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Ice XIX and ice XV are both partly hydrogen-ordered counterparts to disordered ice VI. The ice XIX → XV transition represents the only order-to-order transition in ice physics. Using Raman and dielectric spectroscopies, we investigate the ambient-pressure kinetics of the two individual steps in this transition in real time (of hours), that is, ice XIX → transient ice VI (the latter called VI‡) and ice VI‡ → ice XV. Hydrogen-disordered ice VI‡ appears intermittent between 101 and 120 K, as inferred from the appearance and subsequent disappearance of the ice VI Raman marker bands. A comparison of the rate constants for the H2O ices reported here with those from D2O samples [Thoeny et al., J. Chem. Phys. 156, 154507 (2022)] reveals a large kinetic isotope effect for the ice XIX decay, but a much smaller one for the ice XV buildup. An enhancement of the classical overbarrier rate through quantum tunneling for the former can provide a possible explanation for this finding. The activation barriers for both transitions are in the 18–24 kJ/mol range, which corresponds to the energy required to break a single hydrogen bond. These barriers do not show an H/D isotope effect and are the same, no matter whether they are derived from Raman scattering or from dielectric spectroscopy. These findings favor the notion that a dipolar reorientation, involving the breakage of a hydrogen bond, is the rate determining step at the order-to-order transition. [ABSTRACT FROM AUTHOR]

We present diamond-like carbon (DLC) conversion surfaces to detect particles with energy below 2 keV. Conversion surfaces have been widely applied in measurements of low-energy particles by instruments onboard planetary and heliophysics missions. Their effectiveness is characterized by the efficiency in changing the charge state of the incident particles while maintaining a narrow angular distribution for the reflected particles. DLC as a conversion surface coating material has high conversion efficiency. We developed a conversion surface production process that provides ultra-smooth and ultra-thin DLC conversion surfaces. The process includes substrate preparation through precision cleaning, plasma immersion ion deposition of the DLC film, and diagnostics of the film parameters. The latter includes the measurement of the coating thickness, surface roughness, and the conversion efficiency for ion beams with energy below 2 keV. The process we developed provides the DLC conversion surface coating of repeatable parameters with a mean surface roughness of 3.4 ± 0.2 Å and a mean film thickness of 46.7 ± 0.8 nm uniform across the sample area. Ion beam measurements showed a negative ion yield of 1%–2% for hydrogen atoms and 8%–15% for oxygen atoms with an angular scatter distribution of 10°–20° at full width of half maximum. These results agree with those of other conversion surface coatings in the literature. The DLC conversion surfaces presented here are implemented in the conversion surface subsystem of the Interstellar Mapping and Acceleration Probe (IMAP)-Lo instrument of the IMAP mission scheduled for launch in 2025. [ABSTRACT FROM AUTHOR]

Weeding is at the heart of agriculture. Today, using herbicides is unavoidable in conventional agriculture. However, increasing ecological awareness, the need to reduce carbon dioxide emissions, and the pursuit of sustainable food have driven industries and academics to explore new approaches for growing and protecting crops. In this context, smart spot sprayers emerge as a highly innovative alternative to broadcast treatments, which overuse pesticides, and mechanical weeding, which is limited by restrictive application conditions. Using artificial intelligence (AI) for plant recognition and ultra-precise spraying technology, herbicides are applied directly to weeds with minimal overspray, reducing their use by 90% compared to conventional methods. Spot sprayers' narrowly targeted spray limits chemicals' contact with the crop, resulting in low phytotoxicity, preserving natural crop development while maximizing yield potential. In addition, site-specific application increases the selectivity of chemical products artificially, enabling more concentrated mixtures to be used. Also, AI enables the selective application of non-selective molecules, supporting their use in established cultures. These characteristics open new opportunities for effective weed control where the traditional solutions fall short. This publication demonstrates the potential of the ultra-precise smart spot sprayer ARA in weed management in onion and sugar beet crops. Although comparing the overall performance of ARA with other smart spot sprayers on the market cannot be done in this article, this technology's potential in rendering weed management on farms more effective, sustainable, and saving labor without compromising yield is nevertheless indicated. [ABSTRACT FROM AUTHOR]

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Background and Purpose: Parkinson's disease (PD) is an age‐related condition characterized by substantial phenotypic variability. Consequently, pathways and proteins involved in biological aging, such as the central aging pathway comprising insulin‐like growth factor 1–α‐Klotho–sirtuin 1–forkhead box O3–peroxisome proliferator‐activated receptor γ, may potentially influence disease progression. Methods: Cerebrospinal fluid (CSF) levels of α‐Klotho in 471 PD patients were examined. Of the 471 patients, 96 carried a GBA1 variant (PD GBA1), whilst the 375 non‐carriers were classified as PD wild‐type (PD WT). Each patient was stratified into a CSF α‐Klotho tertile group based on the individual level. Kaplan–Meier survival curves and Cox regression analysis stratified by tertile groups were conducted. These longitudinal data were available for 255 patients. Follow‐up times reached from 8.4 to 12.4 years. The stratification into PD WT and PD GBA1 was undertaken to evaluate potential continuum patterns, particularly in relation to CSF levels. Results: Higher CSF levels of α‐Klotho were associated with a significant later onset of cognitive impairment. Elevated levels of α‐Klotho in CSF were linked to higher Montreal Cognitive Assessment scores in male PD patients with GBA1 mutations. Conclusions: Our results indicate that higher CSF levels of α‐Klotho are associated with a delayed cognitive decline in PD. Notably, this correlation is more prominently observed in PD patients with GBA1 mutations, potentially reflecting the accelerated biological aging profile characteristic of individuals harboring GBA1 variants. [ABSTRACT FROM AUTHOR]

Background: The positive effects of regular physical activity on children and adolescents' physical and mental health are well-established. Despite these health benefits, most Swiss adolescents do not meet WHO's recommended level of physical activity, which includes a daily minimum of 60 min of moderate-to-vigorous physical activity. Due to their inclusivity, schools are identified as a key setting to promote physical activity. Recently, the comprehensive school physical activity program (CSPAP), in which teachers as physical activity leaders (PALs) play a crucial role to advance comprehensive school-based physical activity promotion, has been discussed. However, such comprehensive approaches are still lacking in Switzerland, and specific PAL trainings do not exist. Therefore, the aim of this study is to implement and evaluate Active School, a comprehensive school-based physical activity program for Swiss secondary schools with integrated PAL training. Methods/design: A cluster randomized controlled trial (RCT) involving 12 secondary schools (6 experimental, 6 waiting control schools) will assess baseline data and effectiveness of Active School at 12 and 24 months. Active School includes five components based on the CSPAP. Each school is encouraged to set individual physical activity goals in this regard. This process is guided by the PALs, who will participate in professional development training before and during Active School implementation. As a primary outcome, students' moderate-to-vigorous physical activity will be assessed via accelerometers. As secondary outcomes, inactivity, light physical activity, step counts, aerobic fitness and coordination will be measured, and students' general wellbeing, learning behavior, and multiple psychosocial measures related to physical activity will be assessed by questionnaires. The effectiveness evaluation is accompanied by a process evaluation that focuses on the implementation outcomes of dose of delivery, reach, feasibility, and sustainability. A mixed methods approach, including ripple effect mapping, will be employed to reconstruct and understand the implementation process. Discussion: This study will be the first to implement and evaluate a CSPAP in the Swiss school system. The specific PAL training and the simultaneous application of effectiveness and process evaluation are considered strengths of the study. Trial registration: German Clinical Trials Register (DRKS00033362). Date of registration: January 25, 2024. Retrospectively registered. [ABSTRACT FROM AUTHOR]

