bluuebunny/crossref_metadata_2025 huggingface dataset:
Super-resolution microscopy enabled by high-efficiency surface-migration emission depletion
Authors: Pu Rui , Zhan Qiuqiang , Peng Xingyun , Liu Siying , Guo Xin , Liang Liangliang , Qin Xian , Zhao Ziqing Winston , Liu Xiaogang
Published: November 2022

Nonlinear depletion of fluorescence states by stimulated emission constitutes the basis of stimulated emission depletion (STED) microscopy. Despite significant efforts over the past decade, achieving super-resolution at low saturation intensities by STED remains a major technical challenge. By harnessing the surface quenching effect in NaGdF4:Yb/Tm nanocrystals, we report here high-efficiency emission depletion through surface migration. Using a dual-beam, continuous-wave laser manipulation scheme (975-nm excitation and 730-nm de-excitation), we achieved an emission depletion efficiency of over 95% and a low saturation intensity of 18.3 kW cm−2. Emission depletion by surface migration through gadolinium sublattices enables super-resolution imaging with sub-20 nm lateral resolution. Our approach circumvents the fundamental limitation of high-intensity STED microscopy, providing autofluorescence-free, re-excitation-background-free imaging with a saturation intensity over three orders of magnitude lower than conventional fluorophores. We also demonstrated super-resolution imaging of actin filaments in Hela cells labeled with 8-nm nanoparticles. Combined with the highly photostable lanthanide luminescence, surface-migration emission depletion (SMED) could provide a powerful mechanism for low-power, super-resolution imaging or biological tracking as well as super-resolved optical sensing/writing and lithography.
Retinal chromophore charge delocalization and confinement explain the extreme photophysics of Neorhodopsin
Authors: Palombo Riccardo , Barneschi Leonardo , Pedraza-González Laura , Padula Daniele , Schapiro Igor , Olivucci Massimo
Published: November 2022

The understanding of how the rhodopsin sequence can be modified to exactly modulate the spectroscopic properties of its retinal chromophore, is a prerequisite for the rational design of more effective optogenetic tools. One key problem is that of establishing the rules to be satisfied for achieving highly fluorescent rhodopsins with a near infrared absorption. In the present paper we use multi-configurational quantum chemistry to construct a computer model of a recently discovered natural rhodopsin, Neorhodopsin, displaying exactly such properties. We show that the model, that successfully replicates the relevant experimental observables, unveils a geometrical and electronic structure of the chromophore featuring a highly diffuse charge distribution along its conjugated chain. The same model reveals that a charge confinement process occurring along the chromophore excited state isomerization coordinate, is the primary cause of the observed fluorescence enhancement.
The contribution of common and rare genetic variants to variation in metabolic traits in 288,137 East Asians
Authors: Kim Young Jin , Moon Sanghoon , Hwang Mi Yeong , Han Sohee , Jang Hye-Mi , Kong Jinhwa , Shin Dong Mun , Yoon Kyungheon , Kim Sung Min , Lee Jong-Eun , Mahajan Anubha , Park Hyun-Young , McCarthy Mark I. , Cho Yoon Shin , Kim Bong-Jo
Published: November 2022

Metabolic traits are heritable phenotypes widely-used in assessing the risk of various diseases. We conduct a genome-wide association analysis (GWAS) of nine metabolic traits (including glycemic, lipid, liver enzyme levels) in 125,872 Korean subjects genotyped with the Korea Biobank Array. Following meta-analysis with GWAS from Biobank Japan identify 144 novel signals (MAF ≥ 1%), of which 57.0% are replicated in UK Biobank. Additionally, we discover 66 rare (MAF < 1%) variants, 94.4% of them co-incident to common loci, adding to allelic series. Although rare variants have limited contribution to overall trait variance, these lead, in carriers, substantial loss of predictive accuracy from polygenic predictions of disease risk from common variant alone. We capture groups with up to 16-fold variation in type 2 diabetes (T2D) prevalence by integration of genetic risk scores of fasting plasma glucose and T2D and the I349F rare protective variant. This study highlights the need to consider the joint contribution of both common and rare variants on inherited risk of metabolic traits and related diseases.
Atomic-level structural responsiveness to environmental conditions from 3D electron diffraction
Authors: Ling Yang , Sun Tu , Guo Linshuo , Si Xiaomeng , Jiang Yilan , Zhang Qing , Chen Zhaoxi , Terasaki Osamu , Ma Yanhang
Published: November 2022

Electron microscopy has been widely used in the structural analysis of proteins, pharmaceutical products, and various functional materials in the past decades. However, one fact is often overlooked that the crystal structure might be sensitive to external environments and response manners, which will bring uncertainty to the structure determination and structure-property correlation. Here, we report the atomic-level ab initio structure determinations of microcrystals by combining 3D electron diffraction (3D ED) and environmental transmission electron microscope (TEM). Environmental conditions, including cryo, heating, gas and liquid, have been successfully achieved using in situ holders to reveal the simuli-responsive structures of crystals. Remarkable structural changes have been directly resolved by 3D ED in one flexible metal-organic framework, MIL-53, owing to the response of framework to pressures, temperatures, guest molecules, etc.
Amplification of integrated microscopic motions of high-density [2]rotaxanes in mechanically interlocked networks
Authors: Yang Xue , Cheng Lin , Zhang Zhaoming , Zhao Jun , Bai Ruixue , Guo Zhewen , Yu Wei , Yan Xuzhou
Published: November 2022

