bluuebunny/crossref_metadata_2025 huggingface dataset:
An analog of psychedelics restores functional neural circuits disrupted by unpredictable stress
Authors: Lu Ju , Tjia Michelle , Mullen Brian , Cao Bing , Lukasiewicz Kacper , Shah-Morales Sajita , Weiser Sydney , Cameron Lindsay P. , Olson David E. , Chen Lu , Zuo Yi
Published: May 2021

Psychological stress affects a wide spectrum of brain functions and poses risks for many mental disorders. However, effective therapeutics to alleviate or revert its deleterious effects are lacking. A recently synthesized psychedelic analog tabernanthalog (TBG) has demonstrated anti-addictive and antidepressant potential. Whether TBG can rescue stress-induced affective, sensory, and cognitive deficits, and how it may achieve such effects by modulating neural circuits, remain unknown. Here we show that in mice exposed to unpredictable mild stress (UMS), administration of a single dose of TBG decreases their anxiety level and rescues deficits in sensory processing as well as in cognitive flexibility. Post-stress TBG treatment promotes the regrowth of excitatory neuron dendritic spines lost during UMS, decreases the baseline neuronal activity, and enhances whisking-modulation of neuronal activity in the somatosensory cortex. Moreover, calcium imaging in head-fixed mice performing a whisker-dependent texture discrimination task shows that novel textures elicit responses from a greater proportion of neurons in the somatosensory cortex than do familiar textures. Such differential response is diminished by UMS and is restored by TBG. Together, our study reveals the effects of UMS on cortical neuronal circuit activity patterns and demonstrate that TBG combats the detrimental effects of stress by modulating basal and stimulus-dependent neural activity in cortical networks.
Chemosynthetic and photosynthetic bacteria contribute differentially to primary production across a steep desert aridity gradient
Authors: Bay Sean K , Waite David W , Dong Xiyang , Gillor Osnat , Chown Steven L , Hugenholtz Philip , Greening Chris
Published: May 2021

Desert soils harbour diverse communities of aerobic bacteria despite lacking substantial organic carbon inputs from vegetation. A major question is therefore how these communities maintain their biodiversity and biomass in these resource-limiting ecosystems. Here, we investigated desert topsoils and biological soil crusts collected along an aridity gradient traversing four climatic regions (sub-humid, semi-arid, arid, and hyper-arid). Metagenomic analysis indicated these communities vary in their capacity to use sunlight, organic compounds, and inorganic compounds as energy sources. Thermoleophilia, Actinobacteria, and Acidimicrobiia were the most abundant and prevalent bacterial classes across the aridity gradient in both topsoils and biocrusts. Contrary to the classical view that these taxa are obligate organoheterotrophs, genome-resolved analysis suggested they are metabolically flexible, with the capacity to also use atmospheric H2 to support aerobic respiration and often carbon fixation. In contrast, Cyanobacteria were patchily distributed and only abundant in certain biocrusts. Activity measurements profiled how aerobic H2 oxidation, chemosynthetic CO2 fixation, and photosynthesis varied with aridity. Cell-specific rates of atmospheric H2 consumption increased 143-fold along the aridity gradient, correlating with increased abundance of high-affinity hydrogenases. Photosynthetic and chemosynthetic primary production co-occurred throughout the gradient, with photosynthesis dominant in biocrusts and chemosynthesis dominant in arid and hyper-arid soils. Altogether, these findings suggest that the major bacterial lineages inhabiting hot deserts use different strategies for energy and carbon acquisition depending on resource availability. Moreover, they highlight the previously overlooked roles of Actinobacteriota as abundant primary producers and trace gases as critical energy sources supporting productivity and resilience of desert ecosystems.
OPRD1 SNPs associated with opioid addiction are cis-eQTLs for the phosphatase and actin regulator 4 gene, PHACTR4, a mediator of cytoskeletal dynamics
Authors: Levran Orna , Randesi Matthew , Adelson Miriam , Kreek Mary Jeanne
Published: May 2021

Several OPRD1 intronic variants were associated with opioid addiction (OD) in a population-specific manner. This follow-up study aims to further characterize the OPRD1 haplotype pattern of the risk variants in different populations and apply in silico analysis to identify potential causal variants. A population-specific haplotype pattern was revealed based on six OPRD1 eQTL SNPs and five common haplotypes were identified in a sample of European ancestry (CEU). A European-specific haplotype (‘Hap 3’) that includes SNPs previously associated with OD and is tagged by SNP rs2236861 is more common in subjects with OD. It is quite common (10%) in CEU but is absent in the African sample (YRI) and extends upstream of OPRD1. SNP rs2236857 is most probably a non-causal variant in LD with the causal SNP/s in a population-specific manner. The study provides an explanation for the lack of association in African Americans, despite its high frequency in this population. OD samples homozygous for ‘Hap 3’ were reanalyzed using a denser coverage of the region and revealed at least 25 potentially regulatory SNPs in high LD. Notably, GTEx data indicate that some of the SNPs are eQTLs for the upstream phosphatase and actin regulator 4 (PHACTR4), in the cortex, and others are eQTLs for OPRD1 and the upstream lncRNA ENSG00000270605, in the cerebellum. The study highlights the limitation of single SNP analysis and the sensitivity of association studies of OPRD1 to a genetic background. It proposes a long-range functional connection between OPRD1 and PHACTR4. PHACTR4, a mediator of cytoskeletal dynamics, may contribute to drug addiction by modulating synaptic plasticity.
Essential genes from genome-wide screenings as a resource for neuropsychiatric disorders gene discovery
Authors: Zhang Wei , Quevedo Joao , Fries Gabriel R.
Published: May 2021

