bluuebunny/crossref_metadata_2025 huggingface dataset:
ADHS in der Lerntherapie
Authors: von Wirth Elena , Döpfner Manfred
Published: July 2023

Kinder mit einer Aufmerksamkeitsdefizit-/Hyperaktivitätsstörung (ADHS) zeigen häufig Probleme in der Selbststeuerung, die zu Lernschwierigkeiten führen können. Zudem leiden Kinder mit einer ADHS nicht selten an einer Lese-Rechtschreibstörung (Dyslexie) oder Rechenstörung (Dyskalkulie). In der Lerntherapie fällt es den Betroffenen jedoch oft schwer, über einen längeren Zeitraum still zu sitzen und Aufgaben sorgfältig zu bearbeiten. Häufig sind sie leicht abgelenkt, unruhig und reagieren schnell frustriert, wenn ihnen etwas nicht gelingt. Dieser Praxisleitfaden unterstützt Lerntherapeutinnen und Lerntherapeuten beim Umgang mit hyperaktiven, unaufmerksamen und impulsiven, aber auch oppositionell-verweigernden Verhaltensweisen. Ausgehend von einem verhaltenstherapeutischen Modell werden konkrete und leicht umsetzbare Handlungsempfehlungen vorgestellt. Dazu gehören u.a. die Gestaltung der Rahmenbedingungen in der Lerntherapie, die Einführung von Regeln und Routinen, der Einsatz positiver und negativer Konsequenzen und die Etablierung von Token-Systemen (Belohnungsplänen) sowie Strategien zur Verbesserung der Handlungsplanung in Lernsituationen. Ausführlich wird zudem beschrieben, wie die Zusammenarbeit mit den Eltern konstruktiv gestaltet werden kann. Die vorgestellten Handlungsempfehlungen wurden in der psychotherapeutischen Arbeit mit Familien und Lehrkräften entwickelt und haben sich in vielen Studien als wirksam erwiesen. Anschauliche Beispiele, leicht verständliche Schritt-für-Schritt-Anleitungen sowie zahlreiche Arbeitsblätter und Checklisten helfen dabei, die Strategien auf individuelle Problemsituationen in der Lerntherapie zu übertragen.
Dynamics of Suspended Particulate Matter in an Impounded River Under Dry and Wet Weather Conditions
Authors: Huynh T. T. , Kim J. , Kim W. , Hur J. , Ho Q. N. , Bi Q. , Bui T. V. , Kim J. J. , Lee S. D. , Choi Y. Y. , Lee B. J.
Published: July 2023

The dynamics of suspended particulate matter (SPM) and SPM‐associated biological and physicochemical processes in a river vary under dry and wet weather conditions and hydraulic structures, which moves a free‐flowing river to a semi‐lacustrine environment. This study investigated the response of SPM dynamics and riverbed morphodynamics to climate and anthropogenic stressors based on in‐situ observations and biogeochemical analyses of river water and riverbed sediment. The biochemical analyses and flocculation tests demonstrate abundant biopolymers and high flocculation potential of the river water during the pre‐flood period with algal bloom. This might promote SPM deposition and high‐concentration sediment layer (HCSL) formation on the riverbed. The high fractions of clay minerals and organic carbon in the riverbed sediment indicate the deposition of organic‐rich biomineral flocs. Vertical turbidity profiles with “long tails” of high turbidity near the riverbed also confirmed SPM deposition and HCSL formation. However, the highly turbulent flow conditions during the post‐flood period disturbed the tails of high turbidity and homogenized the vertical profiles of turbidity, temperature, and dissolved oxygen. Additionally, terrestrial humic substances were discharged from the watershed during this period, increasing the deflocculation and stabilization of SPM but decreasing deposition on the riverbed, thereby reducing the fractions of clay minerals and organic carbon in the sediment. This study demonstrated the interaction mechanism of SPM dynamics and riverbed morphodynamics with hydrological and biogeochemical processes in an impounded river under dry and wet weather conditions. The findings provide insights into water resource management to deal with climate change and anthropogenic stressors.
Targeting PP2A-dependent autophagy enhances sensitivity to ruxolitinib in JAK2V617F myeloproliferative neoplasms
Authors: Courdy Charly , Platteeuw Loïc , Ducau Charlotte , De Araujo Isabelle , Boet Emeline , Sahal Ambrine , Saland Estelle , Edmond Valérie , Tavitian Suzanne , Bertoli Sarah , Cougoul Pierre , Granat Fanny , Poillet Laura , Marty Caroline , Plo Isabelle , Sarry Jean-Emmanuel , Manenti Stéphane , Mansat-De Mas Véronique , Joffre Carine
Published: July 2023

The Janus kinase 2 (JAK2)-driven myeloproliferative neoplasms (MPNs) are chronic malignancies associated with high-risk complications and suboptimal responses to JAK inhibitors such as ruxolitinib. A better understanding of cellular changes induced by ruxolitinib is required to develop new combinatory therapies to improve treatment efficacy. Here, we demonstrate that ruxolitinib induced autophagy in JAK2V617F cell lines and primary MPN patient cells through the activation of protein phosphatase 2A (PP2A). Inhibition of autophagy or PP2A activity along with ruxolitinib treatment reduced proliferation and increased the death of JAK2V617F cells. Accordingly, proliferation and clonogenic potential of JAK2V617F-driven primary MPN patient cells, but not of normal hematopoietic cells, were markedly impaired by ruxolitinib treatment with autophagy or PP2A inhibitor. Finally, preventing ruxolitinib-induced autophagy with a novel potent autophagy inhibitor Lys05 improved leukemia burden reduction and significantly prolonged the mice’s overall survival compared with ruxolitinib alone. This study demonstrates that PP2A-dependent autophagy mediated by JAK2 activity inhibition contributes to resistance to ruxolitinib. Altogether, our data support that targeting autophagy or its identified regulator PP2A could enhance sensitivity to ruxolitinib of JAK2V617F MPN cells and improve MPN patient care.
Type 2 immunity in the brain and brain borders
Authors: Mamuladze Tornike , Kipnis Jonathan
Published: July 2023

