bluuebunny/crossref_metadata_2025 huggingface dataset:
Mini right axillary thoracotomy for congenital heart defect repair can become a safe surgical routine
Authors: Dodge-Khatami Jannika , Noor Rabia , Riggs Kyle W. , Dodge-Khatami Ali
Published: February 2022

Objective:

Owing to its obvious cosmetic appeal, minimal invasive repair of congenital heart defects (CHDs) through the mini right axillary thoracotomy is becoming routine in many centres. Besides cosmesis, and before becoming a new norm, it is important to establish its outcomes as safe compared to repairs through traditional median sternotomy.

Methods:

Between 2013 and 2021, 116 consecutive patients underwent defect repairs through mini right axillary thoracotomy. Patient, operative data, and hospital outcomes were compared to contemporary mini right axillary thoracotomy and sternotomy series.

Results:

There was no mortality or need for approach conversion (mean age 4.3 years, range 0.17–17, mean weight 18.6 kg, range 4.8–74.4) in 118 repairs for atrial septal defect, ventricular septal defect, partial anomalous pulmonary venous return, partial atrioventricular canal with mitral cleft, scimitar syndrome, double-chambered right ventricle, cor triatriatum, and tricuspid valve repair. Protocol included on-table extubation, achieved in 97 children, with 23 outliers leading to 0.7 average hours of mechanical ventilation (range 0–66 hours), indwelling chest drain time of 2.6 days (range 1–9 days), intensive care stay of 1.8 days (range 1–10 days), and hospital stay of 3.9 days (range 2–18 days). Late revisions were required in one patient after scimitar repair for scimitar vein stenosis at 2 weeks, and in another for repair of superior caval vein stenosis after a Warden operation at 2 months; reoperations (5/116 = 4.3%) were successfully performed through the same mini right axillary incision.

Conclusions:

While providing obvious cosmetic advantages, the minimally invasive right axillary thoracotomy approach for the surgical repair of common CHDs yields excellent results and is safe compared to the benchmark median sternotomy approach.
The Law Library at the University of Edinburgh: a Criminal History, a Troublesome Future
Authors: McDonald SarahLouise
Published: February 2022

This article, by SarahLouise McDonald, is an examination of the history and recent refurbishment of the Law Library located at the Old College campus at the University of Edinburgh. This article describes notable incidents in the history of the School of Law, and explores how these have combined to create a multifaceted identity for the Law Library. The author considers the challenges which library staff have faced during the latest upgrade to facilities and how this has affected daily operations. Finally, the effect of recent global events on the library's approach to service delivery is discussed, and opportunities for positive growth are identified amongst a complex landscape of resource purchasing and access.
The value of political connections: evidence from China's anti-corruption campaign
Authors: Alonso Marta , Palma Nuno , Simon-Yarza Beatriz
Published: February 2022

We study the value of the political connections of directors on Chinese boards. We build a new dataset that measures connections of directors to members of the Politburo via past school ties, and find that private firms with politically connected directors in the boardroom get on average about 16% higher subsidies over sales per firm (7 million yuan). Connected state-owned enterprises (SOEs) access debt at 11% cheaper cost, which translates into average savings of close to 32 million yuan per firm in lower interest payments. We find that the value of the political connections persisted after the anti-corruption campaign (ACC) of 2012. It became weaker for the cost of debt in SOEs, but stronger for subsidies to private firms. We argue that the value of connections in the private sector increased after the ACC because they became a less risky alternative to corruption. We also show that connected firms do not perform better.
Metasurface-based electromagnetic structure for electromagnetic absorption and radiation application
Authors: Rahman Saeed Ur , Deng Hai , Cao Qunsheng , Wang Yi , Khan Muhammad Irshad , Khan Zakir , Sajjad Muhammad , Khalil Hisham
Published: February 2022

In this paper, a metasurface (MS)-based multi-functional electromagnetic (EM) structure is proposed to realize its two different applications, namely absorption and radiation. The proposed structure is based on periodic arrays of disk-shaped metallic patches and split rings with four embedded lumped resistors. The metallic vias are inserted from top to bottom to connect the disk-shaped patches with a feeding network designed on the bottom layer where two p-i-n switches are embedded in the feeding network to alter the different functions of the proposed structure. For free space incident plan wave, the designed structure works as an absorber when the p-i-n switches are switched OFF. The absorber operates over a frequency band from 6.2 GHz to 8.2 GHz and unchanged over an incident angle from 0° to 30° for both TE and TM polarized incident waves. The same structure also works as a low scattering and high gain radiator when the p-i-n switches are turned ON and radiate within absorbing frequency band, i.e. from 7.5 to 8.0 GHz. The designed structure is fabricated and experimentally verified for EM absorption and radiation applications.
Generalized Effective Biot Theory and Seismic Wave Propagation in Anisotropic, Poroviscoelastic Media
Authors: Huang Xingguo , Greenhalgh Stewart , Han Li , Liu Xu
Published: February 2022

