bluuebunny/crossref_metadata_2025_split huggingface dataset:
ATR and CDK4/6 inhibition target the growth of methotrexate-resistant choriocarcinoma
Authors: Georgiou Marina , Ntavelou Panagiota , Stokes William , Roy Rajat , Maher Geoffrey J. , Stoilova Tsvetana , Choo Josephine A.M.Y. , Rakhit Callum P. , Martins Miguel , Ajuh Paul , Horowitz Neil , Berkowitz Ross S. , Elias Kevin , Seckl Michael J. , Pardo Olivier E. 
Published: March 2022

AbstractLow-risk gestational trophoblastic neoplasia including choriocarcinoma is often effectively treated with Methotrexate (MTX) as a first line therapy. However, MTX resistance (MTX-R) occurs in at least ≈33% of cases. This can sometimes be salvaged with actinomycin-D but often requires more toxic combination chemotherapy. Moreover, additional therapy may be needed and, for high-risk patients, 5% still die from the multidrug-resistant disease. Consequently, new treatments that are less toxic and could reverse MTX-R are needed. Here, we compared the proteome/phosphoproteome of MTX-resistant and sensitive choriocarcinoma cells using quantitative mass-spectrometry to identify therapeutically actionable molecular changes associated with MTX-R. Bioinformatics analysis of the proteomic data identified cell cycle and DNA damage repair as major pathways associated with MTX-R. MTX-R choriocarcinoma cells undergo cell cycle delay in G1 phase that enables them to repair DNA damage more efficiently through non-homologous end joining in an ATR-dependent manner. Increased expression of cyclin-dependent kinase 4 (CDK4) and loss of p16Ink4ain resistant cells suggested that CDK4 inhibition may be a strategy to treat MTX-R choriocarcinoma. Indeed, inhibition of CDK4/6 using genetic silencing or the clinically relevant inhibitor, Palbociclib, induced growth inhibition both in vitro and in an orthotopic in vivo mouse model. Finally, targeting the ATR pathway, genetically or pharmacologically, re-sensitised resistant cells to MTX in vitro and potently prevented the growth of MTX-R tumours in vivo. In short, we identified two novel therapeutic strategies to tackle MTX-R choriocarcinoma that could rapidly be translated into the clinic.
Active control of micrometer plasmon propagation in suspended graphene
Authors: Hu Hai , Yu Renwen , Teng Hanchao , Hu Debo , Chen Na , Qu Yunpeng , Yang Xiaoxia , Chen Xinzhong , McLeod A. S. , Alonso-González Pablo , Guo Xiangdong , Li Chi , Yao Ziheng , Li Zhenjun , Chen Jianing , Sun Zhipei , Liu Mengkun , García de Abajo F. Javier , Dai Qing 
Published: March 2022

AbstractDue to the two-dimensional character of graphene, the plasmons sustained by this material have been invariably studied in supported samples so far. The substrate provides stability for graphene but often causes undesired interactions (such as dielectric losses, phonon hybridization, and impurity scattering) that compromise the quality and limit the intrinsic flexibility of graphene plasmons. Here, we demonstrate the visualization of plasmons in suspended graphene at room temperature, exhibiting high-quality factor Q~33 and long propagation length > 3 μm. We introduce the graphene suspension height as an effective plasmonic tuning knob that enables in situ change of the dielectric environment and substantially modulates the plasmon wavelength, propagation length, and group velocity. Such active control of micrometer plasmon propagation facilitates near-unity-order modulation of nanoscale energy flow that serves as a plasmonic switch with an on-off ratio above 14. The suspended graphene plasmons possess long propagation length, high tunability, and controllable energy transmission simultaneously, opening up broad horizons for application in nano-photonic devices.
Biomimetic hydrogel supports initiation and growth of patient-derived breast tumor organoids
Authors: Prince Elisabeth , Cruickshank Jennifer , Ba-Alawi Wail , Hodgson Kelsey , Haight Jillian , Tobin Chantal , Wakeman Andrew , Avoulov Alona , Topolskaia Valentina , Elliott Mitchell J. , McGuigan Alison P. , Berman Hal K. , Haibe-Kains Benjamin , Cescon David W. , Kumacheva Eugenia 
Published: March 2022