Recent research in neuroimmunology has revolutionized our understanding of the intricate interactions between the immune system and the central nervous system (CNS). The CNS, an “immune-privileged organ”, is now known to be intimately connected to the immune system through different cell types and cytokines. While type 2 immune responses have traditionally been associated with allergy and parasitic infections, emerging evidence suggests that these responses also play a crucial role in CNS homeostasis and disease pathogenesis. Type 2 immunity encompasses a delicate interplay among stroma, Th2 cells, innate lymphoid type 2 cells (ILC2s), mast cells, basophils, and the cytokines interleukin (IL)-4, IL-5, IL-13, IL-25, TSLP and IL-33. In this review, we discuss the beneficial and detrimental roles of type 2 immune cells and cytokines in CNS injury and homeostasis, cognition, and diseases such as tumors, Alzheimer’s disease and multiple sclerosis.
Genome-wide association analysis and Mendelian randomization proteomics identify drug targets for heart failure
Authors: Rasooly Danielle , Peloso Gina M. , Pereira Alexandre C. , Dashti Hesam , Giambartolomei Claudia , Wheeler Eleanor , Aung Nay , Ferolito Brian R. , Pietzner Maik , Farber-Eger Eric H. , Wells Quinn Stanton , Kosik Nicole M. , Gaziano Liam , Posner Daniel C. , Bento A. Patrícia , Hui Qin , Liu Chang , Aragam Krishna , Wang Zeyuan , Charest Brian , Huffman Jennifer E. , Wilson Peter W. F. , Phillips Lawrence S. , Whittaker John , Munroe Patricia B. , Petersen Steffen E. , Cho Kelly , Leach Andrew R. , Magariños María Paula , Gaziano John Michael ,   VA Million Veteran Program, Langenberg Claudia , Sun Yan V. , Joseph Jacob , Casas Juan P.
Published: July 2023

We conduct a large-scale meta-analysis of heart failure genome-wide association studies (GWAS) consisting of over 90,000 heart failure cases and more than 1 million control individuals of European ancestry to uncover novel genetic determinants for heart failure. Using the GWAS results and blood protein quantitative loci, we perform Mendelian randomization and colocalization analyses on human proteins to provide putative causal evidence for the role of druggable proteins in the genesis of heart failure. We identify 39 genome-wide significant heart failure risk variants, of which 18 are previously unreported. Using a combination of Mendelian randomization proteomics and genetic cis-only colocalization analyses, we identify 10 additional putatively causal genes for heart failure. Findings from GWAS and Mendelian randomization-proteomics identify seven (CAMK2D, PRKD1, PRKD3, MAPK3, TNFSF12, APOC3 and NAE1) proteins as potential targets for interventions to be used in primary prevention of heart failure.
QBO deepens MJO convection
Authors: Jin Daeho , Kim Daehyun , Son Seok-Woo , Oreopoulos Lazaros
Published: July 2023

The underlying mechanism that couples the Quasi-Biennial Oscillation (QBO) and the Madden-Julian oscillation (MJO) has remained elusive, challenging our understanding of both phenomena. A popular hypothesis about the QBO-MJO connection is that the vertical extent of MJO convection is strongly modulated by the QBO. However, this hypothesis has not been verified observationally. Here we show that the cloud-top pressure and brightness temperature of deep convection and anvil clouds are systematically lower in the easterly QBO (EQBO) winters than in the westerly QBO (WQBO) winters, indicating that the vertical growth of deep convective systems within MJO envelopes is facilitated by the EQBO mean state. Moreover, the deeper clouds during EQBO winters are more effective at reducing longwave radiation escaping to space and thereby enhancing longwave cloud-radiative feedback within MJO envelopes. Our results provide robust observational evidence of the enhanced MJO activity during EQBO winters by mean state changes induced by the QBO.
Nanoconfinement enabled non-covalently decorated MXene membranes for ion-sieving
Authors: Kang Yuan , Hu Ting , Wang Yuqi , He Kaiqiang , Wang Zhuyuan , Hora Yvonne , Zhao Wang , Xu Rongming , Chen Yu , Xie Zongli , Wang Huanting , Gu Qinfen , Zhang Xiwang
Published: July 2023

Covalent modification is commonly used to tune the channel size and functionality of 2D membranes. However, common synthesis strategies used to produce such modifications are known to disrupt the structure of the membranes. Herein, we report less intrusive yet equally effective non-covalent modifications on Ti3C2Tx MXene membranes by a solvent treatment, where the channels are robustly decorated by protic solvents via hydrogen bond network. The densely functionalized (-O, -F, -OH) Ti3C2Tx channel allows multiple hydrogen bond establishment and its sub-1-nm size induces a nanoconfinement effect to greatly strengthen these interactions by maintaining solvent-MXene distance and solvent orientation. In sub-1-nm ion sieving and separation, as-decorated membranes exhibit stable ion rejection, and proton-cation (H+/Mn+) selectivity that is up to 50 times and 30 times, respectively, higher than that of pristine membranes. It demonstrates the feasibility of non-covalent methods as a broad modification alternative for nanochannels integrated in energy-, resource- and environment-related applications.
Group size and mating system predict sex differences in vocal fundamental frequency in anthropoid primates
Authors: Aung Toe , Hill Alexander K. , Pfefferle Dana , McLester Edward , Fuller James , Lawrence Jenna M. , Garcia-Nisa Ivan , Kendal Rachel L. , Petersdorf Megan , Higham James P. , Galat Gérard , Lameira Adriano R. , Apicella Coren L. , Barelli Claudia , Glenn Mary E. , Ramos-Fernandez Gabriel , Puts David A.
Published: July 2023