The interior of the Earth is quite complex due to the actual geometrical structure and the presence of complex rheological materials, including viscoelastic rocks, porous sediments and the presence of anisotropy. Seismic wavefield forward modeling in such media forms the basis of most wave equation‐based methods for investigating the structure of the Earth and processing and imaging of seismic data, e.g., seismic full waveform inversion. Numerical modeling using Biot's equations that describe the physics of poroelasticity provides a useful framework to investigate wave attenuation and dispersion. Poroelasticity describes the interaction between the deformation of an elastic porous solid and the fluid flow in the porous structure. We present a time‐domain finite‐difference method for seismic wavefield modeling, taking into account both attenuation and anisotropy of poroviscoelastic Earth structure. The mathematical formulations and modeling methods are based on (a) the linear Biot's poroelastic theory and double porosity models in anisotropic media and (b) a relaxation function that uses the generalized standard linear solid model with anisotropic τ parameter for magnitude of attenuation and nearly constant Q model. Using a modified relaxation function that is suggested to describe the anisotropy attenuation, we develop a generalized anisotropic Biot model in the anisotropic, viscoelastic media. In addition to the anisotropic poroelasticity based on Biot theory, we implement the generalized anisotropic Biot model with complex moduli for an effective Biot's model in which the attenuative anisotropic viscoelastic model with the generalized standard linear solid model is used to approximate the attenuation factor function. The method generalizes the linear poroviscoelastic model based on effective Biot theory for seismic wave modeling to the attenuative, anisotropic case. In the anisotropic, poroviscoelastic model, we represent the bulk modulus and shear modulus of the solid frame by the modified relaxation function. We present time‐domain finite‐difference modeling for seismic wavefields in anisotropic, viscoelastic porous media including transversely isotropic media with a vertical, tilted or horizontal symmetry axis (VTI, TTI, and HTI). We also consider the extension of the two new models to nearly constant Q viscoelastic anisotropy.
Assessing the Influence of Input Magnetic Maps on Global Modeling of the Solar Wind and CME‐Driven Shock in the 2013 April 11 Event
Authors: Jin Meng , Nitta Nariaki V. , Cohen Christina M. S.
Published: February 2022

In the past decade, significant efforts have been made in developing physics‐based solar wind and coronal mass ejection (CME) models, which have been or are being transferred to national centers (e.g., SWPC, Community Coordinated Modeling Center) to enable space weather predictive capability. However, the input data coverage for space weather forecasting is extremely limited. One major limitation is the solar magnetic field measurements, which are used to specify the inner boundary conditions of the global magnetohydrodynamic (MHD) models. In this study, using the Alfvén wave solar model, we quantitatively assess the influence of the magnetic field map input (synoptic/diachronic vs. synchronic magnetic maps) on the global modeling of the solar wind and the CME‐driven shock in the 11 April 2013 solar energetic particle event. Our study shows that due to the inhomogeneous background solar wind and dynamical evolution of the CME, the CME‐driven shock parameters change significantly both spatially and temporally as the CME propagates through the heliosphere. The input magnetic map has a great impact on the shock connectivity and shock properties in the global MHD simulation. Therefore this study illustrates the importance of taking into account the model uncertainty due to the imperfect magnetic field measurements when using the model to provide space weather predictions.
Tidally Locked and Loaded with Questions
Authors: Hasler Caroline
Published: February 2022

Tidally locked planets always present the same face to their host stars. What does this mean for their potential to support life?
The enhanced genomic 6 mA metabolism contributes to the proliferation and migration of TSCC cells
Authors: Xi Lei , Yang Ying , Xu Ying , Zhang Fangming , Li Jinghui , Liu Xiyang , Zhang Zhenxi , Du Quan
Published: February 2022

In contrast to the well-established genomic 5-methylcytosine (5mC), the existence of N6-methyladenine (6 mA) in eukaryotic genomes was discovered only recently. Initial studies found that it was actively regulated in cancer cells, suggesting its involvement in the process of carcinogenesis. However, the contribution of 6 mA in tongue squamous cell carcinoma (TSCC) still remains uncharacterized. In this study, a pan-cancer type analysis was first performed, which revealed enhanced 6 mA metabolism in diverse cancer types. The study was then focused on the regulation of 6 mA metabolism, as well as its effects on TSCC cells. To these aspects, genome 6 mA level was found greatly increased in TSCC tissues and cultured cells. By knocking down 6 mA methylases N6AMT1 and METTL4, the level of genomic 6 mA was decreased in TSCC cells. This led to suppressed colony formation and cell migration. By contrast, knockdown of 6 mA demethylase ALKBH1 resulted in an increased 6 mA level, enhanced colony formation, and cell migration. Further study suggested that regulation of the NF-κB pathway might contribute to the enhanced migration of TSCC cells. Therefore, in the case of TSCC, we have shown that genomic 6 mA modification is involved in the proliferation and migration of cancer cells.
Early vascular toxicity after pediatric allogeneic hematopoietic stem cell transplantation
Authors: Leimi Lilli , Jahnukainen Kirsi , Olkinuora Helena , Meri Seppo , Vettenranta Kim
Published: February 2022

Treatment-related mortality and morbidity remain a challenge in hematopoietic stem cell transplantation (HSCT). In this retrospective, single-center study, we analyzed endothelial damage as a potential, common denominator and mechanism for the adverse effects. We evaluated the prevalence of key vascular complications and graft-versus-host disease among 122 pediatric patients with an allogeneic HSCT between 2001 and 2013. The spectrum and frequency of acute adverse events emerging ≤100 days post transplant were graded according to the CTCAE 4.03 and analyzed. We identified a total of 19/122 (15.6%) patients with vascular complications, fulfilling the criteria of capillary leak syndrome, veno-occlusive disease/sinusoidal obstruction syndrome or thrombotic microangiopathy. The patients had a poorer overall survival (77% versus 26%, p < 0.001). Nearly one half (56/122, 45.9%) had at least one, severe (grade 3 or 4) adverse event. Patients with vascular complications had more often edema/effusions (p = 0.023), thrombocytopenia (p = 0.001), gastrointestinal bleeding (p < 0.001), acute kidney injury (p < 0.001), ascites (p < 0.001) or bilirubin increase (p = 0.027). These endotheliopathy-related adverse events appeared early post HSCT, varied in their clinical phenotype and predicted a poor outcome. An unrelated donor but not previous exposure to leukemia or irradiation-based conditioning was identified as a risk factor for vascular complications and endotheliopathy.
Targeting CCL2-CCR4 axis suppress cell migration of head and neck squamous cell carcinoma
Authors: Ling Zihang , Li Wei , Hu Jiaqi , Li Yuanyuan , Deng Miao , Zhang Siyuan , Ren Xianyue , Wu Tong , Xia Juan , Cheng Bin , Tao Xiaoan
Published: February 2022

