bluuebunny/crossref_metadata_2025 huggingface dataset:
Lactobacillus rhamnosus colonisation antagonizes Candida albicans by forcing metabolic adaptations that compromise pathogenicity
Authors: Alonso-Roman Raquel , Last Antonia , Mirhakkak Mohammad H. , Sprague Jakob L. , Möller Lars , Großmann Peter , Graf Katja , Gratz Rena , Mogavero Selene , Vylkova Slavena , Panagiotou Gianni , Schäuble Sascha , Hube Bernhard , Gresnigt Mark S.
Published: June 2022

Intestinal microbiota dysbiosis can initiate overgrowth of commensal Candida species – a major predisposing factor for disseminated candidiasis. Commensal bacteria such as Lactobacillus rhamnosus can antagonize Candida albicans pathogenicity. Here, we investigate the interplay between C. albicans, L. rhamnosus, and intestinal epithelial cells by integrating transcriptional and metabolic profiling, and reverse genetics. Untargeted metabolomics and in silico modelling indicate that intestinal epithelial cells foster bacterial growth metabolically, leading to bacterial production of antivirulence compounds. In addition, bacterial growth modifies the metabolic environment, including removal of C. albicans’ favoured nutrient sources. This is accompanied by transcriptional and metabolic changes in C. albicans, including altered expression of virulence-related genes. Our results indicate that intestinal colonization with bacteria can antagonize C. albicans by reshaping the metabolic environment, forcing metabolic adaptations that reduce fungal pathogenicity.
Tailoring electron beams with high-frequency self-assembled magnetic charged particle micro optics
Authors: Huber R. , Kern F. , Karnaushenko D. D. , Eisner E. , Lepucki P. , Thampi A. , Mirhajivarzaneh A. , Becker C. , Kang T. , Baunack S. , Büchner B. , Karnaushenko D. , Schmidt O. G. , Lubk A.
Published: June 2022

Tunable electromagnets and corresponding devices, such as magnetic lenses or stigmators, are the backbone of high-energy charged particle optical instruments, such as electron microscopes, because they provide higher optical power, stability, and lower aberrations compared to their electric counterparts. However, electromagnets are typically macroscopic (super-)conducting coils, which cannot generate swiftly changing magnetic fields, require active cooling, and are structurally bulky, making them unsuitable for fast beam manipulation, multibeam instruments, and miniaturized applications. Here, we present an on-chip microsized magnetic charged particle optics realized via a self-assembling micro-origami process. These micro-electromagnets can generate alternating magnetic fields of about ±100 mT up to a hundred MHz, supplying sufficiently large optical power for a large number of charged particle optics applications. That particular includes fast spatiotemporal electron beam modulation such as electron beam deflection, focusing, and wave front shaping as required for stroboscopic imaging.
Proteomic and functional analyses of the periodic membrane skeleton in neurons
Authors: Zhou Ruobo , Han Boran , Nowak Roberta , Lu Yunzhe , Heller Evan , Xia Chenglong , Chishti Athar H. , Fowler Velia M. , Zhuang Xiaowei
Published: June 2022

Actin, spectrin, and associated molecules form a membrane-associated periodic skeleton (MPS) in neurons. The molecular composition and functions of the MPS remain incompletely understood. Here, using co-immunoprecipitation and mass spectrometry, we identified hundreds of potential candidate MPS-interacting proteins that span diverse functional categories. We examined representative proteins in several of these categories using super-resolution imaging, including previously unknown MPS structural components, as well as motor proteins, cell adhesion molecules, ion channels, and signaling proteins, and observed periodic distributions characteristic of the MPS along the neurites for ~20 proteins. Genetic perturbations of the MPS and its interacting proteins further suggested functional roles of the MPS in axon-axon and axon-dendrite interactions and in axon diameter regulation, and implicated the involvement of MPS interactions with cell adhesion molecules and non-muscle myosin in these roles. These results provide insights into the interactome of the MPS and suggest previously unknown functions of the MPS in neurons.
Deep neural network trained on gigapixel images improves lymph node metastasis detection in clinical settings
Authors: Huang Shih-Chiang , Chen Chi-Chung , Lan Jui , Hsieh Tsan-Yu , Chuang Huei-Chieh , Chien Meng-Yao , Ou Tao-Sheng , Chen Kuang-Hua , Wu Ren-Chin , Liu Yu-Jen , Cheng Chi-Tung , Huang Yu-Jen , Tao Liang-Wei , Hwu An-Fong , Lin I-Chieh , Hung Shih-Hao , Yeh Chao-Yuan , Chen Tse-Ching
Published: June 2022

The pathological identification of lymph node (LN) metastasis is demanding and tedious. Although convolutional neural networks (CNNs) possess considerable potential in improving the process, the ultrahigh-resolution of whole slide images hinders the development of a clinically applicable solution. We design an artificial-intelligence-assisted LN assessment workflow to facilitate the routine counting of metastatic LNs. Unlike previous patch-based approaches, our proposed method trains CNNs by using 5-gigapixel images, obviating the need for lesion-level annotations. Trained on 5907 LN images, our algorithm identifies metastatic LNs in gastric cancer with a slide-level area under the receiver operating characteristic curve (AUC) of 0.9936. Clinical experiments reveal that the workflow significantly improves the sensitivity of micrometastasis identification (81.94% to 95.83%, P < .001) and isolated tumor cells (67.95% to 96.15%, P < .001) in a significantly shorter review time (−31.5%, P < .001). Cross-site evaluation indicates that the algorithm is highly robust (AUC = 0.9829).
Coherent response of the electronic system driven by non-interfering laser pulses
Authors: Eul Tobias , Prinz Eva , Hartelt Michael , Frisch Benjamin , Aeschlimann Martin , Stadtmüller Benjamin
Published: June 2022

