Induced Endothelial Cell Cycle Arrest Prevents Arteriovenous Malformations in Hereditary Hemorrhagic Telangiectasia.

BACKGROUND: Distinct endothelial cell cycle states (early G1 versus late G1) provide different "windows of opportunity" to enable the differential expression of genes that regulate venous versus arterial specification, respectively. Endothelial cell cycle control and arteriovenous identities are disrupted in vascular malformations including arteriovenous shunts, the hallmark of hereditary hemorrhagic telangiectasia (HHT). To date, the mechanistic link between endothelial cell cycle regulation and the development of arteriovenous malformations (AVMs) in HHT is not known. METHODS: We used BMP (bone morphogenetic protein) 9/10 blocking antibodies and endothelial-specific deletion of activin A receptor like type 1 (Alk1) to induce HHT in Fucci (fluorescent ubiquitination-based cell cycle indicator) 2 mice to assess endothelial cell cycle states in AVMs. We also assessed the therapeutic potential of inducing endothelial cell cycle G1 state in HHT to prevent AVMs by repurposing the Food and Drug Administration-approved CDK (cyclin-dependent kinase) 4/6 inhibitor (CDK4/6i) palbociclib. RESULTS: We found that endothelial cell cycle state and associated gene expressions are dysregulated during the pathogenesis of vascular malformations in HHT. We also showed that palbociclib treatment prevented AVM development induced by BMP9/10 inhibition and Alk1 genetic deletion. Mechanistically, endothelial cell late G1 state induced by palbociclib modulates the expression of genes regulating arteriovenous identity, endothelial cell migration, metabolism, and VEGF-A (vascular endothelial growth factor A) and BMP9 signaling that collectively contribute to the prevention of vascular malformations. CONCLUSIONS: This study provides new insights into molecular mechanisms leading to HHT by defining how endothelial cell cycle is dysregulated in AVMs because of BMP9/10 and Alk1 signaling deficiencies, and how restoration of endothelial cell cycle control may be used to treat AVMs in patients with HHT.

Estimating Nephron Number from Biopsies: Impact on Clinical Studies.

BACKGROUND: Accumulating evidence supports an association between nephron number and susceptibility to kidney disease. However, it is not yet possible to directly measure nephron number in a clinical setting. Recent clinical studies have used glomerular density from a single biopsy and whole kidney cortical volume from imaging to estimate nephron number and single nephron glomerular filtration rate. However, the accuracy of these estimates from individual subjects is unknown. Furthermore, it is not clear how sample size or biopsy location may influence these estimates. These questions are critical to study design, and to the potential translation of these tools to estimate nephron number in individual subjects. METHODS: We measured the variability in estimated nephron number derived from needle or virtual biopsies and cortical volume in human kidneys declined for transplantation. We performed multiple needle biopsies in the same kidney, and examined the three-dimensional spatial distribution of nephron density by magnetic resonance imaging. We determined the accuracy of a single-kidney biopsy to predict the mean nephron number estimated from multiple biopsies from the same kidney. RESULTS: A single needle biopsy had a 15% chance and virtual biopsy had a 60% chance of being within 20% of the whole-kidney nephron number. Single needle biopsies could be used to detect differences in nephron number between large cohorts of several hundred subjects. CONCLUSIONS: The number of subjects required to accurately detect differences in nephron number between populations can be predicted on the basis of natural intrakidney variability in glomerular density. A single biopsy is insufficient to accurately predict nephron number in individual subjects.

Magnetic resonance imaging accurately tracks kidney pathology and heterogeneity in the transition from acute kidney injury to chronic kidney disease.

Acute kidney injury (AKI) increases the risk for chronic kidney disease (CKD). However, there are few tools to detect microstructural changes after AKI. Here, cationic ferritin-enhanced magnetic resonance imaging (CFE-MRI) was applied to examine the heterogeneity of kidney pathology in the transition from AKI to CKD. Adult male mice received folic acid followed by cationic ferritin and were euthanized at four days (AKI), four weeks (CKD-4) or 12 weeks (CKD-12). Kidneys were examined by histologic methods and CFE-MRI. In the CKD-4 and CKD-12 groups, glomerular number was reduced and atubular cortical lesions were observed. Apparent glomerular volume was larger in the AKI, CKD-4 and CKD-12 groups compared to controls. Glomerular hypertrophy occurred with ageing. Interglomerular distance and glomerular density were combined with other MRI metrics to distinguish the AKI and CKD groups from controls. Despite significant heterogeneity, the noninvasive (MRI-based) metrics were as accurate as invasive (histological) metrics at distinguishing AKI and CKD from controls. To assess the toxicity of cationic ferritin in a CKD model, CKD-4 mice received cationic ferritin and were examined one week later. The CKD-4 groups with and without cationic ferritin were similar, except the iron content of the kidney, liver, and spleen was greater in the CKD-4 plus cationic ferritin group. Thus, our study demonstrates the accuracy and safety of CFE-MRI to detect whole kidney pathology allowing for the development of novel biomarkers of kidney disease and providing a foundation for future in vivo longitudinal studies in mouse models of AKI and CKD to track nephron fate.