For head and neck squamous cell carcinoma (HNSCC), the local invasion and distant metastasis represent the predominant causes of mortality. Targeted inhibition of chemokines and their receptors is an ongoing antitumor strategy established on the crucial roles of chemokines in cancer invasion and metastasis. Herein, we showed that C-C motif chemokine ligand 2 (CCL2)- C-C motif chemokine receptor 4 (CCR4) signaling, but not the CCL2- C-C motif chemokine receptor 2 (CCR2) axis, induces the formation of the vav guanine nucleotide exchange factor 2 (Vav2)- Rac family small GTPase 1 (Rac1) complex to activate the phosphorylation of myosin light chain (MLC), which is involved in the regulation of cell motility and cancer metastasis. We identified that targeting CCR4 could effectively interrupt the activation of HNSCC invasion and metastasis induced by CCL2 without the promoting cancer relapse observed during the subsequent withdrawal period. All current findings suggested that CCL2-CCR4-Vav2-Rac1-p-MLC signaling plays an essential role in cell migration and cancer metastasis of HNSCC, and CCR4 may serve as a new potential molecular target for HNSCC therapy.
Cryo-EM structure of the nuclear ring from Xenopus laevis nuclear pore complex
Authors: Huang Gaoxingyu , Zhan Xiechao , Zeng Chao , Zhu Xuechen , Liang Ke , Zhao Yanyu , Wang Pan , Wang Qifan , Zhou Qiang , Tao Qinghua , Liu Minhao , Lei Jianlin , Yan Chuangye , Shi Yigong
Published: February 2022

Nuclear pore complex (NPC) shuttles cargo across the nuclear envelope. Here we present single-particle cryo-EM structure of the nuclear ring (NR) subunit from Xenopus laevis NPC at an average resolution of 5.6 Å. The NR subunit comprises two 10-membered Y complexes, each with the nucleoporin ELYS closely associating with Nup160 and Nup37 of the long arm. Unlike the cytoplasmic ring (CR) or inner ring (IR), the NR subunit contains only one molecule each of Nup205 and Nup93. Nup205 binds both arms of the Y complexes and interacts with the stem of inner Y complex from the neighboring subunit. Nup93 connects the stems of inner and outer Y complexes within the same NR subunit, and places its N-terminal extended helix into the axial groove of Nup205 from the neighboring subunit. Together with other structural information, we have generated a composite atomic model of the central ring scaffold that includes the NR, IR, and CR. The IR is connected to the two outer rings mainly through Nup155. This model facilitates functional understanding of vertebrate NPC.
Antiferromagnetic excitonic insulator state in Sr3Ir2O7
Authors: Mazzone D. G. , Shen Y. , Suwa H. , Fabbris G. , Yang J. , Zhang S.-S. , Miao H. , Sears J. , Jia Ke , Shi Y. G. , Upton M. H. , Casa D. M. , Liu X. , Liu Jian , Batista C. D. , Dean M. P. M.
Published: February 2022

Excitonic insulators are usually considered to form via the condensation of a soft charge mode of bound electron-hole pairs. This, however, presumes that the soft exciton is of spin-singlet character. Early theoretical considerations have also predicted a very distinct scenario, in which the condensation of magnetic excitons results in an antiferromagnetic excitonic insulator state. Here we report resonant inelastic x-ray scattering (RIXS) measurements of Sr3Ir2O7. By isolating the longitudinal component of the spectra, we identify a magnetic mode that is well-defined at the magnetic and structural Brillouin zone centers, but which merges with the electronic continuum in between these high symmetry points and which decays upon heating concurrent with a decrease in the material’s resistivity. We show that a bilayer Hubbard model, in which electron-hole pairs are bound by exchange interactions, consistently explains all the electronic and magnetic properties of Sr3Ir2O7 indicating that this material is a realization of the long-predicted antiferromagnetic excitonic insulator phase.
Recovery coupling in multilayer networks
Authors: Danziger Michael M. , Barabási Albert-László
Published: February 2022

The increased complexity of infrastructure systems has resulted in critical interdependencies between multiple networks—communication systems require electricity, while the normal functioning of the power grid relies on communication systems. These interdependencies have inspired an extensive literature on coupled multilayer networks, assuming a hard interdependence, where a component failure in one network causes failures in the other network, resulting in a cascade of failures across multiple systems. While empirical evidence of such hard failures is limited, the repair and recovery of a network requires resources typically supplied by other networks, resulting in documented interdependencies induced by the recovery process. In this work, we explore recovery coupling, capturing the dependence of the recovery of one system on the instantaneous functional state of another system. If the support networks are not functional, recovery will be slowed. Here we collected data on the recovery time of millions of power grid failures, finding evidence of universal nonlinear behavior in recovery following large perturbations. We develop a theoretical framework to address recovery coupling, predicting quantitative signatures different from the multilayer cascading failures. We then rely on controlled natural experiments to separate the role of recovery coupling from other effects like resource limitations, offering direct evidence of how recovery coupling affects a system’s functionality.
Photodissociation of particulate nitrate as a source of daytime tropospheric Cl2
Authors: Peng Xiang , Wang Tao , Wang Weihao , Ravishankara A. R. , George Christian , Xia Men , Cai Min , Li Qinyi , Salvador Christian Mark , Lau Chiho , Lyu Xiaopu , Poon Chun Nan , Mellouki Abdelwahid , Mu Yujing , Hallquist Mattias , Saiz-Lopez Alfonso , Guo Hai , Herrmann Hartmut , Yu Chuan , Dai Jianing , Wang Yanan , Wang Xinke , Yu Alfred , Leung Kenneth , Lee Shuncheng , Chen Jianmin
Published: February 2022

