bluuebunny/crossref_metadata_2025_split huggingface dataset:
Translational reprogramming in response to accumulating stressors ensures critical threshold levels of Hsp90 for mammalian life
Authors: Bhattacharya Kaushik , Maiti Samarpan , Zahoran Szabolcs , Weidenauer Lorenz , Hany Dina , Wider Diana , Bernasconi Lilia , Quadroni Manfredo , Collart Martine , Picard Didier 
Published: October 2022

AbstractThe cytosolic molecular chaperone Hsp90 is essential for eukaryotic life. Although reduced Hsp90 levels correlate with aging, it was unknown whether eukaryotic cells and organisms can tune the basal Hsp90 levels to alleviate physiologically accumulated stress. We have investigated whether and how mice adapt to the deletion of three out of four alleles of the two genes encoding cytosolic Hsp90, with one Hsp90β allele being the only remaining one. While the vast majority of such mouse embryos die during gestation, survivors apparently manage to increase their Hsp90β protein to at least wild-type levels. Our studies reveal an internal ribosome entry site in the 5’ untranslated region of the Hsp90β mRNA allowing translational reprogramming to compensate for the genetic loss of Hsp90 alleles and in response to stress. We find that the minimum amount of total Hsp90 required to support viability of mammalian cells and organisms is 50–70% of what is normally there. Those that fail to maintain a threshold level are subject to accelerated senescence, proteostatic collapse, and ultimately death. Therefore, considering that Hsp90 levels can be reduced ≥100-fold in the unicellular budding yeast, critical threshold levels of Hsp90 have markedly increased during eukaryotic evolution.
The cholesterol transport protein GRAMD1C regulates autophagy initiation and mitochondrial bioenergetics
Authors: Ng Matthew Yoke Wui , Charsou Chara , Lapao Ana , Singh Sakshi , Trachsel-Moncho Laura , Schultz Sebastian W. , Nakken Sigve , Munson Michael J. , Simonsen Anne 
Published: October 2022

AbstractDuring autophagy, cytosolic cargo is sequestered into double-membrane vesicles called autophagosomes. The contributions of specific lipids, such as cholesterol, to the membranes that form the autophagosome, remain to be fully characterized. Here, we demonstrate that short term cholesterol depletion leads to a rapid induction of autophagy and a corresponding increase in autophagy initiation events. We further show that the ER-localized cholesterol transport protein GRAMD1C functions as a negative regulator of starvation-induced autophagy and that both its cholesterol transport VASt domain and membrane binding GRAM domain are required for GRAMD1C-mediated suppression of autophagy initiation. Similar to its yeast orthologue, GRAMD1C associates with mitochondria through its GRAM domain. Cells lacking GRAMD1C or its VASt domain show increased mitochondrial cholesterol levels and mitochondrial oxidative phosphorylation, suggesting that GRAMD1C may facilitate cholesterol transfer at ER-mitochondria contact sites. Finally, we demonstrate that expression of GRAMD family proteins is linked to clear cell renal carcinoma survival, highlighting the pathophysiological relevance of cholesterol transport proteins.
Single cell transcriptomic profiling of a neuron-astrocyte assembloid tauopathy model
Authors: Rickner Hannah Drew , Jiang Lulu , Hong Rui , O’Neill Nicholas K. , Mojica Chromewell A. , Snyder Benjamin J. , Zhang Lushuang , Shaw Dipan , Medalla Maria , Wolozin Benjamin , Cheng Christine S. 
Published: October 2022

AbstractThe use of iPSC derived brain organoid models to study neurodegenerative disease has been hampered by a lack of systems that accurately and expeditiously recapitulate pathogenesis in the context of neuron-glial interactions. Here we report development of a system, termed AstTau, which propagates toxic human tau oligomers in iPSC derived neuron-astrocyte assembloids. The AstTau system develops much of the neuronal and astrocytic pathology observed in tauopathies including misfolded, phosphorylated, oligomeric, and fibrillar tau, strong neurodegeneration, and reactive astrogliosis. Single cell transcriptomic profiling combined with immunochemistry characterizes a model system that can more closely recapitulate late-stage changes in adult neurodegeneration. The transcriptomic studies demonstrate striking changes in neuroinflammatory and heat shock protein (HSP) chaperone systems in the disease process. Treatment with the HSP90 inhibitor PU-H71 is used to address the putative dysfunctional HSP chaperone system and produces a strong reduction of pathology and neurodegeneration, highlighting the potential of AstTau as a rapid and reproducible tool for drug discovery.
Micro-scale functional modules in the human temporal lobe
Authors: Chapeton Julio I. , Wittig John H. , Inati Sara K. , Zaghloul Kareem A. 
Published: October 2022

