bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phosphoproteomic of the acetylcholine pathway enables discovery of the PKC-β-PIX-Rac1-PAK cascade as a stimulatory signal for aversive learning
Authors: Yamahashi Yukie , Lin You-Hsin , Mouri Akihiro , Iwanaga Sho , Kawashima Kazuhiro , Tokumoto Yuya , Watanabe Yo , Faruk Md. Omar , Zhang Xinjian , Tsuboi Daisuke , Nakano Takashi , Saito Naoaki , Nagai Taku , Yamada Kiyofumi , Kaibuchi Kozo 
Published: June 2022

AbstractAcetylcholine is a neuromodulator critical for learning and memory. The cholinesterase inhibitor donepezil increases brain acetylcholine levels and improves Alzheimer’s disease (AD)-associated learning disabilities. Acetylcholine activates striatal/nucleus accumbens dopamine receptor D2-expressing medium spiny neurons (D2R-MSNs), which regulate aversive learning through muscarinic receptor M1 (M1R). However, how acetylcholine stimulates learning beyond M1Rs remains unresolved. Here, we found that acetylcholine stimulated protein kinase C (PKC) in mouse striatal/nucleus accumbens. Our original kinase-oriented phosphoproteomic analysis revealed 116 PKC substrate candidates, including Rac1 activator β-PIX. Acetylcholine induced β-PIX phosphorylation and activation, thereby stimulating Rac1 effector p21-activated kinase (PAK). Aversive stimulus activated the M1R-PKC-PAK pathway in mouse D2R-MSNs. D2R-MSN-specific expression of PAK mutants by the Cre-Flex system regulated dendritic spine structural plasticity and aversive learning. Donepezil induced PAK activation in both accumbal D2R-MSNs and in the CA1 region of the hippocampus and enhanced D2R-MSN-mediated aversive learning. These findings demonstrate that acetylcholine stimulates M1R-PKC-β-PIX-Rac1-PAK signaling in D2R-MSNs for aversive learning and imply the cascade’s therapeutic potential for AD as aversive learning is used to preliminarily screen AD drugs.
Mitochondrial reactive oxygen is critical for IL-12/IL-18-induced IFN-γ production by CD4+ T cells and is regulated by Fas/FasL signaling
Authors: Rackov Gorjana , Tavakoli Zaniani Parinaz , Colomo del Pino Sara , Shokri Rahman , Monserrat Jorge , Alvarez-Mon Melchor , Martinez-A Carlos , Balomenos Dimitrios 
Published: June 2022

AbstractMitochondrial activation and the production of mitochondrial reactive oxygen species (mROS) are crucial for CD4+ T cell responses and have a role in naïve cell signaling after TCR activation. However, little is known about mROS role in TCR-independent signaling and in recall responses. Here, we found that mROS are required for IL-12 plus IL-18-driven production of IFN-γ, an essential cytokine for inflammatory and autoimmune disease development. Compared to TCR stimulation, which induced similar levels of mROS in naïve and memory-like cells, IL-12/IL-18 showed faster and augmented mROS production in memory-like cells. mROS inhibition significantly downregulated IFN-γ and CD44 expression, suggesting a direct mROS effect on memory-like T cell function. The mechanism that promotes IFN-γ production after IL-12/IL-18 challenge depended on the effect of mROS on optimal activation of downstream signaling pathways, leading to STAT4 and NF-κB activation. To relate our findings to IFN-γ-driven lupus-like disease, we used Fas-deficient memory-like CD4+ T cells from lpr mice. Importantly, we found significantly increased IFN-γ and mROS production in lpr compared with parental cells. Treatment of WT cells with FasL significantly reduced mROS production and the activation of signaling events leading to IFN-γ. Moreover, Fas deficiency was associated with increased mitochondrial levels of cytochrome C and caspase-3 compared with WT memory-like cells. mROS inhibition significantly reduced the population of disease-associated lpr CD44hiCD62LloCD4+ T cells and their IFN-γ production. Overall, these findings uncovered a previously unidentified role of Fas/FasL interaction in regulating mROS production by memory-like T cells. This apoptosis-independent Fas activity might contribute to the accumulation of CD44hiCD62LloCD4+ T cells that produce increased IFN-γ levels in lpr mice. Overall, our findings pinpoint mROS as central regulators of TCR-independent signaling, and support mROS pharmacological targeting to control aberrant immune responses in autoimmune-like disease.
RASAL2 regulates the cell cycle and cyclin D1 expression through PI3K/AKT signalling in prostate tumorigenesis
Authors: Wang Qi , Wu Shiqi , Gu Yanan , Liang Hua , He Fei , Wang Xinyang , He Dalin , Wu Kaijie 
Published: June 2022

