Disease Conditions Research Articles

Circulating Levels of Soluble α-Klotho and FGF23 in Childhood Cancer Survivors: Lack of Association with Nephro- and Cardiotoxicity-A Preliminary Study.

Background/Objectives: The survival rate among pediatric cancer patients has reached 80%; however, these childhood cancer survivors (CCSs) are at a heightened risk of developing chronic conditions in adulthood, particularly kidney and cardiovascular diseases. The aims of this study were to assess the serum α-Klotho and FGF23 levels in CCSs and to determine their association with nephro- and cardiotoxicity. Methods: This study evaluated a cohort of 66 CCSs who remained in continuous remission, with a mean follow-up of 8.41 ± 3.76 years. Results: The results of this study revealed that CCSs exhibited significantly higher levels of soluble α-Klotho compared to healthy peers (1331.4 ± 735.5 pg/mL vs. 566.43 ± 157.7 pg/mL, p < 0.0001), while no significant difference was observed in their FGF23 levels. Within the participant cohort, eight individuals (12%) demonstrated a reduced estimated glomerular filtration rate (eGFR) below 90 mL/min/1.73 m2. The relationship between treatment with abdominal radiotherapy and reduced eGFR was confirmed (p < 0.05). No correlations were found between potential treatment-related risk factors, such as chemotherapy or radiation therapy, serum levels of α-Klotho and FGF23, and nephro- and cardiotoxicity. Conclusions: In conclusion, this preliminary cross-sectional study revealed elevated levels of α-Klotho among childhood cancer survivors but did not establish a direct association with anticancer treatment. The significance of elevated α-Klotho protein levels among CCSs warrants further investigation.

O15 Transcriptomic profiling reveals regulators of dermal fibroblast state switching

Abstract Introduction and aims Fibroblasts, the major cell population in connective tissue, are the guardians of the extracellular matrix homeostasis. In adult tissue they exist in a quiescent state that can persist for years, but upon tissue injury, they become rapidly activated and re-enter the cell cycle, followed by deposition and reorganization of the dermal matrix. The fundamental mechanism by which fibroblasts can maintain quiescence and be primed for prompt activation is currently unknown. Deregulations of this process in the skin and other organs is associated with several pathologies including fibrosis or chronic wounds. Notably, rapid fibroblast state switching is also observed during skin development, where a tightly controlled change from a highly proliferative state to a quiescent state promotes extracellular matrix deposition and maturation of the dermal architecture. Understanding the shared mechanisms and differences between development and wound healing will help in the development of tissue regenerative therapies. Methods Using dermal development as a model for fibroblast state switching, we integrated several single-cell RNA-Seq and assay for transposase-accessible chromatin-Seq datasets of whole skin during embryonic and postnatal growth. Our novel integrated multiomics single-cell dataset can recapitulate skin developmental changes observed in vivo and reveal the major regulatory networks. Results We identified the activating protein (AP)-1 member cJun as the key regulator of fibroblast state switching in skin development and wound repair. Mechanistically, in quiescent adult fibroblasts cJun is highly transcribed, but the protein is constantly ubiquitinated and degraded, priming fibroblasts for rapid activation when needed. Upon injury cJun ubiquitination is reduced, allowing an accumulation of cJun leading to a change in AP-1 dimer composition at the chromatin level, inhibiting fibroblast quiescence and promoting proliferation and activation. Conclusions In normal wounds cJun accumulation is inhibited during the advanced (remodelling) wounding phase; however, chronic wounds and fibrotic disease conditions show a continuous and pathological cJun stabilization, which can be targeted through pharmacological intervention.

Humans vs. Fungi: An Overview of Fungal Pathogens against Humans.