Chlorine atoms (Cl) are highly reactive and can strongly influence the abundances of climate and air quality-relevant trace gases. Despite extensive research on molecular chlorine (Cl2), a Cl precursor, in the polar atmosphere, its sources in other regions are still poorly understood. Here we report the daytime Cl2 concentrations of up to 1 ppbv observed in a coastal area of Hong Kong, revealing a large daytime source of Cl2 (2.7 pptv s−1 at noon). Field and laboratory experiments indicate that photodissociation of particulate nitrate by sunlight under acidic conditions (pH < 3.0) can activate chloride and account for the observed daytime Cl2 production. The high Cl2 concentrations significantly increased atmospheric oxidation. Given the ubiquitous existence of chloride, nitrate, and acidic aerosols, we propose that nitrate photolysis is a significant daytime chlorine source globally. This so far unaccounted for source of chlorine can have substantial impacts on atmospheric chemistry.
Waveguide coupled III-V photodiodes monolithically integrated on Si
Authors: Wen Pengyan , Tiwari Preksha , Mauthe Svenja , Schmid Heinz , Sousa Marilyne , Scherrer Markus , Baumann Michael , Bitachon Bertold Ian , Leuthold Juerg , Gotsmann Bernd , Moselund Kirsten E.
Published: February 2022

The seamless integration of III-V nanostructures on silicon is a long-standing goal and an important step towards integrated optical links. In the present work, we demonstrate scaled and waveguide coupled III-V photodiodes monolithically integrated on Si, implemented as InP/In0.5Ga0.5As/InP p-i-n heterostructures. The waveguide coupled devices show a dark current down to 0.048 A/cm2at −1 V and a responsivity up to 0.2 A/W at −2 V. Using grating couplers centered around 1320 nm, we demonstrate high-speed detection with a cutoff frequency f3dBexceeding 70 GHz and data reception at 50 GBd with OOK and 4PAM. When operated in forward bias as a light emitting diode, the devices emit light centered at 1550 nm. Furthermore, we also investigate the self-heating of the devices using scanning thermal microscopy and find a temperature increase of only ~15 K during the device operation as emitter, in accordance with thermal simulation results.
A late-stage assembly checkpoint of the human mitochondrial ribosome large subunit
Authors: Rebelo-Guiomar Pedro , Pellegrino Simone , Dent Kyle C. , Sas-Chen Aldema , Miller-Fleming Leonor , Garone Caterina , Van Haute Lindsey , Rogan Jack F. , Dinan Adam , Firth Andrew E. , Andrews Byron , Whitworth Alexander J. , Schwartz Schraga , Warren Alan J. , Minczuk Michal
Published: February 2022

Many cellular processes, including ribosome biogenesis, are regulated through post-transcriptional RNA modifications. Here, a genome-wide analysis of the human mitochondrial transcriptome shows that 2’-O-methylation is limited to residues of the mitoribosomal large subunit (mtLSU) 16S mt-rRNA, introduced by MRM1, MRM2 and MRM3, with the modifications installed by the latter two proteins being interdependent. MRM2 controls mitochondrial respiration by regulating mitoribosome biogenesis. In its absence, mtLSU particles (visualized by cryo-EM at the resolution of 2.6 Å) present disordered RNA domains, partial occupancy of bL36m and bound MALSU1:L0R8F8:mtACP anti-association module, allowing five mtLSU biogenesis intermediates with different intersubunit interface configurations to be placed along the assembly pathway. However, mitoribosome biogenesis does not depend on the methyltransferase activity of MRM2. Disruption of the MRM2Drosophila melanogasterorthologue leads to mitochondria-related developmental arrest. This work identifies a key checkpoint during mtLSU assembly, essential to maintain mitochondrial homeostasis.
Facet-dependent electrooxidation of propylene into propylene oxide over Ag3PO4 crystals
Authors: Ke Jingwen , Zhao Jiankang , Chi Mingfang , Wang Menglin , Kong Xiangdong , Chang Qixuan , Zhou Weiran , Long Chengxuan , Zeng Jie , Geng Zhigang
Published: February 2022

