bluuebunny/crossref_metadata_2025 huggingface dataset:
Relationship between total plasma homocysteine and the risk of aneurysms – a meta-analysis
Authors: Zhang Hanji , Yin Dexin , Zhao Yue , Li Yezhou , Yao Dejiang , Sun Dajun
Published: September 2020

Summary: Our meta-analysis focused on the relationship between homocysteine (Hcy) level and the incidence of aneurysms and looked at the relationship between smoking, hypertension and aneurysms. A systematic literature search of Pubmed, Web of Science, and Embase databases (up to March 31, 2020) resulted in the identification of 19 studies, including 2,629 aneurysm patients and 6,497 healthy participants. Combined analysis of the included studies showed that number of smoking, hypertension and hyperhomocysteinemia (HHcy) in aneurysm patients was higher than that in the control groups, and the total plasma Hcy level in aneurysm patients was also higher. These findings suggest that smoking, hypertension and HHcy may be risk factors for the development and progression of aneurysms. Although the heterogeneity of meta-analysis was significant, it was found that the heterogeneity might come from the difference between race and disease species through subgroup analysis. Large-scale randomized controlled studies of single species and single disease species are needed in the future to supplement the accuracy of the results.
Physikalische und klinische Aspekte der Inhalationstherapie bei Asthma und COPD
Authors: Rothe Thomas , Fronkova Andrea , Pein Thomas , Latshang Tsogyal
Published: September 2020

Zusammenfassung. Inhalationen stellen die Grundlage der medikamentösen Behandlung von Atemwegserkrankungen dar. In den vergangenen Jahren ist die Therapie für die Patientinnen und Patienten, aber auch für medizinische Fachpersonen, komplexer geworden, da neue Systeme auf den Markt gekommen sind. Das dazu notwendige Wissen soll in diesem Artikel vermittelt werden.
CME/Antworten zu «Zufallsraumforderung in der Hypophyse bei Erwachsenen: das Wichtigste für die Hausarztpraxis»
Authors: Erlic Zoran , Fischli Stefan
Published: September 2020

Zusammenfassung. Durch die Zunahme der bildgebenden Abklärungen des Schädels (CT/MRI), nimmt die Häufigkeit der inzidentell nachgewiesenen Raumforderungen der Hypophyse, sogenannte Inzidentalome, zu. Die Evaluation der Bildgebung durch einen erfahrenen Neuroradiologen sowie ergänzende endokrinologische und bei Bedarf neuroophtalmologische Untersuchungen sind Bestandteil der Weiterabklärung und beeinflussen den Behandlungsentscheid: bei gutartigen, kleineren und hormoninaktiven Läsionen ohne Chiasmakontakt ist eine Verlaufsbeobachtung indiziert. Hingegen werden potenziell maligne Befunde oder Läsionen mit endokrinologischen oder neuroophtalmologischen Auffälligkeiten behandelt. Bei Grenzfällen wird das Vorgehen interdisziplinär festgelegt.
Ultraschall des Knies (adaptiert nach SGUM-Richtlinien)
Authors: Tamborrini Giorgio , Bianchi Stefano
Published: September 2020

Zusammenfassung. In dieser Übersichtsarbeit wird die vereinfachte Ultraschallanatomie des Knies erläutert. Hierbei werden die adaptierten grundlegenden Standardebenen nach SGUM-Richtlinien im Detail beschrieben und anhand einer Auswahl von hochauflösenden Ultraschall-Bildern illustriert. Fundierte Kenntnisse der sonografischen Anatomie sind unabdingbar, um Pathologien zu erkennen.
CME-EKG 66: Torsade de pointes: die Gefahr der rotierenden Herzachse
Authors: Markendorf Susanne , Saguner Ardan M. , Brunckhorst Corinna
Published: September 2020

Zusammenfassung. Die Torsade-de-pointes-Tachykardie ist eine maligne Herzrhythmusstörung, der eine Verlängerung des QT-Intervalls zugrunde liegt. Diese Verlängerung der QT-Zeit ist entweder angeboren oder erworben. Die erworbene Form wird meist durch medikamentöse Therapie verursacht. Die Torsade-de-pointes-Tachykardie ist durch einen stetigen Achsenwechsel und Undulation der QRS-Amplitude um die Grundlinie charakterisiert und meist selbstlimitierend. Dennoch kann sie in einigen Fällen auch in ein Kammerflimmern degenerieren und damit zum Herzkreislaufstillstand führen. Dieser Artikel soll einen Einblick in Ätiologie, Diagnostik, Prävention und Management dieser Herzrhythmusstörung geben.
Laterally Transported Particles From Margins Serve as a Major Carbon and Energy Source for Dark Ocean Ecosystems
Authors: Shen Jiaming , Jiao Nianzhi , Dai Minhan , Wang Haili , Qiu Guoqiang , Chen Jianfang , Li Hongliang , Kao Shuh‐Ji , Yang Jin‐Yu Terence , Cai Pinghe , Zhou Kuanbo , Yang Weifeng , Zhu Yifan , Liu Zhiyu , Chen Mingming , Zuo Zuhui , Gaye Birgit , Wiesner Martin G. , Zhang Yao
Published: September 2020