The strength of light–matter interaction in condensed matter is fundamentally linked to the orientation and oscillation strength of the materials’ optical transition dipoles. Structurally anisotropic materials, e.g., elongated molecules, exhibit optical transition dipoles with fixed orientations that govern the angular-dependent light–matter interaction. Contrary, free electron-like metals should exhibit isotropic light–matter interaction with the light fields dictating the orientation of the optical transition dipoles. Here, we demonstrate that an anisotropic direction of the optical transition dipoles even exists in highly free electron-like noble metal surfaces. Our time- and phase-resolved photoemission experiment reveals coherent interference effects on the (110)-oriented silver surface after optical excitation with two non-interfering cross-polarized pulses. We explain this coherent material response within the density matrix formalism by an intrinsic coupling of the non-interfering light fields mediated by optical transition dipoles with fixed orientations in silver.
Magnetic field screening in hydrogen-rich high-temperature superconductors
Authors: Minkov V. S. , Bud’ko S. L. , Balakirev F. F. , Prakapenka V. B. , Chariton S. , Husband R. J. , Liermann H. P. , Eremets M. I.
Published: June 2022

In the last few years, the superconducting transition temperature, Tc, of hydrogen-rich compounds has increased dramatically, and is now approaching room temperature. However, the pressures at which these materials are stable exceed one million atmospheres and limit the number of available experimental studies. Superconductivity in hydrides has been primarily explored by electrical transport measurements, whereas magnetic properties, one of the most important characteristic of a superconductor, have not been satisfactory defined. Here, we develop SQUID magnetometry under extreme high-pressure conditions and report characteristic superconducting parameters for Im-3m-H3S and Fm-3m-LaH10—the representative members of two families of high-temperature superconducting hydrides. We determine a lower critical field Hc1 of ∼0.82 T and ∼0.55 T, and a London penetration depth λL of ∼20 nm and ∼30 nm in H3S and LaH10, respectively. The small values of λL indicate a high superfluid density in both hydrides. These compounds have the values of the Ginzburg-Landau parameter κ ∼12–20 and belong to the group of “moderate” type II superconductors, rather than being hard superconductors as would be intuitively expected from their high Tcs.
Longitudinal evidence that Event Related Potential measures of self-regulation do not predict everyday goal pursuit
Authors: Saunders Blair , Milyavskaya Marina , Inzlicht Michael
Published: June 2022

Self-regulation has been studied across levels of analysis; however, little attention has been paid to the extent to which self-report, neural, and behavioral indices predict goal pursuit in real-life. We use a mixed-method approach (N = 201) to triangulate evidence among established measures of different aspects of self-regulation to predict both the process of goal pursuit using experience sampling, as well as longer-term goal progress at 1, 3, and 6-month follow-ups. While self-reported trait self-control predicts goal attainment months later, we observe a null relationship between longitudinal goal attainment and ERPs associated with performance-monitoring and reactivity to positive/rewarding stimuli. Despite evidence that these ERPs are reliable and trait-like, and despite theorizing that suggests otherwise, our findings suggest that these ERPs are not meaningfully associated with everyday goal attainment. These findings challenge the ecological validity of brain measures thought to assess aspects of self-regulation.
Large-scale multi-omics analysis suggests specific roles for intragenic cohesin in transcriptional regulation
Authors: Wang Jiankang , Bando Masashige , Shirahige Katsuhiko , Nakato Ryuichiro
Published: June 2022

Cohesin, an essential protein complex for chromosome segregation, regulates transcription through a variety of mechanisms. It is not a trivial task to assign diverse cohesin functions. Moreover, the context-specific roles of cohesin-mediated interactions, especially on intragenic regions, have not been thoroughly investigated. Here we perform a comprehensive characterization of cohesin binding sites in several human cell types. We integrate epigenomic, transcriptomic and chromatin interaction data to explore the context-specific functions of intragenic cohesin related to gene activation. We identify a specific subset of cohesin binding sites, decreased intragenic cohesin sites (DICs), which are negatively correlated with transcriptional regulation. A subgroup of DICs is enriched with enhancer markers and RNA polymerase II, while the others are more correlated to chromatin architecture. DICs are observed in various cell types, including cells from patients with cohesinopathy. We also implement machine learning to our data and identified genomic features for isolating DICs from all cohesin sites. These results suggest a previously unidentified function of cohesin on intragenic regions for transcriptional regulation.
Slowdown of photoexcited spin dynamics in the non-collinear spin-ordered phases in skyrmion host GaV4S8
Authors: Sekiguchi Fumiya , Budzinauskas Kestutis , Padmanabhan Prashant , Versteeg Rolf B. , Tsurkan Vladimir , Kézsmárki István , Foggetti Francesco , Artyukhin Sergey , van Loosdrecht Paul H. M.
Published: June 2022

