julilili42/papers huggingface dataset:
The Subtilisin-Like Protease Furin Regulates Hemin-Dependent Ectodomain Shedding of Glycoprotein VI
2023-04-10

Introduction Hemolysis results in release of free hemoglobin and hemin liberation from erythrocytes. Hemin has been described to induce platelet activation and to trigger thrombosis. Methods We evaluated the effect of hemin on platelet function and surface expression of the platelet collagen receptor glycoprotein VI (GPVI). Isolated platelets were stimulated with increasing concentrations of hemin. Results We found that hemin strongly enhanced platelet activation, aggregation, and aggregate formation on immobilized collagen under flow. In contrast, we found that surface expression of GPVI was significantly reduced upon hemin stimulation with high hemin concentrations indicating that hemin-induced loss of surface GPVI does not hinder platelet aggregation. Loss of hemin-induced surface expression of GPVI was caused by shedding of the ectodomain of GPVI as verified by immunoblotting and is independent of the GPVI or CLEC-2 mediated ITAM (immunoreceptor-tyrosine-based-activation-motif) signaling pathway as inhibitor studies revealed. Hemin-induced GPVI shedding was independent of metalloproteinases such as ADAM10 or ADAM17, which were previously described to regulate GPVI degradation. Similarly, concentration-dependent shedding of CD62P was also induced by hemin. Unexpectedly, we found that the subtilisin-like proprotein convertase furin controls hemin-dependent GPVI shedding as shown by inhibitor studies using the specific furin inhibitors SSM3 and Hexa-D-arginine. In the presence of SSM3 and Hexa-D-arginine, hemin-associated GPVI degradation was substantially reduced. Further, SSM3 inhibited hemin-induced but not CRP-XL-induced platelet aggregation and thrombus formation, indicating that furin controls specifically hemin-associated platelet functions. Conclusion In summary, we describe a novel mechanism of hemin-dependent GPVI shedding and platelet function mediated by furin.
Behrouz Boochani on Manus Island: Contesting Refugee Experience in the Global South
2023-04-10

This article makes a case for reframing refugee literature through reading Behrouz Boochani’s No Friend but the Mountains, translated from Farsi by Omid Tofighian. Written in detention on Manus Island via text messages on WhatsApp, Boochani’s book has won wide acclaim in Australia and internationally, not only among literary critics, but as a work of popular appeal in writers’ festivals and cultural prizes. The popular narrative around No Friend but the Mountains has introduced it, on the one hand, as a representative specimen of refugee literature, and more specifically as an example of life writing of a stateless Kurd. We argue that Boochani’s work resists reductive characterisations of refugee literature both through its literary investments and its multiple affiliations with political and discursive interests. By attending closely to stylistic properties and its discursive contexts, we emphasise that No Friend but the Mountains is not just a protest against Boochani’s own treatment by the Australian government but a tracing of how the lived experience and literary subjectivity of refugees in the Global South contests facile categorisation and unitary nationalism.
2D Assembly of Atomically Oriented Gold Nanodisks Leads to Tunable Plasmonic Resonance
2023-04-10

Nanocrystals (NCs) are extensively used to create self-assembled nanostructures; however, little has been achieved on the assembly of NCs with an anisotropic shape. A key challenge with the anisotropic NCs is assembling them into positional order with preferential atomic crystallographic orientations. Here, we use the air–liquid interface to prepare two-dimensional (2D) assemblies of crystalline gold nanodisks (AuNDs) with preferentially oriented atomic lattices and report on the in situ structural and optical properties of the nanostructures. The structure of 2D assemblies driven by in-plane surface pressure was monitored using grazing incidence small-angle X-ray scattering (GISAXS) and grazing incidence X-ray diffraction (GIXD), and optical properties were monitored using UV–vis spectroscopy. We observe that the preferentially oriented atomic lattice of the NDs leads to the formation of 2D hexagonal superlattices, exhibiting a continuous blue shift of the plasmonic band with increasing surface pressure. We quantify the packing by X-ray scattering to understand the plasmonic properties induced by the surface pressure. This controlled process to tune the plasmon resonance property paves a novel way to establish the essential correlation between the structure and properties of anisotropic NCs and opens door to the rational design of programmable NC networks.
A novel and highly specific Forssman antigen-binding protein from sheep polyomavirus
2023-04-10

