julilili42/papers huggingface dataset:
The origin of potency and mutant-selective inhibition by bivalent ATP-allosteric EGFR inhibitors
2023-09-26

Targeted small-molecule therapies in mutant epidermal growth factor receptor (EGFR) non-small cell lung cancer (NSCLC) have undergone several generations of development in response to acquired drug resistance. With the emergence of the highly prevalent T790M and C797S drug-resistant mutations, a diverse arsenal of ATP-competitive molecules has led to the front-line drug AZD9291 (osimertinib) and several in clinical development. Several allosteric inhibitors bind a site adjacent to the ATP-binding site and exhibit synergy when dosed in combination with certain ATP-competitive inhibitors. Structure-guided design of molecules that anchor to both sites simultaneously, namely ATP-allosteric bivalent inhibitors, have been reported as proof-of-concept EGFR mutant-selective compounds, however their properties are underexplored and currently exhibit modest activity in human cancer cell lines. To better understand the structural and functional properties of such molecules, we have carried out structure-activity relationships (SAR) defining the groups of the allosteric pocket that are responsible for enabling mutant selectivity and potency of this series. We find that the back pocket phenol ring enables stronger binding while the methylisoindolinone is responsible for enabling selectivity for the oncogenic mutations. An optimized allosteric site-binding group and a C797-targeting ATP-site scaffold exhibit inhibitory effects in a variety of EGFR mutant cell lines, which is improved over earlier examples. Additionally, a closely related reversible-binding analogue exhibits mutant-selective activity and ~1 nM biochemical potency against L858R/T790M/C797S and promising antiproliferative effects in human cancer cells indicating that ATP-allosteric bivalent kinase inhibitors may serve as tool compounds in understanding overcoming these important resistance mechanisms. These results highlight the utility of bivalent ATP-allosteric compounds in understanding the impact certain functional groups have in the potency and mutant-selectivity enabled by allosteric pocket binding. The results of this study incentivize further investigations of compounds that bind within an exit vector made accessible in the inactive αC-helix “out” conformation as a novel approach for kinase inhibitors.
Perivascular space enlargement accelerates with hypertension, white matter hyperintensities, chronic inflammation, and Alzheimer’s disease pathology: evidence from a three-year longitudinal multicentre study
2023-09-26

Abstract Background Perivascular space (PVS) enlargement in ageing and Alzheimer’s disease (AD) and its exacerbators require further investigation. Methods We studied centrum semiovale (CSO) and basal ganglia (BG) PVS computationally over three to four annual visits in 557 participants of the DZNE multicentre DELCODE cohort. We tested volumetric changes of PVS in relation to ageing, sex, years of education, hypertension, AD diagnosis, and cerebrospinal-fluid-derived Amyloid and Tau positivity and interleukin 6 (IL-6). Results PVS volumes increased over time. PVS enlargement was associated with baseline white matter hyperintensities. BG-PVS enlargement was related to age and was faster with hypertension. CSO-PVS volumes increased faster with Amyloid and Tau positivity. Higher CSF IL-6 levels predicted PVS volume expansion in both regions and were associated with accelerated PVS enlargement in individuals with Amyloid and Tau positivity. Conclusion Our work supports the region-specific involvement of white matter hyperintensities, neurotoxic waste accumulation, and inflammation in PVS enlargement.
Dynamic evolutionary interplay between ontogenetic skull patterning and whole-head integration
2023-09-26

Data and code for the analysis in Ollonen et al., 2024, Dynamic evolutionary interplay between ontogenetic skull patterning and whole-head integration, Nature Ecology and Evolution. Raw landmark data, R scripts for the analysis and surface files used for the analysis as well as figure visualisations. Cite the original article, not the dataset citation!!!
Beyond generalization: a theory of robustness in machine learning
2023-09-27

