bluuebunny/crossref_metadata_2025_split huggingface dataset:
CCR5 signaling promotes lipopolysaccharide-induced macrophage recruitment and alveolar developmental arrest
Authors: Chen Ze , Xie Xiaohua , Jiang Na , Li Jianhui , Shen Lei , Zhang Yongjun 
Published: February 2021

AbstractThe pathogenesis of bronchopulmonary dysplasia (BPD), involves inflammatory, mechanisms that are not fully characterized. Here we report that overexpression of C-C chemokine receptor 5 (CCR5) and its ligands is associated with BPD development. Lipopolysaccharide-induced BPD rats have increased CCR5 and interleukin-1β (IL-1β) levels, and decreased alveolarization, while CCR5 or IL-1β receptor antagonist treatments decreased inflammation and increased alveolarization. CCR5 enhances macrophage migration, macrophage infiltration in the lungs, IL-1β levels, lysyl oxidase activity, and alveolar development arrest. CCR5 expression on monocytes, and its ligands in blood samples from BPD infants, are elevated. Furthermore, batyl alcohol supplementation reduced CCR5 expression and IL-1β production in lipopolysaccharide-exposed rat lungs. Moreover, receptor-interacting kinase 3 (RIP3) upstream regulator of CCR5-cultured RIP3−/− macrophages exhibited partly blocked lipopolysaccharide-induced CCR5 expression. We conclude that increased CCR5 expression is a key mechanism in BPD development and represents a novel therapeutic target for treatment.
Inhibition of repulsive guidance molecule-a protects dopaminergic neurons in a mouse model of Parkinson’s disease
Authors: Oda Wakana , Fujita Yuki , Baba Kousuke , Mochizuki Hideki , Niwa Hitoshi , Yamashita Toshihide 
Published: February 2021

AbstractRepulsive guidance molecule-a (RGMa), a glycosylphosphatidylinositol-anchored membrane protein, has diverse functions in axon guidance, cell patterning, and cell survival. Inhibition of RGMa attenuates pathological dysfunction in animal models of central nervous system (CNS) diseases including spinal cord injury, multiple sclerosis, and neuromyelitis optica. Here, we examined whether antibody-based inhibition of RGMa had therapeutic effects in a mouse model of Parkinson’s disease (PD). We treated mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and found increased RGMa expression in the substantia nigra (SN). Intraventricular, as well as intravenous, administration of anti-RGMa antibodies reduced the loss of tyrosine hydroxylase (TH)-positive neurons and accumulation of Iba1-positive microglia/macrophages in the SN of MPTP-treated mice. Selective expression of RGMa in TH-positive neurons in the SN-induced neuronal loss/degeneration and inflammation, resulting in a progressive movement disorder. The pathogenic effects of RGMa overexpression were attenuated by treatment with minocycline, which inhibits microglia and macrophage activation. Increased RGMa expression upregulated pro-inflammatory cytokine expression in microglia. Our observations suggest that the upregulation of RGMa is associated with the PD pathology; furthermore, inhibitory RGMa antibodies are a potential therapeutic option.
Loss of the orphan nuclear receptor NR2F6 enhances CD8+ T-cell memory via IFN-γ
Authors: Jakic Bojana , Olson William J. , Siegmund Kerstin , Klepsch Victoria , Kimpel Janine , Labi Verena , Zehn Dietmar , Baier Gottfried , Hermann-Kleiter Natascha 
Published: February 2021