Integrating individual microscopic motion to perform tasks in macroscopic sale is common in living organisms. However, developing artificial materials in which molecular-level motions could be amplified to behave macroscopically is still challenging. Herein, we present a class of mechanically interlocked networks (MINs) carrying densely rotaxanated backbones as a model system to understand macroscopic mechanical properties stemmed from the integration and amplification of intramolecular motion of the embedded [2]rotaxane motifs. On the one hand, the motion of mechanical bonds introduces the original dangling chains into the network, and the synergy of numerous such microscopic motions leads to an expansion of entire network, imparting good stretchability and puncture resistance to the MINs. On the other hand, the dissociation of host−guest recognition and subsequent sliding motion represent a peculiar energy dissipation pathway, whose integration and amplification result in the bulk materials with favorable toughness and damping capacity. Thereinto, we develop a continuous stress-relaxation method to elucidate the microscopic motion of [2]rotaxane units, which contributes to the understanding of the relationship between cumulative microscopic motions and amplified macroscopic mechanical performance.
Defect free strain relaxation of microcrystals on mesoporous patterned silicon
Authors: Heintz Alexandre , Ilahi Bouraoui , Pofelski Alexandre , Botton Gianluigi , Patriarche Gilles , Barzaghi Andrea , Fafard Simon , Arès Richard , Isella Giovanni , Boucherif Abderraouf
Published: November 2022

A perfectly compliant substrate would allow the monolithic integration of high-quality semiconductor materials such as Ge and III-V on Silicon (Si) substrate, enabling novel functionalities on the well-established low-cost Si technology platform. Here, we demonstrate a compliant Si substrate allowing defect-free epitaxial growth of lattice mismatched materials. The method is based on the deep patterning of the Si substrate to form micrometer-scale pillars and subsequent electrochemical porosification. The investigation of the epitaxial Ge crystalline quality by X-ray diffraction, transmission electron microscopy and etch-pits counting demonstrates the full elastic relaxation of defect-free microcrystals. The achievement of dislocation free heteroepitaxy relies on the interplay between elastic deformation of the porous micropillars, set under stress by the lattice mismatch between Ge and Si, and on the diffusion of Ge into the mesoporous patterned substrate attenuating the mismatch strain at the Ge/Si interface.
Water-stable porous Al24 Archimedean solids for removal of trace iodine
Authors: Liu Ya-Jie , Sun Yi-Fan , Shen Si-Hao , Wang San-Tai , Liu Zhuang-Hua , Fang Wei-Hui , Wright Dominic S. , Zhang Jian
Published: November 2022

In this paper, we report a unique type of core-shell crystalline material that combines an inorganic zeolitic cage structure with a macrocyclic host arrangement and that can remove trace levels of iodine from water effectively. These unique assemblies are made up of an inorganic Archimedean truncatedhexahedron (tcu) polyhedron in the kernel which possesses six calixarene-like shell cavities. The cages have good adaptability to guests and can be assembled into a series of supramolecular structures in the crystalline state with different lattice pore shapes. Due to the unique core-shell porous structures, the compounds are not only stable in organic solvents but also in water. The characteristics of the cages enable rapid iodine capture from low concentration aqueous I2/KI solutions (down to 4 ppm concentration). We have studied the detailed process and mechanism of iodine capture and aggregation at the molecular level. The facile synthesis, considerable adsorption capacity, recyclability, and β- and γ-radiation resistance of the cages should make these materials suitable for the extraction of iodine from aqueous effluent streams (most obviously, radioactive iodide produced by atomic power generation).
A genetically encoded fluorescent biosensor for detecting itaconate with subcellular resolution in living macrophages
Authors: Sun Pengkai , Zhang Zhenxing , Wang Bin , Liu Caiyun , Chen Chao , Liu Ping , Li Xinjian
Published: November 2022

Itaconate is a newly discovered endogenous metabolite promoting an anti-inflammatory program during innate immune response, but the precise mechanisms underlying its effect remains poorly understood owing primarily to the limitations of available itaconate-monitoring techniques. Here, we develop and validate a genetically encoded fluorescent itaconate biosensor, BioITA, for directly monitoring itaconate dynamics in subcellular compartments of living macrophages. Utilizing BioITA, we monitor the itaconate dynamics in response to lipopolysaccharide (LPS) stimulation in the context of modulating itaconate transportation and metabolism. Moreover, we show that STING activation induces itaconate production, and injection of AAVs expressing cytosolic BioITA into mice allows directly reporting elevation of itaconate level in activated macrophages derived from LPS-injected mice. Thus, BioITA enables subcellular resolution imaging of itaconate in living macrophages.
Mitochondrial Fission Process 1 controls inner membrane integrity and protects against heart failure
Authors: Donnarumma Erminia , Kohlhaas Michael , Vimont Elodie , Kornobis Etienne , Chaze Thibault , Gianetto Quentin Giai , Matondo Mariette , Moya-Nilges Maryse , Maack Christoph , Wai Timothy
Published: November 2022