Formation of magnetic order alters the character of spin excitations, which then affects transport properties. We investigate the photoexcited ultrafast spin dynamics in different magnetic phases in Néel-type skyrmion host GaV4S8 with time-resolved magneto-optical Kerr effect experiments. The coherent spin precession, whose amplitude is enhanced in the skyrmion-lattice phase, shows a signature of phase coexistence across the magnetic phase transitions. The incoherent spin relaxation dynamics slows down by a factor of two in the skyrmion-lattice/cycloid phases, indicating significant decrease in thermal conductivity triggered by a small change of magnetic field. The slow heat diffusion in the skyrmion-lattice/cycloid phases is attributed to the stronger magnon scattering off the domain walls formed in abundance in the skyrmion-lattice/cycloid phase. These results highlight the impact of spatial spin structure on the ultrafast heat transport in spin systems, providing a useful insight for the step toward ultrafast photocontrol of the magnets with novel spin orders.
Allotropy in ultra high strength materials
Authors: Pattamatta A. S. L. Subrahmanyam , Srolovitz David J.
Published: June 2022

Allotropic phase transformations may be driven by the application of stresses in many materials; this has been especially well-documented for pressure driven transformations. Recent advances in strengthening materials allow for the application of very large shear stresses as well – opening up vast new regions of stress space. This means that the stress space is six-dimensional (rather than one for pressure) and that phase transformations depend upon crystal/grain orientation. We propose a novel approach for predicting the role of the entire stress tensor on phase transformations in grains of all orientations in any material. This multiscale approach is density functional theory based and guided by nonlinear elasticity. We focus on stress tensor dependent allotropic phase transformations in iron at high pressure and ultra-fine grained nickel and titanium. The results are quantitatively consistent with a range of experimental observations in these disparate systems. This approach enables the balanced design of high strength-high ductility materials.
Expansion of cytotoxic tissue-resident CD8+ T cells and CCR6+CD161+ CD4+ T cells in the nasal mucosa following mRNA COVID-19 vaccination
Authors: Ssemaganda Aloysious , Nguyen Huong Mai , Nuhu Faisal , Jahan Naima , Card Catherine M. , Kiazyk Sandra , Severini Giulia , Keynan Yoav , Su Ruey-Chyi , Ji Hezhao , Abrenica Bernard , McLaren Paul J. , Ball T. Blake , Bullard Jared , Van Caeseele Paul , Stein Derek , McKinnon Lyle R.
Published: June 2022

Vaccines against SARS-CoV-2 have shown high efficacy in clinical trials, yet a full immunologic characterization of these vaccines, particularly within the human upper respiratory tract, is less well known. Here, we enumerate and phenotype T cells in nasal mucosa and blood using flow cytometry before and after vaccination with the Pfizer-BioNTech COVID-19 vaccine (n = 21). Tissue-resident memory (Trm) CD8+ T cells expressing CD69+CD103+ increase in number ~12 days following the first and second doses, by 0.31 and 0.43 log10 cells per swab respectively (p = 0.058 and p = 0.009 in adjusted linear mixed models). CD69+CD103+CD8+ T cells in the blood decrease post-vaccination. Similar increases in nasal CD8+CD69+CD103− T cells are observed, particularly following the second dose. CD4+ cells co-expressing CCR6 and CD161 are also increased in abundance following both doses. Stimulation of nasal CD8+ T cells with SARS-CoV-2 spike peptides elevates expression of CD107a at 2- and 6-months (p = 0.0096) post second vaccine dose, with a subset of donors also expressing increased cytokines. These data suggest that nasal T cells may be induced and contribute to the protective immunity afforded by this vaccine.
Controlling synthetic membraneless organelles by a red-light-dependent singlet oxygen-generating protein
Authors: Li Manjia , Park Byung Min , Dai Xin , Xu Yingjie , Huang Jinqing , Sun Fei
Published: June 2022

Membraneless organelles (MLOs) formed via protein phase separation have great implications for both physiological and pathological processes. However, the inability to precisely control the bioactivities of MLOs has hindered our understanding of their roles in biology, not to mention their translational applications. Here, by combining intrinsically disordered domains such as RGG and mussel-foot proteins, we create an in cellulo protein phase separation system, of which various biological activities can be introduced via metal-mediated protein immobilization and further controlled by the water-soluble chlorophyll protein (WSCP)—a remarkably stable, red-light-responsive singlet oxygen generator. The WSCP-laden protein condensates undergo a liquid-to-solid phase transition on light exposure, due to oxidative crosslinking, providing a means to control catalysis within synthetic MLOs. Moreover, these photoresponsive condensates, which retain the light-induced phase-transition behavior in living cells, exhibit marked membrane localization, reminiscent of the semi-membrane-bound compartments like postsynaptic densities in nervous systems. Together, this engineered system provides an approach toward controllable synthetic MLOs and, alongside its light-induced phase transition, may well serve to emulate and explore the aging process at the subcellular or even molecular level.
SMYD5 catalyzes histone H3 lysine 36 trimethylation at promoters
Authors: Zhang Yanjun , Fang Yuan , Tang Yin , Han Shixun , Jia Junqi , Wan Xinyi , Chen Jiaqi , Yuan Ying , Zhao Bin , Fang Dong
Published: June 2022

Histone marks, carriers of epigenetic information, regulate gene expression. In mammalian cells, H3K36me3 is mainly catalyzed by SETD2 at gene body regions. Here, we find that in addition to gene body regions, H3K36me3 is enriched at promoters in primary cells. Through screening, we identify SMYD5, which is recruited to chromatin by RNA polymerase II, as a methyltransferase catalyzing H3K36me3 at promoters. The enzymatic activity of SMYD5 is dependent on its C-terminal glutamic acid-rich domain. Overexpression of full-length Smyd5, but not the C-terminal domain-truncated Smyd5, restores H3K36me3 at promoters in Smyd5 knockout cells. Furthermore, elevated Smyd5 expression contributes to tumorigenesis in liver hepatocellular carcinoma. Together, our findings identify SMYD5 as the H3K36me3 methyltransferase at promoters that regulates gene expression, providing insights into the localization and function of H3K36me3.
Ultrasensitive detection of local acoustic vibrations at room temperature by plasmon-enhanced single-molecule fluorescence
Authors: Xie Mingcai , Liu Hanyu , Wan Sushu , Lu Xuxing , Hong Daocheng , Du Yu , Yang Weiqing , Wei Zhihong , Fang Susu , Tao Chen-Lei , Xu Dan , Wang Boyang , Lu Siyu , Wu Xue-Jun , Xu Weigao , Orrit Michel , Tian Yuxi
Published: June 2022