Metal complexes have recently attracted a lot of attention, particularly as anticancer and antibacterial agents, owing to their versatile mechanisms and easily tunable characteristics. However, the application of such compounds in a medical context, especially in cancer treatment, has been hampered due to their limited solubility and stability in water and aqueous solutions, as well as a lack of selectivity. To address these limitations, several approaches have been developed to improve the targeted delivery of these compounds and their solubility. The first strategy involves the physical encapsulation of these metal complexes within carriers to facilitate controlled drug release. The second strategy involves covalently linking metal complexes to polymers, creating prodrugs that can be converted to active drugs at a more controllable rate. Despite the increasing variety of polymers available, the need to develop those able to be metabolized by the body, producing non‐toxic residues, remains crucial for effective treatment, particularly in the area of diseases such as cancer. In this perspective article, an overview of recent developments in the encapsulation of metal complexes using biodegradable polymers for cancer therapy is provided. It is specifically highlighting how the formed nanoparticles (NPs) enhance the selectivity and toxicity toward cancer cells compared to the parent metal complex, while simultaneously reducing the harmful side effects of traditional chemotherapies, opening the door for using them in combination therapies (PDT, PTT). [ABSTRACT FROM AUTHOR]

This work outlines an efficient deep learning approach for analyzing vascular wall fractures using experimental data with openly accessible source codes (https://doi.org/10.25835/weuhha72) for reproduction. Vascular disease remains the primary cause of death globally to this day. Tissue damage in these vascular disorders is closely tied to how the diseases develop, which requires careful study. Therefore, the scientific community has dedicated significant efforts to capture the properties of vessel wall fractures. The symmetry-constrained compact tension (symconCT) test combined with digital image correlation (DIC) enabled the study of tissue fracture in various aorta specimens under different conditions. Main purpose of the experiments was to investigate the displacement and strain field ahead of the crack tip. These experimental data were to support the development and verification of computational models. The FEM model used the DIC information for the material parameters identification. Traditionally, the analysis of fracture processes in biological tissues involves extensive computational and experimental efforts due to the complex nature of tissue behavior under stress. These high costs have posed significant challenges, demanding efficient solutions to accelerate research progress and reduce embedded costs. Deep learning techniques have shown promise in overcoming these challenges by learning to indicate patterns and relationships between the input and label data. In this study, we integrate deep learning methodologies with the attention residual U-Net architecture to predict fracture responses in porcine aorta specimens, enhanced with a Monte Carlo dropout technique. By training the network on a sufficient amount of data, the model learns to capture the features influencing fracture progression. These parameterized datasets consist of pictures describing the evolution of tissue fracture path along with the DIC measurements. The integration of deep learning should not only enhance the predictive accuracy, but also significantly reduce the computational and experimental burden, thereby enabling a more efficient analysis of fracture response. [ABSTRACT FROM AUTHOR]

Artificial intelligence (AI) technology has expanded its potential in environmental and renewable energy applications, particularly in the use of artificial neural networks (ANNs) as the most widely used technique. To address the shortage of solar measurement in various places worldwide, several solar radiation methods have been developed to forecast global solar radiation (GSR). With this consideration, this study aims to develop temperature-based GSR models using a commonly utilized approach in machine learning techniques, ANNs, to predict GSR using just temperature data. It also compares the performance of these models to the commonly used empirical technique. Additionally, it develops precise GSR models for five new sites and the entire region, which currently lacks AI-based models despite the presence of proposed solar energy plants in the area. The study also examines the impact of varying lengths of validation datasets on solar radiation models' prediction and accuracy, which has received little attention. Furthermore, it investigates different ANN architectures for GSR estimation and introduces a comprehensive comparative study. The findings indicate that the most advanced models of both methods accurately predict GSR, with coefficient of determination, R2, values ranging from 96% to 98%. Moreover, the local and general formulas of the empirical model exhibit comparable performance at non-coastal sites. Conversely, the local and general ANN-based models perform almost identically, with a high ability to forecast GSR in any location, even during the winter months. Additionally, ANN architectures with fewer neurons in their single hidden layer generally outperform those with more. Furthermore, the efficacy and precision of the models, particularly ANN-based ones, are minimally impacted by the size of the validation data sets. This study also reveals that the performance of the empirical models was significantly influenced by weather conditions such as clouds and rain, especially at coastal sites. In contrast, the ANN-based models were less impacted by such weather variations, with a performance that was approximately 7% better than the empirical ones at coastal sites. The best-developed models, particularly the ANN-based models, are thus highly recommended. They enable the precise and rapid forecast of GSR, which is useful in the design and performance evaluation of various solar applications, with the temperature data continuously and easily recorded for various purposes. [ABSTRACT FROM AUTHOR]

The metastatic cascade includes a blood circulation step for cells detached from the primary tumor. This stage involves significant shear stress as well as large and fast deformation as the cells circulate through the microvasculature. These mechanical stimuli are well reproduced in microfluidic devices. However, the recovery dynamics after deformation is also pivotal to understand how a cell can pass through the multiple capillary constrictions encountered during a single hemodynamic cycle. The microfluidic system developed in this work allows single cell recovery to be studied under flow-free conditions following pressure-actuated cell deformation inside constricted microchannels. We used three breast cancer cell lines – namely MCF-7, SK-BR3 and MDA-MB231 – as cellular models representative of different cancer phenotypes. Changing the size of the constriction allows exploration of moderate to strong deformation regimes, the latter being associated with the formation of plasma membrane blebs. In the regime of moderate deformation, all cell types display a fast elastic recovery behavior followed by a slower viscoelastic regime, well described by a double exponential decay. Among the three cell types, cells of the mesenchymal phenotype, i.e. the MDA-MB231 cells, are softer and the most fluid-like, in agreement with previous studies. Our main finding here is that the fast elastic recovery regime revealed by our novel microfluidic system is under the control of cell contractility ensured by the integrity of the cell cortex. Our results suggest that the cell cortex plays a major role in the transit of circulating tumor cells by allowing their fast morphological recovery after deformation in blood capillaries. [ABSTRACT FROM AUTHOR]

Haemonchus contortus (the barber's pole worm)—a highly pathogenic gastric nematode of ruminants—causes significant economic losses in the livestock industry worldwide. H. contortus has become a valuable model organism for both fundamental and applied research (e.g., drug and vaccine discovery) because of the availability of well-defined laboratory strains (e.g., MHco3(ISE).N1 in the UK and Haecon-5 in Australia) and genomic, transcriptomic and proteomic data sets. Many recent investigations have relied heavily on the use of the chromosome-contiguous genome of MHco3(ISE).N1 in the absence of a genome for Haecon-5. However, there has been no genetic comparison of these and other strains to date. Here, we assembled and characterised the mitochondrial genome (14.1 kb) of Haecon-5 and compared it with that of MHco3(ISE).N1 and two other strains (i.e., McMaster and NZ_Hco_NP) from Australasia. We detected 276 synonymous and 25 non-synonymous single nucleotide polymorphisms (SNPs) within Haecon-5. Between the Haecon-5 and MHco3(ISE).N1 strains, we recorded 345 SNPs, 31 of which were non-synonymous and linked to fixed amino acid differences in seven protein-coding genes (nad5, nad6, nad1, atp6, nad2, cytb and nad4) between these strains. Pronounced variation (344 and 435 SNPs) was seen between Haecon-5 and each of the other two strains from Australasia. The question remains as to what impact these mitogenomic mutations might have on the biology and physiology of H. contortus, which warrants exploration. The high degree of mitogenomic variability recorded here among these strains suggests that further work should be undertaken to assess the nature and extent of the nuclear genomic variation within H. contortus. [ABSTRACT FROM AUTHOR]