Mitochondria are paramount to the metabolism and survival of cardiomyocytes. Here we show that Mitochondrial Fission Process 1 (MTFP1) is an inner mitochondrial membrane (IMM) protein that is dispensable for mitochondrial division yet essential for cardiac structure and function. Constitutive knockout of cardiomyocyte MTFP1 in mice resulted in a fatal, adult-onset dilated cardiomyopathy accompanied by extensive mitochondrial and cardiac remodeling during the transition to heart failure. Prior to the onset of disease, knockout cardiac mitochondria displayed specific IMM defects: futile proton leak dependent upon the adenine nucleotide translocase and an increased sensitivity to the opening of the mitochondrial permeability transition pore, with which MTFP1 physically and genetically interacts. Collectively, our data reveal new functions of MTFP1 in the control of bioenergetic efficiency and cell death sensitivity and define its importance in preventing pathogenic cardiac remodeling.
A potential explanation for the global increase in tropical cyclone rapid intensification
Authors: Bhatia Kieran , Baker Alexander , Yang Wenchang , Vecchi Gabriel , Knutson Thomas , Murakami Hiroyuki , Kossin James , Hodges Kevin , Dixon Keith , Bronselaer Benjamin , Whitlock Carolyn
Published: November 2022

Tropical cyclone rapid intensification events often cause destructive hurricane landfalls because they are associated with the strongest storms and forecasts with the highest errors. Multi-decade observational datasets of tropical cyclone behavior have recently enabled documentation of upward trends in tropical cyclone rapid intensification in several basins. However, a robust anthropogenic signal in global intensification trends and the physical drivers of intensification trends have yet to be identified. To address these knowledge gaps, here we compare the observed trends in intensification and tropical cyclone environmental parameters to simulated natural variability in a high-resolution global climate model. In multiple basins and the global dataset, we detect a significant increase in intensification rates with a positive contribution from anthropogenic forcing. Furthermore, thermodynamic environments around tropical cyclones have become more favorable for intensification, and climate models show anthropogenic warming has significantly increased the probability of these changes.
Non-Abelian anyon collider
Authors: Lee June-Young M. , Sim H.-S.
Published: November 2022

A collider where particles are injected onto a beam splitter from opposite sides has been used for identifying quantum statistics of identical particles. The collision leads to bunching of the particles for bosons and antibunching for fermions. In recent experiments, a collider was applied to a fractional quantum Hall regime hosting Abelian anyons. The observed negative cross-correlation of electrical currents cannot be understood with fermionic antibunching. Here we predict, based on a conformal field theory and a non-perturbative treatment of non-equilibrium anyon injection, that the collider provides a tool for observation of the braiding statistics of various Abelian and non-Abelian anyons. Its dominant process is not direct collision between injected anyons, contrary to common expectation, but braiding between injected anyons and an anyon excited at the collider. The dependence of the resulting negative cross-correlation on the injection currents distinguishes non-Abelian SU(2)k anyons, Ising anyons, and Abelian Laughlin anyons.
Gate-tunable quantum pathways of high harmonic generation in graphene
Authors: Cha Soonyoung , Kim Minjeong , Kim Youngjae , Choi Shinyoung , Kang Sejong , Kim Hoon , Yoon Sangho , Moon Gunho , Kim Taeho , Lee Ye Won , Cho Gil Young , Park Moon Jeong , Kim Cheol-Joo , Kim B. J. , Lee JaeDong , Jo Moon-Ho , Kim Jonghwan
Published: November 2022

Under strong laser fields, electrons in solids radiate high-harmonic fields by travelling through quantum pathways in Bloch bands in the sub-laser-cycle timescales. Understanding these pathways in the momentum space through the high-harmonic radiation can enable an all-optical ultrafast probe to observe coherent lightwave-driven processes and measure electronic structures as recently demonstrated for semiconductors. However, such demonstration has been largely limited for semimetals because the absence of the bandgap hinders an experimental characterization of the exact pathways. In this study, by combining electrostatic control of chemical potentials with HHG measurement, we resolve quantum pathways of massless Dirac fermions in graphene under strong laser fields. Electrical modulation of HHG reveals quantum interference between the multi-photon interband excitation channels. As the light-matter interaction deviates beyond the perturbative regime, elliptically polarized laser fields efficiently drive massless Dirac fermions via an intricate coupling between the interband and intraband transitions, which is corroborated by our theoretical calculations. Our findings pave the way for strong-laser-field tomography of Dirac electrons in various quantum semimetals and their ultrafast electronics with a gate control.
Plastic bending in a semiconducting coordination polymer crystal enabled by delamination
Authors: An Lian-Cai , Li Xiang , Li Zhi-Gang , Li Qite , Beldon Patrick J. , Gao Fei-Fei , Li Zi-Ying , Zhu Shengli , Di Lu , Zhao Sanchuan , Zhu Jian , Comboni Davide , Kupenko Ilya , Li Wei , Ramamurty U. , Bu Xian-He
Published: November 2022

Coordination polymers (CPs) are a class of crystalline solids that are considered brittle, due to the dominance of directional coordination bonding, which limits their utility in flexible electronics and wearable devices. Hence, engineering plasticity into functional CPs is of great importance. Here, we report plastic bending of a semiconducting CP crystal, Cu-Trz (Trz = 1,2,3-triazolate), that originates from delamination facilitated by the discrete bonding interactions along different crystallographic directions in the lattice. The coexistence of strong coordination bonds and weak supramolecular interactions, together with the unique molecular packing, are the structural features that enable the mechanical flexibility and anisotropic response. The spatially resolved analysis of short-range molecular forces reveals that the strong coordination bonds, and the adaptive C–H···π and Cu···Cu interactions, synergistically lead to the delamination of the local structures and consequently the associated mechanical bending. The proposed delamination mechanism offers a versatile tool for designing the plasticity of CPs and other molecular crystals.
Electronic photoreceptors enable prosthetic visual acuity matching the natural resolution in rats
Authors: Wang Bing-Yi , Chen Zhijie Charles , Bhuckory Mohajeet , Huang Tiffany , Shin Andrew , Zuckerman Valentina , Ho Elton , Rosenfeld Ethan , Galambos Ludwig , Kamins Theodore , Mathieson Keith , Palanker Daniel
Published: November 2022