Sensitive detection of local acoustic vibrations at the nanometer scale has promising potential applications involving miniaturized devices in many areas, such as geological exploration, military reconnaissance, and ultrasound imaging. However, sensitive detection of weak acoustic signals with high spatial resolution at room temperature has become a major challenge. Here, we report a nanometer-scale system for acoustic detection with a single molecule as a probe based on minute variations of its distance to the surface of a plasmonic gold nanorod. This system can extract the frequency and amplitude of acoustic vibrations with experimental and theoretical sensitivities of 10 pm Hz−1/2 and 10 fm Hz−1/2, respectively. This approach provides a strategy for the optical detection of acoustic waves based on molecular spectroscopy without electromagnetic interference. Moreover, such a small nano-acoustic detector with 40-nm size can be employed to monitor acoustic vibrations or read out the quantum states of nanomechanical devices.
Efferocytosis requires periphagosomal Ca2+-signaling and TRPM7-mediated electrical activity
Authors: Schappe Michael S. , Stremska Marta E. , Busey Gregory W. , Downs Taylor K. , Seegren Philip V. , Mendu Suresh K. , Flegal Zachary , Doyle Catherine A. , Stipes Eric J. , Desai Bimal N.
Published: June 2022

Efficient clearance of apoptotic cells by phagocytosis, also known as efferocytosis, is fundamental to developmental biology, organ physiology, and immunology. Macrophages use multiple mechanisms to detect and engulf apoptotic cells, but the signaling pathways that regulate the digestion of the apoptotic cell cargo, such as the dynamic Ca2+signals, are poorly understood. Using an siRNA screen, we identify TRPM7 as a Ca2+-conducting ion channel essential for phagosome maturation during efferocytosis.Trpm7-targeted macrophages fail to fully acidify or digest their phagosomal cargo in the absence of TRPM7. Through perforated patch electrophysiology, we demonstrate that TRPM7 mediates a pH-activated cationic current necessary to sustain phagosomal acidification. Using mice expressing a genetically-encoded Ca2+sensor, we observe that phagosome maturation requires peri-phagosomal Ca2+-signals dependent on TRPM7. Overall, we reveal TRPM7 as a central regulator of phagosome maturation during macrophage efferocytosis.
Probing material absorption and optical nonlinearity of integrated photonic materials
Authors: Gao Maodong , Yang Qi-Fan , Ji Qing-Xin , Wang Heming , Wu Lue , Shen Boqiang , Liu Junqiu , Huang Guanhao , Chang Lin , Xie Weiqiang , Yu Su-Peng , Papp Scott B. , Bowers John E. , Kippenberg Tobias J. , Vahala Kerry J.
Published: June 2022

Optical microresonators with high quality (Q) factors are essential to a wide range of integrated photonic devices. Steady efforts have been directed towards increasing microresonator Q factors across a variety of platforms. With success in reducing microfabrication process-related optical loss as a limitation of Q, the ultimate attainable Q, as determined solely by the constituent microresonator material absorption, has come into focus. Here, we report measurements of the material-limited Q factors in several photonic material platforms. High-Q microresonators are fabricated from thin films of SiO2, Si3N4, Al0.2Ga0.8As, and Ta2O5. By using cavity-enhanced photothermal spectroscopy, the material-limited Q is determined. The method simultaneously measures the Kerr nonlinearity in each material and reveals how material nonlinearity and ultimate Q vary in a complementary fashion across photonic materials. Besides guiding microresonator design and material development in four material platforms, the results help establish performance limits in future photonic integrated systems.
Force–reversible chemical reaction at ambient temperature for designing toughened dynamic covalent polymer networks
Authors: Du Mengqi , Houck Hannes A. , Yin Qiang , Xu Yewei , Huang Ying , Lan Yang , Yang Li , Du Prez Filip E. , Chang Guanjun
Published: June 2022

Force-reversible C-N bonds, resulting from the click chemistry reaction between triazolinedione (TAD) and indole derivatives, offer exciting opportunities for molecular-level engineering to design materials that respond to mechanical loads. Here, we displayed that TAD-indole adducts, acting as crosslink points in dry-state covalently crosslinked polymers, enable materials to display reversible stress-responsiveness in real time already at ambient temperature. Whereas the exergonic TAD-indole reaction results in the formation of bench-stable adducts, they were shown to dissociate at ambient temperature when embedded in a polymer network and subjected to a stretching force to recover the original products. Moreover, the nascent TAD moiety can spontaneously and immediately be recombined after dissociation with an indole reaction partners at ambient temperature, thus allowing for the adjustment of the polymer segment conformation and the maintenance of the network integrity by force-reversible behaviors. Overall, our strategy represents a general method to create toughened covalently crosslinked polymer materials with simultaneous enhancement of mechanical strength and ductility, which is quite challenging to achieve by conventional chemical methods.
Spontaneous water-on-water spreading of polyelectrolyte membranes inspired by skin formation
Authors: Tang Sihan , Gong Jiang , Shi Yunsong , Wen Shifeng , Zhao Qiang
Published: June 2022

