bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficient carbon dioxide hydrogenation to formic acid with buffering ionic liquids
Authors: Weilhard Andreas , Argent Stephen P. , Sans Victor
Published: January 2021

The efficient transformation of CO2 into chemicals and fuels is a key challenge for the decarbonisation of the synthetic production chain. Formic acid (FA) represents the first product of CO2 hydrogenation and can be a precursor of higher added value products or employed as a hydrogen storage vector. Bases are typically required to overcome thermodynamic barriers in the synthesis of FA, generating waste and requiring post-processing of the formate salts. The employment of buffers can overcome these limitations, but their catalytic performance has so far been modest. Here, we present a methodology utilising IL as buffers to catalytically transform CO2 into FA with very high efficiency and comparable performance to the base-assisted systems. The combination of multifunctional basic ionic liquids and catalyst design enables the synthesis of FA with very high catalytic efficiency in TONs of >8*105 and TOFs > 2.1*104 h−1.
How ice grows from premelting films and water droplets
Authors: Sibley David N. , Llombart Pablo , Noya Eva G. , Archer Andrew J. , MacDowell Luis G.
Published: January 2021

Close to the triple point, the surface of ice is covered by a thin liquid layer (so-called quasi-liquid layer) which crucially impacts growth and melting rates. Experimental probes cannot observe the growth processes below this layer, and classical models of growth by vapor deposition do not account for the formation of premelting films. Here, we develop a mesoscopic model of liquid-film mediated ice growth, and identify the various resulting growth regimes. At low saturation, freezing proceeds by terrace spreading, but the motion of the buried solid is conveyed through the liquid to the outer liquid–vapor interface. At higher saturations water droplets condense, a large crater forms below, and freezing proceeds undetectably beneath the droplet. Our approach is a general framework that naturally models freezing close to three phase coexistence and provides a first principle theory of ice growth and melting which may prove useful in the geosciences.
Stabilizing the closed SARS-CoV-2 spike trimer
Authors: Juraszek Jarek , Rutten Lucy , Blokland Sven , Bouchier Pascale , Voorzaat Richard , Ritschel Tina , Bakkers Mark J. G. , Renault Ludovic L. R. , Langedijk Johannes P. M.
Published: January 2021

The trimeric spike (S) protein of SARS-CoV-2 is the primary focus of most vaccine design and development efforts. Due to intrinsic instability typical of class I fusion proteins, S tends to prematurely refold to the post-fusion conformation, compromising immunogenic properties and prefusion trimer yields. To support ongoing vaccine development efforts, we report the structure-based design of soluble S trimers with increased yields and stabilities, based on introduction of single point mutations and disulfide-bridges. We identify regions critical for stability: the heptad repeat region 1, the SD1 domain and position 614 in SD2. We combine a minimal selection of mostly interprotomeric mutations to create a stable S-closed variant with a 6.4-fold higher expression than the parental construct while no longer containing a heterologous trimerization domain. The cryo-EM structure reveals a correctly folded, predominantly closed pre-fusion conformation. Highly stable and well producing S protein and the increased understanding of S protein structure will support vaccine development and serological diagnostics.
Alternating quarantine for sustainable epidemic mitigation
Authors: Meidan Dror , Schulmann Nava , Cohen Reuven , Haber Simcha , Yaniv Eyal , Sarid Ronit , Barzel Baruch
Published: January 2021

Absent pharmaceutical interventions, social distancing, lock-downs and mobility restrictions remain our prime response in the face of epidemic outbreaks. To ease their potentially devastating socioeconomic consequences, we propose here an alternating quarantine strategy: at every instance, half of the population remains under lockdown while the other half continues to be active - maintaining a routine of weekly succession between activity and quarantine. This regime minimizes infectious interactions, as it allows only half of the population to interact for just half of the time. As a result it provides a dramatic reduction in transmission, comparable to that achieved by a population-wide lockdown, despite sustaining socioeconomic continuity at  ~50% capacity. The weekly alternations also help address the specific challenge of COVID-19, as their periodicity synchronizes with the natural SARS-CoV-2 disease time-scales, allowing to effectively isolate the majority of infected individuals precisely at the time of their peak infection.
Bidirectional contact tracing could dramatically improve COVID-19 control
Authors: Bradshaw William J. , Alley Ethan C. , Huggins Jonathan H. , Lloyd Alun L. , Esvelt Kevin M.
Published: January 2021

Contact tracing is critical to controlling COVID-19, but most protocols only “forward-trace” to notify people who were recently exposed. Using a stochastic branching-process model, we find that “bidirectional” tracing to identify infector individuals and their other infectees robustly improves outbreak control. In our model, bidirectional tracing more than doubles the reduction in effective reproduction number (Reff) achieved by forward-tracing alone, while dramatically increasing resilience to low case ascertainment and test sensitivity. The greatest gains are realised by expanding the manual tracing window from 2 to 6 days pre-symptom-onset or, alternatively, by implementing high-uptake smartphone-based exposure notification; however, to achieve the performance of the former approach, the latter requires nearly all smartphones to detect exposure events. With or without exposure notification, our results suggest that implementing bidirectional tracing could dramatically improve COVID-19 control.
Two novel venom proteins underlie divergent parasitic strategies between a generalist and a specialist parasite
Authors: Huang Jianhua , Chen Jiani , Fang Gangqi , Pang Lan , Zhou Sicong , Zhou Yuenan , Pan Zhongqiu , Zhang Qichao , Sheng Yifeng , Lu Yueqi , Liu Zhiguo , Zhang Yixiang , Li Guiyun , Shi Min , Chen Xuexin , Zhan Shuai
Published: January 2021