Human fungal diseases are infections caused by any fungus that invades human tissues, causing superficial, subcutaneous, or systemic diseases. Fungal infections that enter various human tissues and organs pose a significant threat to millions of individuals with weakened immune systems globally. Over recent decades, the reported cases of invasive fungal infections have increased substantially and research progress in this field has also been rapidly boosted. This review provides a comprehensive list of human fungal pathogens extracted from over 850 recent case reports, and a summary of the relevant disease conditions and their origins. Details of 281 human fungal pathogens belonging to 12 classes and 104 genera in the divisions ascomycota, basidiomycota, entomophthoromycota, and mucoromycota are listed. Among these, Aspergillus stands out as the genus with the greatest potential of infecting humans, comprising 16 species known to infect humans. Additionally, three other genera, Curvularia, Exophiala, and Trichophyton, are recognized as significant genera, each comprising 10 or more known human pathogenic species. A phylogenetic analysis based on partial sequences of the 28S nrRNA gene (LSU) of human fungal pathogens was performed to show their phylogenetic relationships and clarify their taxonomies. In addition, this review summarizes the recent advancements in fungal disease diagnosis and therapeutics.

Correlation of Simple Laboratory Result Parameters to CTP and MELD Scores, and the Diagnostic Role of Simple Laboratory Indexes to Cirrhosis Decompansation

BackgroundCirrhosis of the liver is a final condition of all chronic liver diseases. Liver cirrhosis is the leading cause of increasing morbidity and mortality in adults worldwide. Systemic inflammation has been suggested to play an important role in causing progressive liver damage and is one of the leading causes of compensated and decompensated liver cirrhosis.Aim of StudyEvaluate the correlation of neutrophil-lymphocyte ratio (NLR), albumin-bilirubin ratio (ABR), albumin-bilirubin score (ALBI), aspartate aminotransferase to platelet ratio (APRI), albumin-creatinine ratio (ACR), lymphocyte-monocyte ratio (LMR), de ritis ratio to the severity of liver cirrhosis as assessed by CTP score and MELD score. In addition, this study also evaluated the diagnostic ability of NLR, ABR, ALBI, APRI, ACR, LMR, de ritis ratio, and CTP and MELD scores in predicting decompensated liver cirrhosis.MethodWe conducted a cross-sectional study involving patients diagnosed with liver cirrhosis at Prof DR IGNG Ngoerah General Hospital. All patients were diagnosed based on clinical history, physical examination, and investigations. This study enrolled 96 cirrhotic patients regardless of etiology. Laboratory examination results recorded platelets, neutrophils, lymphocytes, monocytes, AST, ALT, albumin, and creatinine. Then NLR, ACR, APRI, LMR, de raitis, ALBI, and ABR are calculated. CTP and MELD scores were calculated by taking data from the patient's medical recordResultOf the 96 patients tested in our study, the majority were male (66). The study found a significant moderate to very strong relationship to the MELD score between ACR, APRI, ALBI, ABR, LMR, WBC, sodium, and albumin. Neutrophil to lymphocyte ratio, ACR, De ritis, APRI, LMR, ALBI, ABR, sodium levels, and albumin have a moderate to very strong significant relationship to CTP score. ACR, De ritis, APRI, LMR, ALBI, ABR, WBC, sodium, and albumin levels with respective cut-offs £ 3.6; ≥ 1.5; ≥ 0.3; £ 2.8; ≥ 0.7; £1.6; ≥ 6.7, £ 136.50, and £ 3.0 can be used to help predict decompensated cirrhosisConclusionIn addition to using the CTP score and MELD score as a tool to predict the severity of liver cirrhosis, data from laboratory examination results in the form of albumin and ABR levels can help establish the diagnosis of decompensated cirrhosis. The sensitivity and specificity of ABR were 96.8% and 75.4% with a cut-off of £ 1.6, while albumin levels were 93.5% and 81.5% with an amount off of £ 3.0.

