Search Results (23)

Background/Objectives: The presence of Ehlers–Danlos Syndromes (EDSs) has significant effects on overall health and results in varying levels of pain and disability. The effects of sleep are not well documented in this population. The purpose of this study is to report the sleep characteristics of people with EDS. Methods: An electronic survey regarding sleep characteristics was created and distributed through the EDS website. Results: Sleep disturbance is common in people with EDS, with 65.3% of respondents sleeping fewer than 8 h and 26.2% averaging fewer than 6 h. Those who slept fewer than 6 h reported more days of poor mental and physical health days. Sleep aids were commonly used with 41.40% of patients regularly taking prescription medication to get to sleep. Sleep latency of greater than 30 min was also found in 67.5% of subjects. Conclusions: The results demonstrate an association between people with EDS and poorer sleep duration, increased sleep latency, and increased use of sleep aids including prescription sleep medication compared to the general population. While more research needs to be completed in this area, sleep may be an important aspect to address in the management of EDS. Full article

Introduction: Gentrification, commonly defined as low-socioeconomic-status (SES) neighborhoods experiencing rapid increases in rental value, can lead to changes in the built and social neighborhood environment. Schools are an important location for pollutant exposure and child opportunities because children spend significant time in school. Given their central role in both environmental and social contexts, we examined the relationship between gentrification, pollutants, and child opportunity near schools in New York City. Methods: School locations (N_total = 1482) were classified into gentrifying (n = 624), non-gentrifying (n = 198), and higher-SES (ineligible for gentrification; n = 660) neighborhoods. Annual average pollutant levels (black carbon (BC), fine particulates (PM_2.5), nitrogen dioxide (NO₂)) were assessed near schools. Child opportunity index (COI 2.0) was used to evaluate overall opportunity and three domains: education; health/environment; social/economic. Results: On average, pollution was highest in gentrifying neighborhoods compared to non-gentrifying (5–8.6% difference) and higher-SES (4.8–14.8% difference) neighborhoods. Average air pollution levels remained consistently higher in gentrifying neighborhoods both before and after gentrification compared to non-gentrifying and higher-SES neighborhoods. Regarding childhood opportunity, education, and social/economic opportunities were better and health/environment opportunities were worse in gentrifying compared to non-gentrifying neighborhoods. Conclusions: Gentrifying neighborhoods are at risk for higher exposure to pollutants and lower health/environment childhood opportunities compared to other neighborhoods. Full article

So far, the cellular origin of glioblastoma (GBM) needs to be determined, with prevalent theories suggesting emergence from transformed endogenous stem cells. Adult neurogenesis primarily occurs in two brain regions: the subventricular zone (SVZ) and the subgranular zone (SGZ) of the hippocampal dentate gyrus. Whether the proximity of GBM to these neurogenic niches affects patient outcome remains uncertain. Previous studies often rely on subjective assessments, limiting the reliability of those results. In this study, we assessed the impact of GBM’s relationship with the cortex, SVZ and SGZ on clinical variables using fully automated segmentation methods. In 177 glioblastoma patients, we calculated optimal cutpoints of minimal distances to the SVZ and SGZ to distinguish poor from favorable survival. The impact of tumor contact with neurogenic zones on clinical parameters, such as overall survival, multifocality, MGMT promotor methylation, Ki-67 and KPS score was also examined by multivariable regression analysis, chi-square test and Mann–Whitney-U. The analysis confirmed shorter survival in tumors contacting the SVZ with an optimal cutpoint of 14 mm distance to the SVZ, separating poor from more favorable survival. In contrast, tumor contact with the SGZ did not negatively affect survival. We did not find significant correlations with multifocality or MGMT promotor methylation in tumors contacting the SVZ, as previous studies discussed. These findings suggest that the spatial relationship between GBM and neurogenic niches needs to be assessed differently. Objective measurements disprove prior assumptions, warranting further research on this topic. Full article