AbstractPatient-derived tumor organoids (PDOs) are a highly promising preclinical model that recapitulates the histology, gene expression, and drug response of the donor patient tumor. Currently, PDO culture relies on basement-membrane extract (BME), which suffers from batch-to-batch variability, the presence of xenogeneic compounds and residual growth factors, and poor control of mechanical properties. Additionally, for the development of new organoid lines from patient-derived xenografts, contamination of murine host cells poses a problem. We propose a nanofibrillar hydrogel (EKGel) for the initiation and growth of breast cancer PDOs. PDOs grown in EKGel have histopathologic features, gene expression, and drug response that are similar to those of their parental tumors and PDOs in BME. In addition, EKGel offers reduced batch-to-batch variability, a range of mechanical properties, and suppressed contamination from murine cells. These results show that EKGel is an improved alternative to BME matrices for the initiation, growth, and maintenance of breast cancer PDOs.
Ammonia dimer: extremely fluxional but still hydrogen bonded
Authors: Jing Aling , Szalewicz Krzysztof , van der Avoird Ad 
Published: March 2022

AbstractIn the 1980s, Nelson, Fraser, and Klemperer (NFK) published an experimentally derived structure of the ammonia dimer dramatically different from the structure determined computationally, which led these authors to the question “Does ammonia hydrogen bond?". This question has not yet been answered satisfactorily. To answer it, we have developed an ab initio potential energy surface (PES) for this dimer at the limits of the current computational capabilities and performed essentially exact six-dimensional calculations of the vibration-rotation-tunneling (VRT) spectra of NH3-NH3and ND3-ND3, obtaining an unprecedented agreement with experimental spectra. In agreement with other recent electronic structure calculations, the global minimum on the PES is in a substantially bent hydrogen-bonded configuration. Since the bottom of the PES is exceptionally flat, the dimer is extremely fluxional and the probability of finding it in configurations that are not hydrogen bonded is high. Nevertheless, the probability of hydrogen-bonded configurations is large enough to consider the ammonia dimer to be hydrogen bonded. We also show that NFK’s inference that the ammonia dimer is nearly rigid actually results from unusual cancellations between quantum effects that generate differences in spectra of different isotopologues.
Topotactic fluorination of intermetallics as an efficient route towards quantum materials
Authors: Vaney Jean-Baptiste , Vignolle Baptiste , Demourgues Alain , Gaudin Etienne , Durand Etienne , Labrugère Christine , Bernardini Fabio , Cano Andrés , Tencé Sophie 
Published: March 2022

AbstractIntermetallics represent an important family of compounds, in which insertion of light elements (H, B, C, N) has been widely explored for decades to synthesize novel phases and promote functional materials such as permanent magnets or magnetocalorics. Fluorine insertion, however, has remained elusive so far since the strong reactivity of this atypical element, the most electronegative one, tends to produce the chemical decomposition of these systems. Here, we introduce a topochemical method to intercalate fluorine atoms into intermetallics, using perfluorocarbon reactant with covalent C-F bonds. We demonstrate the potential of this approach with the synthesis of non-stoichiometric mixed anion (Si-F) LaFeSiFx single-crystals, which are further shown to host FeSi-based superconductivity. Fluorine topochemistry on intermetallics is thus proven to be an effective route to provide functional materials where the coexistence of ionic and metallo-covalent blocks, and their interactions through inductive effects, is at the root of their functional properties.
p16INK4A-deficiency predicts response to combined HER2 and CDK4/6 inhibition in HER2+ breast cancer brain metastases
Authors: Ni Jing , Kabraji Sheheryar , Xie Shaozhen , Wang Yanzhi , Pan Peichen , He Xiaofang , Liu Zongming , Leone Jose Palbo , Long Henry W. , Brown Myles A. , Winer Eric P. , Dillon Deborah A. R. , Lin Nancy U. , Zhao Jean J. 
Published: March 2022

AbstractApproximately 50% of patients with metastatic HER2-positive (HER2+) breast cancer develop brain metastases (BCBMs). We report that the tumor suppressor p16INK4A is deficient in the majority of HER2+ BCBMs. p16INK4A-deficiency as measured by protein immunohistochemistry predicted response to combined tucatinib and abemaciclib in orthotopic patient-derived xenografts (PDXs) of HER2 + BCBMs. Our findings establish the rationale for a biomarker-driven clinical trial of combined CDK4/6- and HER2-targeted agents for patients with HER2 + BCBM.
Resonant neutron reflectometry for hydrogen detection
Authors: Guasco L. , Khaydukov Yu. N. , Pütter S. , Silvi L. , Paulin M. A. , Keller T. , Keimer B. 
Published: March 2022

