julilili42/papers huggingface dataset:
Membranous NECTIN-4 Expression Frequently Decreases during Metastatic Spread of Urothelial Carcinoma and Is Associated with Enfortumab Vedotin Resistance
2022-12-19

Abstract Purpose: The antibody–drug conjugate enfortumab vedotin (EV) releases a cytotoxic agent into tumor cells via binding to the membrane receptor NECTIN-4. EV was recently approved for patients with metastatic urothelial carcinoma (mUC) without prior assessment of the tumor receptor status as ubiquitous NECTIN-4 expression is assumed. Our objective was to determine the prevalence of membranous NECTIN-4 protein expression in primary tumors (PRIM) and patient-matched distant metastases (MET). Experimental Design: Membranous NECTIN-4 protein expression was measured (H-score) by IHC in PRIM and corresponding MET (N = 137) and in a multicenter EV-treated cohort (N = 47). Progression-free survival (PFS) after initiation of EV treatment was assessed for the NECTIN-4–negative/weak (H-score 0–99) versus moderate/strong (H-score 100–300) subgroup. The specificity of the NECTIN-4 IHC staining protocol was validated by establishing CRISPR-Cas9–induced polyclonal NECTIN-4 knockouts. Results: In our cohort, membranous NECTIN-4 expression significantly decreased during metastatic spread (Wilcoxon matched pairs P &amp;lt; 0.001; median H-score = 40; interquartile range, 0–140), with 39.4% of MET lacking membranous NECTIN-4 expression. In our multicenter EV cohort, absence or weak membranous NECTIN-4 expression (34.0% of the cohort) was associated with a significantly shortened PFS on EV (log-rank P &amp;lt; 0.001). Conclusions: Membranous NECTIN-4 expression is frequently decreased or absent in mUC tissue. Of note, the clinical benefit of EV strongly depends on membranous NECTIN-4 expression. Thus, our results are of highest clinical relevance and argue for a critical reconsideration of the current practice and suggest that the NECTIN-4 receptor status should be determined (ideally in a metastatic/progressive lesion) before initiation of EV. See related commentary by Aggen et al., p. 1377
A Rating Framework for the Quality of Video Explanations
2022-12-19

Abstract More and more teachers create video explanations for their instruction. Whether or not they are effective for learning depends on the videos’ instructional quality. Reliable measures to assess the quality of video explanations, however, are still rare, especially for videos created by (preservice) teachers. We developed such a measure in a two-step process: First, the categories were theoretically derived. Second, a coding manual was developed and used with 36 videos, which were created by preservice teachers during a university seminar. The resulting framework, which can be used as a coding manual for future research, consists of twelve criteria in five different categories: video content, learner orientation, representation and design, language, and process structure. With this framework, we contribute a reliable measure to evaluate the quality of existing videos. In practice, teachers can also use this measure as a guideline when creating or choosing video explanations for the classroom.
The regulation of a pigmentation gene in the formation of complex color patterns in Drosophila abdomens
2022-12-19

Changes in the control of developmental gene expression patterns have been implicated in the evolution of animal morphology. However, the genetic mechanisms underlying complex morphological traits remain largely unknown. Here we investigated the molecular mechanisms that induce the pigmentation gene yellow in a complex color pattern on the abdomen of Drosophila guttifera . We show that at least five developmental genes may collectively activate one cis -regulatory module of yellow in distinct spot rows and a dark shade to assemble the complete abdominal pigment pattern of Drosophila guttifera . One of these genes, wingless , may play a conserved role in the early phase of spot pattern development in several species of the quinaria group. Our findings shed light on the evolution of complex animal color patterns through modular changes of gene expression patterns.
Parkin-dependent mitophagy occurs via proteasome-dependent steps sequentially targeting separate mitochondrial sub-compartments for autophagy
2022-12-19

