bluuebunny/crossref_metadata_2025 huggingface dataset:
Understanding the Non‐Linear Response of Summer Evapotranspiration to Clouds in a Temperate Forest Under the Impact of Vegetation Water Content
Authors: Wang Yipu , Li Rui , Hu Jiheng , Fu Yuyun , Duan Jiawei , Cheng Yuanxi , Song Binbin
Published: November 2021

Understanding the cloud impact on forest evapotranspiration (ET) is crucial for studying the interaction of vegetation‐cloud‐atmosphere. Combining long‐term (2003–2010) satellite passive microwave observations and in‐situ measurements, a non‐linear response of canopy‐scale ET to cloud increase was found at a temperate forest in Northeast China. As cloud increased, an initial enhancement (4%–10%) in ET occurred under less cloudy sky, while a significant reduction (>20%) in ET occurred under more cloudy sky. The phenomenon existed under both high and low vegetation water content (VWC) indicated by satellite microwave emissivity difference vegetation index (EDVI). Analysis showed that this was the combined effect from the enhancement (5%–30%) in evaporative fraction (EF) and the reduction (5%–50%) in net radiation under cloud increase. Decoupling analysis based on coefficients (ρ) of path analysis model showed that enhanced EF (ρ > 0.61) rather than radiation (ρ < 0.47) dominated the ET enhancement under less cloudy sky, while the control of reduced radiation became stronger (ρ > 0.63) and could not be compensated by increased EF (ρ < 0.48) under more cloudy sky. EF enhancement under clouds was strongly correlated with the decline in canopy resistance (Rs) which was dominated by vapor pressure deficit (VPD). Higher VWC increased ET via reducing Rs and enlarging EF. This positive effect of VWC was more noticeable under less cloudy sky. Associated mechanisms could be related to the dynamic controls of plant physiology and environmental conditions induced by VWC and clouds. This study highlighted the dynamic effect of clouds and VWC on forest ET and improved our knowledge of vegetation‐cloud interactions.
Fibroblast membrane-camouflaged nanoparticles for inflammation treatment in the early stage
Authors: Sun Lizhong , He Libang , Wu Wei , Luo Li , Han Mingyue , Liu Yifang , Shi Shijie , Zhong Kaijing , Yang Jiaojiao , Li Jiyao
Published: November 2021

Unrestrained inflammation is harmful to tissue repair and regeneration. Immune cell membrane-camouflaged nanoparticles have been proven to show promise as inflammation targets and multitargeted inflammation controls in the treatment of severe inflammation. Prevention and early intervention of inflammation can reduce the risk of irreversible tissue damage and loss of function, but no cell membrane-camouflaged nanotechnology has been reported to achieve stage-specific treatment in these conditions. In this study, we investigated the prophylactic and therapeutic efficacy of fibroblast membrane-camouflaged nanoparticles for topical treatment of early inflammation (early pulpitis as the model) with the help of in-depth bioinformatics and molecular biology investigations in vitro and in vivo. Nanoparticles have been proven to act as sentinels to detect and competitively neutralize invasive Escherichia coli lipopolysaccharide (E. coli LPS) with resident fibroblasts to effectively inhibit the activation of intricate signaling pathways. Moreover, nanoparticles can alleviate the secretion of multiple inflammatory cytokines to achieve multitargeted anti-inflammatory effects, attenuating inflammatory conditions in the early stage. Our work verified the feasibility of fibroblast membrane-camouflaged nanoparticles for inflammation treatment in the early stage, which widens the potential cell types for inflammation regulation.
Expert consensus on the clinical application of recombinant adenovirus human p53 for head and neck cancers
Authors: Li Yi , Guo Wei , Li Xiuqin , Zhang Jianguo , Sun Moyi , Tang Zhangui , Ran Wei , Yang Kai , Huang Guilin , Li Longjiang
Published: November 2021

The first gene therapy product, recombinant adenovirus human p53 (rAd-p53), has been approved by CFDA since 2013. During these years, most of the clinical trials and the relevant basic research were carried out by Chinese oncologists. Gendicine was proved to be a safe and promising gene therapy drug for patients who suffered from head and neck squamous cell carcinoma (HNSCC). The basic therapeutic theories of gene therapy were totally different from the traditional ones, such as surgeries or radio- and chemotherapy, and the evaluation of treatment outcomes should also be changed simultaneously. However, there still existed a lot of misunderstandings about gene therapy, which resulted in improper administration, insufficient dosage calculation, and treatment cycles, and the treatment outcomes were unsatisfactory, especially for inexperienced oncologists or hospitals. Therefore, we will provide some practical guidance here on the gene therapy of rAd-p53 based on our previous research and experience, which focused on the basic theories and clinical issues, to answer the questions arising during the clinical of gene therapy and to accelerate the development of gene therapy for the benefit of patients bearing malignant tumors.
MicroRNA-15a-5p acts as a tumor suppressor in histiocytosis by mediating CXCL10-ERK-LIN28a-let-7 axis
Authors: Weissman Ran , Diamond Eli L. , Haroche Julien , Durham Benjamin H. , Cohen Fleur , Buthorn Justin , Amoura Zahir , Emile Jean-François , Mazor Roei D. , Shomron Noam , Abdel-Wahab Omar I. , Shpilberg Ofer , Hershkovitz-Rokah Oshrat
Published: November 2021

