bluuebunny/crossref_metadata_2025 huggingface dataset:
The evolution of critical thermal limits of life on Earth
Authors: Bennett Joanne M. , Sunday Jennifer , Calosi Piero , Villalobos Fabricio , Martínez Brezo , Molina-Venegas Rafael , Araújo Miguel B. , Algar Adam C. , Clusella-Trullas Susana , Hawkins Bradford A. , Keith Sally A. , Kühn Ingolf , Rahbek Carsten , Rodríguez Laura , Singer Alexander , Morales-Castilla Ignacio , Olalla-Tárraga Miguel Ángel
Published: February 2021

Understanding how species’ thermal limits have evolved across the tree of life is central to predicting species’ responses to climate change. Here, using experimentally-derived estimates of thermal tolerance limits for over 2000 terrestrial and aquatic species, we show that most of the variation in thermal tolerance can be attributed to a combination of adaptation to current climatic extremes, and the existence of evolutionary ‘attractors’ that reflect either boundaries or optima in thermal tolerance limits. Our results also reveal deep-time climate legacies in ectotherms, whereby orders that originated in cold paleoclimates have presently lower cold tolerance limits than those with warm thermal ancestry. Conversely, heat tolerance appears unrelated to climate ancestry. Cold tolerance has evolved more quickly than heat tolerance in endotherms and ectotherms. If the past tempo of evolution for upper thermal limits continues, adaptive responses in thermal limits will have limited potential to rescue the large majority of species given the unprecedented rate of contemporary climate change.
Common clonal origin of conventional T cells and induced regulatory T cells in breast cancer patients
Authors: Xydia Maria , Rahbari Raheleh , Ruggiero Eliana , Macaulay Iain , Tarabichi Maxime , Lohmayer Robert , Wilkening Stefan , Michels Tillmann , Brown Daniel , Vanuytven Sebastiaan , Mastitskaya Svetlana , Laidlaw Sean , Grabe Niels , Pritsch Maria , Fronza Raffaele , Hexel Klaus , Schmitt Steffen , Müller-Steinhardt Michael , Halama Niels , Domschke Christoph , Schmidt Manfred , von Kalle Christof , Schütz Florian , Voet Thierry , Beckhove Philipp
Published: February 2021

Regulatory CD4+ T cells (Treg) prevent tumor clearance by conventional T cells (Tconv) comprising a major obstacle of cancer immune-surveillance. Hitherto, the mechanisms of Treg repertoire formation in human cancers remain largely unclear. Here, we analyze Treg clonal origin in breast cancer patients using T-Cell Receptor and single-cell transcriptome sequencing. While Treg in peripheral blood and breast tumors are clonally distinct, Tconv clones, including tumor-antigen reactive effectors (Teff), are detected in both compartments. Tumor-infiltrating CD4+ cells accumulate into distinct transcriptome clusters, including early activated Tconv, uncommitted Teff, Th1 Teff, suppressive Treg and pro-tumorigenic Treg. Trajectory analysis suggests early activated Tconv differentiation either into Th1 Teff or into suppressive and pro-tumorigenic Treg. Importantly, Tconv, activated Tconv and Treg share highly-expanded clones contributing up to 65% of intratumoral Treg. Here we show that Treg in human breast cancer may considerably stem from antigen-experienced Tconv converting into secondary induced Treg through intratumoral activation.
Patient-derived xenografts and organoids model therapy response in prostate cancer
Authors: Karkampouna Sofia , La Manna Federico , Benjak Andrej , Kiener Mirjam , De Menna Marta , Zoni Eugenio , Grosjean Joël , Klima Irena , Garofoli Andrea , Bolis Marco , Vallerga Arianna , Theurillat Jean-Philippe , De Filippo Maria R. , Genitsch Vera , Keller David , Booij Tijmen H. , Stirnimann Christian U. , Eng Kenneth , Sboner Andrea , Ng Charlotte K. Y. , Piscuoglio Salvatore , Gray Peter C. , Spahn Martin , Rubin Mark A. , Thalmann George N. , Kruithof-de Julio Marianna
Published: February 2021

Therapy resistance and metastatic processes in prostate cancer (PCa) remain undefined, due to lack of experimental models that mimic different disease stages. We describe an androgen-dependent PCa patient-derived xenograft (PDX) model from treatment-naïve, soft tissue metastasis (PNPCa). RNA and whole-exome sequencing of the PDX tissue and organoids confirmed transcriptomic and genomic similarity to primary tumor. PNPCa harbors BRCA2 and CHD1 somatic mutations, shows an SPOP/FOXA1-like transcriptomic signature and microsatellite instability, which occurs in 3% of advanced PCa and has never been modeled in vivo. Comparison of the treatment-naïve PNPCa with additional metastatic PDXs (BM18, LAPC9), in a medium-throughput organoid screen of FDA-approved compounds, revealed differential drug sensitivities. Multikinase inhibitors (ponatinib, sunitinib, sorafenib) were broadly effective on all PDX- and patient-derived organoids from advanced cases with acquired resistance to standard-of-care compounds. This proof-of-principle study may provide a preclinical tool to screen drug responses to standard-of-care and newly identified, repurposed compounds.
Interleukin-3 is a predictive marker for severity and outcome during SARS-CoV-2 infections
Authors: Bénard Alan , Jacobsen Anne , Brunner Maximilian , Krautz Christian , Klösch Bettina , Swierzy Izabela , Naschberger Elisabeth , Podolska Malgorzata J. , Kouhestani Dina , David Paul , Birkholz Torsten , Castellanos Ixchel , Trufa Denis , Sirbu Horia , Vetter Marcel , Kremer Andreas E. , Hildner Kai , Hecker Andreas , Edinger Fabian , Tenbusch Matthias , Mühl-Zürbes Petra , Steinkasserer Alexander , Richter Enrico , Streeck Hendrik , Berger Marc M. , Brenner Thorsten , Weigand Markus A. , Swirski Filip K. , Schett Georg , Grützmann Robert , Weber Georg F.
Published: February 2021