Parasitoids are ubiquitous in natural ecosystems. Parasitic strategies are highly diverse among parasitoid species, yet their underlying genetic bases are poorly understood. Here, we focus on the divergent adaptation of a specialist and a generalist drosophilid parasitoids. We find that a novel protein (Lar) enables active immune suppression by lysing the host lymph glands, eventually leading to successful parasitism by the generalist. Meanwhile, another novel protein (Warm) contributes to a passive strategy by attaching the laid eggs to the gut and other organs of the host, leading to incomplete encapsulation and helping the specialist escape the host immune response. We find that these diverse parasitic strategies both originated from lateral gene transfer, followed with duplication and specialization, and that they might contribute to the shift in host ranges between parasitoids. Our results increase our understanding of how novel gene functions originate and how they contribute to host adaptation.
Isolated copper single sites for high-performance electroreduction of carbon monoxide to multicarbon products
Authors: Bao Haihong , Qiu Yuan , Peng Xianyun , Wang Jia-ao , Mi Yuying , Zhao Shunzheng , Liu Xijun , Liu Yifan , Cao Rui , Zhuo Longchao , Ren Junqiang , Sun Jiaqiang , Luo Jun , Sun Xuping
Published: January 2021

Electrochemical carbon monoxide reduction is a promising strategy for the production of value-added multicarbon compounds, albeit yielding diverse products with low selectivities and Faradaic efficiencies. Here, copper single atoms anchored to Ti3C2Tx MXene nanosheets are firstly demonstrated as effective and robust catalysts for electrochemical carbon monoxide reduction, achieving an ultrahigh selectivity of 98% for the formation of multicarbon products. Particularly, it exhibits a high Faradaic efficiency of 71% towards ethylene at −0.7 V versus the reversible hydrogen electrode, superior to the previously reported copper-based catalysts. Besides, it shows a stable activity during the 68-h electrolysis. Theoretical simulations reveal that atomically dispersed Cu–O3 sites favor the C–C coupling of carbon monoxide molecules to generate the key *CO-CHO species, and then induce the decreased free energy barrier of the potential-determining step, thus accounting for the high activity and selectivity of copper single atoms for carbon monoxide reduction.
Light quantum control of persisting Higgs modes in iron-based superconductors
Authors: Vaswani C. , Kang J. H. , Mootz M. , Luo L. , Yang X. , Sundahl C. , Cheng D. , Huang C. , Kim R. H. J. , Liu Z. , Collantes Y. G. , Hellstrom E. E. , Perakis I. E. , Eom C. B. , Wang J.
Published: January 2021

The Higgs mechanism, i.e., spontaneous symmetry breaking of the quantum vacuum, is a cross-disciplinary principle, universal for understanding dark energy, antimatter and quantum materials, from superconductivity to magnetism. Unlike one-band superconductors (SCs), a conceptually distinct Higgs amplitude mode can arise in multi-band, unconventional superconductors  via strong interband Coulomb interaction, but is yet to be accessed. Here we discover such hybrid Higgs mode and demonstrate its quantum control by light in iron-based high-temperature SCs. Using terahertz (THz) two-pulse coherent spectroscopy, we observe a tunable amplitude mode coherent oscillation of the complex order parameter from coupled lower and upper bands. The nonlinear dependence of the hybrid Higgs mode on the THz driving fields is distinct from any known SC results: we observe a large reversible modulation of resonance strength, yet with a persisting mode frequency. Together with quantum kinetic modeling of a hybrid Higgs mechanism, distinct from charge-density fluctuations and without invoking phonons or disorder, our result provides compelling evidence for a light-controlled coupling between the electron and hole amplitude modes assisted by strong interband quantum entanglement. Such light-control of Higgs hybridization can be extended to probe many-body entanglement and hidden symmetries in other complex systems.
Induced organoids derived from patients with ulcerative colitis recapitulate colitic reactivity
Authors: Sarvestani Samaneh K. , Signs Steven , Hu Bo , Yeu Yunku , Feng Hao , Ni Ying , Hill David R. , Fisher Robert C. , Ferrandon Sylvain , DeHaan Reece K. , Stiene Jennifer , Cruise Michael , Hwang Tae Hyun , Shen Xiling , Spence Jason R. , Huang Emina H.
Published: January 2021

The pathogenesis of ulcerative colitis (UC), a major type of inflammatory bowel disease, remains unknown. No model exists that adequately recapitulates the complexity of clinical UC. Here, we take advantage of induced pluripotent stem cells (iPSCs) to develop an induced human UC-derived organoid (iHUCO) model and compared it with the induced human normal organoid model (iHNO). Notably, iHUCOs recapitulated histological and functional features of primary colitic tissues, including the absence of acidic mucus secretion and aberrant adherens junctions in the epithelial barrier both in vitro and in vivo. We demonstrate that the CXCL8/CXCR1 axis was overexpressed in iHUCO but not in iHNO. As proof-of-principle, we show that inhibition of CXCL8 receptor by the small-molecule non-competitive inhibitor repertaxin attenuated the progression of UC phenotypes in vitro and in vivo. This patient-derived organoid model, containing both epithelial and stromal compartments, will generate new insights into the underlying pathogenesis of UC while offering opportunities to tailor interventions to the individual patient.
Important contributions of non-fossil fuel nitrogen oxides emissions
Authors: Song Wei , Liu Xue-Yan , Hu Chao-Chen , Chen Guan-Yi , Liu Xue-Jun , Walters Wendell W. , Michalski Greg , Liu Cong-Qiang
Published: January 2021

