bluuebunny/crossref_metadata_2025_split huggingface dataset:
speedingCARs: accelerating the engineering of CAR T cells by signaling domain shuffling and single-cell sequencing
Authors: Castellanos-Rueda Rocío , Di Roberto Raphaël B. , Bieberich Florian , Schlatter Fabrice S. , Palianina Darya , Nguyen Oanh T. P. , Kapetanovic Edo , Läubli Heinz , Hierlemann Andreas , Khanna Nina , Reddy Sai T. 
Published: November 2022

AbstractChimeric antigen receptors (CARs) consist of an antigen-binding region fused to intracellular signaling domains, enabling customized T cell responses against targets. Despite their major role in T cell activation, effector function and persistence, only a small set of immune signaling domains have been explored. Here we present speedingCARs, an integrated method for engineering CAR T cells via signaling domain shuffling and pooled functional screening. Leveraging the inherent modularity of natural signaling domains, we generate a library of 180 unique CAR variants genomically integrated into primary human T cells by CRISPR-Cas9. In vitro tumor cell co-culture, followed by single-cell RNA sequencing (scRNA-seq) and single-cell CAR sequencing (scCAR-seq), enables high-throughput screening for identifying several variants with tumor killing properties and T cell phenotypes markedly different from standard CARs. Mapping of the CAR scRNA-seq data onto that of tumor infiltrating lymphocytes further helps guide the selection of variants. These results thus help expand the CAR signaling domain combination space, and supports speedingCARs as a tool for the engineering of CARs for potential therapeutic development.
Tempo: an unsupervised Bayesian algorithm for circadian phase inference in single-cell transcriptomics
Authors: Auerbach Benjamin J. , FitzGerald Garret A. , Li Mingyao 
Published: November 2022

AbstractThe circadian clock is a 24 h cellular timekeeping mechanism that regulates human physiology. Answering several fundamental questions in circadian biology will require joint measures of single-cell circadian phases and transcriptomes. However, no widespread experimental approaches exist for this purpose. While computational approaches exist to infer cell phase directly from single-cell RNA-sequencing data, existing methods yield poor circadian phase estimates, and do not quantify estimation uncertainty, which is essential for interpretation of results from very sparse single-cell RNA-sequencing data. To address these unmet needs, we introduce Tempo, a Bayesian variational inference approach that incorporates domain knowledge of the clock and quantifies phase estimation uncertainty. Through simulations and analyses of real data, we demonstrate that Tempo yields more accurate estimates of circadian phase than existing methods and provides well-calibrated uncertainty quantifications. Tempo will facilitate large-scale studies of single-cell circadian transcription.
Deep learning empowered volume delineation of whole-body organs-at-risk for accelerated radiotherapy
Authors: Shi Feng , Hu Weigang , Wu Jiaojiao , Han Miaofei , Wang Jiazhou , Zhang Wei , Zhou Qing , Zhou Jingjie , Wei Ying , Shao Ying , Chen Yanbo , Yu Yue , Cao Xiaohuan , Zhan Yiqiang , Zhou Xiang Sean , Gao Yaozong , Shen Dinggang 
Published: November 2022

AbstractIn radiotherapy for cancer patients, an indispensable process is to delineate organs-at-risk (OARs) and tumors. However, it is the most time-consuming step as manual delineation is always required from radiation oncologists. Herein, we propose a lightweight deep learning framework for radiotherapy treatment planning (RTP), named RTP-Net, to promote an automatic, rapid, and precise initialization of whole-body OARs and tumors. Briefly, the framework implements a cascade coarse-to-fine segmentation, with adaptive module for both small and large organs, and attention mechanisms for organs and boundaries. Our experiments show three merits: 1) Extensively evaluates on 67 delineation tasks on a large-scale dataset of 28,581 cases; 2) Demonstrates comparable or superior accuracy with an average Dice of 0.95; 3) Achieves near real-time delineation in most tasks with <2 s. This framework could be utilized to accelerate the contouring process in the All-in-One radiotherapy scheme, and thus greatly shorten the turnaround time of patients.
Stromal androgen signaling acts as tumor niches to drive prostatic basal epithelial progenitor-initiated oncogenesis
Authors: Hiroto Alex , Kim Won Kyung , Pineda Ariana , He Yongfeng , Lee Dong-Hoon , Le Vien , Olson Adam W. , Aldahl Joseph , Nenninger Christian H. , Buckley Alyssa J. , Xiao Guang-Qian , Geradts Joseph , Sun Zijie 
Published: November 2022