PINK1/parkin-dependent mitophagy initially involves (phospho)ubiquitin-directed proteasome-dependent degradation of certain outer mitochondrial membrane (OMM) proteins (e.g. mitofusins) and the recruitment of autophagy adaptors to a group of ubiquitinated OMM proteins, eventually leading to autophagic removal of damaged mitochondria in stressed cells. Here we provide evidence that mitochondrial degradation occurs via stepwise delivery of separate mitochondrial sub-compartments for autophagic degradation. OMM and inner mitochondrial material appears to become separately isolated for autophagolysosomal degradation, not only in parkin-overexpressing HeLa cells but also in cells that express endogenous parkin (human embryonic kidney cells and neural progenitor cells) with slower mitophagy kinetics. The remaining inner mitochondrial material becomes degraded only after much prolonged membrane depolarization, potentially involving another proteasome-sensitive step. The present combined microscopy and proteomics analyses support the idea that cell stress-induced parkin-dependent mitophagy is a complex multi-step process with distinct mitochondrial sub-compartments being separately targeted for autophagic degradation. <b>Abbreviations:</b> BafA, Bafilomycin A; CCCP, carbonyl cyanide 3-chlorophenylhydrazone; COX IV, cytochrome c oxidase subunit IV; CS, citrate synthase; DMEM, Dulbecco's modified Eagle's medium; EGFP, enhanced green fluorescent protein; FBS, fetal bovine serum; IF, immunofluorescence; IMM, inner mitochondrial membrane; KO, knock-out; LC3, microtubule-associated protein 1 light chain 3; MDVs, mitochondria-derived vesicles; MFN, mitofusin; NPCs, neural progenitor cells; OMM, outer mitochondrial membrane; p62/SQSTM, 62kDa protein sequestosome-1; PBS, phosphate-buffered saline; PINK1, phosphatase and tensin homolog (PTEN)-induced putative kinase protein 1; RT, room temperature; SSBP1, single-stranded DNA binding protein 1; TAX1BP1, Tax1-binding protein 1; TEM, transmission electron microscopy, TOM20, translocase of outer mitochondrial membrane 20kDa subunit; TOM70, translocase of outer mitochondrial membrane 70kDa subunit; Ub, ubiquitin; UPS, ubiquitin proteasome system; VDAC, voltage-dependent anion-selective channel protein; WB, Western blot; WT, wild-type.
Motility and self-organization of gliding Chlamydomonas populations
2022-12-19

Cellular appendages such as cilia and flagella represent universal tools\\nenabling cells and microbes, among other essential functionalities, to propel\\nthemselves in diverse environments. In its planktonic, i.e. freely swimming,\\nstate the unicellular bi-flagellated microbe Chlamydomonas reinhardtii employs\\na periodic breaststroke-like flagellar beating to displace the surrounding\\nfluid. Another flagella-mediated motility mode is observed for\\nsurface-associated Chlamydomonas cells, which glide along the surface by means\\nof force transduction through an intraflagellar transport machinery.\\nExperiments and statistical motility analysis demonstrate that this gliding\\nmotility enhances clustering and supports self-organization of Chlamydomonas\\npopulations. We employ Minkowski functionals to characterize the spatiotemporal\\norganization of the surface-associated cell monolayer. We find that simulations\\nbased on a purely mechanistic approach cannot capture the observed non-random\\ncell configurations. Quantitative agreement with experimental data however is\\nachieved when considering a minimal cognitive model of the flagellar\\nmechanosensing.\\n
AUF-1 knockdown in mice undermines gut microbial butyrate-driven hypocholesterolemia through AUF-1–Dicer-1–mir-122 hierarchy
2022-12-19

