bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multivalent interactions between molecular components involved in fast endophilin mediated endocytosis drive protein phase separation
Authors: Mondal Samsuzzoha , Narayan Karthik , Botterbusch Samuel , Powers Imania , Zheng Jason , James Honey Priya , Jin Rui , Baumgart Tobias 
Published: August 2022

AbstractA specific group of transmembrane receptors, including the β1-adrenergic receptor (β1-AR), is internalized through a non-clathrin pathway known as Fast Endophilin Mediated Endocytosis (FEME). A key question is: how does the endocytic machinery assemble and how is it modulated by activated receptors during FEME. Here we show that endophilin, a major regulator of FEME, undergoes a phase transition into liquid-like condensates, which facilitates the formation of multi-protein assemblies by enabling the phase partitioning of endophilin binding proteins. The phase transition can be triggered by specific multivalent binding partners of endophilin in the FEME pathway such as the third intracellular loop (TIL) of the β1-AR, and the C-terminal domain of lamellipodin (LPD). Other endocytic accessory proteins can either partition into, or target interfacial regions of, these condensate droplets, and LPD also phase separates with the actin polymerase VASP. On the membrane, TIL promotes protein clustering in the presence of endophilin and LPD C-terminal domain. Our results demonstrate how the multivalent interactions between endophilin, LPD, and TIL regulate protein assembly formation on the membrane, providing mechanistic insights into the priming and initiation steps of FEME.
Structure of the human NK cell NKR-P1:LLT1 receptor:ligand complex reveals clustering in the immune synapse
Authors: Bláha Jan , Skálová Tereza , Kalousková Barbora , Skořepa Ondřej , Cmunt Denis , Grobárová Valéria , Pazicky Samuel , Poláchová Edita , Abreu Celeste , Stránský Jan , Kovaľ Tomáš , Dušková Jarmila , Zhao Yuguang , Harlos Karl , Hašek Jindřich , Dohnálek Jan , Vaněk Ondřej 
Published: August 2022

AbstractSignaling by the human C-type lectin-like receptor, natural killer (NK) cell inhibitory receptor NKR-P1, has a critical role in many immune-related diseases and cancer. C-type lectin-like receptors have weak affinities to their ligands; therefore, setting up a comprehensive model of NKR-P1-LLT1 interactions that considers the natural state of the receptor on the cell surface is necessary to understand its functions. Here we report the crystal structures of the NKR-P1 and NKR-P1:LLT1 complexes, which provides evidence that NKR-P1 forms homodimers in an unexpected arrangement to enable LLT1 binding in two modes, bridging two LLT1 molecules. These interaction clusters are suggestive of an inhibitory immune synapse. By observing the formation of these clusters in solution using SEC-SAXS analysis, by dSTORM super-resolution microscopy on the cell surface, and by following their role in receptor signaling with freshly isolated NK cells, we show that only the ligation of both LLT1 binding interfaces leads to effective NKR-P1 inhibitory signaling. In summary, our findings collectively support a model of NKR-P1:LLT1 clustering, which allows the interacting proteins to overcome weak ligand-receptor affinity and to trigger signal transduction upon cellular contact in the immune synapse.
The CCTG PA.7 phase II trial of gemcitabine and nab-paclitaxel with or without durvalumab and tremelimumab as initial therapy in metastatic pancreatic ductal adenocarcinoma
Authors: Renouf Daniel J. , Loree Jonathan M. , Knox Jennifer J. , Topham James T. , Kavan Petr , Jonker Derek , Welch Stephen , Couture Felix , Lemay Frederic , Tehfe Mustapha , Harb Mohammed , Aucoin Nathalie , Ko Yoo-Joung , Tang Patricia A. , Ramjeesingh Ravi , Meyers Brandon M. , Kim Christina A. , Du Pan , Jia Shidong , Schaeffer David F. , Gill Sharlene , Tu Dongsheng , O’Callaghan Chris J 
Published: August 2022

