bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of Amazonian Fires on Atmospheric CO2
Authors: Jiang Xun , Li King‐Fai , Liang Mao‐Chang , Yung Yuk L.
Published: February 2021

Amazon rainforest fires have significant environmental and societal impacts, but the mechanism and impact of the fires on the regional and global carbon cycles have not been fully understood. Over the rainforest, less precipitation, higher surface temperature, and enhanced mid‐tropospheric sinking air over the eastern part of the Amazon characterized the fire/dry season. These meteorological conditions will facilitate more fires in the Amazon rainforest. Using the Orbiting Carbon Observatory‐2 column CO2, we notice that there are ∼2 ppm more CO2 over the Amazon compared with the surrounding area during the fire season. The higher concentrations of atmospheric CO2 are related to the surface biomass burning, enhanced sinking air over the eastern part of the Amazon, and surface winds. Results from this study can help us better understand the carbon sources and sinks over the Amazon during the fire/dry season.
The Position of the Current Warm Period in the Context of the Past 22,000 Years of Summer Climate in China
Authors: Shi Feng , Lu Huayu , Guo Zhengtang , Yin Qiuzhen , Wu Haibin , Xu Chenxi , Zhang Enlou , Shi Jiangfeng , Cheng Jun , Xiao Xiayun , Zhao Cheng
Published: February 2021

Identifying the position of the Current Warm Period (CWP) in the context of the long‐term climatic trend is vital for understanding the impact of human activity on climate change. Reconstructions of summer temperature and precipitation in eight subregions of China over the past 22,000 years show that the CWP summer temperature and precipitation in these subregions are all lower than in the Early to Middle Holocene. The timing of the Holocene temperature and precipitation peaks in northern China (including Northwest China, North China, and Northeast China) is mainly determined by orbital forcing. Greenhouse gas forcing and the land ice‐sheet help to fine‐tune the timing of the climate maxima. These findings show that the climate since the Last Glacial Maximum in northern China is more sensitive to nonanthropogenic external forcings, whereas the summer precipitation in Southwest China since the early 20th century is controlled more by anthropogenically forced changes.
Turning the Orogenic Switch: Slab‐Reversal in the Eastern Alps Recorded by Low‐Temperature Thermochronology
Authors: Eizenhöfer Paul R. , Glotzbach Christoph , Büttner Lukas , Kley Jonas , Ehlers Todd A.
Published: February 2021

Many convergent orogens, such as the eastern European Alps, display an asymmetric doubly vergent wedge geometry. In doubly vergent orogens, deepest exhumation occurs above the retro‐wedge. Deep‐seismic interpretations depict the European plate dipping beneath the Adriatic, suggesting the pro‐wedge location on the north side of the orogen. Our new thermochronometer data across the Eastern Alps confirm distinct shifts in the locus of exhumation associated with orogen‐scale structural reorganizations. Most importantly, we find a general Mid‐Miocene shift in exhumation (in the Tauern Window and the Southern Alps) and focus of modern seismicity across the Southern Alps. Taken together, these observations suggest a subduction polarity reversal at least since the Mid‐Miocene such that the present‐day pro‐wedge is located on the south side of the Alps. We propose a transient tectonic state of a slow‐and‐ongoing slab reversal coeval with motion along the Tauern Ramp, consistent with a present‐day northward migration of drainage divides.
Comment on “Tu et al., An Analytical Solution of Groundwater Flow in a Confined Aquifer With a Single Well Circulation System, Water Resources Research, First Published: 12 June 2020.”
Authors: Kabala Zbigniew J.
Published: February 2021

Although renewed interest in flow around groundwater circulation wells is a positive development, the multiple and unacknowledged republication of previously published results is not. This is what has happened in a recent paper published in Water Resources Research by Tu et al. (2020, https://doi.org/10.1029/2020WR027529). The paper repeats results that appeared in Ni et al. (2011, https://doi.org/10.1016/j.applthermaleng.2011.04.030) as well as in the lead authors' own earlier work: Tu et al. (2019, https://doi.org/10.1016/j.applthermaleng.2018.09.029). And all three papers fail to acknowledge that the same ideas and closely related solutions were published in this Journal much earlier by Kabala (1993, https://doi.org/10.1029/92WR01820) and Zlotnik and Ledder (1996, https://doi.org/10.1029/95WR03813).
Helical Magnetic Cavities: Kinetic Model and Comparison With MMS Observations
Authors: Li Jing‐Huan , Zhou Xu‐Zhi , Yang Fan , Artemyev Anton V. , Zong Qiu‐Gang
Published: February 2021