Genome-wide screenings of “essential genes”, i.e., genes required for an organism or cell survival, have been traditionally conducted in vitro in cancer cell lines, limiting the translation of results to other tissues and non-cancerous cells. Recently, an in vivo screening was conducted in adult mouse striatum tissue, providing the first genome-wide dataset of essential genes in neuronal cells. Here, we aim to investigate the role of essential genes in brain development and disease risk with a comprehensive set of bioinformatics tools, including integration with transcriptomic data from developing human brain, publicly available data from genome-wide association studies, de novo mutation datasets for different neuropsychiatric disorders, and case–control transcriptomic data from postmortem brain tissues. For the first time, we found that the expression of neuronal essential genes (NEGs) increases before birth during the early development of human brain and maintains a relatively high expression after birth. On the contrary, common essential genes from cancer cell line screenings (ACEGs) tend to be expressed at high levels during development but quickly drop after birth. Both gene sets were enriched in neurodevelopmental disorders, but only NEGs were robustly associated with neuropsychiatric disorders risk genes. Finally, NEGs were more likely to show differential expression in the brains of neuropsychiatric disorders patients than ACEGs. Overall, genome-wide central nervous system screening of essential genes can provide new insights into neuropsychiatric diseases.
The KDM4B–CCAR1–MED1 axis is a critical regulator of osteoclast differentiation and bone homeostasis
Authors: Yi Sun-Ju , Jang You-Jee , Kim Hye-Jung , Lee Kyubin , Lee Hyerim , Kim Yeojin , Kim Junil , Hwang Seon Young , Song Jin Sook , Okada Hitoshi , Park Jae-Il , Kang Kyuho , Kim Kyunghwan
Published: May 2021

Bone undergoes a constant and continuous remodeling process that is tightly regulated by the coordinated and sequential actions of bone-resorbing osteoclasts and bone-forming osteoblasts. Recent studies have shown that histone demethylases are implicated in osteoblastogenesis; however, little is known about the role of histone demethylases in osteoclast formation. Here, we identified KDM4B as an epigenetic regulator of osteoclast differentiation. Knockdown of KDM4B significantly blocked the formation of tartrate-resistant acid phosphatase-positive multinucleated cells. Mice with myeloid-specific conditional knockout of KDM4B showed an osteopetrotic phenotype due to osteoclast deficiency. Biochemical analysis revealed that KDM4B physically and functionally associates with CCAR1 and MED1 in a complex. Using genome-wide chromatin immunoprecipitation (ChIP)-sequencing, we revealed that the KDM4B–CCAR1–MED1 complex is localized to the promoters of several osteoclast-related genes upon receptor activator of NF-κB ligand stimulation. We demonstrated that the KDM4B–CCAR1–MED1 signaling axis induces changes in chromatin structure (euchromatinization) near the promoters of osteoclast-related genes through H3K9 demethylation, leading to NF-κB p65 recruitment via a direct interaction between KDM4B and p65. Finally, small molecule inhibition of KDM4B activity impeded bone loss in an ovariectomized mouse model. Taken together, our findings establish KDM4B as a critical regulator of osteoclastogenesis, providing a potential therapeutic target for osteoporosis.
Ligand-dependent kinase activity of MERTK drives efferocytosis in human iPSC-derived macrophages
Authors: Wanke Florian , Gutbier Simon , Rümmelin Anna , Steinberg Malte , Hughes Lindsey D. , Koenen Mascha , Komuczki Juliana , Regan-Komito Daniel , Wagage Sagie , Hesselmann Julia , Thoma Ralf , Brugger Doris , Christopeit Tony , Wang Hayian , Point Floriane , Hallet Remy , Ghosh Sourav , Rothlin Carla V. , Patsch Christoph , Geering Barbara
Published: May 2021

Removal of apoptotic cells by phagocytes (also called efferocytosis) is a crucial process for tissue homeostasis. Professional phagocytes express a plethora of surface receptors enabling them to sense and engulf apoptotic cells, thus avoiding persistence of dead cells and cellular debris and their consequent effects. Dysregulation of efferocytosis is thought to lead to secondary necrosis and associated inflammation and immune activation. Efferocytosis in primarily murine macrophages and dendritic cells has been shown to require TAM RTKs, with MERTK and AXL being critical for clearance of apoptotic cells. The functional role of human orthologs, especially the exact contribution of each individual receptor is less well studied. Here we show that human macrophages differentiated in vitro from iPSC-derived precursor cells express both AXL and MERTK and engulf apoptotic cells. TAM RTK agonism by the natural ligand growth-arrest specific 6 (GAS6) significantly enhanced such efferocytosis. Using a newly-developed mouse model of kinase-dead MERTK, we demonstrate that MERTK kinase activity is essential for efferocytosis in peritoneal macrophages in vivo. Moreover, human iPSC-derived macrophages treated in vitro with blocking antibodies or small molecule inhibitors recapitulated this observation. Hence, our results highlight a conserved MERTK function between mice and humans, and the critical role of its kinase activity in homeostatic efferocytosis.
SARS-CoV-2 nucleocapsid protein impairs stress granule formation to promote viral replication
Authors: Zheng Zhou-Qin , Wang Su-Yun , Xu Zhi-Sheng , Fu Yu-Zhi , Wang Yan-Yi
Published: May 2021