Nuclear Receptor Rev-erbα Role in Fine-Tuning Erythropoietin Gene Expression

The regulation of RBC homeostasis by erythropoietin (EPO) is critical for O2 transport and maintaining the adequate number of RBCs in vertebrates. Therefore, dysregulation in EPO synthesis results in disease conditions like polycythemia in the case of excessive EPO production and anemia, which occurs when EPO is inadequately produced. EPO plays a crucial role in treating anemic patients; however, its overproduction can increase blood viscosity, potentially leading to fatal heart failure. Consequently, the identification of druggable transcription factors (TFs) and their associated ligands capable of regulating EPO offers a promising therapeutic approach to address EPO-related disorders. This study unveils a novel regulatory mechanism involving two pivotal nuclear receptors (NRs), Rev-erbα and RORα, in the control of EPO gene expression. Rev-erbα acts as a cell-intrinsic negative regulator, playing a vital role in maintaining erythropoiesis at the correct level. It accomplishes this by directly binding to newly identified response elements within the human and mouse EPO gene promoter, thereby repressing EPO production. These findings are further supported by the discovery that a Rev-erbα agonist (SR9011) effectively suppresses hypoxia-induced EPO expression in mice. In contrast, RORα functions as a positive regulator of EPO gene expression, also binding to the same response elements in the promoter to induce EPO production. Finally, the results of this study revealed that the two NRs, Rev-erbα, and RORα, influence EPO synthesis in a negative and positive manner, suggesting that the modulating activity of these two NRs could provide a method to target disorders linked with EPO dysregulation.

Using the Nephrology Referral Form in Italian primary care to improve the care pathway of patients with anemia or other complications related to chronic kidney disease: survey findings

Introduction: Anemia is a potentially reversible condition in early chronic kidney disease (CKD) that requires timely intervention. General practitioners (GPs) play a crucial role in recognizing CKD. A new Nephrology Referral Form (NRF) was developed and tested in the Italian setting. Methods: This mixed-methods survey, conducted between 2021 and 2022, introduced the NRF through focus group discussions involving a scientific committee. The NRF was tested in a 6-month trial involving 24 GPs each from Lazio and Puglia regions. GPs provided feedback on the use of the NRF in clinical practice through a questionnaire sent via Microsoft Form. The data were analyzed descriptively. Results: After 6 months, 41.67% of the GPs were using the NRF at least once a week. Diabetes mellitus and hypertension were common triggers for NRF assessments. GPs overwhelmingly agreed (96%) on the NRF’s utility in identifying CKD cases, with 92% citing its effectiveness in diagnosing well-defined cases. The NRF facilitated specialist referrals, with 83% of GPs reporting increased referrals compared to the prior 6 months. Feedback underscored the NRF’s positive impact, suggesting improvements such as additional referral centers, regional/national networks, enhanced GP training, and increased collaboration. Conclusion: GPs regularly used the NRF to identify and diagnose cases of CKD, streamlining the referral process and increasing referrals to specialists. Feedback emphasized the NRF’s positive impact and highlighted its potential as a valuable tool for enhancing early CKD detection, interventions, and fostering multidisciplinary management in primary care for better patient outcomes.

HiPSC-derived macrophages improve drug sensitivity and selectivity in a macrophage-incorporating organoid culture model.

Accurate simulation of different cell type interactions is crucial for physiological and precise in vitro drug testing. Human tissue-resident macrophages are critical for modulating disease conditions and drug-induced injuries in various tissues; however, their limited availability has hindered their use in in vitro modeling. Therefore, this study aimed to create macrophage-containing organoid co-culture models by directly incorporating hiPSC-derived pre-macrophages into organoid and scaffold cell models. The fully differentiated cells in these organoids exhibited functional characteristics of tissue-resident macrophages with enriched pan-macrophage markers and the potential for M1/M2 subtype specialization upon cytokine stimulation. In a hepatic organoid model, the integrated macrophages replicated typical intrinsic properties, including cytokine release, polarization, and phagocytosis, and the co-culture model was more responsive to drug-induced liver injury than a macrophage-free model. Furthermore, alveolar organoid models containing these hiPSC-derived macrophages also showed increased drug and chemical sensitivity to pulmonary toxicants. Moreover, 3D adipocyte scaffold models incorporating macrophages effectively simulated in vivo insulin resistance observed in adipose tissue and showed improved insulin sensitivity on exposure to anti-diabetic drugs. Overall, the findings demonstrated that incorporating hiPSC-derived macrophages into organoid culture models resulted in more physiological and sensitive in vitro drug evaluation and screening systems.&#xD.