Localized stimulation of the inner retinal neurons for high-acuity prosthetic vision requires small pixels and minimal crosstalk from the neighboring electrodes. Local return electrodes within each pixel limit the crosstalk, but they over-constrain the electric field, thus precluding the efficient stimulation with subretinal pixels smaller than 55 μm. Here we demonstrate a high-resolution prosthetic vision based on a novel design of a photovoltaic array, where field confinement is achieved dynamically, leveraging the adjustable conductivity of the diodes under forward bias to turn the designated pixels into transient returns. We validated the computational modeling of the field confinement in such an optically-controlled circuit by in-vitro and in-vivo measurements. Most importantly, using this strategy, we demonstrated that the grating acuity with 40 μm pixels matches the pixel pitch, while with 20 μm pixels, it reaches the 28 μm limit of the natural visual resolution in rats. This method enables customized field shaping based on individual retinal thickness and distance from the implant, paving the way to higher acuity of prosthetic vision in atrophic macular degeneration.
Lamin A/C-dependent chromatin architecture safeguards naïve pluripotency to prevent aberrant cardiovascular cell fate and function
Authors: Wang Yinuo , Elsherbiny Adel , Kessler Linda , Cordero Julio , Shi Haojie , Serke Heike , Lityagina Olga , Trogisch Felix A. , Mohammadi Mona Malek , El-Battrawy Ibrahim , Backs Johannes , Wieland Thomas , Heineke Joerg , Dobreva Gergana
Published: November 2022

Tight control of cell fate choices is crucial for normal development. Here we show that lamin A/C plays a key role in chromatin organization in embryonic stem cells (ESCs), which safeguards naïve pluripotency and ensures proper cell fate choices during cardiogenesis. We report changes in chromatin compaction and localization of cardiac genes in Lmna−/− ESCs resulting in precocious activation of a transcriptional program promoting cardiomyocyte versus endothelial cell fate. This is accompanied by premature cardiomyocyte differentiation, cell cycle withdrawal and abnormal contractility. Gata4 is activated by lamin A/C loss and Gata4 silencing or haploinsufficiency rescues the aberrant cardiovascular cell fate choices induced by lamin A/C deficiency. We uncover divergent functions of lamin A/C in naïve pluripotent stem cells and cardiomyocytes, which have distinct contributions to the transcriptional alterations of patients with LMNA-associated cardiomyopathy. We conclude that disruption of lamin A/C-dependent chromatin architecture in ESCs is a primary event in LMNA loss-of-function cardiomyopathy.
VeChat: correcting errors in long reads using variation graphs
Authors: Luo Xiao , Kang Xiongbin , Schönhuth Alexander
Published: November 2022

Error correction is the canonical first step in long-read sequencing data analysis. Current self-correction methods, however, are affected by consensus sequence induced biases that mask true variants in haplotypes of lower frequency showing in mixed samples. Unlike consensus sequence templates, graph-based reference systems are not affected by such biases, so do not mistakenly mask true variants as errors. We present VeChat, as an approach to implement this idea: VeChat is based on variation graphs, as a popular type of data structure for pangenome reference systems. Extensive benchmarking experiments demonstrate that long reads corrected by VeChat contain 4 to 15 (Pacific Biosciences) and 1 to 10 times (Oxford Nanopore Technologies) less errors than when being corrected by state of the art approaches. Further, using VeChat prior to long-read assembly significantly improves the haplotype awareness of the assemblies. VeChat is an easy-to-use open-source tool and publicly available athttps://github.com/HaploKit/vechat.
Pan-cancer single-cell analysis reveals the heterogeneity and plasticity of cancer-associated fibroblasts in the tumor microenvironment
Authors: Luo Han , Xia Xuyang , Huang Li-Bin , An Hyunsu , Cao Minyuan , Kim Gyeong Dae , Chen Hai-Ning , Zhang Wei-Han , Shu Yang , Kong Xiangyu , Ren Zhixiang , Li Pei-Heng , Liu Yang , Tang Huairong , Sun Ronghao , Li Chao , Bai Bing , Jia Weiguo , Liu Yi , Zhang Wei , Yang Li , Peng Yong , Dai Lunzhi , Hu Hongbo , Jiang Yong , Hu Yiguo , Zhu Jingqiang , Jiang Hong , Li Zhihui , Caulin Carlos , Park Jihwan , Xu Heng
Published: November 2022

Cancer-associated fibroblasts (CAFs) are the predominant components of the tumor microenvironment (TME) and influence cancer hallmarks, but without systematic investigation on their ubiquitous characteristics across different cancer types. Here, we perform pan-cancer analysis on 226 samples across 10 solid cancer types to profile the TME at single-cell resolution, illustrating the commonalities/plasticity of heterogenous CAFs. Activation trajectory of the major CAF types is divided into three states, exhibiting distinct interactions with other cell components, and relating to prognosis of immunotherapy. Moreover, minor CAF components represent the alternative origin from other TME components (e.g., endothelia and macrophages). Particularly, the ubiquitous presentation of endothelial-to-mesenchymal transition CAF, which may interact with proximal SPP1+ tumor-associated macrophages, is implicated in endothelial-to-mesenchymal transition and survival stratifications. Our study comprehensively profiles the shared characteristics and dynamics of CAFs, and highlight their heterogeneity and plasticity across different cancer types. Browser of integrated pan-cancer single-cell information is available at https://gist-fgl.github.io/sc-caf-atlas/.
Modular total syntheses of trans-clerodanes and sesquiterpene (hydro)quinones via tail-to-head cyclization and reductive coupling strategies
Authors: Zhu Wenming , Yin Qishuang , Lou Zhizheng , Yang Ming
Published: November 2022

