julilili42/papers huggingface dataset:
Analysis of Amino Acid Variants in Malignant Melanoma Cells Resistant to BRAF inhibition
2020-12-15

Abstract Analysis of patient-specific nucleotide variants is a cornerstone of personalised medicine. Although only 2% of the genomic sequence is protein-coding, mutations occurring in these regions have the potential to influence protein structure and may have severe impact on disease aetiology. Of special importance are variants that affect modifiable amino acid residues, as protein modifications involved in signal transduction networks cannot be analysed by genomics. Proteogenomics enables analysis of proteomes in context of patient- or tissue-specific non-synonymous nucleotide variants. Here, we developed a proteogenomics workflow and applied it to study resistance to serine/threonine-protein kinase B-raf (BRAF) inhibitor (BRAFi) vemurafenib in malignant melanoma cell line A375. This approach resulted in high identification and quantification of non-synonymous nucleotide variants and (phospho)proteins. We integrated multi-omic datasets to reconstruct the perturbed signalling networks associated with BRAFi resistance and to predict drug therapies with the potential to disrupt BRAFi resistance mechanism in A375 cells. Notably, we showed that aurora kinase A (AURKA) inhibition is effective and specific against BRAFi resistant A375 cells. Furthermore, we investigated nucleotide variants that interfere with protein post-translational modification (PTM) status and potentially influence cell signalling. Mass spectrometry (MS) measurements confirmed variant-driven PTM changes in 12 proteins; among them was the runt-related transcription factor 1 (RUNX1) displaying a variant on a known phosphorylation site S(Ph)276L. We confirmed the loss of phosphorylation site by MS and demonstrated the impact of this variant on RUNX1 interactome.
CD137-stimulated cytotoxic T lymphocytes exert superior tumour control due to an enhanced antimitotic effect on tumour cells
2020-12-15

Abstract Several immunotherapeutic strategies for the treatment of cancer are under development. Two prominent strategies are adoptive cell transfer (ACT) of cytotoxic T lymphocytes (CTLs) and modulation of CTL function with immune checkpoint inhibitors or with costimulatory antibodies. Despite some success with these approaches, there remains a lack of detailed and quantitative descriptions of the events following CTL transfer and the impact of immunomodulation. Here, we have applied ordinary differential equation models to two photon imaging data derived from a B16F10 murine melanoma. Models were parameterised with data from two different treatment conditions: either ACT-only, or ACT with intratumoural costimulation using a CD137 targeted antibody. Model dynamics and best fitting parameters were compared, in order to assess the mode of action of the CTLs and examine how the CD137 antibody influenced their activities. We found that the cytolytic activity of the transferred CTLs was minimal without CD137 costimulation, and that the CD137 targeted antibody did not enhance the per-capita killing ability of the transferred CTLs. Instead, the results of our modelling study suggest that an antiproliferative effect of CTLs exerted upon the tumour likely accounted for the majority of the reduction in tumour growth after CTL transfer. We found that CD137 most likely improved tumour control via enhancement of this antiproliferative effect, as well as prolonging the period in which CTLs were inside the tumour, leading to a sustained duration of their antitumour effects following CD137 stimulation. Significance CTLs play an important role in controlling tumours, and improved understanding of how they accomplish this will benefit immunotherapeutic cancer treatment strategies. Stimulation of CTLs by targeting their CD137 receptor is a strategy currently under investigation for enhancing responses against tumours, yet so far only limited quantitative knowledge regarding the effects of such stimulation upon CTLs has been obtained. Here, we develop mathematical models to describe dynamic in vivo two-photon imaging of tumour infiltrating CTLs, to characterise differences in their function either in the presence or absence of a CD137 agonist antibody. We showed that an increased antiproliferative effect and a more sustained presence of CTLs within the tumour were the most significant effects associated with anti-CD137 treatment.
Non-Telecentric 2P microscopy for 3D random access mesoscale imaging at single cell resolution
2020-12-15