Abstract The term robustness is ubiquitous in modern Machine Learning (ML). However, its meaning varies depending on context and community. Researchers either focus on narrow technical definitions, such as adversarial robustness, natural distribution shifts, and performativity, or they simply leave open what exactly they mean by robustness. In this paper, we provide a conceptual analysis of the term robustness , with the aim to develop a common language, that allows us to weave together different strands of robustness research. We define robustness as the relative stability of a robustness target with respect to specific interventions on a modifier. Our account captures the various sub-types of robustness that are discussed in the research literature, including robustness to distribution shifts, prediction robustness, or the robustness of algorithmic explanations. Finally, we delineate robustness from adjacent key concepts in ML, such as extrapolation, generalization, and uncertainty, and establish it as an independent epistemic concept.
Investigation of the anti-cancer potential of epoxyazadiradione in neuroblastoma: experimental assays and molecular analysis
2023-09-27

Neuroblastoma, the most common childhood solid tumor, originates from primitive sympathetic nervous system cells. Epoxyazadiradione (EAD) is a limonoid derived from <i>Azadirachta indica</i>, belonging to the family Meliaceae. In this study, we isolated the EAD from <i>Azadirachta indica</i> seed and studied the anti-cancer potential against neuroblastoma. Herein, EAD demonstrated significant efficacy against neuroblastoma by suppressing cell proliferation, enhancing the rate of apoptosis and cycle arrest at the SubG<sub>0</sub> and G<sub>2</sub>/M phases. EAD enhanced the pro-apoptotic Caspase 3 and Caspase 9 and inhibited the NF-kβ translocation in a dose-dependent manner. In order to identify the specific EAD target, a gel-free quantitative proteomics study on SH-SY5Y cells using Liquid Chromatography with tandem mass spectrometry was done in a dose-dependent manner, followed by detailed bioinformatics analysis to identify effects on protein. Proteomics data identified that Enolase1 and HSP90 were up-regulated in neuroblastoma. EAD inhibited the expression of Enolase1 and HSP90, validated by mRNA expression, immunoblotting, Enolase1 and HSP90 kit and flow-cytometry based bioassay. Molecular docking study, Molecular dynamic simulation, and along with molecular mechanics/Poisson-Boltzmann surface area analysis also suggested that EAD binds at the active site of the proteins and were stable throughout the 100 ns Molecular dynamic simulation study. Overall, this study suggested EAD exhibited anti-cancer activity against neuroblastoma by targeting Enolase1 and HSP90 pathways.Communicated by Ramaswamy H. Sarma.
Interictal epileptiform discharges contribute to word‐finding difficulty in epilepsy through multiple cognitive mechanisms
2023-09-27

Abstract Objective Cognitive impairment often impacts quality of life in epilepsy even if seizures are controlled. Word‐finding difficulty is particularly prevalent and often attributed to etiological (static, baseline) circuit alterations. We sought to determine whether interictal discharges convey significant superimposed contributions to word‐finding difficulty in patients, and if so, through which cognitive mechanism(s). Methods Twenty‐three patients undergoing intracranial monitoring for drug‐resistant epilepsy participated in multiple tasks involving word production (auditory naming, short‐term verbal free recall, repetition) to probe word‐finding difficulty across different cognitive domains. We compared behavioral performance between trials with versus without interictal discharges across six major brain areas and adjusted for intersubject differences using mixed‐effects models. We also evaluated for subjective word‐finding difficulties through retrospective chart review. Results Subjective word‐finding difficulty was reported by the majority (79%) of studied patients preoperatively. During intracranial recordings, interictal epileptiform discharges (IEDs) in the medial temporal lobe were associated with long‐term lexicosemantic memory impairments as indexed by auditory naming ( p = .009), in addition to their established impact on short‐term verbal memory as indexed by free recall ( p = .004). Interictal discharges involving the lateral temporal cortex and lateral frontal cortex were associated with delayed reaction time in the auditory naming task ( p = .016 and p = .018), as well as phonological working memory impairments as indexed by repetition reaction time ( p = .002). Effects of IEDs across anatomical regions were strongly dependent on their precise timing within the task. Significance IEDs appear to act through multiple cognitive mechanisms to form a convergent basis for the debilitating clinical word‐finding difficulty reported by patients with epilepsy. This was particularly notable for medial temporal spikes, which are quite common in adult focal epilepsy. In parallel with the treatment of seizures, the modulation of interictal discharges through emerging pharmacological means and neurostimulation approaches may be an opportunity to help address devastating memory and language impairments in epilepsy.
Development of a PNGase Rc Column for Online Deglycosylation of Complex Glycoproteins during HDX-MS
2023-09-27