AbstractThe detection and quantification of hydrogen is becoming increasingly important in research on electronic materials and devices, following the identification of the hydrogen content as a potent control parameter for the electronic properties. However, establishing quantitative correlations between the hydrogen content and the physical properties of solids remains a formidable challenge. Here we report neutron reflectometry experiments on 50 nm thick niobium films during hydrogen loading, and show that the momentum-space position of a prominent waveguide resonance allows tracking of the absolute hydrogen content with an accuracy of about one atomic percent on a timescale of less than a minute. Resonance-enhanced neutron reflectometry thus allows fast, direct, and non-destructive measurements of the hydrogen concentration in thin-film structures, with sensitivity high enough for real-time in-situ studies.
Extracellular vesiculo-tubular structures associated with suberin deposition in plant cell walls
Authors: De Bellis Damien , Kalmbach Lothar , Marhavy Peter , Daraspe Jean , Geldner Niko , Barberon Marie 
Published: March 2022

AbstractSuberin is a fundamental plant biopolymer, found in protective tissues, such as seed coats, exodermis and endodermis of roots. Suberin is deposited in most suberizing cells in the form of lamellae just outside of the plasma membrane, below the primary cell wall. How monomeric suberin precursors, thought to be synthesized at the endoplasmic reticulum, are transported outside of the cell, for polymerization into suberin lamellae has remained obscure. Using electron-microscopy, we observed large numbers of extracellular vesiculo-tubular structures (EVs) to accumulate specifically in suberizing cells, in both chemically and cryo-fixed samples. EV presence correlates perfectly with root suberization and we could block suberin deposition and vesicle accumulation by affecting early, as well as late steps in the secretory pathway. Whereas many previous reports have described EVs in the context of biotic interactions, our results suggest a developmental role for extracellular vesicles in the formation of a major cell wall polymer.
The interplay of additivity, dominance, and epistasis on fitness in a diploid yeast cross
Authors: Matsui Takeshi , Mullis Martin N. , Roy Kevin R. , Hale Joseph J. , Schell Rachel , Levy Sasha F. , Ehrenreich Ian M. 
Published: March 2022

AbstractIn diploid species, genetic loci can show additive, dominance, and epistatic effects. To characterize the contributions of these different types of genetic effects to heritable traits, we use a double barcoding system to generate and phenotype a panel of ~200,000 diploid yeast strains that can be partitioned into hundreds of interrelated families. This experiment enables the detection of thousands of epistatic loci, many whose effects vary across families. Here, we show traits are largely specified by a small number of hub loci with major additive and dominance effects, and pervasive epistasis. Genetic background commonly influences both the additive and dominance effects of loci, with multiple modifiers typically involved. The most prominent dominance modifier in our data is the mating locus, which has no effect on its own. Our findings show that the interplay between additivity, dominance, and epistasis underlies a complex genotype-to-phenotype map in diploids.
Precise tumor immune rewiring via synthetic CRISPRa circuits gated by concurrent gain/loss of transcription factors
Authors: Wang Yafeng , Zhang Guiquan , Meng Qingzhou , Huang Shisheng , Guo Panpan , Leng Qibin , Sun Lingyun , Liu Geng , Huang Xingxu , Liu Jianghuai 
Published: March 2022

AbstractReinvigoration of antitumor immunity has recently become the central theme for the development of cancer therapies. Nevertheless, the precise delivery of immunotherapeutic activities to the tumors remains challenging. Here, we explore a synthetic gene circuit-based strategy for specific tumor identification, and for subsequently engaging immune activation. By design, these circuits are assembled from two interactive modules, i.e., an oncogenic TF-driven CRISPRa effector, and a corresponding p53-inducible off-switch (NOT gate), which jointly execute an AND-NOT logic for accurate tumor targeting. In particular, two forms of the NOT gate are developed, via the use of an inhibitory sgRNA or an anti-CRISPR protein, with the second form showing a superior performance in gating CRISPRa by p53 loss. Functionally, the optimized AND-NOT logic circuit can empower a highly specific and effective tumor recognition/immune rewiring axis, leading to therapeutic effects in vivo. Taken together, our work presents an adaptable strategy for the development of precisely delivered immunotherapy.
Thermosensitive hydrogel releasing nitric oxide donor and anti-CTLA-4 micelles for anti-tumor immunotherapy
Authors: Kim Jihoon , Francis David M. , Sestito Lauren F. , Archer Paul A. , Manspeaker Margaret P. , O’Melia Meghan J. , Thomas Susan N. 
Published: March 2022