Since the industrial revolution, it has been assumed that fossil-fuel combustions dominate increasing nitrogen oxide (NOx) emissions. However, it remains uncertain to the actual contribution of the non-fossil fuel NOxto total NOxemissions. Natural N isotopes of NO3−in precipitation (δ15Nw-NO3−) have been widely employed for tracing atmospheric NOxsources. Here, we compiled global δ15Nw-NO3−observations to evaluate the relative importance of fossil and non-fossil fuel NOxemissions. We found that regional differences in human activities directly influenced spatial-temporal patterns of δ15Nw-NO3−variations. Further, isotope mass-balance and bottom-up calculations suggest that the non-fossil fuel NOxaccounts for 55 ± 7% of total NOxemissions, reaching up to 21.6 ± 16.6Mt yr−1in East Asia, 7.4 ± 5.5Mt yr−1in Europe, and 21.8 ± 18.5Mt yr−1in North America, respectively. These results reveal the importance of non-fossil fuel NOxemissions and provide direct evidence for making strategies on mitigating atmospheric NOxpollution.
A comprehensive re-assessment of the association between vitamin D and cancer susceptibility using Mendelian randomization
Authors: Ong Jue-Sheng , Dixon-Suen Suzanne C. , Han Xikun , An Jiyuan ,   Esophageal Cancer Consortium, Fitzgerald Rebecca , Buas Matt , Gammon Marilie D. , Corley Douglas A. , Shaheen Nicholas J. , Hardie Laura J. , Bird Nigel C. , Reid Brian J. , Chow Wong-Ho , Risch Harvey A. , Ye Weimin , Liu Geoffrey , Romero Yvonne , Bernstein Leslie , Wu Anna H. , Whiteman David E. , Vaughan Thomas ,   23 and Me Research Team, Agee M. , Alipanahi B. , Auton A. , Bell R. K. , Bryc K. , Elson S. L. , Fontanillas P. , Furlotte N. A. , Hinds D. A. , Huber K. E. , Kleinman A. , Litterman N. K. , McIntyre M. H. , Mountain J. L. , Noblin E. S. , Northover C. A. M. , Pitts S. J. , Sathirapongsasuti J. Fah , Sazonova O. V. , Shelton J. F. , Shringarpure S. , Tian C. , Tung J. Y. , Vacic V. , Wilson C. H. , Liyanage Upekha , Dusingize Jean-Cluade , Schumacher Johannes , Gockel Ines , Böhmer Anne , Jankowski Janusz , Palles Claire , O’Mara Tracy , Spurdle Amanda , Law Matthew H. , Iles Mark M. , Pharoah Paul , Berchuck Andrew , Zheng Wei , Thrift Aaron P. , Olsen Catherine , Neale Rachel E. , Gharahkhani Puya , Webb Penelope M. , MacGregor Stuart
Published: January 2021

Previous Mendelian randomization (MR) studies on 25-hydroxyvitamin D (25(OH)D) and cancer have typically adopted a handful of variants and found no relationship between 25(OH)D and cancer; however, issues of horizontal pleiotropy cannot be reliably addressed. Using a larger set of variants associated with 25(OH)D (74 SNPs, up from 6 previously), we perform a unified MR analysis to re-evaluate the relationship between 25(OH)D and ten cancers. Our findings are broadly consistent with previous MR studies indicating no relationship, apart from ovarian cancers (OR 0.89; 95% C.I: 0.82 to 0.96 per 1 SD change in 25(OH)D concentration) and basal cell carcinoma (OR 1.16; 95% C.I.: 1.04 to 1.28). However, after adjustment for pigmentation related variables in a multivariable MR framework, the BCC findings were attenuated. Here we report that lower 25(OH)D is unlikely to be a causal risk factor for most cancers, with our study providing more precise confidence intervals than previously possible.
BRD4-mediated repression of p53 is a target for combination therapy in AML
Authors: Latif Anne-Louise , Newcombe Ashley , Li Sha , Gilroy Kathryn , Robertson Neil A. , Lei Xue , Stewart Helen J. S. , Cole John , Terradas Maria Terradas , Rishi Loveena , McGarry Lynn , McKeeve Claire , Reid Claire , Clark William , Campos Joana , Kirschner Kristina , Davis Andrew , Lopez Jonathan , Sakamaki Jun-ichi , Morton Jennifer P. , Ryan Kevin M. , Tait Stephen W. G. , Abraham Sheela A. , Holyoake Tessa , Higgins Brian , Huang Xu , Blyth Karen , Copland Mhairi , Chevassut Timothy J. T. , Keeshan Karen , Adams Peter D.
Published: January 2021

Acute myeloid leukemia (AML) is a typically lethal molecularly heterogeneous disease, with few broad-spectrum therapeutic targets. Unusually, most AML retain wild-type TP53, encoding the pro-apoptotic tumor suppressor p53. MDM2 inhibitors (MDM2i), which activate wild-type p53, and BET inhibitors (BETi), targeting the BET-family co-activator BRD4, both show encouraging pre-clinical activity, but limited clinical activity as single agents. Here, we report enhanced toxicity of combined MDM2i and BETi towards AML cell lines, primary human blasts and mouse models, resulting from BETi’s ability to evict an unexpected repressive form of BRD4 from p53 target genes, and hence potentiate MDM2i-induced p53 activation. These results indicate that wild-type TP53 and a transcriptional repressor function of BRD4 together represent a potential broad-spectrum synthetic therapeutic vulnerability for AML.
BET inhibition disrupts transcription but retains enhancer-promoter contact
Authors: Crump Nicholas T. , Ballabio Erica , Godfrey Laura , Thorne Ross , Repapi Emmanouela , Kerry Jon , Tapia Marta , Hua Peng , Lagerholm Christoffer , Filippakopoulos Panagis , Davies James O. J. , Milne Thomas A.
Published: January 2021