Pannexin 1 as a driver of inflammation and ischemia-reperfusion injury.

Pannexin 1 (Panx1) is a ubiquitously expressed protein forming large conductance channels that are central to many distinct inflammation and injury responses. There is accumulating evidence showing ATP released from Panx1 channels, as well as metabolites, provide effective paracrine and autocrine signaling molecules that regulate different elements of the injury response. As channels with a broad range of permselectivity, Panx1 channels mediate the secretion and uptake of multiple solutes, ranging from calcium to bacterial derived molecules. In this review, we describe how Panx1 functions in response to different pro-inflammatory stimuli, focusing mainly on signaling coordinated by the vasculature. How Panx1 mediates ATP release by injured cells is also discussed. The ability of Panx1 to serve as a central component of many diverse physiologic responses has proven to be critically dependent on the context of expression, post-translational modification, interacting partners, and the mode of stimulation.

Beyond the tubule: pathological variants of LRP2, encoding the megalin receptor, result in glomerular loss and early progressive chronic kidney disease.

Pathogenic variants in the LRP2 gene, encoding the multiligand receptor megalin, cause a rare autosomal recessive syndrome: Donnai-Barrow/Facio-Oculo-Acoustico-Renal (DB/FOAR) syndrome. Because of the rarity of the syndrome, the long-term consequences of the tubulopathy on human renal health have been difficult to ascertain, and the human clinical condition has hitherto been characterized as a benign tubular condition with asymptomatic low-molecular-weight proteinuria. We investigated renal function and morphology in a murine model of DB/FOAR syndrome and in patients with DB/FOAR. We analyzed glomerular filtration rate in mice by FITC-inulin clearance and clinically characterized six families, including nine patients with DB/FOAR and nine family members. Urine samples from patients were analyzed by Western blot analysis and biopsy materials were analyzed by histology. In the mouse model, we used histological methods to assess nephrogenesis and postnatal renal structure and contrast-enhanced magnetic resonance imaging to assess glomerular number. In megalin-deficient mice, we found a lower glomerular filtration rate and an increase in the abundance of injury markers, such as kidney injury molecule-1 and N-acetyl-ß-d-glucosaminidase. Renal injury was validated in patients, who presented with increased urinary kidney injury molecule-1, classical markers of chronic kidney disease, and glomerular proteinuria early in life. Megalin-deficient mice had normal nephrogenesis, but they had 19% fewer nephrons in early adulthood and an increased fraction of nephrons with disconnected glomerulotubular junction. In conclusion, megalin dysfunction, as present in DB/FOAR syndrome, confers an increased risk of progression into chronic kidney disease.

The prevalence of seasonal affective disorder among the blind and patients with serious visual impairment.

BACKGROUND: Seasonal affective disorder (SAD) is an interesting disorder in which depression should occur at a particular time of a year, each year and it should disappear at a specific time of the year. While the prevalence of SAD among generally healthy individuals is well known, the information about the prevalence of this disorder among the blind and visually impaired patients is very limited. The aim of the study was to investigate the prevalence of SAD among the blind and people with serious visual impairment in polish population. SUBJECTS AND METHODS: 250 blind or seriously visually impaired individuals and 258 healthy controls were assessed with the usage of Seasonal Pattern Assessment Questionnaire (SPAQ). In research group survey was conducted with the Computer Assisted Telephone Interview (CATI) technique. In control group the questionnaire was distributed via Internet. The results were analysed with the usage statistical package - Statistica 13.1. RESULTS: The results revealed that among people suffering from SAD there is statistically significant difference in SPAQ scores between completely blind and seriously visually impaired people. The study shows that is the control group age is negatively correlated with score in SPAQ score, while in the study group age is positively correlated with SPAQ score. The data show that there is a difference in occurrence of SAD between men and women. CONCLUSION: The study has shown a significant difference in occurrence of SAD between study and control groups. What is more the analysis has indicated major difference in the occurrence of SAD between men and women from the study group. Taking into consideration the fact that this is the second analysis of this type in Europe further investigations are needed.