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a worldwide health threat. In a prospective multicentric study, we identify IL-3 as an independent prognostic marker for the outcome during SARS-CoV-2 infections. Specifically, low plasma IL-3 levels is associated with increased severity, viral load, and mortality during SARS-CoV-2 infections. Patients with severe COVID-19 exhibit also reduced circulating plasmacytoid dendritic cells (pDCs) and low plasma IFNα and IFNλ levels when compared to non-severe COVID-19 patients. In a mouse model of pulmonary HSV-1 infection, treatment with recombinant IL-3 reduces viral load and mortality. Mechanistically, IL-3 increases innate antiviral immunity by promoting the recruitment of circulating pDCs into the airways by stimulating CXCL12 secretion from pulmonary CD123+ epithelial cells, both, in mice and in COVID-19 negative patients exhibiting pulmonary diseases. This study identifies IL-3 as a predictive disease marker for SARS-CoV-2 infections and as a potential therapeutic target for pulmunory viral infections.
Direct supercritical angle localization microscopy for nanometer 3D superresolution
Authors: Dasgupta Anindita , Deschamps Joran , Matti Ulf , Hübner Uwe , Becker Jan , Strauss Sebastian , Jungmann Ralf , Heintzmann Rainer , Ries Jonas
Published: February 2021

3D single molecule localization microscopy (SMLM) is an emerging superresolution method for structural cell biology, as it allows probing precise positions of proteins in cellular structures. In supercritical angle localization microscopy (SALM), z-positions of single fluorophores are extracted from the intensity of supercritical angle fluorescence, which strongly depends on their distance to the coverslip. Here, we realize the full potential of SALM and improve its z-resolution by more than four-fold compared to the state-of-the-art by directly splitting supercritical and undercritical emission, using an ultra-high NA objective, and applying fitting routines to extract precise intensities of single emitters. We demonstrate nanometer isotropic localization precision on DNA origami structures, and on clathrin coated vesicles and microtubules in cells, illustrating the potential of SALM for cell biology.
Ice-nucleating proteins are activated by low temperatures to control the structure of interfacial water
Authors: Roeters Steven J. , Golbek Thaddeus W. , Bregnhøj Mikkel , Drace Taner , Alamdari Sarah , Roseboom Winfried , Kramer Gertjan , Šantl-Temkiv Tina , Finster Kai , Pfaendtner Jim , Woutersen Sander , Boesen Thomas , Weidner Tobias
Published: February 2021

Ice-nucleation active (INA) bacteria can promote the growth of ice more effectively than any other known material. Using specialized ice-nucleating proteins (INPs), they obtain nutrients from plants by inducing frost damage and, when airborne in the atmosphere, they drive ice nucleation within clouds, which may affect global precipitation patterns. Despite their evident environmental importance, the molecular mechanisms behind INP-induced freezing have remained largely elusive. We investigate the structural basis for the interactions between water and the ice-nucleating protein InaZ from the INA bacterium Pseudomonas syringae. Using vibrational sum-frequency generation (SFG) and two-dimensional infrared spectroscopy, we demonstrate that the ice-active repeats of InaZ adopt a β-helical structure in solution and at water surfaces. In this configuration, interaction between INPs and water molecules imposes structural ordering on the adjacent water network. The observed order of water increases as the interface is cooled to temperatures close to the melting point of water. Experimental SFG data combined with molecular-dynamics simulations and spectral calculations show that InaZ reorients at lower temperatures. This reorientation can enhance water interactions, and thereby the effectiveness of ice nucleation.
Experimental evidence for the existence of a second partially-ordered phase of ice VI
Authors: Yamane Ryo , Komatsu Kazuki , Gouchi Jun , Uwatoko Yoshiya , Machida Shinichi , Hattori Takanori , Ito Hayate , Kagi Hiroyuki
Published: February 2021

Ice exhibits extraordinary structural variety in its polymorphic structures. The existence of a new form of diversity in ice polymorphism has recently been debated in both experimental and theoretical studies, questioning whether hydrogen-disordered ice can transform into multiple hydrogen-ordered phases, contrary to the known one-to-one correspondence between disordered ice and its ordered phase. Here, we report a high-pressure phase, ice XIX, which is a second hydrogen-partially-ordered phase of ice VI. We demonstrate that disordered ice undergoes different manners of hydrogen ordering, which are thermodynamically controlled by pressure in the case of ice VI. Such multiplicity can appear in all disordered ice, and it widely provides a research approach to deepen our knowledge, for example of the crucial issues of ice: the centrosymmetry of hydrogen-ordered configurations and potentially induced (anti-)ferroelectricity. Ultimately, this research opens up the possibility of completing the phase diagram of ice.
Deep learning the collisional cross sections of the peptide universe from a million experimental values
Authors: Meier Florian , Köhler Niklas D. , Brunner Andreas-David , Wanka Jean-Marc H. , Voytik Eugenia , Strauss Maximilian T. , Theis Fabian J. , Mann Matthias
Published: February 2021