AbstractMemory formation is a hallmark of T cell-mediated immunity, but how differentiation into either short-lived effector cells (SLECs, CD127−KLRG1+) or memory precursors cells (MPECs, CD127+KLRG1−) and subsequent regulation of long-term memory is adjusted is incompletely understood. Here, we show that loss of the nuclear orphan receptor NR2F6 in germ-line Nr2f6-deficient mice enhances antigen-specific CD8+ memory formation up to 70 days after bacterial infection with Listeria monocytogenes (LmOVA) and boosts inflammatory IFN-γ, TNFα, and IL-2 cytokine recall responses. Adoptive transfer experiments using Nr2f6−/− OT-I T-cells showed that the augmented memory formation is CD8+ T-cell intrinsic. Although the relative difference between the Nr2f6+/+ and Nr2f6−/− OT-I memory compartment declines over time, Nr2f6-deficient OT-I memory T cells mount significantly enhanced IFN-γ responses upon reinfection with increased clonal expansion and improved host antigen-specific CD8+ T-cell responses. Following a secondary adoptive transfer into naïve congenic mice, Nr2f6-deficient OT-I memory T cells are superior in clearing LmOVA infection. Finally, we show that the commitment to enhanced memory within Nr2f6-deficient OT-I T cells is established in the early phases of the antibacterial immune response and is IFN-γ mediated. IFN-γ blocking normalized MPEC formation of Nr2f6-deficient OT-I T cells. Thus, deletion or pharmacological inhibition of NR2F6 in antigen-specific CD8+ T cells may have therapeutic potential for enhancing early IFN-γ production and consequently the functionality of memory CD8+ T cells in vivo.
Circular RNA circ_103820 suppresses lung cancer tumorigenesis by sponging miR-200b-3p to release LATS2 and SOCS6
Authors: Chi Yongbin , Zheng Wenlong , Bao Guangyu , Wu Lifeng , He Xiaoxue , Gan Ruyi , Shen Yan , Yin Xudong , Jin Mingming 
Published: February 2021

AbstractA growing number of circular RNAs (circRNAs) have been identified and verified in several cancers. However, highly efficient therapeutic methods based on circRNAs in lung cancer remain largely unexplored. In the present study, we identified a novel circular RNA, hsa_circ_103820, based on Gene Expression Omnibus (GEO) data. Functionally, overexpression of hsa_circ_103820 showed significant inhibitory effects on the proliferation, migration and invasion of lung cancer cells, and knockdown of hsa_circ_103820 played promoting roles. Regarding the mechanism, we revealed that miR-200b-3p was a direct target of hsa_circ_103820 and that LATS2 and SOCS6 were the downstream target genes of miR-200b-3p. Therefore, we identified a novel potential tumor suppressive function of hsa_circ_103820 in lung cancer.
Rescue of retinal ganglion cells in optic nerve injury using cell-selective AAV mediated delivery of SIRT1
Authors: Ross Ahmara G. , McDougald Devin S. , Khan Reas S. , Duong Thu T. , Dine Kimberly E. , Aravand Puya , Bennett Jean , Chavali Venkata Ramana Murthy , Shindler Kenneth S. 
Published: February 2021

AbstractSIRT1 prevents retinal ganglion cell (RGC) loss in models of optic neuropathy following pharmacologic activation or genetic overexpression. The exact mechanism of loss is not known, prior evidence suggests this is through oxidative stress to either neighboring cells or RGC specifically. We investigated the neuroprotective potential of RGC-selective SIRT1 gene therapy in the optic nerve crush (ONC) model. We hypothesized that AAV-mediated overexpression of SIRT1 in RGCs reduces RGC loss, thereby preserving visual function. Cohorts of C57Bl/6J mice received intravitreal injection of experimental or control AAVs using either a ganglion cell promoter or a constitutive promoter and ONC was performed. Visual function was examined by optokinetic response (OKR) for 7 days following ONC. Retina and optic nerves were harvested to investigate RGC survival by immunolabeling. The AAV7m8-SNCG.SIRT1 vector showed 44% transduction efficiency for RGCs compared with 25% (P > 0.05) by AAV2-CAG.SIRT1, and AAV7m8-SNCG.SIRT1 drives expression selectively in RGCs in vivo. Animals modeling ONC demonstrated reduced visual acuity compared to controls. Intravitreal delivery of AAV7m8-SNCG.SIRT1 mediated significant preservation of the OKR and RGC survival compared to AAV7m8-SNCG.eGFP controls, an effect not seen with the AAV2 vector. RGC-selective expression of SIRT1 offers a targeted therapy for an animal model with significant ganglion cell loss. Over-expression of SIRT1 through AAV-mediated gene transduction suggests a RGC selective component of neuro-protection using the ONC model. This study expands our understanding of SIRT1 mediated neuroprotection in the context of compressive or traumatic optic neuropathy, making it a strong therapeutic candidate for testing in all optic neuropathies.
2D-3D integration of hexagonal boron nitride and a high-κ dielectric for ultrafast graphene-based electro-absorption modulators
Authors: Agarwal Hitesh , Terrés Bernat , Orsini Lorenzo , Montanaro Alberto , Sorianello Vito , Pantouvaki Marianna , Watanabe Kenji , Taniguchi Takashi , Thourhout Dries Van , Romagnoli Marco , Koppens Frank H. L. 
Published: February 2021