Abstract Polyomaviruses are small, non-enveloped double-stranded DNA viruses of humans and other mammals, birds, and fish. Infections are usually asymptomatic and result in latency, however, some polyomaviruses can induce severe diseases, including cancer, in immunocompromised individuals. Established cellular receptors for polyomavirus infection are sialylated glycolipids (such as gangliosides), membrane proteins, and glycosaminoglycans. Polyomaviruses are usually highly host specific but the exact principles that govern host tropism remain unknown in many cases. Here, glycan array screening shows that the major capsid protein VP1 of sheep polyomavirus (ShPyV) binds to the Forssman glycolipid, an antigen of many vertebrates and a potential tumor marker in humans. Following closer investigation, we can report for the first time that a neutral, non-sialylated glycolipid acts as a polyomavirus receptor. Concurrently, we present the first report of a viral protein that specifically engages the Forssman antigen. We demonstrate that ShPyV VP1 binds to Forssman-positive erythrocytes but not those of human A, B and O blood groups, which is a clear distinction from features thus far described for Forssman lectins. X-ray crystallography and structural analysis of the VP1-Forssman glycan complex define the terminal Forssman disaccharide as the determinant of this protein-receptor interaction. These results strongly suggest that the sheep polyomavirus can use Forssman antigen for infectious cell entry. Furthermore, the ability of ShPyV VP1 to distinguish Forssman-positive from -negative cells may prove useful for monitoring the Forssman-‘status’ of normal, preneoplastic and neoplastic cells and tissues and establishing the antigen level as a biomarker. Author summary Elucidation of host cell receptor specificities of viral infection is crucial to understand the pathobiology of associated diseases and develop treatments. However, for many polyomaviruses the receptor engagement as the initial event in infection is poorly understood. In only a few cases polyomavirus tropism has been pinned down to a single type of glycan receptor. While many polyomaviruses utilize sialyl glycans to attach to host cells, the role of non-sialylated glycans as receptors is so far underestimated. Here, we show for the first time that a glycan of neutral charge, in this case the carbohydrate portion of the Forssman antigen, acts as a ligand for a polyomavirus capsid protein and may thus contribute to host tropism and infective cell entry. These results represent a significant addition to knowledge on polyomavirus-glycan interactions and complement general principles of carbohydrate engagement by viruses. Furthermore, as a specific binding protein of Forssman antigen, VP1 may help to determine levels of this antigen in healthy and malignant tissues in humans.
Visual Functions of the Primate Superior Colliculus
2023-04-11

The superior colliculus (SC) is a subcortical brain structure that is relevant for sensation, cognition, and action. In nonhuman primates, a rich history of studies has provided unprecedented detail about this structure's role in controlling orienting behaviors; as a result, the primate SC has become primarily regarded as a motor control structure. However, as in other species, the primate SC is also a highly visual structure: A fraction of its inputs is retinal and complemented by inputs from visual cortical areas, including the primary visual cortex. Motivated by this, recent investigations are revealing the rich visual pattern analysis capabilities of the primate SC, placing this structure in an ideal position to guide orienting movements. The anatomical proximity of the primate SC to both early visual inputs and final motor control apparatuses, as well as its ascending feedback projections to the cortex, affirms an important role for this structure in active perception.
The landscape of biomedical research
2023-04-11