The size and shape of peptide ions in the gas phase are an under-explored dimension for mass spectrometry-based proteomics. To investigate the nature and utility of the peptide collisional cross section (CCS) space, we measure more than a million data points from whole-proteome digests of five organisms with trapped ion mobility spectrometry (TIMS) and parallel accumulation-serial fragmentation (PASEF). The scale and precision (CV < 1%) of our data is sufficient to train a deep recurrent neural network that accurately predicts CCS values solely based on the peptide sequence. Cross section predictions for the synthetic ProteomeTools peptides validate the model within a 1.4% median relative error (R > 0.99). Hydrophobicity, proportion of prolines and position of histidines are main determinants of the cross sections in addition to sequence-specific interactions. CCS values can now be predicted for any peptide and organism, forming a basis for advanced proteomics workflows that make full use of the additional information.
Entry of spores into intestinal epithelial cells contributes to recurrence of Clostridioides difficile infection
Authors: Castro-Córdova Pablo , Mora-Uribe Paola , Reyes-Ramírez Rodrigo , Cofré-Araneda Glenda , Orozco-Aguilar Josué , Brito-Silva Christian , Mendoza-León María José , Kuehne Sarah A. , Minton Nigel P. , Pizarro-Guajardo Marjorie , Paredes-Sabja Daniel
Published: February 2021

Clostridioides difficile spores produced during infection are important for the recurrence of the disease. Here, we show that C. difficile spores gain entry into the intestinal mucosa via pathways dependent on host fibronectin-α5β1 and vitronectin-αvβ1. The exosporium protein BclA3, on the spore surface, is required for both entry pathways. Deletion of the bclA3 gene in C. difficile, or pharmacological inhibition of endocytosis using nystatin, leads to reduced entry into the intestinal mucosa and reduced recurrence of the disease in a mouse model. Our findings indicate that C. difficile spore entry into the intestinal barrier can contribute to spore persistence and infection recurrence, and suggest potential avenues for new therapies.
Non-CG methylation and multiple histone profiles associate child abuse with immune and small GTPase dysregulation
Authors: Lutz Pierre-Eric , Chay Marc-Aurèle , Pacis Alain , Chen Gary G. , Aouabed Zahia , Maffioletti Elisabetta , Théroux Jean-François , Grenier Jean-Christophe , Yang Jennie , Aguirre Maria , Ernst Carl , Redensek Adriana , van Kempen Léon C. , Yalcin Ipek , Kwan Tony , Mechawar Naguib , Pastinen Tomi , Turecki Gustavo
Published: February 2021

Early-life adversity (ELA) is a major predictor of psychopathology, and is thought to increase lifetime risk by epigenetically regulating the genome. Here, focusing on the lateral amygdala, a major brain site for emotional homeostasis, we describe molecular cross-talk among multiple mechanisms of genomic regulation, including 6 histone marks and DNA methylation, and the transcriptome, in subjects with a history of ELA and controls. In the healthy brain tissue, we first uncover interactions between different histone marks and non-CG methylation in the CAC context. Additionally, we find that ELA associates with methylomic changes that are as frequent in the CAC as in the canonical CG context, while these two forms of plasticity occur in sharply distinct genomic regions, features, and chromatin states. Combining these multiple data indicates that immune-related and small GTPase signaling pathways are most consistently impaired in the amygdala of ELA individuals. Overall, this work provides insights into genomic brain regulation as a function of early-life experience.
Publisher Correction: Engineered bidirectional promoters enable rapid multi-gene co-expression optimization
Authors: Vogl Thomas , Kickenweiz Thomas , Pitzer Julia , Sturmberger Lukas , Weninger Astrid , Biggs Bradley W. , Köhler Eva-Maria , Baumschlager Armin , Fischer Jasmin Elgin , Hyden Patrick , Wagner Marlies , Baumann Martina , Borth Nicole , Geier Martina , Ajikumar Parayil Kumaran , Glieder Anton
Published: February 2021

A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-21369-z
Acoustofluidic rotational tweezing enables high-speed contactless morphological phenotyping of zebrafish larvae
Authors: Chen Chuyi , Gu Yuyang , Philippe Julien , Zhang Peiran , Bachman Hunter , Zhang Jinxin , Mai John , Rufo Joseph , Rawls John F. , Davis Erica E. , Katsanis Nicholas , Huang Tony Jun
Published: February 2021

Modern biomedical research and preclinical pharmaceutical development rely heavily on the phenotyping of small vertebrate models for various diseases prior to human testing. In this article, we demonstrate an acoustofluidic rotational tweezing platform that enables contactless, high-speed, 3D multispectral imaging and digital reconstruction of zebrafish larvae for quantitative phenotypic analysis. The acoustic-induced polarized vortex streaming achieves contactless and rapid (~1 s/rotation) rotation of zebrafish larvae. This enables multispectral imaging of the zebrafish body and internal organs from different viewing perspectives. Moreover, we develop a 3D reconstruction pipeline that yields accurate 3D models based on the multi-view images for quantitative evaluation of basic morphological characteristics and advanced combinations of metrics. With its contactless nature and advantages in speed and automation, our acoustofluidic rotational tweezing system has the potential to be a valuable asset in numerous fields, especially for developmental biology, small molecule screening in biochemistry, and pre-clinical drug development in pharmacology.
Towards tellurium-free thermoelectric modules for power generation from low-grade heat
Authors: Ying Pingjun , He Ran , Mao Jun , Zhang Qihao , Reith Heiko , Sui Jiehe , Ren Zhifeng , Nielsch Kornelius , Schierning Gabi
Published: February 2021