AbstractThe sensory cortices of many mammals are often organized into modules in the form of cortical columns, yet whether modular organization at this spatial scale is a general property of the human neocortex is unknown. The strongest evidence for modularity arises when measures of connectivity, structure, and function converge. Here we use microelectrode recordings in humans to examine functional connectivity and neuronal spiking responses in order to assess modularity in submillimeter scale networks. We find that the human temporal lobe consists of temporally persistent spatially compact modules approximately 1.3mm in diameter. Functionally, the information coded by single neurons during an image categorization task is more similar for neurons belonging to the same module than for neurons from different modules. The geometry, connectivity, and spiking responses of these local cortical networks provide converging evidence that the human temporal lobe is organized into functional modules at the micro scale.
Giant ferroelectric polarization in a bilayer graphene heterostructure
Authors: Niu Ruirui , Li Zhuoxian , Han Xiangyan , Qu Zhuangzhuang , Ding Dongdong , Wang Zhiyu , Liu Qianling , Liu Tianyao , Han Chunrui , Watanabe Kenji , Taniguchi Takashi , Wu Menghao , Ren Qi , Wang Xueyun , Hong Jiawang , Mao Jinhai , Han Zheng , Liu Kaihui , Gan Zizhao , Lu Jianming 
Published: October 2022

AbstractAt the interface of van der Waals heterostructures, the crystal symmetry and the electronic structure can be reconstructed, giving rise to physical properties superior to or absent in parent materials. Here by studying a Bernal bilayer graphene moiré superlattice encapsulated by 30°-twisted boron nitride flakes, we report an unprecedented ferroelectric polarization with the areal charge density up to 1013 cm−2, which is far beyond the capacity of a moiré band. The translated polarization ~5 pC m−1is among the highest interfacial ferroelectrics engineered by artificially stacking van der Waals crystals. The gate-specific ferroelectricity and co-occurring anomalous screening are further visualized via Landau levels, and remain robust for Fermi surfaces outside moiré bands, confirming their independence on correlated electrons. We also find that the gate-specific resistance hysteresis loops could be turned off by the other gate, providing an additional control knob. Furthermore, the ferroelectric switching can be applied to intrinsic properties such as topological valley current. Overall, the gate-specific ferroelectricity with strongly enhanced charge polarization may encourage more explorations to optimize and enrich this novel class of ferroelectricity, and promote device applications for ferroelectric switching of various quantum phenomena.
Thiazolidinedione use and risk of Parkinson’s disease in patients with type 2 diabetes mellitus
Authors: Zhao Houyu , Zhuo Lin , Sun Yexiang , Shen Peng , Lin Hongbo , Zhan Siyan 
Published: October 2022

AbstractThe health burden of Parkinson’s disease (PD) and diabetes increases rapidly in China. However, no population-based study of the association between glucose lowering agents and PD incidence has been conducted in mainland Chinese population. Preclinical studies indicate that thiazolidinediones (TZDs) have neuroprotective effects against PD through stimulating peroxisome proliferator-activated receptor gamma. Nevertheless, debate remains in human studies. We assembled a retrospective cohort of type 2 diabetes mellitus (T2DM) patients who were new users of TZDs or alpha glucosidase inhibitors (AGIs) using the Yinzhou Regional Health Care Database. A Cox model with inverse probability of treatment weighting (IPTW) was applied to estimate the hazard ratio (HR) of PD incidence associated with the use of TZDs compared with AGIs. The final cohort included 12,704 new users of TZDs and 49,696 new users of AGIs. The incidence of PD was 135 per 100,000 person-years in TZD users and 203 per 100,000 person-years in the AGI group. An inverse association between use of TZDs and incidence of PD, with a HR of 0.74 (95% confidence interval, 0.59–0.92), was observed after adjusting for potential confounding using IPTW. The results of various subgroup analyses and sensitivity analyses were consistent with the findings of the primary analysis. Our results indicated that the use of TZD is associated with a decreased risk of PD incidence in a mainland Chinese population with T2DM. Given the heavy disease burden of PD and diabetes in China, these findings could provide some evidence for developing effective prevention and control measures to reduce the future incidence of PD in China.
Documentation of smoking in scheduled asthma contacts in primary health care: a 12-year follow-up study
Authors: Takala Jaana , Vähätalo Iida , Tuomisto Leena E. , Niemelä Onni , Ilmarinen Pinja , Kankaanranta Hannu 
Published: October 2022