Deep ocean microorganisms consume particulate organic matter that is produced in the surface ocean and exported to deeper depths. Such consumption not only enriches inorganic carbon in the deep ocean but also transforms organic carbon into recalcitrant forms, creating an alternative type of carbon sequestration. However, estimates of deep microbial carbon demand substantially exceed the available particulate organic carbon exported from the euphotic zone, resulting in an unbalanced dark ocean carbon budget. Here, we combined field‐based microbial activity parameters, integrated multiyear particle export flux data, sinking particle fluxes measured by sediment traps, and optical data from Biogeochemical‐Argo floats to quantify the main sources of organic carbon to the dark ocean. Laterally transported particles (including sinking and suspended particles) serve as a major energy source, which directly provide organic carbon and enhance new organic carbon production by dark carbon fixation, reconciling the mismatch in the regional carbon budget.
First‐Principles Diffusivity Ratios for Kinetic Isotope Fractionation of Water in Air
Authors: Hellmann Robert , Harvey Allan H.
Published: September 2020

Kinetic isotope fractionation between water vapor and liquid water or ice depends on the ratio of the diffusivities of the isotopic species in air, but there is disagreement as to the values of these ratios and limited information about their temperature dependence. We use state‐of‐the‐art intermolecular potential‐energy surfaces for the water‐nitrogen and water‐oxygen pairs, along with the kinetic theory of molecular gases, to calculate from first principles the diffusivities of water isotopologues in air. The method has sufficient precision to produce accurate diffusivity ratios. For the HDO/H2O ratio, we find that the often used hard‐sphere kinetic theory is significantly in error and confirm the 1978 experimental result of Merlivat. For the ratios involving 17O and 18O, the simple kinetic theory is relatively close to our more rigorous results. We provide diffusivity ratios from 190 K to 500 K, greatly expanding the range of temperatures for which these ratios are available.
Jurassic to Cenozoic Magmatic and Geodynamic Evolution of the Eastern Pontides and Caucasus Belts, and Their Relationship With the Eastern Black Sea Basin Opening
Authors: Hässig Marc , Moritz Robert , Ulianov Alexey , Popkhadze Nino , Galoyan Ghazar , Enukidze Onise
Published: September 2020

The magmatic arcs of the Eastern Pontides and Lesser Caucasus lie in continuation from one another. A comparison of the subduction‐related magmatic rocks outcropping throughout this segment of the Northern Tethyan belt exhibits chronological disparities, questioning the common subduction history of the Eastern Pontides and the Lesser Caucasus regions. New data and observations including geochronological and geochemical data, relative to subduction‐ to collision‐related magmatic rocks, argue a novel paleogeographic reconstruction illustrating Mesozoic and Cenozoic evolution of this region. Jurassic to Early Cretaceous arc magmatism runs mainly from the Sochi‐Ritsa/Bechasyn regions (Greater Caucasus) toward the southeast to the Alaverdi region and further into the Lesser Caucasus. Late Cretaceous and Cenozoic arc magmatism is evidenced throughout the Eastern Pontides extending through the Bolnisi region to the Lesser Caucasus arc. East to west, Jurassic to Early Cretaceous and Late Cretaceous to Cenozoic portions of arc split to the north and south of the Eastern Black Sea, respectively. Throughout Cretaceous subduction, this segment of the magmatic arc of the Southern Eurasian margin was torn in two due to the oblique opening of the Eastern Black Sea as a back‐arc to intra‐arc basin, from west to east. This reconstitution implies that the Jurassic‐Early Cretaceous subduction‐related magmatic rocks of the Greater Caucasus are remnant portions of the Eastern Pontides and Lesser Caucasus arcs. This infers the emplacement of subduction‐ to collision‐related magmatic rocks throughout the Mesozoic and Cenozoic along the entire Southern Eurasian margin is solely due to a single long‐lasting north dipping subduction.
Frequency Dependence of In Situ Transmissivity Estimation of Well‐Aquifer Systems From Periodic Loadings
Authors: Sun Xiaolong , Shi Zheming , Xiang Yang
Published: September 2020

Estimating the hydraulic parameters of a target aquifer is key to properly evaluating the groundwater resources. Conventional methods are costly, and measurements are infrequent. There are currently four popular methods for estimating aquifer parameters using the response of the well water level to a periodic loading. However, the differences and accuracy of the results obtained by these methods are still poorly understood. This study compares the four response models. We analyze the mechanisms of the phase lag between well water level and periodic loadings during such loading and discuss the applicability of each model. Taking the Jingle well in Shanxi Province as an example, hydraulic parameters were estimated using different models and compared. The results show that the aquifer transmissivity estimated using the periodic response methods depends on the loading frequency. This dependency is mainly determined by the difference between the actual aquifer transmissivity and the upper limit of transmissivity resolvable by the model. The tidal and barometric pressure response methods are suitable for low transmissivity aquifers, while seismic wave suitable is responsible for high transmissivity aquifers.
Metastatic status of sentinel lymph nodes in breast cancer determined with photoacoustic microscopy via dual-targeting nanoparticles
Authors: Dai Yanfeng , Yu Xiang , Wei Jianshuang , Zeng Fanxin , Li Yiran , Yang Xiaoquan , Luo Qingming , Zhang Zhihong
Published: September 2020

