julilili42/papers huggingface dataset:
Community standards to facilitate development and address challenges in metabolic modeling
2019-07-14

ABSTRACT Standardization of data and models facilitates effective communication, especially in computational systems biology. However, both the development and consistent use of standards and resources remains challenging. As a result, the amount, quality, and format of the information contained within systems biology models are not consistent and therefore present challenges for widespread use and communication. Here, we focused on these standards, resources, and challenges in the field of metabolic modeling by conducting a community-wide survey. We used this feedback to (1) outline the major challenges that our field faces and to propose solutions and (2) identify a set of features that defines what a “gold standard” metabolic network reconstruction looks like concerning content, annotation, and simulation capabilities. We anticipate that this community-driven outline will help the long-term development of community-inspired resources as well as produce high-quality, accessible models. More broadly, we hope that these efforts can serve as blueprints for other computational modeling communities to ensure continued development of both practical, usable standards and reproducible, knowledge-rich models.
Mutations in RHOT1 Disrupt Endoplasmic Reticulum–Mitochondria Contact Sites Interfering with Calcium Homeostasis and Mitochondrial Dynamics in Parkinson's Disease
2019-07-15

<b><i>Aims:</i></b> The outer mitochondrial membrane protein Miro1 is a crucial player in mitochondrial dynamics and calcium homeostasis. Recent evidence indicated that Miro1 mediates calcium-induced mitochondrial shape transition, which is a prerequisite for the initiation of mitophagy. Moreover, altered Miro1 protein levels have emerged as a shared feature of monogenic and sporadic Parkinson's disease (PD), but, so far, no disease-associated variants in <i>RHOT1</i> have been identified. Here, we aim to explore the genetic and functional contribution of <i>RHOT1</i> mutations to PD in patient-derived cellular models. <b><i>Results:</i></b> For the first time, we describe heterozygous <i>RHOT1</i> mutations in two PD patients (het c.815G>A; het c.1348C>T) and identified mitochondrial phenotypes with reduced mitochondrial mass in patient fibroblasts. Both mutations led to decreased endoplasmic reticulum-mitochondrial contact sites and calcium dyshomeostasis. As a consequence, energy metabolism was impaired, which in turn caused increased mitophagy. <b><i>Innovation and Conclusion:</i></b> Our study provides functional evidence that <i>ROTH1</i> is a genetic risk factor for PD, further implicating Miro1 in calcium homeostasis and mitochondrial quality control.
Expert-validated estimation of diagnostic uncertainty for deep neural networks in diabetic retinopathy detection
2019-07-15

ABSTRACT Deep learning-based systems can achieve a diagnostic performance comparable to physicians in a variety of medical use cases including the diagnosis of diabetic retinopathy. To be useful in clinical practise, it is necessary to have well calibrated measures of the uncertainty with which these systems report their decisions. However, deep neural networks (DNNs) are being often overconfident in their predictions, and are not amenable to a straightforward probabilistic treatment. Here, we describe an intuitive framework based on test-time data augmentation for quantifying the diagnostic uncertainty of a state-of-the-art DNN for diagnosing diabetic retinopathy. We show that the derived measure of uncertainty is well-calibrated and that experienced physicians likewise find cases with uncertain diagnosis difficult to evaluate. This paves the way for an integrated treatment of uncertainty in DNN-based diagnostic systems.
Radiative Lifetime, Non‐Radiative Relaxation, and Sensitization Efficiency in Luminescent Europium and Neodymium Cryptates – The Roles of 2,2′‐Bipyridine‐N,N′‐dioxide and Deuteration
2019-07-15

Abstract Five luminescent tris(bipyridine)‐based cryptates with the lanthanoids Eu and Nd have been prepared with a systematic increase in the number of 2,2′‐bipyridine‐ N,N′ ‐dioxide units and with different deuteration levels in the complexing cryptands for the europium species. Careful analysis of the radiative lifetime τ rad in these systems reveals that an increase in N ‐oxide units around the metal centers uniformly lowers τ rad by about 30–40 %. The potential involvement of nephelauxetic effects is discussed. Exchange of 30 C−D for C−H oscillators around the europium centers does not affect the radiative lifetimes but decreases non‐radiative deactivation and increases the overall luminescence quantum yield in D 2 O by 45 %.
Novel type of sub‐retinal pigment shield in the miniaturized compound eye of Trichogramma evanescens
2019-07-15