Background: In diabetic retinopathy, early detection and intervention are crucial in preventing vision loss and improving patient outcomes. In the era of artificial intelligence (AI) and machine learning, new promising diagnostic tools have emerged. The IDX-DR machine (Digital Diagnostics, Coralville, IA, USA) represents a diagnostic tool that combines advanced imaging techniques, AI algorithms, and deep learning methodologies to identify and classify diabetic retinopathy. Methods: All patients that participated in our AI-based DR screening were considered for this study. For this study, all retinal images were additionally reviewed retrospectively by two experienced retinal specialists. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy were calculated for the IDX-DR machine compared to the graders' responses. Results: We included a total of 2282 images from 1141 patients who were screened between January 2021 and January 2023 at the Jules Gonin Eye Hospital in Lausanne, Switzerland. Sensitivity was calculated to be 100% for 'no DR', 'mild DR', and 'moderate DR'. Specificity for no DR', 'mild DR', 'moderate DR', and 'severe DR' was calculated to be, respectively, 78.4%, 81.2%, 93.4%, and 97.6%. PPV was calculated to be, respectively, 36.7%, 24.6%, 1.4%, and 0%. NPV was calculated to be 100% for each category. Accuracy was calculated to be higher than 80% for 'no DR', 'mild DR', and 'moderate DR'. Conclusions: In this study, based in Jules Gonin Eye Hospital in Lausanne, we compared the autonomous diagnostic AI system of the IDX-DR machine detecting diabetic retinopathy to human gradings established by two experienced retinal specialists. Our results showed that the ID-x DR machine constantly overestimates the DR stages, thus permitting the clinicians to fully trust negative results delivered by the screening software. Nevertheless, all fundus images classified as 'mild DR' or greater should always be controlled by a specialist in order to assert whether the predicted stage is truly present. [ABSTRACT FROM AUTHOR]

Several prior studies have proposed the involvement of various brain regions and cell types in Parkinson's disease (PD) pathology. Here, we performed snRNA-seq on the prefrontal cortex and anterior cingulate regions from a small cohort of post-mortem control and PD brain tissue. We found a significant association of oligodendrocytes (ODCs) and oligodendrocyte precursor cells (OPCs) with PD-linked risk loci and report several dysregulated genes and pathways, including regulation of tau-protein kinase activity, regulation of inclusion body assembly and protein processing involved in protein targeting to mitochondria. In an independent PD cohort with clinical measures (681 cases and 549 controls), polygenic risk scores derived from the dysregulated genes significantly predicted Montreal Cognitive Assessment (MoCA)-, and Beck Depression Inventory-II (BDI-II)-scores but not motor impairment (UPDRS-III). We extended our analysis of clinical outcome prediction by incorporating differentially expressed genes from three separate datasets that were previously published by different laboratories. In the first dataset from the anterior cingulate cortex, we identified an association between ODCs and BDI-II. In the second dataset obtained from the substantia nigra (SN), OPCs displayed an association with UPDRS-III. In the third dataset from the SN region, a distinct subtype of OPCs, labeled OPC_ADM, exhibited an association with UPDRS-III. Intriguingly, the OPC_ADM cluster also demonstrated a significant increase in PD samples. These results suggest that by expanding our focus to glial cells, we can uncover region-specific molecular pathways associated with PD symptoms. [ABSTRACT FROM AUTHOR]

Accumulating evidence suggests that the brain exhibits a remarkable capacity for functional compensation in response to neurological damage, a resilience potential that is deeply rooted in the malleable features of its underlying anatomofunctional architecture. This propensity is particularly exemplified by diffuse low-grade glioma, a subtype of primary brain tumour. However, functional plasticity is not boundless, and surgical resections directed at structures with limited neuroplasticity can lead to incapacitating impairments. Yet, maximizing diffuse low-grade glioma resections offers substantial oncological benefits, especially when the resection extends beyond the tumour margins (i.e. supra-tumour or supratotal resection). In this context, the primary objective of this study was to identify which cerebral structures were associated with less favourable cognitive outcomes after surgery, while accounting for intra-tumour and supra-tumour features of the surgical resections. To achieve this objective, we leveraged a unique cohort of 400 patients with diffuse low-grade glioma who underwent surgery with awake cognitive mapping. Patients benefitted from a neuropsychological assessment consisting of 18 subtests administered before and 3 months after surgery. We analysed changes in performance and applied topography-focused and disconnection-focused multivariate lesion–symptom mapping using support vector regressions, in an attempt to capture resected cortico-subcortical structures less amenable to full cognitive compensation. The observed changes in performance were of a limited magnitude, suggesting an overall recovery (13 of 18 tasks recovered fully despite a mean resection extent of 92.4%). Nevertheless, lesion–symptom mapping analyses revealed that a lack of recovery in picture naming was linked to damage in the left inferior temporal gyrus and inferior longitudinal fasciculus. Likewise, for semantic fluency abilities, an association was established with damage to the left precuneus/posterior cingulate. For phonological fluency abilities, the left dorsomedial frontal cortex and the frontal aslant tract were implicated. Moreover, difficulties in spatial exploration were associated with injury to the right dorsomedial prefrontal cortex and its underlying connectivity. An exploratory analysis suggested that supra-tumour resections were associated with a less pronounced recovery following specific resection patterns, such as supra-tumour resections of the left uncinate fasciculus (picture naming), the left corticostriatal tract and the anterior corpus callosum (phonological fluency), the hippocampus and parahippocampus (episodic memory) and the right frontal–mesial areas (visuospatial exploration). Collectively, these patterns of results shed new light on both low-resilient neural systems and the prediction of cognitive recovery following glioma surgery. Furthermore, they indicate that supra-tumour resections were only occasionally less well tolerated from a cognitive viewpoint. In doing so, they have deep implications for surgical planning and rehabilitation strategies. [ABSTRACT FROM AUTHOR]

A diagnosis of interstitial lung diseases (ILD) can be challenging, and the identification of an associated connective tissue disease (CTD) is crucial to estimate prognosis and to establish the optimal treatment approach. Diagnostic delay, limited expertise, and fragmented care are barriers that impede the delivery of comprehensive health care for patients with rare, complex, and multiorgan diseases such as CTD and ILD. In this article, we present our perspective on the interdisciplinary diagnosis and interprofessional treatment of patients with ILD and suspected CTD or CTD at risk of ILD. We outline the structure of our service, delineating the roles and responsibilities of the team members. Additionally, we provide an overview of our patient population, including diagnostic approaches and specific treatments, and illustrate a patient case. Furthermore, we focus on specific benefits and challenges of joint interdisciplinary and interprofessional patient consultations. The importance of rheumatology and pulmonology assessments in specific patient populations is emphasized. Finally, we explore future directions and discuss potential strategies to improve care delivery for patients with CTD-associated ILD. [ABSTRACT FROM AUTHOR]