Detection of sentinel lymph nodes (SLNs) is critical to guide the treatment of breast cancer. However, distinguishing metastatic SLNs from normal and inflamed lymph nodes (LNs) during surgical resection remains a challenge. Here, we report a CD44 and scavenger receptor class B1 dual-targeting hyaluronic acid nanoparticle (5K-HA-HPPS) loaded with the near-infra-red fluorescent dye DiR-BOA for SLN imaging in breast cancer. The small sized (~40 nm) self-assembled 5K-HA-HPPSs accumulated rapidly in the SLNs after intradermal injection. Compared with normal popliteal LNs (N-LN), there were ~3.2-fold and ~2.4-fold increases in fluorescence intensity in tumour metastatic SLNs (T-MLN) and inflamed LNs (Inf-LN), respectively, 6 h after nanoparticle inoculation. More importantly, photoacoustic microscopy (PAM) of 5K-HA-HPPS showed a significantly distinct distribution in T-MLN compared with N-LN and Inf-LN. Signals were mainly distributed at the centre of T-MLN but at the periphery of N-LN and Inf-LN. The ratio of PA intensity (R) at the centre of the LNs compared with that at the periphery was 5.93 ± 0.75 for T-MLNs of the 5K-HA-HPPS group, which was much higher than that for the Inf-LNs (R = 0.2 ± 0.07) and N-LNs (R = 0.45 ± 0.09). These results suggest that 5K-HA-HPPS injection combined with PAM provides a powerful tool for distinguishing metastatic SLNs from pLNs and inflamed LNs, thus guiding the removal of SLNs during breast cancer surgery.
Novel urinary protein biomarker panel for early diagnosis of gastric cancer
Authors: Shimura Takaya , Dayde Delphine , Wang Hong , Okuda Yusuke , Iwasaki Hiroyasu , Ebi Masahide , Kitagawa Mika , Yamada Tamaki , Yamada Tomonori , Hanash Samir M. , Taguchi Ayumu , Kataoka Hiromi
Published: September 2020

Background

With the goal of discovering non-invasive biomarkers for early diagnosis of GC, we conducted a case-control study utilising urine samples from individuals with predominantly early GC vs. healthy control (HC).

Methods

Among urine samples from 372 patients, age- and sex-matched 282 patients were randomly divided into three groups: 18 patients in a discovery cohort; 176 patients in a training cohort and 88 patients in a validation cohort.

Results

Among urinary proteins identified in the comprehensive quantitative proteomics analysis, urinary levels of TFF1 (uTFF1) and ADAM12 (uADAM12) were significantly independent diagnostic biomarkers for GC, in addition to Helicobacter pylori status. A urinary biomarker panel combining uTFF1, uADAM12 and H. pylori significantly distinguished between HC and GC patients in both training and validation cohorts. On the analysis for sex-specific biomarkers, this combination panel demonstrated a good AUC of 0.858 for male GC, whereas another combination panel of uTFF1, uBARD1 and H. pylori also provided a good AUC of 0.893 for female GC. Notably, each panel could distinguish even stage I GC patients from HC patients (AUC = 0.850 for males; AUC = 0.845 for females).

Conclusions

Novel urinary protein biomarker panels represent promising non-invasive biomarkers for GC, including early-stage disease.
Allogeneic Vγ9Vδ2 T-cell immunotherapy exhibits promising clinical safety and prolongs the survival of patients with late-stage lung or liver cancer
Authors: Xu Yan , Xiang Zheng , Alnaggar Mohammed , Kouakanou Léonce , Li Jiawei , He Junyi , Yang Jiashuang , Hu Yi , Chen Yan , Lin Li , Hao Jianlei , Li Jingxia , Chen Jibing , Li Man , Wu Qingling , Peters Christian , Zhou Qinghua , Li Jianshuang , Liang Yingqing , Wang Xiaohua , Han Baohui , Ma Meili , Kabelitz Dieter , Xu Kecheng , Tu Wenwei , Wu Yangzhe , Yin Zhinan
Published: September 2020

Vγ9Vδ2 T cells are promising candidates for cellular tumor immunotherapy. Due to their HLA-independent mode of action, allogeneic Vγ9Vδ2 T cells can be considered for clinical application. To apply allogeneic Vγ9Vδ2 T cells in adoptive immunotherapy, the methodology used to obtain adequate cell numbers with optimal effector function in vitro needs to be optimized, and clinical safety and efficacy also need to be proven. Therefore, we developed a novel formula to improve the expansion of peripheral γδ T cells from healthy donors. Then, we used a humanized mouse model to validate the therapeutic efficacy of expanded γδ T cells in vivo; furthermore, the expanded γδ T cells were adoptively transferred into late-stage liver and lung cancer patients. We found that the expanded cells possessed significantly improved immune effector functions, including proliferation, differentiation, and cancer cell killing, both in vitro and in the humanized mouse model. Furthermore, a phase I clinical trial in 132 late-stage cancer patients with a total of 414 cell infusions unequivocally validated the clinical safety of allogeneic Vγ9Vδ2 T cells. Among these 132 patients, 8 liver cancer patients and 10 lung cancer patients who received ≥5 cell infusions showed greatly prolonged survival, which preliminarily verified the efficacy of allogeneic Vγ9Vδ2 T-cell therapy. Our clinical studies underscore the safety and efficacy of allogeneic Vγ9Vδ2 T-cell immunotherapy, which will inspire further clinical investigations and eventually benefit cancer patients.
Publisher Correction: Improving the accuracy of medical diagnosis with causal machine learning
Authors: Richens Jonathan G. , Lee Ciarán M. , Johri Saurabh
Published: September 2020

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Rapid climate change results in long-lasting spatial homogenization of phylogenetic diversity
Authors: Saladin Bianca , Pellissier Loïc , Graham Catherine H. , Nobis Michael P. , Salamin Nicolas , Zimmermann Niklaus E.
Published: September 2020

