bluuebunny/crossref_metadata_2025_split huggingface dataset:
A triple distinction of cerebellar function for oculomotor learning and fatigue compensation
Authors: Masselink Jana , Cheviet Alexis , Pélisson Denis , Lappe Markus 
Published: June 2022

AbstractThe cerebellum implements error-based motor learning via synaptic gain adaptation of an inverse model, i.e. the mapping of a spatial movement goal onto a motor command. Recently, we modeled the motor and perceptual changes during learning of saccadic eye movements, showing that learning is actually a threefold process. Besides motor recalibration of the inverse model (1), learning also comprises perceptual recalibration of the visuospatial target map (2) and of a forward dynamics model that estimates the saccade size from corollary discharge (3). Yet, the site of perceptual recalibration remains unclear. Here we dissociate cerebellar contributions to the three stages of learning by modeling the learning data of eight cerebellar patients and eight healthy controls. Results showed that cerebellar pathology restrains short-term recalibration of the visuospatial target map and of the inverse model while the forward dynamics model is well informed about the reduced saccade change. Moreover, patients showed uncompensated oculomotor fatigue caused by insufficient upregulation of saccade duration. According to our model, this could induce long-term perceptual compensation, consistent with the overestimation of target eccentricity found in the patients’ baseline data. We conclude that the cerebellum mediates short-term adaptation of the visuospatial target map and of the inverse model, especially by control of saccade duration. The forward dynamics model was not affected by cerebellar pathology.Author SummaryAchieving a fine-grained understanding of how the cerebellum continuously recalibrates our movements is an ongoing challenge in sensorimotor neuroscience. Recently, we showed that recalibration of saccadic eye movements does not only operate in motor space, i.e. by adjusting the motor command, but also in external and internal visual space, i.e. by adjusting the spatial representation of the target and the internal saccade size. For this purpose, (1) we developed a paradigm that allowed us to monitor changes of the internal saccade size estimated from trans-saccadic target localizations, and (2) we unified the three learning processes in one computational modeling framework. Here we apply this approach to the saccade learning data of patients with a neurodegenerative cerebellar disease. First, we dissociate the cerebellar role in recalibration of these three sites of learning. Second, we show how learning is transposed to saccade kinematics. Third, we provide first insights into the perceptual consequences of cerebellar pathology that, according to our model, may be a mechanism to recover from disease-specific motor deficits. Our modeling framework may help to dissociate the contribution of specific sensorimotor areas to adaptive behavior as well as to improve the understanding of learning deficits and compensatory strategies in the clinical context.
Sphingolipids protect ergosterol in theLeishmania majormembrane from sterol-specific toxins
Authors: Haram Chaitanya S. , Moitra Samrat , Keane Rilee , Matthew Kuhlmann F. , Frankfater Cheryl , Hsu Fong-Fu , Beverley Stephen M. , Zhang Kai , Keyel Peter A. 
Published: June 2022