Vocalizations differ substantially between the sexes in many primates, and low-frequency male vocalizations may be favored by sexual selection because they intimidate rivals and/or attract mates. Sexual dimorphism in fundamental frequency may be more pronounced in species with more intense male mating competition and in those with large group size, where social knowledge is limited and efficient judgment of potential mates and competitors is crucial. These non-mutually exclusive explanations have not been tested simultaneously across primate species. In a sample of vocalizations (n = 1914 recordings) across 37 anthropoid species, we investigated whether fundamental frequency dimorphism evolved in association with increased intensity of mating competition (H1), large group size (H2), multilevel social organization (H3), a trade-off against the intensity of sperm competition (H4), and/or poor acoustic habitats (H5), controlling for phylogeny and body size dimorphism. We show that fundamental frequency dimorphism increased in evolutionary transitions towards larger group size and polygyny. Findings suggest that low-frequency male vocalizations in primates may have been driven by selection to win mating opportunities by avoiding costly fights and may be more important in larger groups, where limited social knowledge affords advantages to rapid assessment of status and threat potential via conspicuous secondary sexual characteristics.
Cell cycle arrest and p53 prevent ON-target megabase-scale rearrangements induced by CRISPR-Cas9
Authors: Cullot G. , Boutin J. , Fayet S. , Prat F. , Rosier J. , Cappellen D. , Lamrissi I. , Pennamen P. , Bouron J. , Amintas S. , Thibault C. , Moranvillier I. , Laharanne E. , Merlio J. P. , Guyonnet-Duperat V. , Blouin J. M. , Richard E. , Dabernat S. , Moreau-Gaudry F. , Bedel A.
Published: July 2023

The CRISPR-Cas9 system has revolutionized our ability to precisely modify the genome and has led to gene editing in clinical applications. Comprehensive analysis of gene editing products at the targeted cut-site has revealed a complex spectrum of outcomes. ON-target genotoxicity is underestimated with standard PCR-based methods and necessitates appropriate and more sensitive detection methods. Here, we present two complementary Fluorescence-Assisted Megabase-scale Rearrangements Detection (FAMReD) systems that enable the detection, quantification, and cell sorting of edited cells with megabase-scale loss of heterozygosity (LOH). These tools reveal rare complex chromosomal rearrangements caused by Cas9-nuclease and show that LOH frequency depends on cell division rate during editing and p53 status. Cell cycle arrest during editing suppresses the occurrence of LOH without compromising editing. These data are confirmed in human stem/progenitor cells, suggesting that clinical trials should consider p53 status and cell proliferation rate during editing to limit this risk by designing safer protocols.
Assembly drives regioselective azide-alkyne cycloaddition reaction
Authors: Jiang Qiaochu , Zhan Wenjun , Liu Xiaoyang , Bai Lin , Wang Manli , Xu Ying , Liang Gaolin
Published: July 2023

Azide-alkyne cycloaddition reaction is a very common organic reaction to synthesize nitrogen-containing heterocycles. Once catalyzed by Cu(I) or Ru(II), it turns out to be a click reaction and thus is widely applied in chemical biology for labeling. However, besides their poor regioselectivity towards this reaction, these metal ions are not biologically friendly. Hence, it is an urgent need to develop a metal-free azide–alkyne cycloaddition reaction for biomedical applications. In this work, we found that, in the absence of metal ions, supramolecular self-assembly in an aqueous solution could realize this reaction with excellent regioselectivity. Nap-Phe-Phe-Lys(azido)-OH firstly self-assembled into nanofibers. Then, Nap-Phe-Phe-Gly(alkynyl)-OH at equivalent concentration approached to react with the assembly to yield the cycloaddition product Nap-Phe-Phe-Lys(triazole)-Gly-Phe-Phe-Nap to form nanoribbons. Due to space confinement effect, the product was obtained with excellent regioselectivity. Employing the excellent properties of supramolecular self-assembly, we are applying this strategy to realize more reactions without metal ion catalysis.
A sodium-ion-conducted asymmetric electrolyzer to lower the operation voltage for direct seawater electrolysis
Authors: Shi Hao , Wang Tanyuan , Liu Jianyun , Chen Weiwei , Li Shenzhou , Liang Jiashun , Liu Shuxia , Liu Xuan , Cai Zhao , Wang Chao , Su Dong , Huang Yunhui , Elbaz Lior , Li Qing
Published: July 2023