<title>Abstract</title> In neuroscience, diffraction limited two-photon (2P) microscopy is a cornerstone technique that permits minimally invasive optical monitoring of neuronal activity. However, most conventional 2P microscopes impose significant constraints on the size of the imaging field-of-view and the specific shape of the effective excitation volume, thus limiting the scope of biological questions that can be addressed and the information obtainable. Here, employing a non-telecentric (nTC) optical design, we present an ultra-low-cost, easily implemented and flexible solution to address these limitations, offering a several-fold expanded three-dimensional field of view that also maintains single-cell resolution. We show that this implementation also allows for straight-forward tailoring of the point-spread-function, increases effective excitation power, and achievable image brightness. Moreover, rapid laser-focus control via an electrically tunable lens allows near-simultaneous imaging of remote regions separated in three dimensions and permits the bending of imaging planes to follow natural curvatures in biological structures. Crucially, our core design is readily implemented (and reversed) within a matter of hours, and compatible with a wide range of existing 2P customizations, making it highly suitable as a base platform for further development. We demonstrate the application of our system for imaging neuronal activity in a variety of examples in zebrafish, mice and fruit flies.
Taking Skills Seriously: Toward an Integrative Model and Agenda for Social, Emotional, and Behavioral Skills
2020-12-16

Success in life is influenced by more than cognitive ability and opportunity. Success is also influenced by social, emotional, and behavioral (SEB) skills: a person’s capacities to maintain social relationships, regulate emotions, and manage goal- and learning-directed behaviors. In this article, we propose an integrative model that defines SEB skills as capacities (what someone is capable of doing) rather than personality traits (what someone tends to do) and identifies five major skill domains: social engagement, cooperation, self-management, emotional resilience, and innovation. We then argue that operational measures of SEB skills should reflect rather than obscure the distinction between skills and traits. Finally, we propose an agenda for future work by highlighting open questions and hypotheses about the assessment, development, and outcomes of SEB skills as well as interventions and public policy targeting these skills.
Saving the most lives—A comparison of European triage guidelines in the context of the COVID‐19 pandemic
2020-12-16

Abstract In March 2020, the rapid increase in severe COVID‐19 cases overwhelmed the healthcare systems in several European countries. The capacities for artificial ventilation in intensive care units were too scarce to care for patients with acute respiratory disorder connected to the disease. Several professional associations published COVID‐19 triage recommendations in an extremely short time: in 21 days between March 6 and March 27. In this article, we compare recommendations from five European countries, which combine medical and ethical reflections on this situation in some detail. Our aim is to provide a detailed overview on the ethical elements of the recommendations, the differences between them and their coherence. In more general terms we want to identify shortcomings in regard to a common European response to the current situation.
Softwarization of Automotive E/E Architectures: A Software-Defined Networking Approach
2020-12-16

Traditional in-vehicle networks are based on low-bandwidth technologies like CAN. They are statically deployed and configured in the manufacturing process depending on the vehicle configuration. With the introduction of additional camera and entertainment applications and increased bandwidth demand, Ethernet technology becomes more relevant in the automotive sector. Use cases like trailer networks and integration of new applications requiring in-vehicle sensor data require reconfigurable network architectures. In this work, we propose a flexible architecture for automotive Ethernet networks accommodating both high-bandwidth multimedia streams and time-critical low bandwidth data. Based on the software-defined networking paradigm, the in-vehicle network can be re-configured for the integration of additional hardware and applications. We illustrate its concepts for operations, management, safety, and security.
Characterization of the GABRB2‐Associated Neurodevelopmental Disorders
2020-12-16