AbstractSusceptibility ofLeishmaniato the first line treatment amphotericin B remains poorly understood. Amphotericin B targets ergosterol, so one approach to improving drug efficacy and reducing side effects could be improving access to ergosterol. While the surface exposure of ergosterol inLeishmaniais unknown, sterols in mammalian cells can be sheltered from sterol-binding agents by membrane components, including sphingolipids. Here, we tested the ability of theLeishmania majorsphingolipids inositol phosphorylceramide (IPC), and ceramide to shelter ergosterol by preventing binding and cytotoxicity of the sterol-specific toxins streptolysin O and perfringolysin O using flow cytometry. In contrast to mammalian systems,Leishmaniasphingolipids did not preclude toxin binding to sterols in the membrane. However, IPC interfered with cytotoxicity. Ceramide reduced perfringolysin O, but not streptolysin O, cytotoxicity in cells. Ceramide sensing was controlled by the toxin L3 loop. Ceramide was sufficient to protectL. majorpromastigotes from amphotericin B. We propose a mechanism whereby pore-forming toxins engage additional lipids like ceramide to determine the optimal environment to sustain pore formation. Thus,L.majoroffers a genetically tractable model organism for understanding toxin-membrane interactions. Furthermore, our findings suggest targeting ceramide may enhance the efficacy of ergosterol-targeting anti-leishmanial drugs.Abstract ImportanceLeishmaniasis is a neglected tropical disease with ∼1.5-2 million new cases and ∼70,000 deaths annually. One first-line treatment for leishmaniasis is liposomal amphotericin B, which is expensive and damages the kidneys. Cost and side effects can be minimized by improving efficacy. To improve efficacy, we must learn how amphotericin’s target—ergosterol—is protected by other components ofLeishmania. The human ergosterol equivalent is protected by components called sphingolipids. We tested the ability of sphingolipids to protect ergosterol using pore-forming toxins. Pore-forming toxins use ergosterol to bind and killLeishmania. Unlike human cells, toxins bound to ergosterol—indicating that they had access—when sphingolipids were present. However, sphingolipids protectedLeishmaniafrom toxins and amphotericin. Thus,Leishmaniaorganizes sterol-protective components differently from humans. Further, toxins andLeishmaniaserve as a system to understand fundamental rules governing sterol-protecting component membrane organization. We can use this information to help improve drugs targeting sterols.
Skin-resident immune cells engulf axonal debris in adult epidermis
Authors: Peterman Eric , Quitevis Elgene , Horton Emma C. , Aelmore Rune L. , White Ethan , Sagasti Alvaro , Rasmussen Jeffrey P. 
Published: June 2022

SummarySomatosensory neurons extend enormous peripheral axons to the skin, where they detect diverse environmental stimuli. Somatosensory peripheral axons are easily damaged due to their small caliber and superficial location. Axonal damage results in Wallerian degeneration, creating vast quantities of cellular debris that phagocytes must remove to maintain organ homeostasis. The cellular mechanisms that ensure efficient clearance of axon debris from stratified adult skin are unknown. Here, we establish zebrafish scales as a tractable model to study axon degeneration in the adult epidermis. Using this system, we demonstrate that skin-resident immune cells known as Langerhans cells engulf the majority of axon debris. In contrast to immature skin, adult keratinocytes do not significantly contribute to debris removal, even in animals lacking Langerhans cells. Our study establishes a powerful new model for studying Wallerian degeneration and identifies a new function for Langerhans cells in maintenance of adult skin homeostasis following injury. These findings have important implications for pathologies that trigger somatosensory axon degeneration.
The Caenorhabditis elegans centrosome is surrounded by a membrane reticulum, the centriculum, that affects centrosome size and function
Authors: Maheshwari Richa , Rahman Mohammad M. , Drey Seth , Onyundo Megan , Fabig Gunar , Martinez Michael A. Q. , Matus David Q. , Müller-Reichert Thomas , Cohen-Fix Orna 
Published: June 2022

SummaryCentrosomes are membraneless organelles that nucleate microtubules. At their core is a pair of centrioles that recruit pericentriolar material (PCM), a phase-separated condensate. In many cell types, including human cells, centrosomes are surrounded by endoplasmic reticulum-derived membranes of unknown structure and function. Using volume electron microscopy, we show that the C. elegans centrosome is surrounded by a membrane reticulum that we call the centriculum, for centrosome-associated membrane reticulum. Increasing centriculum size by genetic means led to expansion of the PCM and increased microtubule nucleation capacity, an unexpected finding given that the PCM is a membraneless condensate. We provide evidence that the centriculum serves as a microtubule “filter” by limiting the number of microtubules that can elongate fully. We also show the centriculum fuses with the nuclear envelope during mitosis. We propose that this fusion contributes to nuclear envelope breakdown by transducing forces from the elongating spindle to the nuclear membranes.
Constitutive Inhibition of Transient Receptor Potential Canonical Type 6 (TRPC6) by O-GlcNAcylation at Threonine-221
Authors: Mishra Sumita , Ma Junfeng , Sasaki Masayuki , Farinelli Federica , Page Richard C. , Ranek Mark J. , Zachara Natasha , Kass David A 
Published: June 2022