Thetrans-clerodanes and sesquiterpene (hydro)quinones are a growing class of natural products that exhibit a wide range of biological activities. Although they are different types of natural products, some of them feature the sametrans-decalin core structure. Here, we report the total syntheses of two members oftrans-clerodanes, five members of sesquiterpene (hydro)quinones as well as the proposed structure of dysidavarone D via a modular synthetic route. A bioinspired tail-to-head cyclization strategy was developed to syntheses of thetrans-decalin architectures by using two diastereochemically complementary radical polyene cyclization reactions catalyzed by Ti(III) and mediated by Mn(III), respectively. The different types of side chains were introduced by challenging nickel catalyzed reductive couplings of sterically hindered alkyl halides. The synthesis of the proposed dysidavarone D proved a wrong structural assignment of the natural product.
Translation regulatory factor BZW1 regulates preimplantation embryo development and compaction by restricting global non-AUG Initiation
Authors: Zhang Jue , Pi Shuai-Bo , Zhang Nan , Guo Jing , Zheng Wei , Leng Lizhi , Lin Ge , Fan Heng-Yu
Published: November 2022

Protein synthesis is an essential step in gene expression during the development of mammalian preimplantation embryos. This is a complex and highly regulated process. The accuracy of the translation initiation codon is important in various gene expression programs. However, the mechanisms that regulate AUG and non-AUG codon initiation in early embryos remain poorly understood. BZW1 is a key factor in determining the mRNA translation start codon. Here, we show that BZW1 is essential for early embryonic development in mice. Bzw1-knockdown embryos fail to undergo compaction, and show decreased blastocyst formation rates. We also observe defects in the differentiation capacity and implantation potential after Bzw1 interference. Further investigation revealed that Bzw1 knockdown causes the levels of translation initiation with CUG as the start codon to increase. The decline in BZW1 levels result in a decrease in protein synthesis in preimplantation embryos, whereas the total mRNA levels are not altered. Therefore, we concluded that BZW1 contributes to protein synthesis during early embryonic development by restricting non-AUG translational initiation.
2′–5′ oligoadenylate synthetase‑like 1 (OASL1) protects against atherosclerosis by maintaining endothelial nitric oxide synthase mRNA stability
Authors: Kim Tae Kyeong , Jeon Sejin , Park Seonjun , Sonn Seong-Keun , Seo Seungwoon , Suh Joowon , Jin Jing , Kweon Hyae Yon , Kim Sinai , Moon Shin Hye , Kweon Okhee , Koo Bon-Hyeock , Kim Nayoung , Lee Hae-Ock , Kim Young-Myeong , Kim Young-Joon , Park Sung Ho , Oh Goo Taeg
Published: November 2022

Endothelial nitric oxide synthase (eNOS) decreases following inflammatory stimulation. As a master regulator of endothelial homeostasis, maintaining optimal eNOS levels is important during cardiovascular events. However, little is known regarding the mechanism of eNOS protection. In this study, we demonstrate a regulatory role for endothelial expression of 2′–5′ oligoadenylate synthetase-like 1 (OASL1) in maintaining eNOS mRNA stability during athero-prone conditions and consider its clinical implications. A lack of endothelial Oasl1 accelerated plaque progression, which was preceded by endothelial dysfunction, elevated vascular inflammation, and decreased NO bioavailability following impaired eNOS expression. Mechanistically, knockdown of PI3K/Akt signaling-dependent OASL expression increased Erk1/2 and NF-κB activation and decreased NOS3 (gene name for eNOS) mRNA expression through upregulation of the negative regulatory, miR-584, whereas a miR-584 inhibitor rescued the effects of OASL knockdown. These results suggest that OASL1/OASL regulates endothelial biology by protecting NOS3 mRNA and targeting miR-584 represents a rational therapeutic strategy for eNOS maintenance in vascular disease.
Updated vaccine protects against SARS-CoV-2 variants including Omicron (B.1.1.529) and prevents transmission in hamsters
Authors: Sharma Sapna , Vercruysse Thomas , Sanchez-Felipe Lorena , Kerstens Winnie , Rasulova Madina , Bervoets Lindsey , De Keyzer Carolien , Abdelnabi Rana , Foo Caroline S. , Lemmens Viktor , Van Looveren Dominique , Maes Piet , Baele Guy , Weynand Birgit , Lemey Philippe , Neyts Johan , Thibaut Hendrik Jan , Dallmeier Kai
Published: November 2022