Objective We aimed to characterize the phenotypic spectrum and functional consequences associated with variants in the gene GABRB2 , coding for the γ‐aminobutyric acid type A (GABA A ) receptor subunit β2. Methods We recruited and systematically evaluated 25 individuals with variants in GABRB2 , 17 of whom are newly described and 8 previously reported with additional clinical data. Functional analysis was performed using a Xenopus laevis oocyte model system. Results Our cohort of 25 individuals from 22 families with variants in GABRB2 demonstrated a range of epilepsy phenotypes from genetic generalized epilepsy to developmental and epileptic encephalopathy. Fifty‐eight percent of individuals had pharmacoresistant epilepsy; response to medications targeting the GABAergic pathway was inconsistent. Developmental disability (present in 84%) ranged from mild intellectual disability to severe global disability; movement disorders (present in 44%) included choreoathetosis, dystonia, and ataxia. Disease‐associated variants cluster in the extracellular N‐terminus and transmembrane domains 1–3, with more severe phenotypes seen in association with variants in transmembrane domains 1 and 2 and the allosteric binding site between transmembrane domains 2 and 3. Functional analysis of 4 variants in transmembrane domains 1 or 2 (p.Ile246Thr, p.Pro252Leu, p.Ile288Ser, p.Val282Ala) revealed strongly reduced amplitudes of GABA‐evoked anionic currents. Interpretation GABRB2 ‐related epilepsy ranges broadly in severity from genetic generalized epilepsy to developmental and epileptic encephalopathies. Developmental disability and movement disorder are key features. The phenotypic spectrum is comparable to other GABA A receptor‐encoding genes. Phenotypic severity varies by protein domain. Experimental evidence supports loss of GABAergic inhibition as the mechanism underlying GABRB2 ‐associated neurodevelopmental disorders. ANN NEUROL 2021;89:573–586
Direct observation of layer-stacking and oriented wrinkles in multilayer hexagonal boron nitride
2020-12-16

Abstract Hexagonal boron nitride ( h -BN) has long been recognized as an ideal substrate for electronic devices due to its dangling-bond-free surface, insulating nature and thermal/chemical stability. These properties of the h -BN multilayer are mainly determined by its lattice structure. Therefore, to analyse the lattice structure and orientation of h -BN crystals becomes important. Here, the stacking order and wrinkles of h -BN are investigated by transmission electron microscopy. It is experimentally confirmed that the layers in the h -BN flakes are arranged in the AA′ stacking. The wrinkles in a form of threefold network throughout the h -BN crystal are oriented along the armchair direction, and their formation mechanism was further explored by molecular dynamics simulations. Our findings provide a deep insight about the microstructure of h -BN and shed light on the structural design/electronic modulations of two-dimensional crystals.
Enfortumab vedotin – next game-changer in urothelial cancer
2020-12-16

<b><i>Introduction</i></b>: The therapeutic landscape of metastatic urothelial carcinoma (mUC) becomes increasingly dense: standard therapy remains cisplatin-based chemotherapy, followed by immunotherapy with checkpoint inhibitors as maintenance or second-line. New directions include erdafitinib, a fibroblast growth factor receptor (FGFR) inhibitor in patients with corresponding mutations in FGFR2/3 receptor. Enfortumab vedotin (EV) is an antibody-drug conjugate targeting nectin-4 and is conjugated with monomethyl auristatin E (MMAE). It received FDA approval based on phase I/II data recently and thus represents an alternative to established third-line chemotherapies with vinflunine, paclitaxel, or docetaxel.<b><i>Areas covered</i></b>: The aim of this review was to evaluate the added value of Enfortumab vedotin in the therapeutic landscape of mUC. Current therapeutic options and alternatives for the affected patients are described, followed by a detailed description of the characteristics and available results of EV. Ongoing studies are explained, the present significance of the substance is assessed and its further future potential is outlined.<b><i>Expert opinion</i></b> Enfortumab vedotin has shown encouraging efficacy and a good tolerability in phase I/II trials, especially in heavily pretreated patients and patients with liver metastases. It appears to outperform third-line chemotherapies; ongoing studies will show the future potential of EV in treatment sequence.
Genome-wide association studies of LRRK2 modifiers of Parkinson's disease
2020-12-16