Scientific understanding of biodiversity dynamics, resulting from past climate oscillations and projections of future changes in biodiversity, has advanced over the past decade. Little is known about how these responses, past or future, are spatially connected. Analyzing the spatial variability in biodiversity provides insight into how climate change affects the accumulation of diversity across space. Here, we evaluate the spatial variation of phylogenetic diversity of European seed plants among neighboring sites and assess the effects of past rapid climate changes during the Quaternary on these patterns. Our work shows a marked homogenization in phylogenetic diversity across Central and Northern Europe linked to high climate change velocity and large distances to refugia. Our results suggest that the future projected loss in evolutionary heritage may be even more dramatic, as homogenization in response to rapid climate change has occurred among sites across large landscapes, leaving a legacy that has lasted for millennia.
Intercalated disc protein Xinβ is required for Hippo-YAP signaling in the heart
Authors: Guo Haipeng , Lu Yao Wei , Lin Zhiqiang , Huang Zhan-Peng , Liu Jianming , Wang Yi , Seok Hee Young , Hu Xiaoyun , Ma Qing , Li Kathryn , Kyselovic Jan , Wang Qingchuan , Lin Jenny L.-C. , Lin Jim J.-C. , Cowan Douglas B. , Naya Francisco , Chen Yuguo , Pu William T. , Wang Da-Zhi
Published: September 2020

Intercalated discs (ICD), specific cell-to-cell contacts that connect adjacent cardiomyocytes, ensure mechanical and electrochemical coupling during contraction of the heart. Mutations in genes encoding ICD components are linked to cardiovascular diseases. Here, we show that loss of Xinβ, a newly-identified component of ICDs, results in cardiomyocyte proliferation defects and cardiomyopathy. We uncovered a role for Xinβ in signaling via the Hippo-YAP pathway by recruiting NF2 to the ICD to modulate cardiac function. In Xinβ mutant hearts levels of phosphorylated NF2 are substantially reduced, suggesting an impairment of Hippo-YAP signaling. Cardiac-specific overexpression of YAP rescues cardiac defects in Xinβ knock-out mice—indicating a functional and genetic interaction between Xinβ and YAP. Our study reveals a molecular mechanism by which cardiac-expressed intercalated disc protein Xinβ modulates Hippo-YAP signaling to control heart development and cardiac function in a tissue specific manner. Consequently, this pathway may represent a therapeutic target for the treatment of cardiovascular diseases.
Translational pharmacology of an inhaled small molecule αvβ6 integrin inhibitor for idiopathic pulmonary fibrosis
Authors: John Alison E. , Graves Rebecca H. , Pun K. Tao , Vitulli Giovanni , Forty Ellen J. , Mercer Paul F. , Morrell Josie L. , Barrett John W. , Rogers Rebecca F. , Hafeji Maryam , Bibby Lloyd I. , Gower Elaine , Morrison Valerie S. , Man Yim , Roper James A. , Luckett Jeni C. , Borthwick Lee A. , Barksby Ben S. , Burgoyne Rachel A. , Barnes Rory , Le Joelle , Flint David J. , Pyne Susan , Habgood Anthony , Organ Louise A. , Joseph Chitra , Edwards-Pritchard Rochelle C. , Maher Toby M. , Fisher Andrew J. , Gudmann Natasja Stæhr , Leeming Diana J. , Chambers Rachel C. , Lukey Pauline T. , Marshall Richard P. , Macdonald Simon J. F. , Jenkins R. Gisli , Slack Robert J.
Published: September 2020

The αvβ6 integrin plays a key role in the activation of transforming growth factor-β (TGFβ), a pro-fibrotic mediator that is pivotal to the development of idiopathic pulmonary fibrosis (IPF). We identified a selective small molecule αvβ6 RGD-mimetic, GSK3008348, and profiled it in a range of disease relevant pre-clinical systems. To understand the relationship between target engagement and inhibition of fibrosis, we measured pharmacodynamic and disease-related end points. Here, we report, GSK3008348 binds to αvβ6 with high affinity in human IPF lung and reduces downstream pro-fibrotic TGFβ signaling to normal levels. In human lung epithelial cells, GSK3008348 induces rapid internalization and lysosomal degradation of the αvβ6 integrin. In the murine bleomycin-induced lung fibrosis model, GSK3008348 engages αvβ6, induces prolonged inhibition of TGFβ signaling and reduces lung collagen deposition and serum C3M, a marker of IPF disease progression. These studies highlight the potential of inhaled GSK3008348 as an anti-fibrotic therapy.
Arrangement and symmetry of the fungal E3BP-containing core of the pyruvate dehydrogenase complex
Authors: Forsberg B. O. , Aibara S. , Howard R. J. , Mortezaei N. , Lindahl E.
Published: September 2020