The electrooxidation of propylene into propylene oxide under ambient conditions represents an attractive approach toward propylene oxide. However, this process suffers from a low yield rate over reported electrocatalysts. In this work, we develop an efficient electrocatalyst of Ag3PO4 for the electrooxidation of propylene into propylene oxide. The Ag3PO4 cubes with (100) facets exhibit the highest yield rate of 5.3 gPO m−2 h−1 at 2.4 V versus reversible hydrogen electrode, which is 1.6 and 2.5 times higher than those over Ag3PO4 rhombic dodecahedra with (110) facets and tetrahedra with (111) facets, respectively. The theoretical calculations reveal that the largest polarization of propylene on Ag3PO4 (100) facets is beneficial to break the symmetric π bonding and facilitate the formation of C-O bond. Meanwhile, Ag3PO4(100) facets exhibit the lowest adsorption energies of *C3H6 and *OH, inducing the lowest energy barrier of the rate-determining step and thus accounting for the highest catalytic performance.
T-cell dysfunction in the glioblastoma microenvironment is mediated by myeloid cells releasing interleukin-10
Authors: Ravi Vidhya M. , Neidert Nicolas , Will Paulina , Joseph Kevin , Maier Julian P. , Kückelhaus Jan , Vollmer Lea , Goeldner Jonathan M. , Behringer Simon P. , Scherer Florian , Boerries Melanie , Follo Marie , Weiss Tobias , Delev Daniel , Kernbach Julius , Franco Pamela , Schallner Nils , Dierks Christine , Carro Maria Stella , Hofmann Ulrich G. , Fung Christian , Sankowski Roman , Prinz Marco , Beck Jürgen , Salié Henrike , Bengsch Bertram , Schnell Oliver , Heiland Dieter Henrik
Published: February 2022

Despite recent advances in cancer immunotherapy, certain tumor types, such as Glioblastomas, are highly resistant due to their tumor microenvironment disabling the anti-tumor immune response. Here we show, by applying an in-silico multidimensional model integrating spatially resolved and single-cell gene expression data of 45,615 immune cells from 12 tumor samples, that a subset of Interleukin-10-releasing HMOX1+ myeloid cells, spatially localizing to mesenchymal-like tumor regions, drive T-cell exhaustion and thus contribute to the immunosuppressive tumor microenvironment. These findings are validated using a human ex-vivo neocortical glioblastoma model inoculated with patient derived peripheral T-cells to simulate the immune compartment. This model recapitulates the dysfunctional transformation of tumor infiltrating T-cells. Inhibition of the JAK/STAT pathway rescues T-cell functionality both in our model and in-vivo, providing further evidence of IL-10 release being an important driving force of tumor immune escape. Our results thus show that integrative modelling of single cell and spatial transcriptomics data is a valuable tool to interrogate the tumor immune microenvironment and might contribute to the development of successful immunotherapies.
Genome-wide functional screens enable the prediction of high activity CRISPR-Cas9 and -Cas12a guides in Yarrowia lipolytica
Authors: Baisya Dipankar , Ramesh Adithya , Schwartz Cory , Lonardi Stefano , Wheeldon Ian
Published: February 2022

Genome-wide functional genetic screens have been successful in discovering genotype-phenotype relationships and in engineering new phenotypes. While broadly applied in mammalian cell lines and in E. coli, use in non-conventional microorganisms has been limited, in part, due to the inability to accurately design high activity CRISPR guides in such species. Here, we develop an experimental-computational approach to sgRNA design that is specific to an organism of choice, in this case the oleaginous yeast Yarrowia lipolytica. A negative selection screen in the absence of non-homologous end-joining, the dominant DNA repair mechanism, was used to generate single guide RNA (sgRNA) activity profiles for both SpCas9 and LbCas12a. This genome-wide data served as input to a deep learning algorithm, DeepGuide, that is able to accurately predict guide activity. DeepGuide uses unsupervised learning to obtain a compressed representation of the genome, followed by supervised learning to map sgRNA sequence, genomic context, and epigenetic features with guide activity. Experimental validation, both genome-wide and with a subset of selected genes, confirms DeepGuide’s ability to accurately predict high activity sgRNAs. DeepGuide provides an organism specific predictor of CRISPR guide activity that with retraining could be applied to other fungal species, prokaryotes, and other non-conventional organisms.
Density of states prediction for materials discovery via contrastive learning from probabilistic embeddings
Authors: Kong Shufeng , Ricci Francesco , Guevarra Dan , Neaton Jeffrey B. , Gomes Carla P. , Gregoire John M.
Published: February 2022

Machine learning for materials discovery has largely focused on predicting an individual scalar rather than multiple related properties, where spectral properties are an important example. Fundamental spectral properties include the phonon density of states (phDOS) and the electronic density of states (eDOS), which individually or collectively are the origins of a breadth of materials observables and functions. Building upon the success of graph attention networks for encoding crystalline materials, we introduce a probabilistic embedding generator specifically tailored to the prediction of spectral properties. Coupled with supervised contrastive learning, our materials-to-spectrum (Mat2Spec) model outperforms state-of-the-art methods for predicting ab initio phDOS and eDOS for crystalline materials. We demonstrate Mat2Spec’s ability to identify eDOS gaps below the Fermi energy, validating predictions with ab initio calculations and thereby discovering candidate thermoelectrics and transparent conductors. Mat2Spec is an exemplar framework for predicting spectral properties of materials via strategically incorporated machine learning techniques.
Development and characterization of functional antibodies targeting NMDA receptors
Authors: Tajima Nami , Simorowski Noriko , Yovanno Remy A. , Regan Michael C. , Michalski Kevin , Gómez Ricardo , Lau Albert Y. , Furukawa Hiro
Published: February 2022