AbstractProstate cancer (PCa) growth and progression are uniquely dependent on androgens, making the androgen receptor pathway a prime target for therapy; however, cancer progression to androgen independence leads to treatment failure and poor prognosis. In recent years, alternative therapeutic pathways for PCa have been extensively explored, such as the PTEN/PI3K/AKT pathway, cell cycle, and DNA repair. In the present study, we discovered that RASAL2, a RAS-GTPase-activating protein, acted as an oncogene to regulate cancer cell proliferation and the cell cycle and contributed to tumorigenesis via the PI3K/AKT/cyclin D1 pathway. First, RASAL2 expression was higher in PCa tumour and metastatic lymph node tissues than in matched adjacent nontumor tissues and was associated with higher PCa tumour stage, Gleason score and poorer prognosis. Mechanistically, we found that RASAL2 promoted tumour cell proliferation, the transition from G1 to S phase in vitro and tumour growth in vivo. Furthermore, we demonstrated that RASAL2 facilitated phosphorylation of AKT, which in turn increased the expression of cyclin D1 encoded by the CCND1 gene. In addition, there was a positive correlation between the expression of RASAL2 and cyclin D1 in subcutaneous xenografts and clinical specimens. Taken together, these findings indicate that RASAL2 plays an oncogenic role in prostate cancer and may promote PCa tumorigenesis through PI3K/AKT signalling and cyclin D1 expression.
Combinatorial physicochemical stimuli in the three-dimensional environment of a hyaluronic acid hydrogel amplify chondrogenesis by stimulating phosphorylation of the Smad and MAPK signaling pathways
Authors: Ahn Jinsung , Arai Yoshie , Kim Byoung Ju , Seo Young-Kwon , Moon James J. , Shin Dong Ah , Choi Bogyu , Lee Soo-Hong 
Published: June 2022

AbstractThe chondrogenesis of stem cells and cartilage tissue regeneration are more efficient in a three-dimensional (3D) environment than in a two-dimensional (2D) environment. Although extensive studies have examined the effects of biochemical or physical cues alone, it is not fully understood how these biochemical and biophysical cues in the 3D environment are intertwined and orchestrated with chondrogenesis for cartilage tissue regeneration. In this study, we used photocrosslinked hyaluronic acid (HA), the extracellular matrix of cartilage, as a general 3D microenvironment to characterize the effects of dimensionality, localization of biochemical cues, regulation of biophysical cues, and external stimulation on chondrogenic signaling pathways in adipose-derived stem cells (hASCs). TGF-β3 was immobilized in HA hydrogels by ionic or covalent conjugation. The stiffness of the hydrogels was tuned by varying the crosslinking density, and an external stimulus for chondrogenesis was provided by ultrasound. The results revealed that the levels of chondrogenic signals in hASCs cultured in the 3D HA hydrogel depended on the presence of TGF-β3, and a reduction in the stiffness of the TGF-β3 covalent conjugated hydrogel increased the chance of interaction with encapsulated hASCs, leading to an increase in chondrogenic signals. External stimulation with ultrasound increased the interaction of hASCs with HA via CD44, thereby increasing chondrogenesis. Our results present a new understanding of the intertwined mechanisms of chondrogenesis in 3D hydrogels connecting TGF-β3 sequestration, mechanical properties, and ultrasound-based external stimulation. Overall, our results suggest that when designing novel biomaterials for tissue engineering, it is necessary to consider the combinatorial mechanism of action in 3D microenvironments.
Diversity of spatiotemporal coding reveals specialized visual processing streams in the mouse cortex
Authors: Han Xu , Vermaercke Ben , Bonin Vincent 
Published: June 2022

