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This study examines the chemical composition, antioxidant properties, and urease inhibitory effects of Hyoscyamus muticus L. subsp. falezlez (Coss.) Maire. Using LC-ESI-MS/MS, 19 distinct phenolic compounds were identified, with chlorogenic acid being the most abundant. The ethanol extract demonstrated notable antioxidant activity, highlighting its potential for therapeutic use. Urease inhibition assays revealed a remarkable 91.35% inhibition by the H. muticus extract, with an IC 50 value of 5.6 ± 1.20 μg/mL, indicating its promising role in addressing conditions linked to urease activity. Molecular docking studies further investigated the interaction between H. muticus phenolic compounds and urease, identifying hyperoside as a leading candidate, with a binding energy of -7.9 kcal/mol. Other compounds, such as rutin, luteolin, apigenin, kaempferol, hesperetin, chlorogenic acid, and rosmarinic acid, also demonstrated significant binding affinities, suggesting their potential to disrupt urease function. These findings highlight the therapeutic potential of H. muticus as a source of natural bioactive compounds, offering promising avenues for the development of novel treatments for urease-related disorders and oxidative stress.

Patients with mild cognitive impairment due to Alzheimer's disease (ADMCI) typically show abnormally high delta (<4 Hz) and low alpha (8-12 Hz) rhythms measured from resting-state eyes-closed electroencephalographic (rsEEG) activity. Here, we hypothesized that the abnormalities in rsEEG activity may be greater in ADMCI patients than in those with MCI not due to AD (noADMCI). Furthermore, they may be associated with the diagnostic cerebrospinal fluid (CSF) amyloid-tau biomarkers in ADMCI patients. An international database provided clinical-demographic-rsEEG datasets for cognitively unimpaired older (Healthy; N = 45), ADMCI (N = 70), and noADMCI (N = 45) participants. The rsEEG rhythms spanned individual delta, theta, and alpha frequency bands. The eLORETA freeware estimated cortical rsEEG sources. Posterior rsEEG alpha source activities were reduced in the ADMCI group compared not only to the Healthy group but also to the noADMCI group ( p < 0.001). Negative associations between the CSF phospho-tau and total tau levels and posterior rsEEG alpha source activities were observed in the ADMCI group ( p < 0.001), whereas those with CSF amyloid beta 42 levels were marginal. These results suggest that neurophysiological brain neural oscillatory synchronization mechanisms regulating cortical arousal and vigilance through rsEEG alpha rhythms are mainly affected by brain tauopathy in ADMCI patients.

Chitosan is widely explored in the field of biomedicine due to its abundance and reported properties, including biocompatibility, biodegradability, non-toxicity, mucoadhesion, and anti-microbial activity. Although our understanding of the immune response to chitosan has evolved, confusion remains regarding whether chitosan is a pro- or anti-inflammatory biomaterial. Tackling this knowledge gap is essential for the translation of chitosan-based biomaterials to clinical use. Herein, we provide an overview of the immune responses to chitosan, exploring the roles of endotoxin contamination and physiochemical properties in immunomodulation. Ultimately, this literature review concludes that various physiochemical properties, including molecular weight, degree of deacetylation and polydispersity, endotoxin contamination, and cellular environment, interplay in the complex process of chitosan immunomodulation, which can lead to both pro- and anti-inflammatory effects.

Background/objectives: Cerebrospinal infusion studies indicate that cerebrospinal fluid outflow resistance (R out ) is elevated in normal pressure hydrocephalus (NPH). These studies assume that the cerebrospinal formation rate (CSF fr ) does not vary during the infusion. If the CSF fr were to increase during the infusion then the R out would be overestimated. Previous estimates of the CSF fr in NPH have suggested a low figure. More recent estimates of the CSF fr suggest that it is increased, indicating it probably varies with measurement technique. This would bring the estimation of R out into doubt. A previous paper using a lumped parameter model suggested the CSF fr could vary with the capillary transmural pressure (TMP) in this disease, suggesting a possible solution to this problem. The current study investigates the possibility that the intracranial pressure manipulation occurring during an infusion study may vary the capillary TMP and CSF fr ., Methods: A lumped parameter model previously developed to describe the hydrodynamics of NPH was modified to investigate the effect of CSF pressure manipulation during infusion studies and to describe how the CSF fr could vary depending on the technique used., Results: The model indicates the capillary transmural pressure is normal in NPH and increases during an infusion study. CSF drainage at the end of an infusion study similarly increases the capillary TMP and, presumably, the CSF fr by increasing the interstitial fluid production., Conclusions: The model suggests that infusion studies and draining CSF increases the CSF fr in NPH compared to earlier techniques. Allowing for an increase in the CSF fr suggests that infusion overestimates the R out by between 23 and 33%. This study indicates that further research may be required into the utility and accuracy of infusion studies and their ability to diagnose NPH.

Triple-negative breast cancer (TNBC) is a highly aggressive breast cancer subtype characterised by the absence of targetable hormone receptors and increased metastatic rates. As nuclear softening strongly contributes to TNBC's enhanced metastatic capacity, increasing the nuclear stiffness of TNBC cells may present a promising therapeutic avenue. Previous evidence has demonstrated the ability of Sirtuin 2 (SIRT2) inhibition to induce cytoskeletal reorganisation, a key factor in regulating nuclear mechanics. Thus, our study aimed to investigate the effect of SIRT2 inhibition on the nuclear mechanics and migratory behaviour of TNBC cells. To achieve this, SIRT2 was pharmacologically inhibited in MDA-MB-231 cells using AGK2, a SIRT2-specific inhibitor. Although SIRT2 inhibition had no effect on LINC complex composition, the AGK2-treated MDA-MB-231 cells displayed more prominent perinuclear organisations of acetylated α-tubulin, vimentin, and F-actin. Additionally, the nuclei of the AGK2-treated MDA-MB-231 cells exhibited greater resistance to collapse under osmotic shock. Scratch-wound assays also revealed that SIRT2 inhibition led to polarity defects in the MDA-MB-231 cells, while in vitro space-restrictive invasion assays highlighted their reduced migratory capacity upon AGK2 treatment. Taken together, our findings suggest that SIRT2 inhibition promotes a perinuclear cytoskeletal organisation in MDA-MB-231 cells, which enhances their nuclear rigidity and impedes their invasion through confined spaces in vitro.

Chronic stress is associated with a higher risk for carcinogenesis as well as age-related diseases and immune dysfunction. There is evidence showing that psychological stress can contribute to premature immunosenescence. Therefore, the question arose whether chronic exposure to catecholamine could drive immune cells into senescence. Peripheral blood mononuclear cells were isolated from whole blood. After repeated ex vivo treatment with isoproterenol, an epinephrine analog, well-established senescence biomarkers were assessed. We found (i) DNA double-strand break induction, (ii) telomere shortening, (iii) failure to proliferate, (iv) higher senescence-associated β-galactosidase activity, (v) decreases in caspases 3 and 7 activity, and (vi) strong upregulation of the proteoglycan versican accompanied by increased cellular adhesion suggesting the induction of a senescence-like phenotype. These results emphasize the complexity of the effect of isoproterenol on multiple cellular processes and provide insights into the molecular mechanisms of stress leading to immunosenescence.