Dark continuous noise from mutant G90D-rhodopsin predominantly underlies congenital stationary night blindness

Congenital stationary night blindness (CSNB) is an inherited retinal disease that causes a profound loss of rod sensitivity without severe retinal degeneration. One well-studied rhodopsin point mutant, G90D-Rho, is thought to cause CSNB because of its constitutive activity in darkness causing rod desensitization. However, the nature of this constitutive activity and its precise molecular source have not been resolved for almost 30 y. In this study, we made a knock-in (KI) mouse line with a very low expression of G90D-Rho (equal in amount to ~0.1% of normal rhodopsin, WT-Rho, in WT rods), with the remaining WT-Rho replaced by REY-Rho, a mutant with a very low efficiency of activating transducin due to a charge reversal of the highly conserved ERY motif to REY. We observed two kinds of constitutive noise: one being spontaneous isomerization (R*) of G90D-Rho at a molecular rate (R* s-1) 175-fold higher than WT-Rho and the other being G90D-Rho-generated dark continuous noise comprising low-amplitude unitary events occurring at a very high molecular rate equivalent in effect to ~40,000-fold of R* s-1 from WT-Rho. Neither noise type originated from G90D-Opsin because exogenous 11-cis-retinal had no effect. Extrapolating the above observations at low (0.1%) expression of G90D-Rho to normal disease exhibited by a KI mouse model with RhoG90D/WTand RhoG90D/G90D genotypes predicts the disease condition very well quantitatively. Overall, the continuous noise from G90D-Rho therefore predominates, constituting the major equivalent background light causing rod desensitization in CSNB.

Biomechanical Integrity Score of the Female Pelvic Floor for Stress Urinary Incontinence.

This study is aimed at developing and validating a new integral parameter, the Biomechanical Integrity score (BI-score) of the female pelvic floor for stress urinary incontinence conditions. A total of 130 subjects were included in the observational cohort study; 70 subjects had normal pelvic floor conditions, and 60 subjects had stress urinary incontinence (SUI). A Vaginal Tactile Imager (VTI) was used to acquire and automatically calculate 52 biomechanical parameters for eight VTI test procedures (probe insertion, elevation, rotation, Valsalva maneuver, voluntary muscle contractions in two planes, relaxation, and reflex contraction). Statistical methods were applied (t test, correlation) to identify the VTI parameters sensitive to the pelvic SUI conditions. Twenty-seven parameters were identified as statistically sensitive to SUI development. They were subdivided into five groups to characterize tissue elasticity (group 1), pelvic support (group 2), pelvic muscle contraction (group 3), involuntary muscle relaxation (group 4), and pelvic muscle mobility (group 5). Every parameter was transformed to its standard deviation units using the dataset for normal pelvic conditions, similar to the T-score for bone density. Linear combinations with specified weights led to the composition of five component parameters for groups 1-5 and to the BI-score in standard deviation units. The p value for the BI-score has p = 4.0 × 10-28 for SUI versus normal conditions. Quantitative transformations of the pelvic tissues, support structures, and functions under diseased conditions may be studied with the SUI BI-score in future research and clinical applications.

Single cells and TRUST4 reveal immunological features of the HFRS transcriptome.