Thermoelectric technology converts heat into electricity directly and is a promising source of clean electricity. Commercial thermoelectric modules have relied on Bi2Te3-based compounds because of their unparalleled thermoelectric properties at temperatures associated with low-grade heat (<550 K). However, the scarcity of elemental Te greatly limits the applicability of such modules. Here we report the performance of thermoelectric modules assembled from Bi2Te3-substitute compounds, including p-type MgAgSb and n-type Mg3(Sb,Bi)2, by using a simple, versatile, and thus scalable processing routine. For a temperature difference of ~250 K, whereas a single-stage module displayed a conversion efficiency of ~6.5%, a module using segmented n-type legs displayed a record efficiency of ~7.0% that is comparable to the state-of-the-art Bi2Te3-based thermoelectric modules. Our work demonstrates the feasibility and scalability of high-performance thermoelectric modules based on sustainable elements for recovering low-grade heat.
Transcription activation by a sliding clamp
Authors: Shi Jing , Wen Aijia , Jin Sha , Gao Bo , Huang Yang , Feng Yu
Published: February 2021

Transcription activation of bacteriophage T4 late genes is accomplished by a transcription activation complex containing RNA polymerase (RNAP), the promoter specificity factor gp55, the coactivator gp33, and a universal component of cellular DNA replication, the sliding clamp gp45. Although genetic and biochemical studies have elucidated many aspects of T4 late gene transcription, no precise structure of the transcription machinery in the process is available. Here, we report the cryo-EM structures of a gp55-dependent RNAP-promoter open complex and an intact gp45-dependent transcription activation complex. The structures reveal the interactions between gp55 and the promoter DNA that mediate the recognition of T4 late promoters. In addition to the σR2 homology domain, gp55 has a helix-loop-helix motif that chaperons the template-strand single-stranded DNA of the transcription bubble. Gp33 contacts both RNAP and the upstream double-stranded DNA. Gp45 encircles the DNA and tethers RNAP to it, supporting the idea that gp45 switches the promoter search from three-dimensional diffusion mode to one-dimensional scanning mode.
Bifurcation in brain dynamics reveals a signature of conscious processing independent of report
Authors: Sergent Claire , Corazzol Martina , Labouret Ghislaine , Stockart François , Wexler Mark , King Jean-Rémi , Meyniel Florent , Pressnitzer Daniel
Published: February 2021

An outstanding challenge for consciousness research is to characterize the neural signature of conscious access independently of any decisional processes. Here we present a model-based approach that uses inter-trial variability to identify the brain dynamics associated with stimulus processing. We demonstrate that, even in the absence of any task or behavior, the electroencephalographic response to auditory stimuli shows bifurcation dynamics around 250–300 milliseconds post-stimulus. Namely, the same stimulus gives rise to late sustained activity on some trials, and not on others. This late neural activity is predictive of task-related reports, and also of reports of conscious contents that are randomly sampled during task-free listening. Source localization further suggests that task-free conscious access recruits the same neural networks as those associated with explicit report, except for frontal executive components. Studying brain dynamics through variability could thus play a key role for identifying the core signatures of conscious access, independent of report.
Moulding hydrodynamic 2D-crystals upon parametric Faraday waves in shear-functionalized water surfaces
Authors: Kharbedia Mikheil , Caselli Niccolò , Herráez-Aguilar Diego , López-Menéndez Horacio , Enciso Eduardo , Santiago José A. , Monroy Francisco
Published: February 2021

Faraday waves, or surface waves oscillating at half of the natural frequency when a liquid is vertically vibrated, are archetypes of ordering transitions on liquid surfaces. Although unbounded Faraday waves patterns sustained upon bulk frictional stresses have been reported in highly viscous fluids, the role of surface rigidity has not been investigated so far. Here, we demonstrate that dynamically frozen Faraday waves—that we call 2D-hydrodynamic crystals—do appear as ordered patterns of nonlinear gravity-capillary modes in water surfaces functionalized with soluble (bio)surfactants endowing in-plane shear stiffness. The phase coherence in conjunction with the increased surface rigidity bears the Faraday waves ordering transition, upon which the hydrodynamic crystals were reversibly molded under parametric control of their degree of order, unit cell size and symmetry. The hydrodynamic crystals here discovered could be exploited in touchless strategies of soft matter and biological scaffolding ameliorated under external control of Faraday waves coherence.
Bioinspired multisensory neural network with crossmodal integration and recognition
Authors: Tan Hongwei , Zhou Yifan , Tao Quanzheng , Rosen Johanna , van Dijken Sebastiaan
Published: February 2021

The integration and interaction of vision, touch, hearing, smell, and taste in the human multisensory neural network facilitate high-level cognitive functionalities, such as crossmodal integration, recognition, and imagination for accurate evaluation and comprehensive understanding of the multimodal world. Here, we report a bioinspired multisensory neural network that integrates artificial optic, afferent, auditory, and simulated olfactory and gustatory sensory nerves. With distributed multiple sensors and biomimetic hierarchical architectures, our system can not only sense, process, and memorize multimodal information, but also fuse multisensory data at hardware and software level. Using crossmodal learning, the system is capable of crossmodally recognizing and imagining multimodal information, such as visualizing alphabet letters upon handwritten input, recognizing multimodal visual/smell/taste information or imagining a never-seen picture when hearing its description. Our multisensory neural network provides a promising approach towards robotic sensing and perception.
KRAS interaction with RAF1 RAS-binding domain and cysteine-rich domain provides insights into RAS-mediated RAF activation
Authors: Tran Timothy H. , Chan Albert H. , Young Lucy C. , Bindu Lakshman , Neale Chris , Messing Simon , Dharmaiah Srisathiyanarayanan , Taylor Troy , Denson John-Paul , Esposito Dominic , Nissley Dwight V. , Stephen Andrew G. , McCormick Frank , Simanshu Dhirendra K.
Published: February 2021