ABSTRACTTransient receptor potential canonical type 6 (TRPC6) is a non-voltage gated cation channel that principally conducts calcium to regulate signaling in cardiac, vascular, neuronal and other cells. Abnormally increased TRPC6 expression/conductance and genetic gain of function mutations contribute to fibrosis, hypertrophy, proteinuria, and edema, notably linked to its stimulation of nuclear factor of activated T-cells (NFAT) signaling. Hyperglycemia (HG) also activates TRPC6/NFAT as a cause of diabetic renal disease. While prior work linked HG-TRPC6 activation to oxidant stress, the role of another major HG modification - O-GlcNAcylation, is unknown. Here we show TRPC6 is constitutively O-GlcNAcylated, TRPC6 and O-GlcNAc transferase proteins interact, this modification potently suppresses basal channel conductance and NFAT activity, and it is unaltered by HG. Proteomics identifies O-GlcNAcylation at Ser14, Thr70, and Thr221 in the N-terminus ankyrin-4 (AR4) and neighboring linker (LH1) domains of TRPC6. Of these, T221 is most impactful as a T221A mutation increases basal NFAT activity 11-fold, TRPC6 conductance 75-80% vs wild-type, and when expressed in cardiomyocytes amplifies NFAT-pro-hypertrophic gene expression. T221 is highly conserved and mutating homologs in TRPC3 and TRPC7 also markedly elevates basal NFAT activity. Molecular models predict electrostatic interactions between T221 O-GlcNAc and Ser199, Glu200, and Glu246, and we find similarly elevated NFAT activity from alanine substitutions at these coordinating sites as well. Thus, O-GlcNAcylation at T221 and its interaction with coordinating residues in AR4-LH1 is required for basal TRPC6 channel conductance and regulation of NFAT.
Effect of Hypokalemia on Screening for Primary Aldosteronism
Authors: Rizer Nicholas W , Ding Xiruo , Cohen Debbie L , Herman Daniel S 
Published: June 2022

ABSTRACTContextPrimary aldosteronism (PA) is a common, underdiagnosed, and treatable cause of hypertension. Guidelines recommend testing for hypokalemia, but current practices and their impact are unknown.ObjectiveTo estimate the impact of hypokalemia on the results of PA screening in clinical practice.MethodsWe studied electronic health records for adults who received longitudinal care within a large, integrated health system between 2007 and 2017 and underwent paired blood aldosterone and renin testing. Patients were grouped based on concurrent blood potassium concentrations.ResultsWe found that 2,940 (82%) of the 3,571 patients screened for PA had concurrent potassium testing. Among all patients with a negative PA screen, 18% of patients did not have concurrent potassium testing and 14% of those tested were hypokalemic. Of the screen-negative hypokalemic patients, 77% were not retested. Among patients with repeated screens, we found that initial potassium concentration was a predictor of PA screen positivity on repeat. A one standard deviation lower initial potassium concentration was associated with a 74% higher odds of screen positivity on repeat, independent of initial aldosterone and renin results.ConclusionsIn-practice clinical data demonstrate that unrecognized and uncorrected hypokalemia contributes to the underdiagnosis of PA. Universal potassium testing and rescreening for PA in the setting of hypokalemia would likely substantially improve the identification and thereby management of PA.
Use of Internally Validated Machine and Deep Learning Models to Predict Outcomes of Percutaneous Nephrolithotomy using data from the BAUS PCNL audit
Authors: Geraghty Robert M , Finch William , Fowler Sarah , Sriprasad Seshadri , Smith Daron , Dickinson Andrew , Gall Zara , Somani Bhaskar K 
Published: June 2022