AbstractSmoking among asthmatics is common and associates with poorer asthma control, more rapid lung function decline and higher health care costs in dose-dependent manner. No previous real-life studies exist, however, on how smoking status and pack-years are documented in scheduled asthma contacts in primary health care (PHC) during long-term follow-up, and how often patients are advised to quit smoking. In this real-life 12-year follow-up study, we showed that out of all scheduled PHC asthma contacts (n = 603) smoking was mentioned only in 17.2% and pack-years only in 6.5%. Smoking data was not recorded even once in 70.9% of never smokers, 64.7% of ex-smokers and 27.3% of current smokers. Smoking including pack-years were mentioned more often if nurse took part on the scheduled contact. For current smokers, smoking cessation was recommended only in 21.7% of their scheduled contacts. Current smokers used more antibiotics and had more unscheduled health care contacts during follow-up.
Understanding relationships between asthma medication use and outcomes in a SABINA primary care database study
Authors: Vervloet Marcia , van Dijk Liset , Weesie Yvette M. , Kocks Janwillem W. H. , Dima Alexandra L. , Korevaar Joke C. 
Published: October 2022

AbstractAdherence to inhaled corticosteroids (ICS) in asthma is suboptimal. Patients may rely more on their short-acting beta-agonist (SABA) to control symptoms, which may increase their risk of exacerbations and uncontrolled asthma. Our objective is to describe ICS adherence and SABA use among Dutch primary care patients with asthma, and how these are related to exacerbations and self-reported asthma control. Patients aged ≥12 years diagnosed with asthma who received ≥2 inhalation medication prescriptions in 2016 were selected from the Nivel Primary Care Database. ICS adherence (continuous measure of medication availability), SABA use (number of prescriptions), exacerbations (short courses of oral corticosteroids with daily dose ≥20 mg), and asthma control (self-reported with the Asthma Control Questionnaire; ACQ) were computed. Multilevel logistic regression analyses, to account for clustering of patients within practices, were used to model associations between ICS adherence, SABA use, and asthma outcomes. Prescription data of 13,756 patients were included. ICS adherence averaged 62% (SD: 32.7), 14% of patients received ≥3 SABA prescriptions, and 13% of patients experienced ≥1 exacerbation. Self-reported asthma control was available for 2183 patients of whom 51% reported controlled asthma (ACQ-5 score <0.75). A higher number of SABA prescriptions was associated with a higher risk of exacerbations and uncontrolled asthma, even with high ICS adherence (>90%). ICS adherence was not associated with exacerbations, whilst poor ICS adherence (≤50%) was associated with uncontrolled asthma. In conclusion, increased SABA use is an important and easily identifiable signal for general practitioners to discuss asthma self-management behavior with their patients.
Severe testing with high-dimensional omics data for enhancing biomedical scientific discovery
Authors: Emmert-Streib Frank 
Published: October 2022

AbstractHigh-throughput omics experiments provide a wealth of data for exploring biomedical questions and for advancing translational research. However, despite this great potential, results that enter the clinical practice are scarce even twenty years after the completion of the human genome project. For this reason in this paper, we revisit problems with scientific discovery commonly summarized under the term reproducibility crisis. We will argue that the major problem that hampers progress in translational research is threefold. First, in order to establish biological foundations of disorders or general complex phenotypes, one needs to embrace emergence. Second, there seems to be confusion about the underlying hypotheses tested by omics studies. Third, most contemporary omics studies are designed to perform what can be seen as incremental corroborations of a hypothesis. In order to improve upon these shortcomings, we define a severe testing framework (STF) that can be applied to a large number of omics studies for enhancing scientific discovery in the biomedical sciences. Briefly, STF provides systematic means to trim wild-grown omics studies in a constructive way.
Comparative transcriptomic analysis of whole blood mycobacterial growth assays and tuberculosis patients’ blood RNA profiles
Authors: Bachanová Petra , Cheyne Ashleigh , Broderick Claire , Newton Sandra M. , Levin Michael , Kaforou Myrsini 
Published: October 2022