Protein glycosylation is one of the most common PTMs and many cell surface receptors, extracellular proteins, and biopharmaceuticals are glycosylated. However, HDX-MS analysis of such important glycoproteins has so far been limited by difficulties in determining the HDX of the protein segments that contain glycans. We have developed a column containing immobilized PNGase Rc (from <i>Rudaea cellulosilytica</i>) that can readily be implemented into a conventional HDX-MS setup to allow improved analysis of glycoproteins. We show that HDX-MS with the PNGase Rc column enables efficient online removal of N-linked glycans and the determination of the HDX of glycosylated regions in several complex glycoproteins. Additionally, we use the PNGase Rc column to perform a comprehensive HDX-MS mapping of the binding epitope of a mAb to c-Met, a complex glycoprotein drug target. Importantly, the column retains high activity in the presence of common quench-buffer additives like TCEP and urea and performed consistent across 114 days of extensive use. Overall, our work shows that HDX-MS with the integrated PNGase Rc column can enable fast and efficient online deglycosylation at harsh quench conditions to provide comprehensive analysis of complex glycoproteins.
Allure of Simplicity
2023-09-27

This paper develops an account of the opacity problem in medical machine learning (ML). Guided by pragmatist assumptions, I argue that opacity in ML models is problematic insofar as it potentially undermines the achievement of two key purposes: ensuring generalizability and optimizing clinician–machine decision-making. Three opacity amelioration strategies are examined, with explainable artificial intelligence (XAI) as the predominant approach, challenged by two revisionary strategies in the form of reliabilism and the interpretability by design. Comparing the three strategies, I argue that interpretability by design is most promising to overcome opacity in medical ML. Looking beyond the individual opacity amelioration strategies, the paper also contributes to a deeper understanding of the problem space and the solution space regarding opacity in medical ML.
Novel drug transporter substrates identification: An innovative approach based on metabolomic profiling, in silico ligand screening and biological validation
2023-09-27

Solute carrier (SLC) transport proteins are fundamental for the translocation of endogenous compounds and drugs across membranes, thus playing a critical role in disease susceptibility and drug response. Because only a limited number of transporter substrates are currently known, the function of a large number of SLC transporters is elusive. Here, we describe the proof-of-concept of a novel strategy to identify SLC transporter substrates exemplarily for the proton-coupled peptide transporter (PEPT) 2 (SLC15A2) and multidrug and toxin extrusion (MATE) 1 transporter (SLC47A1), which are important renal transporters of drug reabsorption and excretion, respectively. By combining metabolomic profiling of mice with genetically-disrupted transporters, in silico ligand screening and in vitro transport studies for experimental validation, we identified nucleobases and nucleoside-derived anticancer and antiviral agents (flucytosine, cytarabine, gemcitabine, capecitabine) as novel drug substrates of the MATE1 transporter. Our data confirms the successful applicability of this new approach for the identification of transporter substrates in general, which may prove particularly relevant in drug research.
Linguistic law-like compression strategies emerge to maximize coding efficiency in marmoset vocal communication
2023-09-27

Human language follows statistical regularities or linguistic laws. For instance, Zipf's law of brevity states that the more frequently a word is used, the shorter it tends to be. All human languages adhere to this word structure. However, it is unclear whether Zipf's law emerged de novo in humans or whether it also exists in the non-linguistic vocal systems of our primate ancestors. Using a vocal conditioning paradigm, we examined the capacity of marmoset monkeys to efficiently encode vocalizations. We observed that marmosets adopted vocal compression strategies at three levels: (i) increasing call rate, (ii) decreasing call duration and (iii) increasing the proportion of short calls. Our results demonstrate that marmosets, when able to freely choose what to vocalize, exhibit vocal statistical regularities consistent with Zipf's law of brevity that go beyond their context-specific natural vocal behaviour. This suggests that linguistic laws emerged in non-linguistic vocal systems in the primate lineage.
XBP1 promotes NRASG12D pre‐B acute lymphoblastic leukaemia through IL‐7 receptor signalling and provides a therapeutic vulnerability for oncogenic RAS
2023-09-27