Background/Objectives: Mismatch repair (MMR) deficiency can be indicative of Lynch syndrome (LS) and guide treatment with immune checkpoint inhibitors. Colorectal cancers (CRCs) and endometrial cancers (ECs) are routinely screened to identify LS, primarily using immunohistochemistry (IHC) or microsatellite instability (MSI) testing, but concordance between these methods is variable in ECs. Here, we investigate this variability in 361 ECs from the Ohio OCCPI/OPTEC ( n = 196) and Manchester PETALS ( n = 165) trials, where concordance between assays differed significantly. Methods: Samples were re-tested using the amplicon-sequencing-based Newcastle MSI assay (NCL&#95;MSI), and analysed with respect to existing IHC, MSI and MLH1 promoter hypermethylation data. Results: NCL&#95;MSI showed consistency with the Ohio results (94% and 97% concordance with IHC and original MSI assays, respectively) and increased concordance within the Manchester cohort from 78% to 86% (MSI) and 84% (IHC). Among discordant Manchester samples, NCL&#95;MSI was significantly associated with MLH1 promoter methylation status ( p = 0.0028) and had the highest concordance with methylation, (62/69 samples, 90%), indicating utility as a screening tool in this tumour type. However, tumours with germline MSH6 defects were only detected efficiently with IHC; seven out of eight LS tumours classified as MSS by either MSI assay had isolated MSH6 loss, compared to four out of twelve classified as MSI-H by both ( p = 0.028). Furthermore, reduced MSI signal was observed in tumours with isolated MSH6 loss ( p = 0.009 Ohio, p = 6.2 × 10 -5 Manchester) and in both ECs and CRCs with germline defects, although this only reached significance in CRCs ( p = 0.002). Conclusions: These results provide further evidence that ECs with MSH6 loss in particular and LS tumours in general have an attenuated MSI signal, providing support for current guidelines specifically recommending IHC for LS detection and immune checkpoint therapy assessment in EC.

Underwater simultaneous localization and mapping (SLAM) has significant challenges due to the complexities of underwater environments, marked by limited visibility, variable conditions, and restricted global positioning system (GPS) availability. This study provides a comprehensive analysis of sensor fusion techniques in underwater SLAM, highlighting the amalgamation of proprioceptive and exteroceptive sensors to improve UUV navigational accuracy and system resilience. Essential sensor applications, including inertial measurement units (IMUs), Doppler velocity logs (DVLs), cameras, sonar, and LiDAR (light detection and ranging), are examined for their contributions to navigation and perception. Fusion methodologies, such as Kalman filters, particle filters, and graph-based SLAM, are evaluated for their benefits, limitations, and computational demands. Additionally, innovative technologies like quantum sensors and AI-driven filtering techniques are examined for their potential to enhance SLAM precision and adaptability. Case studies demonstrate practical applications, analyzing the compromises between accuracy, computational requirements, and adaptability to environmental changes. This paper proceeds to emphasize future directions, stressing the need for advanced filtering and machine learning to address sensor drift, noise, and environmental unpredictability, hence improving autonomous underwater navigation through reliable sensor fusion.

Cognitive impairment and anxiety are common side effects of chemotherapy, particularly with the use of doxorubicin (DOX), known as "chemobrain". This study aimed to examine the dose-dependent effects of DOX on cognitive decline, anxiety, and locomotor activity in healthy female Wistar rats. The rats were divided into groups receiving low (2 mg/kg), intermediate (4 mg/kg), and high (5 mg/kg) doses of DOX for four weeks, alongside a control group. Behavioral tests, including open field, elevated plus maze, and Y-maze tests, assessed anxiety, locomotion, and cognitive performance, while brain tissue analysis evaluated neuroinflammation using markers such as GFAP and Iba-1. The results showed that all doses of DOX induced anxiety-like behavior, reduced locomotion, and caused neuroinflammation in the hippocampus, with more severe effects at higher doses. Notably, high-dose DOX also caused short-term memory deficits. These findings highlight the dose-dependent nature of DOX's impact on behavior and cognition, suggesting that DOX plays a key role in the development of cognitive symptoms during chemotherapy. Further research is needed to understand the mechanisms behind these effects and to explore potential interventions.

Underwater simultaneous localization and mapping (SLAM) is essential for effectively navigating and mapping underwater environments; however, traditional SLAM systems have limitations due to restricted vision and the constantly changing conditions of the underwater environment. This study thoroughly examined the underwater SLAM technology, particularly emphasizing the incorporation of deep learning methods to improve performance. We analyzed the advancements made in underwater SLAM algorithms. We explored the principles behind SLAM and deep learning techniques, examining how these methods tackle the specific difficulties encountered in underwater environments. The main contributions of this work are a thorough assessment of the research into the use of deep learning in underwater image processing and perception and a comparison study of standard and deep learning-based SLAM systems. This paper emphasizes specific deep learning techniques, including generative adversarial networks (GANs), convolutional neural networks (CNNs), long short-term memory (LSTM) networks, and other advanced methods to enhance feature extraction, data fusion, scene understanding, etc. This study highlights the potential of deep learning in overcoming the constraints of traditional underwater SLAM methods, providing fresh opportunities for exploration and industrial use.

Background: Nephronophthisis (NPHP) is an autosomal recessive genetic disorder that can cause early-onset kidney failure. ANKS6 plays an important role in early kidney development and encodes a protein that interacts with other proteins within the primary cilium. ANKS6 mutations are known to cause nephronophthisis 16 (NPHP-16). Little is known regarding fetal ultrasound imaging and the antenatal diagnosis of fetuses with ANKS6 -associated kidney disease. Here, we report the detection of ANKS6 variants in consanguineous families with polycystic kidney antenatally and in the early stages of life., Methods: Three unrelated Saudi Arabian patients (two prenatal patients and one neonate) were investigated. These cases were referred to the hospital due to the presence of echogenic kidneys on antenatal scanning. After clinical and phenotypic evaluation, whole-exome sequencing (WES) was performed on the cord and peripheral blood to identify the molecular genetic causes associated with the echogenic kidney phenotypes., Results: Two homozygous sequence variants were detected in ANKS6 . The homozygous missense novel variant ANKS6 : c.1159A>C was detected in Families 1 and 2. In the third family, the known homozygous loss-of-function variant ANKS6 : c.907+2T>A was detected., Conclusions: We identified homozygous ANKS6 variants in three families presenting with antenatal polycystic kidney disease. The findings provide an expanded clinical presentation of ANKS6 and emphasize the utility of WES in the diagnosis of echogenic kidneys in prenatal settings.

Many tissues have a laminar structure, but there are limited technologies for establishing laminar co-cultures for in vitro testing. Here, we demonstrate that collagen-alginate-fibrin (CAF) hydrogel scaffolds produced using the reactive jet impingement bioprinting technique can produce osteochondral laminar co-cultures with well-defined interfaces between cell types and high cell densities to support cell-cell interaction across the interfaces. The influence of cell density and the presence of the two cell types on the production of extracellular matrix (ECM) and the emergent mechanical properties of gels is investigated using IHC, ELISA, gel mass, and the compression modulus. The results indicate that high-cell-density cultures and co-cultures with these specific cell types produce greater levels of ECM and a more biomimetic in vitro culture than low-cell-density cultures. In laminar scaffolds produced using TC28a2 chondrocytes and SaoS-2 osteoblasts, both cell density and the presence of the two cell types enhance ECM production and the mechanical properties of the cultures, presenting a promising approach for the production of more biomimetic in vitro models.