AbstractImmunotherapy-based monotherapy treatment in metastatic pancreatic ductal adenocarcinoma (mPDAC) has shown limited benefit outside of the mismatch repair deficiency setting, while safety and efficacy of combining dual-checkpoint inhibitor immunotherapy with chemotherapy remains uncertain. Here, we present results from the CCTG PA.7 study (NCT02879318), a randomized phase II trial comparing gemcitabine and nab-paclitaxel with and without immune checkpoint inhibitors durvalumab and tremelimumab in 180 patients with mPDAC. The primary endpoint was overall survival. Secondary endpoints included progression-free survival and objective response rate. Results of the trial were negative as combination immunotherapy did not improve survival among the unselected patient population (p = 0.72) and toxicity was limited to elevation of lymphocytes in the combination immunotherapy group (p = 0.02). Exploratory baseline circulating tumor DNA (ctDNA) sequencing revealed increased survival for patients with KRAS wildtype tumors in both the combination immunotherapy (p = 0.001) and chemotherapy (p = 0.004) groups. These data support the utility of ctDNA analysis in PDAC and the prognostic value of ctDNA-based KRAS mutation status.
Asymmetric 1,4-functionalization of 1,3-enynes via dual photoredox and chromium catalysis
Authors: Zhang Feng-Hua , Guo Xiaochong , Zeng Xianrong , Wang Zhaobin 
Published: August 2022

AbstractThe merger of photoredox and transition-metal catalysis has evolved as a robust platform in organic synthesis over the past decade. The stereoselective 1,4-functionalization of 1,3-enynes, a prevalent synthon in synthetic chemistry, could afford valuable chiral allene derivatives. However, tremendous efforts have been focused on the ionic reaction pathway. The radical-involved asymmetric 1,4-functionalization of 1,3-enynes remains a prominent challenge. Herein, we describe the asymmetric three-component 1,4-dialkylation of 1,3-enynes via dual photoredox and chromium catalysis to provide chiral allenols. This method features readily available starting materials, broad substrate scope, good functional group compatibility, high regioselectivity, and simultaneous control of axial and central chiralities. Mechanistic studies suggest that this reaction proceeds through a radical-involved redox-neutral pathway.
Pneumolysin boosts the neuroinflammatory response to Streptococcus pneumoniae through enhanced endocytosis
Authors: Hupp Sabrina , Förtsch Christina , Graber Franziska , Mitchell Timothy J. , Iliev Asparouh I. 
Published: August 2022

AbstractIn pneumococcal meningitis, bacterial growth in the cerebrospinal fluid results in lysis, the release of toxic factors, and subsequent neuroinflammation. Exposure of primary murine glia toStreptococcus pneumoniaelysates leads to strong proinflammatory cytokine and chemokine production, blocked by inhibition of the intracellular innate receptor Nod1. Lysates enhance dynamin-dependent endocytosis, and dynamin inhibition reduces neuroinflammation, blocking ligand internalization. Here we identify the cholesterol-dependent cytolysin pneumolysin as a pro-endocytotic factor in lysates, its elimination reduces their proinflammatory effect. Only pore-competent pneumolysin enhances endocytosis in a dynamin-, phosphatidylinositol-3-kinase- and potassium-dependent manner. Endocytic enhancement is limited to toxin-exposed parts of the membrane, the effect is rapid and pneumolysin permanently alters membrane dynamics. In a murine model of pneumococcal meningitis, mice treated with chlorpromazine, a neuroleptic with a complementary endocytosis inhibitory effect show reduced neuroinflammation. Thus, the dynamin-dependent endocytosis emerges as a factor in pneumococcal neuroinflammation, and its enhancement by a cytolysin represents a proinflammatory control mechanism.
Midkine expression by stem-like tumor cells drives persistence to mTOR inhibition and an immune-suppressive microenvironment
Authors: Tang Yan , Kwiatkowski David J. , Henske Elizabeth P. 
Published: August 2022

AbstractmTORC1 is hyperactive in multiple cancer types1,2. Here, we performed integrative analysis of single cell transcriptomic profiling, paired T cell receptor (TCR) sequencing, and spatial transcriptomic profiling on Tuberous Sclerosis Complex (TSC) associated tumors with mTORC1 hyperactivity, and identified a stem-like tumor cell state (SLS) linked to T cell dysfunction via tumor-modulated immunosuppressive macrophages. Rapamycin and its derivatives (rapalogs) are the primary treatments for TSC tumors, and the stem-like tumor cells showed rapamycin resistance in vitro, reminiscent of the cytostatic effects of these drugs in patients. The pro-angiogenic factor midkine (MDK) was highly expressed by the SLS population, and associated with enrichment of endothelial cells in SLS-dominant samples. Inhibition of MDK showed synergistic benefit with rapamycin in reducing the growth of TSC cell lines in vitro and in vivo. In aggregate, this study suggests an autocrine rapamycin resistance mechanism and a paracrine tumor survival mechanism via immune suppression adopted by the stem-like state tumor cells with mTORC1 hyperactivity.
Spatially patterned hydrogen peroxide orchestrates stomatal development in Arabidopsis
Authors: Shi Wen , Wang Lingyan , Yao Lianmei , Hao Wei , Han Chao , Fan Min , Wang Wenfei , Bai Ming-Yi 
Published: August 2022