Stable interfaces between immiscible solvents are crucial for chemical synthesis and assembly, but interfaces between miscible solvents have been less explored. Here the authors report the spontaneous water-on-water spreading and self-assembly of polyelectrolyte membranes. An aqueous mixture solution containing poly(ethyleneimine) and poly(sodium 4-styrenesulfonate) spreads efficiently on acidic water, leading to the formation of hierarchically porous membranes. The reduced surface tension of the polyelectrolyte mixture solution drives the surface spreading, while the interfacial polyelectrolytes complexation triggered by the low pH of water mitigates water-in-water mixing. The synergy of surface tension and pH-dependent complexation represents a generic mechanism governing interfaces between miscible solvents for materials engineering, without the need for surfactants or sophisticated equipment. As a proof-of-concept, porous polyelectrolyte hybrid membranes are prepared by surface spreading, exhibiting exceptional solar thermal evaporation performance (2.8 kg/m2h) under 1-sun irradiation.
Imaging translational control by Argonaute with single-molecule resolution in live cells
Authors: Cialek Charlotte A. , Galindo Gabriel , Morisaki Tatsuya , Zhao Ning , Montgomery Taiowa A. , Stasevich Timothy J.
Published: June 2022

A major challenge to our understanding of translational control has been deconvolving the individual impact specific regulatory factors have on the complex dynamics of mRNA translation. MicroRNAs (miRNAs), for example, guide Argonaute and associated proteins to target mRNAs, where they direct gene silencing in multiple ways that are not well understood. To better deconvolve these dynamics, we have developed technology to directly visualize and quantify the impact of human Argonaute2 (Ago2) on the translation and subcellular localization of individual reporter mRNAs in living cells. We show that our combined translation and Ago2 tethering sensor reflects endogenous miRNA-mediated gene silencing. Using the sensor, we find that Ago2 association leads to progressive silencing of translation at individual mRNA. Silencing was occasionally interrupted by brief bursts of translational activity and took 3–4 times longer than a single round of translation, consistent with a gradual increase in the inhibition of translation initiation. At later time points, Ago2-tethered mRNAs cluster and coalesce with P-bodies, where a translationally silent state is maintained. These results provide a framework for exploring miRNA-mediated gene regulation in live cells at the single-molecule level. Furthermore, our tethering-based, single-molecule reporter system will likely have wide-ranging application in studying RNA-protein interactions.
Nickel catalyzed multicomponent stereodivergent synthesis of olefins enabled by electrochemistry, photocatalysis and photo-electrochemistry
Authors: Zhu Chen , Yue Huifeng , Rueping Magnus
Published: June 2022

Trisubstituted alkenes are important organic synthons and have broad applications in the synthesis of many pharmaceuticals and materials. The stereoselective synthesis of such compounds has long been a research focus for organic researchers. Herein, we report a three-component, reductive cascade, cross-coupling reaction for the arylalkylation of alkynes. A wide range of trisubstituted alkenes are obtained in good to high yields with excellent chemo- and stereoselectivity by switching between electrochemistry and photocatalysis. The E isomer of the product is obtained exclusively when the reaction is conducted with electricity and nickel, while the Z isomer is generated with high stereoselectivity when photo- and nickel dual catalysts are used. Moreover, photo-assisted electrochemically enabled nickel catalyzed protocol is demonstrated to selectively deliver Z-trisubstituted alkenes without the addition of photocatalysts.
Molecularly cleavable bioinks facilitate high-performance digital light processing-based bioprinting of functional volumetric soft tissues
Authors: Wang Mian , Li Wanlu , Hao Jin , Gonzales Arthur , Zhao Zhibo , Flores Regina Sanchez , Kuang Xiao , Mu Xuan , Ching Terry , Tang Guosheng , Luo Zeyu , Garciamendez-Mijares Carlos Ezio , Sahoo Jugal Kishore , Wells Michael F. , Niu Gengle , Agrawal Prajwal , Quiñones-Hinojosa Alfredo , Eggan Kevin , Zhang Yu Shrike
Published: June 2022

Digital light processing bioprinting favors biofabrication of tissues with improved structural complexity. However, soft-tissue fabrication with this method remains a challenge to balance the physical performances of the bioinks for high-fidelity bioprinting and suitable microenvironments for the encapsulated cells to thrive. Here, we propose a molecular cleavage approach, where hyaluronic acid methacrylate (HAMA) is mixed with gelatin methacryloyl to achieve high-performance bioprinting, followed by selectively enzymatic digestion of HAMA, resulting in tissue-matching mechanical properties without losing the structural complexity and fidelity. Our method allows cellular morphological and functional improvements across multiple bioprinted tissue types featuring a wide range of mechanical stiffness, from the muscles to the brain, the softest organ of the human body. This platform endows us to biofabricate mechanically precisely tunable constructs to meet the biological function requirements of target tissues, potentially paving the way for broad applications in tissue and tissue model engineering.
Three-dimensional network of filamentary currents and super-thermal electrons during magnetotail magnetic reconnection
Authors: Li Xinmin , Wang Rongsheng , Lu Quanming , Russell Christopher T. , Lu San , Cohen Ian J. , Ergun R. E. , Wang Shui
Published: June 2022