Background: The evaluation of evidence, which frequently takes the form of scientific evidence, necessitates the input of experts in relevant fields. The results are presented as expert opinions or expert evaluations, which are generally accepted as a reliable representation of the facts. A further issue that remains unresolved though is the process of evaluating the expertise and knowledge of an expert in the first instance. In general, earned certificates, grades and other objective criteria are typically regarded as representative documentation to substantiate an expert status. However, there is a possibility that these may not always be sufficiently representative., Objectives: The goal of the present study was to provide evidence that the neural processing of law-relevant and law-irrelevant terms varies significantly between participants who have received training in the field of law (experts) and those who have not (novices)., Methods: To this end, changes in brain activity were recorded via electroencephalography (EEG) during visual presentations of terms belonging to five different categories (fake right, democracy, filler word, basic right and rule of law). Event-related potentials (ERPs) were subsequently averaged for each category and subjected to statistical analysis., Results: The results clearly demonstrate that participants trained in law processed fake rights and filler words in a similar manner. Furthermore, both of these conditions elicited different levels of brain activity compared to all law-relevant terms. This was not the case in participants who had not received legal training. The brains of untrained participants processed all five term categories in a strikingly similar manner. In light of prior knowledge regarding language processing, the primary focus was on two distinct electrode locations: one in the left posterior region, and the other in the left frontal region. In both locations, the most prominent differences in brain activity elicited by the aforementioned term categories in law-trained participants occurred approximately 450 milliseconds after stimulus onset. The results were further corroborated by a repeated-measures ANOVA and subsequent t -tests, which also demonstrated the absence of this effect in law-untrained participants., Conclusions: The findings of this study provide empirical evidence that brain activity measurements, in particular ERPs, can be used to distinguish between experts trained in a specific field of expertise and novices in that field. Such findings have the potential to facilitate objective assessments of expertise, enabling comparisons between experts and novices that extend beyond traditional criteria such as qualifications and experience. Instead, individuals can be evaluated based on their cognitive processes, as observed through brain activity.

Within traditional drug and alcohol (D&A) treatment services, the majority of those accessing support are of white ethnicity, with only a small percentage of people from the British South Asian (BSA) and Muslim community engaging in treatment services. This paper aims to explore perceived barriers to accessing traditional D&A services within the British South Asian and Muslim communities, based on qualitative data from interviews with family members and a practitioner. Qualitative data were obtained via 11 semi-structured interviews involving a practitioner (n = 1), and family and friends (n = 10) of those with historic and current D&A use in the community. Reflexive thematic analysis revealed four themes: (1) awareness of drug and alcohol use in the community, (2) drug and alcohol use as a taboo topic and the impact of admitting use, (3) knowledge of services for treatment, (4) how to increase awareness and accessibility of treatment. There was an increasing awareness of D&A use in the BSA and Muslim community. Despite this, limited conversations and misconceptions around D&A use and recovery led to those using D&A and their family members feeling stigmatised within their community and unable to seek support. This paper concludes by recommending increased communication between the BSA and Muslim communities and D&A treatment services to ensure accessibility of treatment by improving cultural competency.

Self-help groups are increasingly utilised by communities of interest and shared experience, services, and government departments as platforms for supporting and improving health and social care outcomes for drug and alcohol users. Traditional 12-step self-help groups like Narcotics Anonymous and Alcoholics Anonymous (NA and AA) are worldwide organisations and each have their own programme of change, language, criteria for membership, processes for problem resolution, and self-transformation. Within these types of groups, members are openly encouraged to identify with and adopt an (diseased) identity that is consistently invoked to work on the self. In the self-help recovery literature, it is widely recognised that individuals can benefit by thinking about themselves as "diseased" and then acting and behaving in a manner which is congruent with their reframed "identity". Less is known about the processes involved in this and social-, psychological-, and health-related implications for individuals in drug- and alcohol-specific self-help groups. A thematic analysis of data from (n-36) in-depth qualitative interviews with long-term (6 months-10 years) self-help users identified four themes associated with the adoption of a diseased identity and self-help group processes: (1) normalising the disease and illness; (2) identifying as diseased; (3) living as a diseased individual; and (4) one addict helping another addict. The results of this research should not be interpretated as a critique of the 12-step approach or groups. Instead, it should be recognised that whilst improvements to individual wellbeing are reported, identifying as diseased can exacerbate negative self-perceptions that individuals hold about themselves, their character, capabilities, and ability. Being diseased, accepting disease, and identifying as diseased also has the potential to inhibit their engagement with wider social networks and professional services outside of their own fellowship or group. We conclude this paper by exploring the implications of a "diseased identity" and self-help processes for individuals who access self-help groups, and health and social care practitioners who support self-help users as they engage with services and self-help groups.

Esophageal cancer (EC) is one of the most common malignant tumors worldwide, and its two major types, esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC), present a severe global public health problem with an increasing incidence and mortality. Established risk factors include smoking, alcohol consumption, and dietary habits, but recent research has highlighted the substantial role of oral microbiota in EC pathogenesis. This review explores the intricate relationship between the microbiome and esophageal carcinogenesis, focusing on the following eight significant mechanisms: chronic inflammation, microbial dysbiosis, production of carcinogenic metabolites, direct interaction with epithelial cells, epigenetic modifications, interaction with gastroesophageal reflux disease (GERD), metabolic changes, and angiogenesis. Certain harmful bacteria, such as Porphyromonas gingivalis and Fusobacterium nucleatum , are specifically implicated in sustaining irritation and tumor progression through pathways including NF-κB and NLRP3 inflammasome. Additionally, the review explores how microbial byproducts, including short-chain fatty acids (SCFAs) and reactive oxygen species (ROS), contribute to DNA harm and disease advancement. Furthermore, the impact of reflux on microbiota composition and its role in esophageal carcinogenesis is evaluated. By combining epidemiological data with mechanistic understanding, this review underscores the potential to target the microbiota-immune system interplay for novel therapeutic and diagnostic strategies to prevent and treat esophageal cancer.

Optical microscopy is widely regarded to be an indispensable tool in healthcare and manufacturing quality control processes, although its inability to resolve structures separated by a lateral distance under ~200 nm has culminated in the emergence of a new field named fluorescence nanoscopy , while this too is prone to several caveats (namely phototoxicity, interference caused by exogenous probes and cost). In this regard, we present a triplet string of concatenated O-Net ('bead') architectures (termed 'Θ-Net' in the present study) as a cost-efficient and non-invasive approach to enhancing the resolution of non-fluorescent phase-modulated optical microscopical images in silico . The quality of the afore-mentioned enhanced resolution (ER) images was compared with that obtained via other popular frameworks (such as ANNA-PALM, BSRGAN and 3D RCAN), with the Θ-Net-generated ER images depicting an increased level of detail (unlike previous DNNs). In addition, the use of cross-domain (transfer) learning to enhance the capabilities of models trained on differential interference contrast (DIC) datasets [where phasic variations are not as prominently manifested as amplitude/intensity differences in the individual pixels unlike phase-contrast microscopy (PCM)] has resulted in the Θ-Net-generated images closely approximating that of the expected (ground truth) images for both the DIC and PCM datasets. This thus demonstrates the viability of our current Θ-Net architecture in attaining highly resolved images under poor signal-to-noise ratios while eliminating the need for a priori PSF and OTF information, thereby potentially impacting several engineering fronts (particularly biomedical imaging and sensing, precision engineering and optical metrology).