AbstractElectro-absorption (EA) waveguide-coupled modulators are essential building blocks for on-chip optical communications. Compared to state-of-the-art silicon (Si) devices, graphene-based EA modulators promise smaller footprints, larger temperature stability, cost-effective integration and high speeds. However, combining high speed and large modulation efficiencies in a single graphene-based device has remained elusive so far. In this work, we overcome this fundamental trade-off by demonstrating the 2D-3D dielectric integration in a high-quality encapsulated graphene device. We integrated hafnium oxide (HfO2) and two-dimensional hexagonal boron nitride (hBN) within the insulating section of a double-layer (DL) graphene EA modulator. This combination of materials allows for a high-quality modulator device with high performances: a ~39 GHz bandwidth (BW) with a three-fold increase in modulation efficiency compared to previously reported high-speed modulators. This 2D-3D dielectric integration paves the way to a plethora of electronic and opto-electronic devices with enhanced performance and stability, while expanding the freedom for new device designs.
Causal network models of SARS-CoV-2 expression and aging to identify candidates for drug repurposing
Authors: Belyaeva Anastasiya , Cammarata Louis , Radhakrishnan Adityanarayanan , Squires Chandler , Yang Karren Dai , Shivashankar G. V. , Uhler Caroline 
Published: February 2021

AbstractGiven the severity of the SARS-CoV-2 pandemic, a major challenge is to rapidly repurpose existing approved drugs for clinical interventions. While a number of data-driven and experimental approaches have been suggested in the context of drug repurposing, a platform that systematically integrates available transcriptomic, proteomic and structural data is missing. More importantly, given that SARS-CoV-2 pathogenicity is highly age-dependent, it is critical to integrate aging signatures into drug discovery platforms. We here take advantage of large-scale transcriptional drug screens combined with RNA-seq data of the lung epithelium with SARS-CoV-2 infection as well as the aging lung. To identify robust druggable protein targets, we propose a principled causal framework that makes use of multiple data modalities. Our analysis highlights the importance of serine/threonine and tyrosine kinases as potential targets that intersect the SARS-CoV-2 and aging pathways. By integrating transcriptomic, proteomic and structural data that is available for many diseases, our drug discovery platform is broadly applicable. Rigorous in vitro experiments as well as clinical trials are needed to validate the identified candidate drugs.
A scalable molecule-based magnetic thin film for spin-thermoelectric energy conversion
Authors: Oh Inseon , Park Jungmin , Choe Daeseong , Jo Junhyeon , Jeong Hyeonjung , Jin Mi-Jin , Jo Younghun , Suh Joonki , Min Byoung-Chul , Yoo Jung-Woo 
Published: February 2021