Abstract Activating point mutations of the RAS gene act as driver mutations for a subset of precursor‐B cell acute lymphoblastic leukaemias (pre‐B ALL) and represent an ambitious target for therapeutic approaches. The X box‐binding protein 1 (XBP1), a key regulator of the unfolded protein response (UPR), is critical for pre‐B ALL cell survival, and high expression of XBP1 confers poor prognosis in ALL patients. However, the mechanism of XBP1 activation has not yet been elucidated in RAS mutated pre‐B ALL. Here, we demonstrate that XBP1 acts as a downstream linchpin of the IL‐7 receptor signalling pathway and that pharmacological inhibition or genetic ablation of XBP1 selectively abrogates IL‐7 receptor signalling via inhibition of its downstream effectors, JAK1 and STAT5. We show that XBP1 supports malignant cell growth of pre‐B NRAS G12D ALL cells and that genetic loss of XBP1 consequently leads to cell cycle arrest and apoptosis. Our findings reveal that active XBP1 prevents the cytotoxic effects of a dual PI3K/mTOR pathway inhibitor (BEZ235) in pre‐B NRAS G12D ALL cells. This implies targeting XBP1 in combination with BEZ235 as a promising new targeted strategy against the oncogenic RAS in NRAS G12D ‐mutated pre‐B ALL.
Combining traditional and novel techniques to increase our understanding of the lock-in depth of atmospheric gases in polar ice cores - results from the EastGRIP region
2023-09-27

Abstract. We investigate the lock-in zone (LIZ) of the EastGRIP region, Northeast Greenland, in detail. We present results from the firn air pumping campaign of the S6 borehole, forward modeling, and a novel technique for finding the lock-in depth (LID, the top of the LIZ) based on the visual stratigraphy of the EastGRIP ice core. The findings in this work help to deepen our knowledge of how atmospheric gases are trapped in ice cores. CO2, δ15N, and CH4 data suggest the LID lies around 58 to 61 m depth. With the grayscale and bright spot analysis based on visual stratigraphy, we can pinpoint a change in ice properties to exactly 58.3 m depth, which we define as the optical lock-in depth (OLID). This visual change in ice properties is caused by the formation of rounded and enclosed air bubbles, altering the measured refraction of the light pathways. The results for the LID and OLID agree accurately on the depth. We furthermore use the visual stratigraphy images to obtain information on the sharpness of the open to closed porosity transition. Combing traditional methods with the independent optical method presented here, we can now better constrain the bubble closure processes in polar firn.
Using an $$A^*$$-based framework for decomposing combinatorial optimization problems to employ NISQ computers
2023-09-27

Abstract Combinatorial optimization problems such as the traveling salesperson problem are ubiquitous in practical applications and notoriously difficult to solve optimally. Hence, many current endeavors focus on producing approximate solutions. The use of quantum computers could accelerate the generation of those approximate solutions or yield more exact approximations in comparable time. However, quantum computers are presently very limited in size and fidelity. In this work, we aim to address the issue of limited problem size by developing a scheme that decomposes a combinatorial optimization problem instance into arbitrarily small subinstances that can be solved on a quantum machine. This process utilizes A * as a foundation. Additionally, we present heuristics that reduce the runtime of the algorithm effectively, albeit at the cost of optimality. In experiments, we find that the heavy dependence of our approach on the choice of the heuristics used allows for a modifiable framework that can be adapted case by case instead of a concrete procedure.
“[...] naturam [...] divinam seu verum Deum [...] passum esse et mortuum”
2023-09-27

Summary The paper discusses the question to what extent one can speak of a genus tapeinoticum in Luther, or of a communication of the properties of nature to nature that is both direct and symmetrical. The thesis is that in the 1540 s Luther significantly modifies his earlier rejection of the idea of a passibility of divine nature as such by means of the distinctions between ‘concretum’ and ‘abstractum’ as well as between ‘relativum’ and ‘absolutum’. The boundary between passibility and impassibility does not run between the Son on the one hand and the Father and the Spirit on the other, but between the deus relativus and what might be called the ‘absolute-relative’ God.
To whom do people reply in comment sections? Effects of attitude (un)congeniality, age, confidence, and knowledge
2023-09-27