The pyruvate dehydrogenase complex (PDC) is a multienzyme complex central to aerobic respiration, connecting glycolysis to mitochondrial oxidation of pyruvate. Similar to the E3-binding protein (E3BP) of mammalian PDC, PX selectively recruits E3 to the fungal PDC, but its divergent sequence suggests a distinct structural mechanism. Here, we report reconstructions of PDC from the filamentous fungus Neurospora crassa by cryo-electron microscopy, where we find protein X (PX) interior to the PDC core as opposed to substituting E2 core subunits as in mammals. Steric occlusion limits PX binding, resulting in predominantly tetrahedral symmetry, explaining previous observations in Saccharomyces cerevisiae. The PX-binding site is conserved in (and specific to) fungi, and complements possible C-terminal binding motifs in PX that are absent in mammalian E3BP. Consideration of multiple symmetries thus reveals a differential structural basis for E3BP-like function in fungal PDC.
Bacteria are important dimethylsulfoniopropionate producers in marine aphotic and high-pressure environments
Authors: Zheng Yanfen , Wang Jinyan , Zhou Shun , Zhang Yunhui , Liu Ji , Xue Chun-Xu , Williams Beth T. , Zhao Xiuxiu , Zhao Li , Zhu Xiao-Yu , Sun Chuang , Zhang Hong-Hai , Xiao Tian , Yang Gui-Peng , Todd Jonathan D. , Zhang Xiao-Hua
Published: September 2020

Dimethylsulfoniopropionate (DMSP) is an important marine osmolyte. Aphotic environments are only recently being considered as potential contributors to global DMSP production. Here, our Mariana Trench study reveals a typical seawater DMSP/dimethylsulfide (DMS) profile, with highest concentrations in the euphotic zone and decreased but consistent levels below. The genetic potential for bacterial DMSP synthesis via the dsyB gene and its transcription is greater in the deep ocean, and is highest in the sediment.s DMSP catabolic potential is present throughout the trench waters, but is less prominent below 8000 m, perhaps indicating a preference to store DMSP in the deep for stress protection. Deep ocean bacterial isolates show enhanced DMSP production under increased hydrostatic pressure. Furthermore, bacterial dsyB mutants are less tolerant of deep ocean pressures than wild-type strains. Thus, we propose a physiological function for DMSP in hydrostatic pressure protection, and that bacteria are key DMSP producers in deep seawater and sediment.
Materializing efficient methanol oxidation via electron delocalization in nickel hydroxide nanoribbon
Authors: Wang Xiaopeng , Xi Shibo , Lee Wee Siang Vincent , Huang Pengru , Cui Peng , Zhao Lei , Hao Weichang , Zhao Xinsheng , Wang Zhenbo , Wu Haijun , Wang Hao , Diao Caozheng , Borgna Armando , Du Yonghua , Yu Zhi Gen , Pennycook Stephen , Xue Junmin
Published: September 2020

Achieving a functional and durable non-platinum group metal-based methanol oxidation catalyst is critical for a cost-effective direct methanol fuel cell. While Ni(OH)2 has been widely studied as methanol oxidation catalyst, the initial process of oxidizing Ni(OH)2 to NiOOH requires a high potential of 1.35 V vs. RHE. Such potential would be impractical since the theoretical potential of the cathodic oxygen reduction reaction is at 1.23 V. Here we show that a four-coordinated nickel atom is able to form charge-transfer orbitals through delocalization of electrons near the Fermi energy level. As such, our previously reported periodically arranged four-six-coordinated nickel hydroxide nanoribbon structure (NR-Ni(OH)2) is able to show remarkable methanol oxidation activity with an onset potential of 0.55 V vs. RHE and suggests the operability in direct methanol fuel cell configuration. Thus, this strategy offers a gateway towards the development of high performance and durable non-platinum direct methanol fuel cell.
Cage-confined photocatalysis for wide-scope unusually selective [2 + 2] cycloaddition through visible-light triplet sensitization
Authors: Wang Jing-Si , Wu Kai , Yin Changzhen , Li Kang , Huang Yahao , Ruan Jia , Feng Ximin , Hu Peng , Su Cheng-Yong
Published: September 2020

Light-induced [2 + 2] cycloaddition is the most straightforward way to generate cyclobutanes, which are core structures of many natural products, drugs and bioactive compounds. Despite continuous advances in selective [2 + 2] cycloaddition research, general method for intermolecular photocatalysis of acyclic olefins with specific regio- and diastereoselectivity, for example, syn-head-to-head (syn-HH) cyclobutane derivatives, is still lack of development but highly desired. Herein, we report a cage-confined photocatalytic protocol to enable unusual intermolecular [2 + 2] cycloaddition for α,β-unsaturated carbonyl compounds. The syn-HH diastereomers are readily generated with diastereoselectivity up to 99%. The cage-catalyst is highly efficient and robust, covering a diverse substrate range with excellent substituent tolerance. The mimic-enzyme catalysis is proposed through a host-guest mediated procedure expedited by aqueous phase transition of reactant and product, where the supramolecular cage effect plays an important role to facilitate substrates inclusion and pre-orientation, offering a promising avenue for general and eco-friendly cycloaddition photocatalysis with special diastereoselectivity.
Addition of alkynes and osmium carbynes towards functionalized dπ–pπ conjugated systems
Authors: Chen Shiyan , Liu Longzhu , Gao Xiang , Hua Yuhui , Peng Lixia , Zhang Ying , Yang Liulin , Tan Yuanzhi , He Feng , Xia Haiping
Published: September 2020