The etiology of hemorrhagic fever with renal syndrome (HFRS) is significantly impacted by a variety of immune cells. Nevertheless, the existing techniques for sequencing peripheral blood T cell receptor (TCR) or B cell receptor (BCR) libraries in HFRS are constrained by both limitations and high costs. In this investigation, we utilized the computational tool TRUST4 to generate TCR and BCR libraries utilizing comprehensive RNA-seq data from peripheral blood specimens of HFRS patients. This facilitated the examination of clonality and diversity within immune libraries linked to the condition. Despite previous research on immune cell function, the underlying mechanisms remain intricate, and differential gene expression across immune cell types and cell-to-cell interactions within immune cell clusters have not been thoroughly explored. To address this gap, we performed clustering analysis on 11 cell subsets derived from raw single-cell RNA-seq data, elucidating characteristic changes in cell subset proportions under disease conditions. Additionally, we utilized CellChat, a tool for cell-cell communication analysis, to investigate the impact of MIF family, CD70 family, and GALECTIN family cytokines-known to be involved in cell communication-on immune cell subsets. Furthermore, hdWGCNA analysis identified core genes implicated in HFRS pathogenesis within T cells and B cells. Trajectory analysis revealed that most cell subsets were in a developmental stage, with high expression of transcription factors such as NFKB and JUN in Effector CD8+ T cells, as well as in Naive CD4+ T cells and Naive B cells. Our findings provide a comprehensive understanding of the dynamic changes in immune cells during HFRS pathogenesis, identifying specific V genes and J genes in TCR and BCR that contribute to advancing our knowledge of HFRS. These insights offer potential implications for the diagnosis and treatment of this autoimmune disease.

Evaluation of the protective effect of capric acid on behavioral and biochemical alterations in valproic acid-induced model of autism

Aim and objectiveThe purpose of the study is to determine the neuroprotective effect of capric acid on sodium valproate-induced model of autism. MethodsIn this study, the effect of CA was observed in animals with single dose of valproic acid (600 mg/kg, i. p.) where the disease condition was confirmed by developmental impairment in pups. Behavioral tests that assess anxiety, depression, stereotypical and repetitive behavior, social interaction, learning and memory, and other confounding variables were performed. Subsequently, oxidative stress parameters, pro-inflammatory cytokine levels and mitochondrial complex activities in the selected brain regions were analyzed. ResultsValproic acid successfully produced autism-like symptoms from post-natal day 7 and also demonstrated impairment in social behavior, learning and memory, and anxiety and depression. Valproic acid was found to produce oxidative stress and neuro-inflammation in the hippocampus, prefrontal cortex, and cerebellum. Treatment with capric acid produced a positive effect on the alterations with maximum effects evident at 400 mg/kg, p. o. through amelioration of behavioral as well as biochemical changes. ConclusionThe current study concluded that capric acid could act as a likely candidate for the treatment and management of autism via significant modulation of neurobehavioral parameters, oxidative stress, mitochondrial dysfunction and inflammatory markers.

Pediatric Primary Raynaud's Phenomenon: A Comprehensive Cardiovascular Analysis.

Our aim in this study is to evaluate the cardiovascular findings of pediatric patients with primary Raynaud's phenomenon (RP) and to determine if there are any pathological findings. Our study included 42 pediatric patients aged between 7 and 18 who were diagnosed with primary RP and did not have any additional underlying structural vascular disease or secondary rheumatological conditions. The control group consisted of 30 healthy volunteers aged 7-18years, matched by age and sex, without any additional diseases. We evaluated demographic, clinical, and laboratory findings, echocardiographic and capillaroscopic features, as well as carotid intima-media thickness. Compared to the control group, pediatric patients with primary RP showed increased A wave velocity and E/E' ratio parameters in the left ventricle, indicating diastolic dysfunction of the heart. The isovolumetric relaxation time (IVRT) was prolonged in both the left and right ventricles, and the E/A ratio decreased in the left ventricle. The myocardial performance index (MPI), indicating both systolic and diastolic dysfunction, increased in both ventricles. Additionally, the aortic stiffness index, aortic elastic modulus (Ep), and left carotid intima-media thickness (CIMT) significantly increased, while distensibility decreased in pediatric patients with primary RP compared to the control group. The cardiovascular evaluation of pediatric patients with primary RP revealed that diastolic dysfunction is likely present in both the left and right heart. Additionally, based on the aorta and carotid intima measurements, it is suggested that pediatric patients with primary RP are at risk for developing atherosclerosis.