Research on selective exposure typically yields a congeniality bias, a preference to choose attitudinally congenial (vs. uncongenial) information for consumption. Recent work has proposed selective response which yields an uncongeniality bias, a preference to choose uncongenial information for replying in social media contexts. Three studies (total N = 1524) explore boundary conditions of selective response. Studies 1 (student sample) and 2 (non-student sample) generalizesthe uncongeniality bias to different contexts (discussion topic, discussion style). However, Study 3 (representative for age and gender in Germany) yielded a surprising congeniality bias (a preference for replying to congenial posts) which was moderated by age. Moreover, all three studies investigated the moderating role of climate change knowledge and confidence in one’s knowledge. Results suggestthat high confidence is associated with increased engagement (higher likelihood to reply), but reduced antagonism. In contrast, high climate change knowledge reduces engagement, but increases the uncongeniality bias.
Impact of Tracer Dose Reduction in [18 F]-Labelled Fluorodeoxyglucose-Positron Emission Tomography ([18 F]-FDG)-PET) on Texture Features and Histogram Indices: A Study in Homogeneous Tissues of Phantom and Patient
2023-09-27

Background: Histogram indices (HIs) and texture features (TFs) are considered to play an important role in future oncologic PET-imaging and it is unknown how these indices are affected by changes of tracer doses. A randomized undersampling of PET list mode data enables a simulation of tracer dose reduction. We performed a phantom study to compare HIs/TFs of simulated and measured tracer dose reductions and evaluated changes of HIs/TFs in the liver of patients with PETs from simulated reduced tracer doses. Overall, 42 HIs/TFs were evaluated in a NEMA phantom at measured and simulated doses (stepwise reduction of [18 F] from 100% to 25% of the measured dose). [18 F]-FDG-PET datasets of 15 patients were simulated from 3.0 down to 0.5 MBq/kgBW in intervals of 0.25 MBq/kgBW. HIs/TFs were calculated from two VOIs placed in physiological tissue of the right and left liver lobe and linear correlations and coefficients of variation analysis were performed. Results: All 42 TFs did not differ significantly in measured and simulated doses (p &gt; 0.05). Also, 40 TFs showed the same behaviour over dose reduction regarding differences in the same group (measured or simulated), and for 26 TFs a linear behaviour over dose reduction for measured and simulated doses could be validated. Out of these, 13 TFs could be identified, which showed a linear change in TF value in both the NEMA phantom and patient data and therefore should maintain the same informative value when transferred in a dose reduction setting. Out of this Homogeneity 2, Entropy and Zone size non-uniformity are of special interest because they have been described as preferentially considerable for tumour heterogeneity characterization. Conclusions: We could show that there was no significant difference of measured and simulated HIs/TFs in the phantom study and most TFs reveal a linear behaviour over dose reduction, when tested in homogeneous tissue. This indicates that texture analysis in PET might be robust to dose modulations.
Expansion and ongoing cosmic ray acceleration in HESS J1731-347
2023-09-27

Diffusive shock acceleration in supernova remnants (SNRs) is considered one of the prime mechanisms for Galactic Cosmic Ray (GCR) acceleration. It is still unclear, however, whether SNRs can contribute to GCR spectrum up to the ``knee'' (1\\,PeV) band as acceleration to such energies requires an efficient magnetic field amplification process around the shocks. The presence of such a process is challenging to test observationally. Here we report on the detection of fast variability of the X-ray synchrotron emission from the forward shock in the supernova remnant HESS J1731-347, which implies the presence of a strong ( 0.2\\,mG) field exceeding background values and thus of effective field amplification. We also report a direct measurement of the high forward shock expansion velocity of 4000-5500\\,km/s confirming that the SNR is expanding in a tenuous wind bubble blown by the SNR progenitor, is significantly younger (2.4-9\\,kyr) than previously assumed by some authors, and only recently started interaction with the dense material outside the bubble. We finally conclude that there is strong evidence for ongoing hadronic CR acceleration in this SNR.
Data for Center-surround interactions underlie bipolar cell motion sensitivity in the mouse retina
2023-09-27

Data from the publication "Center-surround interactions underlie bipolar cell motion sensitivity in the mouse retina" published in <em>Nature Communications</em> (2022) https://doi.org/10.1038/s41467-022-32762-7. Code for working with this dataset may be found at https://github.com/eulerlab/bc-motion