Current COVID-19 vaccines are based on prototypic spike sequences from ancestral 2019 SARS-CoV-2 strains. However, the ongoing pandemic is fueled by variants of concern (VOC) escaping vaccine-mediated protection. Here we demonstrate how immunization in hamsters using prototypic spike expressed from yellow fever 17D (YF17D) as vector blocks ancestral virus (B lineage) and VOC Alpha (B.1.1.7) yet fails to fully protect from Beta (B.1.351). However, the same YF17D vectored vaccine candidate with an evolved antigen induced considerably improved neutralizing antibody responses against VOCs Beta, Gamma (P.1) and the recently predominant Omicron (B.1.1.529), while maintaining immunogenicity against ancestral virus and VOC Delta (B.1.617.2). Thus vaccinated animals resisted challenge by all VOCs, including vigorous high titre exposure to the most difficult to cover Beta, Delta and Omicron variants, eliminating detectable virus and markedly improving lung pathology. Finally, vaccinated hamsters did not transmit Delta variant to non-vaccinated cage mates. Overall, our data illustrate how current first-generation COVID-19 vaccines may need to be updated to maintain efficacy against emerging VOCs and their spread at community level.
Identification of evolutionarily conserved regulators of muscle mitochondrial network organization
Authors: Katti Prasanna , Ajayi Peter T. , Aponte Angel , Bleck Christopher K. E. , Glancy Brian
Published: November 2022

Mitochondrial networks provide coordinated energy distribution throughout muscle cells. However, pathways specifying mitochondrial networks are incompletely understood and it is unclear how they might affect contractile fiber-type. Here, we show that natural energetic demands placed on Drosophila melanogaster muscles yield native cell-types among which contractile and mitochondrial network-types are regulated differentially. Proteomic analyses of indirect flight, jump, and leg muscles, together with muscles misexpressing known fiber-type specification factor salm, identified transcription factors H15 and cut as potential mitochondrial network regulators. We demonstrate H15 operates downstream of salm regulating flight muscle contractile and mitochondrial network-type. Conversely, H15 regulates mitochondrial network configuration but not contractile type in jump and leg muscles. Further, we find that cut regulates salm expression in flight muscles and mitochondrial network configuration in leg muscles. These data indicate cell type-specific regulation of muscle mitochondrial network organization through evolutionarily conserved transcription factors cut, salm, and H15.
Base-editing-mediated dissection of a γ-globin cis-regulatory element for the therapeutic reactivation of fetal hemoglobin expression
Authors: Antoniou Panagiotis , Hardouin Giulia , Martinucci Pierre , Frati Giacomo , Felix Tristan , Chalumeau Anne , Fontana Letizia , Martin Jeanne , Masson Cecile , Brusson Megane , Maule Giulia , Rosello Marion , Giovannangeli Carine , Abramowski Vincent , de Villartay Jean-Pierre , Concordet Jean-Paul , Del Bene Filippo , El Nemer Wassim , Amendola Mario , Cavazzana Marina , Cereseto Anna , Romano Oriana , Miccio Annarita
Published: November 2022

Sickle cell disease and β-thalassemia affect the production of the adult β-hemoglobin chain. The clinical severity is lessened by mutations that cause fetal γ-globin expression in adult life (i.e., the hereditary persistence of fetal hemoglobin). Mutations clustering ~200 nucleotides upstream of the HBG transcriptional start sites either reduce binding of the LRF repressor or recruit the KLF1 activator. Here, we use base editing to generate a variety of mutations in the −200 region of the HBG promoters, including potent combinations of four to eight γ-globin-inducing mutations. Editing of patient hematopoietic stem/progenitor cells is safe, leads to fetal hemoglobin reactivation and rescues the pathological phenotype. Creation of a KLF1 activator binding site is the most potent strategy – even in long-term repopulating hematopoietic stem/progenitor cells. Compared with a Cas9-nuclease approach, base editing avoids the generation of insertions, deletions and large genomic rearrangements and results in higher γ-globin levels. Our results demonstrate that base editing of HBG promoters is a safe, universal strategy for treating β-hemoglobinopathies.
Metabolite annotation from knowns to unknowns through knowledge-guided multi-layer metabolic networking
Authors: Zhou Zhiwei , Luo Mingdu , Zhang Haosong , Yin Yandong , Cai Yuping , Zhu Zheng-Jiang
Published: November 2022

Liquid chromatography - mass spectrometry (LC-MS) based untargeted metabolomics allows to measure both known and unknown metabolites in the metabolome. However, unknown metabolite annotation is a major challenge in untargeted metabolomics. Here, we develop an approach, namely, knowledge-guided multi-layer network (KGMN), to enable global metabolite annotation from knowns to unknowns in untargeted metabolomics. The KGMN approach integrates three-layer networks, including knowledge-based metabolic reaction network, knowledge-guided MS/MS similarity network, and global peak correlation network. To demonstrate the principle, we apply KGMN in an in vitro enzymatic reaction system and different biological samples, with ~100–300 putative unknowns annotated in each data set. Among them, >80% unknown metabolites are corroborated with in silico MS/MS tools. Finally, we validate 5 metabolites that are absent in common MS/MS libraries through repository mining and synthesis of chemical standards. Together, the KGMN approach enables efficient unknown annotations, and substantially advances the discovery of recurrent unknown metabolites for common biological samples from model organisms, towards deciphering dark matter in untargeted metabolomics.
Hyperbolic material enhanced scattering nanoscopy for label-free super-resolution imaging
Authors: Lee Yeon Ui , Li Shilong , Wisna G. Bimananda M. , Zhao Junxiang , Zeng Yuan , Tao Andrea R. , Liu Zhaowei
Published: November 2022