AbstractIn vitro whole blood infection models are used for elucidating the immune response to Mycobacterium tuberculosis (Mtb). They exhibit commonalities but also differences, to the in vivo blood transcriptional response during natural human Mtb disease. Here, we present a description of concordant and discordant components of the immune response in blood, quantified through transcriptional profiling in an in vitro whole blood infection model compared to whole blood from patients with tuberculosis disease. We identified concordantly and discordantly expressed gene modules and performed in silico cell deconvolution. A high degree of concordance of gene expression between both adult and paediatric in vivo–in vitro tuberculosis infection was identified. Concordance in paediatric in vivo vs in vitro comparison is largely characterised by immune suppression, while in adults the comparison is marked by concordant immune activation, particularly that of inflammation, chemokine, and interferon signalling. Discordance between in vitro and in vivo increases over time and is driven by T-cell regulation and monocyte-related gene expression, likely due to apoptotic depletion of monocytes and increasing relative fraction of longer-lived cell types, such as T and B cells. Our approach facilitates a more informed use of the whole blood in vitro model, while also accounting for its limitations.
A stacking-based artificial intelligence framework for an effective detection and localization of colon polyps
Authors: Albuquerque Carina , Henriques Roberto , Castelli Mauro 
Published: October 2022

AbstractPolyp detection through colonoscopy is a widely used method to prevent colorectal cancer. The automation of this process aided by artificial intelligence allows faster and improved detection of polyps that can be missed during a standard colonoscopy. In this work, we propose to implement various object detection algorithms for polyp detection. To improve the mean average precision (mAP) of the detection, we combine the baseline models through a stacking approach. The experiments demonstrate the potential of this new methodology, which can reduce the workload for oncologists and increase the precision of the localization of polyps. Our proposal achieves a mAP of 0.86, translated into an improvement of 34.9% compared to the best baseline model and 28.8% with respect to the weighted boxes fusion ensemble technique.
Construction of a bioluminescence-based assay for bitter taste receptors (TAS2Rs)
Authors: Tan Shi Min , Seetoh Wei-Guang 
Published: October 2022

AbstractIn humans, a family of 25 bitter taste receptors (TAS2Rs) mediates bitter taste perception. A common approach to characterize bitter causative agents involves expressing TAS2Rs and the appropriate signal transducers in heterologous cell systems, and monitoring changes in the intracellular free calcium levels upon ligand exposure using a fluorescence-based modality, which typically suffers from a low signal window, and is susceptible to interference by autofluorescence, therefore prohibiting its application to screening of plant or food extracts, which are likely to contain autofluorescent compounds. The aim of this study is to develop and validate a bioluminescence-based intracellular calcium release assay for TAS2Rs that has a better assay performance than a fluorescence-based assay. Furthermore, the bioluminescence-based assay enabled the evaluation of TAS2R agonists within an autofluorescent matrix, highlighting its potential utility in the assessment of the bitterness-inducing properties of plant or food fractions by the food industry. Additionally, improvement to the bioluminescence-based assay for some TAS2Rs was achieved by altering their N-terminal signal sequences, leading to signal window enhancement. Altogether, the bioluminescence-based TAS2R assay can be used to perform functional studies of TAS2Rs, evaluate TAS2R-modulating properties of autofluorescent samples, and facilitate the discovery of compounds that can function as promising bitter taste modulators.
Active inference and the two-step task
Authors: Gijsen Sam , Grundei Miro , Blankenburg Felix 
Published: October 2022