In recent times, exploring the protective potential of medicinal plants has attracted increasing attention. To fight reactive oxygen species (ROS), which are key players in hepatic, cerebral and renal diseases, scientists have directed their efforts towards identifying novel compounds with antioxidant effects. Due to its unique composition, significant attention has been given to Cactus Seed Oil (CSO). Iron, as a metal, can be a potent generator of reactive oxygen species, especially hydroxyl radicals, via the Fenton and Haber-Weiss reactions. Here, we employed ferrous sulfate (FeSO4) to induce oxidative stress and DNA damage in mice. Then, we used CSO and Colza oil (CO) and evaluated the levels of the antioxidants (superoxide dismutase [SOD], glutathione peroxidase [GPx] and glutathione [GSH]) as well as a metabolite marker for lipid peroxidation (malondialdehyde [MDA]) relating to the antioxidant balance in the liver, brain and kidney. In addition, we measured DNA damage levels in hepatic tissue and the effects of CSO on it. Our study found that iron-dependent GPx activity decreases in the liver and the kidney tissues. Additionally, while iron decreased SOD activity in the liver, it increased it in the kidney. Interestingly, iron treatment resulted in a significant increase in hepatic MDA levels. In contrast, in brain tissue, there was a significant decrease under iron treatment. In addition, we found varying protective effects of CSO in alleviating oxidative stress in the different tissues with ameliorating DNA damage after iron overload in a mouse liver model, adding compelling evidence to the protective potential of CSO.

Tyrosine kinase inhibitors (TKIs) have emerged as a leading targeted cancer therapy, reducing the side effects often seen with non-targeted treatments, especially the damage to healthy cells. To tackle resistance, typically caused by epidermal growth factor receptor (EGFR) mutations, four generations of TKIs have been developed. Each generation has shown improved effectiveness and fewer side effects, resulting in better patient outcomes. For example, patients on gefitinib, a first-generation TKI, experienced a progression-free survival (PFS) of 10 months compared to 5 months with conventional chemotherapy. Second-generation TKI afatinib outperformed erlotinib and extended PFS to 11.1 months compared to 6.9 months with cisplatin. Third-generation TKIs further increased survival to 38.6 months, compared to 31.8 months with first-generation TKIs. This progress demonstrates the ability of newer TKIs to overcome resistance, particularly the T790M mutation, while reducing adverse effects. Ongoing research focuses on overcoming resistance from newer mutations like C797S to further improve patient survival. These developments highlight the significant progress in TKI therapy and the continued effort to refine cancer treatment. Recent research in South Korea shows that third-generation TKIs are ineffective against non-small cell lung cancer (NSCLC) with the C797S mutation. Several trials have started showing promising in vitro and in vivo results, but more trials are needed before clinical approval. This review underscores notable advancements in the field of EGFR TKIs, offering a comprehensive analysis of their mechanisms of action and the progression of various TKI generations in response to resistance.

Stigmatisation is the process by which an individual is devalued based on their attributes, characteristics, and/or behaviour, with this often leading to prejudice, social and health-related harms, active discrimination, and microaggressions. The aim of this paper is to show how social harms can occur and how stigma is damaging to the health and wellbeing of a person in recovery. To do so, we focus on the harms that arise from the internalisation of labels that mothers who use drugs encounter in a treatment and recovery setting whilst in active recovery, and how this stigmatisation can manifest negative self-beliefs. Qualitative data was used from two semi-structured focus groups involving females with lived experience of substance use ( n = 13). A reflexive thematic analysis approach was used to analyse the interview transcripts, and three themes were identified: (1) the enduring nature of stigma; (2) gender disparity and the need for mothers- and women-only spaces; and (3) stigma as a barrier to services and wellbeing. Findings revealed the enduring nature of stigma amongst mothers who were in active recovery, with women feeling judged more harshly than men and experiencing pressure to live up to a "good mother" ideal whilst in recovery. This paper demonstrates that mothers in recovery are still stigmatised and, as a consequence, approach services with increased sensitivity, with stigma often resulting in disengagement or reluctance to access healthcare settings. We conclude that staff in health, social, and primary care settings need to develop a strong therapeutic alliance with mothers in recovery and promote anti-stigma approaches in their practice, in order to mitigate stigma and reduce harms to health and wellbeing.

The deregulation of monounsaturated, polyunsaturated, and saturated fatty acids (MUFAs, PUFAs, SFAs) from de novo synthesis and hypoxia are central metabolic features of breast tumour. Early response markers for neoadjuvant chemotherapy (NACT) are critical for stratified treatment for patients with breast cancer, and restoration of lipid metabolism and normoxia might precede observable structural change. In this study, we hypothesised that peri-tumoural lipid composition and hypoxia might be predictive and early response markers in patients with breast cancer undergoing NACT. Female patients with breast cancer were scanned on a 3T clinical MRI scanner at baseline and Cycle1, with acquisition of lipid composition maps of MUFAs, PUFAs, and SFAs, and hypoxia maps of effective transverse relaxation rate R2*. The percentage change in lipid composition and hypoxia at Cycle1 was calculated with reference to baseline. Tumour-associated macrophages were analysed based on immunostaining of CD163 from biopsy and resection, with the percentage change in the resected tumour calculated across the entire NACT. We found no significant difference in lipid composition and R2* between good and poor responders at baseline and Cycle1; however, the correlation between the percentage change in MUFAs and PUFAs against CD163 suggested the modulation in lipids with altered immune response might support the development of targeted therapies.

Bicarbonate and CO 2 are essential substrates for carboxylation reactions in bacterial central metabolism. In Staphylococcus aureus , the bicarbonate transporter, MpsABC (membrane potential-generating system) is the only carbon concentrating system. An mpsABC deletion mutant can hardly grow in ambient air. In this study, we investigated the changes that occur in S. aureus when it suffers from CO 2 /bicarbonate deficiency. Electron microscopy revealed that Δ mpsABC has a twofold thicker cell wall thickness compared to the parent strain. The mutant was also substantially inert to cell lysis induced by lysostaphin and the non-ionic surfactant Triton X-100. Mass spectrometry analysis of muropeptides revealed the incorporation of alanine into the pentaglycine interpeptide bridge, which explains the mutant's lysostaphin resistance. Flow cytometry analysis of wall teichoic acid (WTA) glycosylation patterns revealed a significantly lower α-glycosylated and higher ß-glycosylated WTA, explaining the mutant's increased resistance towards Triton X-100. Comparative transcriptome analysis showed altered gene expression profiles. Autolysin-encoding genes such as sceD , a lytic transglycosylase encoding gene, were upregulated, like in vancomycin-intermediate S. aureus mutants (VISA). Genes related to cell wall-anchored proteins, secreted proteins, transporters, and toxins were downregulated. Overall, we demonstrate that bicarbonate deficiency is a stress response that causes changes in cell wall composition and global gene expression resulting in increased resilience to cell wall lytic enzymes and detergents.