Abstract The number of publications in biomedicine and life sciences has rapidly grown over the last decades, with over 1.5 million papers now being published every year. This makes it difficult to keep track of new scientific works and to have an overview of the evolution of the field as a whole. Here we present a 2D map of the entire corpus of biomedical literature, and argue that it provides a unique and useful overview of the life sciences research. We based our atlas on the abstract texts of 21 million English articles from the PubMed database. To embed the abstracts into 2D, we used the large language model PubMedBERT, combined with t -SNE tailored to handle samples of our size. We used our atlas to study the emergence of the Covid-19 literature, the evolution of the neuroscience discipline, the uptake of machine learning, the distribution of gender imbalance in academic authorship, and the distribution of retracted paper mill articles. Furthermore, we present an interactive web version of our atlas that allows easy exploration and will enable further insights and facilitate future research.
Is consolidative thoracic radiotherapy of extensive-stage small cell lung cancer still beneficial in the era of immunotherapy? A retrospective analysis
2023-04-11

Abstract Purpose Extensive-stage small cell lung cancer (ES-SCLC) carries a dismal prognosis. The benefit of consolidative thoracic radiotherapy (TR) after first-line chemoimmunotherapy with PD-L1 inhibitors in this setting remains unclear. As TR can improve overall survival (OS) after conventional chemotherapy, we retrospectively analyzed OS of an inhouse cohort treated either with TR or with chemoimmunotherapy alone. Methods A total of 41 patients treated with chemoimmunotherapy with PD-L1 inhibitors (atezolizumab or durvalumab) for ES-SCLC at our hospital since 2019 were analyzed. TR was administered in 10 fractions of 3 Gy. Patient characteristics, number of immunotherapy cycles received, brain irradiation, and presence of hepatic and cerebral metastasis at diagnosis were assessed. Primary endpoint was OS after first diagnosis. Results Consolidative TR was associated with a significantly longer OS than systemic therapy alone (1-year OS 78.6% and 2‐year OS 37.1% vs. 1‐year OS 39.7% and 2 years not reached, p = 0.019). With regard to radiotherapy indication, survival at 1 year was 88.9% (log-rank p = 0.016) for patients receiving consolidative TR. For patients receiving TR in case of progression, 1‐year survival was 66.7%. Hepatic and cerebral metastasis at first diagnosis had no significant effect on OS. Conclusion TR was significantly associated with longer OS. The survival benefit of TR was most pronounced for consolidative radiotherapy after initial chemoimmunotherapy compared to TR in case of progression. Although retrospective findings need to be interpreted with caution, in the absence of prospective data, our findings provide a basis for offering consolidative TR in the era of chemoimmunotherapy.
Inductive biases in deep learning models for weather prediction
2023-04-11

Deep learning has gained immense popularity in the Earth sciences as it enables us to formulate purely data-driven models of complex Earth system processes. Deep learning-based weather prediction (DLWP) models have made significant progress in the last few years, achieving forecast skills comparable to established numerical weather prediction models with comparatively lesser computational costs. In order to train accurate, reliable, and tractable DLWP models with several millions of parameters, the model design needs to incorporate suitable inductive biases that encode structural assumptions about the data and the modelled processes. When chosen appropriately, these biases enable faster learning and better generalisation to unseen data. Although inductive biases play a crucial role in successful DLWP models, they are often not stated explicitly and their contribution to model performance remains unclear. Here, we review and analyse the inductive biases of state-of-the-art DLWP models with respect to five key design elements: data selection, learning objective, loss function, architecture, and optimisation method. We identify the most important inductive biases and highlight potential avenues towards more efficient and probabilistic DLWP models.
Extreme outcomes accentuate overweighting of low probabilities and underweighting of high probabilities in experience-based choice
2023-04-11

