bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tissue-specific activation of gene expression by the Synergistic Activation Mediator (SAM) CRISPRa system in mice
Authors: Hunt Charleen , Hartford Suzanne A. , White Derek , Pefanis Evangelos , Hanna Timothy , Herman Clarissa , Wiley Jarrell , Brown Heather , Su Qi , Xin Yurong , Voronin Dennis , Nguyen Hien , Altarejos Judith , Crosby Keith , Haines Jeffery , Cancelarich Sarah , Drummond Meghan , Moller-Tank Sven , Malpass Ryan , Buckley Jacqueline , del Pilar Molina-Portela Maria , Droguett Gustavo , Frendewey David , Chiao Eric , Zambrowicz Brian , Gong Guochun 
Published: May 2021

AbstractCRISPR-based transcriptional activation is a powerful tool for functional gene interrogation; however, delivery difficulties have limited its applications in vivo. Here, we created a mouse model expressing all components of the CRISPR-Cas9 guide RNA-directed Synergistic Activation Mediator (SAM) from a single transcript that is capable of activating target genes in a tissue-specific manner. We optimized Lipid Nanoparticles and Adeno-Associated Virus guide RNA delivery approaches to achieve expression modulation of one or more genes in vivo. We utilized the SAM mouse model to generate a hypercholesteremia disease state that we could bidirectionally modulate with various guide RNAs. Additionally, we applied SAM to optimize gene expression in a humanized Transthyretin mouse model to recapitulate human expression levels. These results demonstrate that the SAM gene activation platform can facilitate in vivo research and drug discovery.
Towards single-chip radiofrequency signal processing via acoustoelectric electron–phonon interactions
Authors: Hackett Lisa , Miller Michael , Brimigion Felicia , Dominguez Daniel , Peake Greg , Tauke-Pedretti Anna , Arterburn Shawn , Friedmann Thomas A. , Eichenfield Matt 
Published: May 2021

AbstractThe addition of active, nonlinear, and nonreciprocal functionalities to passive piezoelectric acoustic wave technologies could enable all-acoustic and therefore ultra-compact radiofrequency signal processors. Toward this goal, we present a heterogeneously integrated acoustoelectric material platform consisting of a 50 nm indium gallium arsenide epitaxial semiconductor film in direct contact with a 41° YX lithium niobate piezoelectric substrate. We then demonstrate three of the main components of an all-acoustic radiofrequency signal processor: passive delay line filters, amplifiers, and circulators. Heterogeneous integration allows for simultaneous, independent optimization of the piezoelectric-acoustic and electronic properties, leading to the highest performing surface acoustic wave amplifiers ever developed in terms of gain per unit length and DC power dissipation, as well as the first-ever demonstrated acoustoelectric circulator with an isolation of 46 dB with a pulsed DC bias. Finally, we describe how the remaining components of an all-acoustic radiofrequency signal processor are an extension of this work.
A cytokine receptor-masked IL2 prodrug selectively activates tumor-infiltrating lymphocytes for potent antitumor therapy
Authors: Hsu Eric J. , Cao Xuezhi , Moon Benjamin , Bae Joonbeom , Sun Zhichen , Liu Zhida , Fu Yang-Xin 
Published: May 2021

AbstractAs a potent lymphocyte activator, interleukin-2 (IL-2) is an FDA-approved treatment for multiple metastatic cancers. However, its clinical use is limited by short half-life, low potency, and severe in vivo toxicity. Current IL-2 engineering strategies exhibit evidence of peripheral cytotoxicity. Here, we address these issues by engineering an IL-2 prodrug (ProIL2). We mask the activity of a CD8 T cell-preferential IL-2 mutein/Fc fusion protein with IL2 receptor beta linked to a tumor-associated protease substrate. ProIL2 restores activity after cleavage by tumor-associated enzymes, and preferentially activates inside tumors, where it expands antigen-specific CD8 T cells. This significantly reduces IL-2 toxicity and mortality without compromising antitumor efficacy. ProIL2 also overcomes resistance of cancers to immune checkpoint blockade. Lastly, neoadjuvant ProIL2 treatment can eliminate metastatic cancer through an abscopal effect. Taken together, our approach presents an effective tumor targeting therapy with reduced toxicity.
Contrasting epigenetic control of transgenes and endogenous genes promotes post-transcriptional transgene silencing in Arabidopsis
Authors: Butel Nicolas , Yu Agnès , Le Masson Ivan , Borges Filipe , Elmayan Taline , Taochy Christelle , Gursanscky Nial R. , Cao Jiangling , Bi Shengnan , Sawyer Anne , Carroll Bernard J. , Vaucheret Hervé 
Published: May 2021