Pancreatic cancer (pancreatic ductal adenocarcinoma, PDAC) remains a deadly cancer worldwide with a need for new therapeutic approaches. A dysregulation in the equilibrium between pro- and anti-inflammatory responses with a predominant immunosuppressive inflammatory reaction in advanced stage tumors seem to contribute to tumor growth and metastasis. The current therapies do not include strategies against pro-tumorigenic inflammation in cancer patients. We have shown that the upregulated cell surface expression of Toll-like Receptor (TLR) 2 and of TLR9 inside PDAC cells maintain chronic inflammatory responses, support chemotherapeutic resistance, and mediate tumor progression in human pancreatic cancer. We further demonstrated intracellular TLR2 and TLR9 targeting using specific intrabodies, which resulted in downregulated inflammatory signaling. In this study, we tested, for the first time, an intrabody-mediated TLR blockade in human TLR2- and TLR9-expressing pancreatic cancer cells for its effects on inflammatory signaling-mediated tumor growth. Newly designed anti-TLR2- and anti-TLR9-specific intrabodies inhibited PDAC growth. Co-expression analysis of the intrabodies and corresponding human TLRs showed efficient retention and accumulation of both intrabodies within the endoplasmic reticulum (ER), while co-immunoprecipitation studies indicated both intrabodies interacting with their cognate TLR antigen within the pancreatic cancer cells. Cancer cells with attenuated proliferation expressing accumulated TLR2 and TRL9 intrabodies demonstrated reduced STAT3 phosphorylation signaling, while apoptotic markers Caspases 3 and 8 were upregulated. To conclude, our results demonstrate the TLR2 and TLR9-specific intrabody-mediated signaling pathway inhibition of autoregulatory inflammation inside cancer cells and their proliferation, resulting in the suppression of pancreatic tumor cell growth. These findings underscore the potential of specific intrabody-mediated TLR inhibition in the ER relevant for tumor growth inhibition and open up a new therapeutic intervention strategy for the treatment of pancreatic cancer. [ABSTRACT FROM AUTHOR]

The search for new metal-based anticancer drug candidates is a fundamental task in medicinal inorganic chemistry. In this work, we assessed the potential of two new Ru(II)–phosphine–mercapto complexes as potential anticancer agents. The complexes, with the formula [Ru(bipy)(dppen)(Lx)]PF6 [(1), HL1 = 2-mercapto–pyridine and (2), HL2 = 2-mercapto–pyrimidine, bipy = 2,2′-bipyridine, dppen = cis-1,2-bis(diphenylphosphino)-ethylene] were synthesized and characterized by nuclear magnetic resonance (NMR) [1H, 31P(1H), and 13C], high resolution mass spectrometry (HR-MS), cyclic voltammetry, infrared and UV-Vis spectroscopies. Complex 2 was obtained as a mixture of two isomers, 2a and 2b, respectively. The composition of these metal complexes was confirmed by elemental analysis and liquid chromatography-mass spectrometry (LC-MS). To obtain insights into their lipophilicity, their distribution coefficients between n-octanol/PBS were determined. Both complexes showed affinity mainly for the organic phase, presenting positive log P values. Also, their stability was confirmed over 48 h in different media (i.e., DMSO, PBS and cell culture medium) via HPLC, UV-Vis and 31P{1H} NMR spectroscopies. Since enzymes from the P-450 system play a crucial role in cellular detoxification and metabolism, the microsomal stability of 1, which was found to be the most interesting compound of this study, was investigated using human microsomes to verify its potential oxidation in the liver. The analyses by LC-MS and ESI-MS reveal three main metabolites, obtained by oxidation in the dppen and bipy moieties. Moreover, 1 was able to interact with human serum albumin (HSA). The cytotoxicity of the metal complexes was tested in different cancerous and non-cancerous cell lines. Complex 1 was found to be more selective than cisplatin against MDA-MB-231 breast cancer cells when compared to MCF-10A non-cancerous cells. In addition, complex 1 affects cell morphology and migration, and inhibits colony formation in MDA-MB-231 cells, making it a promising cytotoxic agent against breast cancer. [ABSTRACT FROM AUTHOR]

Background: Lymnaeid snails of the genus Austropeplea are an important vector of the liver fluke (Fasciola hepatica), contributing to livestock production losses in Australia and New Zealand. However, the species status within Austropeplea is ambiguous due to heavy reliance on morphological analysis and a relative lack of genetic data. This study aimed to characterise the mitochondrial genome of A. cf. brazieri, an intermediate host of liver fluke in eastern Victoria. Methods: The mitochondrial genome was assembled and annotated from a combination of second- and third-generation sequencing data. For comparative purposes, we performed phylogenetic analyses of the concatenated nucleotide sequences of the mitochondrial protein-coding genes, cytochrome c oxidase subunit 1 and 16S genes. Results: The assembled mt genome was 13,757 base pairs and comprised 37 genes, including 13 protein-coding genes, 22 transfer RNA genes and 2 ribosomal RNA genes. The mt genome length, gene order and nucleotide compositions were similar to related species of lymnaeids. Phylogenetic analyses of the mt nucleotide sequences placed A. cf. brazieri within the same clade as Orientogalba ollula with strong statistical supports. Phylogenies of the cox1 and 16S mt sequences were constructed due to the wide availability of these sequences representing the lymnaeid taxa. As expected in both these phylogenies, A. cf. brazieri clustered with other Austropeplea sequences, but the nodal supports were low. Conclusions: The representative mt genome of A. cf. brazieri should provide a useful resource for future molecular, epidemiology and parasitological studies of this socio-economically important lymnaeid species. [ABSTRACT FROM AUTHOR]

Background: Mutations in the Leucine Rich Repeat Kinase 2 gene are highly relevant in both sporadic and familial cases of Parkinson's disease. Specific therapies are entering clinical trials but patient stratification remains challenging. Dysregulated microRNA expression levels have been proposed as biomarker candidates in sporadic Parkinson's disease. Objective: In this proof-of concept study we evaluate the potential of extracellular miRNA signatures to identify LRRK2-driven molecular patterns in Parkinson's disease. Methods: We measured expression levels of 91 miRNAs via RT-qPCR in ten individuals with sporadic Parkinson's disease, ten LRRK2 mutation carriers and eleven healthy controls using both plasma and cerebrospinal fluid. We compared miRNA signatures using heatmaps and t-tests. Next, we applied group sorting algorithms and tested sensitivity and specificity of their group predictions. Results: miR-29c-3p was differentially expressed between LRRK2 mutation carriers and sporadic cases, with miR-425-5p trending towards significance. Individuals clustered in principal component analysis along mutation status. Group affiliation was predicted with high accuracy in the prediction models (sensitivity up to 89%, specificity up to 70%). miRs-128-3p, 29c-3p, 223-3p, and 424-5p were identified as promising discriminators among all analyses. Conclusions: LRRK2 mutation status impacts the extracellular miRNA signature measured in plasma and separates mutation carriers from sporadic Parkinson's disease patients. Monitoring LRRK2 miRNA signatures could be an interesting approach to test drug efficacy of LRRK2-targeting therapies. In light of small sample size, the suggested approach needs to be validated in larger cohorts. Plain Language Summary: We know that alterations in a gene called Leucine Rich Repeat Kinase 2 are important in both inherited and non-inherited cases of Parkinson's disease. We also know that treatments for Parkinson's disease specifically targeting LRRK2 are currently being developed. Challenges for developing such a treatment, however, are how to accurately identify patients who could benefit from these therapies and to observe whether the treatment interacts with its target on a molecular level. In this study, we tested whether individuals with an alteration in the LRRK2 gene display a distinct pattern of small RNA molecules, called microRNAs. We measured the amount of 91 microRNAs present in blood of individuals with an alteration in the LRRK2 gene and compared their pattern to patients with a non-inherited form of Parkinson's disease and healthy controls. We found that the amount of a specific microRNA called miR-29c-3p was different between individuals with or without an alteration of the LRRK2 gene. Additionally, we developed models that could predict whether someone had a LRRK2 mutation based on the microRNA pattern in the plasma. Of course, we have easier methods to find these gene alterations, but our findings suggest that changes of LRRK2 result in a shift of microRNA patterns in the blood. This could help us to observe the effects of a LRRK2 specific treatment which tries to revert these changes. As we know that LRRK2 also plays a role in some patients with a non-inherited form of Parkinson's disease, this microRNA pattern could maybe even help us to identify these individuals. It is important to note that our study involved a small number of individuals, so that further research with larger groups is needed to confirm our findings. [ABSTRACT FROM AUTHOR]