The newly emerging coronavirus SARS-CoV-2 causes severe lung disease and substantial mortality. How the virus evades host defense for efficient replication is not fully understood. In this report, we found that the SARS-CoV-2 nucleocapsid protein (NP) impaired stress granule (SG) formation induced by viral RNA. SARS-CoV-2 NP associated with the protein kinase PKR after dsRNA stimulation. SARS-CoV-2 NP did not affect dsRNA-induced PKR oligomerization, but impaired dsRNA-induced PKR phosphorylation (a hallmark of its activation) as well as SG formation. SARS-CoV-2 NP also targeted the SG-nucleating protein G3BP1 and impaired G3BP1-mediated SG formation. Deficiency of PKR or G3BP1 impaired dsRNA-triggered SG formation and increased SARS-CoV-2 replication. The NP of SARS-CoV also targeted both PKR and G3BP1 to impair dsRNA-induced SG formation, whereas the NP of MERS-CoV targeted PKR, but not G3BP1 for the impairment. Our findings suggest that SARS-CoV-2 NP promotes viral replication by impairing formation of antiviral SGs, and reveal a conserved mechanism on evasion of host antiviral responses by highly pathogenic human betacoronaviruses.
Disproportionate exposure to urban heat island intensity across major US cities
Authors: Hsu Angel , Sheriff Glenn , Chakraborty Tirthankar , Manya Diego
Published: May 2021

Urban heat stress poses a major risk to public health. Case studies of individual cities suggest that heat exposure, like other environmental stressors, may be unequally distributed across income groups. There is little evidence, however, as to whether such disparities are pervasive. We combine surface urban heat island (SUHI) data, a proxy for isolating the urban contribution to additional heat exposure in built environments, with census tract-level demographic data to answer these questions for summer days, when heat exposure is likely to be at a maximum. We find that the average person of color lives in a census tract with higher SUHI intensity than non-Hispanic whites in all but 6 of the 175 largest urbanized areas in the continental United States. A similar pattern emerges for people living in households below the poverty line relative to those at more than two times the poverty line.
Ultrastrong magnon–magnon coupling dominated by antiresonant interactions
Authors: Makihara Takuma , Hayashida Kenji , Noe II G. Timothy , Li Xinwei , Marquez Peraca Nicolas , Ma Xiaoxuan , Jin Zuanming , Ren Wei , Ma Guohong , Katayama Ikufumi , Takeda Jun , Nojiri Hiroyuki , Turchinovich Dmitry , Cao Shixun , Bamba Motoaki , Kono Junichiro
Published: May 2021

Exotic quantum vacuum phenomena are predicted in cavity quantum electrodynamics systems with ultrastrong light-matter interactions. Their ground states are predicted to be vacuum squeezed states with suppressed quantum fluctuations owing to antiresonant terms in the Hamiltonian. However, such predictions have not been realized because antiresonant interactions are typically negligible compared to resonant interactions in light-matter systems. Here we report an unusual, ultrastrongly coupled matter-matter system of magnons that is analytically described by a unique Hamiltonian in which the relative importance of resonant and antiresonant interactions can be easily tuned and the latter can be made vastly dominant. We found a regime where vacuum Bloch-Siegert shifts, the hallmark of antiresonant interactions, greatly exceed analogous frequency shifts from resonant interactions. Further, we theoretically explored the system’s ground state and calculated up to 5.9 dB of quantum fluctuation suppression. These observations demonstrate that magnonic systems provide an ideal platform for exploring exotic quantum vacuum phenomena predicted in ultrastrongly coupled light-matter systems.
Evidence from oyster suggests an ancient role for Pdx in regulating insulin gene expression in animals
Authors: Xu Fei , Marlétaz Ferdinand , Gavriouchkina Daria , Liu Xiao , Sauka-Spengler Tatjana , Zhang Guofan , Holland Peter W. H.
Published: May 2021

Hox and ParaHox genes encode transcription factors with similar expression patterns in divergent animals. ThePdx(Xlox) homeobox gene, for example, is expressed in a sharp spatial domain in the endodermal cell layer of the gut in chordates, echinoderms, annelids and molluscs. The significance of comparable gene expression patterns is unclear because it is not known if downstream transcriptional targets are also conserved. Here, we report evidence indicating that a classic transcriptional target of Pdx1 in vertebrates, theinsulingene, is a likely direct target of Pdx in Pacific oyster adults. We show that oneinsulin-related gene,cgILP, is co-expressed withcgPdxin oyster digestive tissue. Transcriptomic comparison suggests that this tissue plays a similar role to the vertebrate pancreas. Using ATAC-seq and ChIP, we identify an upstream regulatory element of the cgILPgene which shows binding interaction with cgPdx protein in oyster hepatopancreas and demonstrate, using a cell culture assay, that the oyster Pdx can act as a transcriptional activator through this site, possibly in synergy with NeuroD. These data argue that a classic homeodomain-target gene interaction dates back to the origin of Bilateria.
The neutral rate of whole-genome duplication varies among yeast species and their hybrids
Authors: Marsit S. , Hénault M. , Charron G. , Fijarczyk A. , Landry C. R.
Published: May 2021