The first step of RAF activation involves binding to active RAS, resulting in the recruitment of RAF to the plasma membrane. To understand the molecular details of RAS-RAF interaction, we present crystal structures of wild-type and oncogenic mutants of KRAS complexed with the RAS-binding domain (RBD) and the membrane-interacting cysteine-rich domain (CRD) from the N-terminal regulatory region of RAF1. Our structures reveal that RBD and CRD interact with each other to form one structural entity in which both RBD and CRD interact extensively with KRAS. Mutations at the KRAS-CRD interface result in a significant reduction in RAF1 activation despite only a modest decrease in binding affinity. Combining our structures and published data, we provide a model of RAS-RAF complexation at the membrane, and molecular insights into RAS-RAF interaction during the process of RAS-mediated RAF activation.
Neuronal fragile X mental retardation protein activates glial insulin receptor mediated PDF-Tri neuron developmental clearance
Authors: Vita Dominic J. , Meier Cole J. , Broadie Kendal
Published: February 2021

Glia engulf and phagocytose neurons during neural circuit developmental remodeling. Disrupting this pruning process contributes to Fragile X syndrome (FXS), a leading cause of intellectual disability and autism spectrum disorder in mammals. Utilizing a Drosophila FXS model central brain circuit, we identify two glial classes responsible for Draper-dependent elimination of developmentally transient PDF-Tri neurons. We find that neuronal Fragile X Mental Retardation Protein (FMRP) drives insulin receptor activation in glia, promotes glial Draper engulfment receptor expression, and negatively regulates membrane-molding ESCRT-III Shrub function during PDF-Tri neuron clearance during neurodevelopment in Drosophila. In this context, we demonstrate genetic interactions between FMRP and insulin receptor signaling, FMRP and Draper, and FMRP and Shrub in PDF-Tri neuron elimination. We show that FMRP is required within neurons, not glia, for glial engulfment, indicating FMRP-dependent neuron-to-glia signaling mediates neuronal clearance. We conclude neuronal FMRP drives glial insulin receptor activation to facilitate Draper- and Shrub-dependent neuronal clearance during neurodevelopment in Drosophila.
Human cortical encoding of pitch in tonal and non-tonal languages
Authors: Li Yuanning , Tang Claire , Lu Junfeng , Wu Jinsong , Chang Edward F.
Published: February 2021

Languages can use a common repertoire of vocal sounds to signify distinct meanings. In tonal languages, such as Mandarin Chinese, pitch contours of syllables distinguish one word from another, whereas in non-tonal languages, such as English, pitch is used to convey intonation. The neural computations underlying language specialization in speech perception are unknown. Here, we use a cross-linguistic approach to address this. Native Mandarin- and English- speaking participants each listened to both Mandarin and English speech, while neural activity was directly recorded from the non-primary auditory cortex. Both groups show language-general coding of speaker-invariant pitch at the single electrode level. At the electrode population level, we find language-specific distribution of cortical tuning parameters in Mandarin speakers only, with enhanced sensitivity to Mandarin tone categories. Our results show that speech perception relies upon a shared cortical auditory feature processing mechanism, which may be tuned to the statistics of a given language.
Spatiotemporally programmable cascade hybridization of hairpin DNA in polymeric nanoframework for precise siRNA delivery
Authors: Li Feng , Yu Wenting , Zhang Jiaojiao , Dong Yuhang , Ding Xiaohui , Ruan Xinhua , Gu Zi , Yang Dayong
Published: February 2021

DNA nanostructures have been demonstrated as promising carriers for gene delivery. In the carrier design, spatiotemporally programmable assembly of DNA under nanoconfinement is important but has proven highly challenging due to the complexity–scalability–error of DNA. Herein, a DNA nanotechnology-based strategy via the cascade hybridization chain reaction (HCR) of DNA hairpins in polymeric nanoframework has been developed to achieve spatiotemporally programmable assembly of DNA under nanoconfinement for precise siRNA delivery. The nanoframework is prepared via precipitation polymerization with Acrydite-DNA as cross-linker. The potential energy stored in the loops of DNA hairpins can overcome the steric effect in the nanoframework, which can help initiate cascade HCR of DNA hairpins and achieve efficient siRNA loading. The designer tethering sequence between DNA and RNA guarantees a triphosadenine triggered siRNA release specifically in cellular cytoplasm. Nanoframework provides stability and ease of functionalization, which helps address the complexity–scalability–error of DNA. It is exemplified that the phenylboronate installation on nanoframework enhanced cellular uptake and smoothed the lysosomal escape. Cellular results show that the siRNA loaded nanoframework down-regulated the levels of relevant mRNA and protein. In vivo experiments show significant therapeutic efficacy of using siPLK1 loaded nanoframework to suppress tumor growth.
Optimal marker gene selection for cell type discrimination in single cell analyses
Authors: Dumitrascu Bianca , Villar Soledad , Mixon Dustin G. , Engelhardt Barbara E.
Published: February 2021