Objective: The aim of this study was to search for genes/variants that modify the effect of LRRK2 mutations in terms of penetrance and age-at-onset of Parkinson's disease. Methods: We performed the first genome-wide association study of penetrance and age-at-onset of Parkinson's disease in LRRK2 mutation carriers (776 cases and 1,103 non-cases at their last evaluation). Cox proportional hazard models and linear mixed models were used to identify modifiers of penetrance and age-at-onset of LRRK2 mutations, respectively. We also investigated whether a polygenic risk score derived from a published genome-wide association study of Parkinson's disease was able to explain variability in penetrance and age-at-onset in LRRK2 mutation carriers. Results: A variant located in the intronic region of CORO1C on chromosome 12 (rs77395454; P-value=2.5E-08, beta=1.27, SE=0.23, risk allele: C) met genome-wide significance for the penetrance model. A region on chromosome 3, within a previously reported linkage peak for Parkinson's disease susceptibility, showed suggestive associations in both models (penetrance top variant: P-value=1.1E-07; age-at-onset top variant: P-value=9.3E-07). A polygenic risk score derived from publicly available Parkinson's disease summary statistics was a significant predictor of penetrance, but not of age-at-onset. Interpretation: This study suggests that variants within or near CORO1C may modify the penetrance of LRRK2 mutations. In addition, common Parkinson's disease associated variants collectively increase the penetrance of LRRK2 mutations.
Neurobiobehavioral responses to virtual social rejection in females—exploring the influence of oxytocin
2020-12-16

Abstract In recent years, especially adolescents and young adults interact frequently via social media and digital communication. Mimicking an online communication platform where participants could initiate short conversations with two computerized interlocutors, the Verbal Interaction Social Threat Task (VISTTA) was used to induce feelings of social rejection. Motivational and physiological reactions were investigated in 43 healthy young women undergoing functional magnetic resonance imaging (fMRI), of which 22 received 24 international units (IU) intranasal oxytocin and 21 received placebo. Replicating previous findings, social rejection entailed a lower willingness to cooperate with the two peers. Increased activation in the anterior cingulate cortex and bilateral insula/inferior frontal gyrus was observed when receiving negative feedback from others, and in the precuneus when subsequently rating one’s willingness to cooperate with them in the future. Oxytocin did not seem to alter responses to social rejection. The current findings provide validation of the VISTTA for examining consequences of rejection in a virtual social interaction that bears a strong resemblance to online communication platforms.
Comparison of regolith physical and chemical characteristics with geophysical data along a climate and ecological gradient, Chilean Coastal Cordillera (26 to 38° S)
2020-12-16

Abstract. We combine geophysical observations from ground-penetrating radar (GPR) with regolith physical and chemical properties from pedons excavated in four study areas spanning 1300 km of the climate and ecological gradient in the Chilean Coastal Cordillera. Our aims are the following: (1) to relate GPR observations to depth-varying regolith physical and weathering-related chemical properties in adjacent pedons and (2) to evaluate the lateral extent to which these properties can be extrapolated along a hillslope using GPR observations. Physical observations considered include regolith bulk density and grain size distribution, whereas chemical observations are based on major and trace element analysis. Results indicate that visually determined pedolith thickness and the transition from the B to C horizons generally correlate with maximums in the 500 and 1000 MHz GPR envelope profiles. To a lesser degree, these maximums in the GPR envelope profiles agree with maximums in weathering-related indices such as the chemical index of alteration (CIA) and the chemical index of mass transfer (τ) for Na. Finally, we find that upscaling from the pedon to hillslope scale is possible with geophysical methods for certain pedon properties. Taken together, these findings suggest that the GPR profiles down hillslopes can be used to infer lateral thickness variations in pedolith horizons in different ecologic and climate settings, and to some degree the physical and chemical variations with depth.
The Impact of Biomaterial Cell Contact on the Immunopeptidome
2020-12-16