AbstractThe cerebral cortex contains diverse neural representations of the visual scene, each enabling distinct visual and spatial abilities. However, the extent to which representations are distributed or segregated across cortical areas remains poorly understood. By determining the spatial and temporal responses of >30,000 layer 2/3 pyramidal neurons, we characterize the functional organization of parallel visual streams across eight areas of the mouse cortex. While dorsal and ventral areas form complementary representations of spatiotemporal frequency, motion speed, and spatial patterns, the anterior and posterior dorsal areas show distinct specializations for fast and slow oriented contrasts. At the cellular level, while diverse spatiotemporal tuning lies along a continuum, oriented and non-oriented spatial patterns are encoded by distinct tuning types. The identified tuning types are present across dorsal and ventral streams. The data underscore the highly specific and highly distributed nature of visual cortical representations, which drives specialization of cortical areas and streams.
Cross-sectional seroprevalence surveys of SARS-CoV-2 antibodies in children in Germany, June 2020 to May 2021
Authors: Sorg Anna-Lisa , Bergfeld Leon , Jank Marietta , Corman Victor , Semmler Ilia , Goertz Anna , Beyerlein Andreas , Verjans Eva , Wagner Norbert , Von Bernuth Horst , Lander Fabian , Weil Katharina , Hufnagel Markus , Spiekerkoetter Ute , Chao Cho-Ming , Naehrlich Lutz , Muntau Ania Carolina , Schulze-Sturm Ulf , Hansen Gesine , Wetzke Martin , Jung Anna-Maria , Niehues Tim , Fricke-Otto Susanne , Von Both Ulrich , Huebner Johannes , Behrends Uta , Liese Johannes G. , Schwerk Christian , Drosten Christian , Von Kries Ruediger , Schroten Horst 
Published: June 2022

AbstractThe rate of SARS-CoV-2 infections in children remains unclear due to many asymptomatic cases. We present a study of cross-sectional seroprevalence surveys of anti-SARS-CoV-2 IgG in 10,358 children recruited in paediatric hospitals across Germany from June 2020 to May 2021. Seropositivity increased from 2.0% (95% CI 1.6, 2.5) to 10.8% (95% CI 8.7, 12.9) in March 2021 with little change up to May 2021. Rates increased by migrant background (2.8%, 4.4% and 7.8% for no, one and two parents born outside Germany). Children under three were initially 3.6 (95% CI 2.3, 5.7) times more likely to be seropositive with levels equalising later. The ratio of seropositive cases per recalled infection decreased from 8.6 to 2.8. Since seropositivity exceeds the rate of recalled infections considerably, serologic testing may provide a more valid estimate of infections, which is required to assess both the spread and the risk for severe outcomes of SARS-CoV-2 infections.
Experimental demonstration of highly reliable dynamic memristor for artificial neuron and neuromorphic computing
Authors: Park See-On , Jeong Hakcheon , Park Jongyong , Bae Jongmin , Choi Shinhyun 
Published: June 2022