This article discusses the role of mucosal-associated invariant T (MAIT) cells in allergic airway inflammation. MAIT cells are a type of T cell that have been found to have both anti-microbial and homeostatic functions. The article presents findings from a study that examined the contribution of MAIT cells to allergic diseases, specifically in the context of allergic march, which refers to the progression of allergies from the skin to the lungs. The study found that MAIT cells have a pathogenic role in allergic diseases when sensitization occurs through the skin, but they have a protective function when allergens are encountered through the airways. The article suggests that further research is needed to understand the underlying mechanisms and interactions involved. [Extracted from the article]

Nematodes of the genus Trichinella are important pathogens of humans and animals. This study aimed to enhance the genomic and transcriptomic resources for T. pseudospiralis (non-encapsulated phenotype) and T. spiralis (encapsulated phenotype) and to explore transcriptional profiles. First, we improved the assemblies of the genomes of T. pseudospiralis (code ISS13) and T. spiralis (code ISS534), achieving genome sizes of 56.6 Mb (320 scaffolds, and an N50 of 1.02 Mb) and 63.5 Mb (568 scaffolds, and an N50 value of 0.44 Mb), respectively. Then, for each species, we produced RNA sequence data for three key developmental stages (first-stage muscle larvae [L1s], adults, and newborn larvae [NBLs]; three replicates for each stage), analysed differential transcription between stages, and explored enriched pathways and processes between species. Stage-specific upregulation was linked to cellular processes, metabolism, and host–parasite interactions, and pathway enrichment analysis showed distinctive biological processes and cellular localisations between species. Indeed, the secreted molecules calmodulin, calreticulin, and calsyntenin—with possible roles in modulating host immune responses and facilitating parasite survival—were unique to T. pseudospiralis and not detected in T. spiralis. These insights into the molecular mechanisms of Trichinella–host interactions might offer possible avenues for developing new interventions against trichinellosis. [ABSTRACT FROM AUTHOR]

Background: Polymorphism rs1049434 characterizes the nonsynonymous exchange of adenosine (A) by thymidine (T) in the gene for monocarboxylate transporter 1 (MCT1). We tested whether T-allele carriers of rs1049434 demonstrate increased accumulation of markers of metabolic strain. Methods: Physically active, healthy, young male subjects (n = 22) conducted a power-matched one-legged cycling exercise to exhaustion. Metabolic substrates in capillary blood, selected metabolic compounds, and indices for the slow oxidative phenotype of vastus lateralis muscle were quantified in samples collected before and after exercise. The genotypes of the rs1049434 polymorphism were determined with polymerase chain reactions. Results: One-legged exercise affected the concentration of muscle metabolites entering the tricarboxylic acid cycle, such as acetyl-co-enzyme A (+448%) and acetyl-L-carnitine (+548%), muscle glycogen (−59%), and adenosine monophosphate (−39%), 30 min post-exercise. Exercise-related variability in the muscular concentration of glycogen, long-chain acyl co-enzyme As and a triglyceride, nicotinamide adenine dinucleotide (NADH), and adenosine monophosphate (AMP) interacted with rs1049434. T-allele carriers demonstrated a 39% lesser reduction in glycogen after exercise than non-carriers when NADH increased only in the non-carriers. Muscle lactate concentration was 150% higher, blood triacyl-glyceride concentration was 53% lower, and slow fiber percentage was 20% lower in T-allele carriers. Discussion: The observations suggest a higher anaerobic glycolytic strain during exhaustive exercise and a lowered lipid handling in T-allele non-carriers. [ABSTRACT FROM AUTHOR]

Since late 2019, the world has been devastated by the coronavirus disease 2019 (COVID‐19) induced by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), with more than 760 million people affected and ∼seven million deaths reported. Although effective treatments for COVID‐19 are currently limited, there has been a strong focus on developing new therapeutic approaches to address the morbidity and mortality linked to this disease. An approach that is currently being investigated is the use of exosome‐based therapies. Exosomes are small, extracellular vesicles that play a role in many clinical diseases, including viral infections, infected cells release exosomes that can transmit viral components, such as miRNAs and proteins, and can also include receptors for viruses that facilitate viral entry into recipient cells. SARS‐CoV‐2 has the ability to impact the formation, secretion, and release of exosomes, thereby potentially facilitating or intensifying the transmission of the virus among cells, tissues and individuals. Therefore, designing synthetic exosomes that carry immunomodulatory cargo and antiviral compounds are proposed to be a promising strategy for the treatment of COVID‐19 and other viral diseases. Moreover, exosomes generated from mesenchymal stem cells (MSC) might be employed as cell‐free therapeutic agents, as MSC‐derived exosomes can diminish the cytokine storm and reverse the suppression of host anti‐viral defences associated with COVID‐19, and boost the repair of lung damage linked to mitochondrial activity. The present article discusses the significance and roles of exosomes in COVID‐19, and explores potential future applications of exosomes in combating this disease. Despite the challenges posed by COVID‐19, exosome‐based therapies could represent a promising avenue for improving patient outcomes and reducing the impact of this disease. [ABSTRACT FROM AUTHOR]

Background: Most Parkinson's disease (PD) loci have shown low prevalence in the Indian population, highlighting the need for further research. Objective: The aim of this study was to characterize a novel phosphatase tensin homolog‐induced serine/threonine kinase 1 (PINK1) mutation causing PD in an Indian family. Methods: Exome sequencing of a well‐characterized Indian family with PD. A novel PINK1 mutation was studied by in silico modeling using AlphaFold2, expression of mutant PINK1 in human cells depleted of functional endogenous PINK1, followed by quantitative image analysis and biochemical assessment. Results: We identified a homozygous chr1:20648535–20648535 T>C on GRCh38 (p.F385S) mutation in exon 6 of PINK1, which was absent in 1029 genomes from India and in other known databases. PINK1 F385S lies within the highly conserved DFG motif, destabilizes its active state, and impairs phosphorylation of ubiquitin at serine 65 and proper engagement of parkin upon mitochondrial depolarization. Conclusions: We characterized a novel nonconservative mutation in the DFG motif of PINK1, which causes loss of its ubiquitin kinase activity and inhibition of mitophagy. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

The compressibility of soft colloids influences their phase behavior and flow properties, especially in concentrated suspensions. Particle compressibility, which is proportional to the reciprocal of the bulk modulus K, is a key parameter for soft polymer‐based particles that can be compressed in crowded environments. Here, microgels with different degrees of cross‐linking, i.e., softness, are investigated below and above their volume phase transition temperature (VPTT). By combining molecular dynamics simulations with small‐angle neutron scattering with contrast variation, a change in the particle bulk moduli of two orders of magnitude is observed. The degree of cross‐linking has a significant impact on the bulk modulus of the swollen microgel, while above the VPTT the values of K are almost independent of the cross‐linking density. The excellent agreement between experimental results and simulations also highlight that the model microgels from computer simulations possess both the internal architecture and the elastic properties of real polymeric networks. This paves the way to a systematic use of simulations to investigate the behavior of dense microgel suspensions below and above their VPTT. [ABSTRACT FROM AUTHOR]