Enhancers are DNA sequences that enable complex temporal and tissue-specific regulation of genes in higher eukaryotes. Although it is not entirely clear how enhancer-promoter interactions can increase gene expression, this proximity has been observed in multiple systems at multiple loci and is thought to be essential for the maintenance of gene expression. Bromodomain and Extra-Terminal domain (BET) and Mediator proteins have been shown capable of forming phase condensates and are thought to be essential for super-enhancer function. Here, we show that targeting of cells with inhibitors of BET proteins or pharmacological degradation of BET protein Bromodomain-containing protein 4 (BRD4) has a strong impact on transcription but very little impact on enhancer-promoter interactions. Dissolving phase condensates reduces BRD4 and Mediator binding at enhancers and can also strongly affect gene transcription, without disrupting enhancer-promoter interactions. These results suggest that activation of transcription and maintenance of enhancer-promoter interactions are separable events. Our findings further indicate that enhancer-promoter interactions are not dependent on high levels of BRD4 and Mediator, and are likely maintained by a complex set of factors including additional activator complexes and, at some sites, CTCF and cohesin.
Engineering of a bona fide light-operated calcium channel
Authors: He Lian , Wang Liuqing , Zeng Hongxiang , Tan Peng , Ma Guolin , Zheng Sisi , Li Yaxin , Sun Lin , Dou Fei , Siwko Stefan , Huang Yun , Wang Youjun , Zhou Yubin
Published: January 2021

The current optogenetic toolkit lacks a robust single-component Ca2+-selective ion channel tailored for remote control of Ca2+ signaling in mammals. Existing tools are either derived from engineered channelrhodopsin variants without strict Ca2+ selectivity or based on the stromal interaction molecule 1 (STIM1) that might crosstalk with other targets. Here, we describe the design of a light-operated Ca2+ channel (designated LOCa) by inserting a plant-derived photosensory module into the intracellular loop of an engineered ORAI1 channel. LOCa displays biophysical features reminiscent of the ORAI1 channel, which enables precise optical control over Ca2+ signals and hallmark Ca2+-dependent physiological responses. Furthermore, we demonstrate the use of LOCa to modulate aberrant hematopoietic stem cell self-renewal, transcriptional programming, cell suicide, as well as neurodegeneration in a Drosophila model of amyloidosis.
Moiré metrology of energy landscapes in van der Waals heterostructures
Authors: Halbertal Dorri , Finney Nathan R. , Sunku Sai S. , Kerelsky Alexander , Rubio-Verdú Carmen , Shabani Sara , Xian Lede , Carr Stephen , Chen Shaowen , Zhang Charles , Wang Lei , Gonzalez-Acevedo Derick , McLeod Alexander S. , Rhodes Daniel , Watanabe Kenji , Taniguchi Takashi , Kaxiras Efthimios , Dean Cory R. , Hone James C. , Pasupathy Abhay N. , Kennes Dante M. , Rubio Angel , Basov D. N.
Published: January 2021

The emerging field of twistronics, which harnesses the twist angle between two-dimensional materials, represents a promising route for the design of quantum materials, as the twist-angle-induced superlattices offer means to control topology and strong correlations. At the small twist limit, and particularly under strain, as atomic relaxation prevails, the emergent moiré superlattice encodes elusive insights into the local interlayer interaction. Here we introduce moiré metrology as a combined experiment-theory framework to probe the stacking energy landscape of bilayer structures at the 0.1 meV/atom scale, outperforming the gold-standard of quantum chemistry. Through studying the shapes of moiré domains with numerous nano-imaging techniques, and correlating with multi-scale modelling, we assess and refine first-principle models for the interlayer interaction. We document the prowess of moiré metrology for three representative twisted systems: bilayer graphene, double bilayer graphene and H-stacked MoSe2/WSe2. Moiré metrology establishes sought after experimental benchmarks for interlayer interaction, thus enabling accurate modelling of twisted multilayers.
Spite is contagious in dynamic networks
Authors: Fulker Zachary , Forber Patrick , Smead Rory , Riedl Christoph
Published: January 2021

Spite, costly behavior that harms others, presents an evolutionary puzzle: given that both the actor and recipient do worse, how could it emerge? We show that dynamically evolving interaction networks provide a novel explanation for the evolution of costly harm. Previous work has shown that anti-correlated interaction (e.g., negative assortment or negative relatedness) among behavioral strategies in populations can lead to the evolution of costly harm. We show that these approaches are blind to important features of interaction brought about by a co-evolution of network and behavior and that these features enable the emergence of spite. We analyze a new model in which agents can inflict harm on others at a cost to themselves, and simultaneously learn how to behave and with whom to interact. We find spite emerges reliably under a wide range of conditions. Our model reveals that when interactions occur in dynamic networks the population can exhibit correlated and anti-correlated behavioral interactions simultaneously, something not possible in standard models. In dynamic networks spite evolves due to transient and partial anti-correlated interaction, even when other behaviors are positively correlated and average degree of correlated interaction in the population is low.
Isolation of MERS-related coronavirus from lesser bamboo bats that uses DPP4 and infects human-DPP4-transgenic mice
Authors: Lau Susanna K. P. , Fan Rachel Y. Y. , Zhu Longchao , Li Kenneth S. M. , Wong Antonio C. P. , Luk Hayes K. H. , Wong Emily Y. M. , Lam Carol S. F. , Lo George C. S. , Fung Joshua , He Zirong , Fok Felix C. H. , Au-Yeung Rex K. H. , Zhang Libiao , Kok Kin-Hang , Yuen Kwok-Yung , Woo Patrick C. Y.
Published: January 2021