AbstractNeuromorphic computing, a computing paradigm inspired by the human brain, enables energy-efficient and fast artificial neural networks. To process information, neuromorphic computing directly mimics the operation of biological neurons in a human brain. To effectively imitate biological neurons with electrical devices, memristor-based artificial neurons attract attention because of their simple structure, energy efficiency, and excellent scalability. However, memristor’s non-reliability issues have been one of the main obstacles for the development of memristor-based artificial neurons and neuromorphic computings. Here, we show a memristor 1R cross-bar array without transistor devices for individual memristor access with low variation, 100% yield, large dynamic range, and fast speed for artificial neuron and neuromorphic computing. Based on the developed memristor, we experimentally demonstrate a memristor-based neuron with leaky-integrate and fire property with excellent reliability. Furthermore, we develop a neuro-memristive computing system based on the short-term memory effect of the developed memristor for efficient processing of sequential data. Our neuro-memristive computing system successfully trains and generates bio-medical sequential data (antimicrobial peptides) while using a small number of training parameters. Our results open up the possibility of memristor-based artificial neurons and neuromorphic computing systems, which are essential for energy-efficient edge computing devices.
Ex vivo-expanded human CD19+TIM-1+ regulatory B cells suppress immune responses in vivo and are dependent upon the TIM-1/STAT3 axis
Authors: Shankar S. , Stolp J. , Juvet S. C. , Beckett J. , Macklin P. S. , Issa F. , Hester J. , Wood K. J. 
Published: June 2022

AbstractRegulatory B cells (Breg) are a heterogenous population with immune-modulating functions. The rarity of human IL-10+ Breg makes translational studies difficult. Here we report ex vivo expansion of human B cells with in vivo regulatory function (expBreg). CD154-stimulation of human CD19+ B cells drives >900-fold expansion of IL-10+ B cells that is maintained in culture for 14 days. Whilst expBreg-mediated suppressive function is partially dependent on IL-10 expression, CRISPR-mediated gene deletions demonstrate predominant roles for TIM-1 and CD154. TIM-1 regulates STAT3 signalling and modulates downstream suppressive function. In a clinically relevant humanised mouse model of skin transplantation, expBreg prolongs human allograft survival. Meanwhile, CD19+CD73-CD25+CD71+TIM-1+CD154+ Breg cells are enriched in the peripheral blood of human donors with cutaneous squamous cell carcinoma (SCC). TIM-1+ and pSTAT3+ B cells are also identified in B cell clusters within histological sections of human cutaneous SCC tumours. Our findings thus provide insights on Breg homoeostasis and present possible targets for Breg-related therapies.
A continuum of bright and dark-pulse states in a photonic-crystal resonator
Authors: Yu Su-Peng , Lucas Erwan , Zang Jizhao , Papp Scott B. 
Published: June 2022

AbstractNonlinearity is a powerful determinant of physical systems. Controlling nonlinearity leads to interesting states of matter and new applications. In optics, diverse families of continuous and discrete states arise from balance of nonlinearity and group-velocity dispersion (GVD). Moreover, the dichotomy of states with locally enhanced or diminished field intensity depends critically on the relative sign of nonlinearity and either anomalous or normal GVD. Here, we introduce a resonator with unconditionally normal GVD and a single defect mode that supports both dark, reduced-intensity states and bright, enhanced-intensity states. We access and explore this dark-to-bright pulse continuum by phase-matching with a photonic-crystal resonator, which mediates the competition of nonlinearity and normal GVD. These stationary temporal states are coherent frequency combs, featuring highly designable spectra and ultralow noise repetition-frequency and intensity characteristics. The dark-to-bright continuum illuminates physical roles of Kerr nonlinearity, GVD, and laser propagation in a gapped nanophotonic medium.
Integrative epigenomic and transcriptomic analysis reveals the requirement of JUNB for hematopoietic fate induction
Authors: Chen Xia , Wang Peiliang , Qiu Hui , Zhu Yonglin , Zhang Xingwu , Zhang Yaxuan , Duan Fuyu , Ding Shuangyuan , Guo Jianying , Huang Yue , Na Jie 
Published: June 2022