AbstractSpin thermoelectrics, an emerging thermoelectric technology, offers energy harvesting from waste heat with potential advantages of scalability and energy conversion efficiency, thanks to orthogonal paths for heat and charge flow. However, magnetic insulators previously used for spin thermoelectrics pose challenges for scale-up due to high temperature processing and difficulty in large-area deposition. Here, we introduce a molecule-based magnetic film for spin thermoelectric applications because it entails versatile synthetic routes in addition to weak spin-lattice interaction and low thermal conductivity. Thin films of CrII[CrIII(CN)6], Prussian blue analogue, electrochemically deposited on Cr electrodes at room temperature show effective spin thermoelectricity. Moreover, the ferromagnetic resonance studies exhibit an extremely low Gilbert damping constant ~(2.4 ± 0.67) × 10−4, indicating low loss of heat-generated magnons. The demonstrated STE applications of a new class of magnet will pave the way for versatile recycling of ubiquitous waste heat.
microRNA-33 maintains adaptive thermogenesis via enhanced sympathetic nerve activity
Authors: Horie Takahiro , Nakao Tetsushi , Miyasaka Yui , Nishino Tomohiro , Matsumura Shigenobu , Nakazeki Fumiko , Ide Yuya , Kimura Masahiro , Tsuji Shuhei , Rodriguez Randolph Ruiz , Watanabe Toshimitsu , Yamasaki Tomohiro , Xu Sijia , Otani Chiharu , Miyagawa Sawa , Matsushita Kazuki , Sowa Naoya , Omori Aoi , Tanaka Jin , Nishimura Chika , Nishiga Masataka , Kuwabara Yasuhide , Baba Osamu , Watanabe Shin , Nishi Hitoo , Nakashima Yasuhiro , Picciotto Marina R. , Inoue Haruhisa , Watanabe Dai , Nakamura Kazuhiro , Sasaki Tsutomu , Kimura Takeshi , Ono Koh 
Published: February 2021

AbstractAdaptive thermogenesis is essential for survival, and therefore is tightly regulated by a central neural circuit. Here, we show that microRNA (miR)-33 in the brain is indispensable for adaptive thermogenesis. Cold stress increases miR-33 levels in the hypothalamus and miR-33−/− mice are unable to maintain body temperature in cold environments due to reduced sympathetic nerve activity and impaired brown adipose tissue (BAT) thermogenesis. Analysis of miR-33f/f dopamine-β-hydroxylase (DBH)-Cre mice indicates the importance of miR-33 in Dbh-positive cells. Mechanistically, miR-33 deficiency upregulates gamma-aminobutyric acid (GABA)A receptor subunit genes such as Gabrb2 and Gabra4. Knock-down of these genes in Dbh-positive neurons rescues the impaired cold-induced thermogenesis in miR-33f/fDBH-Cre mice. Conversely, increased gene dosage of miR-33 in mice enhances thermogenesis. Thus, miR-33 in the brain contributes to maintenance of BAT thermogenesis and whole-body metabolism via enhanced sympathetic nerve tone through suppressing GABAergic inhibitory neurotransmission. This miR-33-mediated neural mechanism may serve as a physiological adaptive defense mechanism for several stresses including cold stress.
Quantum confinement of the Dirac surface states in topological-insulator nanowires
Authors: Münning Felix , Breunig Oliver , Legg Henry F. , Roitsch Stefan , Fan Dingxun , Rößler Matthias , Rosch Achim , Ando Yoichi 
Published: February 2021

AbstractThe non-trivial topology of three-dimensional topological insulators dictates the appearance of gapless Dirac surface states. Intriguingly, when made into a nanowire, quantum confinement leads to a peculiar gapped Dirac sub-band structure. This gap is useful for, e.g., future Majorana qubits based on TIs. Furthermore, these sub-bands can be manipulated by a magnetic flux and are an ideal platform for generating stable Majorana zero modes, playing a key role in topological quantum computing. However, direct evidence for the Dirac sub-bands in TI nanowires has not been reported so far. Here, using devices fabricated from thin bulk-insulating (Bi1−xSbx)2Te3 nanowires we show that non-equidistant resistance peaks, observed upon gate-tuning the chemical potential across the Dirac point, are the unique signatures of the quantized sub-bands. These TI nanowires open the way to address the topological mesoscopic physics, and eventually the Majorana physics when proximitized by an s-wave superconductor.
Pancreatic glycoprotein 2 is a first line of defense for mucosal protection in intestinal inflammation
Authors: Kurashima Yosuke , Kigoshi Takaaki , Murasaki Sayuri , Arai Fujimi , Shimada Kaoru , Seki Natsumi , Kim Yun-Gi , Hase Koji , Ohno Hiroshi , Kawano Kazuya , Ashida Hiroshi , Suzuki Toshihiko , Morimoto Masako , Saito Yukari , Sasou Ai , Goda Yuki , Yuki Yoshikazu , Inagaki Yutaka , Iijima Hideki , Suda Wataru , Hattori Masahira , Kiyono Hiroshi 
Published: February 2021