Objective: Oral lichen planus carries a risk for malignancy. The pathogenesis of the disease is mediated by various inflammatory mediators. Several mediators could be responsible for the oncogenic behavior in certain cases. Hypoxia-inducible factor-1a (HIF-1), and its possible correlation to Galactin-3 (Gal-3) and matrix metalloproteinase-9 (MMP-9) over expression represents an important indicator for malignant transformation. The investigation of these factors may present evidence-based information on malignant transformation of the disease. Subjects and methods: The study investigated the expression of HIF-1, Gla-3 and MMP-9 in tissue samples of OLP compared to control subjects of un-inflamed gingival overgrowth. 20 biospecimen were allocated in each group. Results: Immunohistochemical findings of OLP showed immunoreactivity for Galectin 3, HIF1a and MMP-9 by most of the epithelial cells. There was a positive correlation between HIF1α and MMP-9, r = 0.9301 (P-value < 0.00001). A positive correlation was detected between Galectin 3 and MMP-9, r = 0.7292 (P-value = 0.000264) between Galectin 3 and HIF1α, r = 0.5893 (P-value = 0.006252). Conclusion: These findings confirm the hypothesis that the adaptive pathways to hypoxia as Gal 3 and MMP-9 expressions and their HIF-1 may play a crucial role in carcinogenesis of OLP. [ABSTRACT FROM AUTHOR]

Background: Cystic fibrosis (CF) is a genetic multisystem disorder. Inflammatory processes, which presumably begin early in infancy, play a crucial role in the progression of the disease. The detection of inflammatory biomarkers, especially in the airways, has therefore gained increasing attention. Due to improved treatment options, patients with CF produce less sputum. Nasal lavage samples therefore represent a promising alternative to induced sputum or bronchoalveolar lavage specimens. However, methodology of cytokine measurements is not standardised and comparisons of results are therefore often difficult. The aim of this study was to identify suitable detection methods of cytokines in nasal lavage samples by comparison of two different assays. Methods: Nasal lavage samples were obtained from the same patient at the same time by trained respiratory physiotherapists using a disposable syringe and 10 ml of 0.9% sodium chloride per nostril during outpatient visits. The cytokines IL-17 A, IL-2, IL-6 and IL-10 were measured using two different assays (BD™ and Milliplex®), which have already been applied in sputum and nasal lavage samples, despite different lower detection limits. Results: 22 participants were included in the study. In 95.5% of measurements, values were below the limit of detection with respect to the BD™ assay. Only IL-6 could be detected in approximately half of the patients. Individual cytokine levels were considerably higher when measured with Milliplex®, which is also reflected in a statistically significant manner (p = < 0.01). Conclusion: The right choice of analysis method is crucial for measuring inflammatory markers in nasal lavage samples. Compared to the literature, Milliplex® showed higher detection rates and similar concentrations to other studies. Trial registration: Ethics approval was obtained from the ethics committee at Medical University of Innsbruck (EK Nr: 1055/2022). [ABSTRACT FROM AUTHOR]

Background: Patients with heart failure with preserved ejection fraction (HFpEF) commonly experience exercise intolerance, resulting in reduced cardiorespiratory fitness. This is characterised by a decreased maximal oxygen uptake (V̇O2peak), which is determined by the product of cardiac output (CO) and arteriovenous oxygen difference (a-vDO2). While exercise training has been shown to improve V̇O2peak in HFpEF patients, the effects on CO remain unclear. The aim of this study is to systematically review and analyse the current evidence on the effects of supervised exercise training on CO in patients with HFpEF. Methods: We will systematically search for literature describing the effects of supervised exercise training on CO in patients with HFpEF. All eligible studies published before 30 June 2023 in the following electronic databases will be included: MEDLINE (Ovid), Embase (Ovid), SPORTDiscus (EBSCOhost), and CENTRAL (Cochrane Library). Effect sizes will be extracted for CO before and after a supervised exercise training intervention at rest and maximal exercise. Mass of heterogeneity (I2) will be calculated, and either fixed-effect models or random-effect models will be used for meta-analysis. To detect a potential publication bias, funnel plot analyses will be performed. Discussion: While several studies have reported a positive effect of supervised exercise training on cardiorespiratory fitness, attempts to assess the underlying determinants of V̇O2peak, CO, and a-vDO2 are much scarcer, especially in patients with HFpEF. From a physiological perspective, measuring CO before and after supervised exercise training seems to be a reasonable way to accurately operationalise a potential improvement in cardiac function. Systematic review registration: PROSPERO CRD42022361485. [ABSTRACT FROM AUTHOR]

The pace at which Next Generation Sequence data is being produced continues to accelerate as technology improves. As a result, such data are increasingly becoming accessible to biologists outside of the field of bioinformatics. In contrast, access to training in the methods of genome assembly and annotation are not growing at a similar rate. In this issue, we report on a Genome Assembly Workshop for Mycologists that was held at the Forestry and Agricultural Biotechnology Institute (FABI) at the University of Pretoria, South Africa and make available the 12 draft genome sequences emanating from the event. With the aim of making the process of genome assembly and annotation more accessible to biologists, we provide a step-by-step guide to both genome assembly and annotation, intended to encourage and empower mycologists to use genome data in their research. [ABSTRACT FROM AUTHOR]

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The pyoverdine siderophore is produced by Pseudomonas aeruginosa to access iron. Its synthesis involves the complex coordination of four nonribosomal peptide synthetases (NRPSs), which are responsible for assembling the pyoverdine peptide backbone. The precise cellular organization of these NRPSs and their mechanisms of interaction remain unclear. Here, we used a combination of several single-molecule microscopy techniques to elucidate the spatial arrangement of NRPSs within pyoverdine-producing cells. Our findings reveal that PvdL differs from the three other NRPSs in terms of localization and mobility patterns. PvdL is predominantly located in the inner membrane, while the others also explore the cytoplasmic compartment. Leveraging the power of multicolor single-molecule localization, we further reveal co-localization between PvdL and the other NRPSs, suggesting a pivotal role for PvdL in orchestrating the intricate biosynthetic pathway. Our observations strongly indicates that PvdL serves as a central orchestrator in the assembly of NRPSs involved in pyoverdine biosynthesis, assuming a critical regulatory function. [ABSTRACT FROM AUTHOR]

Construction Engineering and Management (CEM) is a broad domain with publications covering interrelated subdisciplines and considered a key source of knowledge sharing. Previous studies used scientometric methods to assess the current impact of CEM publications; however, there is a need to predict future citations of CEM publications to identify the expected high-impact trends in the future and guide new research efforts. To tackle this gap in the literature, the authors conducted a study using Machine Learning (ML) algorithms and Social Network Analysis (SNA) to predict CEM-related citation metrics. Using a dataset of 93,868 publications, the authors trained and tested two machine learning classification algorithms: Random Forest and XGBoost. Validation of the RF and XGBoost resulted in a balanced accuracy of 79.1% and 79.5%, respectively. Accordingly, XGBoost was selected. Testing of the XGBoost model revealed a balanced accuracy of 80.71%. Using SNA, it was found that while the top CEM subdisciplines in terms of the number of predicted impactful papers are "Project planning and design", "Organizational issues", and "Information technologies, robotics, and automation"; the lowest was "Legal and contractual issues". This paper contributes to the body of knowledge by studying the citation level, strength, and interconnectivity between CEM subdisciplines as well as identifying areas more likely to result in highly cited publications. [ABSTRACT FROM AUTHOR]