During the last decade, we have witnessed several milestones in the treatment of various resistant cancers including immunotherapeutic strategies that have proven to be superior to conventional treatment options, such as chemotherapy and radiation. This approach utilizes the host’s immune response, which is triggered by cancer cells expressing tumor-associated antigens or neoantigens. The responsive immune cytotoxic CD8⁺ T cells specifically target and kill tumor cells, leading to tumor regression and prolongation of survival in some cancers; however, some cancers may exhibit resistance due to the inactivation of anti-tumor CD8⁺ T cells. One mechanism by which the anti-tumor CD8⁺ T cells become dysfunctional is through the activation of the inhibitory receptor programmed death-1 (PD-1) by the corresponding tumor cells (or other cells in the tumor microenvironment (TME)) that express the programmed death ligand-1 (PD-L1). Hence, blocking the PD-1/PD-L1 interaction via specific monoclonal antibodies (mAbs) restores the CD8⁺ T cells’ functions, leading to tumor regression. Accordingly, the Food and Drug Administration (FDA) has approved several checkpoint antibodies which act as immune checkpoint inhibitors. Their clinical use in various resistant cancers, such as metastatic melanoma and non-small-cell lung cancer (NSCLC), has shown significant clinical responses. We have investigated an alternative approach to prevent the expression of PD-L1 on tumor cells, through targeting the oncogenic transcription factor Yin Yang 1 (YY1), a known factor overexpressed in many cancers. We report the regulation of PD-L1 by YY1 at the transcriptional, post-transcriptional, and post-translational levels, resulting in the restoration of CD8⁺ T cells’ anti-tumor functions. We have performed bioinformatic analyses to further explore the relationship between both YY1 and PD-L1 in cancer and to corroborate these findings. In addition to its regulation of PD-L1, YY1 has several other anti-cancer activities, such as the regulation of proliferation and cell viability, invasion, epithelial–mesenchymal transition (EMT), metastasis, and chemo-immuno-resistance. Thus, targeting YY1 will have a multitude of anti-tumor activities resulting in a significant obliteration of cancer oncogenic activities. Various strategies are proposed to selectively target YY1 in human cancers and present a promising novel therapeutic approach for treating unresponsive cancer phenotypes. These findings underscore the distinct regulatory roles of YY1 and PD-L1 (CD274) in cancer progression and therapeutic response. Full article

Background: The aim of this study was to develop and validate radiogenomic models to predict the MDM2 gene amplification status and differentiate between ALTs and lipomas on preoperative MR images. Methods: MR images were obtained in 257 patients diagnosed with ALTs (n = 65) or lipomas (n = 192) using histology and the MDM2 gene analysis as a reference standard. The protocols included T2-, T1-, and fat-suppressed contrast-enhanced T1-weighted sequences. Additionally, 50 patients were obtained from a different hospital for external testing. Radiomic features were selected using mRMR. Using repeated nested cross-validation, the machine-learning models were trained on radiomic features and demographic information. For comparison, the external test set was evaluated by three radiology residents and one attending radiologist. Results: A LASSO classifier trained on radiomic features from all sequences performed best, with an AUC of 0.88, 70% sensitivity, 81% specificity, and 76% accuracy. In comparison, the radiology residents achieved 60–70% accuracy, 55–80% sensitivity, and 63–77% specificity, while the attending radiologist achieved 90% accuracy, 96% sensitivity, and 87% specificity. Conclusion: A radiogenomic model combining features from multiple MR sequences showed the best performance in predicting the MDM2 gene amplification status. The model showed a higher accuracy compared to the radiology residents, though lower compared to the attending radiologist. Full article

Olive cake, the solid byproduct of three-phase centrifugation olive oil production, has a high organic and polyphenol content, rendering it an environmental threat when landfilled as well as limiting its animal feed potential. This residue can be a good candidate for biomethane production due to its rich polysaccharide content (pectin, hemicellulose, and cellulose). Two strategies were compared to maximize biomethane production: destoning (i.e., removal of the seed fragments via mechanical means) and enzymatic pretreatment of the pulp. After 30 days of batch anaerobic digestion at 35 °C, both enzymatically pretreated and destoned olive cakes produced similar amounts of methane (~295 mL CH₄/g volatile solids (VS)), 42% more than the control. A comparison of olive cake’s biomethane yields with a broad range of agricultural residues in the literature demonstrated its suitability for biomethane production. Additionally, the digestate recovered from the anaerobic digestion of olive cake had high Kjeldahl nitrogen contents (3.6%, db) and low polyphenol concentrations (0.02 mg gallic acid equivalent (GAE)/g), qualifying it as an ingredient for soil amendment. This study demonstrated olive cake can be diverted from landfills for second-generation biofuel production, and that the resulting digestate may have value for soil amendment. Full article