AbstractIncreases in adhesive and invasive commensal bacteria, such as Escherichia coli, and subsequent disruption of the epithelial barrier is implicated in the pathogenesis of inflammatory bowel disease (IBD). However, the protective systems against such barrier disruption are not fully understood. Here, we show that secretion of luminal glycoprotein 2 (GP2) from pancreatic acinar cells is induced in a TNF–dependent manner in mice with chemically induced colitis. Fecal GP2 concentration is also increased in Crohn’s diease patients. Furthermore, pancreas-specific GP2-deficient colitis mice have more severe intestinal inflammation and a larger mucosal E. coli population than do intact mice, indicating that digestive-tract GP2 binds commensal E. coli, preventing epithelial attachment and penetration. Thus, the pancreas–intestinal barrier axis and pancreatic GP2 are important as a first line of defense against adhesive and invasive commensal bacteria during intestinal inflammation.
HPF1 remodels the active site of PARP1 to enable the serine ADP-ribosylation of histones
Authors: Sun Fa-Hui , Zhao Peng , Zhang Nan , Kong Lu-Lu , Wong Catherine C. L. , Yun Cai-Hong 
Published: February 2021

AbstractUpon binding to DNA breaks, poly(ADP-ribose) polymerase 1 (PARP1) ADP-ribosylates itself and other factors to initiate DNA repair. Serine is the major residue for ADP-ribosylation upon DNA damage, which strictly depends on HPF1. Here, we report the crystal structures of human HPF1/PARP1-CAT ΔHD complex at 1.98 Å resolution, and mouse and human HPF1 at 1.71 Å and 1.57 Å resolution, respectively. Our structures and mutagenesis data confirm that the structural insights obtained in a recent HPF1/PARP2 study by Suskiewicz et al. apply to PARP1. Moreover, we quantitatively characterize the key residues necessary for HPF1/PARP1 binding. Our data show that through salt-bridging to Glu284/Asp286, Arg239 positions Glu284 to catalyze serine ADP-ribosylation, maintains the local conformation of HPF1 to limit PARP1 automodification, and facilitates HPF1/PARP1 binding by neutralizing the negative charge of Glu284. These findings, along with the high-resolution structural data, may facilitate drug discovery targeting PARP1.
Pharmacological but not physiological GDF15 suppresses feeding and the motivation to exercise
Authors: Klein Anders B. , Nicolaisen Trine S. , Ørtenblad Niels , Gejl Kasper D. , Jensen Rasmus , Fritzen Andreas M. , Larsen Emil L. , Karstoft Kristian , Poulsen Henrik E. , Morville Thomas , Sahl Ronni E. , Helge Jørn W. , Lund Jens , Falk Sarah , Lyngbæk Mark , Ellingsgaard Helga , Pedersen Bente K. , Lu Wei , Finan Brian , Jørgensen Sebastian B. , Seeley Randy J. , Kleinert Maximilian , Kiens Bente , Richter Erik A. , Clemmensen Christoffer 
Published: February 2021