AbstractThe androgen receptor (AR)-signaling pathways are essential for prostate tumorigenesis. Although significant effort has been devoted to directly targeting AR-expressing tumor cells, these therapies failed in most prostate cancer patients. Here, we demonstrate that loss of AR in stromal sonic-hedgehog Gli1-lineage cells diminishes prostate epithelial oncogenesis and tumor development using in vivo assays and mouse models. Single-cell RNA sequencing and other analyses identified a robust increase of insulin-like growth factor (IGF) binding protein 3 expression in AR-deficient stroma through attenuation of AR suppression on Sp1-regulated transcription, which further inhibits IGF1-induced Wnt/β-catenin activation in adjacent basal epithelial cells and represses their oncogenic growth and tumor development. Epithelial organoids from stromal AR-deficient mice can regain IGF1-induced oncogenic growth. Loss of human prostate tumor basal cell signatures reveals in basal cells of stromal AR-deficient mice. These data demonstrate a distinct mechanism for prostate tumorigenesis and implicate co-targeting stromal and epithelial AR-signaling for prostate cancer.
N6-methyladenosine RNA modification promotes viral genomic RNA stability and infection
Authors: Zhang Tianye , Shi Chaonan , Hu Haichao , Zhang Zhuo , Wang Ziqiong , Chen Zhiqing , Feng Huimin , Liu Peng , Guo Jun , Lu Qisen , Zhong Kaili , Chen ZhiHui , Liu Jiaqian , Yu Jiancheng , Chen Jianping , Chen Feng , Yang Jian 
Published: November 2022

AbstractMolecular manipulation of susceptibility (S) genes that are antipodes to resistance (R) genes has been adopted as an alternative strategy for controlling crop diseases. Here, we show the S gene encoding Triticum aestivum m6A methyltransferase B (TaMTB) is identified by a genome-wide association study and subsequently shown to be a positive regulator for wheat yellow mosaic virus (WYMV) infection. TaMTB is localized in the nucleus, is translocated into the cytoplasmic aggregates by binding to WYMV NIb to upregulate the m6A level of WYMV RNA1 and stabilize the viral RNA, thus promoting viral infection. A natural mutant allele TaMTB-SNP176C is found to confer an enhanced susceptibility to WYMV infection through genetic variation analysis on 243 wheat varieties. Our discovery highlights this allele can be a useful target for the molecular wheat breeding in the future.
Optical gearbox enabled versatile multiscale high-throughput multiphoton functional imaging
Authors: Lin Jianian , Cheng Zongyue , Yang Guang , Cui Meng 
Published: November 2022