AbstractBackgroundMachine (ML) and Deep learning (DL) are subsets of artificial intelligence that use data to build algorithms. These can be used to predict specific outcomes. To date there have been a few small studies on post-PCNL outcomes.ObjectiveWe aimed to build and internally validate ML/DL models for post-PCNL transfusion and infection using a comprehensive national database.DesignMachine Learning study using prospective national database. Eight machine learning models for 11 outcomes using 43 predictors. Models were ‘complete-case’ analyses.SettingNational databaseParticipantsPatients undergoing PCNL in the UK between 2014-2019.Outcome MeasurementsDiagnostic accuracy statistics including overall accuracy, area-under-the-curve (AUC), sensitivity and specificity.Results and Limitations4412 patients were included, with 3088 in the training set and 1324 in the test set. The models predicted need for transfusion and post-operative infection with a very high degree of accuracy (99%) and high AUC (0.99-1.00). Unfortunately, the remainder of the outcomes did not achieve the same high levels. These two outcomes were therefore included in the provisional web-based application: https://endourology.shinyapps.io/PCNL_Prediction_tool/ConclusionsThis is the largest machine learning study on post-PCNL outcomes to date. These models can predict the need for post-PCNL transfusion and post-PCNL infection at an individual level with excellent accuracy. Further work will be done on model tuning and external validation.Patient SummaryWe used a national database of people having a major kidney stone operation (PCNL). Using this data, we built and tested 8 machine learning models for 11 different outcomes from the operation. Using this method, we can give individual predictions for the likely need for a blood transfusion and development of an infection. We have developed an app to allow surgeons to calculate an individual patient’s risk prior to surgery.
DNA methylation analysis of archival lymphoreticular tissues in Creutzfeldt-Jakob disease and the prevalence of vCJD infection in the UK
Authors: Guntoro Fernando , Viré Emmanuelle , Giordani Chiara , Darwent Lee , Hummerich Holger , Linehan Jacqueline , Sinka Katy , Jaunmuktane Zane , Brandner Sebastian , Collinge John , Mead Simon 
Published: June 2022

AbstractThe exposure of the UK and other European populations to bovine spongiform encephalopathy (BSE) prions caused human variant Creutzfeldt-Jakob Disease (vCJD) and a prolonged public health crisis. Throughout, a key question has been the prevalence of vCJD prion infection in the UK population. vCJD has several distinct features including immunohistochemically detectable abnormal prion protein (PrP) in peripheral lymphoreticular system tissues (LRS eg. tonsil, appendix). Surveys have detected abnormal PrP in the LRS of the UK population, but it remains unclear if these represent carriers of vCJD infection, some other form of prion infection, or another phenomenon altogether. Concern about the infectiousness of these possible carriers has been used to justify precautionary, expensive and ongoing health protection measures. Archival appendix samples are formalin fixed and paraffin embedded, a process that makes conventional assays of prion infection challenging. Here, we sought to use methylation array technology that assays >850,000 sites where chemically stable DNA modification occurs to develop a computational method to classify tissue samples by prion disease status. We assembled nearly 450 lymphoreticular tissue samples from patients with different prion diseases following biopsy or autopsy, and non-prion disease patients following tonsillectomy and appendicectomy, either frozen or processed as formalin fixed or formalin fixed paraffin embedded. DNA was extracted, bisulphite converted and assayed using Illumina Infinium Methylation EPIC (850K) BeadChips. Data were normalised and filtered, then analysed by case-control study, t-distributed stochastic neighbour embedding plots, and random forest classification methods. We show substantial differences in DNA methylation between prion diseases cases and controls, which can be exploited to classify LRS samples with reasonable levels of accuracy (82-97%). Archival appendix samples with abnormal PrP were most similar to, and classified with, control appendix samples, rather than prion disease samples; several interpretations are compatible with these findings.
Addiction Potential of Combustible Menthol Cigarette Alternatives: A Randomized Crossover Trial
Authors: Wagener Theodore L. , Mehta Toral , Hinton Alice , Schulz Jonathan , Erath Tyler , Tidey Jennifer W. , Villanti Andrea C. 
Published: June 2022