Hybridization and polyploidization are powerful mechanisms of speciation. Hybrid speciation often coincides with whole-genome duplication (WGD) in eukaryotes. This suggests that WGD may allow hybrids to thrive by increasing fitness, restoring fertility and/or increasing access to adaptive mutations. Alternatively, it has been suggested that hybridization itself may trigger WGD. Testing these models requires quantifying the rate of WGD in hybrids without the confounding effect of natural selection. Here we show, by measuring the spontaneous rate of WGD of more than 1300 yeast crosses evolved under relaxed selection, that some genotypes or combinations of genotypes are more prone to WGD, including some hybrids between closely related species. We also find that higher WGD rate correlates with higher genomic instability and that WGD increases fertility and genetic variability. These results provide evidence that hybridization itself can promote WGD, which in turn facilitates the evolution of hybrids.
Arbuscular mycorrhizal trees influence the latitudinal beta-diversity gradient of tree communities in forests worldwide
Authors: Zhong Yonglin , Chu Chengjin , Myers Jonathan A. , Gilbert Gregory S. , Lutz James A. , Stillhard Jonas , Zhu Kai , Thompson Jill , Baltzer Jennifer L. , He Fangliang , LaManna Joseph A. , Davies Stuart J. , Aderson-Teixeira Kristina J. , Burslem David F.R.P. , Alonso Alfonso , Chao Kuo-Jung , Wang Xugao , Gao Lianming , Orwig David A. , Yin Xue , Sui Xinghua , Su Zhiyao , Abiem Iveren , Bissiengou Pulchérie , Bourg Norm , Butt Nathalie , Cao Min , Chang-Yang Chia-Hao , Chao Wei-Chun , Chapman Hazel , Chen Yu-Yun , Coomes David A. , Cordell Susan , de Oliveira Alexandre A. , Du Hu , Fang Suqin , Giardina Christian P. , Hao Zhanqing , Hector Andrew , Hubbell Stephen P. , Janík David , Jansen Patrick A. , Jiang Mingxi , Jin Guangze , Kenfack David , Král Kamil , Larson Andrew J. , Li Buhang , Li Xiankun , Li Yide , Lian Juyu , Lin Luxiang , Liu Feng , Liu Yankun , Liu Yu , Luan Fuchen , Luo Yahuang , Ma Keping , Malhi Yadvinder , McMahon Sean M. , McShea William , Memiaghe Hervé , Mi Xiangcheng , Morecroft Mike , Novotny Vojtech , O’Brien Michael J. , Ouden Jan den , Parker Geoffrey G. , Qiao Xiujuan , Ren Haibao , Reynolds Glen , Samonil Pavel , Sang Weiguo , Shen Guochun , Shen Zhiqiang , Song Guo-Zhang Michael , Sun I-Fang , Tang Hui , Tian Songyan , Uowolo Amanda L. , Uriarte María , Wang Bin , Wang Xihua , Wang Youshi , Weiblen George D. , Wu Zhihong , Xi Nianxun , Xiang Wusheng , Xu Han , Xu Kun , Ye Wanhui , Yu Mingjian , Zeng Fuping , Zhang Minhua , Zhang Yingming , Zhu Li , Zimmerman Jess K.
Published: May 2021

Arbuscular mycorrhizal (AM) and ectomycorrhizal (EcM) associations are critical for host-tree performance. However, how mycorrhizal associations correlate with the latitudinal tree beta-diversity remains untested. Using a global dataset of 45 forest plots representing 2,804,270 trees across 3840 species, we test how AM and EcM trees contribute to total beta-diversity and its components (turnover and nestedness) of all trees. We find AM rather than EcM trees predominantly contribute to decreasing total beta-diversity and turnover and increasing nestedness with increasing latitude, probably because wide distributions of EcM trees do not generate strong compositional differences among localities. Environmental variables, especially temperature and precipitation, are strongly correlated with beta-diversity patterns for both AM trees and all trees rather than EcM trees. Results support our hypotheses that latitudinal beta-diversity patterns and environmental effects on these patterns are highly dependent on mycorrhizal types. Our findings highlight the importance of AM-dominated forests for conserving global forest biodiversity.
INPP4B promotes PI3Kα-dependent late endosome formation and Wnt/β-catenin signaling in breast cancer
Authors: Rodgers Samuel J. , Ooms Lisa M. , Oorschot Viola M. J. , Schittenhelm Ralf B. , Nguyen Elizabeth V. , Hamila Sabryn A. , Rynkiewicz Natalie , Gurung Rajendra , Eramo Matthew J. , Sriratana Absorn , Fedele Clare G. , Caramia Franco , Loi Sherene , Kerr Genevieve , Abud Helen E. , Ramm Georg , Papa Antonella , Ellisdon Andrew M. , Daly Roger J. , McLean Catriona A. , Mitchell Christina A.
Published: May 2021

INPP4B suppresses PI3K/AKT signaling by converting PI(3,4)P2 to PI(3)P and INPP4B inactivation is common in triple-negative breast cancer. Paradoxically, INPP4B is also a reported oncogene in other cancers. How these opposing INPP4B roles relate to PI3K regulation is unclear. We report PIK3CA-mutant ER+ breast cancers exhibit increased INPP4B mRNA and protein expression and INPP4B increased the proliferation and tumor growth of PIK3CA-mutant ER+ breast cancer cells, despite suppression of AKT signaling. We used integrated proteomics, transcriptomics and imaging to demonstrate INPP4B localized to late endosomes via interaction with Rab7, which increased endosomal PI3Kα-dependent PI(3,4)P2 to PI(3)P conversion, late endosome/lysosome number and cargo trafficking, resulting in enhanced GSK3β lysosomal degradation and activation of Wnt/β-catenin signaling. Mechanistically, Wnt inhibition or depletion of the PI(3)P-effector, Hrs, reduced INPP4B-mediated cell proliferation and tumor growth. Therefore, INPP4B facilitates PI3Kα crosstalk with Wnt signaling in ER+ breast cancer via PI(3,4)P2 to PI(3)P conversion on late endosomes, suggesting these tumors may be targeted with combined PI3K and Wnt/β-catenin therapies.
Evolution of spin excitations from bulk to monolayer FeSe
Authors: Pelliciari Jonathan , Karakuzu Seher , Song Qi , Arpaia Riccardo , Nag Abhishek , Rossi Matteo , Li Jiemin , Yu Tianlun , Chen Xiaoyang , Peng Rui , García-Fernández Mirian , Walters Andrew C. , Wang Qisi , Zhao Jun , Ghiringhelli Giacomo , Feng Donglai , Maier Thomas A. , Zhou Ke-Jin , Johnston Steven , Comin Riccardo
Published: May 2021