While a number of human coronaviruses are believed to be originated from ancestral viruses in bats, it remains unclear if bat coronaviruses are ready to cause direct bat-to-human transmission. Here, we report the isolation of a MERS-related coronavirus, Tylonycteris-bat-CoV-HKU4, from lesser bamboo bats. Tylonycteris-bat-CoV-HKU4 replicates efficiently in human colorectal adenocarcinoma and hepatocarcinoma cells with cytopathic effects, and can utilize human-dipeptidyl-peptidase-4 and dromedary camel-dipeptidyl-peptidase-4 as the receptors for cell entry. Flow cytometry, co-immunoprecipitation and surface plasmon resonance assays show that Tylonycteris-bat-CoV-HKU4-receptor-binding-domain can bind human-dipeptidyl-peptidase-4, dromedary camel-dipeptidyl-peptidase-4, and Tylonycteris pachypus-dipeptidyl-peptidase-4. Tylonycteris-bat-CoV-HKU4 can infect human-dipeptidyl-peptidase-4-transgenic mice by intranasal inoculation with self-limiting disease. Positive virus and inflammatory changes were detected in lungs and brains of infected mice, associated with suppression of antiviral cytokines and activation of proinflammatory cytokines and chemokines. The results suggest that MERS-related bat coronaviruses may overcome species barrier by utilizing dipeptidyl-peptidase-4 and potentially emerge in humans by direct bat-to-human transmission.
Cooperative function of synaptophysin and synapsin in the generation of synaptic vesicle-like clusters in non-neuronal cells
Authors: Park Daehun , Wu Yumei , Lee Sang-Eun , Kim Goeun , Jeong Seonyoung , Milovanovic Dragomir , De Camilli Pietro , Chang Sunghoe
Published: January 2021

Clusters of tightly packed synaptic vesicles (SVs) are a defining feature of nerve terminals. While SVs are mobile within the clusters, the clusters have no boundaries consistent with a liquid phase. We previously found that purified synapsin, a peripheral SV protein, can assemble into liquid condensates and trap liposomes into them. How this finding relates to the physiological formation of SV clusters in living cells remains unclear. Here, we report that synapsin alone, when expressed in fibroblasts, has a diffuse cytosolic distribution. However, when expressed together with synaptophysin, an integral SV membrane protein previously shown to be localized on small synaptic-like microvesicles when expressed in non-neuronal cells, is sufficient to organize such vesicles in clusters highly reminiscent of SV clusters and with liquid-like properties. This minimal reconstitution system can be a powerful model to gain mechanistic insight into the assembly of structures which are of fundamental importance in synaptic transmission.
Cryo-EM structure of Helicobacter pylori urease with an inhibitor in the active site at 2.0 Å resolution
Authors: Cunha Eva S. , Chen Xiaorui , Sanz-Gaitero Marta , Mills Deryck J. , Luecke Hartmut
Published: January 2021

Infection of the human stomach by Helicobacter pylori remains a worldwide problem and greatly contributes to peptic ulcer disease and gastric cancer. Without active intervention approximately 50% of the world population will continue to be infected with this gastric pathogen. Current eradication, called triple therapy, entails a proton-pump inhibitor and two broadband antibiotics, however resistance to either clarithromycin or metronidazole is greater than 25% and rising. Therefore, there is an urgent need for a targeted, high-specificity eradication drug. Gastric infection by H. pylori depends on the expression of a nickel-dependent urease in the cytoplasm of the bacteria. Here, we report the 2.0 Å resolution structure of the 1.1 MDa urease in complex with an inhibitor by cryo-electron microscopy and compare it to a β-mercaptoethanol-inhibited structure at 2.5 Å resolution. The structural information is of sufficient detail to aid in the development of inhibitors with high specificity and affinity.
CXCR5 CAR-T cells simultaneously target B cell non-Hodgkin’s lymphoma and tumor-supportive follicular T helper cells
Authors: Bunse Mario , Pfeilschifter Janina , Bluhm Julia , Zschummel Maria , Joedicke Jara J. , Wirges Anthea , Stark Helen , Kretschmer Vivien , Chmielewski Markus , Uckert Wolfgang , Abken Hinrich , Westermann Jörg , Rehm Armin , Höpken Uta E.
Published: January 2021

CAR-T cell therapy targeting CD19 demonstrated strong activity against advanced B cell leukemia, however shows less efficacy against lymphoma with nodal dissemination. To target both B cell Non-Hodgkin’s lymphoma (B-NHLs) and follicular T helper (Tfh) cells in the tumor microenvironment (TME), we apply here a chimeric antigen receptor (CAR) that recognizes human CXCR5 with high avidity. CXCR5, physiologically expressed on mature B and Tfh cells, is also highly expressed on nodal B-NHLs. Anti-CXCR5 CAR-T cells eradicate B-NHL cells and lymphoma-supportive Tfh cells more potently than CD19 CAR-T cells in vitro, and they efficiently inhibit lymphoma growth in a murine xenograft model. Administration of anti-murine CXCR5 CAR-T cells in syngeneic mice specifically depletes endogenous and malignant B and Tfh cells without unexpected on-target/off-tumor effects. Collectively, anti-CXCR5 CAR-T cells provide a promising treatment strategy for nodal B-NHLs through the simultaneous elimination of lymphoma B cells and Tfh cells of the tumor-supporting TME.
3D printing of inherently nanoporous polymers via polymerization-induced phase separation
Authors: Dong Zheqin , Cui Haijun , Zhang Haodong , Wang Fei , Zhan Xiang , Mayer Frederik , Nestler Britta , Wegener Martin , Levkin Pavel A.
Published: January 2021