AbstractStomatal pores allow gas exchange between plant and atmosphere. Stomatal development is regulated by multiple intrinsic developmental and environmental signals. Here, we show that spatially patterned hydrogen peroxide (H2O2) plays an essential role in stomatal development. H2O2 is remarkably enriched in meristemoids, which is established by spatial expression patterns of H2O2-scavenging enzyme CAT2 and APX1. SPEECHLESS (SPCH), a master regulator of stomatal development, directly binds to the promoters of CAT2 and APX1 to repress their expression in meristemoid cells. Mutations in CAT2 or APX1 result in an increased stomatal index. Ectopic expression of CAT2 driven by SPCH promoter significantly inhibits the stomatal development. Furthermore, H2O2 activates the energy sensor SnRK1 by inducing the nuclear localization of the catalytic α-subunit KIN10, which stabilizes SPCH to promote stomatal development. Overall, these results demonstrate that the spatial pattern of H2O2 in epidermal leaves is critical for the optimal stomatal development in Arabidopsis.
Magnetically assisted drop-on-demand 3D printing of microstructured multimaterial composites
Authors: Liu Wing Chung , Chou Vanessa Hui Yin , Behera Rohit Pratyush , Le Ferrand Hortense 
Published: August 2022

AbstractMicrostructured composites with hierarchically arranged fillers fabricated by three-dimensional (3D) printing show enhanced properties along the fillers’ alignment direction. However, it is still challenging to achieve good control of the filler arrangement and high filler concentration simultaneously, which limits the printed material’s properties. In this study, we develop a magnetically assisted drop-on-demand 3D printing technique (MDOD) to print aligned microplatelet reinforced composites. By performing drop-on-demand printing using aqueous slurry inks while applying an external magnetic field, MDOD can print composites with microplatelet fillers aligned at set angles with high filler concentrations up to 50 vol%. Moreover, MDOD allows multimaterial printing with voxelated control. We showcase the capabilities of MDOD by printing multimaterial piezoresistive sensors with tunable performances based on the local microstructure and composition. MDOD thus creates a large design space to enhance the mechanical and functional properties of 3D printed electronic or sensing devices using a wide range of materials.
The state prediction method of the silk dryer based on the GA-BP model
Authors: Jiang Hao , Yu Zegang , Wang Yonghua , Zhang Baowei , Song Jiuxiang , Wei Jingdian 
Published: August 2022

AbstractConsidering the under-maintenance and over-maintenance of existing equipment maintenance methods, this paper studies a Condition Based Maintenance method for silk dryers. The entropy method is used to eliminate the influence of subjective factors to more objectively reflect the weight of different input parameters; optimizing the number of nodes in the hidden layer of the network to improve the prediction accuracy; and using the GA-BP neural network to establish a state prediction model of the equipment to solve the disadvantages of the BP neural network, for example, unstable prediction, easily falling into local optimum, and slow global search ability. Simulation experiments show that this method can effectively compensate for the shortcomings of the existing maintenance methods, and provide an effective scientific basis for dryer state maintenance.
A new perspective on Workload Control by measuring operating performances through an economic valorization
Authors: Mezzogori Davide , Romagnoli Giovanni , Zammori Francesco 
Published: August 2022