The metal-carbon triple bonds and carbon-carbon triple bonds are both highly unsaturated bonds. As a result, their reactions tend to afford cycloaddition intermediates or products. Herein, we report a reaction of M≡C and C≡C bonds that affords acyclic addition products. These newly discovered reactions are highly efficient, regio- and stereospecific, with good functional group tolerance, and are robust under air at room temperature. The isotope labeling NMR experiments and theoretical calculations reveal the reaction mechanism. Employing these reactions, functionalizeddπ-pπconjugated systems can be easily constructed and modified. The resultingdπ-pπconjugated systems were found to be good electron transport layer materials in organic solar cells, with power conversion efficiency up to 16.28% based on the PM6: Y6 non-fullerene system. This work provides a facile, efficient methodology for the preparation ofdπ-pπconjugated systems for use in functional materials.
Systemic muscle wasting and coordinated tumour response drive tumourigenesis
Authors: Newton Holly , Wang Yi-Fang , Camplese Laura , Mokochinski Joao B. , Kramer Holger B. , Brown André E. X. , Fets Louise , Hirabayashi Susumu
Published: September 2020

Cancer cells demand excess nutrients to support their proliferation, but how tumours exploit extracellular amino acids during systemic metabolic perturbations remain incompletely understood. Here, we use aDrosophilamodel of high-sugar diet (HSD)-enhanced tumourigenesis to uncover a systemic host-tumour metabolic circuit that supports tumour growth. We demonstrate coordinate induction of systemic muscle wasting with tumour-autonomous Yorkie-mediated SLC36-family amino acid transporter expression as a proline-scavenging programme to drive tumourigenesis. We identify Indole-3-propionic acid as an optimal amino acid derivative to rationally target the proline-dependency of tumour growth. Insights from this whole-animalDrosophilamodel provide a powerful approach towards the identification and therapeutic exploitation of the amino acid vulnerabilities of tumourigenesis in the context of a perturbed systemic metabolic network.
IRF1-mediated downregulation of PGC1α contributes to cardiorenal syndrome type 4
Authors: Huang Yinghui , Wang Shaobo , Zhou Jie , Liu Yong , Du Changhong , Yang Ke , Bi Xianjin , Liu Mingying , Han Wenhao , Wang Kailong , Xiong Jiachuan , Wang Song , Wang Yue , Nie Ling , Liu Chi , Zhang Daohai , Gu Jun , Zeng Chunyu , Zhao Jinghong
Published: September 2020

Cardiorenal syndrome type 4 (CRS4) is a common complication of chronic kidney disease (CKD), but the pathogenic mechanisms remain elusive. Here we report that morphological and functional changes in myocardial mitochondria are observed in CKD mice, especially decreases in oxidative phosphorylation and fatty acid metabolism. High phosphate (HP), a hallmark of CKD, contributes to myocardial energy metabolism dysfunction by downregulating peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1α). Furthermore, the transcriptional factor interferon regulatory factor 1 (IRF1) is revealed as the key molecule upregulated by HP through histone H3K9 acetylation, and responsible for the HP-mediated transcriptional inhibition of PGC1α by directly binding to its promoter region. Conversely, restoration of PGC1α expression or genetic knockdown of IRF1 significantly attenuates HP-induced alterations in vitro and in vivo. These findings demonstrate that IRF1-PGC1α axis-mediated myocardial energy metabolism remodeling plays a crucial role in the pathogenesis of CRS4.
Author Correction: Ancient genomes reveal social and genetic structure of Late Neolithic Switzerland
Authors: Furtwängler Anja , Rohrlach A. B. , Lamnidis Thiseas C. , Papac Luka , Neumann Gunnar U. , Siebke Inga , Reiter Ella , Steuri Noah , Hald Jürgen , Denaire Anthony , Schnitzler Bernadette , Wahl Joachim , Ramstein Marianne , Schuenemann Verena J. , Stockhammer Philipp W. , Hafner Albert , Lösch Sandra , Haak Wolfgang , Schiffels Stephan , Krause Johannes
Published: September 2020

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Author Correction: Giant room temperature anomalous Hall effect and tunable topology in a ferromagnetic topological semimetal Co2MnAl
Authors: Li Peigang , Koo Jahyun , Ning Wei , Li Jinguo , Miao Leixin , Min Lujin , Zhu Yanglin , Wang Yu , Alem Nasim , Liu Chao-Xing , Mao Zhiqiang , Yan Binghai
Published: September 2020

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Mechanism for the reactivation of the peroxidase activity of human cyclooxygenases: investigation using phenol as a reducing cosubstrate
Authors: Yang Chengxi , Li Peng , Ding Xiaoli , Sui Hao Chen , Rao Shun , Hsu Chia-Hsiang , Leung Wing-Por , Cheng Gui-Juan , Wang Pan , Zhu Bao Ting
Published: September 2020

It has been known for many years that the peroxidase activity of cyclooxygenase 1 and 2 (COX-1 and COX-2) can be reactivated in vitro by the presence of phenol, which serves as a reducing compound, but the underlying mechanism is still poorly understood. In the present study, we use phenol as a model compound to investigate the mechanism by which the peroxidase activity of human COXs is reactivated after each catalytic cycle. Molecular docking and quantum mechanics calculations are carried out to probe the interaction of phenol with the peroxidase site of COXs and the reactivation mechanism. It is found that the oxygen atom associated with the Fe ion in the heme group (i.e., the complex of Fe ion and porphyrin) of COXs can be removed by addition of two protons. Following its removal, phenol can readily bind inside the peroxidase active sites of the COX enzymes, and directly interact with Fe in heme to facilitate electron transfer from phenol to heme. This investigation provides theoretical evidence for several intermediates formed in the COX peroxidase reactivation cycle, thereby unveiling mechanistic details that would aid in future rational design of drugs that target the peroxidase site.
Characterisation of the novel spontaneously immortalized and invasively growing human skin keratinocyte line HaSKpw
Authors: Pavez Lorie Elizabeth , Stricker Nicola , Plitta-Michalak Beata , Chen I.-Peng , Volkmer Beate , Greinert Rüdiger , Jauch Anna , Boukamp Petra , Rapp Alexander
Published: September 2020