Hydrogen produced from neutral seawater electrolysis faces many challenges including high energy consumption, the corrosion/side reactions caused by Cl-, and the blockage of active sites by Ca2+/Mg2+precipitates. Herein, we design a pH-asymmetric electrolyzer with a Na+exchange membrane for direct seawater electrolysis, which can simultaneously prevent Cl-corrosion and Ca2+/Mg2+precipitation and harvest the chemical potentials between the different electrolytes to reduce the required voltage. In-situ Raman spectroscopy and density functional theory calculations reveal that water dissociation can be promoted with a catalyst based on atomically dispersed Pt anchored to Ni-Fe-P nanowires with a reduced energy barrier (by 0.26 eV), thus accelerating the hydrogen evolution kinetics in seawater. Consequently, the asymmetric electrolyzer exhibits current densities of 10 mA cm−2and 100 mA cm−2at voltages of 1.31 V and 1.46 V, respectively. It can also reach 400 mA cm−2at a low voltage of 1.66 V at 80 °C, corresponding to the electricity cost of US$1.36 per kg of H2($0.031/kW h for the electricity bill), lower than the United States Department of Energy 2025 target (US$1.4 per kg of H2).
Realizing long-cycling all-solid-state Li-In||TiS2 batteries using Li6+xMxAs1-xS5I (M=Si, Sn) sulfide solid electrolytes
Authors: Lu Pushun , Xia Yu , Sun Guochen , Wu Dengxu , Wu Siyuan , Yan Wenlin , Zhu Xiang , Lu Jiaze , Niu Quanhai , Shi Shaochen , Sha Zhengju , Chen Liquan , Li Hong , Wu Fan
Published: July 2023

Inorganic sulfide solid-state electrolytes, especially Li6PS5X (X = Cl, Br, I), are considered viable materials for developing all-solid-state batteries because of their high ionic conductivity and low cost. However, this class of solid-state electrolytes suffers from structural and chemical instability in humid air environments and a lack of compatibility with layered oxide positive electrode active materials. To circumvent these issues, here, we propose Li6+xMxAs1-xS5I (M=Si, Sn) as sulfide solid electrolytes. When the Li6+xSixAs1-xS5I (x = 0.8) is tested in combination with a Li-In negative electrode and Ti2S-based positive electrode at 30 °C and 30 MPa, the Li-ion lab-scale Swagelok cells demonstrate long cycle life of almost 62500 cycles at 2.44 mA cm−2, decent power performance (up to 24.45 mA cm−2) and areal capacity of 9.26 mAh cm−2 at 0.53 mA cm−2.
Bioinspired one-pot furan-thiol-amine multicomponent reaction for making heterocycles and its applications
Authors: Wang Yuwen , Czabala Patrick , Raj Monika
Published: July 2023

One-pot multicomponent coupling of different units in a chemoselective manner and their late-stage diversification has wide applicability in varying chemistry fields. Here, we report a simple multicomponent reaction inspired by enzymes that combines thiol and amine nucleophiles in one pot via a furan-based electrophile to generate stable pyrrole heterocycles independent of the diverse functionalities on furans, thiols and amines under physiological conditions. The resulting pyrrole provides a reactive handle to introduce diverse payloads. We demonstrate the application of Furan-Thiol-Amine (FuTine) reaction for the selective and irreversible labeling of peptides, synthesis of macrocyclic and stapled peptides, selective modification of twelve different proteins with varying payloads, homogeneous engineering of proteins, homogeneous stapling of proteins, dual modification of proteins with different fluorophores using the same chemistry and labeling of lysine and cysteine in a complex human proteome.
Establishing mammalian GLUT kinetics and lipid composition influences in a reconstituted-liposome system
Authors: Suades Albert , Qureshi Aziz , McComas Sarah E. , Coinçon Mathieu , Rudling Axel , Chatzikyriakidou Yurie , Landreh Michael , Carlsson Jens , Drew David
Published: July 2023

Glucose transporters (GLUTs) are essential for organism-wide glucose homeostasis in mammals, and their dysfunction is associated with numerous diseases, such as diabetes and cancer. Despite structural advances, transport assays using purified GLUTs have proven to be difficult to implement, hampering deeper mechanistic insights. Here, we have optimized a transport assay in liposomes for the fructose-specific isoform GLUT5. By combining lipidomic analysis with native MS and thermal-shift assays, we replicate the GLUT5 transport activities seen in crude lipids using a small number of synthetic lipids. We conclude that GLUT5 is only active under a specific range of membrane fluidity, and that human GLUT1-4 prefers a similar lipid composition to GLUT5. Although GLUT3 is designated as the high-affinity glucose transporter, in vitro D-glucose kinetics demonstrates that GLUT1 and GLUT3 actually have a similar KM, but GLUT3 has a higher turnover. Interestingly, GLUT4 has a high KM for D-glucose and yet a very slow turnover, which may have evolved to ensure uptake regulation by insulin-dependent trafficking. Overall, we outline a much-needed transport assay for measuring GLUT kinetics and our analysis implies that high-levels of free fatty acid in membranes, as found in those suffering from metabolic disorders, could directly impair glucose uptake.
Mechanism of ATP hydrolysis dependent rotation of bacterial ATP synthase
Authors: Nakano Atsuki , Kishikawa Jun-ichi , Mitsuoka Kaoru , Yokoyama Ken
Published: July 2023