AbstractHuman pluripotent stem cell differentiation towards hematopoietic progenitor cell can serve as an in vitro model for human embryonic hematopoiesis, but the dynamic change of epigenome and transcriptome remains elusive. Here, we systematically profile the chromatin accessibility, H3K4me3 and H3K27me3 modifications, and the transcriptome of intermediate progenitors during hematopoietic progenitor cell differentiation in vitro. The integrative analyses reveal sequential opening-up of regions for the binding of hematopoietic transcription factors and stepwise epigenetic reprogramming of bivalent genes. Single-cell analysis of cells undergoing the endothelial-to-hematopoietic transition and comparison with in vivo hemogenic endothelial cells reveal important features of in vitro and in vivo hematopoiesis. We find that JUNB is an essential regulator for hemogenic endothelium specialization and endothelial-to-hematopoietic transition. These studies depict an epigenomic roadmap from human pluripotent stem cells to hematopoietic progenitor cells, which may pave the way to generate hematopoietic progenitor cells with improved developmental potentials.
Designing 1D correlated-electron states by non-Euclidean topography of 2D monolayers
Authors: Gupta Sunny , Yu Henry , Yakobson Boris I. 
Published: June 2022

AbstractTwo-dimensional (2D) bilayers, twisted to particular angles to display electronic flat bands, are being extensively explored for physics of strongly correlated 2D systems. However, the similar rich physics of one-dimensional (1D) strongly correlated systems remains elusive as it is largely inaccessible by twists. Here, a distinctive way to create 1D flat bands is proposed, by either stamping or growing a 2D monolayer on a non-Euclidean topography-patterned surface. Using boron nitride (hBN) as an example, our analysis employing elastic plate theory, density-functional and coarse-grained tight-binding method reveals that hBN’s bi-periodic sinusoidal deformation creates pseudo- electric and magnetic fields with unexpected spatial dependence. A combination of these fields leads to anisotropic confinement and 1D flat bands. Moreover, changing the periodic undulations can tune the bandwidth, to drive the system to different strongly correlated regimes such as density waves, Luttinger liquid, and Mott insulator. The 1D nature of these states differs from those obtained in twisted materials and can be exploited to study the exciting physics of 1D quantum systems.
On the damage tolerance of 3-D printed Mg-Ti interpenetrating-phase composites with bioinspired architectures
Authors: Zhang Mingyang , Zhao Ning , Yu Qin , Liu Zengqian , Qu Ruitao , Zhang Jian , Li Shujun , Ren Dechun , Berto Filippo , Zhang Zhefeng , Ritchie Robert O. 
Published: June 2022

AbstractBioinspired architectures are effective in enhancing the mechanical properties of materials, yet are difficult to construct in metallic systems. The structure-property relationships of bioinspired metallic composites also remain unclear. Here, Mg-Ti composites were fabricated by pressureless infiltrating pure Mg melt into three-dimensional (3-D) printed Ti-6Al-4V scaffolds. The result was composite materials where the constituents are continuous, mutually interpenetrated in 3-D space and exhibit specific spatial arrangements with bioinspired brick-and-mortar, Bouligand, and crossed-lamellar architectures. These architectures promote effective stress transfer, delocalize damage and arrest cracking, thereby bestowing improved strength and ductility than composites with discrete reinforcements. Additionally, they activate a series of extrinsic toughening mechanisms, including crack deflection/twist and uncracked-ligament bridging, which enable crack-tip shielding from the applied stress and lead to “Γ”-shaped rising fracture resistance R-curves. Quantitative relationships were established for the stiffness and strengths of the composites by adapting classical laminate theory to incorporate their architectural characteristics.
Estrogen receptor positive breast cancers have patient specific hormone sensitivities and rely on progesterone receptor
Authors: Scabia Valentina , Ayyanan Ayyakkannu , De Martino Fabio , Agnoletto Andrea , Battista Laura , Laszlo Csaba , Treboux Assia , Zaman Khalil , Stravodimou Athina , Jallut Didier , Fiche Maryse , Bucher Philip , Ambrosini Giovanna , Sflomos George , Brisken Cathrin 
Published: June 2022