AbstractTransgenes that are stably expressed in plant genomes over many generations could be assumed to behave epigenetically the same as endogenous genes. Here, we report that whereas the histone H3K9me2 demethylase IBM1, but not the histone H3K4me3 demethylase JMJ14, counteracts DNA methylation of Arabidopsis endogenous genes, JMJ14, but not IBM1, counteracts DNA methylation of expressed transgenes. Additionally, JMJ14-mediated specific attenuation of transgene DNA methylation enhances the production of aberrant RNAs that readily induce systemic post-transcriptional transgene silencing (PTGS). Thus, the JMJ14 chromatin modifying complex maintains expressed transgenes in a probationary state of susceptibility to PTGS, suggesting that the host plant genome does not immediately accept expressed transgenes as being epigenetically the same as endogenous genes.
Combining density functional theory with macroscopic QED for quantum light-matter interactions in 2D materials
Authors: Svendsen Mark Kamper , Kurman Yaniv , Schmidt Peter , Koppens Frank , Kaminer Ido , Thygesen Kristian S. 
Published: May 2021

AbstractA quantitative and predictive theory of quantum light-matter interactions in ultra thin materials involves several fundamental challenges. Any realistic model must simultaneously account for the ultra-confined plasmonic modes and their quantization in the presence of losses, while describing the electronic states from first principles. Herein we develop such a framework by combining density functional theory (DFT) with macroscopic quantum electrodynamics, which we use to show Purcell enhancements reaching 107 for intersubband transitions in few-layer transition metal dichalcogenides sandwiched between graphene and a perfect conductor. The general validity of our methodology allows us to put several common approximation paradigms to quantitative test, namely the dipole-approximation, the use of 1D quantum well model wave functions, and the Fermi’s Golden rule. The analysis shows that the choice of wave functions is of particular importance. Our work lays the foundation for practical ab initio-based quantum treatments of light-matter interactions in realistic nanostructured materials.
Plant DNA polymerases α and δ mediate replication of geminiviruses
Authors: Wu Mengshi , Wei Hua , Tan Huang , Pan Shaojun , Liu Qi , Bejarano Eduardo R. , Lozano-Durán Rosa 
Published: May 2021

AbstractGeminiviruses are causal agents of devastating diseases in crops. Geminiviruses have circular single-stranded (ss) DNA genomes that are replicated in the nucleus of the infected plant cell through double-stranded (ds) DNA intermediates by the plant DNA replication machinery. Which host DNA polymerase mediates geminiviral multiplication, however, has so far remained elusive. Here, we show that subunits of the nuclear replicative DNA polymerases α and δ physically interact with the geminivirus-encoded replication enhancer protein, C3, and that these polymerases are required for viral replication. Our results suggest that, while DNA polymerase α is essential to generate the viral dsDNA intermediate, DNA polymerase δ mediates the synthesis of new copies of the geminiviral ssDNA genome, and that the virus-encoded C3 may act selectively, recruiting DNA polymerase δ over ε to favour productive replication.
A continuous metal-insulator transition driven by spin correlations
Authors: Feng Yejun , Wang Yishu , Silevitch D. M. , Cooper S. E. , Mandrus D. , Lee Patrick A. , Rosenbaum T. F. 
Published: May 2021

AbstractWhile Mott insulators induced by Coulomb interactions are a well-recognized class of metal-insulator transitions, insulators purely driven by spin correlations are much less common, as the reduced energy scale often invites competition from other degrees of freedom. Here, we demonstrate a clean example of a spin-correlation-driven metal-insulator transition in the all-in-all-out pyrochlore antiferromagnet Cd2Os2O7, where the lattice symmetry is preserved by the antiferromagnetism. After the antisymmetric linear magnetoresistance from conductive, ferromagnetic domain walls is removed experimentally, the bulk Hall coefficient reveals four Fermi surfaces of both electron and hole types, sequentially departing the Fermi level with decreasing temperature below the Néel temperature, TN = 227 K. In Cd2Os2O7, the charge gap of a continuous metal-insulator transition opens only at T ~ 10 K << TN. The insulating mechanism parallels the Slater picture, but without a folded Brillouin zone, and contrasts sharply with Mott insulators and spin density waves, where the electronic gap opens above and at TN, respectively.
Alteration of circadian machinery in monocytes underlies chronic kidney disease-associated cardiac inflammation and fibrosis
Authors: Yoshida Yuya , Matsunaga Naoya , Nakao Takaharu , Hamamura Kengo , Kondo Hideaki , Ide Tomomi , Tsutsui Hiroyuki , Tsuruta Akito , Kurogi Masayuki , Nakaya Michio , Kurose Hitoshi , Koyanagi Satoru , Ohdo Shigehiro 
Published: May 2021