Magnetic cavities are sudden depressions of magnetic field strength widely observed in the space plasma environments, which are often accompanied by plasma density and pressure enhancement. To describe these cavities, self‐consistent kinetic models have been proposed as equilibrium solutions to the Vlasov‐Maxwell equations. However, observations from the Magnetospheric Multi‐Scale (MMS) constellation have shown the existence of helical magnetic cavities characterized by the presence of azimuthal magnetic field, which could not be reconstructed by the aforementioned models. Here, we take into account another invariant of motion, the canonical axial momentum, to construct the particle distributions and accordingly modify the equilibrium model. The reconstructed magnetic cavity shows excellent agreement with the MMS1 observations not only in the electromagnetic field and plasma moment profiles but also in electron pitch‐angle distributions. With the same set of parameters, the model also predicts signatures of the neighboring MMS3 spacecraft, matching its observations satisfactorily.
Effects of innate immune receptor stimulation on extracellular α-synuclein uptake and degradation by brain resident cells
Authors: Kim Changyoun , Kwon Somin , Iba Michiyo , Spencer Brian , Rockenstein Edward , Mante Michael , Adame Anthony , Shin Soo Jean , Fields Jerel A. , Rissman Robert A. , Lee Seung-Jae , Masliah Eliezer
Published: February 2021

Synucleinopathies are age-related neurological disorders characterized by the progressive deposition of α-synuclein (α-syn) aggregates and include Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). Although cell-to-cell α-syn transmission is thought to play a key role in the spread of α-syn pathology, the detailed mechanism is still unknown. Neuroinflammation is another key pathological feature of synucleinopathies. Previous studies have identified several immune receptors that mediate neuroinflammation in synucleinopathies, such as Toll-like receptor 2 (TLR2). However, the species of α-syn aggregates varies from study to study, and how different α-syn aggregate species interact with innate immune receptors has yet to be addressed. Therefore, we investigated whether innate immune receptors can facilitate the uptake of different species of α-syn aggregates. Here, we examined whether stimulation of TLRs could modulate the cellular uptake and degradation of α-syn fibrils despite a lack of direct interaction. We observed that stimulation of TLR2 in vitro accelerated α-syn fibril uptake in neurons and glia while delaying the degradation of α-syn in neurons and astrocytes. Internalized α-syn was rapidly degraded in microglia regardless of whether TLR2 was stimulated. However, cellular α-syn uptake and degradation kinetics were not altered by TLR4 stimulation. In addition, upregulation of TLR2 expression in a synucleinopathy mouse model increased the density of Lewy-body-like inclusions and induced morphological changes in microglia. Together, these results suggest that cell type-specific modulation of TLR2 may be a multifaceted and promising therapeutic strategy for synucleinopathies; inhibition of neuronal and astroglial TLR2 decreases pathogenic α-syn transmission, but activation of microglial TLR2 enhances microglial extracellular α-syn clearance.
Relapse of pathological angiogenesis: functional role of the basement membrane and potential treatment strategies
Authors: Mukwaya Anthony , Jensen Lasse , Lagali Neil
Published: February 2021

Blinding eye diseases such as corneal neovascularization, proliferative diabetic retinopathy, and age-related macular degeneration are driven by pathological angiogenesis. In cancer, angiogenesis is key for tumor growth and metastasis. Current antiangiogenic treatments applied clinically interfere with the VEGF signaling pathway—the main angiogenic pathway—to inhibit angiogenesis. These treatments are, however, only partially effective in regressing new pathologic vessels, and the disease relapses following cessation of treatment. Moreover, the relapse of pathological angiogenesis can be rapid, aggressive and more difficult to treat than angiogenesis in the initial phase. The manner in which relapse occurs is poorly understood; however, recent studies have begun to shed light on the mechanisms underlying the revascularization process. Hypotheses have been generated to explain the rapid angiogenic relapse and increased resistance of relapsed disease to treatment. In this context, the present review summarizes knowledge of the various mechanisms of disease relapse gained from different experimental models of pathological angiogenesis. In addition, the basement membrane—a remnant of regressed vessels—is examined in detail to discuss its potential role in disease relapse. Finally, approaches for gaining a better understanding of the relapse process are discussed, including prospects for the management of relapse in the context of disease.
Impact of the ambulatory blood pressure monitoring profile on cognitive and imaging findings of cerebral small-vessel disease in older adults with cognitive complaints
Authors: Shim Yong S. , Shin Hae-Eun
Published: February 2021