Association between affective disorders and the usage of low and medium doses of corticosteroids.

It is well known that high doses of corticosteroids can induce psychiatric disorders, especially the maniacal states. However there are only a few studies that investigate the effects of low and medium doses of such drugs used for a long period of time on the patient's mental health. The aim of the study was to investigate the prevalence and severity of affective disorders among the patients using up to 40 mg of corticosteroids (prednisone or equivalent). 54 patients during the corticosteroid therapy and 51 healthy controls were assessed with the use of the following questionnaires: Hypomania Checklist 16 (HCL-16), Beck Depression Inventory (BDI) and authors' questionnaire. The results were analysed using SPSS Statistics version 12.5. The results indicated statistically significant differences in the prevalence of hypomania and depression between controls and study group. There were no evident correlations between either the dose or the length of the therapy and the severity of affective disorders. The study has shown that the usage of corticosteroids doses below 40 mg does have an effect on the prevalence of affective disorders. The occurrence of hypomania and depression was more common among the study group. To assess correlations further studies are needed.

Association between depression and hemodialysis in patients with chronic kidney disease.

Depression is the most common and serious psychiatric disorder that affects patients with chronic kidney disease and end-stage renal disease, and, has a significant impact on their quality of life. The aim of this study was to investigate and compare prevalence rates of depression among hemodialyzed patients, and non-dialyzed patients with a glomerular filtration rate<30 ml/min/1.73m2 receiving conservative treatment or following kidney transplantation. A total of 50 hemodialyzed and 50 non-dialyzed patients with stage 4/5 of CKD was assessed using the following questionnaires: Hamilton Anxiety Rating Scale (HAM-A), Hamilton Depression Rating Scale (HAM-D), The Satisfaction with Life Scale (SWLS), The Acceptance of Illness Scale (AIS), and The Life Orientation Test-Revised (LOT-R). The use of steroids and immunosuppressant drugs was also investigated. Symptoms of depression and anxiety were present in both groups, however the proportion of persons with mild or severe depression was higher among dialyzed patients. The AIS, LOT-R and SWLS scores were very similar in both the groups. The patients using steroids and/or immunosuppressant drugs were more prone to develop mild or severe depression according to the HAM-D scores. The results indicated a high prevalence of depression and anxiety among patients with CKD. Furthermore, the fraction of patients with depression is greater among hemodialyzed patients. This indicates the importance of monitoring the mental state of the patients as well as the necessity of providing timely psychological care for patients with CKD.

Using artificial intelligence to explore sound symbolic expressions of gender in American English.

This study investigates the extent to which gender can be inferred from the phonemes that make up given names and words in American English. Two extreme gradient boosted algorithms were constructed to classify words according to gender, one using a list of the most common given names (N∼1,000) in North America and the other using the Glasgow Norms (N∼5,500), a corpus consisting of nouns, verbs, adjectives, and adverbs which have each been assigned a psycholinguistic score of how they are associated with male or female behaviour. Both models report significant findings, but the model constructed using given names achieves a greater accuracy despite being trained on a smaller dataset suggesting that gender is expressed more robustly in given names than in other word classes. Feature importance was examined to determine which features were contributing to the decision-making process. Feature importance scores revealed a general pattern across both models, but also show that not all word classes express gender the same way. Finally, the models were reconstructed and tested on the opposite dataset to determine whether they were useful in classifying opposite samples. The results showed that the models were not as accurate when classifying opposite samples, suggesting that they are more suited to classifying words of the same class.

Sound symbolism in Japanese names: Machine learning approaches to gender classification.