F1 domain of ATP synthase is a rotary ATPase complex in which rotation of central γ-subunit proceeds in 120° steps against a surrounding α3β3 fueled by ATP hydrolysis. How the ATP hydrolysis reactions occurring in three catalytic αβ dimers are coupled to mechanical rotation is a key outstanding question. Here we describe catalytic intermediates of the F1 domain in FoF1 synthase from Bacillus PS3 sp. during ATP mediated rotation captured using cryo-EM. The structures reveal that three catalytic events and the first 80° rotation occur simultaneously in F1 domain when nucleotides are bound at all the three catalytic αβ dimers. The remaining 40° rotation of the complete 120° step is driven by completion of ATP hydrolysis at αDβD, and proceeds through three sub-steps (83°, 91°, 101°, and 120°) with three associated conformational intermediates. All sub-steps except for one between 91° and 101° associated with phosphate release, occur independently of the chemical cycle, suggesting that the 40° rotation is largely driven by release of intramolecular strain accumulated by the 80° rotation. Together with our previous results, these findings provide the molecular basis of ATP driven rotation of ATP synthases.
In situ activation of flexible magnetoelectric membrane enhances bone defect repair
Authors: Liu Wenwen , Zhao Han , Zhang Chenguang , Xu Shiqi , Zhang Fengyi , Wei Ling , Zhu Fangyu , Chen Ying , Chen Yumin , Huang Ying , Xu Mingming , He Ying , Heng Boon Chin , Zhang Jinxing , Shen Yang , Zhang Xuehui , Huang Houbing , Chen Lili , Deng Xuliang
Published: July 2023

For bone defect repair under co-morbidity conditions, the use of biomaterials that can be non-invasively regulated is highly desirable to avoid further complications and to promote osteogenesis. However, it remains a formidable challenge in clinical applications to achieve efficient osteogenesis with stimuli-responsive materials. Here, we develop polarized CoFe2O4@BaTiO3/poly(vinylidene fluoridetrifluoroethylene) [P(VDF-TrFE)] core-shell particle-incorporated composite membranes with high magnetoelectric conversion efficiency for activating bone regeneration. An external magnetic field force conduct on the CoFe2O4 core can increase charge density on the BaTiO3 shell and strengthens the β-phase transition in the P(VDF-TrFE) matrix. This energy conversion increases the membrane surface potential, which hence activates osteogenesis. Skull defect experiments on male rats showed that repeated magnetic field applications on the membranes enhanced bone defect repair, even when osteogenesis repression is elicited by dexamethasone or lipopolysaccharide-induced inflammation. This study provides a strategy of utilizing stimuli-responsive magnetoelectric membranes to efficiently activate osteogenesis in situ.
Structures of a FtsZ single protofilament and a double-helical tube in complex with a monobody
Authors: Fujita Junso , Amesaka Hiroshi , Yoshizawa Takuya , Hibino Kota , Kamimura Natsuki , Kuroda Natsuko , Konishi Takamoto , Kato Yuki , Hara Mizuho , Inoue Tsuyoshi , Namba Keiichi , Tanaka Shun-ichi , Matsumura Hiroyoshi
Published: July 2023

FtsZ polymerizes into protofilaments to form the Z-ring that acts as a scaffold for accessory proteins during cell division. Structures of FtsZ have been previously solved, but detailed mechanistic insights are lacking. Here, we determine the cryoEM structure of a single protofilament of FtsZ from Klebsiella pneumoniae (KpFtsZ) in a polymerization-preferred conformation. We also develop a monobody (Mb) that binds to KpFtsZ and FtsZ from Escherichia coli without affecting their GTPase activity. Crystal structures of the FtsZ–Mb complexes reveal the Mb binding mode, while addition of Mb in vivo inhibits cell division. A cryoEM structure of a double-helical tube of KpFtsZ–Mb at 2.7 Å resolution shows two parallel protofilaments. Our present study highlights the physiological roles of the conformational changes of FtsZ in treadmilling that regulate cell division.
IL-9 aggravates SARS-CoV-2 infection and exacerbates associated airway inflammation
Authors: Sadhu Srikanth , Dalal Rajdeep , Dandotiya Jyotsna , Binayke Akshay , Singh Virendra , Tripathy Manas Ranjan , Das Vinayaka , Goswami Sandeep , Kumar Shakti , Rizvi Zaigham Abbas , Awasthi Amit
Published: July 2023

SARS-CoV-2 infection is known for causing broncho-alveolar inflammation. Interleukin 9 (IL-9) induces airway inflammation and bronchial hyper responsiveness in respiratory viral illnesses and allergic inflammation, however, IL-9 has not been assigned a pathologic role in COVID-19. Here we show, in a K18-hACE2 transgenic (ACE2.Tg) mouse model, that IL-9 contributes to and exacerbates viral spread and airway inflammation caused by SARS-CoV-2 infection. ACE2.Tg mice with CD4+ T cell-specific deficiency of the transcription factor Forkhead Box Protein O1 (Foxo1) produce significantly less IL-9 upon SARS-CoV-2 infection than the wild type controls and they are resistant to the severe inflammatory disease that characterises the control mice. Exogenous IL-9 increases airway inflammation in Foxo1-deficient mice, while IL-9 blockade reduces and suppresses airway inflammation in SARS-CoV-2 infection, providing further evidence for a Foxo1-Il-9 mediated Th cell-specific pathway playing a role in COVID-19. Collectively, our study provides mechanistic insight into an important inflammatory pathway in SARS-CoV-2 infection, and thus represents proof of principle for the development of host-directed therapeutics to mitigate disease severity.
Lysine methylation promotes NFAT5 activation and determines temozolomide efficacy in glioblastoma
Authors: Li Yatian , Gao Zhenyue , Wang Yuhong , Pang Bo , Zhang Binbin , Hu Ruxin , Wang Yuqing , Liu Chao , Zhang Xuebin , Yang Jingxuan , Mei Mei , Wang Yongzhi , Zhou Xuan , Li Min , Ren Yu
Published: July 2023