Exploring the role of digital tools in rare disease management: An interview-based study.

While digital tools, such as the Internet, smartphones, and social media, are an important part of modern society, little is known about the specific role they play in the healthcare management of individuals and caregivers affected by rare disease. Collectively, rare diseases directly affect up to 10% of the global population, suggesting that a significant number of individuals might benefit from the use of digital tools. The purpose of this qualitative interview-based study was to explore: (a) the ways in which digital tools help the rare disease community; (b) the healthcare gaps not addressed by current digital tools; and (c) recommended digital tool features. Individuals and caregivers affected by rare disease who were comfortable using a smartphone and at least 18 years old were eligible to participate. We recruited from rare disease organizations using purposive sampling in order to achieve a diverse and information rich sample. Interviews took place over Zoom and reflexive thematic analysis was utilized to conceptualize themes. Eight semistructured interviews took place with four individuals and four caregivers. Three themes were conceptualized which elucidated key aspects of how digital tools were utilized in disease management: (1) digital tools should lessen the burden of managing a rare disease condition; (2) digital tools should foster community building and promote trust; and (3) digital tools should provide trusted and personalized information to understand the condition and what the future may hold. These results suggest that digital tools play a central role in the lives of individuals with rare disease and their caregivers. Digital tools that centralize trustworthy information, and that bring the relevant community together to interact and promote trust are needed. Genetic counselors can consider these ideal attributes of digital tools when providing resources to individuals and caretakers of rare disease.

Antioxidant, Enzyme Inhibitory, and Protective Effect of Amelanchier lamarckii Extract.

The present study aimed to investigate the chemical content of Romanian juneberries (Amelanchier lamarckii), their effect on antioxidant and enzyme inhibition activities, and their bioaccessibility after simulated in-vitro digestion. In Amelanchier lamarckii extract (AME), 16 polyphenolic compounds were identified by LC-ESI+-MS analysis. The most representative compounds found in the extract were cyanidin-galactoside, 3,4-dihydroxy-5-methoxybenzoic acid, feruloylquinic acid, and kaempferol, all belonging to the anthocyanins, phenolic acids, and flavonols subclasses. The polyphenols of AME exert quenching abilities of harmful reactive oxygen species, as the CUPRAC antioxidant assay value was 323.99 µmol Trolox/g fruit (FW), whereas the FRAP antioxidant value was 4.10 μmol Fe2+/g fruit (FW). Enzyme inhibition assays targeting tyrosinase (IC50 = 8.843 mg/mL), α-glucosidase (IC50 = 14.03 mg/mL), and acetylcholinesterase (IC50 = 49.55 mg/mL) were used for a screening of AME's inhibitory potential against these key enzymes as a common approach for the discovery of potential antidiabetic, skin pigmentation, and neurodegenerative effects. The screening for the potential antidiabetic effects due to the α-glucosidase inhibition was performed in glucose-induced disease conditions in a human retinal pigmented epithelial cell experimental model, proving that AME could have protective potential. In conclusion, AME is a valuable source of phenolic compounds with promising antioxidant potential and metabolic disease-protective effects, warranting further investigation for its use in the nutraceutical and health industries.

Progress in the diagnose and treatment of pulmonary arterial thrombosis in situ

In situ pulmonary arterial thrombosis (ISPAT) refers to the formation of new blood clots in the pulmonary arterial system in the absence of pre-existing clots in the peripheral venous system. With the emergence and prevalence of COVID-19, ISPAT has become an increasingly important cause of pulmonary arterial thrombosis (PAT) alongside thromboembolism. Several factors such as hypoxia, inflammation, endothelial dysfunction, and hypercoagulable state can lead to ISPAT, which is associated with a number of conditions such as thoracic trauma, partial lung resection, pulmonary infectious disease, pulmonary vasculitis, connective tissue diseases, severe pulmonary hypertension, radiation pneumonitis, and acute chest syndrome in sickle cell disease. It is important to differentiate between pulmonary thromboembolism (PTE) and ISPAT for proper disease management and prognosis. In this review, we summarized the characteristics of ISPAT under different disease conditions, the methods to distinguish ISPAT from PTE, and the best treatment strategies. We hoped that this review could improve clinicians' understanding of this independent disease and provide guidance for the refined treatment of patients with PAT.