3D printing offers enormous flexibility in fabrication of polymer objects with complex geometries. However, it is not suitable for fabricating large polymer structures with geometrical features at the sub-micrometer scale. Porous structure at the sub-micrometer scale can render macroscopic objects with unique properties, including similarities with biological interfaces, permeability and extremely large surface area, imperative inter alia for adsorption, separation, sensing or biomedical applications. Here, we introduce a method combining advantages of 3D printing via digital light processing and polymerization-induced phase separation, which enables formation of 3D polymer structures of digitally defined macroscopic geometry with controllable inherent porosity at the sub-micrometer scale. We demonstrate the possibility to create 3D polymer structures of highly complex geometries and spatially controlled pore sizes from 10 nm to 1000 µm. Produced hierarchical polymers combining nanoporosity with micrometer-sized pores demonstrate improved adsorption performance due to better pore accessibility and favored cell adhesion and growth for 3D cell culture due to surface porosity. This method extends the scope of applications of 3D printing to hierarchical inherently porous 3D objects combining structural features ranging from 10 nm up to cm, making them available for a wide variety of applications.
Disulfide disruption reverses mucus dysfunction in allergic airway disease
Authors: Morgan Leslie E. , Jaramillo Ana M. , Shenoy Siddharth K. , Raclawska Dorota , Emezienna Nkechinyere A. , Richardson Vanessa L. , Hara Naoko , Harder Anna Q. , NeeDell James C. , Hennessy Corinne E. , El-Batal Hassan M. , Magin Chelsea M. , Grove Villalon Diane E. , Duncan Gregg , Hanes Justin S. , Suk Jung Soo , Thornton David J. , Holguin Fernando , Janssen William J. , Thelin William R. , Evans Christopher M.
Published: January 2021

Airway mucus is essential for lung defense, but excessive mucus in asthma obstructs airflow, leading to severe and potentially fatal outcomes. Current asthma treatments have minimal effects on mucus, and the lack of therapeutic options stems from a poor understanding of mucus function and dysfunction at a molecular level and in vivo. Biophysical properties of mucus are controlled by mucin glycoproteins that polymerize covalently via disulfide bonds. Once secreted, mucin glycopolymers can aggregate, form plugs, and block airflow. Here we show that reducing mucin disulfide bonds disrupts mucus in human asthmatics and reverses pathological effects of mucus hypersecretion in a mouse allergic asthma model. In mice, inhaled mucolytic treatment loosens mucus mesh, enhances mucociliary clearance, and abolishes airway hyperreactivity (AHR) to the bronchoprovocative agent methacholine. AHR reversal is directly related to reduced mucus plugging. These findings establish grounds for developing treatments to inhibit effects of mucus hypersecretion in asthma.
Stream-specific feedback inputs to the primate primary visual cortex
Authors: Federer Frederick , Ta’afua Seminare , Merlin Sam , Hassanpour Mahlega S. , Angelucci Alessandra
Published: January 2021

The sensory neocortex consists of hierarchically-organized areas reciprocally connected via feedforward and feedback circuits. Feedforward connections shape the receptive field properties of neurons in higher areas within parallel streams specialized in processing specific stimulus attributes. Feedback connections have been implicated in top-down modulations, such as attention, prediction and sensory context. However, their computational role remains unknown, partly because we lack knowledge about rules of feedback connectivity to constrain models of feedback function. For example, it is unknown whether feedback connections maintain stream-specific segregation, or integrate information across parallel streams. Using viral-mediated labeling of feedback connections arising from specific cytochrome-oxidase stripes of macaque visual area V2, here we show that feedback to the primary visual cortex (V1) is organized into parallel streams resembling the reciprocal feedforward pathways. This suggests that functionally-specialized V2 feedback channels modulate V1 responses to specific stimulus attributes, an organizational principle potentially extending to feedback pathways in other sensory systems.
RETRACTED ARTICLE:The Arabidopsis NOT4A E3 ligase promotes PGR3 expression and regulates chloroplast translation
Authors: Bailey Mark , Ivanauskaite Aiste , Grimmer Julia , Akintewe Oluwatunmise , Payne Adrienne C. , Osborne Rory , Labandera Anne-Marie , Etherington Ross D. , Rantala Marjaana , Baginsky Sacha , Mulo Paula , Gibbs Daniel J.
Published: January 2021

Chloroplast function requires the coordinated action of nuclear- and chloroplast-derived proteins, including several hundred nuclear-encoded pentatricopeptide repeat (PPR) proteins that regulate plastid mRNA metabolism. Despite their large number and importance, regulatory mechanisms controlling PPR expression are poorly understood. Here we show that the Arabidopsis NOT4A ubiquitin-ligase positively regulates the expression of PROTON GRADIENT REGULATION 3 (PGR3), a PPR protein required for translating several thylakoid-localised photosynthetic components and ribosome subunits within chloroplasts. Loss of NOT4A function leads to a strong depletion of cytochrome b6f and NAD(P)H dehydrogenase (NDH) complexes, as well as plastid 30 S ribosomes, which reduces mRNA translation and photosynthetic capacity, causing pale-yellow and slow-growth phenotypes. Quantitative transcriptome and proteome analysis of thenot4amutant reveal it lacksPGR3expression, and that its molecular defects resemble those of apgr3mutant. Furthermore, we show that normal plastid function is restored tonot4athrough transgenicPGR3expression. Our work identifies NOT4A as crucial for ensuring robust photosynthetic function during development and stress-response, through promoting PGR3 production and chloroplast translation.
Data-independent acquisition method for ubiquitinome analysis reveals regulation of circadian biology
Authors: Hansen Fynn M. , Tanzer Maria C. , Brüning Franziska , Bludau Isabell , Stafford Che , Schulman Brenda A. , Robles Maria S. , Karayel Ozge , Mann Matthias
Published: January 2021

