clinical use
The Capacity of Drug-Metabolising Enzymes in Modulating the Therapeutic Efficacy of Drugs to Treat Rhabdomyosarcoma
No full textYesRhabdomyosarcoma (RMS) is a rare soft tissue sarcoma (STS) that predominantly affects children and teenagers. It is the most common STS in children (40%) and accounts for 5–8% of total childhood malignancies. Apart from surgery and radiotherapy in eligible patients, standard chemotherapy is the only therapeutic option clinically available for RMS patients. While survival rates for this childhood cancer have considerably improved over the last few decades for low-risk and intermediate-risk cases, the mortality rate remains exceptionally high in high-risk RMS patients with recurrent and/or metastatic disease. The intensification of chemotherapeutic protocols in advanced-stage RMS has historically induced aggravated toxicity with only very modest therapeutic gain. In this review, we critically analyse what has been achieved so far in RMS therapy and provide insight into how a diverse group of drug-metabolising enzymes (DMEs) possess the capacity to modify the clinical efficacy of chemotherapy. We provide suggestions for new therapeutic strategies that exploit the presence of DMEs for prodrug activation, targeted chemotherapy that does not rely on DMEs, and RMS-molecular-subtype-targeted therapies that have the potential to enter clinical evaluation
Repurposing of USFDA-approved drugs to identify leads for inhibition of acetylcholinesterase enzyme: a plausible utility as an anti-Alzheimer agent
No full textNoIn the quest to identify new anti-Alzheimer agents, we employed drug repositioning or drug repositioning techniques on approved USFDA small molecules. Herein, we report the structure-based virtual screening (SBVS) of 1880 USFDA-approved drugs. The in silico-based identification was followed by calculating Prime MMGB-SA binding energy and molecular dynamics simulation studies. The cumulative analysis led to identifying domperidone as an identified hit. Domperidone was further corroborated in vitro using anticholinesterase-based assessment, keeping donepezil as a positive control. The analysis revealed that the identified lead (domperidone) could induce an inhibitory effect on AChE in a dose-dependent manner with an IC50 of 3.67 μM as compared to donepezil, which exhibited an IC50 of 1.37 μM. However, as domperidone is known to have poor BBB permeability, we rationally proposed new analogues utilizing the principles of bioisosterism. The bioisostere-clubbed analogues were found to have better BBB permeability, affinity, and stability within the catalytic domain of AChE via molecular docking and dynamics studies. The proposed bioisosteres may be synthesized in the future. They may plausibly be explored for their implication in the developmental progress of new anti-Alzheimer agent achieved via repurposing techniques in future
Availability and barriers to access post-stroke rehabilitation in Latin America
No full textYesObjectives
To describe the availability and barriers to access post-stroke rehabilitation services in Latin America.
Materials and methods
We conducted a multi-national survey in Latin American countries. The survey consisted of three sections: (1) the national state of post-stroke rehabilitation; (2) the local state of post-stroke rehabilitation; and (3) the coverage and financing of post-stroke services. Stroke leaders from the surveyed countries were involved in developing and disseminating the survey.
Results
261 responses were collected from 17 countries. The mean age of respondents was 42.4 ± 10.1 years, and 139 (54.5 %) of the respondents were male. National clinical guidelines for post-stroke rehabilitation were reported by 67 (25.7 %) of the respondents. However, there were discrepancies between respondents within the same country. Stroke units, physiotherapy, occupational therapy, speech therapy, and neuropsychological therapy services were less common in public than private settings. The main barriers for inpatient and outpatient services included limited rehabilitation facilities, coverage, and rehabilitation personnel. The main source of financing for the inpatient and outpatient services was the national health insurance, followed by out-of-pocket payments. Private and out-of-pocket costs were more frequently reported in outpatient services.