Temozolomide (TMZ) therapy offers minimal clinical benefits in patients with glioblastoma multiforme (GBM) with high EGFR activity, underscoring the need for effective combination therapy. Here, we show that tonicity-responsive enhancer binding protein (NFAT5) lysine methylation, is a determinant of TMZ response. Mechanistically, EGFR activation induces phosphorylated EZH2 (Ser21) binding and triggers NFAT5 methylation at K668. Methylation prevents NFAT5 cytoplasm interaction with E3 ligase TRAF6, thus blocks NFAT5 lysosomal degradation and cytosol localization restriction, which was mediated by TRAF6 induced K63-linked ubiquitination, resulting in NFAT5 protein stabilization, nuclear accumulation and activation. Methylated NFAT5 leads to the upregulation of MGMT, a transcriptional target of NFAT5, which is responsible for unfavorable TMZ response. Inhibition of NFAT5 K668 methylation improved TMZ efficacy in orthotopic xenografts and patient-derived xenografts (PDX) models. Notably, NFAT5 K668 methylation levels are elevated in TMZ-refractory specimens and confer poor prognosis. Our findings suggest targeting NFAT5 methylation is a promising therapeutic strategy to improve TMZ response in tumors with EGFR activation.
Histone H1 facilitates restoration of H3K27me3 during DNA replication by chromatin compaction
Authors: Liu Cuifang , Yu Juan , Song Aoqun , Wang Min , Hu Jiansen , Chen Ping , Zhao Jicheng , Li Guohong
Published: July 2023

During cell renewal, epigenetic information needs to be precisely restored to maintain cell identity and genome integrity following DNA replication. The histone mark H3K27me3 is essential for the formation of facultative heterochromatin and the repression of developmental genes in embryonic stem cells. However, how the restoration of H3K27me3 is precisely achieved following DNA replication is still poorly understood. Here we employ ChOR-seq (Chromatin Occupancy after Replication) to monitor the dynamic re-establishment of H3K27me3 on nascent DNA during DNA replication. We find that the restoration rate of H3K27me3 is highly correlated with dense chromatin states. In addition, we reveal that the linker histone H1 facilitates the rapid post-replication restoration of H3K27me3 on repressed genes and the restoration rate of H3K27me3 on nascent DNA is greatly compromised after partial depletion of H1. Finally, our in vitro biochemical experiments demonstrate that H1 facilitates the propagation of H3K27me3 by PRC2 through compacting chromatin. Collectively, our results indicate that H1-mediated chromatin compaction facilitates the propagation and restoration of H3K27me3 after DNA replication.
Roving methyltransferases generate a mosaic epigenetic landscape and influence evolution in Bacteroides fragilis group
Authors: Tisza Michael J. , Smith Derek D. N. , Clark Andrew E. , Youn Jung-Ho ,   NISC Comparative Sequencing Program, Barnabas Beatrice B. , Black Sean , Bouffard Gerard G. , Brooks Shelise Y. , Crawford Juyun , Marfani Holly , Dekhtyar Lyudmila , Han Joel , Ho Shi-Ling , Legaspi Richelle , Maduro Quino L. , Masiello Catherine A. , McDowell Jennifer C. , Montemayor Casandra , Mullikin James C. , Park Morgan , Schandler Karen , Schmidt Brian , Sison Christina , Stantripop Sirintorn , Thomas James W. , Thomas Pamela J. , Vemulapalli Meghana , Young Alice C. , Khil Pavel P. , Dekker John P.
Published: July 2023

Three types of DNA methyl modifications have been detected in bacterial genomes, and mechanistic studies have demonstrated roles for DNA methylation in physiological functions ranging from phage defense to transcriptional control of virulence and host-pathogen interactions. Despite the ubiquity of methyltransferases and the immense variety of possible methylation patterns, epigenomic diversity remains unexplored for most bacterial species. Members of theBacteroides fragilisgroup (BFG) reside in the human gastrointestinal tract as key players in symbiotic communities but also can establish anaerobic infections that are increasingly multi-drug resistant. In this work, we utilize long-read sequencing technologies to perform pangenomic (n = 383) and panepigenomic (n = 268) analysis of clinical BFG isolates cultured from infections seen at the NIH Clinical Center over four decades. Our analysis reveals that single BFG species harbor hundreds of DNA methylation motifs, with most individual motif combinations occurring uniquely in single isolates, implying immense unsampled methylation diversity within BFG epigenomes. Mining of BFG genomes identified more than 6000 methyltransferase genes, approximately 1000 of which were associated with intact prophages. Network analysis revealed substantial gene flow among disparate phage genomes, implying a role for genetic exchange between BFG phages as one of the ultimate sources driving BFG epigenome diversity.
Real-time multiaxial strain mapping using computer vision integrated optical sensors
Authors: Hong Sunguk , Rachim Vega Pradana , Baek Jin-Hyeok , Park Sung-Min
Published: July 2023

Soft strain sensors pose great potential for emerging human–machine interfaces. However, their real-world applications have been limited due to challenges such as low reproducibility, susceptibility to environmental noise, and short lifetimes, which are attributed to nanotechnologies, including microfabrication techniques. In this study, we present a computer vision-based optical strain (CVOS) sensor system that integrates computer vision with streamlined microfabrication techniques to overcome these challenges and facilitate real-time multiaxial strain mapping. The proposed CVOS sensor consists of an easily fabricated soft silicone substrate with micro-markers and a tiny camera for highly sensitive marker detection. Real-time multiaxial strain mapping allows for measuring and distinguishing complex multi-directional strain patterns, providing the proposed CVOS sensor with higher scalability. Our results indicate that the proposed CVOS sensor is a promising approach for the development of highly sensitive and versatile human–machine interfaces that can operate long-term under real-world conditions.
A lipidated TLR7/8 adjuvant enhances the efficacy of a vaccine against fentanyl in mice
Authors: Miller Shannon M. , Crouse Bethany , Hicks Linda , Amin Hardik , Cole Shelby , Bazin Helene G. , Burkhart David J. , Pravetoni Marco , Evans Jay T.
Published: July 2023