AbstractSequential decision problems distill important challenges frequently faced by humans. Through repeated interactions with an uncertain world, unknown statistics need to be learned while balancing exploration and exploitation. Reinforcement learning is a prominent method for modeling such behaviour, with a prevalent application being the two-step task. However, recent studies indicate that the standard reinforcement learning model sometimes describes features of human task behaviour inaccurately and incompletely. We investigated whether active inference, a framework proposing a trade-off to the exploration-exploitation dilemma, could better describe human behaviour. Therefore, we re-analysed four publicly available datasets of the two-step task, performed Bayesian model selection, and compared behavioural model predictions. Two datasets, which revealed more model-based inference and behaviour indicative of directed exploration, were better described by active inference, while the models scored similarly for the remaining datasets. Learning using probability distributions appears to contribute to the improved model fits. Further, approximately half of all participants showed sensitivity to information gain as formulated under active inference, although behavioural exploration effects were not fully captured. These results contribute to the empirical validation of active inference as a model of human behaviour and the study of alternative models for the influential two-step task.
Contrast volume and in-hospital outcomes of dialysis patients undergoing percutaneous coronary intervention
Authors: Kuno Toshiki , Numasawa Yohei , Shoji Satoshi , Ueda Ikuko , Suzuki Masahiro , Noma Shigetaka , Fukuda Keiichi , Kohsaka Shun 
Published: October 2022

AbstractToxicity resulting from retained contrast media may cause adverse cardiovascular outcomes (e.g., heart failure and cardiogenic shock) for dialysis patients. However, the association between the administered contrast volume and outcomes of dialysis patients after percutaneous coronary intervention (PCI) has not been sufficiently investigated. We evaluated 953 consecutive dialysis patients (age, 67.9 ± 9.9 years; 30.1% with acute coronary syndrome) who underwent PCI between September 2008 and March 2019. Patients were divided into two groups: those with a contrast volume ≥ 200 ml and those with a contrast volume < 200 ml. The cutoff was 200 ml because 100 ml increment of contrast volume is known to raise the risk of acute kidney injury, and 200 ml is more than the average volume used at most PCI centers. The primary endpoint was a composite of in-hospital death, post-PCI cardiogenic shock and post-PCI heart failure. A multivariable logistic regression model and smooth spline curve were constructed to assess the association between contrast volume and the primary endpoint. The median contrast volume was 157 ml (interquartile range, 115–210 ml). The overall primary endpoint incidence was 6.8% (N = 65). A contrast volume ≥ 200 ml was associated with a higher risk of the primary endpoint (odds ratio 2.91; 95% confidence interval 1.42–6.05; P = 0.004). The smooth spline curve demonstrated a linear relationship between the contrast volume and primary endpoint. In conclusions, the contrast volume was associated with adverse in-hospital outcomes of dialysis patients undergoing PCI. Attention should be focused on the contrast volume used for dialysis patients undergoing PCI.
Utilization trends for endoscopic ablation therapy and esophagectomy in Barrett’s esophagus from 2005 to 2019
Authors: Trindade Arvind J. , Zhang Jianying , Raphael Kara L. , Qiu Jiejing , Hauschild John , Benias Petros C. 
Published: October 2022

AbstractGuidelines have shifted to now recommend endoscopic eradication therapy for Barrett’s esophagus (BE) with low and high-grade dysplasia. Previously, esophagectomy was the standard therapy for high-grade dysplasia. However, it is unclear to what degree ablation therapy has affected utilization of esophagectomy. In this retrospective observational cohort study of BE patients without cancer from the Premier Healthcare Database, the prevalence of utilization of endoscopic ablation therapy and of esophagectomy in BE were calculated and temporal trends were evaluated. A total of 938, 333 BE cases were included in the study. There was a significantly increasing trend of ablation over the period 2006 to 2010 (Annual Percentage Change (APC); 95% CI 0.56% [0.51%, 0.61%]), a significantly decreasing trend for the period 2011 to 2015 (APC; 95% CI − 0.15% [− 0.20%, − 0.11%]), and a shallow increasing trend for the period 2016 to 2019 (APC; 95% CI 0.09% [0.06%, 0.11%]). For esophagectomy, there was a significantly decreasing trend for the period 2006 to 2009 (APC; 95% CI − 0.03% [− 0.04%, − 0.02%]; P < 0.001) that corresponded to the uptrend in utilization of endoscopic ablation. There was a stable trend of esophagectomy over the period 2010 to 2019 (APC; 95% CI − 0.0006% [− 0.0002%, 0.0005%]; P = 0.1947). Adoption and increased utilization of endoscopic ablation therapy for BE has coincided with a decrease in esophagectomy, and is the predominate method of therapy for BE with dysplasia.