Erdheim–Chester disease (ECD) is characterized by excessive production and accumulation of histiocytes within multiple tissues and organs. ECD patients harbor recurrent mutations of genes associated with the RAS/RAF/MEK/ERK signaling pathway, particularly, the BRAFV600E mutation. Following our previous finding that miR-15a-5p is the most prominently downregulated microRNA in ECD patients compared to healthy individuals, we elucidated its role in ECD pathogenesis. Bioinformatics analysis followed by a luciferase assay showed that chemokine ligand 10 (CXCL10) is a target gene regulated by miRNA-15a-5p. This was confirmed in 24/34 ECD patients that had low expression of miR-15a-5p concurrent with upregulated CXCL10. Overexpression of miR-15a-5p in cell lines harboring BRAF or RAS mutations (Ba/F3, KG-1a and OCI-AML3) resulted in CXCL10 downregulation, followed by LIN28a and p-ERK signaling downregulation and let-7 family upregulation. Overexpression of miR-15a-5p inhibited cell growth and induced apoptosis by decreasing Bcl-2 and Bcl-xl levels. Analysis of sequential samples from 7 ECD patients treated with MAPK inhibitors (vemurafenib/cobimetinib) for 4 months showed miR-15a-5p upregulation and CXCL10 downregulation. Our findings suggest that miR-15a-5p is a tumor suppressor in ECD through the CXCL10-ERK-LIN28a-let7 axis, highlighting another layer of post-transcriptional regulation in this disease. Upregulation of miR-15a-5p in ECD patients may have a potential therapeutic role.
A missense variant in SHARPIN mediates Alzheimer’s disease-specific brain damages
Authors: Park Jun Young , Lee Dongsoo , Lee Jang Jae , Gim Jungsoo , Gunasekaran Tamil Iniyan , Choi Kyu Yeong , Kang Sarang , Do Ah Ra , Jo Jinyeon , Park Juhong , Park Kyungtaek , Li Donghe , Lee Sanghun , Kim Hoowon , Dhanasingh Immanuel , Ghosh Suparna , Keum Seula , Choi Jee Hye , Song Gyun Jee , Sael Lee , Rhee Sangmyung , Lovestone Simon , Kim Eunae , Moon Seung Hwan , Kim Byeong C. , Kim SangYun , Saykin Andrew J. , Nho Kwangsik , Lee Sung Haeng , Farrer Lindsay A. , Jun Gyungah R. , Won Sungho , Lee Kun Ho ,   for the Alzheimer’s Disease Neuroimaging Initiative
Published: November 2021

Established genetic risk factors for Alzheimer’s disease (AD) account for only a portion of AD heritability. The aim of this study was to identify novel associations between genetic variants and AD-specific brain atrophy. We conducted genome-wide association studies for brain magnetic resonance imaging measures of hippocampal volume and entorhinal cortical thickness in 2643 Koreans meeting the clinical criteria for AD (n = 209), mild cognitive impairment (n = 1449) or normal cognition (n = 985). A missense variant, rs77359862 (R274W), in the SHANK-associated RH Domain Interactor (SHARPIN) gene was associated with entorhinal cortical thickness (p = 5.0 × 10−9) and hippocampal volume (p = 5.1 × 10−12). It revealed an increased risk of developing AD in the mediation analyses. This variant was also associated with amyloid-β accumulation (p = 0.03) and measures of memory (p = 1.0 × 10−4) and executive function (p = 0.04). We also found significant association of other SHARPIN variants with hippocampal volume in the Alzheimer’s Disease Neuroimaging Initiative (rs3417062, p = 4.1 × 10−6) and AddNeuroMed (rs138412600, p = 5.9 × 10−5) cohorts. Further, molecular dynamics simulations and co-immunoprecipitation indicated that the variant significantly reduced the binding of linear ubiquitination assembly complex proteins, SHPARIN and HOIL-1 Interacting Protein (HOIP), altering the downstream NF-κB signaling pathway. These findings suggest that SHARPIN plays an important role in the pathogenesis of AD.
Activated naïve γδ T cells accelerate deep molecular response to BCR-ABL inhibitors in patients with chronic myeloid leukemia
Authors: Chang Yu-Cheng , Chiang Yi-Hao , Hsu Kate , Chuang Chih-Kuang , Kao Chen-Wei , Chang Yi-Fang , Chang Ming-Chih , Lim Ken-Hong , Cheng Hung-I , Hsu Yen-Ning , Chen Caleb G.
Published: November 2021

Tyrosine kinase inhibitors (TKIs) that target BCR-ABL are the frontline treatments in chronic myeloid leukemia (CML). Growing evidence has shown that TKIs also enhance immunity. Since gamma-delta T (γδT) cells possess the potent anticancer capability, here we investigated the potential involvement of γδT cells in TKI treatments for CML. We characterized γδT cells isolated from chronic-phase CML patients before and during TKI treatments. γδT expression increased significantly in CML patients who achieved major molecular response (MMR) and deep molecular response (DMR). Their Vδ2 subset of γδT also expanded, and increased expression of activating molecules, namely IFN-γ, perforin, and CD107a, as well as γδT cytotoxicity. Mechanistically, TKIs augmented the efflux of isopentenyl pyrophosphate (IPP) from CML cells, which stimulated IFN-γ production and γδT expansion. Notably, the size of the IFN-γ+ naïve γδT population in TKI-treated CML patients was strongly correlated with their rates to reach DMR and with the duration on DMR. Statistical analysis suggests that a cutoff of 7.5% IFN-γ+ naïve subpopulation of γδT in CML patients could serve as a determinant for MR4.0 sustainability. Our results highlight γδT cells as a positive regulator for TKI responses in CML patients.
The distinct responsiveness of cytokeratin 19-positive hepatocellular carcinoma to regorafenib
Authors: Zhuo Jianyong , Lu Di , Lin Zuyuan , Yang Xinyu , Yang Modan , Wang Jianguo , Tao Yaoye , Wen Xue , Li Huihui , Lian Zhengxing , Cen Beini , Dong Siyi , Wei Xuyong , Xie Haiyang , Zheng Shusen , Shen Youqing , Xu Xiao
Published: November 2021