Abstract Pigment granules, found in different cell types of the retina in insect compound eyes, fulfill important functions. They isolate the individual ommatidia from stray light, regulate the angular sensitivity, and restrict the light that reaches the photoreceptor according to ambient light intensities. Descriptions of pigment cells within the retina are included in ultrastructural eye descriptions, but knowledge of pigment cell types beneath the retina and basal matrix (BM) are relatively limited in insects. In the miniaturized parasitoid wasp Trichogramma evanescens Westwood 1833, a sub‐retinal pigment shield is formed by pigment‐bearing cells, which appear in two‐dimensional TEM sections to form a separate population beneath the BM. By using three‐dimensional reconstructions of serial‐section transmission electron microscopy, it was possible to reveal that the sub‐retinal pigment shield of T. evanescens is not formed by a separate cell type, but by extensions of the lateral rim pigment cells that penetrate gaps in the BM. The reconstruction is supported by evidence from a statistical analysis of pigment granule volumes of all pigment bearing cell types in the retina and rim region. The study reveals the first known case of the participation of lateral rim cells in a sub‐retinal pigment shield in an insect eye. As neither pigmented extensions of secondary pigment cells, nor pigment granules in the extensions of the cone cell projections are present above the BM in T. evanescens , the sub‐retinal extensions of the lateral rim cells can be seen as a functional adaptation to miniaturization in order to maintain a proximal shielding function.
Judging the mental states of others: ‘mindreading’ in legal decision-making
2019-07-15

Legal processes very often require judges and jurors to make determinations as to what mental states other individuals were in at a particular point in time, i.e., what they intended, believed, considered etc. However, there are two ways that one can try to determine what mental states another person was or is in. One is to apply the information that one has about human psychology in the way that one applies a theory. The other is to mentally pretend that one is in the same situation as the other individual and see what mental states one would have oneself, before attributing these to the other individual. I show that the two methods can lead to different conclusions in the same circumstances and urge that this is a very serious problem.
Brain‐based ranking of cognitive domains to predict schizophrenia
2019-07-16

Abstract Schizophrenia is a devastating brain disorder that disturbs sensory perception, motor action, and abstract thought. Its clinical phenotype implies dysfunction of various mental domains, which has motivated a series of theories regarding the underlying pathophysiology. Aiming at a predictive benchmark of a catalog of cognitive functions, we developed a data‐driven machine‐learning strategy and provide a proof of principle in a multisite clinical dataset ( n = 324). Existing neuroscientific knowledge on diverse cognitive domains was first condensed into neurotopographical maps. We then examined how the ensuing meta‐analytic cognitive priors can distinguish patients and controls using brain morphology and intrinsic functional connectivity. Some affected cognitive domains supported well‐studied directions of research on auditory evaluation and social cognition. However, rarely suspected cognitive domains also emerged as disease relevant, including self‐oriented processing of bodily sensations in gustation and pain. Such algorithmic charting of the cognitive landscape can be used to make targeted recommendations for future mental health research.
Acid sphingomyelinase – a regulator of canonical transient receptor potential channel 6 (TRPC6) activity
2019-07-16