N-methyl-D-aspartate receptors (NMDARs) are critically involved in basic brain functions and neurodegeneration as well as tumor invasiveness. Targeting specific subtypes of NMDARs with distinct activities has been considered an effective therapeutic strategy for neurological disorders and diseases. However, complete elimination of off-target effects of small chemical compounds has been challenging and thus, there is a need to explore alternative strategies for targeting NMDAR subtypes. Here we report identification of a functional antibody that specifically targets the GluN1-GluN2B NMDAR subtype and allosterically down-regulates ion channel activity as assessed by electrophysiology. Through biochemical analysis, x-ray crystallography, single-particle electron cryomicroscopy, and molecular dynamics simulations, we show that this inhibitory antibody recognizes the amino terminal domain of the GluN2B subunit and increases the population of the non-active conformational state. The current study demonstrates that antibodies may serve as specific reagents to regulate NMDAR functions for basic research and therapeutic objectives.
Functionally selective signaling and broad metabolic benefits by novel insulin receptor partial agonists
Authors: Wu Margaret , Carballo-Jane Ester , Zhou Haihong , Zafian Peter , Dai Ge , Liu Mindy , Lao Julie , Kelly Terri , Shao Dan , Gorski Judith , Pissarnitski Dmitri , Kekec Ahmet , Chen Ying , Previs Stephen F. , Scapin Giovanna , Gomez-Llorente Yacob , Hollingsworth Scott A. , Yan Lin , Feng Danqing , Huo Pei , Walford Geoffrey , Erion Mark D. , Kelley David E. , Lin Songnian , Mu James
Published: February 2022

Insulin analogs have been developed to treat diabetes with focus primarily on improving the time action profile without affecting ligand-receptor interaction or functional selectivity. As a result, inherent liabilities (e.g. hypoglycemia) of injectable insulin continue to limit the true therapeutic potential of related agents. Insulin dimers were synthesized to investigate whether partial agonism of the insulin receptor (IR) tyrosine kinase is achievable, and to explore the potential for tissue-selective systemic insulin pharmacology. The insulin dimers induced distinct IR conformational changes compared to native monomeric insulin and substrate phosphorylation assays demonstrated partial agonism. Structurally distinct dimers with differences in conjugation sites and linkers were prepared to deliver desirable IR partial agonist (IRPA). Systemic infusions of a B29-B29 dimer in vivo revealed sharp differences compared to native insulin. Suppression of hepatic glucose production and lipolysis were like that attained with regular insulin, albeit with a distinctly shallower dose-response. In contrast, there was highly attenuated stimulation of glucose uptake into muscle. Mechanistic studies indicated that IRPAs exploit tissue differences in receptor density and have additional distinctions pertaining to drug clearance and distribution. The hepato-adipose selective action of IRPAs is a potentially safer approach for treatment of diabetes.
Spatiotemporal dynamics of clonal selection and diversification in normal endometrial epithelium
Authors: Yamaguchi Manako , Nakaoka Hirofumi , Suda Kazuaki , Yoshihara Kosuke , Ishiguro Tatsuya , Yachida Nozomi , Saito Kyota , Ueda Haruka , Sugino Kentaro , Mori Yutaro , Yamawaki Kaoru , Tamura Ryo , Revathidevi Sundaramoorthy , Motoyama Teiichi , Tainaka Kazuki , Verhaak Roel G. W. , Inoue Ituro , Enomoto Takayuki
Published: February 2022

It has become evident that somatic mutations in cancer-associated genes accumulate in the normal endometrium, but spatiotemporal understanding of the evolution and expansion of mutant clones is limited. To elucidate the timing and mechanism of the clonal expansion of somatic mutations in cancer-associated genes in the normal endometrium, we sequence 1311 endometrial glands from 37 women. By collecting endometrial glands from different parts of the endometrium, we show that multiple glands with the same somatic mutations occupy substantial areas of the endometrium. We demonstrate that “rhizome structures”, in which the basal glands run horizontally along the muscular layer and multiple vertical glands rise from the basal gland, originate from the same ancestral clone. Moreover, mutant clones detected in the vertical glands diversify by acquiring additional mutations. These results suggest that clonal expansions through the rhizome structures are involved in the mechanism by which mutant clones extend their territories. Furthermore, we show clonal expansions and copy neutral loss-of-heterozygosity events occur early in life, suggesting such events can be tolerated many years in the normal endometrium. Our results of the evolutionary dynamics of mutant clones in the human endometrium will lead to a better understanding of the mechanisms of endometrial regeneration during the menstrual cycle and the development of therapies for the prevention and treatment of endometrium-related diseases.
In-situ transfer vat photopolymerization for transparent microfluidic device fabrication
Authors: Xu Yang , Qi Fangjie , Mao Huachao , Li Songwei , Zhu Yizhen , Gong Jingwen , Wang Lu , Malmstadt Noah , Chen Yong
Published: February 2022

While vat photopolymerization has many advantages over soft lithography in fabricating microfluidic devices, including efficiency and shape complexity, it has difficulty achieving well-controlled micrometer-sized (smaller than 100 μm) channels in the layer building direction. The considerable light penetration depth of transparent resin leads to over-curing that inevitably cures the residual resin inside flow channels, causing clogs. In this paper, a 3D printing process — in-situ transfer vat photopolymerization is reported to solve this critical over-curing issue in fabricating microfluidic devices. We demonstrate microchannels with highZ-resolution (within 10 μm level) and high accuracy (within 2 μm level) using a general method with no requirements on liquid resins such as reduced transparency nor leads to a reduced fabrication speed. Compared with all other vat photopolymerization-based techniques specialized for microfluidic channel fabrication, our universal approach is compatible with commonly used 405 nm light sources and commercial photocurable resins. The process has been verified by multifunctional devices, including 3D serpentine microfluidic channels, microfluidic valves, and particle sorting devices. This work solves a critical barrier in 3D printing microfluidic channels using the high-speed vat photopolymerization process and broadens the material options. It also significantly advances vat photopolymerization’s use in applications requiring small gaps with high accuracy in theZ-direction.
Recurrent chromosome reshuffling and the evolution of neo-sex chromosomes in parrots
Authors: Huang Zhen , De O. Furo Ivanete , Liu Jing , Peona Valentina , Gomes Anderson J. B. , Cen Wan , Huang Hao , Zhang Yanding , Chen Duo , Xue Ting , Zhang Qiujin , Yue Zhicao , Wang Quanxi , Yu Lingyu , Chen Youling , Suh Alexander , de Oliveira Edivaldo H. C. , Xu Luohao
Published: February 2022