Chronic infection with the hepatitis B virus (HBV) affects an estimated 257 million people worldwide and can lead to liver diseases such as cirrhosis and liver cancer. Viral replication is generally considered not to be cytopathic, and although some HBV proteins may have direct carcinogenic effects, the majority of HBV infection-related disease is related to chronic inflammation resulting from disrupted antiviral responses and aberrant innate immune reactions. Like all cells, healthy and HBV-infected cells communicate with each other, as well as with other cell types, such as innate and adaptive immune cells. They do so by both interacting directly and by secreting factors into their environment. Such factors may be small molecules, such as metabolites, single viral proteins or host proteins, but can also be more complex, such as virions, protein complexes, and extracellular vesicles. The latter are small, membrane-enclosed vesicles that are exchanged between cells, and have recently gained a lot of attention for their potential to mediate complex communication and their potential for therapeutic repurposing. Here, we review how HBV infection affects the communication between HBV-infected cells and cells in their environment. We discuss the impact of these interactions on viral persistence in chronic infection, as well as their relation to HBV infection-related pathology. Full article

Historically, disease burden and treatment responses in patients with Gaucher disease (GD) was assessed by monitoring clinical data, laboratory, imaging, chitotriosidase (CHITO), and other biomarkers; however, these biomarkers lack specificity and CHITO is uninformative in patients heterozygous or homozygous for the CHIT1 c.1049_1072dup24 variant. Recently, glucosylsphingosine (lyso-Gb₁), a sensitive and specific GD biomarker, has been recommended for patient monitoring. Furthermore, studies measuring lyso-Gb₁ and CHITO in patients on long-term treatment with enzyme replacement therapy (ERT) and/or substrate reduction therapy (SRT) reported as group data show a reduction in both analytes, yet individualized patient data are generally unavailable. We describe seven patients on long-term treatment with longitudinal clinical data with monitoring based on current treatment guidelines. We present four patients who exhibit stable disease with normalized CHITO despite elevated lyso-Gb₁. We present one patient who transitioned from ERT to SRT due to lack of a clinical response with life-threatening thrombocytopenia who responded with marked improvement in platelets, and normalized levels of both CHITO and lyso-Gb₁. Finally, we present two ERT to SRT switch patients with stable disease on ERT who exhibited non-compliance on SRT, one with mirrored marked elevations of CHITO and lyso-Gb₁; and another with normal CHITO and platelets, but increasing lyso-Gb₁ levels and enlarged spleen. These clinical vignettes highlight the role of lyso-Gb₁ as a sensitive biomarker in management of patients with GD, and its further value when CHITO is normal and thus uninformative. We highlight the personalized medicine approach needed to optimize treatment outcomes and recommendations for these patients. Full article

Recognition of RNA by receptors of the innate immune system is regulated by various posttranslational modifications. Different single 2′-O-ribose (2′-O-) methylations have been shown to convert TLR7/TLR8 ligands into specific TLR8 ligands, so we investigated whether the position of 2′-O-methylation is crucial for its function. To this end, we designed different 2′-O-methylated RNA oligoribonucleotides (ORN), investigating their immune activity in various cell systems and analyzing degradation under RNase T2 treatment. We found that the 18S rRNA-derived TLR7/8 ligand, RNA63, was differentially digested as a result of 2′-O-methylation, leading to variations in TLR8 and TLR7 inhibition. The suitability of certain 2′-O-methylated RNA63 derivatives as TLR8 agonists was further demonstrated by the fact that other RNA sequences were only weak TLR8 agonists. We were thus able to identify specific 2′-O-methylated RNA derivatives as optimal TLR8 ligands. Full article

This paper proposes a new spatial lag regression model which addresses global spatial autocorrelation arising from cross-sectional dependence between counts. Our approach offers an intuitive interpretation of the spatial correlation parameter as a measurement of the impact of neighbouring observations on the conditional expectation of the counts. It allows for flexible likelihood-based inference based on different distributional assumptions using standard numerical procedures. In addition, we advocate the use of data-coherent diagnostic tools in spatial count regression models. The application revisits a data set on the location choice of single unit start-up firms in the manufacturing industry in the US. Full article

Pyruvate (CH₃COCOOH) is the simplest of the alpha-keto acids and is at the interface of several metabolic pathways both in prokaryotes and eukaryotes. In an amino acid-rich environment, fast-growing bacteria excrete pyruvate instead of completely metabolizing it. The role of pyruvate uptake in pathological conditions is still unclear. In this study, we identified two pyruvate-specific transporters, BtsT and CstA, in Salmonella enterica serovar Typhimurium (S. Typhimurium). Expression of btsT is induced by the histidine kinase/response regulator system BtsS/BtsR upon sensing extracellular pyruvate, whereas expression of cstA is maximal in the stationary phase. Both pyruvate transporters were found to be important for the uptake of this compound, but also for chemotaxis to pyruvate, survival under oxidative and nitrosative stress, and persistence of S. Typhimurium in response to gentamicin. Compared with the wild-type cells, the ΔbtsTΔcstA mutant has disadvantages in antibiotic persistence in macrophages, as well as in colonization and systemic infection in gnotobiotic mice. These data demonstrate the surprising complexity of the two pyruvate uptake systems in S. Typhimurium. Full article