Abstract Recent investigations propose the acid sphingomyelinase (ASM)/ceramide system as a novel target for antidepressant action. ASM catalyzes the breakdown of the abundant membrane lipid sphingomyelin to the lipid messenger ceramide. This ASM‐induced lipid modification induces a local shift in membrane properties, which influences receptor clustering and downstream signaling. Canonical transient receptor potential channels 6 (TRPC6) are non‐selective cation channels located in the cell membrane that play an important role in dendritic growth, synaptic plasticity and cognition in the brain. They can be activated by hyperforin, an ingredient of the herbal remedy St. John’s wort for treatment of depression disorders. Because of their role in the context of major depression, we investigated the crosstalk between the ASM/ceramide system and TRPC6 ion channels in a pheochromocytoma cell line 12 neuronal cell model (PC12 rat pheochromocytoma cell line). Ca 2+ imaging experiments indicated that hyperforin‐induced Ca 2+ influx through TRPC6 channels is modulated by ASM activity. While antidepressants, known as functional inhibitors of ASM activity, reduced TRPC6‐mediated Ca 2+ influx, extracellular application of bacterial sphingomyelinase rebalanced TRPC6 activity in a concentration‐related way. This effect was confirmed in whole‐cell patch clamp electrophysiology recordings. Lipidomic analyses revealed a decrease in very long chain ceramide/sphingomyelin molar ratio after ASM inhibition, which was connected with changes in the abundance of TRPC6 channels in flotillin‐1–positive lipid rafts as visualized by western blotting. Our data provide evidence that the ASM/ceramide system regulates TRPC6 channels likely by controlling their recruitment to specific lipid subdomains and thereby fine‐tuning their physical properties. image
Consolidation of reward memory during sleep does not require dopaminergic activation
2019-07-16

Abstract Sleep enhances memories, especially, if they are related to future rewards. Although dopamine has been shown to be a key determinant during reward learning, the role of dopaminergic neurotransmission for amplifying reward-related memories during sleep remains unclear. In the present study, we scrutinize the idea that dopamine is needed for the preferential consolidation of rewarded information. We blocked dopaminergic neurotransmission, thereby aiming to wipe out preferential sleep-dependent consolidation of high over low rewarded memories during sleep. Following a double-blind, balanced, crossover design 20 young healthy men received the dopamine d2-like receptor blocker Sulpiride (800 mg) or placebo, after learning a Motivated Learning Task. The task required participants to memorize 80 highly and 80 lowly rewarded pictures. Half of them were presented for a short (750 ms) and a long duration (1500 ms), respectively, which enabled to dissociate effects of reward on sleep-associated consolidation from those of mere encoding depth. Retrieval was tested after a retention interval of 20 h that included 8 h of nocturnal sleep. As expected, at retrieval, highly rewarded memories were remembered better than lowly rewarded memories, under placebo. However, there was no evidence for an effect of blocking dopaminergic neurotransmission with Sulpiride during sleep on this differential retention of rewarded information. This result indicates that dopaminergic activation is not required for the preferential consolidation of reward-associated memory. Rather it appears that dopaminergic activation only tags such memories at encoding for intensified reprocessing during sleep.
Effects of Diazepam on Low-Frequency and High-Frequency Electrocortical γ-Power Mediated by α1- and α2-GABAA Receptors
2019-07-16

Patterns of spontaneous electric activity in the cerebral cortex change upon administration of benzodiazepines. Here we are testing the hypothesis that the prototypical benzodiazepine, diazepam, affects spectral power density in the low (20–50 Hz) and high (50–90 Hz) γ-band by targeting GABAA receptors harboring α1- and α2-subunits. Local field potentials (LFPs) and action potentials were recorded in the barrel cortex of wild type mice and two mutant strains in which the drug exclusively acted via GABAA receptors containing either α1- (DZα1-mice) or α2-subunits (DZα2-mice). In wild type mice, diazepam enhanced low γ-power. This effect was also evident in DZα2-mice, while diazepam decreased low γ-power in DZα1-mice. Diazepam increased correlated local LFP-activity in wild type animals and DZα2- but not in DZα1-mice. In all genotypes, spectral power density in the high γ-range and multi-unit action potential activity declined upon diazepam administration. We conclude that diazepam modifies low γ-power in opposing ways via α1- and α2-GABAA receptors. The drug’s boosting effect involves α2-receptors and an increase in local intra-cortical synchrony. Furthermore, it is important to make a distinction between high- and low γ-power when evaluating the effects of drugs that target GABAA receptors.
Structural control energy of resting-state functional brain states reveals inefficient brain dynamics in psychosis vulnerability
2019-07-16