Single-cell technologies characterize complex cell populations across multiple data modalities at unprecedented scale and resolution. Multi-omic data for single cell gene expression, in situ hybridization, or single cell chromatin states are increasingly available across diverse tissue types. When isolating specific cell types from a sample of disassociated cells or performing in situ sequencing in collections of heterogeneous cells, one challenging task is to select a small set of informative markers that robustly enable the identification and discrimination of specific cell types or cell states as precisely as possible. Given single cell RNA-seq data and a set of cellular labels to discriminate, scGeneFit selects gene markers that jointly optimize cell label recovery using label-aware compressive classification methods. This results in a substantially more robust and less redundant set of markers than existing methods, most of which identify markers that separate each cell label from the rest. When applied to a data set given a hierarchy of cell types as labels, the markers found by our method improves the recovery of the cell type hierarchy with fewer markers than existing methods using a computationally efficient and principled optimization.
E3 ligase Nedd4l promotes antiviral innate immunity by catalyzing K29-linked cysteine ubiquitination of TRAF3
Authors: Gao Peng , Ma Xianwei , Yuan Ming , Yi Yulan , Liu Guoke , Wen Mingyue , Jiang Wei , Ji Ruihua , Zhu Lingxi , Tang Zhen , Yu Qingzhuo , Xu Jing , Yang Rui , Xia Sheng , Yang Mingjin , Pan Jianping , Yuan Hongbin , An Huazhang
Published: February 2021

Ubiquitination is one of the most prevalent protein posttranslational modifications. Here, we show that E3 ligase Nedd4l positively regulates antiviral immunity by catalyzing K29-linked cysteine ubiquitination of TRAF3. Deficiency of Nedd4l significantly impairs type I interferon and proinflammatory cytokine production induced by virus infection both in vitro and in vivo. Nedd4l deficiency inhibits virus-induced ubiquitination of TRAF3, the binding between TRAF3 and TBK1, and subsequent phosphorylation of TBK1 and IRF3. Nedd4l directly interacts with TRAF3 and catalyzes K29-linked ubiquitination of Cys56 and Cys124, two cysteines that constitute zinc fingers, resulting in enhanced association between TRAF3 and E3 ligases, cIAP1/2 and HECTD3, and also increased K48/K63-linked ubiquitination of TRAF3. Mutation of Cys56 and Cys124 diminishes Nedd4l-catalyzed K29-linked ubiquitination, but enhances association between TRAF3 and the E3 ligases, supporting Nedd4l promotes type I interferon production in response to virus by catalyzing ubiquitination of the cysteines in TRAF3.
Inflammation status modulates the effect of host genetic variation on intestinal gene expression in inflammatory bowel disease
Authors: Hu Shixian , Uniken Venema Werna T. , Westra Harm-Jan , Vich Vila Arnau , Barbieri Ruggero , Voskuil Michiel D. , Blokzijl Tjasso , Jansen Bernadien H. , Li Yanni , Daly Mark J. , Xavier Ramnik J. , Dijkstra Gerard , Festen Eleonora A. , Weersma Rinse K.
Published: February 2021

More than 240 genetic risk loci have been associated with inflammatory bowel disease (IBD), but little is known about how they contribute to disease development in involved tissue. Here, we hypothesized that host genetic variation affects gene expression in an inflammation-dependent way, and investigated 299 snap-frozen intestinal biopsies from inflamed and non-inflamed mucosa from 171 IBD patients. RNA-sequencing was performed, and genotypes were determined using whole exome sequencing and genome wide genotyping. In total, 28,746 genes and 6,894,979 SNPs were included. Linear mixed models identified 8,881 independent intestinal cis-expression quantitative trait loci (cis-eQTLs) (FDR < 0.05) and interaction analysis revealed 190 inflammation-dependent intestinal cis-eQTLs (FDR < 0.05), including known IBD-risk genes and genes encoding immune-cell receptors and antibodies. The inflammation-dependent cis-eQTL SNPs (eSNPs) mainly interact with prevalence of immune cell types. Inflammation-dependent intestinal cis-eQTLs reveal genetic susceptibility under inflammatory conditions that can help identify the cell types involved in and the pathways underlying inflammation, knowledge that may guide future drug development and profile patients for precision medicine in IBD.
Stable single atomic silver wires assembling into a circuitry-connectable nanoarray
Authors: Chen Yaxin , Tang Daiming , Huang Zhiwei , Liu Xi , Chen Jun , Sekiguchi Takashi , Qu Weiye , Chen Junxiao , Xu Dongrun , Bando Yoshio , Hu Xiaolei , Wang Xiaoping , Golberg Dmitri , Tang Xingfu
Published: February 2021

Atomic metal wires have great promise for practical applications in devices due to their unique electronic properties. Unfortunately, such atomic wires are extremely unstable. Here we fabricate stable atomic silver wires (ASWs) with appreciably unoccupied states inside the parallel tunnels of α-MnO2 nanorods. These unoccupied Ag 4d orbitals strengthen the Ag–Ag bonds, greatly enhancing the stability of ASWs while the presence of delocalized 5s electrons makes the ASWs conducting. These stable ASWs form a coherently oriented three-dimensional wire array of over 10 nm in width and up to 1 μm in length allowing us to connect it to nano-electrodes. Current-voltage characteristics of ASWs show a temperature-dependent insulator-to-metal transition, suggesting that the atomic wires could be used as thermal electrical devices.
Histamine H1 receptor deletion in cholinergic neurons induces sensorimotor gating ability deficit and social impairments in mice
Authors: Cheng Li , Xu Cenglin , Wang Lu , An Dadao , Jiang Lei , Zheng Yanrong , Xu Yixin , Wang Yi , Wang Yujing , Zhang Kuo , Wang Xiaodong , Zhang Xiangnan , Bao Aimin , Zhou Yudong , Yang Jingyu , Duan Shumin , Swaab Dick F. , Hu Weiwei , Chen Zhong
Published: February 2021