Immune checkpoint inhibitors have shown great promise, emerging as a new pillar of treatment for cancer; however, only a relatively small proportion of recipients show a durable response to treatment. Strategies that reliably differentiate durably-responding tumours from non-responsive tumours are a critical unmet need. Persistent and durable immunological responses are associated with the generation of memory T cells. Effector memory T cells associated with tumour response to immune therapies are characterized by substantial upregulation of the potassium channel Kv1.3 after repeated antigen stimulation. We have developed a new Kv1.3 targeting radiopharmaceutical, [¹⁸F]AlF-NOTA-KCNA3P, and evaluated whether it can reliably differentiate tumours successfully responding to immune checkpoint inhibitor (ICI) therapy targeting PD-1 alone or combined with CLTA4. In a syngeneic colon cancer model, we compared tumour retention of [¹⁸F]AlF-NOTA-KCNA3P with changes in the tumour immune microenvironment determined by flow cytometry. Imaging with [¹⁸F]AlF-NOTA-KCNA3P reliably differentiated tumours responding to ICI therapy from non-responding tumours and was associated with substantial tumour infiltration of T cells, especially Kv1.3-expressing CD8⁺ effector memory T cells. Full article

Approximately 70 million humans worldwide are affected by chronic hepatitis D, which rapidly leads to liver cirrhosis and hepatocellular carcinoma due to chronic inflammation. The triggers and consequences of this chronic inflammation, induced by co-infection with the hepatitis D virus (HDV) and the hepatitis B virus (HBV), are poorly understood. Using CRISPR technology, we characterized the recognition of HDV mono- and co-infection by intracellular innate immunity and determined its influence on the viral life cycle and effector T-cell responses using different HBV and HDV permissive hepatoma cell lines. We showed that HDV infection is detected by MDA5 and -after a lag phase -induces a profound type I interferon response in the infected cells. The type I interferon response, however, was not able to suppress HDV replication or spread, thus providing a persistent trigger. Using engineered T-cells directed against the envelope proteins commonly used by HBV and HDV, we found that HDV immune recognition enhanced T-cell cytotoxicity. Interestingly, the T-cell effector function was enhanced independently of antigen presentation. These findings help to explain immune mediated tissue damage in chronic hepatitis D patients and indicate that combining innate triggers with T-cell activating therapies might allow for a curative approach. Full article

Over recent years, the food industry has striven to reduce waste, mostly because of rising awareness of the detrimental environmental impacts of food waste. While the edible oils market (mostly represented by soybean oil) is forecasted to reach 632 million tons by 2022, there is increasing interest to produce non-soybean, plant-based oils including, but not limited to, coconut, flaxseed and hemp seed. Expeller pressing and organic solvent extractions are common methods for oil extraction in the food industry. However, these two methods come with some concerns, such as lower yields for expeller pressing and environmental concerns for organic solvents. Meanwhile, supercritical CO₂ and enzyme-assisted extractions are recognized as green alternatives, but their practicality and economic feasibility are questioned. Finding the right balance between oil extraction and phytochemical yields and environmental and economic impacts is challenging. This review explores the advantages and disadvantages of various extraction methods from an economic, environmental and practical standpoint. The novelty of this work is how it emphasizes the valorization of seed by-products, as well as the discussion on life cycle, environmental and techno-economic analyses of oil extraction methods. Full article

Reassortment is a viral genome-segment recomposition known for many viruses, including the orthobunyaviruses. The co-infection of a host cell with two viruses of the same serogroup, such as the Bunyamwera orthobunyavirus and the Batai orthobunyavirus, can give rise to novel viruses. One example is the Ngari virus, which has caused major outbreaks of human infections in Central Africa. This study aimed to investigate the potential for reassortment of Bunyamwera orthobunyavirus and the Batai orthobunyavirus during co-infection studies and the replication properties of the reassortants in different mammalian and insect cell lines. In the co-infection studies, a Ngari-like virus reassortant and a novel reassortant virus, the Batunya virus, arose in BHK-21 cells (Mesocricetus auratus). In contrast, no reassortment was observed in the examined insect cells from Aedes aegypti (Aag2) and Aedes albopictus (U4.4 and C6/36). The growth kinetic experiments show that both reassortants are replicated to higher titers in some mammalian cell lines than the parental viruses but show impaired growth in insect cell lines. Full article