AbstractTo understand the function and mechanism of biological systems, it is crucial to observe the cellular dynamics at high spatiotemporal resolutions within live animals. The recent advances in genetically encoded function indicators have significantly improved the response rate to a near millisecond time scale. However, the widely employed in vivo imaging systems often lack the temporal solution to capture the fast biological dynamics. To broadly enable the capability of high-speed in vivo deep-tissue imaging, we developed an optical gearbox. As an add-on module, the optical gearbox can convert the common multiphoton imaging systems for versatile multiscale high-throughput imaging applications. In this work, we demonstrate in vivo 2D and 3D function imaging in mammalian brains at frame rates ranging from 50 to 1000 Hz. The optical gearbox’s versatility and compatibility with the widely employed imaging components will be highly valuable to a variety of deep tissue imaging applications.
Nociceptor neurons affect cancer immunosurveillance
Authors: Balood Mohammad , Ahmadi Maryam , Eichwald Tuany , Ahmadi Ali , Majdoubi Abdelilah , Roversi Karine , Roversi Katiane , Lucido Christopher T. , Restaino Anthony C. , Huang Siyi , Ji Lexiang , Huang Kai-Chih , Semerena Elise , Thomas Sini C. , Trevino Alexandro E. , Merrison Hannah , Parrin Alexandre , Doyle Benjamin , Vermeer Daniel W. , Spanos William C. , Williamson Caitlin S. , Seehus Corey R. , Foster Simmie L. , Dai Hongyue , Shu Chengyi J. , Rangachari Manu , Thibodeau Jacques , V. Del Rincon Sonia , Drapkin Ronny , Rafei Moutih , Ghasemlou Nader , Vermeer Paola D. , Woolf Clifford J. , Talbot Sebastien 
Published: November 2022

AbstractSolid tumours are innervated by nerve fibres that arise from the autonomic and sensory peripheral nervous systems1–5. Whether the neo-innervation of tumours by pain-initiating sensory neurons affects cancer immunosurveillance remains unclear. Here we show that melanoma cells interact with nociceptor neurons, leading to increases in their neurite outgrowth, responsiveness to noxious ligands and neuropeptide release. Calcitonin gene-related peptide (CGRP)—one such nociceptor-produced neuropeptide—directly increases the exhaustion of cytotoxic CD8+ T cells, which limits their capacity to eliminate melanoma. Genetic ablation of the TRPV1 lineage, local pharmacological silencing of nociceptors and antagonism of the CGRP receptor RAMP1 all reduced the exhaustion of tumour-infiltrating leukocytes and decreased the growth of tumours, nearly tripling the survival rate of mice that were inoculated with B16F10 melanoma cells. Conversely, CD8+ T cell exhaustion was rescued in sensory-neuron-depleted mice that were treated with local recombinant CGRP. As compared with wild-type CD8+ T cells, Ramp1−/− CD8+ T cells were protected against exhaustion when co-transplanted into tumour-bearing Rag1-deficient mice. Single-cell RNA sequencing of biopsies from patients with melanoma revealed that intratumoral RAMP1-expressing CD8+ T cells were more exhausted than their RAMP1-negative counterparts, whereas overexpression of RAMP1 correlated with a poorer clinical prognosis. Overall, our results suggest that reducing the release of CGRP from tumour-innervating nociceptors could be a strategy to improve anti-tumour immunity by eliminating the immunomodulatory effects of CGRP on cytotoxic CD8+ T cells.
Broad transcriptomic dysregulation occurs across the cerebral cortex in ASD
Authors: Gandal Michael J. , Haney Jillian R. , Wamsley Brie , Yap Chloe X. , Parhami Sepideh , Emani Prashant S. , Chang Nathan , Chen George T. , Hoftman Gil D. , de Alba Diego , Ramaswami Gokul , Hartl Christopher L. , Bhattacharya Arjun , Luo Chongyuan , Jin Ting , Wang Daifeng , Kawaguchi Riki , Quintero Diana , Ou Jing , Wu Ye Emily , Parikshak Neelroop N. , Swarup Vivek , Belgard T. Grant , Gerstein Mark , Pasaniuc Bogdan , Geschwind Daniel H. 
Published: November 2022