In ultrathin films of FeSe grown on SrTiO3 (FeSe/STO), the superconducting transition temperature Tc is increased by almost an order of magnitude, raising questions on the pairing mechanism. As in other superconductors, antiferromagnetic spin fluctuations have been proposed to mediate SC making it essential to study the evolution of the spin dynamics of FeSe from the bulk to the ultrathin limit. Here, we investigate the spin excitations in bulk and monolayer FeSe/STO using resonant inelastic x-ray scattering (RIXS) and quantum Monte Carlo (QMC) calculations. Despite the absence of long-range magnetic order, bulk FeSe displays dispersive magnetic excitations reminiscent of other Fe-pnictides. Conversely, the spin excitations in FeSe/STO are gapped, dispersionless, and significantly hardened relative to its bulk counterpart. By comparing our RIXS results with simulations of a bilayer Hubbard model, we connect the evolution of the spin excitations to the Fermiology of the two systems revealing a remarkable reconfiguration of spin excitations in FeSe/STO, essential to understand the role of spin fluctuations in the pairing mechanism.
Health improvement framework for actionable treatment planning using a surrogate Bayesian model
Authors: Nakamura Kazuki , Kojima Ryosuke , Uchino Eiichiro , Ono Koh , Yanagita Motoko , Murashita Koichi , Itoh Ken , Nakaji Shigeyuki , Okuno Yasushi
Published: May 2021

Clinical decision-making regarding treatments based on personal characteristics leads to effective health improvements. Machine learning (ML) has been the primary concern of diagnosis support according to comprehensive patient information. A prominent issue is the development of objective treatment processes in clinical situations. This study proposes a framework to plan treatment processes in a data-driven manner. A key point of the framework is the evaluation of the actionability for personal health improvements by using a surrogate Bayesian model in addition to a high-performance nonlinear ML model. We first evaluate the framework from the viewpoint of its methodology using a synthetic dataset. Subsequently, the framework is applied to an actual health checkup dataset comprising data from 3132 participants, to lower systolic blood pressure and risk of chronic kidney disease at the individual level. We confirm that the computed treatment processes are actionable and consistent with clinical knowledge for improving these values. We also show that the improvement processes presented by the framework can be clinically informative. These results demonstrate that our framework can contribute toward decision-making in the medical field, providing clinicians with deeper insights.
Reversible formation of coordination bonds in Sn-based metal-organic frameworks for high-performance lithium storage
Authors: Liu Jingwei , Xie Daixi , Xu Xiufang , Jiang Luozhen , Si Rui , Shi Wei , Cheng Peng
Published: May 2021

Sn-based compounds with buffer matrixes possessing high theoretical capacity, low working voltage, and alleviation of the volume expansion of Sn are ideal materials for lithium storage. However, it is challenging to confine well-dispersed Sn within a lithium active matrix because low-melting-point Sn tends to agglomerate. Here, we apply a metal-organic framework (MOF) chemistry between Sn-nodes and lithium active ligands to create two Sn-based MOFs comprising Sn2(dobdc) and Sn2(dobpdc) with extended ligands from H4dobdc (2,5-dioxido-1,4-benzenedicarboxylate acid) to H4dobpdc (4,4’-dioxidobiphenyl-3,3’-dicarboxylate acid) with molecule-level homodispersion of Sn in organic matrixes for lithium storage. The enhanced utilization of active sites and reaction kinetics are achieved by the isoreticular expansion of the organic linkers. The reversible formation of coordination bonds during lithium storage processes is revealed by X-ray absorption fine structure characterization, providing an in-depth understanding of the lithium storage mechanism in coordination compounds.
A graph-based network for predicting chemical reaction pathways in solid-state materials synthesis
Authors: McDermott Matthew J. , Dwaraknath Shyam S. , Persson Kristin A.
Published: May 2021

Accelerated inorganic synthesis remains a significant challenge in the search for novel, functional materials. Many of the principles which enable “synthesis by design” in synthetic organic chemistry do not exist in solid-state chemistry, despite the availability of extensive computed/experimental thermochemistry data. In this work, we present a chemical reaction network model for solid-state synthesis constructed from available thermochemistry data and devise a computationally tractable approach for suggesting likely reaction pathways via the application of pathfinding algorithms and linear combination of lowest-cost paths in the network. We demonstrate initial success of the network in predicting complex reaction pathways comparable to those reported in the literature for YMnO3, Y2Mn2O7, Fe2SiS4, and YBa2Cu3O6.5. The reaction network presents opportunities for enabling reaction pathway prediction, rapid iteration between experimental/theoretical results, and ultimately, control of the synthesis of solid-state materials.
An electronic neuromorphic system for real-time detection of high frequency oscillations (HFO) in intracranial EEG
Authors: Sharifshazileh Mohammadali , Burelo Karla , Sarnthein Johannes , Indiveri Giacomo
Published: May 2021

The analysis of biomedical signals for clinical studies and therapeutic applications can benefit from embedded devices that can process these signals locally and in real-time. An example is the analysis of intracranial EEG (iEEG) from epilepsy patients for the detection of High Frequency Oscillations (HFO), which are a biomarker for epileptogenic brain tissue. Mixed-signal neuromorphic circuits offer the possibility of building compact and low-power neural network processing systems that can analyze data on-line in real-time. Here we present a neuromorphic system that combines a neural recording headstage with a spiking neural network (SNN) processing core on the same die for processing iEEG, and show how it can reliably detect HFO, thereby achieving state-of-the-art accuracy, sensitivity, and specificity. This is a first feasibility study towards identifying relevant features in iEEG in real-time using mixed-signal neuromorphic computing technologies.
Intratumoral CXCR5+CD8+T associates with favorable clinical outcomes and immunogenic contexture in gastric cancer
Authors: Wang Jieti , Li Ruochen , Cao Yifan , Gu Yun , Fang Hanji , Fei Yuchao , Lv Kunpeng , He Xudong , Lin Chao , Liu Hao , Zhang Heng , Li He , He Hongyong , Xu Jiejie , Huang Hua
Published: May 2021