AbstractWorkload Control (WLC) is a production planning and control system conceived to reduce queuing times of job-shop systems, and to offer a solution to the lead time syndrome; a critical issue that often bewilders make-to-order manufacturers. Nowadays, advantages of WLC are unanimously acknowledged, but real successful stories are still limited. This paper starts from the lack of a consistent way to assess performance of WLC, an important burden for its acceptance in the industry. As researchers often put more focus on the performance measures that better confirm their hypotheses, many measures, related to different WLC features, have emerged over years. However, this excess of measures may even mislead practitioners, in the evaluation of alternative production planning and control systems. To close this gap, we propose quantifying the main benefit of WLC in economic terms, as this is the easiest, and probably only way, to compare different and even conflicting performance measures. Costs and incomes are identified and used to develop an overall economic measure that can be used to evaluate, or even to fine tune, the operating features of WLC. The quality of our approach is finally demonstrated via simulation, considering the 6-machines job-shop scenario typically adopted as benchmark in technical literature.
Task-dependent learning and memory deficits in the TgF344-AD rat model of Alzheimer’s disease: three key timepoints through middle-age in females
Authors: Bernaud Victoria E. , Bulen Haidyn L. , Peña Veronica L. , Koebele Stephanie V. , Northup-Smith Steven N. , Manzo Alma A. , Valenzuela Sanchez Maria , Opachich Zorana , Ruhland Ashley M. , Bimonte-Nelson Heather A. 
Published: August 2022

AbstractThe TgF344 rat model of Alzheimer’s disease (AD) provides a comprehensive neuropathology presentation, with age-dependent development of tau tangles, amyloid-beta (A$${\beta}$$
β
) plaques, neuronal loss, and increased gliosis. The behavioral trajectory of this model, particularly relating to spatial learning and memory, has yet to be fully characterized. The current experiment evaluated spatial working and reference memory performance, as well as several physiological markers of health, at 3 key age points in female TgF344-AD rats: 6-months, 9-months, and 12-months. At 6 months of age, indications of working and reference memory impairments were observed in transgenic (Tg) rats on the water radial-arm maze, a complex task that requires working and reference memory simultaneously; at 12 months old, Tg impairments were observed for two working memory measures on this task. Notably, no impairments were observed at the 9-month timepoint on this maze. For the Morris maze, a measure of spatial reference memory, Tg rats demonstrated significant impairment relative to wildtype (WT) controls at all 3 age-points. Frontal cortex, entorhinal cortex, and dorsal hippocampus were evaluated for A$${\beta}$$
β
1–42 expression via western blot in Tg rats only. Analyses of A$${\beta}$$
β
1–42 expression revealed age-dependent increases in all 3 regions critical to spatial learning and memory. Measures of physiological health, including heart, uterine, and body weights, revealed unique age-specific outcomes for female Tg rats, with the 9-month timepoint identified as critical for further research within the trajectory of AD-like behavior, physiology, and pathology.
Outcomes of endoscopic mucosal resection for large superficial non-ampullary duodenal adenomas
Authors: Amoyel Maxime , Belle Arthur , Dhooge Marion , Ali Einas Abou , Pellat Anna , Hallit Rachel , Terris Benoit , Prat Frédéric , Chaussade Stanislas , Coriat Romain , Barret Maximilien 
Published: August 2022

AbstractEndoscopic mucosal resection (EMR) is the recommended treatment for superficial non-ampullary duodenal epithelial tumors larger than 6 mm. This endoscopic technique carries a high risk of adverse events. Our aim was to identify the risk factors for adverse events following EMR for non-ampullary duodenal adenomatous lesions. We retrospectively analyzed a prospectively collected database of consecutive endoscopic resections for duodenal lesions at a tertiary referral center for therapeutic endoscopy. We analyzed patients with non-ampullary duodenal adenomatous lesions ≥ 10 mm resected by EMR, and searched for factors associated with adverse events after EMR. 167 duodenal adenomatous lesions, with a median size of 25 (25–40) mm, were resected by EMR between January 2015 and December 2020. Adverse events occurred in 37/167 (22.2%) after endoscopic resection, with 29/167 (17.4%) delayed bleeding, 4/167 (2.4%) immediate perforation and 4/167 (2.4%) delayed perforation. In logistic regression, the size of the lesion was the only associated risk factor of adverse events (OR = 2.81, 95% CI [1.27; 6.47], p = 0.012). Adverse events increased mean hospitalization time (7.7 ± 9 vs. 1.9 ± 1 days, p < 0.01). None of the currently recommended preventive methods, particularly clips, affected the adverse event rate. EMR of centimetric and supracentimetric duodenal adenomatous lesions carries a high risk of adverse events, increasing with the size of the lesion and with no benefit from any preventive method. These results suggest that these procedures should be performed in expert centers, and underline the need for novel endoscopic tools to limit the rate of adverse events.
A high birefringence liquid crystal for lenses with large aperture
Authors: Bennis N. , Jankowski T. , Strzezysz O. , Pakuła A. , Zografopoulos D. C. , Perkowski P. , Sánchez-Pena J. M. , López-Higuera J. M. , Algorri J. F. 
Published: August 2022