AbstractNeuropsychiatric disorders classically lack defining brain pathologies, but recent work has demonstrated dysregulation at the molecular level, characterized by transcriptomic and epigenetic alterations1–3. In autism spectrum disorder (ASD), this molecular pathology involves the upregulation of microglial, astrocyte and neural–immune genes, the downregulation of synaptic genes, and attenuation of gene-expression gradients in cortex1,2,4–6. However, whether these changes are limited to cortical association regions or are more widespread remains unknown. To address this issue, we performed RNA-sequencing analysis of 725 brain samples spanning 11 cortical areas from 112 post-mortem samples from individuals with ASD and neurotypical controls. We find widespread transcriptomic changes across the cortex in ASD, exhibiting an anterior-to-posterior gradient, with the greatest differences in primary visual cortex, coincident with an attenuation of the typical transcriptomic differences between cortical regions. Single-nucleus RNA-sequencing and methylation profiling demonstrate that this robust molecular signature reflects changes in cell-type-specific gene expression, particularly affecting excitatory neurons and glia. Both rare and common ASD-associated genetic variation converge within a downregulated co-expression module involving synaptic signalling, and common variation alone is enriched within a module of upregulated protein chaperone genes. These results highlight widespread molecular changes across the cerebral cortex in ASD, extending beyond association cortex to broadly involve primary sensory regions.
Entorhinal cortex directs learning-related changes in CA1 representations
Authors: Grienberger Christine , Magee Jeffrey C. 
Published: November 2022

AbstractLearning-related changes in brain activity are thought to underlie adaptive behaviours1,2. For instance, the learning of a reward site by rodents requires the development of an over-representation of that location in the hippocampus3–6. How this learning-related change occurs remains unknown. Here we recorded hippocampal CA1 population activity as mice learned a reward location on a linear treadmill. Physiological and pharmacological evidence suggests that the adaptive over-representation required behavioural timescale synaptic plasticity (BTSP)7. BTSP is known to be driven by dendritic voltage signals that we proposed were initiated by input from entorhinal cortex layer 3 (EC3). Accordingly, the CA1 over-representation was largely removed by optogenetic inhibition of EC3 activity. Recordings from EC3 neurons revealed an activity pattern that could provide an instructive signal directing BTSP to generate the over-representation. Consistent with this function, our observations show that exposure to a second environment possessing a prominent reward-predictive cue resulted in both EC3 activity and CA1 place field density that were more elevated at the cue than at the reward. These data indicate that learning-related changes in the hippocampus are produced by synaptic plasticity directed by an instructive signal from the EC3 that seems to be specifically adapted to the behaviourally relevant features of the environment.
Hydroclimatic vulnerability of peat carbon in the central Congo Basin
Authors: Garcin Yannick , Schefuß Enno , Dargie Greta C. , Hawthorne Donna , Lawson Ian T. , Sebag David , Biddulph George E. , Crezee Bart , Bocko Yannick E. , Ifo Suspense A. , Mampouya Wenina Y. Emmanuel , Mbemba Mackline , Ewango Corneille E. N. , Emba Ovide , Bola Pierre , Kanyama Tabu Joseph , Tyrrell Genevieve , Young Dylan M. , Gassier Ghislain , Girkin Nicholas T. , Vane Christopher H. , Adatte Thierry , Baird Andy J. , Boom Arnoud , Gulliver Pauline , Morris Paul J. , Page Susan E. , Sjögersten Sofie , Lewis Simon L. 
Published: November 2022