Studies that examined an association between CD8+T and prognosis in gastric cancer are inconsistent, and a distinct population of CXCR5+CD8+T associated with better overall survival has been reported among various malignancies. Here, we show that the abundance of intratumoral CXCR5+CD8+T cells is associated with better overall survival in patients with gastric cancer. Patients with TNM II + III gastric cancer with higher intratumoral CXCR5+CD8+T cell infiltration are more likely to benefit from adjuvant chemotherapy. Microsatellite-unstable and Epstein–Barr virus positive tumors are enriched with CXCR5+CD8+T cells. Gastric cancer infiltrating CXCR5+CD8+T cells represent a specific subtype of stem-like CD8+T with effector memory feature. Identification of the clinical significance and phenotype of gastric cancer infiltrating CXCR5+CD8+T provides a roadmap for patient stratification and trials of targeted therapies.
Sulfide catabolism ameliorates hypoxic brain injury
Authors: Marutani Eizo , Morita Masanobu , Hirai Shuichi , Kai Shinichi , Grange Robert M. H. , Miyazaki Yusuke , Nagashima Fumiaki , Traeger Lisa , Magliocca Aurora , Ida Tomoaki , Matsunaga Tetsuro , Flicker Daniel R. , Corman Benjamin , Mori Naohiro , Yamazaki Yumiko , Batten Annabelle , Li Rebecca , Tanaka Tomohiro , Ikeda Takamitsu , Nakagawa Akito , Atochin Dmitriy N. , Ihara Hideshi , Olenchock Benjamin A. , Shen Xinggui , Nishida Motohiro , Hanaoka Kenjiro , Kevil Christopher G. , Xian Ming , Bloch Donald B. , Akaike Takaaki , Hindle Allyson G. , Motohashi Hozumi , Ichinose Fumito
Published: May 2021

The mammalian brain is highly vulnerable to oxygen deprivation, yet the mechanism underlying the brain’s sensitivity to hypoxia is incompletely understood. Hypoxia induces accumulation of hydrogen sulfide, a gas that inhibits mitochondrial respiration. Here, we show that, in mice, rats, and naturally hypoxia-tolerant ground squirrels, the sensitivity of the brain to hypoxia is inversely related to the levels of sulfide:quinone oxidoreductase (SQOR) and the capacity to catabolize sulfide. Silencing SQOR increased the sensitivity of the brain to hypoxia, whereas neuron-specific SQOR expression prevented hypoxia-induced sulfide accumulation, bioenergetic failure, and ischemic brain injury. Excluding SQOR from mitochondria increased sensitivity to hypoxia not only in the brain but also in heart and liver. Pharmacological scavenging of sulfide maintained mitochondrial respiration in hypoxic neurons and made mice resistant to hypoxia. These results illuminate the critical role of sulfide catabolism in energy homeostasis during hypoxia and identify a therapeutic target for ischemic brain injury.
Control of mouse limb initiation and antero-posterior patterning by Meis transcription factors
Authors: Delgado Irene , Giovinazzo Giovanna , Temiño Susana , Gauthier Yves , Balsalobre Aurelio , Drouin Jacques , Torres Miguel
Published: May 2021

Meis1 and Meis2 are homeodomain transcription factors that regulate organogenesis through cooperation with Hox proteins. Elimination of Meis genes after limb induction has shown their role in limb proximo-distal patterning; however, limb development in the complete absence of Meis function has not been studied. Here, we report thatMeis1/2inactivation in the lateral plate mesoderm of mouse embryos leads to limb agenesis. Meis and Tbx factors converge in this function, extensively co-binding with Tbx to genomic sites and co-regulating enhancers ofFgf10, a critical factor in limb initiation. Limbs with three deleted Meis alleles show proximal-specific skeletal hypoplasia and agenesis of posterior skeletal elements. This failure in posterior specification results from an early role of Meis factors in establishing the limb antero-posterior prepattern required forShhactivation. Our results demonstrate roles for Meis transcription factors in early limb development and identify their involvement in previously undescribed interaction networks that regulate organogenesis.
Label-free characterization of organic nanocarriers reveals persistent single molecule cores for hydrocarbon sequestration
Authors: McAfee Terry , Ferron Thomas , Cordova Isvar A. , Pickett Phillip D. , McCormick Charles L. , Wang Cheng , Collins Brian A.
Published: May 2021

Self-assembled molecular nanostructures embody an enormous potential for new technologies, therapeutics, and understanding of molecular biofunctions. Their structure and function are dependent on local environments, necessitating in-situ/operando investigations for the biggest leaps in discovery and design. However, the most advanced of such investigations involve laborious labeling methods that can disrupt behavior or are not fast enough to capture stimuli-responsive phenomena. We utilize X-rays resonant with molecular bonds to demonstrate an in-situ nanoprobe that eliminates the need for labels and enables data collection times within seconds. Our analytical spectral model quantifies the structure, molecular composition, and dynamics of a copolymer micelle drug delivery platform using resonant soft X-rays. We additionally apply this technique to a hydrocarbon sequestrating polysoap micelle and discover that the critical organic-capturing domain does not coalesce upon aggregation but retains distinct single-molecule cores. This characteristic promotes its efficiency of hydrocarbon sequestration for applications like oil spill remediation and drug delivery. Such a technique enables operando, chemically sensitive investigations of any aqueous molecular nanostructure, label-free.
Finding gene network topologies for given biological function with recurrent neural network
Authors: Shen Jingxiang , Liu Feng , Tu Yuhai , Tang Chao
Published: May 2021