Key message: Inheritance of the presence/absence of seeds in Annona squamosa is mediated by a single fully recessive gene and is caused by a deletion of the INNER NO OUTER (INO) locus. For some fruits, seedless varieties are desirable for consumption and processing. In the sugar apple tree (Annona squamosa L.), the seedless trait in the Thai seedless (Ts) and Brazilian seedless (Bs) accessions was associated with defective ovules and an apparent deletion of the INNER NO OUTER (INO) ovule development gene locus. Segregation analysis of F2 and backcross descendants of crosses of Bs to fertile wild-type varieties in this species with a multi-year generation time showed that seedlessness was recessive and controlled by a single locus. Comparison of whole genome sequence of a wild-type plant and a third accession, Hawaiian seedless (Hs), identified a 16 kilobase deletion including INO in this line. Ts and Bs lines were shown to have an identical deletion, indicating a common origin from a single deletion event. Analysis of microsatellite markers could not preclude the possibility that all three seedless accessions are vegetatively propagated clones. The sequence of the deletion site enabled a codominant assay for the wild-type and mutant genes allowing observation of complete cosegregation of the seedless/defective ovule phenotype with the INO deletion, showing maximal separation of less than 3.5 cM. The observed deletion is the only significant difference between the wild-type and Hs line over 587 kilobases, likely encompassing much more than 3.5 cM, showing that the deletion is the cause of seedless trait. The codominant markers and obtained progenies will be useful for introgression of the seedless trait into elite sugar apple lines and into other Annonas through interspecific crossings. [ABSTRACT FROM AUTHOR]

The fracture of vascular tissue, and load-bearing soft tissue in general, is relevant to various biomechanical and clinical applications, from the study of traumatic injury and disease to the design of medical devices and the optimisation of patient treatment outcomes. The fundamental mechanisms associated with the inception and development of damage, leading to tissue failure, have yet to be wholly understood. We present the novel coupling of a microstructurally motivated continuum damage model that incorporates the time-dependent interfibrillar failure of the collagenous matrix with an embedded phenomenological representation of the fracture surface. Tissue separation is therefore accounted for through the integration of the cohesive crack concept within the partition of unity finite element method. A transversely isotropic cohesive potential per unit undeformed area is introduced that comprises a rate-dependent evolution of damage and accounts for mixed-mode failure. Importantly, a novel crack initialisation procedure is detailed that identifies the occurrence of localised deformation in the continuum material and the orientation of the inserted discontinuity. Proof of principle is demonstrated by the application of the computational framework to two representative numerical simulations, illustrating the robustness and versatility of the formulation. [ABSTRACT FROM AUTHOR]

Monoclonal antibodies, as tixagevimab/cilgavimab, have been introduced as prophylaxis against COVID-19 infections in high-risk populations. However, data on efficacy are limited. This study investigates efficacy and tolerability of tixagevimab/cilgavimab in hematological patients under real-life conditions. Tixagevimab/cilgavimab was administered to 155 hematological patients (March-August 2022) at two Austrian centres. S/RBD-antibody assessments were performed before (T0), four weeks (T1), and six months (T2) after application. Side effects, the occurrence of COVID-19 infections, and the course of S/RBD-antibody titres were analysed retrospectively in relation to clinical variables. 155 hematological patients, who refused tixagevimab/cilgavimab, were included as a control group to compare the frequency of COVID-19 infections. Of all immunised patients (52.3% males; 91% triple vaccinated), 25.8% had a COVID-19 breakthrough infection (76% mild) compared to 43.9% in the control group. Patients with chronic lymphocytic leukaemia (CLL)/lymphoma were at highest risk of a COVID-19 infection (OR = 2.21; 95% CI 1.05–4.65; p = 0.037). After immunisation, a steep increase in median antibody levels (1193.4BAU/ml, IQR 0–2318.94) was observed in 67.8%, followed by a rapid decrease between T1 and T2 (465.95BAU/ml, IQR 0–1900.65.3) with the greatest declines in CLL/lymphoma (848.7BAU/ml, IQR 0–1949.6, p = 0.026). Side-effects occurred in 21.2% (CTCAE I/II). These real-world data indicate that S/RBD antibodies respond rapidly after passive immunisation in all hematological patients without safety concerns. Given the rapid decline in S/RBD antibodies, early booster immunisations should be considered for future scenarios in this vulnerable group. [ABSTRACT FROM AUTHOR]

Background: G-quadruplex DNA (G4) is a non-canonical structure forming in guanine-rich regions, which play a vital role in cancer biology and are now being acknowledged in both nuclear and mitochondrial (mt) genome. However, the impact of G4-based targeted therapy on both nuclear and mt genome, affecting mt function and its underlying mechanisms remain largely unexplored. Methods: The mechanisms of action and therapeutic effects of a G4-binding platinum(II) complex, Pt-ttpy, on mitochondria were conducted through a comprehensive approaches with in vitro and in vivo models, including ICP-MS for platinum measurement, PCR-based genetic analysis, western blotting (WB), confocal microscope for mt morphology study, extracellular flux analyzer, JC1 and Annexin V apoptosis assay, flow cytometry and high content microscope screening with single-cell quantification of both ROS and mt specific ROS, as well as click-chemistry for IF study of mt translation. Decipher Pt-ttpy effects on nuclear-encoded mt related genes expression were undertaken via RNA-seq, Chip-seq and CUT-RUN assays. Results: Pt-ttpy, shows a highest accumulation in the mitochondria of A2780 cancer cells as compared with two other platinum(II) complexes with no/weak G4-binding properties, Pt-tpy and cisplatin. Pt-ttpy induces mtDNA deletion, copy reduction and transcription inhibition, hindering mt protein translation. Functional analysis reveals potent mt dysfunction without reactive oxygen species (ROS) induction. Mechanistic study provided first evidence that most of mt ribosome genes are highly enriched in G4 structures in their promoter regions, notably, Pt-ttpy impairs most nuclear-encoded mt ribosome genes' transcription through dampening the recruiting of transcription initiation and elongation factors of NELFB and TAF1 to their promoter with G4-enriched sequences. In vivo studies show Pt-ttpy's efficient anti-tumor effects, disrupting mt genome function with fewer side effects than cisplatin. Conclusion: This study underscores Pt-ttpy as a G4-binding platinum(II) complex, effectively targeting cancer mitochondria through dual action on mt and nuclear G4-enriched genomes without inducing ROS, offering promise for safer and effective platinum-based G4-targeted cancer therapy. [ABSTRACT FROM AUTHOR]

The post‐Caledonian thermal and geomorphological evolution of onshore Western Norway is poorly understood, including the formation and age of the high‐elevation low‐relief surfaces seen across the Norwegian landscape. We present new apatite fission track (AFT) and (U‐Th‐Sm)/He analyses from an elevation transect (ET) covering ∼1,800 m vertical distance below a high‐elevation low‐relief surface in the inner Nordfjord. The AFT ages increase with elevation from 159 ± 11 Ma to 256 ± 21 Ma and apatite (U‐Th‐Sm)/He ages increase with elevation from 80 ± 4 Ma to 277 ± 15 Ma. In order to test different possible thermal evolutions, we present the first multi‐sample thermal history models from Norway using HeFTy combining both AFT and (U‐Th‐Sm)/He ages along the ET, refining available thermal history models for the area considerably. The best modeling results are found for a thermal evolution with slow cooling throughout the Mesozoic and increased cooling rates from the Late Cretaceous until present, indicating a Cenozoic age for the low‐relief surface at the top of the transect. The models also allow for cooling to surface conditions in the Late Jurassic, but such an evolution must have been followed by rapid burial by 1.5–3 km Cretaceous sediments, and by re‐exhumation in the Cenozoic, indicating that the low‐relief surface cannot represent a simply uplifted Jurassic or Cretaceous peneplain. We compare our results with multi‐sample models from the wider North Atlantic region, supporting previous findings of Cenozoic exhumation and landscape forming processes within that region. Key Points: We provide new apatite fission track (AFT) and (U‐Th‐Sm)/He age constraints from an elevation transect (ET) in Western Norway showing Late Cretaceous to Permian agesMulti‐sample thermal history modeling of an ∼2 km high ET improves the understanding of the thermal evolution in the areaHigh‐elevation low‐relief surfaces of Western Norway are not uplifted Mesozoic peneplains [ABSTRACT FROM AUTHOR]