Abstract How the brain’s white-matter anatomy constrains brain activity is an open question that might give insights into the mechanisms that underlie mental disorders such as schizophrenia. Chromosome 22q11.2 deletion syndrome (22q11DS) is a neurodevelopmental disorder with an extremely high risk for psychosis providing a test case to study developmental aspects of schizophrenia. In this study, we used principles from network control theory to probe the implications of aberrant structural connectivity for the brain’s functional dynamics in 22q11DS. We retrieved brain states from resting-state functional magnetic resonance images of 78 patients with 22q11DS and 85 healthy controls. Then, we compared them in terms of persistence control energy; i.e., the control energy that would be required to persist in each of these states based on individual structural connectivity and a dynamic model. Persistence control energy was altered in a broad pattern of brain states including both energetically more demanding and less demanding brain states in 22q11DS. Further, we found a negative relationship between persistence control energy and resting-state activation time, which suggests that the brain reduces energy by spending less time in energetically demanding brain states. In patients with 22q11DS, this behavior was less pronounced, suggesting a dynamic inefficiency of brain function in the disease. In summary, our results provide initial insights into the dynamic implications of altered structural connectivity in 22q11DS, which might improve our understanding of the mechanisms underlying the disease.
Interoptic, Trans-lamina Terminalis, Opticocarotid Triangle, and Caroticosylvian Windows From Mini-Supraorbital, Frontomedial, and Pterional Perspectives: A Comparative Cadaver Study With Artificial Lesions
2019-07-16

<b>Introduction:</b> The mini-supraorbital (MSO) and pterional (PT) approaches have been compared in a number of studies focusing on the treatment of aneurysms, craniopharyngiomas, and meningiomas. The goal of this study was to analyze the surgical exposure to different artificial lesions through interoptic (IO), trans-lamina terminalis (TLT), opticocarotid triangle (OCT), and caroticosylvian (CS) windows from the MSO, frontomedial (FM), and PT perspectives. <b>Methods:</b> The MSO, PT, and FM approaches were performed sequentially in two fixed cadaver heads. Three colored spheres were placed around the optic chiasm: (1) between the optic nerves; (2) between the optic nerve and the internal carotid artery; and (3) between the internal carotid artery and the oculomotor nerve. The surgical exposures to these structures by using the IO, TLT, OCT, and CS windows were compared. <b>Results:</b> (1) IO window: from the MSO and PT approaches, the total surgical exposure mainly allows visualization of contralateral lesions. The FM approach was superior for exploration of both sides of the area between the optic nerves. (2) TLT pathway: the MSO and PT approaches mainly expose the contralateral third ventricle wall. (3) OCT window: the PT approach allows exposure of a larger part of the sphere between the optic nerve and the internal carotid artery than the MSO approach. (4) CS window: the PT approach allows a better exposure of lateral structures such as the oculomotor nerve and of the medial prepontine area in comparison to the MSO approach. <b>Conclusion:</b> Simulation of the surgical situation with artificial lesions is a good model for comparing surgical perspectives and for analyzing feasibility of lesion exposure and resection.
Deep learning outperformed 11 pathologists in the classification of histopathological melanoma images
2019-07-17

With limited image information available, a CNN was able to outperform 11 histopathologists in the classification of histopathological melanoma images and thus shows promise to assist human melanoma diagnoses.
Baseline Toxicity and Volatility Cutoff in Reporter Gene Assays Used for High-Throughput Screening
2019-07-17