Searching for possible biochemical networks that perform a certain function is a challenge in systems biology. For simple functions and small networks, this can be achieved through an exhaustive search of the network topology space. However, it is difficult to scale this approach up to larger networks and more complex functions. Here we tackle this problem by training a recurrent neural network (RNN) to perform the desired function. By developing a systematic perturbative method to interrogate the successfully trained RNNs, we are able to distill the underlying regulatory network among the biological elements (genes, proteins, etc.). Furthermore, we show several cases where the regulation networks found by RNN can achieve the desired biological function when its edges are expressed by more realistic response functions, such as the Hill-function. This method can be used to link topology and function by helping uncover the regulation logic and network topology for complex tasks.
Non-invasive super-resolution imaging through dynamic scattering media
Authors: Wang Dong , Sahoo Sujit K. , Zhu Xiangwen , Adamo Giorgio , Dang Cuong
Published: May 2021

Super-resolution imaging has been revolutionizing technical analysis in various fields from biological to physical sciences. However, many objects are hidden by strongly scattering media such as biological tissues that scramble light paths, create speckle patterns and hinder object’s visualization, let alone super-resolution imaging. Here, we demonstrate non-invasive super-resolution imaging through scattering media based on a stochastic optical scattering localization imaging (SOSLI) technique. After capturing multiple speckle patterns of photo-switchable point sources, our computational approach utilizes the speckle correlation property of scattering media to retrieve an image with a 100-nm resolution, an eight-fold enhancement compared to the diffraction limit. More importantly, we demonstrate our SOSLI to do non-invasive super-resolution imaging through not only static scattering media, but also dynamic scattering media with strong decorrelation such as biological tissues. Our approach paves the way to non-invasively visualize various samples behind scattering media at nanometer levels of detail.
Subcellular three-dimensional imaging deep through multicellular thick samples by structured illumination microscopy and adaptive optics
Authors: Lin Ruizhe , Kipreos Edward T. , Zhu Jie , Khang Chang Hyun , Kner Peter
Published: May 2021

Structured Illumination Microscopy enables live imaging with sub-diffraction resolution. Unfortunately, optical aberrations can lead to loss of resolution and artifacts in Structured Illumination Microscopy rendering the technique unusable in samples thicker than a single cell. Here we report on the combination of Adaptive Optics and Structured Illumination Microscopy enabling imaging with 150 nm lateral and 570 nm axial resolution at a depth of 80 µm throughCaenorhabditis elegans. We demonstrate that Adaptive Optics improves the three-dimensional resolution, especially along the axial direction, and reduces artifacts, successfully realizing 3D-Structured Illumination Microscopy in a variety of biological samples.
Activation of Prp28 ATPase by phosphorylated Npl3 at a critical step of spliceosome remodeling
Authors: Yeh Fu-Lung , Chang Shang-Lin , Ahmed Golam Rizvee , Liu Hsin-I , Tung Luh , Yeh Chung-Shu , Lanier Leah Stands , Maeder Corina , Lin Che-Min , Tsai Shu-Chun , Hsiao Wan-Yi , Chang Wei-Hau , Chang Tien-Hsien
Published: May 2021

Splicing, a key step in the eukaryotic gene-expression pathway, converts precursor messenger RNA (pre-mRNA) into mRNA by excising introns and ligating exons. This task is accomplished by the spliceosome, a macromolecular machine that must undergo sequential conformational changes to establish its active site. Each of these major changes requires a dedicated DExD/H-box ATPase, but how these enzymes are activated remain obscure. Here we show that Prp28, a yeast DEAD-box ATPase, transiently interacts with the conserved 5′ splice-site (5′SS) GU dinucleotide and makes splicing-dependent contacts with the U1 snRNP protein U1C, and U4/U6.U5 tri-snRNP proteins, Prp8, Brr2, and Snu114. We further show that Prp28’s ATPase activity is potentiated by the phosphorylated Npl3, but not the unphosphorylated Npl3, thus suggesting a strategy for regulating DExD/H-box ATPases. We propose that Npl3 is a functional counterpart of the metazoan-specific Prp28 N-terminal region, which can be phosphorylated and serves as an anchor to human spliceosome.
Caerulomycin and collismycin antibiotics share a trans-acting flavoprotein-dependent assembly line for 2,2’-bipyridine formation
Authors: Pang Bo , Liao Rijing , Tang Zhijun , Guo Shengjie , Wu Zhuhua , Liu Wen
Published: May 2021

Linear nonribosomal peptide synthetases (NRPSs) and polyketide synthases (PKSs) template the modular biosynthesis of numerous nonribosomal peptides, polyketides and their hybrids through assembly line chemistry. This chemistry can be complex and highly varied, and thus challenges our understanding in NRPS and PKS-programmed, diverse biosynthetic processes using amino acid and carboxylate building blocks. Here, we report that caerulomycin and collismycin peptide-polyketide hybrid antibiotics share an assembly line that involves unusual NRPS activity to engage a trans-acting flavoprotein in C-C bond formation and heterocyclization during 2,2’-bipyridine formation. Simultaneously, this assembly line provides dethiolated and thiolated 2,2’-bipyridine intermediates through differential treatment of the sulfhydryl group arising from l-cysteine incorporation. Subsequent l-leucine extension, which does not contribute any atoms to either caerulomycins or collismycins, plays a key role in sulfur fate determination by selectively advancing one of the two 2,2’-bipyridine intermediates down a path to the final products with or without sulfur decoration. These findings further the appreciation of assembly line chemistry and will facilitate the development of related molecules using synthetic biology approaches.
Cornelia de Lange syndrome-associated mutations cause a DNA damage signalling and repair defect
Authors: Olley Gabrielle , Pradeepa Madapura M. , Grimes Graeme R. , Piquet Sandra , Polo Sophie E. , FitzPatrick David R. , Bickmore Wendy A. , Boumendil Charlene
Published: May 2021