Cytokeratin 19-positive (CK19+) hepatocellular carcinoma (HCC) is an aggressive subtype characterized by early recurrence and chemotherapy tolerance. However, there is no specific therapeutic option for CK19+ HCC. The correlation between tumor recurrence and expression status of CK19 were studied in 206 patients undergoing liver transplantation for HCC. CK19−/+ HCC cells were isolated to screen effective antitumor drugs. The therapeutic effects of regorafenib were evaluated in patient-derived xenograft (PDX) models from 10 HCC patients. The mechanism of regorafenib on CK19+ HCC was investigated. CK19 positiveness indicated aggressiveness of tumor and higher recurrence risk of HCC after liver transplantation. The isolated CK19+ HCC cells had more aggressive behaviors than CK19− cells. Regorafenib preferentially increased the growth inhibition and apoptosis of CK19+ cells in vitro, whereas sorafenib, apatinib, and 5-fluorouracil did not. In PDX models from CK19−/+ HCC patients, the tumor control rate of regorafenib achieved 80% for CK19+ HCCs, whereas 0% for CK19− HCCs. RNA-sequencing revealed that CK19+ cells had elevated expression of mitochondrial ribosomal proteins, which are essential for mitochondrial function. Further experiments confirmed that regorafenib attenuated the mitochondrial respiratory capacity in CK19+ cells. However, the mitochondrial respiration in CK19− cells were faint and hardly repressed by regorafenib. The mitochondrial respiration was regulated by the phosphorylation of signal transducer and activator of transcription 3 (STAT3), which was inhibited by regorafenib in CK19+ cells. Hence, CK19 could be a potential marker of the therapeutic benefit of regorafenib, which facilitates the individualized therapy for HCC. STAT3/mitochondria axis determines the distinct response of CK19+ cells to regorafenib treatment.
Defective chromatin architectures in embryonic stem cells derived from somatic cell nuclear transfer impair their differentiation potentials
Authors: Wu Dan-Ya , Li Xinxin , Sun Qiao-Ran , Dou Cheng-Li , Xu Tian , He Hainan , Luo Han , Fu Haitao , Bu Guo-Wei , Luo Bingbing , Zhang Xia , Ma Bin-Guang , Peng Cheng , Miao Yi-Liang
Published: November 2021

Nuclear transfer embryonic stem cells (ntESCs) hold enormous promise for individual-specific regenerative medicine. However, the chromatin states of ntESCs remain poorly characterized. In this study, we employed ATAC-seq and Hi-C techniques to explore the chromatin accessibility and three-dimensional (3D) genome organization of ntESCs. The results show that the chromatin accessibility and genome structures of somatic cells are re-arranged to ESC-like states overall in ntESCs, including compartments, topologically associating domains (TADs) and chromatin loops. However, compared to fertilized ESCs (fESCs), ntESCs show some abnormal openness and structures that have not been reprogrammed completely, which impair the differentiation potential of ntESCs. The histone modification H3K9me3 may be involved in abnormal structures in ntESCs, including incorrect compartment switches and incomplete TAD rebuilding. Moreover, ntESCs and iPSCs show high similarity in 3D genome structures, while a few differences are detected due to different somatic cell origins and reprogramming mechanisms. Through systematic analyses, our study provides a global view of chromatin accessibility and 3D genome organization in ntESCs, which can further facilitate the understanding of the similarities and differences between ntESCs and fESCs.
Directional reorientation of migrating neutrophils is limited by suppression of receptor input signaling at the cell rear through myosin II activity
Authors: Hadjitheodorou Amalia , Bell George R. R. , Ellett Felix , Shastry Shashank , Irimia Daniel , Collins Sean R. , Theriot Julie A.
Published: November 2021

To migrate efficiently to target locations, cells must integrate receptor inputs while maintaining polarity: a distinct front that leads and a rear that follows. Here we investigate what is necessary to overwrite pre-existing front-rear polarity in neutrophil-like HL60 cells migrating inside straight microfluidic channels. Using subcellular optogenetic receptor activation, we show that receptor inputs can reorient weakly polarized cells, but the rear of strongly polarized cells is refractory to new inputs. Transient stimulation reveals a multi-step repolarization process, confirming that cell rear sensitivity to receptor input is the primary determinant of large-scale directional reversal. We demonstrate that the RhoA/ROCK/myosin II pathway limits the ability of receptor inputs to signal to Cdc42 and reorient migrating neutrophils. We discover that by tuning the phosphorylation of myosin regulatory light chain we can modulate the activity and localization of myosin II and thus the amenability of the cell rear to ‘listen’ to receptor inputs and respond to directional reprogramming.
Nanoscale π-conjugated ladders
Authors: Meißner Stefanie A. , Eder Theresa , Keller Tristan J. , Hofmeister David A. , Spicher Sebastian , Jester Stefan-S. , Vogelsang Jan , Grimme Stefan , Lupton John M. , Höger Sigurd
Published: November 2021