The karyotype of most birds has remained considerably stable during more than 100 million years’ evolution, except for some groups, such as parrots. The evolutionary processes and underlying genetic mechanism of chromosomal rearrangements in parrots, however, are poorly understood. Here, using chromosome-level assemblies of four parrot genomes, we uncover frequent chromosome fusions and fissions, with most of them occurring independently among lineages. The increased activities of chromosomal rearrangements in parrots are likely associated with parrot-specific loss of two genes, ALC1 and PARP3, that have known functions in the repair of double-strand breaks and maintenance of genome stability. We further find that the fusion of the ZW sex chromosomes and chromosome 11 has created a pair of neo-sex chromosomes in the ancestor of parrots, and the chromosome 25 has been further added to the sex chromosomes in monk parakeet. Together, the combination of our genomic and cytogenetic analyses characterizes the complex evolutionary history of chromosomal rearrangements and sex chromosomes in parrots.
RIF1-ASF1-mediated high-order chromatin structure safeguards genome integrity
Authors: Feng Sumin , Ma Sai , Li Kejiao , Gao Shengxian , Ning Shaokai , Shang Jinfeng , Guo Ruiyuan , Chen Yingying , Blumenfeld Britny , Simon Itamar , Li Qing , Guo Rong , Xu Dongyi
Published: February 2022

The 53BP1-RIF1 pathway antagonizes resection of DNA broken ends and confers PARP inhibitor sensitivity on BRCA1-mutated tumors. However, it is unclear how this pathway suppresses initiation of resection. Here, we identify ASF1 as a partner of RIF1 via an interacting manner similar to its interactions with histone chaperones CAF-1 and HIRA. ASF1 is recruited to distal chromatin flanking DNA breaks by 53BP1-RIF1 and promotes non-homologous end joining (NHEJ) using its histone chaperone activity. Epistasis analysis shows that ASF1 acts in the same NHEJ pathway as RIF1, but via a parallel pathway with the shieldin complex, which suppresses resection after initiation. Moreover, defects in end resection and homologous recombination (HR) in BRCA1-deficient cells are largely suppressed by ASF1 deficiency. Mechanistically, ASF1 compacts adjacent chromatin by heterochromatinization to protect broken DNA ends from BRCA1-mediated resection. Taken together, our findings identify a RIF1-ASF1 histone chaperone complex that promotes changes in high-order chromatin structure to stimulate the NHEJ pathway for DSB repair.
Stroke induces disease-specific myeloid cells in the brain parenchyma and pia
Authors: Beuker Carolin , Schafflick David , Strecker Jan-Kolja , Heming Michael , Li Xiaolin , Wolbert Jolien , Schmidt-Pogoda Antje , Thomas Christian , Kuhlmann Tanja , Aranda-Pardos Irene , A-Gonzalez Noelia , Kumar Praveen Ashok , Werner Yves , Kilic Ertugrul , Hermann Dirk M. , Wiendl Heinz , Stumm Ralf , Meyer zu Hörste Gerd , Minnerup Jens
Published: February 2022

Inflammation triggers secondary brain damage after stroke. The meninges and other CNS border compartments serve as invasion sites for leukocyte influx into the brain thus promoting tissue damage after stroke. However, the post-ischemic immune response of border compartments compared to brain parenchyma remains poorly characterized. Here, we deeply characterize tissue-resident leukocytes in meninges and brain parenchyma and discover that leukocytes respond differently to stroke depending on their site of residence. We thereby discover a unique phenotype of myeloid cells exclusive to the brain after stroke. These stroke-associated myeloid cells partially resemble neurodegenerative disease-associated microglia. They are mainly of resident microglial origin, partially conserved in humans and exhibit a lipid-phagocytosing phenotype. Blocking markers specific for these cells partially ameliorates stroke outcome thus providing a potential therapeutic target. The injury-response of myeloid cells in the CNS is thus compartmentalized, adjusted to the type of injury and may represent a therapeutic target.
Heterotypic interactions drive antibody synergy against a malaria vaccine candidate
Authors: Ragotte Robert J. , Pulido David , Lias Amelia M. , Quinkert Doris , Alanine Daniel G. W. , Jamwal Abhishek , Davies Hannah , Nacer Adéla , Lowe Edward D. , Grime Geoffrey W. , Illingworth Joseph J. , Donat Robert F. , Garman Elspeth F. , Bowyer Paul W. , Higgins Matthew K. , Draper Simon J.
Published: February 2022

Understanding mechanisms of antibody synergy is important for vaccine design and antibody cocktail development. Examples of synergy between antibodies are well-documented, but the mechanisms underlying these relationships often remain poorly understood. The leading blood-stage malaria vaccine candidate, CyRPA, is essential for invasion of Plasmodium falciparum into human erythrocytes. Here we present a panel of anti-CyRPA monoclonal antibodies that strongly inhibit parasite growth in in vitro assays. Structural studies show that growth-inhibitory antibodies bind epitopes on a single face of CyRPA. We also show that pairs of non-competing inhibitory antibodies have strongly synergistic growth-inhibitory activity. These antibodies bind to neighbouring epitopes on CyRPA and form lateral, heterotypic interactions which slow antibody dissociation. We predict that such heterotypic interactions will be a feature of many immune responses. Immunogens which elicit such synergistic antibody mixtures could increase the potency of vaccine-elicited responses to provide robust and long-lived immunity against challenging disease targets.
Chemical reversible crosslinking enables measurement of RNA 3D distances and alternative conformations in cells
Authors: Van Damme Ryan , Li Kongpan , Zhang Minjie , Bai Jianhui , Lee Wilson H. , Yesselman Joseph D. , Lu Zhipeng , Velema Willem A.
Published: February 2022