Opioid use disorders (OUD) and opioid-related fatal overdoses are a public health concern in the United States. Approximately 100,000 fatal opioid-related overdoses occurred annually from mid-2020 to the present, the majority of which involved fentanyl or fentanyl analogs. Vaccines have been proposed as a therapeutic and prophylactic strategy to offer selective and long-lasting protection against accidental or deliberate exposure to fentanyl and closely related analogs. To support the development of a clinically viable anti-opioid vaccine suitable for human use, the incorporation of adjuvants will be required to elicit high titers of high-affinity circulating antibodies specific to the target opioid. Here we demonstrate that the addition of a synthetic TLR7/8 agonist, INI-4001, but not a synthetic TLR4 agonist, INI-2002, to a candidate conjugate vaccine consisting of a fentanyl-based hapten, F1, conjugated to the diphtheria cross-reactive material (CRM), significantly increased generation of high-affinity F1-specific antibody concentrations, and reduced drug distribution to the brain after fentanyl administration in mice.
Integrated internal ion-gated organic electrochemical transistors for stand-alone conformable bioelectronics
Authors: Cea Claudia , Zhao Zifang , Wisniewski Duncan J. , Spyropoulos George D. , Polyravas Anastasios , Gelinas Jennifer N. , Khodagholy Dion
Published: July 2023

Organic electronics can be biocompatible and conformable, enhancing the ability to interface with tissue. However, the limitations of speed and integration have, thus far, necessitated reliance on silicon-based technologies for advanced processing, data transmission and device powering. Here we create a stand-alone, conformable, fully organic bioelectronic device capable of realizing these functions. This device, vertical internal ion-gated organic electrochemical transistor (vIGT), is based on a transistor architecture that incorporates a vertical channel and a miniaturized hydration access conduit to enable megahertz-signal-range operation within densely packed integrated arrays in the absence of crosstalk. These transistors demonstrated long-term stability in physiologic media, and were used to generate high-performance integrated circuits. We leveraged the high-speed and low-voltage operation of vertical internal ion-gated organic electrochemical transistors to develop alternating-current-powered conformable circuitry to acquire and wirelessly communicate signals. The resultant stand-alone device was implanted in freely moving rodents to acquire, process and transmit neurophysiologic brain signals. Such fully organic devices have the potential to expand the utility and accessibility of bioelectronics to a wide range of clinical and societal applications.
Adeno-associated viral vectors for functional intravenous gene transfer throughout the non-human primate brain
Authors: Chuapoco Miguel R. , Flytzanis Nicholas C. , Goeden Nick , Christopher Octeau J. , Roxas Kristina M. , Chan Ken Y. , Scherrer Jon , Winchester Janet , Blackburn Roy J. , Campos Lillian J. , Man Kwun Nok Mimi , Sun Junqing , Chen Xinhong , Lefevre Arthur , Singh Vikram Pal , Arokiaraj Cynthia M. , Shay Timothy F. , Vendemiatti Julia , Jang Min J. , Mich John K. , Bishaw Yemeserach , Gore Bryan B. , Omstead Victoria , Taskin Naz , Weed Natalie , Levi Boaz P. , Ting Jonathan T. , Miller Cory T. , Deverman Benjamin E. , Pickel James , Tian Lin , Fox Andrew S. , Gradinaru Viviana
Published: July 2023

Crossing the blood–brain barrier in primates is a major obstacle for gene delivery to the brain. Adeno-associated viruses (AAVs) promise robust, non-invasive gene delivery from the bloodstream to the brain. However, unlike in rodents, few neurotropic AAVs efficiently cross the blood–brain barrier in non-human primates. Here we report on AAV.CAP-Mac, an engineered variant identified by screening in adult marmosets and newborn macaques, which has improved delivery efficiency in the brains of multiple non-human primate species: marmoset, rhesus macaque and green monkey. CAP-Mac is neuron biased in infant Old World primates, exhibits broad tropism in adult rhesus macaques and is vasculature biased in adult marmosets. We demonstrate applications of a single, intravenous dose of CAP-Mac to deliver functional GCaMP for ex vivo calcium imaging across multiple brain areas, or a cocktail of fluorescent reporters for Brainbow-like labelling throughout the macaque brain, circumventing the need for germline manipulations in Old World primates. As such, CAP-Mac is shown to have potential for non-invasive systemic gene transfer in the brains of non-human primates.
Spatial differences and influence mechanisms of construction land development intensity in China, 2002–2020
Authors: Gu Guanhai , Wu Bin , Chen Qichen , Zhang Wenzhu , Lu Rucheng , Lu Shengquan , Feng Xiaoling , Liao Wenhui
Published: July 2023