Protein ubiquitination is involved in virtually all cellular processes. Enrichment strategies employing antibodies targeting ubiquitin-derived diGly remnants combined with mass spectrometry (MS) have enabled investigations of ubiquitin signaling at a large scale. However, so far the power of data independent acquisition (DIA) with regards to sensitivity in single run analysis and data completeness have not yet been explored. Here, we develop a sensitive workflow combining diGly antibody-based enrichment and optimized Orbitrap-based DIA with comprehensive spectral libraries together containing more than 90,000 diGly peptides. This approach identifies 35,000 diGly peptides in single measurements of proteasome inhibitor-treated cells – double the number and quantitative accuracy of data dependent acquisition. Applied to TNF signaling, the workflow comprehensively captures known sites while adding many novel ones. An in-depth, systems-wide investigation of ubiquitination across the circadian cycle uncovers hundreds of cycling ubiquitination sites and dozens of cycling ubiquitin clusters within individual membrane protein receptors and transporters, highlighting new connections between metabolism and circadian regulation.
Reaction kinetics and interplay of two different surface states on hematite photoanodes for water oxidation
Authors: Li Jingguo , Wan Wenchao , Triana Carlos A. , Chen Hang , Zhao Yonggui , Mavrokefalos Christos K. , Patzke Greta R.
Published: January 2021

Understanding the function of surface states on photoanodes is crucial for unraveling the underlying reaction mechanisms of water oxidation. For hematite photoanodes, only one type of surface states with higher oxidative energy (S1) has been proposed and verified as reaction intermediate, while the other surface state located at lower potentials (S2) was assigned to inactive or recombination sites. Through employing rate law analyses and systematical (photo)electrochemical characterizations, here we show that S2 is an active reaction intermediate for water oxidation as well. Furthermore, we demonstrate that the reaction kinetics and dynamic interactions of both S1 and S2 depend significantly on operational parameters, such as illumination intensity, nature of the electrolyte, and applied potential. These insights into the individual reaction kinetics and the interplay of both surface states are decisive for designing efficient photoanodes.
In situ NMR reveals real-time nanocrystal growth evolution via monomer-attachment or particle-coalescence
Authors: Mashiach Reut , Weissman Haim , Avram Liat , Houben Lothar , Brontvein Olga , Lavie Anna , Arunachalam Vaishali , Leskes Michal , Rybtchinski Boris , Bar-Shir Amnon
Published: January 2021

Understanding inorganic nanocrystal (NC) growth dynamic pathways under their native fabrication environment remains a central goal of science, as it is crucial for rationalizing novel nanoformulations with desired architectures and functionalities. We here present an in-situ method for quantifying, in real time, NCs’ size evolution at sub-nm resolution, their concentration, and reactants consumption rate for studying NC growth mechanisms. Analyzing sequential high-resolution liquid-state 19F-NMR spectra obtained in-situ and validating by ex-situ cryoTEM, we explore the growth evolution of fluoride-based NCs (CaF2 and SrF2) in water, without disturbing the synthesis conditions. We find that the same nanomaterial (CaF2) can grow by either a particle-coalescence or classical-growth mechanism, as regulated by the capping ligand, resulting in different crystallographic properties and functional features of the fabricated NC. The ability to reveal, in real time, mechanistic pathways at which NCs grow open unique opportunities for tunning the properties of functional materials.
Transcription shapes genome-wide histone acetylation patterns
Authors: Martin Benjamin J. E. , Brind’Amour Julie , Kuzmin Anastasia , Jensen Kristoffer N. , Liu Zhen Cheng , Lorincz Matthew , Howe LeAnn J.
Published: January 2021

Histone acetylation is a ubiquitous hallmark of transcription, but whether the link between histone acetylation and transcription is causal or consequential has not been addressed. Using immunoblot and chromatin immunoprecipitation-sequencing in S. cerevisiae, here we show that the majority of histone acetylation is dependent on transcription. This dependency is partially explained by the requirement of RNA polymerase II (RNAPII) for the interaction of H4 histone acetyltransferases (HATs) with gene bodies. Our data also confirms the targeting of HATs by transcription activators, but interestingly, promoter-bound HATs are unable to acetylate histones in the absence of transcription. Indeed, HAT occupancy alone poorly predicts histone acetylation genome-wide, suggesting that HAT activity is regulated post-recruitment. Consistent with this, we show that histone acetylation increases at nucleosomes predicted to stall RNAPII, supporting the hypothesis that this modification is dependent on nucleosome disruption during transcription. Collectively, these data show that histone acetylation is a consequence of RNAPII promoting both the recruitment and activity of histone acetyltransferases.
Graphene active sensor arrays for long-term and wireless mapping of wide frequency band epicortical brain activity
Authors: Garcia-Cortadella R. , Schwesig G. , Jeschke C. , Illa X. , Gray Anna L. , Savage S. , Stamatidou E. , Schiessl I. , Masvidal-Codina E. , Kostarelos K. , Guimerà-Brunet A. , Sirota A. , Garrido J. A.
Published: January 2021

Graphene active sensors have demonstrated promising capabilities for the detection of electrophysiological signals in the brain. Their functional properties, together with their flexibility as well as their expected stability and biocompatibility have raised them as a promising building block for large-scale sensing neural interfaces. However, in order to provide reliable tools for neuroscience and biomedical engineering applications, the maturity of this technology must be thoroughly studied. Here, we evaluate the performance of 64-channel graphene sensor arrays in terms of homogeneity, sensitivity and stability using a wireless, quasi-commercial headstage and demonstrate the biocompatibility of epicortical graphene chronic implants. Furthermore, to illustrate the potential of the technology to detect cortical signals from infra-slow to high-gamma frequency bands, we perform proof-of-concept long-term wireless recording in a freely behaving rodent. Our work demonstrates the maturity of the graphene-based technology, which represents a promising candidate for chronic, wide frequency band neural sensing interfaces.
Self-assembled organic nanomedicine enables ultrastable photo-to-heat converting theranostics in the second near-infrared biowindow
Authors: Xiang Huijing , Zhao Lingzhi , Yu Luodan , Chen Hongzhong , Wei Chenyang , Chen Yu , Zhao Yanli
Published: January 2021