AbstractDysfunction of the circadian clock has been implicated in the pathogenesis of cardiovascular disease. The CLOCK protein is a core molecular component of the circadian oscillator, so that mice with a mutated Clock gene (Clk/Clk) exhibit abnormal rhythms in numerous physiological processes. However, here we report that chronic kidney disease (CKD)-induced cardiac inflammation and fibrosis are attenuated in Clk/Clk mice even though they have high blood pressure and increased serum angiotensin II levels. A search for the underlying cause of the attenuation of heart disorder in Clk/Clk mice with 5/6 nephrectomy (5/6Nx) led to identification of the monocytic expression of G protein-coupled receptor 68 (GPR68) as a risk factor of CKD-induced inflammation and fibrosis of heart. 5/6Nx induces the expression of GPR68 in circulating monocytes via altered CLOCK activation by increasing serum levels of retinol and its binding protein (RBP4). The high-GPR68-expressing monocytes have increased potential for producing inflammatory cytokines, and their cardiac infiltration under CKD conditions exacerbates inflammation and fibrosis of heart. Serum retinol and RBP4 levels in CKD patients are also sufficient to induce the expression of GPR68 in human monocytes. Our present study reveals an uncovered role of monocytic clock genes in CKD-induced heart failure.
The role of maternal preconception vitamin D status in human offspring sex ratio
Authors: Purdue-Smithe Alexandra C. , Kim Keewan , Nobles Carrie , Schisterman Enrique F. , Schliep Karen C. , Perkins Neil J. , Sjaarda Lindsey A. , Freeman Joshua R. , Robinson Sonia L. , Radoc Jeannie G. , Mills James L. , Silver Robert M. , Ye Aijun , Mumford Sunni L. 
Published: May 2021

AbstractEvolutionary theory suggests that some animal species may experience shifts in their offspring sex ratio in response to maternal health and environmental conditions, and in some unfavorable conditions, females may be less likely to bear sons. Experimental data in both animals and humans indicate that maternal inflammation may disproportionately impact the viability of male conceptuses; however, it is unknown whether other factors associated with both pregnancy and inflammation, such as vitamin D status, are associated with the offspring sex ratio. Here, we show that among 1,228 women attempting pregnancy, preconception 25-hydroxyvitamin D concentrations are positively associated with the live birth of a male infant, with notably stronger associations among women with elevated high sensitivity C-reactive protein, a marker of systemic low-grade inflammation. Our findings suggest that vitamin D may mitigate maternal inflammation that would otherwise be detrimental to the implantation or survival of male conceptuses in utero.
Role of neutrophil extracellular traps in radiation resistance of invasive bladder cancer
Authors: Shinde-Jadhav Surashri , Mansure Jose Joao , Rayes Roni F. , Marcq Gautier , Ayoub Mina , Skowronski Rodrigo , Kool Ronald , Bourdeau France , Brimo Fadi , Spicer Jonathan , Kassouf Wassim 
Published: May 2021

AbstractRadiation therapy (RT) is used in the management of several cancers; however, tumor radioresistance remains a challenge. Polymorphonuclear neutrophils (PMNs) are recruited to the tumor immune microenvironment (TIME) post-RT and can facilitate tumor progression by forming neutrophil extracellular traps (NETs). Here, we demonstrate a role for NETs as players in tumor radioresistance. Using a syngeneic bladder cancer model, increased NET deposition is observed in the TIME of mice treated with RT and inhibition of NETs improves overall radiation response. In vitro, the protein HMGB1 promotes NET formation through a TLR4-dependent manner and in vivo, inhibition of both HMGB1 and NETs significantly delays tumor growth. Finally, NETs are observed in bladder tumors of patients who did not respond to RT and had persistent disease post-RT, wherein a high tumoral PMN-to-CD8 ratio is associated with worse overall survival. Together, these findings identify NETs as a potential therapeutic target to increase radiation efficacy.
Characterization of an attenuated SARS-CoV-2 variant with a deletion at the S1/S2 junction of the spike protein
Authors: Wang Pui , Lau Siu-Ying , Deng Shaofeng , Chen Pin , Mok Bobo Wing-Yee , Zhang Anna Jinxia , Lee Andrew Chak-Yiu , Chan Kwok-Hung , Tam Rachel Chun-Yee , Xu Haoran , Zhou Runhong , Song Wenjun , Liu Li , To Kelvin Kai-Wang , Chan Jasper Fuk-Woo , Chen Zhiwei , Yuen Kwok-Yung , Chen Honglin 
Published: May 2021