Limited substrate availability because of the blood–brain barrier (BBB) has made the brain develop specific molecular mechanisms to survive, using lactate synthesized by astrocytes as a source of energy in neurons. To understand if lactate improves cellular viability and susceptibility to glutamate toxicity, primary cortical cells were incubated in glucose- or lactate-containing media and toxic concentrations of glutamate for 24 h. Cell death was determined by immunostaining and lactate dehydrogenase (LDH) release. Mitochondrial membrane potential and nitric oxide (NO) levels were measured using Tetramethylrhodamine, methyl ester (TMRM) and 4-Amino-5-Methylamino-2′,7′-Difluorofluorescein Diacetate (DAF-FM) live staining, respectively. LDH activity was quantified in single cells in the presence of lactate (LDH substrate) and oxamate (LDH inhibitor). Nuclei of cells were stained with DAPI and neurons with MAP2. Based on the distance between neurons and glial cells, they were classified as linked (<10 µm) and non-linked (>10 µm) neurons. Lactate increased cell death rate and the mean value of endogenous NO levels compared to glucose incubations. Mitochondrial membrane potential was lower in the cells cultured with lactate, but this effect was reversed when glutamate was added to the lactate medium. LDH activity was higher in linked neurons compared to non-linked neurons, supporting the hypothesis of the existence of the lactate shuttle between astrocytes and at least a portion of neurons. In conclusion, glucose or lactate can equally preserve primary cortical neurons, but those neurons having a low level of LDH activity and incubated with lactate cannot cover high energetic demand solely with lactate and become more susceptible to glutamate toxicity. [ABSTRACT FROM AUTHOR]

The identification of carotid atherosclerotic lesion at risk for plaque rupture, eventually resulting in cerebral embolism and stroke, is of paramount clinical importance. High stress in the fibrous plaque cap has been proposed as risk factor. However, among others, residual strains influence said stress predictions, but quantitative and qualitative implications of residual strains in this context are not well explored. We therefore propose a multiplicative kinematics-based Growth and Remodeling (G&R) framework to predict residual strains from homogenizing tissue stress and then investigate its implication on plaque stress. Carotid vessel morphology of four patients was reconstructed from clinical Computed Tomography-Angiography (CT-A) images and equipped with heterogeneous tissue constitutive properties assigned through a histology-based artificial intelligence image segmentation tool. As compared to a purely elastic analysis and depending on patient-specific morphology and tissue distributions, the incorporation of residual strains reduced the maximum wall stress by up to 30 % and resulted in a fundamentally different distribution of stress across the atherosclerotic wall. Regardless residual strains homogenized tissue stresses, the fibrous plaque cap may persistently be exposed to spots of high stress. In conclusion, the incorporation of residual strains in biomechanical studies of atherosclerotic carotids may be important for a reliable assessment of fibrous plaque cap stress. [ABSTRACT FROM AUTHOR]

Background Dystonia is one of the most common movement disorders. To date, the genetic causes of dystonia in populations of European descent have been extensively studied. However, other populations, particularly those from the Middle East, have not been adequately studied. The purpose of this study is to discover the genetic basis of dystonia in a clinically and genetically well-characterised dystonia cohort from Turkey, which harbours poorly studied populations. Methods Exome sequencing analysis was performed in 42 Turkish dystonia families. Using co-expression network (CEN) analysis, identified candidate genes were interrogated for the networks including known dystonia-associated genes and genes further associated with the protein-protein interaction, animal model-based characteristics and clinical findings. Results We identified potentially disease-causing variants in the established dystonia genes (PRKRA, SGCE, KMT2B, SLC2A1, GCH1, THAP1, HPCA, TSPOAP1, AOPEP; n=11 families (26%)), in the uncommon forms of dystonia-associated genes (PCCB, CACNA1A, ALDH5A1, PRKN; n=4 families (10%)) and in the candidate genes prioritised based on the pathogenicity of the variants and CEN-based analyses (n=11 families (21%)). The diagnostic yield was found to be 36%. Several pathways and gene ontologies implicated in immune system, transcription, metabolic pathways, endosomal-lysosomal and neurodevelopmental mechanisms were over-represented in our CEN analysis. Conclusions Here, using a structured approach, we have characterised a clinically and genetically well-defined dystonia cohort from Turkey, where dystonia has not been widely studied, and provided an uncovered genetic basis, which will facilitate diagnostic dystonia research. [ABSTRACT FROM AUTHOR]

Background: Information on the predictive determinants of abdominal aortic aneurysm rupture from CT angiography are scarce. The aim of this study was to investigate biomechanical parameters in abdominal aortic aneurysms and their association with risk of subsequent rupture. Methods: In this retrospective study, the digital radiological archive was searched for 363 patients with ruptured abdominal aortic aneurysms. All patients who underwent at least one CT angiography examination before aneurysm rupture were included. CT angiography results were analysed to determine maximum aneurysm diameter, aneurysm volume, and biomechanical parameters (peak wall stress and peak wall rupture index). In the primary survival analysis, patients with abdominal aortic aneurysms less than 70 mm were considered. Sensitivity analyses including control patients and abdominal aortic aneurysms of all sizes were performed. Results: A total of 67 patients who underwent 109 CT angiography examinations before aneurysm rupture were identified. The majority were men (47, 70%) and the median age at the time of CTA examination was 77 (71–83) years. The median maximum aneurysm diameter was 56 (interquartile range 46–65) mm and the median time to rupture was 2.13 (interquartile range 0.64–4.72) years. In univariable analysis, maximum aneurysm diameter, aneurysm volume, peak wall stress, and peak wall rupture index were all associated with risk of rupture. Women had an increased HR for rupture when adjusted for maximum aneurysm diameter or aneurysm volume (HR 2.16, 95% c.i. 1.23 to 3.78 (P = 0.007) and HR 1.92, 95% c.i. 1.06 to 3.50 (P = 0.033) respectively). In multivariable analysis, the peak wall rupture index was associated with risk of rupture. The HR for peak wall rupture index was 1.05 (95% c.i. 1.03 to 1.08) per % (P < 0.001) when adjusted for maximum aneurysm diameter and 1.05 (95% c.i. 1.02 to 1.08) per % (P < 0.001) when adjusted for aneurysm volume. Conclusion: Biomechanical factors appear to be important in the prediction of abdominal aortic aneurysm rupture. Women are at increased risk of rupture when adjustments are made for maximum aneurysm diameter alone. [ABSTRACT FROM AUTHOR]

Phytochemical profiling followed by antimicrobial and anthelmintic activity evaluation of the Australian plant Geijera parviflora, known for its customary use in Indigenous Australian ceremonies and bush medicine, was performed. In the present study, seven previously reported compounds were isolated including auraptene, 6′-dehydromarmin, geiparvarin, marmin acetonide, flindersine, and two flindersine derivatives from the bark and leaves, together with a new compound, chlorogeiparvarin, formed as an artefact during the isolation procedure and isolated as a mixture with geiparvarin. Chemical profiling allowed for a qualitative and quantitative comparison of the compounds in the leaves, bark, flowers, and fruit of this plant. Subsequently, a subset of these compounds as well as crude extracts from the plant were evaluated for their antimicrobial and anthelmintic activities. Anthelmintic activity assays showed that two of the isolated compounds, auraptene and flindersine, as well as the dichloromethane and methanol crude extracts of G. parviflora, displayed significant activity against a parasitic nematode (Haemonchus contortus). This is the first report of the anthelmintic activity associated with these compounds and indicates the importance of such fundamental explorations for the discovery of bioactive phytochemicals for therapeutic application(s). [ABSTRACT FROM AUTHOR]