This study investigates the sound symbolic expressions of gender in Japanese names with machine learning algorithms. The main goal of this study is to explore how gender is expressed in the phonemes that make up Japanese names and whether systematic sound-meaning mappings, observed in Indo-European languages, extend to Japanese. In addition to this, this study compares the performance of machine learning algorithms. Random Forest and XGBoost algorithms are trained using the sounds of names and the typical gender of the referents as the dependent variable. Each algorithm is cross-validated using k-fold cross-validation (28 folds) and tested on samples not included in the training cycle. Both algorithms are shown to be reasonably accurate at classifying names into gender categories; however, the XGBoost model performs significantly better than the Random Forest algorithm. Feature importance scores reveal that certain sounds carry gender information. Namely, the voiced bilabial nasal /m/ and voiceless velar consonant /k/ were associated with femininity, and the high front vowel /i/ were associated with masculinity. The association observed for /i/ and /k/ stand contrary to typical patterns found in other languages, suggesting that Japanese is unique in the sound symbolic expression of gender. This study highlights the importance of considering cultural and linguistic nuances in sound symbolism research and underscores the advantage of XGBoost in capturing complex relationships within the data for improved classification accuracy. These findings contribute to the understanding of sound symbolism and gender associations in language.

Random forests, sound symbolism and Pokémon evolution.

This study constructs machine learning algorithms that are trained to classify samples using sound symbolism, and then it reports on an experiment designed to measure their understanding against human participants. Random forests are trained using the names of Pokémon, which are fictional video game characters, and their evolutionary status. Pokémon undergo evolution when certain in-game conditions are met. Evolution changes the appearance, abilities, and names of Pokémon. In the first experiment, we train three random forests using the sounds that make up the names of Japanese, Chinese, and Korean Pokémon to classify Pokémon into pre-evolution and post-evolution categories. We then train a fourth random forest using the results of an elicitation experiment whereby Japanese participants named previously unseen Pokémon. In Experiment 2, we reproduce those random forests with name length as a feature and compare the performance of the random forests against humans in a classification experiment whereby Japanese participants classified the names elicited in Experiment 1 into pre-and post-evolution categories. Experiment 2 reveals an issue pertaining to overfitting in Experiment 1 which we resolve using a novel cross-validation method. The results show that the random forests are efficient learners of systematic sound-meaning correspondence patterns and can classify samples with greater accuracy than the human participants.

A cross-linguistic, sound symbolic relationship between labial consonants, voiced plosives, and Pokémon friendship.

Introduction: This paper presents a cross-linguistic study of sound symbolism, analysing a six-language corpus of all Pokémon names available as of January 2022. It tests the effects of labial consonants and voiced plosives on a Pokémon attribute known as friendship. Friendship is a mechanic in the core series of Pokémon video games that arguably reflects how friendly each Pokémon is. Method: Poisson regression is used to examine the relationship between the friendship mechanic and the number of times /p/, /b/, /d/, /m/, /g/, and /w/ occur in the names of English, Japanese, Korean, Chinese, German, and French Pokémon. Results: Bilabial plosives, /p/ and /b/, typically represent high friendship values in Pokémon names while /m/, /d/, and /g/ typically represent low friendship values. No association is found for /w/ in any language. Discussion: Many of the previously known cases of cross-linguistic sound symbolic patterns can be explained by the relationship between how sounds in words are articulated and the physical qualities of the referents. This study, however, builds upon the underexplored relationship between sound symbolism and abstract qualities.

The bouba/kiki effect is robust across cultures and writing systems.

The bouba/kiki effect-the association of the nonce word bouba with a round shape and kiki with a spiky shape-is a type of correspondence between speech sounds and visual properties with potentially deep implications for the evolution of spoken language. However, there is debate over the robustness of the effect across cultures and the influence of orthography. We report an online experiment that tested the bouba/kiki effect across speakers of 25 languages representing nine language families and 10 writing systems. Overall, we found strong evidence for the effect across languages, with bouba eliciting more congruent responses than kiki. Participants who spoke languages with Roman scripts were only marginally more likely to show the effect, and analysis of the orthographic shape of the words in different scripts showed that the effect was no stronger for scripts that use rounder forms for bouba and spikier forms for kiki. These results confirm that the bouba/kiki phenomenon is rooted in crossmodal correspondence between aspects of the voice and visual shape, largely independent of orthography. They provide the strongest demonstration to date that the bouba/kiki effect is robust across cultures and writing systems. This article is part of the theme issue 'Voice modulation: from origin and mechanism to social impact (Part II)'.

Premature differentiation of nephron progenitor cell and dysregulation of gene pathways critical to kidney development in a model of preterm birth.