Prostate cancer is a lethal solid malignancy and a leading cause of cancer-related deaths in males worldwide. Treatments, including radical prostatectomy, radiotherapy, and hormone therapy, are available and have improved patient survival; however, recurrence remains a huge clinical challenge. Enzalutamide is a second-generation androgen receptor antagonist that is used to treat castrate-resistant prostate cancer. Among patients who initially respond to enzalutamide, virtually all acquire secondary resistance, and an improved understanding of the mechanisms involved is urgently needed. Aberrant glycosylation, and, in particular, alterations to sialylated glycans, have been reported as mediators of therapy resistance in cancer, but a link between tumour-associated glycans and resistance to therapy in prostate cancer has not yet been investigated. Here, using cell line models, we show that prostate cancer cells with acquired resistance to enzalutamide therapy have an upregulation of the sialyltransferase ST6 beta-galactoside alpha-2,6-sialyltransferase 1 (ST6GAL1) and increased levels of α2,6-sialylated N -glycans. Furthermore, using the sialyltransferase inhibitor P-SiaFNEtoc, we discover that acquired resistance to enzalutamide can be partially reversed by combining enzalutamide therapy with sialic acid blockade. Our findings identify a potential role for ST6GAL1-mediated aberrant sialylation in acquired resistance to enzalutamide therapy for prostate cancer and suggest that sialic acid blockade in combination with enzalutamide may represent a novel therapeutic approach in patients with advanced disease. Our study also highlights the potential to bridge the fields of cancer biology and glycobiology to develop novel combination therapies for prostate cancer.

An asymmetric synthesis is a favorable approach for obtaining enantiomerically pure substances, but racemic resolution remains an efficient strategy. This study aims to elucidate the chiral resolution of aromatic amino acids and their elution order using glycopeptides as chiral selectors through molecular docking analysis. Chiral separation experiments were conducted using Vancomycin as a chiral additive in the mobile phase (CMPA) at various concentrations, coupled with an achiral amino column as the stationary phase. The Autodock Vina 1.1.2 software was employed to perform molecular docking simulations between each enantiomer (ligand) and Vancomycin (receptor) to evaluate binding affinities, demonstrate enantiomeric resolution feasibility, and elucidate chiral recognition mechanisms. Utilizing Vancomycin as CMPA at a concentration of 1.5 mM enabled the separation of tryptophan enantiomers with a resolution of 3.98 and tyrosine enantiomers with a resolution of 2.97. However, a poor chiral resolution was observed for phenylalanine and phenylglycine. Molecular docking analysis was employed to elucidate the lack of separation and elution order for tryptophan and tyrosine enantiomers. By calculating the binding energy, docking results were found to be in good agreement with experimental findings, providing insights into the underlying mechanisms governing chiral recognition in this system and the interaction sites. This comprehensive approach clarifies the complex relationship between chiral discrimination and molecular architecture, offering valuable information for creating and improving chiral separation protocols.

Hexagonal boron nitride is rapidly gaining interest as a platform for photonic quantum technologies, due to its two-dimensional nature and its ability to host defects deep within its large band gap that may act as room-temperature single-photon emitters. In this review paper we provide an overview of (1) the structure, properties, growth and transfer of hexagonal boron nitride; (2) the creationof colour centres in hexagonal boron nitride and assignment of defects by comparison with ab initio calculations for applications in photonic quantum technologies; and (3) heterostructure devices for the electrical tuning and charge control of colour centres that form the basis for photonic quantum technology devices. The aim of this review is to provide readers a summary of progress in both defect engineering and device fabrication in hexagonal boron nitride based photonic quantum technologies.

Recycling fly ash (FA) and furnace bottom ash (FBA) help with reducing greenhouse gas emissions, conserving natural resources, and minimizing waste accumulation. However, research on recycling FBA is progressing more slowly compared to FA. This research aims to investigate the combined use of FBA as a replacement for both fine aggregate and cement and its influence on the performance of mortar. The findings indicated that incorporating 25% FBA as a fine aggregate replacement and 10% or 20% ground FBA (GFBA) as a cement replacement significantly enhanced compressive strength after 28 and 56 days. Flexural strength was comparable to control mortar at 28 days and superior at 56 days. However, increasing the FBA content beyond 25% as a fine aggregate replacement reduced workability and increased porosity, which negatively affected mechanical performance and water absorption. Microstructural analyses revealed denser and more compact structures in the mortar with combined FBA replacement for both fine aggregate and cement, specifically 25% as a fine aggregate replacement and 10% and 20% as cement replacements. Optimal performance was noted in mixtures with Ca/Si and Ca/Al ratios within the ranges of 1.8-1.5 and 0.24-0.19, respectively. Trace element leaching analysis has not shown significant differences between GFBA, FA, and OPC. Regarding environmental impact assessment, using FBA as a fine aggregate replacement did not show a significant reduction in CO 2 emissions, but replacing cement with FBA reduced emissions remarkably. Generally, using FBA as a replacement for both fine aggregate and cement in mortar enhances compressive and flexural strengths at optimal levels, promotes sustainability by reducing landfill waste and CO 2 emissions, and supports cleaner production practices despite some workability challenges.

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.

Well-controlled type 1 diabetes (T1DM) is characterized by inflammation and endothelial dysfunction, thus constituting a suitable model of subclinical cardiovascular disease (CVD). miR-199b-5p overexpression in murine CVD has shown proatherosclerotic effects. We hypothesized that miR-199b-5p would be overexpressed in subclinical CVD yet downregulated following metformin therapy. Inflammatory and vascular markers were measured in 29 individuals with T1DM and 20 matched healthy controls (HCs). miR-199b-5p expression in CFU-Hill's colonies was analyzed from each study group, and correlations with inflammatory/vascular health indices were evaluated. Significant upregulation of miR-199b-5p was observed in T1DM, which was significantly downregulated by metformin. miR-199b-5p correlated positively with vascular endothelial growth factor-D and c-reactive protein (CRP: nonsignificant). ROC analysis determined miR-199b-5p to define subclinical CVD by discriminating between HCs and T1DM individuals. ROC analyses of HbA1c and CRP showed that the upregulation of miR-199b-5p in T1DM individuals defined subclinical CVD at HbA1c > 44.25 mmol and CRP > 4.35 × 10 6 pg/mL. Ingenuity pathway analysis predicted miR-199b-5p to inhibit the target genes SIRT1 , ETS1 , and JAG1 . Metformin was predicted to downregulate miR-199b-5p via NFATC2 and STAT3 and reverse its downstream effects. This study validated the antiangiogenic properties of miR-199b-5p and substantiated miR-199b-5p overexpression as a biomarker of subclinical CVD. The downregulation of miR-199b-5p by metformin confirmed its cardio-protective effect.

Duchenne and Becker muscular dystrophies, caused by pathogenic variants in DMD , are the most common inherited neuromuscular conditions in childhood. These diseases follow an X-linked recessive inheritance pattern, and mainly males are affected. The most prevalent pathogenic variants in the DMD gene are copy number variants (CNVs), and most patients achieve their genetic diagnosis through Multiplex Ligation-dependent Probe Amplification (MLPA) or exome sequencing. Here, we investigated a female patient presenting with muscular dystrophy who remained genetically undiagnosed after MLPA and exome sequencing. RNA sequencing (RNAseq) from the patient's muscle biopsy identified an 85% reduction in DMD expression compared to 116 muscle samples included in the cohort. A de novo balanced translocation between chromosome 17 and the X chromosome (t(X;17)(p21.1;q23.2)) disrupting the DMD and BCAS3 genes was identified through trio whole genome sequencing (WGS). The combined analysis of RNAseq and WGS played a crucial role in the detection and characterisation of the disease-causing variant in this patient, who had been undiagnosed for over two decades. This case illustrates the diagnostic odyssey of female DMD patients with complex structural variants that are not detected by current panel or exome sequencing analysis.