AbstractSARS-CoV-2 is of zoonotic origin and contains a PRRA polybasic cleavage motif which is considered critical for efficient infection and transmission in humans. We previously reported on a panel of attenuated SARS-CoV-2 variants with deletions at the S1/S2 junction of the spike protein. Here, we characterize pathogenicity, immunogenicity, and protective ability of a further cell-adapted SARS-CoV-2 variant, Ca-DelMut, in in vitro and in vivo systems. Ca-DelMut replicates more efficiently than wild type or parental virus in Vero E6 cells, but causes no apparent disease in hamsters, despite replicating in respiratory tissues. Unlike wild type virus, Ca-DelMut causes no obvious pathological changes and does not induce elevation of proinflammatory cytokines, but still triggers a strong neutralizing antibody and T cell response in hamsters and mice. Ca-DelMut immunized hamsters challenged with wild type SARS-CoV-2 are fully protected, with little sign of virus replication in the upper or lower respiratory tract, demonstrating sterilizing immunity.
Serum metabolic biomarkers for synucleinopathy conversion in isolated REM sleep behavior disorder
Authors: Laguna Ariadna , Xicoy Helena , Tolosa Eduardo , Serradell Mònica , Vilas Dolores , Gaig Carles , Fernández Manel , Yanes Oscar , Santamaria Joan , Amigó Núria , Iranzo Alex , Vila Miquel 
Published: May 2021

AbstractIsolated rapid eye movement (REM) sleep behavior disorder (iRBD) is a prodromal stage of Lewy-type synucleinopathies (LTS), which can present either with an initial predominant parkinsonism (Parkinson’s disease (PD)) or dementia (dementia with Lewy bodies (DLB)). To provide insights into the underlying pathogenic mechanisms, the lipoprotein and protein glycosylation profile of 82 iRBD patients, collected before and/or after their conversion to an overt LTS, and 29 matched control serum samples were assessed by nuclear magnetic resonance (NMR) spectroscopy. Data were statistically analyzed to identify altered metabolites and construct predictive models. Univariant analysis detected no differences between iRBD patients with an LTS compared to controls. However, significant differences were found when the analysis distinguished between iRBD patients that manifested initially predominant parkinsonism (pre-PD) or dementia (pre-DLB). Significant differences were also found in the analysis of paired iRBD samples pre- and post-LTS diagnosis. Predictive models were built and distinguished between controls and pre-DLB patients, and between pre-DLB and pre-PD patients. This allowed a prediction of the possible future clinical outcome of iRBD patients. We provide evidence of altered lipoprotein and glycosylation profiles in subgroups of iRBD patients. Our results indicate that metabolic alterations and inflammation are involved in iRBD pathophysiology, and suggest biological differences underlying the progression of LTS in iRBD patients. Our data also indicate that profiling of serum samples by NMR may be a useful tool for identifying short-term high-risk iRBD patients for conversion to parkinsonism or dementia.
Ex vivo expansion of dysfunctional regulatory T lymphocytes restores suppressive function in Parkinson’s disease
Authors: Thome Aaron D. , Atassi Farah , Wang Jinghong , Faridar Alireza , Zhao Weihua , Thonhoff Jason R. , Beers David R. , Lai Eugene C. , Appel Stanley H. 
Published: May 2021