Magnetic reconnection is a fundamental plasma process by which magnetic field lines on two sides of the current sheet flow inward to yield an X-line topology. It is responsible for producing energetic electrons in explosive phenomena in space, astrophysical, and laboratorial plasmas. The X-line region is supposed to be the important place for generating energetic electrons. However, how these energetic electrons are generated in such a limited region is still poorly understood. Here, using Magnetospheric multiscale mission data acquired in Earth’s magnetotail, we present direct evidence of super-thermal electrons up to 300 keV inside an X-line region, and the electrons display a power-law spectrum with an index of about 8.0. Concurrently, three-dimensional network of dynamic filamentary currents in electron scale is observed and leads to electromagnetic turbulence therein. The observations indicate that the electrons are effectively accelerated while the X-line region evolves into turbulence with a complex filamentary current network.
Iridium-catalyzed direct asymmetric reductive amination utilizing primary alkyl amines as the N-sources
Authors: Wu Zitong , Wang Wenji , Guo Haodong , Gao Guorui , Huang Haizhou , Chang Mingxin
Published: June 2022

Direct asymmetric reductive amination is one of the most efficient methods for the construction of chiral amines, in which the scope of the applicable amine coupling partners remains a significant challenge. In this study we describe primary alkyl amines effectively serve as the N-sources in direct asymmetric reductive amination catalyzed by the iridium precursor and sterically tunable chiral phosphoramidite ligands. The density functional theory studies of the reaction mechanism imply the alkyl amine substrates serve as a ligand of iridium strengthened by a (N)H-O(P) hydrogen-bonding attraction, and the hydride addition occurs via an outer-sphere transition state, in which the Cl-H H-bonding plays an important role. Through this concise procedure, cinacalcet, tecalcet, fendiline and many other related chiral amines have been synthesized in one single step with high yields and excellent enantioselectivity.
Association between resting-state functional brain connectivity and gene expression is altered in autism spectrum disorder
Authors: Berto Stefano , Treacher Alex H. , Caglayan Emre , Luo Danni , Haney Jillian R. , Gandal Michael J. , Geschwind Daniel H. , Montillo Albert A. , Konopka Genevieve
Published: June 2022

Gene expression covaries with brain activity as measured by resting state functional magnetic resonance imaging (MRI). However, it is unclear how genomic differences driven by disease state can affect this relationship. Here, we integrate from the ABIDE I and II imaging cohorts with datasets of gene expression in brains of neurotypical individuals and individuals with autism spectrum disorder (ASD) with regionally matched brain activity measurements from fMRI datasets. We identify genes linked with brain activity whose association is disrupted in ASD. We identified a subset of genes that showed a differential developmental trajectory in individuals with ASD compared with controls. These genes are enriched in voltage-gated ion channels and inhibitory neurons, pointing to excitation-inhibition imbalance in ASD. We further assessed differences at the regional level showing that the primary visual cortex is the most affected region in ASD. Our results link disrupted brain expression patterns of individuals with ASD to brain activity and show developmental, cell type, and regional enrichment of activity linked genes.
Extracellular release of two peptidases dominates generation of the trypanosome quorum-sensing signal
Authors: Tettey Mabel Deladem , Rojas Federico , Matthews Keith R.
Published: June 2022

Trypanosomes causing African sleeping sickness use quorum-sensing (QS) to generate transmission-competent stumpy forms in mammalian hosts. This density-dependent process is signalled by oligopeptides that stimulate the signal transduction pathway leading to stumpy formation. Here, using mass spectrometry analysis, we identify peptidases released by trypanosomes and, for 12 peptidases, confirm their extracellular delivery. Thereafter, we determine the contribution of each peptidase to QS signal production using systematic inducible overexpression in vivo, and confirm this activity operates through the physiological QS signalling pathway. Gene knockout of the QS-active peptidases identifies two enzymes, oligopeptidase B and metallocarboxypeptidase 1, that significantly reduce QS when ablated individually. Further, combinatorial gene knockout of both peptidases confirms their dominance in the generation of the QS signal, with peptidase release of oligopeptidase B mediated via an unconventional protein secretion pathway. This work identifies how the QS signal driving trypanosome virulence and transmission is generated in mammalian hosts.
Airway Prevotella promote TLR2-dependent neutrophil activation and rapid clearance of Streptococcus pneumoniae from the lung
Authors: Horn Kadi J. , Schopper Melissa A. , Drigot Zoe G. , Clark Sarah E.
Published: June 2022

This study investigates how specific members of the lung microbiome influence the early immune response to infection. Prevotella species are a major component of the endogenous airway microbiota. Increased abundance of Prevotella melaninogenica correlates with reduced infection with the bacterial pathogen Streptococcus pneumoniae, indicating a potentially beneficial role. Here, we show that P. melaninogenica enhances protection against S. pneumoniae, resulting in rapid pathogen clearance from the lung and improved survival in a mouse lung co-infection model. This response requires recognition of P. melaninogenica lipoproteins by toll-like receptor (TLR)2, the induction of TNFα, and neutrophils, as the loss of any of these factors abrogates Prevotella-induced protection. Improved clearance of S. pneumoniae is associated with increased serine protease-mediated killing by lung neutrophils and restraint of P. melaninogenica-induced inflammation by IL-10 in co-infected mice. Together, these findings highlight innate immune priming by airway Prevotella as an important protective feature in the respiratory tract.
Converting waste PET plastics into automobile fuels and antifreeze components
Authors: Gao Zhiwen , Ma Bing , Chen Shuang , Tian Jingqing , Zhao Chen
Published: June 2022