Negative symptoms in schizophrenia strongly contribute to poor functional outcomes, however its pathogenesis is still unclear. Here, we found that histamine H1 receptor (H1R) expression in basal forebrain (BF) cholinergic neurons was decreased in patients with schizophrenia having negative symptoms. Deletion of H1R gene in cholinergic neurons in mice resulted in functional deficiency of cholinergic projections from the BF to the prefrontal cortex and in the formation of sensorimotor gating deficit, social impairment and anhedonia-like behavior. These behavioral deficits can be rescued by re-expressing H1R or by chemogenetic activation of cholinergic neurons in the BF. Direct chemogenetic inhibition of BF cholinergic neurons produced such behavioral deficits and also increased the susceptibility to hyperlocomotion. Our results suggest that the H1R deficiency in BF cholinergic neurons is critical for sensorimotor gating deficit, social impairments and anhedonia-like behavior. This finding may help to understand the genetic and biochemical bases of negative symptoms in schizophrenia.
Ultra-sensitive nanometric flat laser prints for binocular stereoscopic image
Authors: Hu Dejiao , Li Hao , Zhu Yupeng , Lei Yuqiu , Han Jing , Xian Shilin , Zheng Jiajin , Guan Bai-Ou , Cao Yaoyu , Bi Lei , Li Xiangping
Published: February 2021

Two-dimensional (2D) transition metal dichalcogenides (TMDs) with tantalizing layer-dependent electronic and optical properties have emerged as a paradigm for integrated flat opto-electronic devices, but their widespread applications are hampered by challenges in deterministic fabrication with demanded shapes and thicknesses, as well as light field manipulation in such atomic-thick layers with negligible thicknesses compared to the wavelength. Here we demonstrate ultra-sensitive light field manipulation in full visible ranges based on MoS2 laser prints exfoliated with nanometric precisions. The nontrivial interfacial phase shifts stemming from the unique dispersion of MoS2 layers integrated on the metallic substrate empower an ultra-sensitive resonance manipulation up to 13.95 nm per MoS2 layer across the entire visible bands, which is up to one-order-of-magnitude larger than their counterparts. The interlayer van der Waals interactions and the anisotropic thermal conductivity of layered MoS2 films endow a laser exfoliation method for on-demand patterning MoS2 with atomic thickness precision and subwavelength feature sizes. With this, nanometric flat color prints and further amplitude-modulated diffractive components for binocular stereoscopic images can be realized in a facile and lithography-free fashion. Our results with demonstrated practicality unlock the potentials of, and pave the way for, widespread applications of emerging 2D flat optics.
Dual- versus single-agent HER2 inhibition and incidence of intracranial metastatic disease: a systematic review and meta-analysis
Authors: Erickson Anders Wilder , Habbous Steven , Hoey Christianne , Jerzak Katarzyna J. , Das Sunit
Published: February 2021

Observational studies have suggested that HER2 inhibition with trastuzumab may be associated with an increased incidence of intracranial metastatic disease (IMD) due to its ability to prolong survival. We hypothesized that prolonged survival associated with dual-agent HER2 inhibition may be associated with an even higher incidence of IMD. This study pooled estimates of IMD incidence and survival among patients with HER2-positive breast cancer receiving dual- versus single-agent HER2 targeted therapy, as well as trastuzumab versus chemotherapy, observation, or another HER2-targeted agent. We searched PubMed, EMBASE, and CENTRAL from inception to 25 March 2020. We included randomized controlled trials that reported IMD incidence for patients with HER2-positive breast cancer receiving trastuzumab as the experimental or control arm irrespective of disease stage. Among 465 records identified, 19 randomized controlled trials (32,572 patients) were included. Meta-analysis of four studies showed that dual HER2-targeted therapy was associated with improved overall survival (HR 0.76; 95% CI, 0.66–0.87) and progression-free survival (HR 0.77; 95% CI, 0.68–0.87) compared to single HER2-targeted therapy, but the risk of IMD was similar (RR 1.03; 95% CI, 0.83–1.27). Our study challenges the hypothesis that prolonged survival afforded by improved extracranial disease control is associated with increased IMD incidence.
Endocranial volume is variable and heritable, but not related to fitness, in a free-ranging primate
Authors: Colby Abigail E. , Kimock Clare M. , Higham James P.
Published: February 2021

Large relative brain size is a defining characteristic of the order Primates. Arguably, this can be attributed to selection for behavioral aptitudes linked to a larger brain size. In order for selection of a trait to occur, the trait must vary, that variation must be heritable, and enhance fitness. In this study, we use a quantitative genetic approach to investigate the production and maintenance of variation in endocranial volume in a population of free-ranging rhesus macaques. We measured the endocranial volume and body mass proxies of 542 rhesus macaques from Cayo Santiago. We investigated variation in endocranial volume within and between sexes. Using a genetic pedigree, we estimated heritability of absolute and relative endocranial volume, and selection gradients of both traits as well as estimated body mass in the sample. Within this population, both absolute and relative endocranial volume display variation and sexual dimorphism. Both absolute and relative endocranial volume are highly heritable, but we found no evidence of selection on absolute or relative endocranial volume. These findings suggest that endocranial volume is not undergoing selection, or that we did not detect it because selection is neither linear nor quadratic, or that we lacked sufficient sample sizes to detect it.
Syntenin-knock out reduces exosome turnover and viral transduction
Authors: Kashyap Rudra , Balzano Marielle , Lechat Benoit , Lambaerts Kathleen , Egea-Jimenez Antonio Luis , Lembo Frédérique , Fares Joanna , Meeussen Sofie , Kügler Sebastian , Roebroek Anton , David Guido , Zimmermann Pascale
Published: February 2021