It is challenging to increase the rigidity of a macromolecule while maintaining solubility. Established strategies rely on templating by dendrons, or by encapsulation in macrocycles, and exploit supramolecular arrangements with limited robustness. Covalently bonded structures have entailed intramolecular coupling of units to resemble the structure of an alternating tread ladder with rungs composed of a covalent bond. We introduce a versatile concept of rigidification in which two rigid-rod polymer chains are repeatedly covalently associated along their contour by stiff molecular connectors. This approach yields almost perfect ladder structures with two well-defined π-conjugated rails and discretely spaced nanoscale rungs, easily visualized by scanning tunnelling microscopy. The enhancement of molecular rigidity is confirmed by the fluorescence depolarization dynamics and complemented by molecular-dynamics simulations. The covalent templating of the rods leads to self-rigidification that gives rise to intramolecular electronic coupling, enhancing excitonic coherence. The molecules are characterized by unprecedented excitonic mobility, giving rise to excitonic interactions on length scales exceeding 100 nm. Such interactions lead to deterministic single-photon emission from these giant rigid macromolecules, with potential implications for energy conversion in optoelectronic devices.
scPower accelerates and optimizes the design of multi-sample single cell transcriptomic studies
Authors: Schmid Katharina T. , Höllbacher Barbara , Cruceanu Cristiana , Böttcher Anika , Lickert Heiko , Binder Elisabeth B. , Theis Fabian J. , Heinig Matthias
Published: November 2021

Single cell RNA-seq has revolutionized transcriptomics by providing cell type resolution for differential gene expression and expression quantitative trait loci (eQTL) analyses. However, efficient power analysis methods for single cell data and inter-individual comparisons are lacking. Here, we present scPower; a statistical framework for the design and power analysis of multi-sample single cell transcriptomic experiments. We modelled the relationship between sample size, the number of cells per individual, sequencing depth, and the power of detecting differentially expressed genes within cell types. We systematically evaluated these optimal parameter combinations for several single cell profiling platforms, and generated broad recommendations. In general, shallow sequencing of high numbers of cells leads to higher overall power than deep sequencing of fewer cells. The model, including priors, is implemented as an R package and is accessible as a web tool. scPower is a highly customizable tool that experimentalists can use to quickly compare a multitude of experimental designs and optimize for a limited budget.
Organ-specific genome diversity of replication-competent SARS-CoV-2
Authors: Van Cleemput Jolien , van Snippenberg Willem , Lambrechts Laurens , Dendooven Amélie , D’Onofrio Valentino , Couck Liesbeth , Trypsteen Wim , Vanrusselt Jan , Theuns Sebastiaan , Vereecke Nick , van den Bosch Thierry P. P. , Lammens Martin , Driessen Ann , Achten Ruth , Bracke Ken R. , Van den Broeck Wim , Von der Thüsen Jan , Nauwynck Hans , Van Dorpe Jo , Gerlo Sarah , Maes Piet , Cox Janneke , Vandekerckhove Linos
Published: November 2021

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is not always confined to the respiratory system, as it impacts people on a broad clinical spectrum from asymptomatic to severe systemic manifestations resulting in death. Further, accumulation of intra-host single nucleotide variants during prolonged SARS-CoV-2 infection may lead to emergence of variants of concern (VOCs). Still, information on virus infectivity and intra-host evolution across organs is sparse. We report a detailed virological analysis of thirteen postmortem coronavirus disease 2019 (COVID-19) cases that provides proof of viremia and presence of replication-competent SARS-CoV-2 in extrapulmonary organs of immunocompromised patients, including heart, kidney, liver, and spleen (NCT04366882). In parallel, we identify organ-specific SARS-CoV-2 genome diversity and mutations of concern N501Y, T1027I, and Y453F, while the patient had died long before reported emergence of VOCs. These mutations appear in multiple organs and replicate in Vero E6 cells, highlighting their infectivity. Finally, we show two stages of fatal disease evolution based on disease duration and viral loads in lungs and plasma. Our results provide insights about the pathogenesis and intra-host evolution of SARS-CoV-2 and show that COVID-19 treatment and hygiene measures need to be tailored to specific needs of immunocompromised patients, even when respiratory symptoms cease.
Two-input protein logic gate for computation in living cells
Authors: Vishweshwaraiah Yashavantha L. , Chen Jiaxing , Chirasani Venkat R. , Tabdanov Erdem D. , Dokholyan Nikolay V.
Published: November 2021

Advances in protein design have brought us within reach of developing a nanoscale programming language, in which molecules serve as operands and their conformational states function as logic gates with precise input and output behaviors. Combining these nanoscale computing agents into larger molecules and molecular complexes will allow us to write and execute “code”. Here, in an important step toward this goal, we report an engineered, single protein design that is allosterically regulated to function as a ‘two-input logic OR gate’. Our system is based on chemo- and optogenetic regulation of focal adhesion kinase. In the engineered FAK, all of FAK domain architecture is retained and key intramolecular interactions between the kinase and the FERM domains are externally controlled through a rapamycin-inducible uniRapR module in the kinase domain and a light-inducible LOV2 module in the FERM domain. Orthogonal regulation of protein function was possible using the chemo- and optogenetic switches. We demonstrate that dynamic FAK activation profoundly increased cell multiaxial complexity in the fibrous extracellular matrix microenvironment and decreased cell motility. This work provides proof-of-principle for fine multimodal control of protein function and paves the way for construction of complex nanoscale computing agents.
Electrochemical C–H phosphorylation of arenes in continuous flow suitable for late-stage functionalization
Authors: Long Hao , Huang Chong , Zheng Yun-Tao , Li Zhao-Yu , Jie Liang-Hua , Song Jinshuai , Zhu Shaobin , Xu Hai-Chao
Published: November 2021