We here present the spontaneously immortalised cell line, HaSKpw, as a novel model for the multistep process of skin carcinogenesis. HaSKpw cells were established from the epidermis of normal human adult skin that, without crisis, are now growing unrestricted and feeder-independent. At passage 22, clonal populations were established and clone7 (HaSKpwC7) was further compared to the also spontaneously immortalized HaCaT cells. As important differences, the HaSKpw cells express wild-type p53, remain pseudodiploid, and show a unique chromosomal profile with numerous complex aberrations involving chromosome 20. In addition, HaSKpw cells overexpress a pattern of genes and miRNAs such as KRT34, LOX, S100A9, miR21, and miR155; all pointing to a tumorigenic status. In concordance, HaSKpw cells exhibit reduced desmosomal contacts that provide them with increased motility and a highly migratory/invasive phenotype as demonstrated in scratch- and Boyden chamber assays. In 3D organotypic cultures, both HaCaT and HaSKpw cells form disorganized epithelia but only the HaSKpw cells show tumorcell-like invasive growth. Together, HaSKpwC7 and HaCaT cells represent two spontaneous (non-genetically engineered) “premalignant” keratinocyte lines from adult human skin that display different stages of the multistep process of skin carcinogenesis and thus represent unique models for analysing skin cancer development and progression.
Modified parylene-N films as chemical microenvironments for differentiation and spheroid formation of osteoblast cells
Authors: Kim Tae-Hun , Lee Jong-Sook , Jo Hanhee , Park Yusun , Yun Mijin , Song Zhiquan , Pyun Jae-Chul , Lee Misu
Published: September 2020

In this work, the influence of parylene N film on the spheroid formation of osteoblast-like cells (MG-63) was determined and compared with that of high-hydrophilicity microenvironments, such as hydrophilic culture matrix and ultraviolet-treated parylene N film. To elucidate the change in cell properties due to the microenvironment of parylene N film, global gene expression profiles of MG-63 cells on parylene N film were analyzed. We confirmed the upregulated expression of osteoblast differentiation- and proliferation-related genes, such as Runx2, ALPL, and BGLAP and MKi67 and PCNA, respectively, using the real-time polymerase chain reaction. In addition, the differentiation and proliferation of osteoblast cells cultured on parylene N film were validated using immunostaining. Finally, the formation of spheroids and regulation of differentiation in human mesenchymal stem cells (MSCs) on parylene N film was demonstrated. The results of this study confirm that the microenvironment with the controlled hydrophobic property of parylene N film could effectively trigger the bone differentiation and maintains the proliferation of MSCs, similar to MG-63 cells without any scaffold structures or physical treatments.
Biogeographic problem-solving reveals the Late Pleistocene translocation of a short-faced bear to the California Channel Islands
Authors: Mychajliw Alexis M. , Rick Torben C. , Dagtas Nihan D. , Erlandson Jon M. , Culleton Brendan J. , Kennett Douglas J. , Buckley Michael , Hofman Courtney A.
Published: September 2020

An accurate understanding of biodiversity of the past is critical for contextualizing biodiversity patterns and trends in the present. Emerging techniques are refining our ability to decipher otherwise cryptic human-mediated species translocations across the Quaternary, yet these techniques are often used in isolation, rather than part of an interdisciplinary hypothesis-testing toolkit, limiting their scope and application. Here we illustrate the use of such an integrative approach and report the occurrence of North America’s largest terrestrial mammalian carnivore, the short-faced bear,Arctodus simus,from Daisy Cave (CA-SMI-261), an important early human occupation site on the California Channel Islands. We identified the specimen by corroborating morphological, protein, and mitogenomic lines of evidence, and evaluated the potential natural and anthropogenic mechanisms of its transport and deposition. While representing just a single specimen, our combination of techniques opened a window into the behavior of an enigmatic species, suggesting thatA. simuswas a wide-ranging scavenger utilizing terrestrial and marine carcasses. This discovery highlights the utility of bridging archaeological and paleontological datasets to disentangle complex biogeographic scenarios and reveal unexpected biodiversity for island systems worldwide.
Small-residue packing motifs modulate the structure and function of a minimal de novo membrane protein
Authors: Curnow Paul , Hardy Benjamin J. , Dufour Virginie , Arthur Christopher J. , Stenner Richard , Hodgson Lorna R. , Verkade Paul , Williams Christopher , Shoemark Deborah K. , Sessions Richard B. , Crump Matthew P. , Jones Michael R. , Anderson J. L. Ross
Published: September 2020