Introduction and objective Cholesterol homeostasis is a culmination of cellular synthesis, efflux, and catabolism to important physiological entities where short chain fatty acid, butyrate embodied as a key player. This discourse probes the mechanistic molecular details of butyrate action in maintaining host-cholesterol balance. Methods Hepatic mir-122 being the most indispensable regulator of cholesterol metabolic enzymes, we studied upstream players of mir-122 biogenesis in the presence and absence of butyrate in Huh7 cells and mice model. We synthesized unique self-transfecting GMO (guanidinium-morpholino-oligo) linked PMO (Phosphorodiamidate-Morpholino Oligo)-based antisense cell-penetrating reagent to selectively knock down the key player in butyrate mediated cholesterol regulation. Results We showed that butyrate treatment caused upregulation of RNA-binding protein, AUF1 resulting in RNase-III nuclease, Dicer1 instability, and significant diminution of mir-122. We proved the importance of AUF1 and sequential downstream players in AUF1-knock-down mice. Injection of GMO-PMO of AUF1 in mouse caused near absence of AUF1 coupled with increased Dicer1 and mir-122, and reduced serum cholesterol regardless of butyrate treatment indicating that butyrate acts through AUF1. Conclusion The roster of intracellular players was as follows: AUF1-Dicer1-mir-122 for triggering butyrate driven hypocholesterolemia. To our knowledge this is the first report linking AUF-1 with cholesterol biogenesis.
Gender differences in juvenile systemic sclerosis patients: Results from the international juvenile scleroderma inception cohort
2022-12-19

Objective: To compare organ involvement and disease severity between male and female patients with juvenile onset systemic sclerosis. Methods: Demographics, organ involvement, laboratory evaluation, patient-reported outcomes and physician assessment variables were compared between male and female juvenile onset systemic sclerosis patients enrolled in the prospective international juvenile systemic sclerosis cohort at their baseline visit and after 12 months. Results: One hundred and seventy-five juvenile onset systemic sclerosis patients were evaluated, 142 females and 33 males. Race, age of onset, disease duration, and disease subtypes (70% diffuse cutaneous) were similar between males and females. Active digital ulceration, very low body mass index, and tendon friction rubs were significantly more frequent in males. Physician global assessment of disease severity and digital ulcer activity was significantly higher in males. Composite pulmonary involvement was also more frequent in males, though not statistically significantly. After 12 months, they are the pattern of differences changed female patients had significantly more frequent pulmonary involvement. Conclusion: In this cohort, juvenile onset systemic sclerosis had a more severe course in males at baseline and but the pattern changed after 12 months. Some differences from adult findings persisted, there is no increased signal of pulmonary arterial hypertension or heart failure in male pediatric patients. While monitoring protocols of organ involvement in juvenile onset systemic sclerosis need to be identical for males and females.
The effects of diachronous surface uplift of the European Alps on regional climate and the oxygen isotopic composition of precipitation
2022-12-19

Abstract. The European Alps are hypothesized to have experienced diachronous surface uplift in response to post-collisional processes such as, e.g., slab break-off. Therefore, understanding the geodynamic and geomorphic evolution of the Alps requires knowledge of its surface uplift history. This study presents the simulated response of regional climate and oxygen isotopic composition of precipitation (δ18Op) to different along-strike topographic evolution scenarios. These responses are modeled to determine if diachronous surface uplift in the Western and Eastern Alps would produce δ18Op signals in the geologic record that are sufficiently large and distinct for stable isotope paleoaltimetry. This is tested with a series of sensitivity experiments conducted with the water isotope tracking atmospheric General Circulation Model (GCM) ECHAM5-wiso. The topographic scenarios are created from the variation of two free parameters, (1) the elevation of the West-Central Alps and (2) the elevation of the Eastern Alps. Results suggest significant changes in the spatial patterns of δ18Op, the elevation-dependent rate of change in δ18Op (“isotopic lapse rate”), near-surface temperatures, precipitation amounts, and atmospheric circulation patterns in response to the different scenarios. The predictions for the diachronous surface uplift experiments are distinctly different from simulations forced with present-day topography and for simulations where the entire Alps experience synchronous surface uplift. Topographic scenarios with higher elevations in the West-Central Alps produce higher magnitude changes and an expansion of the affected geographical domain surrounding the Alps when compared to present-day topography. Furthermore, differences in δ18Op values of up to −2 to −8 ‰ are predicted along the strike of the Alps for the diachronous uplift scenarios, suggesting that the signal can be preserved and measured in geologic archives. Lastly, the results highlight the importance of sampling far-field and low-elevation sites using the δ-δ paleoaltimetry approach to discern between different surface uplift histories.
Exploring the Flexibility of the Glycopeptide Antibiotic Crosslinking Cascade for Extended Peptide Backbones
2022-12-19