The development of efficient and sustainable methods for carbon-phosphorus bond formation is of great importance due to the wide application of organophosphorus compounds in chemistry, material sciences and biology. Previous C–H phosphorylation reactions under nonelectrochemical or electrochemical conditions require directing groups, transition metal catalysts, or chemical oxidants and suffer from limited scope. Herein we disclose a catalyst- and external oxidant-free, electrochemical C–H phosphorylation reaction of arenes in continuous flow for the synthesis of aryl phosphorus compounds. The C–P bond is formed through the reaction of arenes with anodically generated P-radical cations, a class of reactive intermediates remained unexplored for synthesis despite intensive studies of P-radicals. The high reactivity of the P-radical cations coupled with the mild conditions of the electrosynthesis ensures not only efficient reactions of arenes of diverse electronic properties but also selective late-stage functionalization of complex natural products and bioactive compounds. The synthetic utility of the electrochemical method is further demonstrated by the continuous production of 55.0 grams of one of the phosphonate products.
In vivo volumetric imaging of calcium and glutamate activity at synapses with high spatiotemporal resolution
Authors: Chen Wei , Natan Ryan G. , Yang Yuhan , Chou Shih-Wei , Zhang Qinrong , Isacoff Ehud Y. , Ji Na
Published: November 2021

Studying neuronal activity at synapses requires high spatiotemporal resolution. For high spatial resolution in vivo imaging at depth, adaptive optics (AO) is required to correct sample-induced aberrations. To improve temporal resolution, Bessel focus has been combined with two-photon fluorescence microscopy (2PFM) for fast volumetric imaging at subcellular lateral resolution. To achieve both high-spatial and high-temporal resolution at depth, we develop an efficient AO method that corrects the distorted wavefront of Bessel focus at the objective focal plane and recovers diffraction-limited imaging performance. Applying AO Bessel focus scanning 2PFM to volumetric imaging of zebrafish larval and mouse brains down to 500 µm depth, we demonstrate substantial improvements in the sensitivity and resolution of structural and functional measurements of synapses in vivo. This enables volumetric measurements of synaptic calcium and glutamate activity at high accuracy, including the simultaneous recording of glutamate activity of apical and basal dendritic spines in the mouse cortex.
Poly (Orange CD) sensor for paracetamol in presence of folic acid and dopamine
Authors: Sukanya S. D. , Swamy B. E. Kumara , Shashikumara J. K. , Sharma S. C. , Hariprasad S. A.
Published: November 2021

In the present work, Orange CD was chosen as an intriguing modifier for the electropolymerization on the surface of CPE by the CV technique. A novel, sensitive, and cost-effective poly (Orange CD) MCPE (PoOCD/MCPE) sensor was utilized for the selective detection of paracetamol (PA) in 0.2 M phosphate buffer solution (PBS) of pH 7.4. The oxidation peak current of PA was vastly enhanced at the sensor. The scan rate study is suggested that electro-oxidation of PA was adsorption-controlled. The pH study testifies the redox pathways transport with the same quantity of electrons and protons. The detection limit of PA is found to be 2.64 µM. DPV results show that substantial peak separation between PA, folic acid (FA), and dopamine (DA) could be facilitating their individual and simultaneous determination on the sensor. The decorated sensor demonstrates high sensitivity, stability, reproducibility, repeatability and has been successfully exploited for the detection of PA in a tablet with promising results.
Space oddity: musical syntax is mapped onto visual space
Authors: Maimon Neta B. , Lamy Dominique , Eitan Zohar
Published: November 2021

Increasing evidence has uncovered associations between the cognition of abstract schemas and spatial perception. Here we examine such associations for Western musical syntax,tonality.Spatial metaphors are ubiquitous when describing tonality: stable, closural tones are considered to be spatially central and, as gravitational foci, spatially lower. We investigated whether listeners, musicians and nonmusicians, indeed associate tonal relationships with visuospatial dimensions, including spatial height, centrality, laterality, and size, implicitly or explicitly, and whether such mappings are consistent with established metaphors. In the explicit paradigm, participants heard a tonality-establishing prime followed by a probe tone and coupled each probe with a subjectively appropriate location (Exp.1) or size (Exp.4). The implicit paradigm used a version of the Implicit Association Test to examine associations of tonal stability with vertical position (Exp.2), lateral position (Exp3) and size (Exp.5). Tonal stability was indeed associated with perceived physical space: the spatial distances between the locations associated with different scale-degrees significantly correlated with the tonal stability differences between these scale-degrees. However, inconsistently with musical discourse, stable tones were associated with leftward (instead of central) and higher (instead of lower) spatial positions. We speculate that these mappings are influenced by emotion, embodying the “good is up” metaphor, and by the spatial structure of music keyboards. Taken together, the results demonstrate a new type of cross-modal correspondence and a hitherto under-researched connotative function of musical structure. Importantly, the results suggest that the spatial mappings of an abstract domain may be independent of the spatial metaphors used to describe that domain.
High fidelity blood flow in a patient-specific arteriovenous fistula
Authors: McCullough J. W. S. , Coveney P. V.
Published: November 2021

An arteriovenous fistula, created by artificially connecting segments of a patient’s vasculature, is the preferred way to gain access to the bloodstream for kidney dialysis. The increasing power and availability of supercomputing infrastructure means that it is becoming more realistic to use simulations to help identify the best type and location of a fistula for a specific patient. We describe a 3D fistula model that uses the lattice Boltzmann method to simultaneously resolve blood flow in patient-specific arteries and veins. The simulations conducted here, comprising vasculatures of the whole forearm, demonstrate qualified validation against clinical data. Ongoing research to further encompass complex biophysics on realistic time scales will permit the use of human-scale physiological models for basic and clinical medicine.
A wavelet features derived radiomics nomogram for prediction of malignant and benign early-stage lung nodules
Authors: Jing Rui , Wang Jingtao , Li Jiangbing , Wang Xiaojuan , Li Baijie , Xue Fuzhong , Shao Guangrui , Xue Hao
Published: November 2021

