julilili42/papers huggingface dataset:
CNGB1 ‐related rod‐cone dystrophy: A mutation review and update
2021-04-13

Cyclic nucleotide-gated channel β1 (CNGB1) encodes the 240-kDa β subunit of the rod photoreceptor cyclic nucleotide-gated ion channel. Disease-causing sequence variants in CNGB1 lead to autosomal recessive rod-cone dystrophy/retinitis pigmentosa (RP). We herein present a comprehensive review and analysis of all previously reported CNGB1 sequence variants, and add 22 novel variants, thereby enlarging the spectrum to 84 variants in total, including 24 missense variants (two of which may also affect splicing), 21 nonsense, 19 splicing defects (7 at noncanonical positions), 10 small deletions, 1 small insertion, 1 small insertion-deletion, 7 small duplications, and 1 gross deletion. According to the American College of Medical Genetics and Genomics classification criteria, 59 variants were considered pathogenic or likely pathogenic and 25 were variants of uncertain significance. In addition, we provide further phenotypic data from 34 CNGB1-related RP cases, which, overall, are in line with previous findings suggesting that this form of RP has long-term retention of useful central vision despite the early onset of night blindness, which is valuable for patient counseling, but also has implications for it being considered a priority target for gene therapy trials.
Trustworthy medical AI systems need to know when they don’t know
2021-04-13

There is much to learn from Duran and Jongsma’s paper.1 One particularly important insight concerns the relationship between epistemology and ethics in medical artificial intelligence (AI). In clinical environments, the task of AI systems is to provide risk estimates or diagnostic decisions, which then need to be weighed by physicians. Hence, while the implementation of AI systems might give rise to ethical issues—for example, overtreatment, defensive medicine or paternalism2—the issue that lies at the heart is an epistemic problem: how can physicians know whether to trust decisions made by AI systems? In this manner, various studies examining the interaction of AI systems and physicians have shown that without being able to evaluate their trustworthiness, especially novice physicians become over-reliant on algorithmic support—and ultimately are led astray by incorrect decisions.3–5 This leads to a second insight from the paper, namely that even if some (deep learning-based) AI system happens to be opaque, it is still not built on the moon. To assess its trustworthiness, AI developers or physicians have different sorts of higher order evidence at hand. Most importantly, ...
Picturing yourself: a social-cognitive process model to integrate third-person imagery effects
2021-04-13

People have a fascinating capacity to picture their actions from an external vantage point. Much of the research on this third-person imagery has focused on the specific effects it has on cognition due to the elements of episodic experience that it lacks relative to first-person imagery. Other research focuses on the information that the third-person provides that first-person imagery lacks. We propose a more systematic approach that conceptualises how third-person imagery's various effects interrelate due to a common underlying social-cognitive function. Specifically, we outline an integrative model proposing that third-person and first-person imagery cause people to adopt qualitatively distinct processing styles. This model explains many of the diverse effects that have been documented in the literature and helps reconcile seemingly discrepant findings. We conclude with recommendations for strategies to more systematically investigate the functions of visual perspective in mental imagery to build more comprehensive understanding of this phenomenological variable.
Supercritical Fluid Technology for the Development of 3D Printed Controlled Drug Release Dosage Forms
2021-04-13

Supercritical CO2 loading of preformed 3D printed drug carriers with active pharmaceutical ingredients (APIs) shows great potential in the development of oral dosage forms for future personalized medicine. We designed 3D printed scaffold like drug carriers with varying pore sizes made from polylactic acid (PLA) using a fused deposition modelling (FDM) 3D printer. The 3D printed drug carriers were then loaded with Ibuprofen as a model drug, employing the controlled particle deposition (CPD) process from supercritical CO2. Carriers with varying pore sizes (0.027–0.125 mm) were constructed and loaded with Ibuprofen to yield drug-loaded carriers with a total amount of 0.83–2.67 mg API (0.32–1.41% w/w). Dissolution studies of the carriers show a significantly decreasing dissolution rate with decreasing pore sizes with a mean dissolution time (MDT) of 8.7 min for the largest pore size and 128.2 min for the smallest pore size. The API dissolution mechanism from the carriers was determined to be Fickian diffusion from the non-soluble, non-swelling carriers. Using 3D printing in combination with the CPD process, we were able to develop dosage forms with individually tailored controlled drug release. The dissolution rate of our dosage forms can be easily adjusted to the individual needs by modifying the pore sizes of the 3D printed carriers.
Synthesis of the Core Structure of Palhinine A
2021-04-13