AbstractInflammation is a pathological hallmark of Parkinson’s disease (PD). Chronic pro-inflammatory responses contribute to the loss of neurons in the neurodegenerative process. The present study was undertaken to define the peripheral innate and adaptive immune contributions to inflammation in patients with PD. Immunophenotyping revealed a shift of peripheral myeloid and lymphoid cells towards a pro-inflammatory phenotype. Regulatory T cells (Tregs) were reduced in number, and their suppression of T responder proliferation decreased. The PD Tregs did not suppress activated pro-inflammatory myeloid cells. Ex vivo expansion of Tregs from patients with PD restored and enhanced their suppressive functions while expanded Tregs displayed increased expression of foxp3, il2ra (CD25), nt5e (CD73), il10, il13, ctla4, pdcd1 (PD1), and gzmb. Collectively, these findings documented a shift towards a pro-inflammatory peripheral immune response in patients with PD; the loss of Treg suppressive functions may contribute significantly to this response, supporting PD as a disorder with extensive systemic pro-inflammatory responses. The restoration and enhancement of Treg suppressive functions following ex vivo expansion may provide a potential cell therapeutic approach for patients with PD.
Volumetric and shape analysis of the hippocampus in temporal lobe epilepsy with GAD65 antibodies compared with non-immune epilepsy
Authors: Conde-Blanco Estefanía , Pascual-Diaz Saül , Carreño Mar , Muñoz-Moreno Emma , Pariente José Carlos , Boget Teresa , Manzanares Isabel , Donaire Antonio , Centeno María , Graus Francesc , Bargalló Nuria 
Published: May 2021

AbstractGlutamic acid decarboxylase 65 antibodies (anti-GAD65) have been found in patients with late-onset chronic temporal lobe epilepsy (TLE). No prior neuroimaging studies have addressed how they affect hippocampal volume and shape and how they relate to cognitive abnormalities. We aimed to investigate both brain structure and function in patients with isolated TLE and high anti-GAD65 levels (RIA ≥ 2000 U/ml) compared to 8 non-immune mesial TLE (niTLE) and 8 healthy controls (HC). Hippocampal subfield volume properties were correlated with the duration of the disease and cognitive test scores. The affected hippocampus of GAD-TLE patients showed no volume changes to matched HC whereas niTLE volumes were significantly smaller. Epilepsy duration in GAD-TLE patients correlated negatively with volumes in the presubiculum, subiculum, CA1, CA2–3, CA4, molecular layer and granule cell-molecular layer of the dentate nucleus. We found differences by advanced vertex-wise shape analysis in the anterior hippocampus of the left GAD-TLE compared to HC whereas left niTLE showed bilateral posterior hippocampus deformation. Verbal deficits were similar in GAD-TLE and niTLE but did not correlate to volume changes. These data might suggest a distinct expression of hippocampal structural and functional abnormalities based on the immune response.
Cumulative incidence and risk factors for radiation induced leukoencephalopathy in high grade glioma long term survivors
Authors: Terziev Robert , Psimaras Dimitri , Marie Yannick , Feuvret Loic , Berzero Giulia , Jacob Julian , Dehais Caroline , Bompaire Flavie , Mueller Wolf , Kinnersley Ben , Delattre Jean-Yves , Idbaih Ahmed , Hoang-Xuan Khe , Sanson Marc , Ricard Damien 
Published: May 2021

AbstractThe incidence and risk factors associated with radiation-induced leukoencephalopathy (RIL) in long-term survivors of high-grade glioma (HGG) are still poorly investigated. We performed a retrospective research in our institutional database for patients with supratentorial HGG treated with focal radiotherapy, having a progression-free overall survival > 30 months and available germline DNA. We reviewed MRI scans for signs of leukoencephalopathy on T2/FLAIR sequences, and medical records for information on cerebrovascular risk factors and neurological symptoms. We investigated a panel of candidate single nucleotide polymorphisms (SNPs) to assess genetic risk. Eighty-one HGG patients (18 grade IV and 63 grade III, 50M/31F) were included in the study. The median age at the time of radiotherapy was 48 years old (range 18–69). The median follow-up after the completion of radiotherapy was 79 months. A total of 44 patients (44/81, 54.3%) developed RIL during follow-up. Twenty-nine of the 44 patients developed consistent symptoms such as subcortical dementia (n = 28), gait disturbances (n = 12), and urinary incontinence (n = 9). The cumulative incidence of RIL was 21% at 12 months, 42% at 36 months, and 48% at 60 months. Age > 60 years, smoking, and the germline SNP rs2120825 (PPARg locus) were associated with an increased risk of RIL. Our study identified potential risk factors for the development of RIL (age, smoking, and the germline SNP rs2120825) and established the rationale for testing PPARg agonists in the prevention and management of late-delayed radiation-induced neurotoxicity.