This study was to develop a radiomics nomogram mainly using wavelet features for identifying malignant and benign early-stage lung nodules for high-risk screening. A total of 116 patients with early-stage solitary pulmonary nodules (SPNs) (≤ 3 cm) were divided into a training set (N = 70) and a validation set (N = 46). Radiomics features were extracted from plain LDCT images of each patient. A radiomics signature was then constructed with the LASSO with the training set. Combined with independent risk factors, a radiomics nomogram was built with a multivariate logistic regression model. This radiomics signature, consisting of one original and nine wavelet features, achieved favorable predictive efficacy than Mayo Clinic Model. The radiomics nomogram with radiomics signature and age also showed good calibration and discrimination in the training set (AUC 0.9406; 95% CI 0.8831–0.9982) and the validation set (AUC 0.8454; 95% CI 0.7196–0.9712). The decision curve indicated the clinical usefulness of our nomogram. The presented radiomics nomogram shows favorable predictive accuracy for identifying malignant and benign lung nodules in early-stage patients and is much better than the Mayo Clinic Model.
Research on boundary slip of hydrostatic lead screw under different driving modes
Authors: Liu Yandong , Feng Xianying , Li Yanfei , Lu Jiajia , Su Zhe
Published: November 2021

The flow state of oil film in the hydrostatic lead screw directly affects the transmission performance of the screw pair. The static and dynamic characteristics of a new type of double driven hydrostatic screw-nut pair (DDHSNP) are studied under different motion modes. The boundary condition of navier slip model is introduced into the lubricating mathematical model of DDHSNP, and the influences of boundary slip on the axial bearing capacity, axial stiffness and damping coefficient in micro scale are researched by finite difference method. The results show that when the motor runs at high speed (the rotating speed range of the screw and nut driven motor is 1000–9000 rpm), the existence of boundary slip leads to a improvement of the axial bearing capacity and stiffness coefficient of DDHSNP in the case of single-drive operation and dual-drive differential feed (the range of rotation difference is 10–100 rpm), which is more obvious under the single-drive mode. The increase rate of stiffness coefficient induced by boundary slip is much larger than that of bearing capacity. In addition, the boundary slip has little effect on the damping coefficient of DDHSNP in either single drive operation or dual drive differential operation.
Dramatic activation of an antibody by a single amino acid change in framework
Authors: Liang Wei-Ching , Yin Jianping , Lupardus Patrick , Zhang Jianhuan , Loyet Kelly M. , Sudhamsu Jawahar , Wu Yan
Published: November 2021

Antibody function is typically entirely dictated by the Complementarity Determining Regions (CDRs) that directly bind to the antigen, while the framework region acts as a scaffold for the CDRs and maintains overall structure of the variable domain. We recently reported that the rabbit monoclonal antibody 4A11 (rbt4A11) disrupts signaling through both TGFβ2 and TGFβ3 (Sun et al. in Sci Transl Med, 2021. https://doi.org/10.1126/scitranslmed.abe0407). Here, we report a dramatic, unexpected discovery during the humanization of rbt4A11 where, two variants of humanized 4A11 (h4A11), v2 and v7 had identical CDRs, maintained high affinity binding to TGFβ2/3, yet exhibited distinct differences in activity. While h4A11.v7 completely inhibited TGFβ2/3 signaling like rbt4A11, h4A11.v2 did not. We solved crystal structures of TGFβ2 complexed with Fab fragments of h4A11.v2 or h4A11.v7 and identified a novel interaction between the two heavy chain molecules in the 2:2 TGFb2:h4A11.v2-Fab complex. Further characterization revealed that framework residue variations at either position 19, 79 or 81 (Kabat numbering) of the heavy chain strikingly converts h4A11.v2 into an inhibitory antibody. Our work suggests that in addition to CDRs, framework residues and interactions between Fabs in an antibody could be engineered to further modulate activity of antibodies.
Comparative transcriptomic profiling of susceptible and resistant cultivars of pigeonpea demonstrates early molecular responses during Fusarium udum infection
Authors: Purohit Arnab , Ghosh Sanatan , Ganguly Shreeparna , Negi Madan Singh , Tripathi Shashi Bhushan , Chaudhuri Rituparna Kundu , Chakraborti Dipankar
Published: November 2021

Vascular wilt caused by Fusarium udum Butler is the most important disease of pigeonpea throughout the world. F. udum isolate MTCC 2204 (M1) inoculated pigeonpea plants of susceptible (ICP 2376) and resistant (ICP 8863) cultivars were taken at invasion stage of pathogenesis process for transcriptomic profiling to understand defense signaling reactions that interplay at early stage of this plant–pathogen encounter. Differential transcriptomic profiles were generated through cDNA-AFLP from M1 inoculated resistant and susceptible pigeonpea root tissues. Twenty five percent of transcript derived fragments (TDFs) were found to be pathogen induced. Among them 73 TDFs were re-amplified and sequenced. Homology search of the TDFs in available databases and thorough study of scientific literature identified several pathways, which could play crucial role in defense responses of the F. udum inoculated resistant plants. Some of the defense responsive pathways identified to be active during this interaction are, jasmonic acid and salicylic acid mediated defense responses, cell wall remodeling, vascular development and pattering, abscisic acid mediated responses, effector triggered immunity, and reactive oxygen species mediated signaling. This study identified important wilt responsive regulatory pathways in pigeonpea which will be helpful for further exploration of these resistant components for pigeonpea improvement.
An assessment of uranium in groundwater in the Grand Canyon region
Authors: Tillman Fred D , Beisner Kimberly R. , Anderson Jessica R. , Unema Joel A.
Published: November 2021