We investigated ambulatory blood pressure (BP) monitoring (ABPM) profiles and magnetic resonance imaging (MRI) findings of cerebral small-vessel disease (cSVD) in older adults with cognitive complaints who were grouped as follows: subjective cognitive decline, mild cognitive impairment, and dementia of Alzheimer’s type. Group comparisons and correlation analyses among demographic characteristics, cognitive and MRI findings, and ABPM profiles were performed. Furthermore, multivariate logistic regression analyses for dependent variables of (1) dementia or not and (2) MRI criteria of subcortical vascular dementia (SVaD) or not were conducted with independent variables of dichotomized ABPM profiles. A total of 174 subjects (55 males and 119 females) were included: mean age 75.36 ± 7.13 years; Mini-Mental State Examination (MMSE) score 20.51 ± 6.23. No MRI and ABPM findings except medial temporal atrophy were different between three groups. Twenty-four-hour systolic BP (sBP) was correlated with MMSE score (r = –0.182; p = 0.022) and the severity of white matter hyperintensity (WMH) (r = 0.157; p = 0.048). A higher daytime sBP was associated with dementia (odds ratio (OR): 3.734; 95% confidence interval (CI): 1.041–13.390; p = 0.043) and MRI finding of SVaD (OR: 10.543; 95% CI: 1.161–95.740; p = 0.036). Although there were no differences in ABPM profiles between three groups, a higher BP—especially a higher sBP—correlated with cognitive dysfunction and severity of WMH in older adults. Only higher daytime sBP was an independent predictor for dementia and MRI findings of SVaD. Among various ABPM profiles in this study, a higher BP, especially a higher sBP, may be considered the most important for clinical and MRI findings of cSVD.
Intercellular mitochondrial transfer as a means of tissue revitalization
Authors: Liu Delin , Gao Youshui , Liu Jiao , Huang Yigang , Yin Junhui , Feng Yuyao , Shi Linjing , Meloni Bruno P. , Zhang Changqing , Zheng Minghao , Gao Junjie
Published: February 2021

As the crucial powerhouse for cell metabolism and tissue survival, the mitochondrion frequently undergoes morphological or positional changes when responding to various stresses and energy demands. In addition to intracellular changes, mitochondria can also be transferred intercellularly. Besides restoring stressed cells and damaged tissues due to mitochondrial dysfunction, the intercellular mitochondrial transfer also occurs under physiological conditions. In this review, the phenomenon of mitochondrial transfer is described according to its function under both physiological and pathological conditions, including tissue homeostasis, damaged tissue repair, tumor progression, and immunoregulation. Then, the mechanisms that contribute to this process are summarized, such as the trigger factors and transfer routes. Furthermore, various perspectives are explored to better understand the mysteries of cell–cell mitochondrial trafficking. In addition, potential therapeutic strategies for mitochondria-targeted application to rescue tissue damage and degeneration, as well as the inhibition of tumor progression, are discussed.
Dopamine regulates pancreatic glucagon and insulin secretion via adrenergic and dopaminergic receptors
Authors: Aslanoglou Despoina , Bertera Suzanne , Sánchez-Soto Marta , Benjamin Free R. , Lee Jeongkyung , Zong Wei , Xue Xiangning , Shrestha Shristi , Brissova Marcela , Logan Ryan W. , Wollheim Claes B. , Trucco Massimo , Yechoor Vijay K. , Sibley David R. , Bottino Rita , Freyberg Zachary
Published: February 2021

Dopamine (DA) and norepinephrine (NE) are catecholamines primarily studied in the central nervous system that also act in the pancreas as peripheral regulators of metabolism. Pancreatic catecholamine signaling has also been increasingly implicated as a mechanism responsible for the metabolic disturbances produced by antipsychotic drugs (APDs). Critically, however, the mechanisms by which catecholamines modulate pancreatic hormone release are not completely understood. We show that human and mouse pancreatic α- and β-cells express the catecholamine biosynthetic and signaling machinery, and that α-cells synthesize DA de novo. This locally-produced pancreatic DA signals via both α- and β-cell adrenergic and dopaminergic receptors with different affinities to regulate glucagon and insulin release. Significantly, we show DA functions as a biased agonist at α2A-adrenergic receptors, preferentially signaling via the canonical G protein-mediated pathway. Our findings highlight the interplay between DA and NE signaling as a novel form of regulation to modulate pancreatic hormone release. Lastly, pharmacological blockade of DA D2-like receptors in human islets with APDs significantly raises insulin and glucagon release. This offers a new mechanism where APDs act directly on islet α- and β-cell targets to produce metabolic disturbances.
Intravenous and subcutaneous formulations of trastuzumab, and trastuzumab biosimilars: implications for clinical practice
Authors: Waller Cornelius F. , Möbius Julia , Fuentes-Alburo Adolfo
Published: February 2021