Most studies using high-throughput <i>in vitro</i> cell-based bioassays tested chemicals up to a certain fixed concentration. It would be more appropriate to test up to concentrations predicted to elicit baseline toxicity because this is the minimal toxicity of every chemical. Baseline toxicity is also called narcosis and refers to nonspecific intercalation of chemicals in biological membranes, leading to loss of membrane structure and impaired functioning of membrane-related processes such as mitochondrial respiration. In cells, baseline toxicity manifests as cytotoxicity, which was quantified by a robust live-cell imaging method. Inhibitory concentrations for baseline toxicity varied by orders of magnitude between chemicals and were described by a simple quantitative structure activity relationship (QSAR) with the liposome-water partition constant as a sole descriptor. The QSAR equations were remarkably similar for eight reporter gene cell lines of different cellular origin, six of which were used in Tox21. Mass-balance models indicated constant critical membrane concentrations for all cells and all chemicals with a mean of 69 mmol·kg<sub>lip</sub><sup>-1</sup>(95% CI: 49-89), which is in the same range as for bacteria and aquatic organisms and consistent with the theory of critical membrane burden of narcosis. The challenge of developing baseline QSARs for cell lines is that many confirmed baseline toxicants are rather volatile. We deduced from cytotoxicity experiments with semi-volatile chemicals that only chemicals with medium-air partition constants >10,000 L/L can be tested in standard robotic setups without appreciable loss of effect. Chemicals just below that cutoff showed crossover effects in neighboring wells, whereas the effects of chemicals with lower medium-air partition constants were plainly lost. Applying the "volatility cut-off" to >8000 chemicals tested in Tox21 indicated that approximately 20% of Tox21 chemicals could have partially been lost during the experiments. We recommend applying the baseline QSARs together with volatility cut-offs for experimental planning of reporter gene assays, that is, to dose only chemicals with medium-air partition constants >10,000 at concentrations up to the baseline toxicity level.
Quantification of hydroxyl exchange of D‐Glucose at physiological conditions for optimization of glucoCEST MRI at 3, 7 and 9.4 Tesla
2019-07-17

Aims To determine individual glucose hydroxyl exchange rates at physiological conditions and use this information for numerical optimization of glucoCEST/CESL preparation. To give guidelines for in vivo glucoCEST/CESL measurement parameters at clinical and ultra‐high field strengths. Methods Five glucose solution samples at different pH values were measured at 14.1 T at various B 1 power levels. Multi‐B 1 ‐Z‐spectra Bloch‐McConnell fits at physiological pH were further improved by the fitting of Z‐spectra of five pH values simultaneously. The obtained exchange rates were used in a six‐pool Bloch‐McConnell simulation including a tissue‐like water pool and semi‐solid MT pool with different CEST and CESL presaturation pulse trains. In vivo glucose injection experiments were performed in a tumor mouse model at 7 T. Results and discussion Glucose Z‐spectra could be fitted with four exchanging pools at 0.66, 1.28, 2.08 and 2.88 ppm. Corresponding hydroxyl exchange rates could be determined at pH = 7.2, T = 37°C and 1X PBS. Simulation of saturation transfer for this glucose system in a gray matter‐like and a tumor‐like system revealed optimal pulses at different field strengths of 9.4, 7 and 3 T. Different existing sequences and approaches are simulated and discussed. The optima found could be experimentally verified in an animal model at 7 T. Conclusion For the determined fast exchange regime, presaturation pulses in the spin‐lock regime (long recover time, short yet strong saturation) were found to be optimal. This study gives an estimation for optimization of the glucoCEST signal in vivo on the basis of glucose exchange rate at physiological conditions.
SPRTN protease and checkpoint kinase 1 cross-activation loop safeguards DNA replication
2019-07-17

Abstract The SPRTN metalloprotease is essential for DNA-protein crosslink (DPC) repair and DNA replication in vertebrate cells. Cells deficient in SPRTN protease exhibit DPC-induced replication stress and genome instability, manifesting as premature ageing and liver cancer. Here, we provide a body of evidence suggesting that SPRTN activates the ATR-CHK1 phosphorylation signalling cascade during physiological DNA replication by proteolysis-dependent eviction of CHK1 from replicative chromatin. During this process, SPRTN proteolyses the C-terminal/inhibitory part of CHK1, liberating N-terminal CHK1 kinase active fragments. Simultaneously, CHK1 full length and its N-terminal fragments phosphorylate SPRTN at the C-terminal regulatory domain, which stimulates SPRTN recruitment to chromatin to promote unperturbed DNA replication fork progression and DPC repair. Our data suggest that a SPRTN-CHK1 cross-activation loop plays a part in DNA replication and protection from DNA replication stress. Finally, our results with purified components of this pathway further support the proposed model of a SPRTN-CHK1 cross-activation loop.