The Grand Canyon region in northern Arizona is a home or sacred place of origin for many Native Americans and is visited by over 6 million tourists each year. Most communities in the area depend upon groundwater for all water uses. Some of the highest-grade uranium ore in the United States also is found in the Grand Canyon region. A withdrawal of over 4000 km2 of Federal land in the Grand Canyon region from new uranium mining activities for 20 years was instituted in 2012, owing in part to a lack of scientific data on potential effects from uranium mining on water resources in the area. The U.S. Geological Survey has collected groundwater chemistry samples since 1981 in the Grand Canyon region to better understand the current state of groundwater quality, to monitor for changes in groundwater quality that may be the result of mining activities, and to identify "hot spots" with elevated metal concentrations and investigate the causes. This manuscript presents results for the assessment of uranium in groundwater in the Grand Canyon region. Analytical results for uranium in groundwater in the Grand Canyon region were available for 573 samples collected from 180 spring sites and 26 wells from September 1, 1981 to October 7, 2020. Samples were collected from springs issuing from stratigraphic units above, within, and below the Permian strata that host uranium ore in breccia pipes in the area. Maximum uranium concentrations at groundwater sites in the region ranged from less than 1 µg/L at 23 sites (11%) to 100 µg/L or more at 4 sites (2%). Of the 206 groundwater sites sampled, 195 sites (95%) had maximum observed uranium concentrations less than the U.S. Environmental Protection Agency’s Maximum Contaminant Level of 30 µg/L for drinking water and 177 sites (86%) had uranium concentrations less than the 15 µg/L Canadian benchmark for protection of aquatic life in freshwater. The establishment of baseline groundwater quality is an important first step in monitoring for change in water chemistry throughout mining lifecycles and beyond to ensure the health of these critical groundwater resources.
Artificial intelligence model comparison for risk factor analysis of patent ductus arteriosus in nationwide very low birth weight infants cohort
Authors: Na Jae Yoon , Kim Dongkyun , Kwon Amy M. , Jeon Jin Yong , Kim Hyuck , Kim Chang-Ryul , Lee Hyun Ju , Lee Joohyun , Park Hyun-Kyung
Published: November 2021

Despite the many comorbidities and high mortality rate in preterm infants with patent ductus arteriosus (PDA), therapeutic strategies vary depending on the clinical setting, and most studies of the related risk factors are based on small sample populations. We aimed to compare the performance of artificial intelligence (AI) analysis with that of conventional analysis to identify risk factors associated with symptomatic PDA (sPDA) in very low birth weight infants. This nationwide cohort study included 8369 very low birth weight (VLBW) infants. The participants were divided into an sPDA group and an asymptomatic PDA or spontaneously close PDA (nPDA) group. The sPDA group was further divided into treated and untreated subgroups. A total of 47 perinatal risk factors were collected and analyzed. Multiple logistic regression was used as a standard analytic tool, and five AI algorithms were used to identify the factors associated with sPDA. Combining a large database of risk factors from nationwide registries and AI techniques achieved higher accuracy and better performance of the PDA prediction tasks, and the ensemble methods showed the best performances.
The influence of M-CSF on fracture healing in a mouse model
Authors: Starlinger Julia , Sarahrudi Kambiz , Kecht Mathias , Koerbler Florian , Pietschmann Peter , Aharinejad Seyedhossein
Published: November 2021

Macrophage colony-stimulating factor 1 (M-CSF) is known to play a critical role during fracture repair e.g. by recruiting stem cells to the fracture site and impacting hard callus formation by stimulating osteoclastogenesis. The aim of this experiment was to study the impact of systemic M-CSF application and its effect on bony healing in a mouse model of femoral osteotomy. Doing so, we studied 61 wild type (wt) mice (18-week-old female C57BL/6) which were divided into three groups: (1) femoral osteotomy, (2) femoral osteotomy + stabilization with external fixator and (3) femoral osteotomy + stabilization with external fixator + systemic M-CSF application. Further, 12 op/op mice underwent femoral osteotomy and served as proof of concept. After being sacrificed at 28 days bony bridging was evaluated ex vivo with µCT, histological and biomechanical testing. Systemic M-CSF application impacted osteoclasts numbers, which were almost as low as found in op/op mice. Regarding callus size, the application of M-CSF in wt mice resulted in significantly larger calluses compared to wt mice without systemic M-CSF treatment. We further observed an anabolic effect of M-CSF application resulting in increased trabecular thickness compared to wt animals without additional M-CSF application. Systemic M-CSF application did not alter biomechanical properties in WT mice. The impact of M-CSF application in a mouse model of femoral osteotomy was oppositional to what we were expecting. While M-CSF application had a distinct anabolic effect on callus size as well as trabecular thickness, this on bottom line did not improve biomechanical properties. We hypothesize that in addition to the well-recognized negative effects of M-CSF on osteoclast numbers this seems to further downstream cause a lack of feedback on osteoblasts. Ultimately, continuous M-CSF application in the absence of co-stimulatory signals (e.g. RANKL) might overstimulate the hematopoietic linage in favor of tissue macrophages instead of osteoclasts.
A phase I study of the WT2725 dosing emulsion in patients with advanced malignancies
Authors: Fu Siqing , Piccioni David E. , Liu Hongtao , Lukas Rimas V. , Kesari Santosh , Aregawi Dawit , Hong David S. , Yamaguchi Kenichiro , Whicher Kate , Zhang Yi , Chen Yu-Luan , Poola Nagaraju , Eddy John , Blum David
Published: November 2021