Abstract The glycopeptide antibiotics (GPAs) are a clinically approved class of antimicrobial agents that classically function through the inhibition of bacterial cell‐wall biosynthesis by sequestration of the precursor lipid II. The oxidative crosslinking of the core peptide by cytochrome P450 (Oxy) enzymes during GPA biosynthesis is both essential to their function and the source of their synthetic challenge. Thus, understanding the activity and selectivity of these Oxy enzymes is of key importance for the future engineering of this important compound class. Recent reports of GPAs that display an alternative mode of action and a wider range of core peptide structures compared to classic lipid II‐binding GPAs raises the question of the tolerance of Oxy enzymes for larger changes in their peptide substrates. In this work, we explore the ability of Oxy enzymes from the biosynthesis pathways of lipid II‐binding GPAs to accept altered peptide substrates based on a vancomycin template. Our results show that Oxy enzymes are more tolerant of changes at the N terminus of their substrates, whilst C‐terminal extension of the peptide substrates is deleterious to the activity of all Oxy enzymes. Thus, future studies should prioritise the study of Oxy enzymes from atypical GPA biosynthesis pathways bearing C‐terminal peptide extension to increase the substrate scope of these important cyclisation enzymes.
Supplementary material to "The effects of diachronous surface uplift of the European Alps on regional climate and the oxygen isotopic composition of precipitation"
2022-12-19

Additional results from the topography experiments are presented here.The reader is advised to check Table 1 or section 2.2 of the main text to understand the exact meanings of the experiment labels (as also shown in Fig. S1).Since only the seasonal, long-term mean differences (i.e., ID -CTL) are shown and discussed in the main text, the absolute values for longterm seasonal means are shown in supplemental figures S2, S3, and S4.Moreover, the annual long-term mean differences
The Evolution of Gendered Software: Products, Scientific Reasoning, Criticism, and Tools
2022-12-19

Over the past 7 decades, gendered software has become globally established. In this theoretical distribution, I outline the evolution of gendered software. The journey of gendered software started with the raw idea fueled by Alan Turing’s imitation game in the 1950s. And only shortly thereafter, in the 1960s and 1970s, the first gendered software products like Joseph Weizenbaum’s ELIZA were developed. Thus, academia took its time to not only explore technological aspects, but to further investigate the matter of gender in the 1990s CASA-paradigm (Nass et al., 1994) and Media Equation (Reeves &amp; Nass, 1996). As these theories reasoned the social impact of gendered software, voice assistants of the 2010s provided to be real-world examples stirring criticism. By posing the question of “boy or girl” through the decades, I take a deeper look at aspects such as raison d’être, realization, consequences, and future possibilities that ultimately challenge the applied gender binary. In doing so, it becomes evident that gendered software is situated in the bigger context of gender inequalities. Therefore, I propose to consider the listing of (1) product name, (2) voice, and (3) personality traits as decisive features forming to be powerful tools in the process of gendering software.
Comparison of a Group-/Home-Based and a Weight-Machine-Based Exercise Training for Patients with Hip or Knee Osteoarthritis—A Secondary Analysis of Two Trial Interventions in a Real-World Context
2022-12-19

This study aimed to compare an individual weight-machine-based strengthening program (MbT) with a group-/homebased training offering strengthening/functional exercises (GHT) in a general health care setting. A total of 657 participants (GHT = 521, MbT = 136) suffering from hip/knee OA were included and analysed with a pre–post design (baseline (T0)/3-months (T1)). Primary outcomes were pain and physical functioning (Western Ontario and McMaster Universities Osteoarthritis Index, range 0–10). Additionally, adherence and perceived patient benefit were measured (T1). Data were analysed with linear mixed models (time, treatment, baseline pain/physical impairment severity) adjusted for patient characteristics. No significant between-group differences in pain reduction/functional improvements (time*treatment*baseline pain/physical impairment severity, pain/function: n.s.; time*treatment, pain: p = 0.884, function: p = 0.067). Within-group improvements were dependent on baseline severity: Higher severity levels demonstrated larger changes from baseline. Perceived patient-benefit (very high to high, GHT: 78%, MbT: 92%) and exercise adherence (Dropouts T1: GHT: 27.8%, MbT: 16.2%; adherence to supervised sessions: GHT: 89%, MbT: 92%) was slightly better in the MbT. In summary, both MbT and GHT, showed positive results for patients with at least moderate disease symptoms. Findings for physical functioning, perceived patient-benefit, exercise adherence hint towards a superiority of MbT. Individual preferences should be considered when prescribing exercise therapy. Trial registration: (1) German Clinical Trial Register DRKS00009251. Registered 10 September 2015. (2) German Clinical Trial Register DRKS00009257. Registered 11 September 2015.
Certifying Maximum Likelihood Degrees of Matroid Strata
2022-12-19