AbstractDue to their autosynchronous roles in shaping the anti-tumor immune response, complex immune regulatory networks acting both locally within the tumor microenvironment as well as in its draining lymph nodes play critical roles in the cancer immunotherapy response. We describe herein a thermosensitive co-polymer hydrogel system formed from biocompatible polymers gelatin and Pluronic® F127 that are widely used in humans to enable the sustained release of a nitric oxide donor and antibody blocking immune checkpoint cytotoxic T-lymphocyte-associated protein-4 for efficient and durable anti-tumor immunotherapy. By virtue of its unique gel formation and degradation properties that sustain drug retention at the tumor tissue site for triggered release by the tumor microenvironment and formation of in situ micelles optimum in size for lymphatic uptake, this rationally designed thermosensitive hydrogel facilitates modulation of two orthogonal immune signaling networks relevant to the regulation of the anti-tumor immune response to improve local and abscopal effects of cancer immunotherapy.
Genome-wide maps of nucleolus interactions reveal distinct layers of repressive chromatin domains
Authors: Bersaglieri Cristiana , Kresoja-Rakic Jelena , Gupta Shivani , Bär Dominik , Kuzyakiv Rostyslav , Panatta Martina , Santoro Raffaella 
Published: March 2022

AbstractEukaryotic chromosomes are folded into hierarchical domains, forming functional compartments. Nuclear periphery and nucleolus are two nuclear landmarks contributing to repressive chromosome architecture. However, while the role of nuclear lamina (NL) in genome organization has been well documented, the function of the nucleolus remains under-investigated due to the lack of methods for the identification of nucleolar associated domains (NADs). Here we have established DamID- and HiC-based methodologies to generate accurate genome-wide maps of NADs in embryonic stem cells (ESCs) and neural progenitor cells (NPCs), revealing layers of genome compartmentalization with distinct, repressive chromatin states based on the interaction with the nucleolus, NL, or both. NADs show higher H3K9me2 and lower H3K27me3 content than regions exclusively interacting with NL. Upon ESC differentiation into NPCs, chromosomes around the nucleolus acquire a more compact, rigid architecture with neural genes moving away from nucleoli and becoming unlocked for later activation. Further, histone modifications and the interaction strength within A and B compartments of NADs and LADs in ESCs set the choice to associate with NL or nucleoli upon dissociation from their respective compartments during differentiation. The methodologies here developed will make possible to include the nucleolar contribution in nuclear space and genome function in diverse biological systems.
Direct imaging of the disconnection climb mediated point defects absorption by a grain boundary
Authors: Wei Jiake , Feng Bin , Tochigi Eita , Shibata Naoya , Ikuhara Yuichi 
Published: March 2022

AbstractGrain boundaries (GBs) are considered as the effective sinks for point defects, which improve the radiation resistance of materials. However, the fundamental mechanisms of how the GBs absorb and annihilate point defects under irradiation are still not well understood at atomic scale. With the aid of the atomic resolution scanning transmission electron microscope, we experimentally investigate the atomistic mechanism of point defects absorption by a ∑31 GB in α-Al2O3 under high energy electron beam irradiation. It is shown that a disconnection pair is formed, during which all the Al atomic columns are tracked. We demonstrate that the formation of the disconnection pair is proceeded with disappearing of atomic columns in the GB core, which suggests that the GB absorbs vacancies. Such point defect absorption is attributed to the nucleation and climb motion of disconnections. These experimental results provide an atomistic understanding of how GBs improve the radiation resistance of materials.
Large field-of-view non-invasive imaging through scattering layers using fluctuating random illumination
Authors: Zhu Lei , Soldevila Fernando , Moretti Claudio , d’Arco Alexandra , Boniface Antoine , Shao Xiaopeng , de Aguiar Hilton B. , Gigan Sylvain 
Published: March 2022

AbstractNon-invasive optical imaging techniques are essential diagnostic tools in many fields. Although various recent methods have been proposed to utilize and control light in multiple scattering media, non-invasive optical imaging through and inside scattering layers across a large field of view remains elusive due to the physical limits set by the optical memory effect, especially without wavefront shaping techniques. Here, we demonstrate an approach that enables non-invasive fluorescence imaging behind scattering layers with field-of-views extending well beyond the optical memory effect. The method consists in demixing the speckle patterns emitted by a fluorescent object under variable unknown random illumination, using matrix factorization and a novel fingerprint-based reconstruction. Experimental validation shows the efficiency and robustness of the method with various fluorescent samples, covering a field of view up to three times the optical memory effect range. Our non-invasive imaging technique is simple, neither requires a spatial light modulator nor a guide star, and can be generalized to a wide range of incoherent contrast mechanisms and illumination schemes.
Programmable black phosphorus image sensor for broadband optoelectronic edge computing
Authors: Lee Seokhyeong , Peng Ruoming , Wu Changming , Li Mo 
Published: March 2022