Risk permeates decision making because choice outcomes are often uncertain. When basing decisions on prior experience, previous research suggests that the prospects of gain and loss differentially produce subjective inflation and deflation of risk-associated values, respectively. These effects have been explained in terms of an “extreme-outcome rule”, which posits that valuations of risky options are biased towards the best/worst possible outcome. However, prior studies typically examined risky choices only at the 50% level, and it was unclear whether the risk-preferences predicted by the “extreme outcome rule” would generalize to other probabilities. Furthermore, the cognitive processes underlying risk preferences remained unclear. We addressed these questions through three pre-registered experiments where the critical condition involved decisions between equivaluable safe and risky options across three probabilities (20%, 50%, 80%) with the goals of either maximizing gains or minimizing losses. We found that probability and risk context mutually influenced choice-behavior: low probabilities were particularly subjectively inflated, leading to a strong preference for rare, risky options when seeking gains and a strong aversion when mitigating losses. We also found that decisions involving risk require more cognitive resources, as indicated by longer decision times. Additionally, a risk-sensitive reinforcement model showed that risk-seeking/averse individuals tended to overweight positive/negative outcomes. This study highlights that outcome uncertainty, the range of possible outcomes a given choice option could yield, is a critical component in probability distortion and that subjective probability distortions may drive risk attitudes.
Cutaneous manifestations induced by check point inhibitors in 120 melanoma patients—The European MelSkinTox study
2023-04-12

Abstract Background Checkpoint inhibitors provide an effective approach for the melanoma treatment. They prolong lymphocyte effects, which explains the cytotoxicity underlying immune‐related adverse events (IrAEs). Cutaneous IrAEs affect nearly 40% of PD‐1i and 50% of CTLA4i‐treated patients. Severe cutaneous irAE do not often occur but could be life‐threatening and may persist despite treatment discontinuation. Methods We aimed to investigate cutaneous IrAEs in a cohort of patients treated with ICI across Europe in an effort to characterize the reactions in a real‐world, phase IV, post‐marketing study using a follow‐up questionnaire. Data since November 2016 until March 2021 were obtained from the Melskintox database, a European multicentric biobank dedicated to the follow‐up of melanoma and cutaneous adverse events, supported by EADO. The dermatoses reported were pooled into four categories: inflammatory dermatosis, bullous diseases, drug‐related eruptions and pigmentary diseases. Results Inflammatory benign dermatoses ( n = 63) represented the most common group of reactions (52.5%), followed by drug‐related eruptions ( n = 24, 20%), pigmentary diseases ( n = 23, 19.2%) and bullous diseases ( n = 10, 8.3%). Grade II ( n = 41, 34.2%) are represented by bullous pemphigoid, eczema, hypodermitis, lichenoid eruption, maculopapular rash, pruritus, psoriasis‐like rash, urticarial eruption and vitiligo. Grade III ( n = 18, 15.0%) are represented by bullous pemphigoid, lichenoid eruption and rashes. Grade IV ( n = 2, 1.7%) is only represented by bullous disease. Most cutaneous IrAEs led to immunotherapy continuation ( n = 95, 88.0%). CR is associated with more severe the cutaneous irAEs. We report an average time‐to‐onset of 208 days and some late‐onset events. Conclusion Our study has characterized the clinical spectrum of cutaneous irAEs, their timing and severity and their relationship with tumour response. Grade I–II cutaneous IrAE are easily managed allowing ongoing anticancer treatment. Severe late‐onset cutaneous irAE are not uncommon. A dermatological follow‐up helps mitigate the risk of life‐threatening adverse events. These findings highlight the importance of oncodermatological involvement in management of patients with melanoma receiving immunotherapy.
Brain insulin responsiveness is linked to age and peripheral insulin sensitivity
2023-04-12