AbstractEstrogen and progesterone receptor (ER, PR) signaling control breast development and impinge on breast carcinogenesis. ER is an established driver of ER + disease but the role of the PR, itself an ER target gene, is debated. We assess the issue in clinically relevant settings by a genetic approach and inject ER + breast cancer cell lines and patient-derived tumor cells to the milk ducts of immunocompromised mice. Such ER + xenografts were exposed to physiologically relevant levels of 17-β-estradiol (E2) and progesterone (P4). We find that independently both premenopausal E2 and P4 levels increase tumor growth and combined treatment enhances metastatic spread. The proliferative responses are patient-specific with MYC and androgen receptor (AR) signatures determining P4 response. PR is required for tumor growth in patient samples and sufficient to drive tumor growth and metastasis in ER signaling ablated tumor cells. Our findings suggest that endocrine therapy may need to be personalized, and that abrogating PR expression can be a therapeutic option.
Sotigalimab and/or nivolumab with chemotherapy in first-line metastatic pancreatic cancer: clinical and immunologic analyses from the randomized phase 2 PRINCE trial
Authors: Padrón Lacey J. , Maurer Deena M. , O’Hara Mark H. , O’Reilly Eileen M. , Wolff Robert A. , Wainberg Zev A. , Ko Andrew H. , Fisher George , Rahma Osama , Lyman Jaclyn P. , Cabanski Christopher R. , Yu Jia Xin , Pfeiffer Shannon M. , Spasic Marko , Xu Jingying , Gherardini Pier Federico , Karakunnel Joyson , Mick Rosemarie , Alanio Cécile , Byrne Katelyn T. , Hollmann Travis J. , Moore Jonni S. , Jones Derek D. , Tognetti Marco , Chen Richard O. , Yang Xiaodong , Salvador Lisa , Wherry E. John , Dugan Ute , O’Donnell-Tormey Jill , Butterfield Lisa H. , Hubbard-Lucey Vanessa M. , Ibrahim Ramy , Fairchild Justin , Bucktrout Samantha , LaVallee Theresa M. , Vonderheide Robert H. 
Published: June 2022

AbstractChemotherapy combined with immunotherapy has improved the treatment of certain solid tumors, but effective regimens remain elusive for pancreatic ductal adenocarcinoma (PDAC). We conducted a randomized phase 2 trial evaluating the efficacy of nivolumab (nivo; anti-PD-1) and/or sotigalimab (sotiga; CD40 agonistic antibody) with gemcitabine/nab-paclitaxel (chemotherapy) in patients with first-line metastatic PDAC (NCT03214250). In 105 patients analyzed for efficacy, the primary endpoint of 1-year overall survival (OS) was met for nivo/chemo (57.7%, P = 0.006 compared to historical 1-year OS of 35%, n = 34) but was not met for sotiga/chemo (48.1%, P = 0.062, n = 36) or sotiga/nivo/chemo (41.3%, P = 0.223, n = 35). Secondary endpoints were progression-free survival, objective response rate, disease control rate, duration of response and safety. Treatment-related adverse event rates were similar across arms. Multi-omic circulating and tumor biomarker analyses identified distinct immune signatures associated with survival for nivo/chemo and sotiga/chemo. Survival after nivo/chemo correlated with a less suppressive tumor microenvironment and higher numbers of activated, antigen-experienced circulating T cells at baseline. Survival after sotiga/chemo correlated with greater intratumoral CD4 T cell infiltration and circulating differentiated CD4 T cells and antigen-presenting cells. A patient subset benefitting from sotiga/nivo/chemo was not identified. Collectively, these analyses suggest potential treatment-specific correlates of efficacy and may enable biomarker-selected patient populations in subsequent PDAC chemoimmunotherapy trials.