The androgen receptor (AR) is a key driver of prostate cancer (PCa) and, as such, current mainstay treatments target this molecule. However, resistance commonly arises to these therapies and, therefore, additional targets must be evaluated to improve patient outcomes. Consequently, alternative approaches for indirectly targeting the AR are sought. AR crosstalk with other signalling pathways, including several protein kinase signalling cascades, has been identified as a potential route to combat therapy resistance. The casein kinase 1 (CK1) family of protein kinases phosphorylate a multitude of substrates, allowing them to regulate a diverse range of pathways from the cell cycle to DNA damage repair. As well as its role in several signalling pathways that are de-regulated in PCa, mutational data suggest its potential to promote prostate carcinogenesis. CK1α is one isoform predicted to regulate AR activity via phosphorylation and has been implicated in the progression of several other cancer types. In this review, we explore how the normal biological function of CK1 is de-regulated in cancer, the impact on signalling pathways and how this contributes towards prostate tumourigenesis, with a particular focus on the CK1α isoform as a novel therapeutic target for PCa.

Understandings of how visual hallucinations appear have been highly influenced by generative approaches, in particular Friston's Active Inference conceptualization. Their core proposition is that these phenomena occur when hallucinatory expectations outweigh actual sensory data. This imbalance occurs as the brain seeks to minimize informational free energy, a measure of the distance between predicted and actual sensory data in a stationary open system. We review this approach in the light of old and new information on the role of environmental factors in episodic hallucinations. In particular, we highlight the possible relationship of specific visual triggers to the onset and offset of some episodes. We use an analogy from phase transitions in physics to explore factors which might account for intermittent shifts between veridical and hallucinatory vision. In these triggered forms of hallucinations, we suggest that there is a transient disturbance in the normal one-to-one correspondence between a real object and the counterpart perception such that this correspondence becomes between the real object and a hallucination. Generative models propose that a lack of information transfer from the environment to the brain is one of the key features of hallucinations. In contrast, we submit that specific information transfer is required at onset and offset in these cases. We propose that this transient one-to-one correspondence between environment and hallucination is mediated more by aberrant discriminative than by generative inference. Discriminative inference can be conceptualized as a process for maximizing shared information between the environment and perception within a self-organizing nonstationary system. We suggest that generative inference plays the greater role in established hallucinations and in the persistence of individual hallucinatory episodes. We further explore whether thermodynamic free energy may be an additional factor in why hallucinations are temporary. Future empirical research could productively concentrate on three areas. Firstly, subjective perceptual changes and parallel variations in brain function during specific transitions between veridical and hallucinatory vision to inform models of how episodes occur. Secondly, systematic investigation of the links between environment and hallucination episodes to probe the role of information transfer in triggering transitions between veridical and hallucinatory vision. Finally, changes in hallucinatory episodes over time to elucidate the role of learning on phenomenology. These empirical data will allow the potential roles of different forms of inference in the stages of hallucinatory episodes to be elucidated.

Current clinical diagnostic imaging methods for lung metastases are sensitive only to large tumours (1-2 mm cross-sectional diameter), and early detection can dramatically improve treatment. We have previously demonstrated that an antibody-targeted MRI contrast agent based on microparticles of iron oxide (MPIO; 1 μm diameter) enables the imaging of endothelial vascular cell adhesion molecule-1 (VCAM-1). Using a mouse model of lung metastasis, upregulation of endothelial VCAM-1 expression was demonstrated in micrometastasis-associated vessels but not in normal lung tissue, and binding of VCAM-MPIO to these vessels was evident histologically. Owing to the lack of proton MRI signals in the lungs, we modified the VCAM-MPIO to include zirconium-89 ( 89 Zr, t 1/2 = 78.4 h) in order to allow the in vivo detection of lung metastases by positron emission tomography (PET). Using this new agent ( 89 Zr-DFO-VCAM-MPIO), it was possible to detect the presence of micrometastases within the lung in vivo from ca. 140 μm in diameter. Histological analysis combined with autoradiography confirmed the specific binding of the agent to the VCAM-1 expressing vasculature at the sites of pulmonary micrometastases. By retaining the original VCAM-MPIO as the basis for this new molecular contrast agent, we have created a dual-modality (PET/MRI) agent for the concurrent detection of lung and brain micrometastases.

Violin is one of the most complex musical instruments to learn. The learning process requires constant training and many hours of exercise and is primarily based on a student-teacher interaction where the latter guides the beginner through verbal instructions, visual demonstrations, and physical guidance. The teacher's instruction and practice allow the student to learn gradually how to perform the correct gesture autonomously. Unfortunately, these traditional teaching methods require the constant supervision of a teacher and the interpretation of non-real-time feedback provided after the performance. To address these limitations, this work presents a novel interface (Visual Interface for Bowing Evaluation-VIBE) to facilitate student's progression throughout the learning process, even in the absence of direct teacher intervention. The proposed interface allows two key parameters of bowing movements to be monitored, namely, the angle between the bow and the string (i.e., α angle) and the bow tilt (i.e., β angle), providing real-time visual feedback on how to correctly move the bow. Results collected on 24 beginners (12 exposed to visual feedback, 12 in a control group) showed a positive effect of the real-time visual feedback on the improvement of bow control. Moreover, the subjects exposed to visual feedback judged the latter as useful to correct their movement and clear in terms of the presentation of data. Although the task was rated as harder when performed with the additional feedback, the subjects did not perceive the presence of a violin teacher as essential to interpret the feedback.

MUC2 mucin, the primary gel-forming component of intestinal mucus, is well researched and a model of polymerisation and post-secretory organisation has been published previously. Recently, several significant developments have been made which either introduce new ideas or challenge previous theories. New ideas include an overhaul of the MUC2 C-terminal globular structure which is proposed to harbour several previously unobserved domains, and include a site for an extra intermolecular disulphide bridge dimer between the cysteine 4379 of adjacent MUC2 C-termini. MUC2 polymers are also now thought to be secreted attached to the epithelial surface of goblet cells in the small intestine and removed following secretion via a metalloprotease meprin β-mediated cleavage of the von Willebrand D2 domain of the N-terminus. It remains unclear whether MUC2 forms intermolecular dimers, trimers, or both, at the N-termini during polymerisation, with several articles supporting either trimer or dimer formation. The presence of a firm inner mucus layer in the small intestine is similarly unclear. Considering this recent research, this review proposes an update to the previous model of MUC2 polymerisation and secretion, considers conflicting theories and data, and highlights the importance of this research to the understanding of MUC2 mucus layers in health and disease.

Three-dimensional printing (3DP) has emerged as a promising method for creating intricate scaffold designs. This study assessed three 3DP scaffold designs fabricated using biodegradable poly(lactic) acid (PLA) through fused deposition modelling (FDM): mesh, two channels (2C), and four channels (4C). To address the limitations of PLA, such as hydrophobic properties and poor cell attachment, a post-fabrication modification technique employing Polyelectrolyte Multilayers (PEMs) coating was implemented. The scaffolds underwent aminolysis followed by coating with SiCHA nanopowders dispersed in hyaluronic acid and collagen type I, and finally crosslinked the outermost coated layers with EDC/NHS solution to complete the hybrid scaffold production. The study employed rotating wall vessels (RWVs) to investigate how simulating microgravity affects cell proliferation and differentiation. Human mesenchymal stem cells (hMSCs) cultured on these scaffolds using proliferation medium (PM) and osteogenic media (OM), subjected to static (TCP) and dynamic (RWVs) conditions for 21 days, revealed superior performance of 4C hybrid scaffolds, particularly in OM. Compared to commercial hydroxyapatite scaffolds, these hybrid scaffolds demonstrated enhanced cell activity and survival. The pre-vascularisation concept on 4C hybrid scaffolds showed the proliferation of both HUVECs and hMSCs throughout the scaffolds, with a positive expression of osteogenic and angiogenic markers at the early stages.