AbstractThis work presents the application of an experimental nematic liquid crystal (LC) mixture (1929) in a large aperture lens. The LC material is composed of terphenyl and biphenyl derivatives compounds with an isothiocyanate terminal group and fluorinated lateral substituents. The substitution with a strongly polar isothiocyanate group and an aromatic rigid core provides $$\pi$$
π
-electron coupling, providing high birefringence ($$\Delta n = 0.3375$$

Δ
n
=
0.3375

at 636 nm and 23 °C) and low viscosity ($$\eta$$
η
= 17.03 mPa s). In addition, it also shows high values of birefringence at near infrared (0.318 at 1550 nm). The synthesis process is simple when comparing materials with high melting temperatures. The excellent properties of this LC mixture are demonstrated in a large aperture LC-tunable lens based on a transmission electrode structure. Thanks to the particular characteristics of this mixture, the optical power is high. The high birefringence makes this LC of specific interest for lenses and optical phase modulators and devices, both in the visible and infrared regions.
Prehospital diagnostic algorithm for acute coronary syndrome using machine learning: a prospective observational study
Authors: Takeda Masahiko , Oami Takehiko , Hayashi Yosuke , Shimada Tadanaga , Hattori Noriyuki , Tateishi Kazuya , Miura Rie E. , Yamao Yasuo , Abe Ryuzo , Kobayashi Yoshio , Nakada Taka-aki 
Published: August 2022

AbstractRapid and precise prehospital recognition of acute coronary syndrome (ACS) is key to improving clinical outcomes. The aim of this study was to investigate a predictive power for predicting ACS using the machine learning-based prehospital algorithm. We conducted a multicenter observational prospective study that included 10 participating facilities in an urban area of Japan. The data from consecutive adult patients, identified by emergency medical service personnel with suspected ACS, were analyzed. In this study, we used nested cross-validation to evaluate the predictive performance of the model. The primary outcomes were binary classification models for ACS prediction based on the nine machine learning algorithms. The voting classifier model for ACS using 43 features had the highest area under the receiver operating curve (AUC) (0.861 [95% CI 0.775–0.832]) in the test score. After validating the accuracy of the model using the external cohort, we repeated the analysis with a limited number of selected features. The performance of the algorithms using 17 features remained high AUC (voting classifier, 0.864 [95% CI 0.830–0.898], support vector machine (radial basis function), 0.864 [95% CI 0.829–0.887]) in the test score. We found that the machine learning-based prehospital algorithms showed a high predictive power for predicting ACS.
Large extensional earthquakes push-up terrific amount of fluids
Authors: Chiarabba Claudio , De Gori Pasquale , Valoroso Luisa , Petitta Marco , Carminati Eugenio 
Published: August 2022

AbstractHow large earthquakes are triggered is a key question in Earth science, and the role played by fluid pressure seems to be crucial. Nevertheless, evaluation of involved fluid volumes is seldom investigated, if not unaccounted for. Moreover, fluid flow along fault zones is a driving factor for seismicity migration, episodic heat and chemical transport. Here we show that time repeated (4D) seismic tomography resolves changes of Vp and Vp/Vs during the Mw6.2 2009 L’Aquila normal faulting sequence, that indicate a post-failure fluid migration from hypocentral depths to the surface, with a volume estimated between 5 and 100 × 106 m3 rising at rates up to 100 m/day. This amount inferred by tomograms is surprisingly consistent with the about 50 × 106 m3 surplus water volume additionally measured at spring discharge, spread in time and space along the 700 km2-wide regional carbonate fractured aquifer. Fluids were pushed-up within a huge volume across the fault and expelled from the area of large coseismic slip. Such quantities of fluids liberated during earthquakes add unprecedented constraints to the discussion on the role of fluids during and possibly before earthquake, as well as to the potential impact on the pristine high-quality drinkable groundwater, possibly affecting the biodiversity of groundwater dependent ecosystems too.