Abstract We present a strategy to the core structure of the alkaloid palhinine A passing through a 2,5‐difunctionalized cyclohexenone. This enone was prepared by a domino Michael/aldol condensation sequence. An allylation reaction on the cyclohexenone followed by oxy‐Cope rearrangement introduced an allyl group at C3. After the generation of an aldehyde function on the terminus of the C5 substituent, an intramolecular aldol reaction led to a bicyclo[2.2.2]octanone. The five‐membered ring of the core structure could be established by an intramolecular nitrile oxide‐alkene [3+2]‐cycloaddition. Prior to this key transformation, the keto function was converted to an alkene and the allyl group to an oxime.
Effect of rock uplift and Milankovitch timescale variations in precipitation and vegetation cover on catchment erosion rates
2021-04-13

Abstract. Catchment erosion and sedimentation are influenced by variations in the rates of rock uplift (tectonics), and periodic fluctuations in climate and vegetation cover. In this study we applied the Landlab-SPACE landscape evolution modelling approach. This study focuses on quantifying the effects changing climate and vegetation on erosion and sedimentation over distinct climate-vegetation settings. As catchment evolution is subjected to tectonic and climate forcings at millennial to million-year time-scales, the simulations are performed over different tectonic scenarios and periodicities of climate-vegetation change. We present a series of generalized experiments that explore the sensitivity of catchment hillslope and fluvial erosion and sedimentation for different rock uplift rates (0.05 mm a−1, 0.1 mm a−1, 0.2 mm a−1) and Milankovitch climate periodicities (23 kyr, 41 kyr and 100 kyr). Model inputs were parameterized for two different climate and vegetation conditions at two sites in the Chilean Coastal Cordillera at ~26° S (arid and sparsely vegetated) and ~33° S (mediterranean). For each setting, steady state topographies were produced for each uplift rate before introducing periodic variations in precipitation and vegetation cover. Following this, the sensitivity of these landscapes was analysed for 3 Myr in a transient state. Results suggest that regardless of the uplift rate, transients in precipitation and vegetation cover resulted in transients in erosion rates in the direction of change in precipitation and vegetation. While the transients in sedimentation were observed to be in the opposite direction of change in the precipitation and vegetation cover, with phase lags of ~1.5–2.5 kyr. These phase lags can be attributed to the changes in plant functional type (PFT) distribution induced by the changes in climatic conditions, which is beyond the scope of this study. These effects being most pronounced over longer period changes (100 kyr) and higher rock uplift rates (0.2 mm yr−1). This holds true for both vegetation and climate settings. Furthermore, transient changes in catchment erosion due to varying vegetation and precipitation were between ~35 %–110 % of the background (rock uplift) rate and are measureable with some techniques (e.g. sediment flux histories, cosmogenic nuclides). Taken together, we find that vegetation-dependent erosion and sedimentation are influenced by Milankovitch timescale changes in climate, but that these transient changes are superimposed upon tectonically driven rates of rock uplift.
Posts on Facebook by Schools and Districts and the Potential Risks to Students’ Privacy
2021-04-13