Three-dimensional (3D) structures dictate the functions of RNA molecules in a wide variety of biological processes. However, direct determination of RNA 3D structures in vivo is difficult due to their large sizes, conformational heterogeneity, and dynamics. Here we present a method, Spatial 2′-Hydroxyl Acylation Reversible Crosslinking (SHARC), which uses chemical crosslinkers of defined lengths to measure distances between nucleotides in cellular RNA. Integrating crosslinking, exonuclease (exo) trimming, proximity ligation, and high throughput sequencing, SHARC enables transcriptome-wide tertiary structure contact maps at high accuracy and precision, revealing heterogeneous RNA structures and interactions. SHARC data provide constraints that improves Rosetta-based RNA 3D structure modeling at near-nanometer resolution. Integrating SHARC-exo with other crosslinking-based methods, we discover compact folding of the 7SK RNA, a critical regulator of transcriptional elongation. These results establish a strategy for measuring RNA 3D distances and alternative conformations in their native cellular context.
A cattle graph genome incorporating global breed diversity
Authors: Talenti A. , Powell J. , Hemmink J. D. , Cook E. A. J. , Wragg D. , Jayaraman S. , Paxton E. , Ezeasor C. , Obishakin E. T. , Agusi E. R. , Tijjani A. , Amanyire W. , Muhanguzi D. , Marshall K. , Fisch A. , Ferreira B. R. , Qasim A. , Chaudhry U. , Wiener P. , Toye P. , Morrison L. J. , Connelley T. , Prendergast J. G. D.
Published: February 2022

Despite only 8% of cattle being found in Europe, European breeds dominate current genetic resources. This adversely impacts cattle research in other important global cattle breeds, especially those from Africa for which genomic resources are particularly limited, despite their disproportionate importance to the continent’s economies. To mitigate this issue, we have generated assemblies of African breeds, which have been integrated with genomic data for 294 diverse cattle into a graph genome that incorporates global cattle diversity. We illustrate how this more representative reference assembly contains an extra 116.1 Mb (4.2%) of sequence absent from the current Hereford sequence and consequently inaccessible to current studies. We further demonstrate how using this graph genome increases read mapping rates, reduces allelic biases and improves the agreement of structural variant calling with independent optical mapping data. Consequently, we present an improved, more representative, reference assembly that will improve global cattle research.
Ammonia pools in zeolites for direct fabrication of catalytic centers
Authors: Yao Jie , He Yingluo , Zeng Yan , Feng Xiaobo , Fan Jiaqi , Komiyama Shoya , Yong Xiaojing , Zhang Wei , Zhao Tiejian , Guo Zhongshan , Peng Xiaobo , Yang Guohui , Tsubaki Noritatsu
Published: February 2022

Reduction process is a key step to fabricate metal-zeolite catalysts in catalytic synthesis. However, because of the strong interaction force, metal oxides in zeolites are very difficult to be reduced. Existing reduction technologies are always energy-intensive, and inevitably cause the agglomeration of metallic particles in metal-zeolite catalysts or destroy zeolite structure in severe cases. Herein, we disclose that zeolites after ion exchange of ammonium have an interesting and unexpected self-reducing feature. It can accurately control the reduction of metal-zeolite catalysts, via in situ ammonia production from ‘ammonia pools’, meanwhile, restrains the growth of the size of metals. Such new and reliable ammonia pool effect is not influenced by topological structures of zeolites, and works well on reducible metals. The ammonia pool effect is ultimately attributed to an atmosphere-confined self-regulation mechanism. This methodology will significantly promote the fabrication for metal-zeolite catalysts, and further facilitate design and development of low-cost and high-activity catalysts.
TrkB agonist antibody ameliorates fertility deficits in aged and cyclophosphamide-induced premature ovarian failure model mice
Authors: Qin Xunsi , Zhao Yue , Zhang Tianyi , Yin Chenghong , Qiao Jie , Guo Wei , Lu Bai
Published: February 2022

Premature ovarian failure (POF) is a leading cause of women’s infertility without effective treatment. Here we show that intravenous injection of Ab4B19, an agonistic antibody for the BDNF receptor TrkB, penetrates into ovarian follicles, activates TrkB signaling, and promotes ovary development. In both natural aging and cyclophosphamide-induced POF models, treatment with Ab4B19 completely reverses the reduction of pre-antral and antral follicles, and normalizes gonadal hormone. Ab4B19 also attenuates gonadotoxicity and inhibits apoptosis in cyclophosphamide-induced POF ovaries. Further, treatment with Ab4B19, but not BDNF, restores the number and quality of oocytes and enhances fertility. In human, BDNF levels are high in granulosa cells and TrkB levels increase in oocytes as they mature. Moreover, BDNF expression is down-regulated in follicles of aged women, and Ab4B19 activates TrkB signaling in human ovary tissue ex vivo. These results identify TrkB as a potential target for POF with differentiated mechanisms, and confirms superiority of TrkB activating antibody over BDNF as therapeutic agents.