Trastuzumab is a biologic therapy indicated for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer and metastatic gastric cancer. Trastuzumab was originally approved as an intravenous (IV) formulation but has since been developed for subcutaneous (SC) administration for patients with HER2-positive breast cancer. Both formulations demonstrate generally comparable pharmacological and clinical profiles. Therefore, when deciding between treatment options, factors such as the route of administration, patient preference, value and cost must be considered. Studies comparing IV with SC trastuzumab indicate that each formulation offers unique advantages to patients depending on their individual needs. Concurrent with the development of SC trastuzumab, IV trastuzumab biosimilars comprise another treatment option that, in view of their reduced cost, might improve patient access and increase cost-effectiveness for healthcare providers and payers. In this review, we seek to raise awareness of the current options available for trastuzumab so that healthcare providers can optimally treat patients according to their individual situations and preferences.
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

The 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

Repulsive 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

Memory 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

A 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

SIRT1 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

Electro-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

Given 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

Spin 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

Adaptive 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

The 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

Increases 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

Upon 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

Growing 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

The 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

The 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

Nonlinear 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%.
Discrete SARS-CoV-2 antibody titers track with functional humoral stability
Authors: Bartsch Yannic C. , Fischinger Stephanie , Siddiqui Sameed M. , Chen Zhilin , Yu Jingyou , Gebre Makda , Atyeo Caroline , Gorman Matthew J. , Zhu Alex Lee , Kang Jaewon , Burke John S. , Slein Matthew , Gluck Matthew J. , Beger Samuel , Hu Yiyuan , Rhee Justin , Petersen Eric , Mormann Benjamin , Aubin Michael de St , Hasdianda Mohammad A. , Jambaulikar Guruprasad , Boyer Edward W. , Sabeti Pardis C. , Barouch Dan H. , Julg Boris D. , Musk Elon R. , Menon Anil S. , Lauffenburger Douglas A. , Nilles Eric J. , Alter Galit
Published: February 2021

Antibodies serve as biomarkers of infection, but if sustained can confer long-term immunity. Yet, for most clinically approved vaccines, binding antibody titers only serve as a surrogate of protection. Instead, the ability of vaccine induced antibodies to neutralize or mediate Fc-effector functions is mechanistically linked to protection. While evidence has begun to point to persisting antibody responses among SARS-CoV-2 infected individuals, cases of re-infection have begun to emerge, calling the protective nature of humoral immunity against this highly infectious pathogen into question. Using a community-based surveillance study, we aimed to define the relationship between titers and functional antibody activity to SARS-CoV-2 over time. Here we report significant heterogeneity, but limited decay, across antibody titers amongst 120 identified seroconverters, most of whom had asymptomatic infection. Notably, neutralization, Fc-function, and SARS-CoV-2 specific T cell responses were only observed in subjects that elicited RBD-specific antibody titers above a threshold. The findings point to a switch-like relationship between observed antibody titer and function, where a distinct threshold of activity—defined by the level of antibodies—is required to elicit vigorous humoral and cellular response. This response activity level may be essential for durable protection, potentially explaining why re-infections occur with SARS-CoV-2 and other common coronaviruses.
PrimeDesign software for rapid and simplified design of prime editing guide RNAs
Authors: Hsu Jonathan Y. , Grünewald Julian , Szalay Regan , Shih Justine , Anzalone Andrew V. , Lam Kin Chung , Shen Max W. , Petri Karl , Liu David R. , Joung J. Keith , Pinello Luca
Published: February 2021

Prime editing (PE) is a versatile genome editing technology, but design of the required guide RNAs is more complex than for standard CRISPR-based nucleases or base editors. Here we describe PrimeDesign, a user-friendly, end-to-end web application and command-line tool for the design of PE experiments. PrimeDesign can be used for single and combination editing applications, as well as genome-wide and saturation mutagenesis screens. Using PrimeDesign, we construct PrimeVar, a comprehensive and searchable database that includes candidate prime editing guide RNA (pegRNA) and nicking sgRNA (ngRNA) combinations for installing or correcting >68,500 pathogenic human genetic variants from the ClinVar database. Finally, we use PrimeDesign to design pegRNAs/ngRNAs to install a variety of human pathogenic variants in human cells.
Asymmetric introgression reveals the genetic architecture of a plumage trait
Authors: Semenov Georgy A. , Linck Ethan , Enbody Erik D. , Harris Rebecca B. , Khaydarov David R. , Alström Per , Andersson Leif , Taylor Scott A.
Published: February 2021