Dissociative Amnesia: Remembrances Under Cover.

The existence or questionability of "repressed memories" can be discussed as being a matter of definition. It seems, however, far-fetched to consider all "lost" memories as caused by encoding problems, brain damage, forgetfulness, failure to disclose events, and so on. We argue that dissociative amnesia (DA) (or "psychogenic amnesia," or "functional amnesia," or, as we favor to call it, "mnestic block syndrome") is caused by psychic alterations, but ultimately they can be traced to changes in the physiology of the brain, as we are of the opinion that all memory processes-positive or negative-alter brain functions, sometimes more permanently, sometimes transiently. We have proven this idea using functional imaging techniques, in particular fluoro-deoxy-d-glucose positron emission tomography. Having investigated dozens of patients with severe and long-lasting DA conditions, we believe it to be disrespectful to many (but not to all) of the affected patients to question their disease condition, which can be proven to be not caused by feigning, malingering, or direct brain damage.

Angiotensin II Directly Increases Endothelial Calcium and Nitric Oxide in Kidney and Brain Microvessels InVivo With Reduced Efficacy in Hypertension.

The vasoconstrictor effects of angiotensin II via type 1 angiotensin II receptors in vascular smooth muscle cells are well established, but the direct effects of angiotensin II on vascular endothelial cells (VECs) invivo and the mechanisms how VECs may mitigate angiotensin II-mediated vasoconstriction are not fully understood. The present study aimed to explore the molecular mechanisms and pathophysiological relevance of the direct actions of angiotensin II on VECs in kidney and brain microvessels invivo. Changes in VEC intracellular calcium ([Ca2+]i) and nitric oxide (NO) production were visualized by intravital multiphoton microscopy of cadherin 5-Salsa6f mice or the endothelial uptake of NO-sensitive dye 4-amino-5-methylamino-2',7'-difluorofluorescein diacetate, respectively. Kidney fibrosis by unilateral ureteral obstruction and Ready-to-use adeno-associated virus expressing Mouse Renin 1 gene (Ren1-AAV) hypertension were used as disease models. Acute systemic angiotensin II injections triggered >4-fold increases in VEC [Ca2+]i in brain and kidney resistance arterioles and capillaries that were blocked by pretreatment with the type 1 angiotensin II receptor inhibitor losartan, but not by the type 2 angiotensin II receptor inhibitor PD123319. VEC responded to acute angiotensin II by increased NO production as indicated by >1.5-fold increase in 4-amino-5-methylamino-2',7'-difluorofluorescein diacetate fluorescence intensity. In mice with kidney fibrosis or hypertension, the angiotensin II-induced VEC [Ca2+]i and NO responses were significantly reduced, which was associated with more robust vasoconstrictions, VEC shedding, and microthrombi formation. The present study directly visualized angiotensin II-induced increases in VEC [Ca2+]i and NO production that serve to counterbalance agonist-induced vasoconstriction and maintain residual organ blood flow. These direct and endothelium-specific angiotensin II effects were blunted in disease conditions and linked to endothelial dysfunction and the development of vascular pathologies.

Generalized sleep decoding with basal ganglia signals in multiple movement disorders

Sleep disturbances profoundly affect the quality of life in individuals with neurological disorders. Closed-loop deep brain stimulation (DBS) holds promise for alleviating sleep symptoms, however, this technique necessitates automated sleep stage decoding from intracranial signals. We leveraged overnight data from 121 patients with movement disorders (Parkinson’s disease, Essential Tremor, Dystonia, Essential Tremor, Huntington’s disease, and Tourette’s syndrome) in whom synchronized polysomnograms and basal ganglia local field potentials were recorded, to develop a generalized, multi-class, sleep specific decoder – BGOOSE. This generalized model achieved 85% average accuracy across patients and across disease conditions, even in the presence of recordings from different basal ganglia targets. Furthermore, we also investigated the role of electrocorticography on decoding performances and proposed an optimal decoding map, which was shown to facilitate channel selection for optimal model performances. BGOOSE emerges as a powerful tool for generalized sleep decoding, offering exciting potentials for the precision stimulation delivery of DBS and better management of sleep disturbances in movement disorders.