Metabolomics can uncover physiological responses to prebiotic fibre and omega-3 fatty acid supplements with known health benefits and identify response-specific metabolites. We profiled 534 stool and 799 serum metabolites in 64 healthy adults following a 6-week randomised trial comparing daily omega-3 versus inulin supplementation. Elastic net regressions were used to separately identify the serum and stool metabolites whose change in concentration discriminated between the two types of supplementations. Random forest was used to explore the gut microbiome's contribution to the levels of the identified metabolites from matching stool samples. Changes in serum 3-carboxy-4-methyl-5-propyl-2-furanpropanoate and indoleproprionate levels accurately discriminated between fibre and omega-3 (area under the curve (AUC) = 0.87 [95% confidence interval (CI): 0.63-0.99]), while stool eicosapentaenoate indicated omega-3 supplementation (AUC = 0.86 [95% CI: 0.64-0.98]). Univariate analysis also showed significant increases in indoleproprionate with fibre, 3-carboxy-4-methyl-5-propyl-2-furanpropanoate, and eicosapentaenoate with omega-3. Out of these, only the change in indoleproprionate was partly explained by changes in the gut microbiome composition (AUC = 0.61 [95% CI: 0.58-0.64] and Rho = 0.21 [95% CI: 0.08-0.34]) and positively correlated with the increase in the abundance of the genus Coprococcus ( p = 0.005). Changes in three metabolites discriminated between fibre and omega-3 supplementation. The increase in indoleproprionate with fibre was partly explained by shifts in the gut microbiome, particularly Coprococcus , previously linked to better health.

Respiratory viruses cause airway inflammation, resulting in epithelial injury and repair. miRNAs, including miR-149-5p, regulate different pathological conditions. We aimed to determine how miR-149-5p functions in regulating pro-inflammatory IL-6 and p63, key regulators of airway epithelial wound repair, in response to viral proteins in bronchial (BEAS-2B) and alveolar (A549) epithelial cells. BEAS-2B or A549 cells were incubated with poly (I:C, 0.5 µg/mL) for 48 h or SARS-CoV-2 spike protein-1 or 2 subunit (S1 or S2, 1 μg/mL) for 24 h. miR-149-5p was suppressed in BEAS-2B challenged with poly (I:C), correlating with IL-6 and p63 upregulation. miR-149-5p was down-regulated in A549 stimulated with poly (I:C); IL-6 expression increased, but p63 protein levels were undetectable. miR-149-5p remained unchanged in cells exposed to S1 or S2, while S1 transfection increased IL-6 expression in BEAS-2B cells. Ectopic over-expression of miR-149-5p in BEAS-2B cells suppressed IL-6 and p63 mRNA levels and inhibited poly (I:C)-induced IL-6 and p63 mRNA expressions. miR-149-5p directly suppressed IL-6 mRNA in BEAS-2B cells. Hence, BEAS-2B cells respond differently to poly (I:C), S1 or S2 compared to A549 cells. Thus, miR-149-5p dysregulation may be involved in poly (I:C)-stimulated but not S1- or S2-stimulated increased IL-6 production and p63 expression in BEAS-2B cells.

Eukaryotic cells tether the nucleoskeleton to the cytoskeleton via a conserved molecular bridge, called the LINC complex. The core of the LINC complex comprises SUN-domain and KASH-domain proteins that directly associate within the nuclear envelope lumen. Intra- and inter-chain disulphide bonds, along with KASH-domain protein interactions, both contribute to the tertiary and quaternary structure of vertebrate SUN-domain proteins. The significance of these bonds and the role of PDIs (protein disulphide isomerases) in LINC complex biology remains unclear. Reducing and non-reducing SDS-PAGE analyses revealed a prevalence of SUN2 homodimers in non-tumorigenic breast epithelia MCF10A cells, but not in the invasive triple-negative breast cancer MDA-MB-231 cell line. Furthermore, super-resolution microscopy revealed SUN2 staining alterations in MCF10A, but not in MDA-MB-231 nuclei, upon reducing agent exposure. While PDIA1 levels were similar in both cell lines, pharmacological inhibition of PDI activity in MDA-MB-231 cells led to SUN-domain protein down-regulation, as well as Nesprin-2 displacement from the nucleus. This inhibition also caused changes in perinuclear cytoskeletal architecture and lamin downregulation, and increased the invasiveness of PDI-inhibited MDA-MB-231 cells in space-restrictive in vitro environments, compared to untreated cells. These results emphasise the key roles of PDIs in regulating LINC complex biology, cellular architecture, biomechanics, and invasion.

Efficacy to biologics in rheumatoid arthritis (RA) patients is variable and is likely influenced by each patient's circulating drug levels. Using modelling and simulation, the aim of this study was to investigate whether adalimumab and etanercept biosimilar dosing intervals can be altered to achieve therapeutic drug levels at a faster/similar time compared to the recommended interval. RA patients starting subcutaneous Amgevita or Benepali (adalimumab and etanercept biosimilars, respectively) were recruited and underwent sparse serum sampling for drug concentrations. Drug levels were measured using commercially available kits. Pharmacokinetic data were analysed using a population approach (popPK) and potential covariates were investigated in models. Models were compared using goodness-of-fit criteria. Final models were selected and used to simulate alternative dosing intervals. Ten RA patients starting the adalimumab biosimilar and six patients starting the etanercept biosimilar were recruited. One-compartment PK models were used to describe the popPK models for both drugs; no significant covariates were found. Typical individual parameter estimates were used to simulate altered dosing intervals for both drugs. A simulation of dosing the etanercept biosimilar at a lower rate of every 10 days reached steady-state concentrations earlier than the usual dosing rate of every 7 days. Simulations of altered dosing intervals could form the basis for future personalised dosing studies, potentially saving costs whilst increasing efficacy.

Within recent years, there has been an increased interest towards organic photovoltaics (OPVs), especially with their significant device performance reaching beyond 19% since 2022. With these advances in the device performance of laboratory-scaled OPVs, there has also been more attention directed towards using printing and coating methods that are compatible with large-scale fabrication. Though large-area (>100 cm 2 ) OPVs have reached an efficiency of 15%, this is still behind that of laboratory-scale OPVs. There also needs to be more focus on determining strategies for improving the lifetime of OPVs that are suitable for scalable manufacturing, as well as methods for reducing material and manufacturing costs. In this paper, we compare several printing and coating methods that are employed to fabricate OPVs, with the main focus towards the deposition of the active layer. This includes a comparison of performances at laboratory (<1 cm 2 ), small (1-10 cm 2 ), medium (10-100 cm 2 ), and large (>100 cm 2 ) active area fabrications, encompassing devices that use scalable printing and coating methods for only the active layer, as well as "fully printed/coated" devices. The article also compares the research focus of each of the printing and coating techniques and predicts the general direction that scalable and large-scale OPVs will head towards.