Preterm birth is a leading cause of neonatal morbidity. Survivors have a greater risk for kidney dysfunction and hypertension. Little is known about the molecular changes that occur in the kidney of individuals born preterm. Here, we demonstrate that mice delivered two days prior to full term gestation undergo premature cessation of nephrogenesis, resulting in a lower glomerular density. Kidneys from preterm and term groups exhibited differences in gene expression profiles at 20- and 27-days post-conception, including significant differences in the expression of fat-soluble vitamin-related genes. Kidneys of the preterm mice exhibited decreased proportions of endothelial cells and a lower expression of genes promoting angiogenesis compared to the term group. Kidneys from the preterm mice also had altered nephron progenitor subpopulations, early Six2 depletion, and altered Jag1 expression in the nephrogenic zone, consistent with premature differentiation of nephron progenitor cells. In conclusion, preterm birth alone was sufficient to shorten the duration of nephrogenesis and cause premature differentiation of nephron progenitor cells. These candidate genes and pathways may provide targets to improve kidney health in preterm infants.

Inhibition of the ʟ-glutamine transporter ASCT2 sensitizes plasma cell myeloma cells to proteasome inhibitors.

Proteasome inhibitors (PIs), used in the treatment of plasma cell myeloma (PCM), interfere with the degradation of misfolded proteins leading to activation of unfolded protein response (UPR) and cell death. However, despite initial strong antimyeloma effects, PCM cells eventually develop acquired resistance to PIs. The pleiotropic role of ʟ-glutamine (Gln) in cellular functions makes inhibition of Gln metabolism a potentially good candidate for combination therapy. Here, we show that PCM cells, both sensitive and resistant to PIs, express membrane Gln transporter (ASCT2), require extracellular Gln for survival, and are sensitive to ASCT2 inhibitors (ASCT2i). ASCT2i synergistically potentiate the cytotoxic activity of PIs by inducing apoptosis and modulating autophagy. Combination of ASCT2 inhibitor V9302 and proteasome inhibitor carfilzomib upregulates the intracellular levels of ROS and oxidative stress markers and triggers catastrophic UPR as shown by upregulated spliced Xbp1 mRNA, ATF3 and CHOP levels. Moreover, analysis of RNA sequencing revealed that the PI in combination with ASCT2i reduced the levels of Gln metabolism regulators such as MYC and NRAS. Analysis of PCM patients' data revealed that upregulated ASCT2 and other Gln metabolism regulators are associated with advanced disease stage and with PIs resistance. Altogether, we identified a potent therapeutic approach that may prevent acquired resistance to PIs and may contribute to the improvement of treatment of patients suffering from PCM.

Novel vocalizations are understood across cultures.

Linguistic communication requires speakers to mutually agree on the meanings of words, but how does such a system first get off the ground? One solution is to rely on iconic gestures: visual signs whose form directly resembles or otherwise cues their meaning without any previously established correspondence. However, it is debated whether vocalizations could have played a similar role. We report the first extensive cross-cultural study investigating whether people from diverse linguistic backgrounds can understand novel vocalizations for a range of meanings. In two comprehension experiments, we tested whether vocalizations produced by English speakers could be understood by listeners from 28 languages from 12 language families. Listeners from each language were more accurate than chance at guessing the intended referent of the vocalizations for each of the meanings tested. Our findings challenge the often-cited idea that vocalizations have limited potential for iconic representation, demonstrating that in the absence of words people can use vocalizations to communicate a variety of meanings.

Does pop-culture affect perception of medical procedures? Report on knowledge and attitude towards electroconvulsive therapy among Polish students. / Czy popkultura wplywa na postrzeganie procedur medycznych? Raport o stanie wiedzy i nastawieniu polskich studentów do terapii elektrowstrzasowej.

OBJECTIVES: The aim of the study was to investigate the general knowledge and attitudes towards ECT among Polish students, including students of medical faculties. Furthermore, the influence of pop-culture on society's opinion about ECT was investigated. METHODS: For this purpose, 1,370 students have been examined with the usage of the author's questionnaire, which consisted of questions about socio-demographic data, detailed questions about ECT as well as questions about their opinion about influence of pop-culture on the reception of this procedure. The respondents were divided into four subgroups depending on the faculty of their studies: human sciences, technical, medical and health sciences. RESULTS: The results show that the knowledge about ECT among Polish students is on avery low level, as in many cases the therapy is considered as painful, ineffective or even illegal. CONCLUSIONS: The influence of the media, especially film industry, on creating a negative opinion on the subject of ECT is significant. Furthermore, many respondents obtain their knowledge about this procedure from television or from the Internet, where the information is often incorrect.