With the aim to solve the serious problem of white plastic pollution, we report herein a low-cost process to quantitatively convert polyethylene terephthalate (PET) into p-xylene (PX) and ethylene glycol (EG) over modified Cu/SiO2 catalyst using methanol as both solvent and hydrogen donor. Kinetic and in-situ Fourier-transform infrared spectroscopy (FTIR) studies demonstrate that the degradation of PET into PX involves tandem PET methanolysis and dimethyl terephthalate (DMT) selective hydro-deoxygenation (HDO) steps with the in-situ produced H2 from methanol decomposition at 210 °C. The overall high activities are attributed to the high Cu+/Cu0 ratio derived from the dense and granular copper silicate precursor, as formed by the induction of proper NaCl addition during the hydrothermal synthesis. This hydrogen-free one-pot approach allows to directly produce gasoline fuels and antifreeze components from waste poly-ester plastic, providing a feasible solution to the plastic problem in islands.
Parallel ventral hippocampus-lateral septum pathways differentially regulate approach-avoidance conflict
Authors: Yeates Dylan C. M. , Leavitt Dallas , Sujanthan Sajeevan , Khan Nisma , Alushaj Denada , Lee Andy C. H. , Ito Rutsuko
Published: June 2022

The ability to resolve an approach-avoidance conflict is critical to adaptive behavior. The ventral CA3 (vCA3) and CA1 (vCA1) subfields of the ventral hippocampus (vHPC) have been shown to facilitate avoidance and approach behavior, respectively, in the face of motivational conflict, but the neural circuits by which this subfield-specific regulation is implemented is unknown. We demonstrate that two distinct pathways from these subfields to lateral septum (LS) contribute to this divergent control. In Long-Evans rats, chemogenetic inhibition of the vCA3- LS caudodorsal (cd) pathway potentiated approach towards a learned conflict-eliciting stimulus, while inhibition of the vCA1-LS rostroventral (rv) pathway potentiated approach non-specifically. Additionally, vCA3-LScd inhibited animals were less hesitant to explore food during environmental uncertainty, while the vCA1- LSrv inhibited animals took longer to initiate food exploration. These findings suggest that the vHPC influences multiple behavioral systems via differential projections to the LS, which in turn send inhibitory projections to motivational centres of the brain.
A Catharanthus roseus Fe(II)/α-ketoglutarate-dependent dioxygenase catalyzes a redox-neutral reaction responsible for vindolinine biosynthesis
Authors: Eng Jasmine Ga May , Shahsavarani Mohammadamin , Smith Daniel Patrick , Hájíček Josef , De Luca Vincenzo , Qu Yang
Published: June 2022

The Madagascar’s periwinkle is the model plant for studies of plant specialized metabolism and monoterpenoid indole alkaloids (MIAs), and an important source for the anticancer medicine vinblastine. The elucidation of entire 28-step biosynthesis of vinblastine allowed further investigations for the formation of other remarkably complex bioactive MIAs. In this study, we describe the discovery and characterization of vindolinine synthase, a Fe(II)/α-ketoglutarate-dependent (Fe/2OG) dioxygenase, that diverts assembly of tabersonine to vinblastine toward the formation of three alternatively cyclized MIAs: 19S-vindolinine, 19R-vindolinine, and venalstonine. Vindolinine synthase catalyzes a highly unusual, redox-neutral reaction to form a radical from dehydrosecodine, which is further cyclized by hydrolase 2 to form the three MIA isomers. We further show the biosynthesis of vindolinine epimers from tabersonine using hydrolase 2 catalyzed reverse cycloaddition. While the occurrence of vindolinines is rare in nature, the more widely found venalstonine derivatives are likely formed from similar redox-neutral reactions by homologous Fe/2OG dioxygenases.
A statistical perspective on baseline adjustment in pharmacogenomic genome-wide association studies of quantitative change
Authors: Zhang Hong , Chhibber Aparna , Shaw Peter M. , Mehrotra Devan V. , Shen Judong
Published: June 2022

In pharmacogenetic (PGx) studies, drug response phenotypes are often measured in the form of change in a quantitative trait before and after treatment. There is some debate in recent literature regarding baseline adjustment, or inclusion of pre-treatment or baseline value as a covariate, in PGx genome-wide association studies (GWAS) analysis. Here, we provide a clear statistical perspective on this baseline adjustment issue by running extensive simulations based on nine statistical models to evaluate the influence of baseline adjustment on type I error and power. We then apply these nine models to analyzing the change in low-density lipoprotein cholesterol (LDL-C) levels with ezetimibe + simvastatin combination therapy compared with simvastatin monotherapy therapy in the 5661 participants of the IMPROVE-IT (IMProved Reduction of Outcomes: Vytroin Efficacy International Trial) PGx GWAS, supporting the conclusions drawn from our simulations. Both simulations and GWAS analyses consistently show that baseline-unadjusted models inflate type I error for the variants associated with baseline value if the baseline value is also associated with change from baseline (e.g., when baseline value is a mediator between a variant and change from baseline), while baseline-adjusted models can control type I error in various scenarios. We thus recommend performing baseline-adjusted analyses in PGx GWASs of quantitative change.
Lipase regulation of cellular fatty acid homeostasis as a Parkinson’s disease therapeutic strategy
Authors: Fanning Saranna , Cirka Haley , Thies Jennifer L. , Jeong Jooyoung , Niemi Sarah M. , Yoon Joon , Ho Gary P. H. , Pacheco Julian A. , Dettmer Ulf , Liu Lei , Clish Clary B. , Hodgetts Kevin J. , Hutchinson John N. , Muratore Christina R. , Caldwell Guy A. , Caldwell Kim A. , Selkoe Dennis
Published: June 2022