Development of organic theranostic agents that are active in the second near-infrared (NIR-II, 1000–1700 nm) biowindow is of vital significance for treating deep-seated tumors. However, studies on organic NIR-II absorbing agents for photo-to-heat energy-converting theranostics are still rare simply because of tedious synthetic routes to construct extended π systems in the NIR-II region. Herein, we design a convenient strategy to engineer highly stable organic NIR-II absorbing theranostic nanoparticles (Nano-BFF) for effective phototheranostic applications via co-assembling first NIR (NIR-I, 650–1000 nm) absorbing boron difluoride formazanate (BFF) dye with a biocompatible polymer, endowing the Nano-BFF with remarkable theranostic performance in the NIR-II region. In vitro and in vivo investigations validate that Nano-BFF can serve as an efficient theranostic agent to achieve photoacoustic imaging guided deep-tissue photonic hyperthermia in the NIR-II biowindow, achieving dramatic inhibition toward orthotopic hepatocellular carcinoma. This work thus provides an insight into the exploration of versatile organic NIR-II absorbing nanoparticles toward future practical applications.
Topographic maps representing haptic numerosity reveals distinct sensory representations in supramodal networks
Authors: Hofstetter Shir , Cai Yuxuan , Harvey Ben M. , Dumoulin Serge O.
Published: January 2021

Dedicated maps for cognitive quantities such as timing, size and numerosity support the view that topography is a general principle of brain organization. To date, however, all of these maps were driven by the visual system. Here, we ask whether there are supramodal topographic maps representing cognitive dimensions irrespective of the stimulated sensory modality. We measured haptically and visually driven numerosity-selective neural responses using model-based analyses and ultra-high field (7T) fMRI. We found topographically organized neural populations tuned to haptic numerosity. The responses to visual or haptic numerosity shared a similar cortical network. However, the maps of the two modalities only partially overlap. Thus, although both visual and haptic numerosities are processed in a similar supramodal functional network, the underlying neural populations may be related, but distinct. Therefore, we hypothesize that overlap between modality-specific maps facilitates cross-modal interactions and supramodal representation of cognitive quantities.
Duration and key determinants of infectious virus shedding in hospitalized patients with coronavirus disease-2019 (COVID-19)
Authors: van Kampen Jeroen J. A. , van de Vijver David A. M. C. , Fraaij Pieter L. A. , Haagmans Bart L. , Lamers Mart M. , Okba Nisreen , van den Akker Johannes P. C. , Endeman Henrik , Gommers Diederik A. M. P. J. , Cornelissen Jan J. , Hoek Rogier A. S. , van der Eerden Menno M. , Hesselink Dennis A. , Metselaar Herold J. , Verbon Annelies , de Steenwinkel Jurriaan E. M. , Aron Georgina I. , van Gorp Eric C. M. , van Boheemen Sander , Voermans Jolanda C. , Boucher Charles A. B. , Molenkamp Richard , Koopmans Marion P. G. , Geurtsvankessel Corine , van der Eijk Annemiek A.
Published: January 2021

Key questions in COVID-19 are the duration and determinants of infectious virus shedding. Here, we report that infectious virus shedding is detected by virus cultures in 23 of the 129 patients (17.8%) hospitalized with COVID-19. The median duration of shedding infectious virus is 8 days post onset of symptoms (IQR 5–11) and drops below 5% after 15.2 days post onset of symptoms (95% confidence interval (CI) 13.4–17.2). Multivariate analyses identify viral loads above 7 log10 RNA copies/mL (odds ratio [OR] of 14.7 (CI 3.57-58.1; p < 0.001) as independently associated with isolation of infectious SARS-CoV-2 from the respiratory tract. A serum neutralizing antibody titre of at least 1:20 (OR of 0.01 (CI 0.003-0.08; p < 0.001) is independently associated with non-infectious SARS-CoV-2. We conclude that quantitative viral RNA load assays and serological assays could be used in test-based strategies to discontinue or de-escalate infection prevention and control precautions.
Characterization of a new Leishmania major strain for use in a controlled human infection model
Authors: Ashwin Helen , Sadlova Jovana , Vojtkova Barbora , Becvar Tomas , Lypaczewski Patrick , Schwartz Eli , Greensted Elizabeth , Van Bocxlaer Katrien , Pasin Marion , Lipinski Kai S. , Parkash Vivak , Matlashewski Greg , Layton Alison M. , Lacey Charles J. , Jaffe Charles L. , Volf Petr , Kaye Paul M.
Published: January 2021

Leishmaniasis is widely regarded as a vaccine-preventable disease, but the costs required to reach pivotal Phase 3 studies and uncertainty about which candidate vaccines should be progressed into human studies significantly limits progress in vaccine development for this neglected tropical disease. Controlled human infection models (CHIMs) provide a pathway for accelerating vaccine development and to more fully understand disease pathogenesis and correlates of protection. Here, we describe the isolation, characterization and GMP manufacture of a new clinical strain ofLeishmania major. Two fresh strains ofL. majorfrom Israel were initially compared by genome sequencing, in vivo infectivity and drug sensitivity in mice, and development and transmission competence in sand flies, allowing one to be selected for GMP production. This study addresses a major roadblock in the development of vaccines for leishmaniasis, providing a key resource for CHIM studies of sand fly transmitted cutaneous leishmaniasis.