ABSTRACTIntroductionThe FDA announced its intention to issue proposed product standards banning menthol as a characterizing flavor in cigarettes and cigars. The public health benefits of these product standards may be attenuated by the role of plausible substitutes in the marketplace. Therefore, the present study examined the addiction potential of plausible combustible menthol alternatives compared to usual brand menthol cigarettes (UBMC).MethodsEighty adult menthol cigarette smokers completed four visits, smoking their UBMC at the first session and 3 menthol cigarette alternatives in random order at the subsequent visits: 1) a pre-assembled menthol roll-your-own cigarette using menthol pipe tobacco and mentholated cigarette tube (mRYO), 2) a menthol filtered little cigar (mFLC), and 3) a non-menthol cigarette (NMC). Measures of smoking topography, exhaled carbon monoxide (CO), craving and withdrawal, subjective effects, and behavioral economic demand indices were assessed.ResultsCompared to UBMC, menthol cigarette alternatives resulted in similar topography and CO exposure but significantly lower levels of positive subjective experience and behavioral economic demand indices. Among the alternative products, participants reported the highest level of positive subjective experience and higher demand for mRYO, compared with mFLC and NMC. Similarly, participants were significantly more likely to want to try again, purchase, and use the mRYO product regularly compared with mFLC and NMC.Conclusions and RelevancemRYO cigarettes were the most highly rated cigarette alternative among study products, suggesting their potential appeal as a menthol cigarette substitute and needed inclusion of menthol pipe tobacco and cigarette tubes in FDA’s proposed ban.What is already known on this topicMenthol cigarettes are associated with increased smoking initiation, higher nicotine dependence, and decreased adult cessation, particularly among vulnerable populations. To address this public health issue, the FDA announced in April 2021 its intention to issue product standards banning menthol as a characterizing flavor in both cigarettes and cigars within a year. However, the public health benefits of these product standards may be attenuated by the role of plausible substitutes available in the marketplaceWhat this study addsIn this randomized cross-over design study that included 80 adult menthol cigarette smokers, each of the alternative products demonstrated the ability to significantly reduce nicotine craving and withdrawal symptoms, but the combination of mentholated pipe tobacco and tubes in a menthol roll-your-own cigarette, resulted in the highest behavioral economic demand and positive subjective experience.How this study may affect policyTo maximize the benefits of a menthol cigarette ban, restrictions should extend to plausible substitutes, particularly menthol pipe tobacco and cigarette tubes.
The timid invasion
Authors: Eccard Jana A. , Mazza Valeria , Holland Celia , Stuart Peter 
Published: June 2022

SUMMARYIn biological invasion processes animal behavior moderates the success of invasive species, and the native fauna’s ability to adapt. The importance of behavioral syndromes and flexibility of invading species for invasion success remains debated. We investigated behavior of rodents, the bank vole (Myodes glareolus) currently invading Ireland, and the native wood mouse (Apodemus sylvaticus) that declines with vole invasion, at replicated sites at pre-invasion, edge, and source of the invasion. We found that individual rodents varied consistently in risk-taking behaviors, and mice had not adapted to the presence of invasive voles. Voles at the invasion edge were more careful but also more flexible compared to voles the invasion source. The ability to develop timid and flexible phenotypes may contribute to the invasion success of rodents worldwide.
Downregulation of Dickkopf-3, a Wnt antagonist elevated in Alzheimer’s disease, restores synapse integrity and memory in a disease mouse model
Authors: Martin-Flores Nuria , Podpolny Marina , McLeod Faye , Workman Isaac , Crawford Karen , Ivanov Dobril , Leonenko Ganna , Escott-Price Valentina , Salinas Patricia C. 
Published: June 2022

ABSTRACTIncreasing evidence supports a role for deficient Wnt signaling in Alzheimer’s disease (AD). Studies reveal that the secreted Wnt antagonist Dickkopf-3 (DKK3) colocalizes to amyloid plaques in AD patients. Here, we investigate the contribution of DKK3 to synapse integrity in healthy and AD brains. Our findings show that DKK3 expression is upregulated in the brains of AD subjects and that DKK3 protein levels increase at early stages in the disease. In hAPP-J20 and hAPPNL-G-F/NL-G-FAD models, extracellular DKK3 levels are increased and DKK3 accumulates at dystrophic neuronal processes around plaques. Functionally, DKK3 triggers the loss of excitatory synapses through blockade of the Wnt/GSK3β signaling with a concomitant increase in inhibitory synapses signaling via activation of the Wnt/JNK pathway. In contrast, DKK3 knockdown restores synapse number and memory in hAPP-J20 mice. Collectively, our findings identify DKK3 as a novel driver of synaptic defects and memory impairment in AD.