Exosomal transfers represent an important mode of intercellular communication. Syntenin is a small scaffold protein that, when binding ALIX, can direct endocytosed syndecans and syndecan cargo to budding endosomal membranes, supporting the formation of intraluminal vesicles that compose the source of a major class of exosomes. Syntenin, however, can also support the recycling of these same components to the cell surface. Here, by studying mice and cells with syntenin-knock out, we identify syntenin as part of dedicated machinery that integrates both the production and the uptake of secreted vesicles, supporting viral/exosomal exchanges. This study significantly extends the emerging role of heparan sulfate proteoglycans and syntenin as key components for macromolecular cargo internalization into cells.
Probing the floral developmental stages, bisexuality and sex reversions in castor (Ricinus communis L.)
Authors: Parvathy Sujatha Thankeswaran , Prabakaran Amala Joseph , Jayakrishna Thadakamalla
Published: February 2021

Castor (Ricinus communis L) is an ideal model species for sex mechanism studies in monoecious angiosperms, due to wide variations in sex expression. Sex reversion to monoecy in pistillate lines, along with labile sex expression, negatively influences hybrid seed purity. The study focuses on understanding the mechanisms of unisexual flower development, sex reversions and sex variations in castor, using various genotypes with distinct sex expression pattern. Male and female flowers had 8 and 12 developmental stages respectively, were morphologically similar till stage 4, with an intermediate bisexual state and were intermediate between type 1 and type 2 flowers. Pistil abortion was earlier than stamen inhibition. Sex alterations occurred at floral and inflorescence level. While sex-reversion was unidirectional towards maleness via bisexual stage, at high day temperatures (Tmax > 38 °C), femaleness was restored with subsequent drop in temperatures. Temperature existing for 2–3 weeks during floral meristem development, influences sexuality of the flower. We report for first time that unisexuality is preceded by bisexuality in castor flowers which alters with genotype and temperature, and sex reversions as well as high sexual polymorphisms in castor are due to alterations in floral developmental pathways. Differentially expressed (male-abundant or male-specific) genes Short chain dehydrogenase reductase 2a (SDR) and WUSCHEL are possibly involved in sex determination of castor.
Isolation and characterization of chitosan from Ugandan edible mushrooms, Nile perch scales and banana weevils for biomedical applications
Authors: Ssekatawa Kenneth , Byarugaba Denis K. , Wampande Eddie M. , Moja Tlou N. , Nxumalo Edward , Maaza Malik , Sackey Juliet , Ejobi Francis , Kirabira John Baptist
Published: February 2021

Of recent, immense attention has been given to chitosan in the biomedical field due to its valuable biochemical and physiological properties. Traditionally, the chief source of chitosan is chitin from crab and shrimp shells. Chitin is also an important component of fish scales, insects and fungal cell walls. Thus, the aim of this study was to isolate and characterize chitosan from locally available material for potential use in the biomedical field. Chitosan ash and nitrogen contents ranged from 1.55 to 3.5% and 6.6 to 7.0% respectively. Molecular weight varied from 291 to 348KDa. FTIR spectra revealed high degree of similarity between locally isolated chitosan and commercial chitosan with DD ranging from 77.8 to 79.1%. XRD patterns exhibited peaks at 2θ values of 19.5° for both mushroom and banana weevil chitosan while Nile perch scales chitosan registered 3 peaks at 2θ angles of 12.3°, 20.1° and 21.3° comparable to the established commercial chitosan XRD pattern. Locally isolated chitosan exhibited antimicrobial activity at a very high concentration. Ash content, moisture content, DD, FTIR spectra and XRD patterns revealed that chitosan isolated from locally available materials has physiochemical properties comparable to conventional chitosan and therefore it can be used in the biomedical field.
Genome-wide CRISPR/Cas9-knockout in human induced Pluripotent Stem Cell (iPSC)-derived macrophages
Authors: Navarro-Guerrero Elena , Tay Chwen , Whalley Justin P. , Cowley Sally A. , Davies Ben , Knight Julian C. , Ebner Daniel
Published: February 2021

Genome engineering using CRISPR/Cas9 technology enables simple, efficient and precise genomic modifications in human cells. Conventional immortalized cell lines can be easily edited or screened using genome-wide libraries with lentiviral transduction. However, cell types derived from the differentiation of induced Pluripotent Stem Cells (iPSC), which often represent more relevant, patient-derived models for human pathology, are much more difficult to engineer as CRISPR/Cas9 delivery to these differentiated cells can be inefficient and toxic. Here, we present an efficient, lentiviral transduction protocol for delivery of CRISPR/Cas9 to macrophages derived from human iPSC with efficiencies close to 100%. We demonstrate CRISPR/Cas9 knockouts for three nonessential proof-of-concept genes—HPRT1, PPIBandCDK4. We then scale the protocol and validate for a genome-wide pooled CRISPR/Cas9 loss-of-function screen. This methodology enables, for the first time, systematic exploration of macrophage involvement in immune responses, chronic inflammation, neurodegenerative diseases and cancer progression, using efficient genome editing techniques.