For many schools and districts in the United States, Facebook has emerged as an important communication tool. Facebook has been used for many purposes including sharing timely information, building a sense of community, and highlighting staff and students. However, neither researchers nor, we think, most schools and districts have paid enough attention to how their Facebook use may pose a risk to the privacy of the individuals—often students who are minors. One of our recent social media studies showed that between 15 and 20 million photos of students have been shared on strictly publicly accessible Facebook pages of public schools and districts. We estimated that at least 150,000 of these photos—and perhaps as many as a million or more—depict students who are identifiable by name and school and/or district. In this article, we review some of the risks to students that might result from their identification through social media posts and offer practical steps that schools and districts can take to minimize these risks.
The Role of Behavioral Ecotoxicology in Environmental Protection
2021-04-14

For decades, we have known that chemicals affect human and wildlife behavior. Moreover, due to recent technological and computational advances, scientists are now increasingly aware that a wide variety of contaminants and other environmental stressors adversely affect organismal behavior and subsequent ecological outcomes in terrestrial and aquatic ecosystems. There is also a groundswell of concern that regulatory ecotoxicology does not adequately consider behavior, primarily due to a lack of standardized toxicity methods. This has, in turn, led to the exclusion of many behavioral ecotoxicology studies from chemical risk assessments. To improve understanding of the challenges and opportunities for behavioral ecotoxicology within regulatory toxicology/risk assessment, a unique workshop with international representatives from the fields of behavioral ecology, ecotoxicology, regulatory (eco)toxicology, neurotoxicology, test standardization, and risk assessment resulted in the formation of consensus perspectives and recommendations, which promise to serve as a roadmap to advance interfaces among the basic and translational sciences, and regulatory practices.
Controls by rheological structure of the lithosphere on the temporal evolution of continental magmatism: Inferences from the Pannonian Basin system
2021-04-14

Physical-chemical controls of continental magmatism evolution remain enigmatic. Of prime and controversial nature is the temporal transition from calc-alkaline magmas to alkali basalts, correlated with a switch in tectonic regime from extension to compression. We perform 1D thermo-kinematic modelling to analyze the evolution of the thermo-rheological structure of the lithosphere in such settings using the Northwestern Pannonian Basin as a test-bed. Given well-known evidence for major reduction of brittle deformation parameters due to melt-related softening, we use a relatively low internal angle of friction. We demonstrate that at the termination of extension, the presence of intra-crustal low-viscosity layers in the lithosphere provides optimal condition for emplacement and differentiation of intermediate crustal magmatic chambers along the pathway of deep-sourced basaltic melts. In contrast, subsequent lithosphere cooling after the end of extension combined with tectonic and magmatic thickening lead to a disappearance of the low-viscosity layers and formation of lithospheric-scale faults. The latter serve as conduits for rapid ascent of uncontaminated alkali basaltic melts from the mantle to the surface. These findings shed new light on the geodynamic controls of magmatism in extensional settings.
RNA Proximity Labeling: A New Detection Tool for RNA–Protein Interactions
2021-04-14

Multiple cellular functions are controlled by the interaction of RNAs and proteins. Together with the RNAs they control, RNA interacting proteins form RNA protein complexes, which are considered to serve as the true regulatory units for post-transcriptional gene expression. To understand how RNAs are modified, transported, and regulated therefore requires specific knowledge of their interaction partners. To this end, multiple techniques have been developed to characterize the interaction between RNAs and proteins. In this review, we briefly summarize the common methods to study RNA–protein interaction including crosslinking and immunoprecipitation (CLIP), and aptamer- or antisense oligonucleotide-based RNA affinity purification. Following this, we focus on in vivo proximity labeling to study RNA–protein interactions. In proximity labeling, a labeling enzyme like ascorbate peroxidase or biotin ligase is targeted to specific RNAs, RNA-binding proteins, or even cellular compartments and uses biotin to label the proteins and RNAs in its vicinity. The tagged molecules are then enriched and analyzed by mass spectrometry or RNA-Seq. We highlight the latest studies that exemplify the strength of this approach for the characterization of RNA protein complexes and distribution of RNAs in vivo.
Determination of Ischemia Onset Based on Automatically Generated Spectralis SD-OCT Values in Acute Central Retinal Artery Occlusion
2021-04-14