HIV-associated neurocognitive disorders (HAND) are highly prevalent in those ageing with HIV. High-income country data suggest that vascular risk factors (VRFs) may be stronger predictors of HAND than HIV-disease severity, but data from sub-Saharan Africa are lacking. We evaluated relationships of VRFs, vascular end-organ damage and HAND in individuals aged ≥ 50 in Tanzania. c-ART-treated individuals were assessed for HAND using consensus criteria. The prevalence of VRFs and end organ damage markers were measured. The independent associations of VRFs, end organ damage and HAND were examined using multivariable logistic regression. Data were available for 153 individuals (median age 56, 67.3% female). HAND was highly prevalent (66.7%, 25.5% symptomatic) despite well-managed HIV (70.5% virally suppressed). Vascular risk factors included hypertension (34%), obesity (10.5%), hypercholesterolemia (33.3%), diabetes (5.3%) and current smoking (4.6%). End organ damage prevalence ranged from 1.3% (prior myocardial infarction) to 12.5% (left ventricular hypertrophy). Measured VRFs and end organ damage were not independently associated with HAND. The only significant association was lower diastolic BP ( p 0.030, OR 0.969 (0.943-0.997). Our results suggest that vascular risk factors are not major drivers of HAND in this setting. Further studies should explore alternative aetiologies such as chronic inflammation.

In efforts to achieve the goal of reducing ship emissions in the fight against climate change, reducing fuel consumption by making ships lighter is stated as one of the solutions. In this study, the possibilities of making composite equivalents of propellers, which are the most complex ship elements and traditionally produced from metal materials, are investigated with the advantages of additive manufacturing, which offers a rapid production opportunity for such forms. In this way, a lighter composite propeller and, therefore, a lighter ship will be achieved, and negative environmental impacts, especially harmful emissions, will be reduced. In the study, a 1/14-scale ship propeller was produced through the material extrusion method of additive manufacturing using an HDPE composite containing long carbon fiber with a 15% weight fraction. An attempt to reduce flexibility with an epoxy-carbon fabric prepreg coating was made, as the flexibility has negative effects on the performance of the produced propeller. The propeller tunnel test showed that the applied carbon fabric epoxy prepreg helped to improve the propeller's performance by decreasing the flexibility of the propeller and reducing the deformation at the tips. At the same time, the propeller weight was decreased by 60% compared to its metal counterparts.

Skin ageing is defined, in part, by collagen depletion and fragmentation that leads to a loss of mechanical tension. This is currently believed to reflect, in part, the accumulation of senescent cells. We compared the expression of genes and proteins for components of the extracellular matrix (ECM) as well as their regulators and found that in vitro senescent cells produced more matrix metalloproteinases (MMPs) than proliferating cells from adult and neonatal donors. This was consistent with previous reports of senescent cells contributing to increased matrix degradation with age; however, cells from adult donors proved significantly less capable of producing new collagen than neonatal or senescent cells, and they showed significantly lower myofibroblast activation as determined by the marker α-SMA. Functionally, adult cells also showed slower migration than neonatal cells. We concluded that the increased collagen degradation of aged fibroblasts might reflect senescence, the reduced collagen production likely reflects senescence-independent processes.

Surface plasmons, continuous and cumulative electron vibrations confined to metal-dielectric interfaces, play a pivotal role in aggregating optical fields and energies on nanostructures. This confinement exploits the intrinsic subwavelength nature of their spatial profile, significantly enhancing light-matter interactions. Metals, semiconductors, and 2D materials exhibit plasmonic resonances at diverse wavelengths, spanning from ultraviolet (UV) to far infrared, dictated by their unique properties and structures. Surface plasmons offer a platform for various light-matter interaction mechanisms, capitalizing on the orders-of-magnitude enhancement of the electromagnetic field within plasmonic structures. This enhancement has been substantiated through theoretical, computational, and experimental studies. In this comprehensive review, we delve into the plasmon-enhanced processes on metallic and metamaterial-based sensors, considering factors such as geometrical influences, resonating wavelengths, chemical properties, and computational methods. Our exploration extends to practical applications, encompassing localized surface plasmon resonance ( LSPR )-based planar waveguides, polymer-based biochip sensors, and LSPR -based fiber sensors. Ultimately, we aim to provide insights and guidelines for the development of next-generation, high-performance plasmonic technological devices.

The IFN-type-I pathway is involved in radiotherapy (RT)-mediated immune responses. Large RT fractions have been suggested to potently induce this pathway. Neoadjuvant hypofractionated short-course (scRT) and conventional long-course (lcRT) RT applied for the treatment of locally advanced rectal adenocarcinoma patients provides a unique model to address the immuno-stimulatory properties of RT on a systemic level. We prospectively analyzed the IFNβ plasma levels and lymphocyte counts (LCs) of rectal adenocarcinoma patients before and after treatment with scRT (n = 22) and lcRT (n = 40). Flow cytometry was conducted to assess the effects on lymphocytic subpopulations in a subset of 20 patients. A statistically significant increase in the post-RT IFNβ plasma levels was noted in patients undergoing scRT ( p = 0.004). Improved pathological tumor regression was associated with elevated post-RT IFNβ levels ( p = 0.003). Although all patients experienced substantial lymphopenia after treatment, the post-RT LC of patients treated with scRT were significantly higher compared to lcRT ( p = 0.001). Patients undergoing scRT displayed significantly lower percentages of regulatory CD4+/CD25+ T-cells after therapy ( p = 0.02). scRT enables effective stimulation of the IFN-type-I pathway on a systemic level and confers decreased lymphocytic cytotoxicity and limited regulatory T-cell activation compared to lcRT, supporting its increasing role in immuno-RT trials.

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), is a frequent clinical condition globally. Single nucleotide polymorphisms (SNPs) associated with NAFLD have been proposed in the literature and based on bioinformatic screening. The association between NAFLD and genetic variants in Egyptians is still unclear. Hence, we sought to investigate the association of some genetic variants with NAFLD in Egyptians. Egyptians have been categorized into either the MASLD group (n = 205) or the healthy control group (n = 187). The severity of hepatic steatosis and liver fibrosis was assessed by a Fibroscan device. TaqMan-based genotyping assays were employed to explore the association of selected SNPs with MASLD. PNPLA3 rs738409 C>G variant is associated with the presence of MASLD with liver fibrosis, the severity of both hepatic steatosis and liver fibrosis, increased systolic and diastolic blood pressure and increased alanine aminotransferase (all p < 0.05), while the TM6SF2 rs58542926 C>T, HSD17B13 rs9992651 G>A, and GCKR rs1260326 T>C variants were not (all p > 0.05). The TM6SF2 rs58542926 T allele is associated with increased fasting blood glucose and a decreased waist circumference. The GCKR rs1260326 C allele is associated with decreased aspartate transaminase and diastolic blood pressure (all p < 0.05). Only after adjusting for the risk factors (age, sex, BMI, WC, HDL, TG, diabetes mellitus, and hypertension) F2 liver fibrosis score is negatively correlated with the HSD17B13 rs9992651 GA genotype. This study offers evidence for the association of the PNPLA3 rs738409 C>G variant with MASLD among Egyptians and for the association of the PNPLA3 rs738409 G allele, the TM6SF2 rs58542926 T allele, and the GCKR rs1260326 C allele with some parameters of cardiometabolic criteria.