Biomaterials play an increasing role in clinical applications and regenerative medicine. A perfectly designed biomaterial should restore the function of damaged tissue without triggering an undesirable immune response, initiate self-regeneration of the surrounding tissue and gradually degrade after implantation. The immune system is well recognized to play a major role in influencing the biocompatibility of implanted medical devices. To obtain a better understanding of the effects of biomaterials on the immune response, we have developed a highly sensitive novel test system capable of examining changes in the immune system by biomaterial. Here, we evaluated for the first time the immunopeptidome, a highly sensitive system that reflects cancer transformation, virus or drug influences and passes these cellular changes directly to T cells, as a test system to examine the effects of contact with materials. Since monocytes are one of the first immune cells reacting to biomaterials, we have tested the influence of different materials on the immunopeptidome of the monocytic THP-1 cell line. The tested materials included stainless steel, aluminum, zinc, high-density polyethylene, polyurethane films containing zinc diethyldithiocarbamate, copper, and zinc sulfate. The incubation with all material types resulted in significantly modulated peptides in the immunopeptidome, which were material-associated. The magnitude of induced changes in the immunopeptidome after the stimulation appeared comparable to that of bacterial lipopolysaccharides (LPS). The source proteins of many detected peptides are associated with cytotoxicity, fibrosis, autoimmunity, inflammation, and cellular stress. Considering all tested materials, it was found that the LPS-induced cytotoxicity-, inflammation- and cellular stress-associated HLA class I peptides were mainly induced by aluminum, whereas HLA class II peptides were mainly induced by stainless steel. These findings provide the first insights into the effects of biomaterials on the immunopeptidome. A more thorough understanding of these effects may enable the design of more biocompatible implant materials using in vitro models in future. Such efforts will provide a deeper understanding of possible immune responses induced by biomaterials such as fibrosis, inflammation, cytotoxicity, and autoimmune reactions.
Constraints on CP-Odd ALP Couplings from EDM Limits of Fermions
2020-12-16

We discuss constraints on soft CP-violating couplings of axion-like particles with photon and fermions by using data on electric dipole moments of standard model particles. In particular, for the axion-like particle (ALP) leptophilic scenario, we derive bounds on CP-odd ALP-photon-photon coupling from data of the ACME collaboration on electron EDM. We also discuss prospects of the storage ring experiment to constrain the ALP–photon–photon coupling from data on proton EDM for the simplified hadrophilic interactions of ALP. The resulting constraints from experimental bounds on the muon and neutron EDMs are weak. We set constraint on the CP-odd ALP coupling with electron and derive bounds on combinations of coupling constants, which involve soft CP-violating terms.
23.5% efficient monolithic perovskite/organic tandem solar cells based on an ultra-thin metal-like metal-oxide interconnect.
2020-12-16

<title>Abstract</title> Multi-junction solar cells provide an avenue to overcome fundamental efficiency limits of single-junction devices. The facile bandgap tunability of metal-halide perovskite solar cells renders them attractive building blocks for multi-junction architectures. Combinations with crystalline silicon and copper indium gallium selenide (CIGS) cells have been reported. All-perovskite tandem cells have likewise shown promising results. Meanwhile, narrow-gap non-fullerene acceptors (NFA) have revived the area of organic solar cells (OSCs) and unlocked skyrocketing efficiencies. Organic and perovskite semiconductors share similar processing technologies, which renders them attractive partners in multi junction architectures. As of yet, perovskite/organic tandem cells show subpar efficiencies of 20 per cent, limited by the low open circuit voltage (Voc) of wide-gap perovskite cells and losses introduced by the interconnect between the sub-cells. Here, we demonstrate two-terminal p-i-n perovskite/organic tandem cells with an efficiency of 23.5 per cent and a high Voc of 2.15 volts, operating near the levels predicted by a semi-empirical model. The perovskite sub-cells with optimized charge extraction layers afford an unsurpassed combination of a high Voc and fill-factor. The organic back-cells provide a high external quantum efficiency in the near-infrared. In surprising contrast to paradigmatic concerns about limited photostability of non-fullerene cells, we evidence an outstanding operational stability if excitons are predominantly generated on the NFA, which is the case in a tandem cell, where the illumination is spectrally filtered by the perovskite cell. A novel interconnect based on an ultra-thin (1.5 nanometers) metal like indium oxide layer offers unprecedented low optical/electrical losses. This work sets a new milestone for perovskite/organic tandem devices, that outperform the best p-i-n perovskite single junctions and are at par with perovskite/CIGS and all-perovskite multi-junctions. Perovskite/organic tandem architectures bear a realistic potential to reach an efficiency above 31%.