Acute central retinal artery occlusion (CRAO) induces a time-dependent increase in retinal thickness. By manually measuring the relative retinal thickness increase (RRTI) in comparison to the contralateral eye based on optical coherence tomography (OCT), ischemia onset within the past 4.5 hours could be determined with 100% sensitivity and 94.3% specificity. To enable examiner-independent and quicker diagnostics, we analyzed the RRTI using the automatic retinal thickness measurement. In this retrospective study, 28 eyes were evaluated with an acute CRAO (&lt;46 hours). All patients received a Spectralis SD-OCT image of both eyes. The RRTI was calculated for the ETDRS sectors using the Segmentation Module for Single Retinal Layer Analysis. Receiver operating characteristic (ROC) analysis was performed to determine patients ≤4.5 hours by RRTI. In all sectors, time to OCT (TTO) and RRTI correlated positively. The optimal cutoff point to detect CRAOs ≤4.5 hours was between 18.7% nasally and 22.9% RRTI temporally. Sensitivity and specificity varied between the sectors with 90–95% sensitivity and 89–100% specificity. In conclusion, the automatic measurement of RRTI also allows the differentiation of CRAOs within a possible therapeutic time window ≤4.5 hours and CRAOs ≥4.5 hours with a high sensitivity and specificity. Additionally, it offers quicker, easier, and a user-independent assessment of ischemia onset, helping to set a base for establishing automatic indices generated by the OCT machines.
Bispecific NKG2D-CD3 and NKG2D-CD16 Fusion Proteins as Novel Treatment Option in Advanced Soft Tissue Sarcomas
2021-04-14

Soft tissue sarcoma (STS) constitutes a rare group of heterogeneous malignancies. Effective treatment options for most subtypes of STS are still limited. As a result, especially in metastatic disease, prognosis is still dismal. The ligands for the activating immunoreceptor NKG2D (NKG2DL) are commonly expressed in STS, but generally absent in healthy tissues. This provides the rationale for utilization of NKG2DL as targets for immunotherapeutic approaches. We here report on the preclinical characterization of bispecific fusion proteins (BFP) consisting of the extracellular domain of the NKG2D receptor fused to Fab-fragments directed against CD3 (NKG2D-CD3) or CD16 (NKG2D-CD16) for treatment of STS. After characterization of NKG2DL expression patterns on various STS cell lines, we demonstrated that both NKG2D-CD16 and NKG2D-CD3 induce profound T and NK cell reactivity as revealed by analysis of activation, degranulation and secretion of IFNγ as well as granule associated proteins, resulting in potent target cell lysis. In addition, the stimulatory capacity of the constructs to induce T and NK cell activation was analyzed in heavily pretreated STS patients and found to be comparable to healthy donors. Our results emphasize the potential of NKG2D-CD3 and NKG2D-CD16 BFP to target STS even in an advanced disease.
Arithmetic Errors in Financial Contexts in Parkinson’s Disease
2021-04-14

Research on dyscalculia in neurodegenerative diseases is still scarce, despite high impact on patients’ independence and activities of daily living function. Most studies address Alzheimer’s Disease; however, patients with Parkinson’s Disease (PD) also have a higher risk for cognitive impairment while the relation to arithmetic deficits in financial contexts has rarely been studied. Therefore, the current exploratory study investigates deficits in two simple arithmetic tasks in financial contexts administered within the Clinical Dementia Rating in a sample of 100 PD patients. Patients were classified as cognitively normal (PD-NC) or mildly impaired (PD-MCI) according to Level I consensus criteria, and assessed using a comprehensive neuropsychological test battery, neurological motor examination, and sociodemographic and clinical questionnaires. In total, 18% showed arithmetic deficits: they were predominately female, had longer disease duration, more impaired global cognition, but minor signs of depression compared to PD patients without arithmetic deficits. When correcting for clinical and sociodemographic confounders, greater impairments in attention and visuo-spatial/constructional domains predicted occurrence of arithmetic deficits. The type of deficit did not seem to be arbitrary but seemed to involve impaired place × value processing frequently. Our results argue for the importance of further systematic investigations of arithmetic deficits in PD with sensitive tests to confirm the results of our exploratory study that a specific subgroup of PD patients present themselves with dyscalculia.
Pharmacogene Sequencing of a Gabonese Population with Severe Plasmodium falciparum Malaria Reveals Multiple Novel Variants with Putative Relevance for Antimalarial Treatment
2021-04-14