Conclusions
Post-stroke rehabilitation services in Latin American countries are restricted due to a lack of coverage by the public health system and private insurers, human resources, and financial aid. Public settings offer fewer post-stroke rehabilitation services compared to private settings. Developing consensus guidelines, increasing coverage, and using innovative approaches to deliver post-stroke rehabilitation is paramount to increase access without posing a financial burden
Understanding the anomaly: reinterpreting Porolissum Roman town with emerging GPR and ER data
Get PDFYesThe Roman Porolissum (Romania) was first surveyed with magnetics in 2010. Local geology is propitious for magnetic prospection. In 2021 the Polish-Romanian team carried out a complementary ER and GPR survey. Emerging geophysical data allowed reinterpretation of the previous survey results. Complementary survey data and geological setting analysis yet enhanced the archaeological interpretation
Selectivity analysis of diaminopyrimidine-based inhibitors of MTHFD1, MTHFD2 and MTHFD2L
No full textYesThe mitochondrial enzyme methylenetetrahydrofolate dehydrogenase (MTHFD2) is involved in purine and thymidine synthesis via 1C metabolism. MTHFD2 is exclusively overexpressed in cancer cells but absent in most healthy adult human tissues. However, the two close homologs of MTHFD2 known as MTHFD1 and MTHFD2L are expressed in healthy adult human tissues and share a great structural resemblance to MTHFD2 with 54% and 89% sequence similarity, respectively. It is therefore notably challenging to find selective inhibitors of MTHFD2 due to the structural similarity, in particular protein binding site similarity with MTHFD1 and MTHFD2L. Tricyclic coumarin-based compounds (substrate site binders) and xanthine derivatives (allosteric site binders) are the only selective inhibitors of MTHFD2 reported till date. Nanomolar potent diaminopyrimidine-based inhibitors of MTHFD2 have been reported recently, however, they also demonstrate significant inhibitory activities against MTHFD1 and MTHFD2L. In this study, we have employed extensive computational modeling involving molecular docking and molecular dynamics simulations in order to investigate the binding modes and key interactions of diaminopyrimidine-based inhibitors at the substrate binding sites of MTHFD1, MTHFD2 and MTHFD2L, and compare with the tricyclic coumarin-based selective MTHFD2 inhibitor. The outcomes of our study provide significant insights into desirable and undesirable structural elements for rational structure-based design of new and selective inhibitors of MTHFD2 against cancer.University of Gothenbur
Proportion of Antipsychotics with CYP2D6 Pharmacogenetic (PGx) Associations Prescribed in an Early Intervention in Psychosis (EIP) Cohort: A Cross-Sectional Study
No full textYesBackground: Prescribing drugs for psychosis (antipsychotics) is challenging due to high rates of poor treatment outcomes, which are in part explained
by an individual’s genetics. Pharmacogenomic (PGx) testing can help clinicians tailor the choice or dose of psychosis drugs to an individual’s genetics,
particularly psychosis drugs with known variable response due to CYP2D6 gene variants (‘CYP2D6-PGx antipsychotics’).
Aims: This study aims to investigate differences between demographic groups prescribed ‘CYP2D6-PGx antipsychotics’ and estimate the proportion of
patients eligible for PGx testing based on current pharmacogenomics guidance.
Methods: A cross-sectional study took place extracting data from 243 patients’ medical records to explore psychosis drug prescribing, including drug
transitions. Demographic data such as age, sex, ethnicity, and clinical sub-team were collected and summarised. Descriptive statistics explored the
proportion of ‘CYP2D6-PGx antipsychotic’ prescribing and the nature of transitions. We used logistic regression analysis to investigate associations
between demographic variables and prescription of ‘CYP2D6-PGx antipsychotic’ versus ‘non-CYP2D6-PGx antipsychotic’.
Results: Two-thirds (164) of patients had been prescribed a ‘CYP2D6-PGx antipsychotic’ (aripiprazole, risperidone, haloperidol or zuclopenthixol).
Over a fifth (23%) of patients would have met the suggested criteria for PGx testing, following two psychosis drug trials. There were no statistically
significant differences between age, sex, or ethnicity in the likelihood of being prescribed a ‘CYP2D6-PGx antipsychotic’.
Conclusions: This study demonstrated high rates of prescribing ‘CYP2D6-PGx-antipsychotics’ in an EIP cohort, providingThis research was supported by the National Institute for Health and Care Research (NIHR) Yorkshire and Humber Patient Safety Translational Research Centre (NIHR Yorkshire and Humber PSTRC). This research has been funded through a scholarship from the Bradford District Care NHS Foundation Trust in partnership with the University of Bradford