Fluorescence super-resolution microscopy has, over the last two decades, been extensively developed to access deep-subwavelength nanoscales optically. Label-free super-resolution technologies however have only achieved a slight improvement compared to the diffraction limit. In this context, we demonstrate a label-free imaging method, i.e., hyperbolic material enhanced scattering (HMES) nanoscopy, which breaks the diffraction limit by tailoring the light-matter interaction between the specimens and a hyperbolic material substrate. By exciting the highly confined evanescent hyperbolic polariton modes with dark-field detection, HMES nanoscopy successfully shows a high-contrast scattering image with a spatial resolution around 80 nm. Considering the wavelength at 532 nm and detection optics with a 0.6 numerical aperture (NA) objective lens, this value represents a 5.5-fold resolution improvement beyond the diffraction limit. HMES provides capabilities for super-resolution imaging where fluorescence is not available or challenging to apply.
A machine learning enabled hybrid optimization framework for efficient coarse-graining of a model polymer
Authors: Shireen Zakiya , Weeratunge Hansani , Menzel Adrian , Phillips Andrew W. , Larson Ronald G. , Smith-Miles Kate , Hajizadeh Elnaz
Published: November 2022

This work presents a framework governing the development of an efficient, accurate, and transferable coarse-grained (CG) model of a polyether material. The framework combines bottom-up and top-down approaches of coarse-grained model parameters by integrating machine learning (ML) with optimization algorithms. In the bottom-up approach, bonded interactions of the CG model are optimized using deep neural networks (DNN), where atomistic bonded distributions are matched. In the top-down approach, optimization of nonbonded parameters is accomplished by reproducing the temperature-dependent experimental density. We demonstrate that developed framework addresses the thermodynamic consistency and transferability issues associated with the classical coarse-graining approaches. The efficiency and transferability of the CG model is demonstrated through accurate predictions of chain statistics, the limiting behavior of the glass transition temperature, diffusion, and stress relaxation, where none were included in the parametrization process. The accuracy of the predicted properties are evaluated in context of molecular theories and available experimental data.
Hybrid combination of advanced oxidation and biological processes for the micropollutant removal of carbamazepine
Authors: Lee You-Yi , Fan Chihhao , Haque Fatima
Published: November 2022

Carbamazepine (CBZ) is a frequently-detected aqueous pharmaceutical due to its extensive use and persistence in the environment. CBZ could not be efficiently removed by biological processes which led to its disposal in natural water bodies. This study coupled the Fenton process as pretreatment with the activated sludge process for aqueous CBZ removal. Fenton degradation studies showed that the application of excessive reagents might cause a decrease in CBZ removal. Apparent CBZ degradation at neutral pH supported the use of the Fenton process as pretreatment for CBZ removal. Treated with the hybrid combination system, CBZ, COD, and TOC removal were enhanced. The EEM analysis evidenced the biodegradable intermediates formed during the hybrid process. CBZ degradation pathways were explored using LC-MS analytical results and literature studies. Given the low biodegradability of CBZ, using the Fenton process as a pretreatment before sequencing batch reactor-activated sludge (SBR-AS) is an alternative to improve the aqueous CBZ treatment.
Human mobile robot interaction in the retail environment
Authors: Chen Yuhao , Luo Yue , Yang Chizhao , Yerebakan Mustafa Ozkan , Hao Shuai , Grimaldi Nicolas , Li Song , Hayes Read , Hu Boyi
Published: November 2022

As technology advances, Human-Robot Interaction (HRI) is boosting overall system efficiency and productivity. However, allowing robots to be present closely with humans will inevitably put higher demands on precise human motion tracking and prediction. Datasets that contain both humans and robots operating in the shared space are receiving growing attention as they may facilitate a variety of robotics and human-systems research. Datasets that track HRI with rich information other than video images during daily activities are rarely seen. In this paper, we introduce a novel dataset that focuses on social navigation between humans and robots in a future-oriented Wholesale and Retail Trade (WRT) environment (https://uf-retail-cobot-dataset.github.io/). Eight participants performed the tasks that are commonly undertaken by consumers and retail workers. More than 260 minutes of data were collected, including robot and human trajectories, human full-body motion capture, eye gaze directions, and other contextual information. Comprehensive descriptions of each category of data stream, as well as potential use cases are included. Furthermore, analysis with multiple data sources and future directions are discussed.
A database of seed plants on taxonomy, geography and ecology in the Qinling-Daba Mountains and adjacent areas
Authors: Zhang Xinghang , Zhang Baiping , Li Jiayu , Yao Yonghui , Wang Jing , Liu Junjie , Yu Fuqin
Published: November 2022

The Qinling-Daba Mountains span subtropical and warm temperate zones and are one of the most remarkable biodiversity hotspots in China. Establishing a complete checklist of seed plants organized by nature reserves in the Qinling-Daba Mountains and adjacent areas is an important basis for managing and utilizing plant resources. First, we collected seed plant species data from published checklists representing 58 nature reserves in the Qinling-Daba Mountains and adjacent areas; second, we comprehensively and systematically sorted and integrated these data; third, we proofread and revised the data with the help of the R language and Flora of China dataset; and finally, we set up a seed plant database containing 96148 records, including the name, order, family, genus, life form, and endemism of each species for the entirety of the Qinling-Daba Mountains. The database contains 9491 species of seed plants belonging to 1729 genera, 211 families, and 59 orders, accounting for 39% of China’s seed plants.
Kallikrein proteoforms and reproductive parameters in stallion are conditioned by climate
Authors: Senra Renato Lima , Ramírez-López Camilo José , Magalhães-Júnior Marcos Jorge , Neves João Gabriel da Silva , Barros Edvaldo , Waddington Bruna , Guimarães Simone Eliza Facioni , Guimarães José Domingos , Baracat-Pereira Maria Cristina
Published: November 2022