Malaria remains one of the deadliest diseases in Africa, particularly for children. While successful in reducing morbidity and mortality, antimalarial treatments are also a major cause of adverse drug reactions (ADRs).
Computational modeling and quantitative physiology reveal central parameters for brassinosteroid-regulated early cell physiological processes linked to elongation growth of theArabidopsisroot
2021-04-14

Abstract Brassinosteroids (BR) are key hormonal regulators of plant development. However, whereas the individual components of BR perception and signaling are well characterized experimentally, the question of how they can act and whether they are sufficient to carry out the critical function of cellular elongation remains open. Here, we combined computational modeling with quantitative cell physiology to understand the dynamics of the plasma membrane (PM)-localized BR response pathway during the initiation of cellular responses in the epidermis of the Arabidopsis root tip that are be linked to cell elongation. The model, consisting of ordinary differential equations, comprises the BR induced hyperpolarization of the PM, the acidification of the apoplast and subsequent cell wall swelling. We demonstrate that the competence of the root epidermal cells for the BR response predominantly depends on the amount and activity of H + -ATPases in the PM. The model further predicts that an influx of cations is required to compensate for the shift of positive charges caused by the apoplastic acidification. A potassium channel was subsequently identified and experimentally characterized, fulfilling this function. Thus, we established the landscape of components and parameters for physiological processes potentially linked to cell elongation, a central process in plant development.
Does Plant Biodiversity Influence Nutrient Cycles?
2021-04-14

All living things, like humans, animals, plants, and even microbes, need to take up the same nutrient elements to live, most importantly nitrogen and phosphorus. Understanding the cycling of these elements through the ecosystem is one key to understanding why ecosystems work the way they do. One of the questions we are asking is if the diversity of organisms, like plants or insects, is related to these nutrient cycles. When plant communities are made up of many different plant species, they seem to make better use of the available soil nutrients than plant communities made up of fewer species. This may be because of something called complementarity, which means different plant species access the available nutrients in different ways, for example from different soil depths. In this article, we will describe the connections between plant biodiversity and soil nutrient cycling and discuss the implications for the functioning of the whole ecosystem.
An Early Holocene Lithic Assemblage from Dibé Rockshelter, South-Central Ethiopia
2021-04-14

Abstract The dearth of securely dated assemblages in the Horn of Africa limits a comprehensive understanding of human adaptation across the Early Holocene. This paper presents results from initial analyses of lithic material from Dibé rockshelter in the Arsi lowlands, Ethiopia. Radiocarbon dates confirm occupation of Dibé rockshelter by hunter-gatherers directly following improved climatic conditions marking the onset of the Holocene. Microliths dominate both the surface and excavated sub-assemblages. Micro-burins and Levallois items are present, although more frequent as surface finds. Regionally available siliceous rocks were extensively exploited, with greater variety in the older occupation layers signifying differential access to raw material sources and/or wider foraging ranges. Largely similar reduction patterns and toolkits across the sampled sequence imply continuity in lithic tradition. This, coupled with the total absence of finds commonly associated with early food production, suggests that Dibé was abandoned during one of the abrupt arid episodes of the Early/Mid-Holocene.