Construction land development intensity is a spatial mapping of modern urbanization level, which integrally reflects urban development strategy, land use efficiency, and population carrying intensity. This article analyzed the spatial and temporal evolution of construction land development intensity using panel data of 31 provincial administrative divisions in China from 2002 to 2020, with the application of the Theil index and spatial autocorrelation. To further investigate the relationship between human activities and land development, the article used geographic detectors to analyze the influencing mechanisms. The results showed that: (1) The average intensity of construction land development of Chinese provinces from 2002 to 2020 showed a trend of "steady increase, a short decline, and then a steady increase," and there were significant differences in the characteristics of construction land development intensity changes in different regions. (2) The regional differences in construction land development intensity between provinces showed a decreasing trend. There were uneven differences among regions, with more minor regional differences in Central, South, and North China but more significant differences in Northwest, East, Southwest, and Northeast China. (3) The spatial agglomeration of construction land development intensity in the region increased initially and then decreased during the study period. The overall pattern was "small agglomeration and large dispersion." (4) Economic development factors such as GDP per land, industrial structure, and fixed asset investment completion significantly affect land development intensity. The interaction between the factors was apparent, and the effect of “1 + 1 > 2” was produced. Based on the study's results, it is suggested that scientific regional development planning, guiding inter-provincial factor flow, and rational control of land development efforts are the key to promoting sustainable regional development.
Single event response of ferroelectric spacer engineered SOI FinFET at 14 nm technology node
Authors: Liu Baojun , Zhu Jing
Published: July 2023

The impact of spacer on the single event response of SOI FinFET at 14 nm technology node is investigated. Based on the device TCAD model, well-calibrated by the experimental data, it is found that the spacer presents the enhancement on single event transient (SET) compared with no spacer configuration. For single spacer configuration, due to enhanced gate control capability and fringing field, the increments in SET current peak and collected charge for HfO2 are the least with 2.21%, 0.97%, respectively. Four possible dual ferroelectric spacer configurations are proposed. The placement of ferroelectric spacer at S side and HfO2 spacer at D side brings to weaken SET with the variation in current peak and collected charge by 6.93%, 1.86%, respectively. The reason may be its enhanced gate controllability over the S/D extension region, which improves the driven current. With linear energy transfer increasing, SET current peak and collected charge present the trend of increase while the bipolar amplification coefficient reduces.
Assessment of the impact of reopening strategies on the spatial transmission risk of COVID-19 based on a data-driven transmission model
Authors: Wang Jing , Huang YuHui , Dong Ying , Wu BingYing
Published: July 2023

COVID-19 has dramatically changed people's mobility geste patterns and affected the operations of different functional spots. In the environment of the successful reopening of countries around the world since 2022, it's pivotal to understand whether the reopening of different types of locales poses a threat of wide epidemic transmission. In this paper, by establishing an epidemiological model based on mobile network data, combining the data handed by the Safegraph website, and taking into account the crowd inflow characteristics and the changes of susceptible and latent populations, the trends of the number of crowd visits and the number of epidemic infections at different functional points of interest after the perpetration of continuing strategies were simulated. The model was also validated with daily new cases in ten metropolitan areas in the United States from March to May 2020, and the results showed that the model fitted the evolutionary trend of realistic data more accurately. Further, the points of interest were classified into risk levels, and the corresponding reopening minimum standard prevention and control measures were proposed to be implemented according to different risk levels. The results showed that restaurants and gyms became high-risk points of interest after the perpetration of the continuing strategy, especially the general dine-in restaurants were at higher risk levels. Religious exertion centers were the points of interest with the loftiest average infection rates after the perpetration of the continuing strategy. Points of interest such as convenience stores, large shopping malls, and pharmacies were at a lower risk for outbreak impact after the continuing strategy was enforced. Based on this, continuing forestallment and control strategies for different functional points of interest are proposed to provide decision support for the development of precise forestallment and control measures for different spots.
Early detection of colorectal cancer by leveraging Dutch primary care consultation notes with free text embeddings
Authors: Luik Torec T. , Abu-Hanna Ameen , van Weert Henk C. P. M. , Schut Martijn C.
Published: July 2023

We aimed to assess the added predictive performance that free-text Dutch consultation notes provide in detecting colorectal cancer in primary care, in comparison to currently used models. We developed, evaluated and compared three prediction models for colorectal cancer (CRC) in a large primary care database with 60,641 patients. The prediction model with both known predictive features and free-text data (with TabTxt AUROC: 0.823) performs statistically significantly better (p < 0.05) than the other two models with only tabular (as used nowadays) and text data, respectively (AUROC Tab: 0.767; Txt: 0.797). The specificity of the two models that use demographics and known CRC features (with specificity Tab: 0.321; TabTxt: 0.335) are higher than that of the model with only free-text (specificity Txt: 0.234). The Txt and, to a lesser degree, TabTxt model are well calibrated, while the Tab model shows slight underprediction at both tails. As expected with an outcome prevalence below 0.01, all models show much uncalibrated predictions in the extreme upper tail (top 1%). Free-text consultation notes show promising results to improve the predictive performance over established prediction models that only use structured features. Clinical future implications for our CRC use case include that such improvement may help lowering the number of referrals for suspected CRC to medical specialists.
Shear behavior and construction method of steel shear keyed joints in precast segmental beams
Authors: Zou Yu , Xiang Tianyu , Xu Dong
Published: July 2023

The joints between segments represent weak points and introduce discontinuity into structures, therefore they are particularly significant in precast concrete segmental bridges. In this study, a new steel shear key was designed, and 6 full-scale tests were conducted. Various shear keys and joint types were taken as experimental parameters to study crack propagation, failure mode, shear slip, ultimate bearing capacity, and the residual bearing capacity of various joints under direct shear loading. The results show that the stiffness and shear capacity of steel shear keyed joints were higher than concrete key joints, and the structural system was more stable than concrete keyed joints at the moment of cracking. Both the concrete key and steel key epoxied joints suffered direct shear failure. However, different to the concrete epoxied joints which experienced brittle failure, steel key epoxied joints demonstrated a large residual capacity. Based on traditional segmental bridges construction, construction methods involving steel shear keyed joints included short-line match, long-line match, and modular methods are introduced. Finally, the feasibility of steel shear keyed joints construction was verified via engineering tests.