AbstractGrowing evidence supports that pharmacological application of growth differentiation factor 15 (GDF15) suppresses appetite but also promotes sickness-like behaviors in rodents via GDNF family receptor α-like (GFRAL)-dependent mechanisms. Conversely, the endogenous regulation of GDF15 and its physiological effects on energy homeostasis and behavior remain elusive. Here we show, in four independent human studies that prolonged endurance exercise increases circulating GDF15 to levels otherwise only observed in pathophysiological conditions. This exercise-induced increase can be recapitulated in mice and is accompanied by increased Gdf15 expression in the liver, skeletal muscle, and heart muscle. However, whereas pharmacological GDF15 inhibits appetite and suppresses voluntary running activity via GFRAL, the physiological induction of GDF15 by exercise does not. In summary, exercise-induced circulating GDF15 correlates with the duration of endurance exercise. Yet, higher GDF15 levels after exercise are not sufficient to evoke canonical pharmacological GDF15 effects on appetite or responsible for diminishing exercise motivation.
Expectations of reward and efficacy guide cognitive control allocation
Authors: Frömer R. , Lin H. , Dean Wolf C. K. , Inzlicht M. , Shenhav A. 
Published: February 2021

AbstractThe amount of mental effort we invest in a task is influenced by the reward we can expect if we perform that task well. However, some of the rewards that have the greatest potential for driving these efforts are partly determined by factors beyond one’s control. In such cases, effort has more limited efficacy for obtaining rewards. According to the Expected Value of Control theory, people integrate information about the expected reward and efficacy of task performance to determine the expected value of control, and then adjust their control allocation (i.e., mental effort) accordingly. Here we test this theory’s key behavioral and neural predictions. We show that participants invest more cognitive control when this control is more rewarding and more efficacious, and that these incentive components separately modulate EEG signatures of incentive evaluation and proactive control allocation. Our findings support the prediction that people combine expectations of reward and efficacy to determine how much effort to invest.
LIGHT/LTβR signaling regulates self-renewal and differentiation of hematopoietic and leukemia stem cells
Authors: Höpner S. S. , Raykova Ana , Radpour R. , Amrein M. A. , Koller D. , Baerlocher G. M. , Riether C. , Ochsenbein A. F. 
Published: February 2021

AbstractThe production of blood cells during steady-state and increased demand depends on the regulation of hematopoietic stem cell (HSC) self-renewal and differentiation. Similarly, the balance between self-renewal and differentiation of leukemia stem cells (LSCs) is crucial in the pathogenesis of leukemia. Here, we document that the TNF receptor superfamily member lymphotoxin-β receptor (LTβR) and its ligand LIGHT regulate quiescence and self-renewal of murine and human HSCs and LSCs. Cell-autonomous LIGHT/LTβR signaling on HSCs reduces cell cycling, promotes symmetric cell division and prevents primitive HSCs from exhaustion in serial re-transplantation experiments and genotoxic stress. LTβR deficiency reduces the numbers of LSCs and prolongs survival in a murine chronic myeloid leukemia (CML) model. Similarly, LIGHT/LTβR signaling in human G-CSF mobilized HSCs and human LSCs results in increased colony forming capacity in vitro. Thus, our results define LIGHT/LTβR signaling as an important pathway in the regulation of the self-renewal of HSCs and LSCs.
All-optical switching of an epsilon-near-zero plasmon resonance in indium tin oxide
Authors: Bohn Justus , Luk Ting Shan , Tollerton Craig , Hutchings Sam W. , Brener Igal , Horsley Simon , Barnes William L. , Hendry Euan 
Published: February 2021

AbstractNonlinear optical devices and their implementation into modern nanophotonic architectures are constrained by their usually moderate nonlinear response. Recently, epsilon-near-zero (ENZ) materials have been found to have a strong optical nonlinearity, which can be enhanced through the use of cavities or nano-structuring. Here, we study the pump dependent properties of the plasmon resonance in the ENZ region in a thin layer of indium tin oxide (ITO). Exciting this mode using the Kretschmann-Raether configuration, we study reflection switching properties of a 60 nm layer close to the resonant plasmon frequency. We demonstrate a thermal switching mechanism, which results in a shift in the plasmon resonance frequency of 20 THz for a TM pump intensity of 70 GW cm−2. For degenerate pump and probe frequencies, we highlight an additional two-beam coupling contribution, not previously isolated in ENZ nonlinear optics studies, which leads to an overall pump induced change in reflection from 1% to 45%.