Abstract Aims Insulin action in the brain influences cognitive processes, peripheral metabolism and eating behaviour. However, the influence of age and peripheral insulin sensitivity on brain insulin action remains unclear. Materials and Methods We used intranasal administration of insulin and functional magnetic resonance imaging in a randomized, placebo‐controlled within‐subject design in 110 participants (54 women, body mass index 18‐49 kg/m 2 , age 21‐74 years). Cerebral blood flow was measured before and after nasal spray application to assess brain insulin action. Peripheral insulin sensitivity was assessed by a five‐point oral glucose tolerance test. Linear regressions were used to investigate associations between age and peripheral insulin sensitivity with brain insulin action in predefined region of interests (i.e. insulin‐sensitive brain regions). Results We found significant negative associations between age and insulin action in the hippocampus (β = –0.215; p = .017) and caudate nucleus (β = –0.184; p = .047); and between peripheral insulin sensitivity and insulin action in the amygdala (β = –0.190, p = .023). Insulin action in the insular cortex showed an interaction effect between age and peripheral insulin sensitivity (β = –0.219 p = .005). Furthermore, women showed the strongest negative association between age and hippocampal insulin action, while men showed the strongest associations with peripheral insulin sensitivity and age in reward‐related brain regions. Conclusion We could show a region‐specific relationship between brain insulin responsiveness, age and peripheral insulin sensitivity. Our findings underline the need to study brain insulin action in both men and women and further substantiate that brain insulin sensitivity is a possible link between systemic metabolism and neurocognitive functions.
Functional membrane microdomains and the hydroxamate siderophore transporter ATPase FhuC govern Isd-dependent heme acquisition in Staphylococcus aureus
2023-04-12

Sufficient access to transition metals such as iron is essential for bacterial proliferation and their active limitation within host tissues effectively restricts infection. To overcome iron limitation, the invasive pathogen Staphylococcus aureus uses the iron-regulated surface determinant (Isd) system to acquire hemoglobin-derived heme. While heme transport over the cell wall is well understood, its transport over the membrane is hardly investigated. In this study, we show the heme-specific permease IsdF to be energized by the general ATPase FhuC. Additionally, we show that IsdF needs appropriate location within the membrane for functionality. The membrane of S. aureus possesses special compartments (functional membrane microdomains [FMMs]) to organize membrane complexes. We show IsdF to be associated with FMMs, to directly interact with the FMM scaffolding protein flotillin A (FloA) and to co-localize with the latter on intact bacterial cells. Additionally, Isd-dependent bacterial growth required FMMs and FloA. Our study shows that Isd-dependent heme acquisition requires a highly structured cell envelope to allow coordinated transport over the cell wall and membrane and it gives the first example of a bacterial nutrient acquisition system that depends on FMMs.
Paradigm model of online learning experience during COVID-19 crisis in higher education
2023-04-12

The study presents qualitative research on university students' online learning experience process at the higher education level. It used a grounded theory through semi-structured in-depth interviews with 25 university students for framing and structuring the paradigm model of university students' online learning experiences. A paradigm model illustrating this developmental process is presented, which includes the casual and contextual conditions that caused and evolved the central phenomenon for their online learning, the strategies used by the students to overcome external/internal disturbances in continuing their learning process, the conditions that helped/hindered those strategies, and the consequences. Finally, the following meaning units were discovered through the preceding paradigm model. The students started learning with a negative impression of unfamiliar learning methods such as online learning, but over time, they improved their self-management abilities and gained a broader understanding of self-discipline. In the midst of this, competence in digital literacy according to generational differences was also discovered as one of the factors affecting learning, forming a virtual community, and increasing personal learning through online interaction. Finally, the implications of the overall learning ecology for the future role of online learning were also considered. Based on this analysis of students' online learning experiences, the direction for online learning was suggested.
Relevant Membrane Transport Proteins as Possible Gatekeepers for Effective Pharmacological Ascorbate Treatment in Cancer
2023-04-12

Despite the increasing number of newly diagnosed malignancies worldwide, therapeutic options for some tumor diseases are unfortunately still limited. Interestingly, preclinical but also some clinical data suggest that the administration of pharmacological ascorbate seems to respond well, especially in some aggressively growing tumor entities. The membrane transport and channel proteins are highly relevant for the use of pharmacological ascorbate in cancer therapy and are involved in the transfer of active substances such as ascorbate, hydrogen peroxide, and iron that predominantly must enter malignant cells to induce antiproliferative effects and especially ferroptosis. In this review, the relevant conveying proteins from cellular surfaces are presented as an integral part of the efficacy of pharmacological ascorbate, considering the already known genetic and functional features in tumor tissues. Accordingly, candidates for diagnostic markers and therapeutic targets are mentioned.