AbstractThe forested swamps of the central Congo Basin store approximately 30 billion metric tonnes of carbon in peat1,2. Little is known about the vulnerability of these carbon stocks. Here we investigate this vulnerability using peat cores from a large interfluvial basin in the Republic of the Congo and palaeoenvironmental methods. We find that peat accumulation began at least at 17,500 calibrated years before present (cal. yr bp; taken asad1950). Our data show that the peat that accumulated between around 7,500 to around 2,000 cal. yr bpis much more decomposed compared with older and younger peat. Hydrogen isotopes of plant waxes indicate a drying trend, starting at approximately 5,000 cal. yrbpand culminating at approximately 2,000 cal. yr bp, coeval with a decline in dominant swamp forest taxa. The data imply that the drying climate probably resulted in a regional drop in the water table, which triggered peat decomposition, including the loss of peat carbon accumulated prior to the onset of the drier conditions. After approximately 2,000 cal. yr bp, our data show that the drying trend ceased, hydrologic conditions stabilized and peat accumulation resumed. This reversible accumulation–loss–accumulation pattern is consistent with other peat cores across the region, indicating that the carbon stocks of the central Congo peatlands may lie close to a climatically driven drought threshold. Further research should quantify the combination of peatland threshold behaviour and droughts driven by anthropogenic carbon emissions that may trigger this positive carbon cycle feedback in the Earth system.
Extracellular fluid viscosity enhances cell migration and cancer dissemination
Authors: Bera Kaustav , Kiepas Alexander , Godet Inês , Li Yizeng , Mehta Pranav , Ifemembi Brent , Paul Colin D. , Sen Anindya , Serra Selma A. , Stoletov Konstantin , Tao Jiaxiang , Shatkin Gabriel , Lee Se Jong , Zhang Yuqi , Boen Adrianna , Mistriotis Panagiotis , Gilkes Daniele M. , Lewis John D. , Fan Chen-Ming , Feinberg Andrew P. , Valverde Miguel A. , Sun Sean X. , Konstantopoulos Konstantinos 
Published: November 2022

AbstractCells respond to physical stimuli, such as stiffness1, fluid shear stress2and hydraulic pressure3,4. Extracellular fluid viscosity is a key physical cue that varies under physiological and pathological conditions, such as cancer5. However, its influence on cancer biology and the mechanism by which cells sense and respond to changes in viscosity are unknown. Here we demonstrate that elevated viscosity counterintuitively increases the motility of various cell types on two-dimensional surfaces and in confinement, and increases cell dissemination from three-dimensional tumour spheroids. Increased mechanical loading imposed by elevated viscosity induces an actin-related protein 2/3 (ARP2/3)-complex-dependent dense actin network, which enhances Na+/H+exchanger 1 (NHE1) polarization through its actin-binding partner ezrin. NHE1 promotes cell swelling and increased membrane tension, which, in turn, activates transient receptor potential cation vanilloid 4 (TRPV4) and mediates calcium influx, leading to increased RHOA-dependent cell contractility. The coordinated action of actin remodelling/dynamics, NHE1-mediated swelling and RHOA-based contractility facilitates enhanced motility at elevated viscosities. Breast cancer cells pre-exposed to elevated viscosity acquire TRPV4-dependent mechanical memory through transcriptional control of the Hippo pathway, leading to increased migration in zebrafish, extravasation in chick embryos and lung colonization in mice. Cumulatively, extracellular viscosity is a physical cue that regulates both short- and long-term cellular processes with pathophysiological relevance to cancer biology.
Bioinformatics analysis of prognostic value and immunological role of MeCP2 in pan-cancer
Authors: Wang Yanfeng , Zhang Yunqing , Wang Fenghui , Li Ting , Song Xinqiu , Shi Haiyan , Du Juan , Zhang Huahua , Jing Hongmei , Han Jiaqi , Tong Dongdong , Zhang Jing 
Published: November 2022