AbstractImage sensors with internal computing capability enable in-sensor computing that can significantly reduce the communication latency and power consumption for machine vision in distributed systems and robotics. Two-dimensional semiconductors have many advantages in realizing such intelligent vision sensors because of their tunable electrical and optical properties and amenability for heterogeneous integration. Here, we report a multifunctional infrared image sensor based on an array of black phosphorous programmable phototransistors (bP-PPT). By controlling the stored charges in the gate dielectric layers electrically and optically, the bP-PPT’s electrical conductance and photoresponsivity can be locally or remotely programmed with 5-bit precision to implement an in-sensor convolutional neural network (CNN). The sensor array can receive optical images transmitted over a broad spectral range in the infrared and perform inference computation to process and recognize the images with 92% accuracy. The demonstrated bP image sensor array can be scaled up to build a more complex vision-sensory neural network, which will find many promising applications for distributed and remote multispectral sensing.
Aged bone matrix-derived extracellular vesicles as a messenger for calcification paradox
Authors: Wang Zhen-Xing , Luo Zhong-Wei , Li Fu-Xing-Zi , Cao Jia , Rao Shan-Shan , Liu Yi-Wei , Wang Yi-Yi , Zhu Guo-Qiang , Gong Jiang-Shan , Zou Jing-Tao , Wang Qiang , Tan Yi-Juan , Zhang Yan , Hu Yin , Li You-You , Yin Hao , Wang Xiao-Kai , He Ze-Hui , Ren Lu , Liu Zheng-Zhao , Hu Xiong-Ke , Yuan Ling-Qing , Xu Ran , Chen Chun-Yuan , Xie Hui 
Published: March 2022

AbstractAdipocyte differentiation of bone marrow mesenchymal stem/stromal cells (BMSCs) instead of osteoblast formation contributes to age- and menopause-related marrow adiposity and osteoporosis. Vascular calcification often occurs with osteoporosis, a contradictory association called “calcification paradox”. Here we show that extracellular vesicles derived from aged bone matrix (AB-EVs) during bone resorption favor BMSC adipogenesis rather than osteogenesis and augment calcification of vascular smooth muscle cells. Intravenous or intramedullary injection of AB-EVs promotes bone-fat imbalance and exacerbates Vitamin D3 (VD3)-induced vascular calcification in young or old mice. Alendronate (ALE), a bone resorption inhibitor, down-regulates AB-EVs release and attenuates aging- and ovariectomy-induced bone-fat imbalance. In the VD3-treated aged mice, ALE suppresses the ovariectomy-induced aggravation of vascular calcification. MiR-483-5p and miR-2861 are enriched in AB-EVs and essential for the AB-EVs-induced bone-fat imbalance and exacerbation of vascular calcification. Our study uncovers the role of AB-EVs as a messenger for calcification paradox by transferring miR-483-5p and miR-2861.
Identifying regions for enhanced control of gambiense sleeping sickness in the Democratic Republic of Congo
Authors: Huang Ching-I , Crump Ronald E. , Brown Paul E. , Spencer Simon E. F. , Miaka Erick Mwamba , Shampa Chansy , Keeling Matt J. , Rock Kat S. 
Published: March 2022

AbstractGambiense human African trypanosomiasis (sleeping sickness, gHAT) is a disease targeted for elimination of transmission by 2030. While annual new cases are at a historical minimum, the likelihood of achieving the target is unknown. We utilised modelling to study the impacts of four strategies using currently available interventions, including active and passive screening and vector control, on disease burden and transmission across 168 endemic health zones in the Democratic Republic of the Congo. Median projected years of elimination of transmission show only 98 health zones are on track despite significant reduction in disease burden under medical-only strategies (64 health zones if > 90% certainty required). Blanket coverage with vector control is impractical, but is predicted to reach the target in all heath zones. Utilising projected disease burden under the uniform medical-only strategy, we provide a priority list of health zones for consideration for supplementary vector control alongside medical interventions.