Synucleinopathy (Parkinson’s disease (PD); Lewy body dementia) disease-modifying treatments represent a huge unmet medical need. Although the PD-causing protein α-synuclein (αS) interacts with lipids and fatty acids (FA) physiologically and pathologically, targeting FA homeostasis for therapeutics is in its infancy. We identified the PD-relevant target stearoyl-coA desaturase: inhibiting monounsaturated FA synthesis reversed PD phenotypes. However, lipid degradation also generates FA pools. Here, we identify the rate-limiting lipase enzyme, LIPE, as a candidate target. Decreasing LIPE in human neural cells reduced αS inclusions. Patient αS triplication vs. corrected neurons had increased pSer129 and insoluble αS and decreased αS tetramer:monomer ratios. LIPE inhibition rescued all these and the abnormal unfolded protein response. LIPE inhibitors decreased pSer129 and restored tetramer:monomer equilibrium in αS E46K-expressing human neurons. LIPE reduction in vivo alleviated αS-induced dopaminergic neurodegeneration in Caenorhabditis elegans. Co-regulating FA synthesis and degradation proved additive in rescuing PD phenotypes, signifying co-targeting as a therapeutic strategy.
Translocating proteins compartment-specifically alter the fate of epithelial-mesenchymal transition in a compartmentalized Boolean network model
Authors: Mendik Péter , Kerestély Márk , Kamp Sebestyén , Deritei Dávid , Kunšič Nina , Vassy Zsolt , Csermely Péter , Veres Daniel V.
Published: June 2022

Regulation of translocating proteins is crucial in defining cellular behaviour. Epithelial-mesenchymal transition (EMT) is important in cellular processes, such as cancer progression. Several orchestrators of EMT, such as key transcription factors, are known to translocate. We show that translocating proteins become enriched in EMT-signalling. To simulate the compartment-specific functions of translocating proteins we created a compartmentalized Boolean network model. This model successfully reproduced known biological traits of EMT and as a novel feature it also captured organelle-specific functions of proteins. Our results predicted that glycogen synthase kinase-3 beta (GSK3B) compartment-specifically alters the fate of EMT, amongst others the activation of nuclear GSK3B halts transforming growth factor beta-1 (TGFB) induced EMT. Moreover, our results recapitulated that the nuclear activation of glioma associated oncogene transcription factors (GLI) is needed to achieve a complete EMT. Compartmentalized network models will be useful to uncover novel control mechanisms of biological processes. Our algorithmic procedures can be automatically rerun on the https://translocaboole.linkgroup.hu website, which provides a framework for similar future studies.
Third-party punishment by preverbal infants
Authors: Kanakogi Yasuhiro , Miyazaki Michiko , Takahashi Hideyuki , Yamamoto Hiroki , Kobayashi Tessei , Hiraki Kazuo
Published: June 2022

Third-party punishment of antisocial others is unique to humans and seems to be universal across cultures. However, its emergence in ontogeny remains unknown. We developed a participatory cognitive paradigm using gaze-contingency techniques, in which infants can use their gaze to affect agents displayed on a monitor. In this paradigm, fixation on an agent triggers the event of a stone crushing the agent. Throughout five experiments (total N = 120), we show that eight-month-old infants punished antisocial others. Specifically, infants increased their selective looks at the aggressor after watching aggressive interactions. Additionally, three control experiments excluded alternative interpretations of their selective gaze, suggesting that punishment-related decision-making influenced looking behaviour. These findings indicate that a disposition for third-party punishment of antisocial others emerges in early infancy and emphasize the importance of third-party punishment for human cooperation. This behavioural tendency may be a human trait acquired over the course of evolution.
Programmable gear-based mechanical metamaterials
Authors: Fang Xin , Wen Jihong , Cheng Li , Yu Dianlong , Zhang Hongjia , Gumbsch Peter
Published: June 2022

Elastic properties of classical bulk materials can hardly be changed or adjusted in operando, while such tunable elasticity is highly desired for robots and smart machinery. Although possible in reconfigurable metamaterials, continuous tunability in existing designs is plagued by issues such as structural instability, weak robustness, plastic failure and slow response. Here we report a metamaterial design paradigm using gears with encoded stiffness gradients as the constituent elements and organizing gear clusters for versatile functionalities. The design enables continuously tunable elastic properties while preserving stability and robust manoeuvrability, even under a heavy load. Such gear-based metamaterials enable excellent properties such as continuous modulation of Young’s modulus by two orders of magnitude, shape morphing between ultrasoft and solid states, and fast response. This allows for metamaterial customization and brings fully programmable materials and adaptive robots within reach.
Auto-generating databases of Yield Strength and Grain Size using ChemDataExtractor
Authors: Kumar Pankaj , Kabra Saurabh , Cole Jacqueline M.
Published: June 2022

The emerging field of material-based data science requires information-rich databases to generate useful results which are currently sparse in the stress engineering domain. To this end, this study uses the’materials-aware’ text-mining toolkit, ChemDataExtractor, to auto-generate databases of yield-strength and grain-size values by extracting such information from the literature. The precision of the extracted data is 83.0% for yield strength and 78.8% for grain size. The automatically-extracted data were organised into four databases: a Yield Strength, Grain Size, Engineering-Ready Yield Strength and Combined database. For further validation of the databases, the Combined database was used to plot the Hall-Petch relationship for, the alloy, AZ31, and similar results to the literature were found, demonstrating how one can make use of these automatically-extracted datasets.