Genome-wide variation in introgression rates across hybrid zones offers a powerful opportunity for studying population differentiation. One poorly understood pattern of introgression is the geographic displacement of a trait implicated in lineage divergence from genome-wide population boundaries. While difficult to interpret, this pattern can facilitate the dissection of trait genetic architecture because traits become uncoupled from their ancestral genomic background. We studied an example of trait displacement generated by the introgression of head plumage coloration from personata to alba subspecies of the white wagtail. A previous study of their hybrid zone in Siberia revealed that the geographic transition in this sexual signal that mediates assortative mating was offset from other traits and genetic markers. Here we show that head plumage is associated with two small genetic regions. Despite having a simple genetic architecture, head plumage inheritance is consistent with partial dominance and epistasis, which could contribute to its asymmetric introgression.
Maternal aryl hydrocarbon receptor activation protects newborns against necrotizing enterocolitis
Authors: Lu Peng , Yamaguchi Yukihiro , Fulton William B. , Wang Sanxia , Zhou Qinjie , Jia Hongpeng , Kovler Mark L. , Salazar Andres Gonzalez , Sampah Maame , Prindle Thomas , Wipf Peter , Sodhi Chhinder P. , Hackam David J.
Published: February 2021

Necrotizing enterocolitis (NEC) is a disease of premature infants characterized by acute intestinal necrosis. Current dogma suggests that NEC develops in response to post-natal dietary and bacterial factors, and so a potential role for in utero factors in NEC remains unexplored. We now show that during pregnancy, administration of a diet rich in the aryl hydrocarbon receptor (AHR) ligand indole-3-carbinole (I3C), or of breast milk, activates AHR and prevents NEC in newborn mice by reducing Toll-like receptor 4 (TLR4) signaling in the newborn gut. Protection from NEC requires activation of AHR in the intestinal epithelium which is reduced in mouse and human NEC, and is independent of leukocyte activation. Finally, we identify an AHR ligand (“A18”) that limits TLR4 signaling in mouse and human intestine, and prevents NEC in mice when administered during pregnancy. In summary, AHR signaling is critical in NEC development, and maternally-delivered, AHR-based therapies may alleviate NEC.
Loop competition and extrusion model predicts CTCF interaction specificity
Authors: Xi Wang , Beer Michael A.
Published: February 2021

Three-dimensional chromatin looping interactions play an important role in constraining enhancer–promoter interactions and mediating transcriptional gene regulation. CTCF is thought to play a critical role in the formation of these loops, but the specificity of which CTCF binding events form loops and which do not is difficult to predict. Loops often have convergent CTCF binding site motif orientation, but this constraint alone is only weakly predictive of genome-wide interaction data. Here we present an easily interpretable and simple mathematical model of CTCF mediated loop formation which is consistent with Cohesin extrusion and can predict ChIA-PET CTCF looping interaction measurements with high accuracy. Competition between overlapping loops is a critical determinant of loop specificity. We show that this model is consistent with observed chromatin interaction frequency changes induced by CTCF binding site deletion, inversion, and mutation, and is also consistent with observed constraints on validated enhancer–promoter interactions.
Author Correction: Loss of NARS1 impairs progenitor proliferation in cortical brain organoids and leads to microcephaly
Authors: Wang Lu , Li Zhen , Sievert David , Smith Desirée E. C. , Mendes Marisa I. , Chen Dillon Y. , Stanley Valentina , Ghosh Shereen , Wang Yulu , Kara Majdi , Aslanger Ayca Dilruba , Rosti Rasim O. , Houlden Henry , Salomons Gajja S. , Gleeson Joseph G.
Published: February 2021

A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-21448-1
Author Correction: Tailoring the separation properties of flexible metal-organic frameworks using mechanical pressure
Authors: Chanut Nicolas , Ghoufi Aziz , Coulet Marie-Vanessa , Bourrelly Sandrine , Kuchta Bogdan , Maurin Guillaume , Llewellyn Philip L.
Published: February 2021

A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-21523-7