Comparative genomic profiling of transport inhibitor Response1/Auxin signaling F-box (TIR1/AFB) genes in eight Pyrus genomes revealed the intraspecies diversity and stress responsiveness patterns.

In the genomics of plants and the phytoecosystem, Pyrus (pear) is among the most nutritious fruits and contains fiber that has great health benefits to humans. It is mostly cultivated in temperate regions and is one of the most cultivated pome fruits globally. Pears are highly subjected to biotic and abiotic stresses that affect their yield. TIR1/AFB proteins act as auxin co-receptors during the signaling of nuclear auxins and play a primary role in development-related regulatory processes and responses to biotic and abiotic stresses. However, this gene family and its members have not been explored in Pyrus genomes, and understanding these genes will help obtain useful insights into stress tolerance and ultimately help maintain a high yield of pears. This study reports a pangenome-wide investigation of TIR1/AFB genes from eight Pyrus genomes: Cuiguan (Pyrus pyrifolia), Shanxi Duli (P. betulifolia), Zhongai 1 [(P. ussuriensis × communis) × spp.], Nijisseiki (P. pyrifolia), Yunhong No.1 (P. pyrifolia), d'Anjou (P. communis), Bartlett v2.0 (P. communis), and Dangshansuli v.1.1 (P. bretschneideri). These genes were randomly distributed on 17 chromosomes in each genome. Based on phylogenetics, the identified TIR1/AFB genes were divided into six groups. Their gene structure and motif pattern showed the intraspecific structural conservation as well as evolutionary patterns of Pyrus TIR1/AFBs. The expansion of this gene family in Pyrus is mainly caused by segmental duplication; however, a few genes showed tandem duplication. Moreover, positive and negative selection pressure equally directed the gene's duplication process. The GO and PPI analysis showed that Pyrus TIR1/AFB genes are associated with abiotic stress- and development-related signaling pathways. The promoter regions of Pyrus TIR1/AFB genes were enriched in hormone-, light-, development-, and stress-related cis elements. Furthermore, publicly available RNA-seq data analysis showed that DaTIR1/AFBs have varied levels of expression in various tissues and developmental stages, fruit hardening disease conditions, and drought stress conditions. This indicated that DaTIR1/AFB genes might play critical roles in response to biotic and abiotic stresses. The DaTIR1/AFBs have similar protein structures, which show that they are involved in the same function. Hence, this study will broaden our knowledge of the TIR1/AFB gene family in Pyrus, elucidating their contribution to conferring resistance against various environmental stresses, and will also provide valuable insights for future researchers.

Incidence of statin-associated muscle symptoms in patients taking statins with RYR1 or CACNA1S variants.

Background: Statins are commonly used medications. Variants in SLCO1B1, CYP2C9, and ABCG2 are known predictors of muscle effects when taking statins. More exploratory genes include RYR1 and CACNA1S, which can also be associated with disease conditions. Methods: Patients with pathogenic/likely pathogenic variants in RYR1 or CACNA1S were identified through an elective genomic testing program. Through chart review, patients with a history of statin use were assessed for statin-associated muscle symptoms (SAMS) along with collection of demographics and other known risk factors for SAMS. Results: Of the 23 patients who had a pathogenic or likely pathogenic RYR1 or CACNA1S variant found, 12 had previous statin use; of these, SAMS were identified in four patients. Conclusion: These data contribute to previous literature suggesting patients with RYR1 variants may have an increased SAMS risk. Additional research will be helpful in further investigating this relationship and providing recommendations.