Cornelia de Lange syndrome is a multisystem developmental disorder typically caused by mutations in the gene encoding the cohesin loader NIPBL. The associated phenotype is generally assumed to be the consequence of aberrant transcriptional regulation. Recently, we identified a missense mutation in BRD4 associated with a Cornelia de Lange-like syndrome that reduces BRD4 binding to acetylated histones. Here we show that, although this mutation reduces BRD4-occupancy at enhancers it does not affect transcription of the pluripotency network in mouse embryonic stem cells. Rather, it delays the cell cycle, increases DNA damage signalling, and perturbs regulation of DNA repair in mutant cells. This uncovers a role for BRD4 in DNA repair pathway choice. Furthermore, we find evidence of a similar increase in DNA damage signalling in cells derived from NIPBL-deficient individuals, suggesting that defective DNA damage signalling and repair is also a feature of typical Cornelia de Lange syndrome.
Single-inhaler fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) triple therapy versus tiotropium monotherapy in patients with COPD
Authors: Bansal Sandeep , Anderson Martin , Anzueto Antonio , Brown Nicola , Compton Chris , Corbridge Thomas C. , Erb David , Harvey Catherine , Kaisermann Morrys C. , Kaye Mitchell , Lipson David A. , Martin Neil , Zhu Chang-Qing , Papi Alberto
Published: May 2021

Chronic obstructive pulmonary disease (COPD) treatment guidelines do not currently include recommendations for escalation directly from monotherapy to triple therapy. This 12-week, double-blind, double-dummy study randomized 800 symptomatic moderate-to-very-severe COPD patients receiving tiotropium (TIO) for ≥3 months to once-daily fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) 100/62.5/25 mcg via ELLIPTA (n = 400) or TIO 18 mcg via HandiHaler (n = 400) plus matched placebo. Study endpoints included change from baseline in trough forced expiratory volume in 1 s (FEV1) at Days 85 (primary), 28 and 84 (secondary), health status (St George’s Respiratory Questionnaire [SGRQ] and COPD Assessment Test [CAT]) and safety. FF/UMEC/VI significantly improved trough FEV1 at all timepoints (Day 85 treatment difference [95% CI] 95 mL [62–128]; P < 0.001), and significantly improved SGRQ and CAT versus TIO. Treatment safety profiles were similar. Once-daily single-inhaler FF/UMEC/VI significantly improved lung function and health status versus once-daily TIO in symptomatic moderate-to-very-severe COPD patients, with a similar safety profile.
Multi-exponential error extrapolation and combining error mitigation techniques for NISQ applications
Authors: Cai Zhenyu
Published: May 2021

Noise in quantum hardware remains the biggest roadblock for the implementation of quantum computers. To fight the noise in the practical application of near-term quantum computers, instead of relying on quantum error correction which requires large qubit overhead, we turn to quantum error mitigation, in which we make use of extra measurements. Error extrapolation is an error mitigation technique that has been successfully implemented experimentally. Numerical simulation and heuristic arguments have indicated that exponential curves are effective for extrapolation in the large circuit limit with an expected circuit error count around unity. In this Article, we extend this to multi-exponential error extrapolation and provide more rigorous proof for its effectiveness under Pauli noise. This is further validated via our numerical simulations, showing orders of magnitude improvements in the estimation accuracy over single-exponential extrapolation. Moreover, we develop methods to combine error extrapolation with two other error mitigation techniques: quasi-probability and symmetry verification, through exploiting features of these individual techniques. As shown in our simulation, our combined method can achieve low estimation bias with a sampling cost multiple times smaller than quasi-probability while without needing to be able to adjust the hardware error rate as required in canonical error extrapolation.
Quantum nonlocality without entanglement: explicit dependence on prior probabilities of nonorthogonal mirror-symmetric states
Authors: Ha Donghoon , Kwon Younghun
Published: May 2021

In the case of a multi-party system, through local operations and classical communication (LOCC), each party may not perform perfect discrimination of quantum states that are separable and orthogonal. This property of quantum ensemble is called “nonlocality without entanglement” since each local party has a limit to full information of given quantum states. When this property is extended to the case of minimum-error discrimination, one can see that it is revealed when a nonlocal measurement provides more information about the unentangled states than LOCC does. One may infer the fact that the property depends on quantum states composing the quantum ensemble. However, an essential but unsettled question about the property is whether an explicit dependence on prior probabilities in terms of minimum-error discrimination could be shown in nonlocality without entanglement. In a simple term, one can ask whether different quantum ensembles made of the same separable quantum states could exhibit explicitly different behavior of the nonlocality. We answer this question in the positive, and we furthermore provide the explicit functional dependence of guessing probability on prior probabilities for the mirror-symmetric ensemble.
Critical charge fluctuations and emergent coherence in a strongly correlated excitonic insulator
Authors: Volkov P. A. , Ye Mai , Lohani H. , Feldman I. , Kanigel A. , Blumberg G.
Published: May 2021

Excitonic insulator is a coherent electronic phase that results from the formation of a macroscopic population of bound particle-hole pairs—excitons. With only a few candidate materials known, the collective excitonic behavior is challenging to observe, being obscured by crystalline lattice effects. Here we use polarization-resolved Raman spectroscopy to reveal the quadrupolar excitonic mode in the candidate zero-gap semiconductor Ta2NiSe5 disentangling it from the lattice phonons. The excitonic mode pronouncedly softens close to the phase transition, showing its electronic character, while its coupling to noncritical lattice modes is shown to enhance the transition temperature. On cooling, we observe the gradual emergence of coherent superpositions of band states at the correlated insulator gap edge, with strong departures from mean-field theory predictions. Our results demonstrate the realization of a strongly correlated excitonic state in an equilibrium bulk material.