Horses are seasonal polyoestrous animals, and the photoperiod is the main factor modulating their reproductive activity. There is no consensus on the andrological and biochemical factors that influence breeding seasonality. To assess the involvement of climate in reproduction, Mangalarga Marchador stallions were monitored over 1 year regarding semen quality and seminal plasma proteome. Here, we show that kallikrein (KLKs) proteoforms in seminal plasma are involved in climate conditioning of reproduction. During the breeding season, greater abundance and different types of KLKs occurred simultaneously to lower sperm motility, greater semen volumes and higher concentrations of glucose and cholesterol. Considering that vasodilation due to activation of the kallikrein-kinin system and the consequent inhibition of the renin-angiotensin system may be associated with lower sperm motility, unravelling the involvement of KLK proteoforms in reproductive seasonality is a priority in horse breeding.
Significantly increased risk of chronic obstructive pulmonary disease amongst adults with predominantly mild congenital heart disease
Authors: Byrne Dominic J. F. , Williams Simon G. , Nakev Apostol , Frain Simon , Baross Stephanie L. , Vestbo Jørgen , Keavney Bernard D. , Talavera David
Published: November 2022

Adults with congenital heart disease (CHD) face increased risk of various comorbid diseases. Previous work on lung dysfunction in this population has mainly focused on restrictive lung disease, in patients with severe CHD phenotypes. We examined the association of mild CHD with chronic obstructive pulmonary disease (COPD) in the UK Biobank (UKB). Electronic health records (EHR) were used to identify 3385 CHD cases and 479,765 healthy controls in UKB, before performing a case–control analysis over a 20-year study period for a total of > 9.5 M person-years of follow-up. Our analysis showed that UKB participants with CHD are at substantially greater risk of developing COPD than healthy controls (8.7% vs 3.1% prevalence, unadjusted OR 2.98, 95% CI 2.63, 3.36, P = 1.40e−53). Slightly increased rates of smoking were observed amongst CHD cases, however the association with COPD was shown to be robust to adjustment for smoking and other factors known to modulate COPD risk within a multivariable-adjusted Cox regression framework (fully adjusted HR 2.21, 95% CI 1.97, 2.48, P = 5.5e−41). Care for adults with CHD should aim to mitigate their increased risk of COPD, possibly via increased smoking cessation support.
CdGAP maintains podocyte function and modulates focal adhesions in a Src kinase-dependent manner
Authors: Matsuda Jun , Greenberg Dina , Ibrahim Sajida , Maier Mirela , Aoudjit Lamine , Chapelle Jennifer , Baldwin Cindy , He Yi , Lamarche-Vane Nathalie , Takano Tomoko
Published: November 2022

Rho GTPases are regulators of the actin cytoskeleton and their activity is modulated by GTPase-activating proteins (GAPs) and guanine nucleotide exchanging factors (GEFs). Glomerular podocytes have numerous actin-based projections called foot processes and their alteration is characteristic of proteinuric kidney diseases. We reported previously that Rac1 hyperactivation in podocytes causes proteinuria and glomerulosclerosis in mice. However, which GAP and GEF modulate Rac1 activity in podocytes remains unknown. Here, using a proximity-based ligation assay, we identified CdGAP (ARHGAP31) and β-PIX (ARHGEF7) as the major regulatory proteins interacting with Rac1 in human podocytes. CdGAP interacted with β-PIX through its basic region, and upon EGF stimulation, they both translocated to the plasma membrane in podocytes. CdGAP-depleted podocytes had altered cell motility and increased basal Rac1 and Cdc42 activities. When stimulated with EGF, CdGAP-depleted podocytes showed impaired β-PIX membrane-translocation and tyrosine phosphorylation, and reduced activities of Src kinase, focal adhesion kinase, and paxillin. Systemic and podocyte-specific CdGAP-knockout mice developed mild but significant proteinuria, which was exacerbated by Adriamycin. Collectively, these findings show that CdGAP contributes to maintain podocyte function and protect them from injury.
Predicting the efficacy of opioid sequestration by intravenous lipid emulsion using biologically relevant in vitro models of drug distribution
Authors: Tikhomirov Marta , Jajor Paweł , Śniegocki Tomasz , Poźniak Błażej
Published: November 2022

Intravenous lipid emulsions (ILE), among other uses, are utilized in the treatment of poisonings caused by lipophilic substances. The body of evidence regarding the benefits of this treatment is growing but information about opioids-ILE interaction is still very scarce. In this work, the impact of ILE on the distribution of buprenorphine, fentanyl and butorphanol used in various concentrations (100–500 ng/ml) was investigated. Two different in vitro models were used: disposition of the drugs in plasma after ultracentrifugation and distribution into the simulated biophase (cell monolayer of 3T3 fibroblasts or J774.E macrophages). We confirmed the ability of ILE to sequester the three drugs of interest which results in their decrease in the aqueous part of the plasma by 34.2–38.2%, 11.7–28.5% and 6.0–15.5% for buprenorphine, fentanyl and butorphanol, respectively. Moreover, ILE affected the drug distribution to the biophase in vitro, however, in this case the drug concentration in cells decreased by 97.3 ± 3.1%, 28.6 ± 5.4% and 13.0 ± 7.5% for buprenorphine, fentanyl and butorphanol, respectively. The two models revealed notable differences in ILE’s potential for drug sequestration, especially for buprenorphine. Similar, but not as pronounced tendencies were observed for the two other drugs. These discrepancies may result from the difference in protein abundance and resulting drug-protein binding in both systems. Nevertheless, the results obtained with both in vitro models correlated well with the partition coefficient (logP) values for these drugs.