AbstractMethyl-CpG-binding protein 2(MeCP2) is an important epigenetic regulatory factor that promotes many tumor developments, such as liver cancer, breast cancer, and colorectal cancer. So far, no pan-cancer analysis has been reported. Therefore, this study aims to explore pan-cancer's prognostic value, immune infiltration pattern, and biological function. We used bioinformatics methods to analyze the expression and prognostic significance of MeCP2, and the relationship between MeCP2 and clinicopathological parameters, genetic variation, methylation, phosphorylation, immune cell infiltration, and biological function in pan-cancer from using a public database. The results showed that expression of MeCP2 was up-regulated in 8 cancers and down-regulated in 2 cancers, which was remarkably correlated with the prognosis, pathological stage, grade and subtype of cancers. The promoter methylation level of MeCP2 DNA was decreased in bladder urothelial carcinoma (BLCA), breast invasive carcinoma (BRCA), liver hepatocellular carcinoma (LIHC), prostate adenocarcinoma (PRAD), uterine corpus endometrial carcinoma (UCEC), testicular germ cell tumors (TGCT), and stomach adenocarcinoma (STAD);decreased phosphorylation of S25, S90, S92, S241, S286, S325 and S435 was found in MeCP2, such as UCEC, lung adenocarcinoma (LUAD), ovarian serous cystadenocarcinoma (OV), colon adenocarcinoma (COAD), and kidney renal clear cell carcinoma (KIRC). Furthermore, MeCP2 expression was significantly associated with multiple immunomodulators and immune cell infiltration levels across most tumors. Therefore, our pan-cancer explored the prognostic markers and immunotherapeutic value of MeCP2 in different cancers.
Thermo diffusion impacts on the flow of second grade fluid with application of (ABC), (CF) and (CPC) subject to exponential heating
Authors: Rehman Aziz Ur , Riaz Muhammad Bilal , Wojciechowski Adam 
Published: November 2022

AbstractThe aim of this article is to investigate the exact solution by using a new approach for the thermal transport phenomena of second grade fluid flow under the impact of MHD along with exponential heating as well as Darcy’s law. The phenomenon has been expressed in terms of partial differential equations, then transformed the governing equations in non-dimentional form. For the sake of better rheology of second grade fluid, developed a fractional model by applying the new definition of Constant Proportional-Caputo hybrid derivative (CPC), Atangana Baleanu in Caputo sense (ABC) and Caputo Fabrizio (CF) fractional derivative operators that describe the generalized memory effects. For seeking exact solutions in terms of Mittag-Leffler and G-functions for velocity, temperature and concentration equations, Laplace integral transformation technique is applied. For physical significance of various system parameters on fluid velocity, concentration and temperature distributions are demonstrated through various graphs by using graphical software. Furthermore, for being validated the acquired solutions, accomplished a comparative analysis with some published work. It is also analyzed that for exponential heating and non-uniform velocity conditions, the CPC fractional operator is the finest fractional model to describe the memory effect of velocity, energy and concentration profile. Moreover, the graphical representations of the analytical solutions illustrated the main results of the present work. Also, in the literature, it is observed that to derived analytical results from fractional fluid models developed by the various fractional operators, is difficult and this article contributing to answer the open problem of obtaining analytical solutions the fractionalized fluid models.
Characterization of collagen response to bone fracture healing using polarization-SHG
Authors: Nair Anupama , Chuang Shu-Chun , Lin Yi-Shan , Chen Chung-Hwan , Fang Ting-Chen , Chiu Hsiao-Chi , Lien Chi-Hsiang , Chen Shean-Jen 
Published: November 2022

AbstractIn this study, we extend on the three parameter analysis approach of utilizing a noninvasive dual-liquid–crystal-based polarization-resolved second harmonic generation (SHG) microscopy to facilitate the quantitative characterization of collagen types I and II in fracture healing tissues. The SHG images under various linear and circular polarization states are analyzed and quantified in terms of the peptide pitch angle (PA), SHG-circular dichroism (CD), and anisotropy parameter (AP). The results show that the collagen PA has a value of 49.26° after 2 weeks of fracture healing (collagen type II domination) and 49.05° after 4 weeks (collagen type I domination). Moreover, the SHG-CD and AP values of the different collagen types differ by 0.05. The change tendencies of the extracted PA, SHG-CD, and AP parameters over the healing time are consistent with the collagen properties of healthy nonfractured bone. Thus, the feasibility of the proposed dual-liquid–crystal-based polarization-SHG method for differentiating between collagen types I and II in bone fracture healing tissue is confirmed.