WT2725 is a Wilms’ tumor gene 1 (WT1)-derived-oligopeptide vaccine designed to induce WT1-specific cytotoxic T-lymphocytes against WT1+ tumors in human leukocyte antigen (HLA)-A*0201+ and/or HLA-A*0206+ patients. Here, we report the results of a phase I study of WT2725. In this phase I, open-label, dose-escalation and expansion two-part study, the WT2725 dosing emulsion was administered as a monotherapy to patients with advanced malignancies known to overexpress WT1, including glioblastoma. In part 1, 44 patients were sequentially allocated to four doses: 0.3 mg (n = 5), 0.9 mg (n = 5), 3 mg (n = 6), and 9 mg (n = 28). In part 2, 18 patients were allocated to two doses: 18 mg (n = 9) and 27 mg (n = 9). No dose-limiting toxicities were observed, so the maximum tolerated dose was not reached. Median progression-free survival was 58 (95% confidence interval [CI] 56–81) days (~ 2 months) across all patients with solid tumors; median overall survival was 394 days (13.0 months) (95% CI 309–648). Overall immune-related response rate in solid tumor patients was 7.5% (95% CI 2.6–19.9); response was most prominent in the glioblastoma subgroup. Overall, 62.3% of patients were considered cytotoxic T-lymphocyte responders; the proportion increased with increasing WT2725 dosing emulsion dose. WT2725 dosing emulsion was well tolerated. Preliminary tumor response and biological marker data suggest that WT2725 dosing emulsion may exert antitumor activity in malignancies known to overexpress the WT1 protein, particularly glioblastoma, and provide a rationale for future clinical development.

Trial registration: NCT01621542.
A simple and reliable approach for the fabrication of nanoporous silver patterns for surface-enhanced Raman spectroscopy applications
Authors: Capaccio Angela , Sasso Antonio , Rusciano Giulia
Published: November 2021

The fabrication of plasmonic nanostructures with a reliable, low cost and easy approach has become a crucial and urgent challenge in many fields, including surface-enhanced Raman spectroscopy (SERS) based applications. In this frame, nanoporous metal films are quite attractive, due to their intrinsic large surface area and high density of metal nanogaps, acting as hot-spots for Raman signal enhancement. In this paper, we report a detailed study on the fabrication of nanoporous silver-based SERS substrates, obtained by the application of two successive treatments with an Inductively Coupled Plasma (ICP) system, using synthetic air and Ar as feeding gases. The obtained substrates exhibit a quite broad plasmonic response, covering the Vis–NIR range, and an enhancement factor reaching 6.5 $$\times\, 10^7$$

×

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7

, estimated by using 4-mercaptobenzoic acid (4-MBA) as probe molecule at 532 nm. Moreover, the substrates exhibit a quite good spatial reproducibility on a centimeter scale, which assures a good signal stability for analytical measurements. Globally, the developed protocol is easy and cost effective, potentially usable also for mass production thanks to the remarkable inter-batches reproducibility. As such, it holds promise for its use in SERS-based sensing platforms for sensitive detection of targets molecules.
Enhanced osseointegration through direct energy deposition porous coating for cementless orthopedic implant fixation
Authors: Ryu Dong Jin , Jung Ara , Ban Hun Yeong , Kwak Tae Yang , Shin Eun Joo , Gweon Bomi , Lim Dohyung , Wang Joon Ho
Published: November 2021

Direct energy deposition (DED) is a newly developed 3D metal printing technique that can be utilized on a porous surface coating of joint implants, however there is still a lack of studies on what advantages DED has over conventional techniques. We conducted a systematic mechanical and biological comparative study of porous coatings prepared using the DED method and other commercially available technologies including titanium plasma spray (TPS), and powder bed fusion (PBF). DED showed higher porosity surface (48.54%) than TPS (21.4%) and PBF (35.91%) with comparable fatigue cycle. At initial cell adhesion, cells on DED and PBF surface appeared to spread well with distinct actin stress fibers through immunofluorescence study. It means that the osteoblasts bind more strongly to the DED and PBF surface. Also, DED surface showed higher cell proliferation (1.27 times higher than TPS and PBF) and osteoblast cell activity (1.28 times higher than PBF) for 2 weeks culture in vitro test. In addition, DED surface showed better bone to implant contact and new bone formation than TPS in in vivo study. DED surface also showed consistently good osseointegration performance throughout the early and late period of osseointegration. Collectively, these results show that the DED coating method is an innovative technology that can be utilized to make cementless joint implants.
A movable type bioelectronics printing technology for modular fabrication of biosensors
Authors: Yang Muqun , Liu Mingyang , Cheng Jing , Wang Han
Published: November 2021

Biosensors have been widely used in various fields such as food industry, environmental testing and medical testing for their high sensitivity. However, current fabrication methods of biosensors, such as screen printing, micro fabrication and 3D printing suffer from complex procedures, requirement of cleanroom facility and limited fabrication materials, which significantly restrict the development and utilization of biosensors. Here, we propose a movable type bioelectronics printing method for the fabrication of biosensors by directly transferring bioelectronic materials onto various substrates using pre-fabricated molds. This simple, low-cost, yet robust method facilitates on-demand printing of master molds of partial or complete circuits on both rigid or flexible substrates. With this method, bioactive materials such as enzymes can be directly transferred onto substrates together with other electronic components, without complex modification after electrode fabrication using conventional methods. For demonstration, a dual-channel flexible electrochemical biosensor was fabricated by the movable type bioelectronics printing method for continuous monitoring of glucose and lactate. The movable type bioelectronics printing technology holds advantages of repeatability, flexibility and low cost for fabrication of biosensors on rigid and flexible substrates, as well as direct transfer printing of bioactive materials, which greatly promotes small-scale production of biosensors.