We present the result of the certification method described in [1] for the computation of the ML degree for matroids of rank k on m elements. The main theorem in Section 4 of [1], for fixed k, m, illustrates the matroid strata by dimension, and all occurring ML degrees together with their multiplicity of occurrences. In each folder 'CertificatesAndSummaries'*k*m, for each simple rank k matroid on m atoms indexed by the database we used (with the exceptions of (3,9) #1#2#3#5 and (4,8) #1#2) there are two files: MatroidSummary_i and Certificate_i. MatroidSummary_i summarizes the certification attempts we made - that is, how many, and what the certified lower bound for the ML degree was. An instance of a certification which obtained the maximum bound is saved in Certificate_i.<br> <br> For some matroids, we had the resources to run the certification process multiple times, whereas for matroids with large ML degrees, we only ran it once. Nonetheless, each certificate produces a <strong>lower bound</strong> for the ML degree of the corresponding matroid. <br> If an additional index exists, this indicates that the realization space of the matroid had multiple irreducible components (see (4,8) # 160 which has two components) and each file corresponds to the above process for a single irreducible component. Finally, the file Certificate_48 certifies the lower bound of the Euler characteristic of the space X(4,8) discussed in Section 6 of [1]. <strong>References</strong> [1] D. Agostini, T. Brysiewicz, C. Fevola, L. Kühne, B. Sturmfels, and S. Telen: <em>Likelihood Degenerations</em>, arXiv:2107.10518. [2] P. Breiding, K. Rose, and S. Timme: <em>Certifying zeros of polynomial systems using interval arithmetic</em>, arXiv:2011.05000.
JUNO Sensitivity on Proton Decay $p\\to \\barνK^+$ Searches
2022-12-19

The Jiangmen Underground Neutrino Observatory (JUNO) is a large liquid scintillator detector designed to explore many topics in fundamental physics. In this paper, the potential on searching for proton decay in mode with JUNO is investigated.The kaon and its decay particles feature a clear three-fold coincidence signature that results in a high efficiency for identification. Moreover, the excellent energy resolution of JUNO permits to suppress the sizable background caused by other delayed signals. Based on these advantages, the detection efficiency for the proton decay via is 36.9% with a background level of 0.2 events after 10 years of data taking. The estimated sensitivity based on 200 kton-years exposure is years, competitive with the current best limits on the proton lifetime in this channel.
Extra-corporeal detoxification in insects.
2022-12-19

Upon uptake of toxins, insects launch a detoxification program. This program is deployed in multiple organs and cells to raise their tolerance against the toxin. The molecular mechanisms of this program inside the insect body have been studied and understood in detail. Here, we report on a yet unexplored extra-corporeal detoxification of insecticides in Drosophila melanogaster. Wild-type D. melanogaster incubated with DDT, a contact insecticide, in a closed environment die as expected. However, incubation of a second cohort in the same environment after removal of the dead flies was not lethal. Consistent to the kin selection theory, the effect is significantly lower if the flies of the two cohorts are unrelated. Incubation assays with Chlorpyrifos, another contact insecticide, yielded identical results, while incubation assays with Chlorantraniliprole, again a contact insecticide, was toxic for the second cohort of flies. A cohort of flies incubated in a DDT environment after an initial incubation of a honeybee survived treatment. Together, our data suggest that insects including Apis mellifera and D. melanogaster have the capacity to modify their proximate environment. Consequently, in their ecological niche, following individuals might be saved from intoxication thereby facilitating colonisation of an attractive site.