Alpha-helical integral membrane proteins contain conserved sequence motifs that are known to be important in helix packing. These motifs are a promising starting point for the construction of artificial proteins, but their potential has not yet been fully explored. Here, we study the impact of introducing a common natural helix packing motif to the transmembrane domain of a genetically-encoded and structurally dynamic de novo membrane protein. The resulting construct is an artificial four-helix bundle with lipophilic regions that are defined only by the amino acids L, G, S, A and W. This minimal proto-protein could be recombinantly expressed by diverse prokaryotic and eukaryotic hosts and was found to co-sediment with cellular membranes. The protein could be extracted and purified in surfactant micelles and was monodisperse and stable in vitro, with sufficient structural definition to support the rapid binding of a heme cofactor. The reduction in conformational diversity imposed by this design also enhances the nascent peroxidase activity of the protein-heme complex. Unexpectedly, strains ofEscherichia coliexpressing this artificial protein specifically accumulated zinc protoporphyrin IX, a rare cofactor that is not used by natural metalloenzymes. Our results demonstrate that simple sequence motifs can rigidify elementary membrane proteins, and that orthogonal artificial membrane proteins can influence the cofactor repertoire of a living cell. These findings have implications for rational protein design and synthetic biology.
Simultaneous molecular MRI of extracellular matrix collagen and inflammatory activity to predict abdominal aortic aneurysm rupture
Authors: Adams Lisa C. , Brangsch Julia , Reimann Carolin , Kaufmann Jan O. , Buchholz Rebecca , Karst Uwe , Botnar Rene M. , Hamm Bernd , Makowski Marcus R.
Published: September 2020

Abdominal aortic aneurysm (AAA) is a life-threatening vascular disease with an up to 80% mortality in case of rupture. Current biomarkers fail to account for size-independent risk of rupture. By combining the information of different molecular probes, multi-target molecular MRI holds the potential to enable individual characterization of AAA. In this experimental study, we aimed to examine the feasibility of simultaneous imaging of extracellular collagen and inflammation for size-independent prediction of risk of rupture in murine AAA. The study design consisted of: (1) A outcome-based longitudinal study with imaging performed once after one week with follow-up and death as the end-point for assessment of rupture risk. (2) A week-by-week study for the characterization of AAA development with imaging after 1, 2, 3 and 4 weeks. For both studies, the animals were administered a type 1 collagen-targeted gadolinium-based probe (surrogate marker for extracellular matrix (ECM) remodeling) and an iron oxide-based probe (surrogate marker for inflammatory activity), in one imaging session. In vivo measurements of collagen and iron oxide probes showed a significant correlation with ex vivo histology (p < 0.001) and also corresponded well to inductively-coupled plasma-mass spectrometry and laser-ablation inductively-coupled plasma mass spectrometry. Combined evaluation of collagen-related ECM remodeling and inflammatory activity was the most accurate predictor for AAA rupture (sensitivity 80%, specificity 100%, area under the curve 0.85), being superior to information from the individual probes alone. Our study supports the feasibility of a simultaneous assessment of collagen-related extracellular matrix remodeling and inflammatory activity in a murine model of AAA.
Multiscale electronic and thermomechanical dynamics in ultrafast nanoscale laser structuring of bulk fused silica
Authors: Somayaji Madhura , Bhuyan Manoj K. , Bourquard Florent , Velpula Praveen K. , D’Amico Ciro , Colombier Jean-Philippe , Stoian Razvan
Published: September 2020

We describe the evolution of ultrafast-laser-excited bulk fused silica over the entire relaxation range in one-dimensional geometries fixed by non-diffractive beams. Irradiation drives local embedded modifications of the refractive index in the form of index increase in densified glass or in the form of nanoscale voids. A dual spectroscopic and imaging investigation procedure is proposed, coupling electronic excitation and thermodynamic relaxation. Specific sub-ps and ns plasma decay times are respectively correlated to these index-related electronic and thermomechanical transformations. For the void formation stages, based on time-resolved spectral imaging, we first observe a dense transient plasma phase that departs from the case of a rarefied gas, and we indicate achievable temperatures in the excited matter in the 4,000–5,500 K range, extending for tens of ns. High-resolution speckle-free microscopy is then used to image optical signatures associated to structural transformations until the evolution stops. Multiscale imaging indicates characteristic timescales for plasma decay, heat diffusion, and void cavitation, pointing out key mechanisms of material transformation on the nanoscale in a range of processing conditions. If glass densification is driven by sub-ps electronic decay, for nanoscale structuring we advocate the passage through a long-living dense ionized phase that decomposes on tens of ns, triggering cavitation.
Identification of serum IFN-α and IL-33 as novel biomarkers for type 1 autoimmune pancreatitis and IgG4-related disease
Authors: Minaga Kosuke , Watanabe Tomohiro , Hara Akane , Kamata Ken , Omoto Shunsuke , Nakai Atsushi , Otsuka Yasuo , Sekai Ikue , Yoshikawa Tomoe , Yamao Kentaro , Takenaka Mamoru , Chiba Yasutaka , Kudo Masatoshi
Published: September 2020

IgG4-related disease (IgG4-RD) is a multi-organ autoimmune disease characterized by elevated serum IgG4 concentration. Although serum IgG4 concentration is widely used as a biomarker for IgG4-RD and type 1 autoimmune pancreatitis (AIP), a pancreatic manifestation of IgG4-RD, a significant number of patients have normal serum IgG4 levels, even in the active phase of the disease. Recently, we reported that the development of experimental AIP and human type 1 AIP is associated with increased expression of IFN-α and IL-33 in the pancreas. In this study, we assessed the utility of serum IFN-α and IL-33 levels as biomarkers for type 1 AIP and IgG4-RD. Serum IFN-α and IL-33 concentrations in patients who met the diagnostic criteria for definite type 1 AIP and/or IgG4-RD were significantly higher than in those with chronic pancreatitis or in healthy controls. Strong correlations between serum IFN-α, IL-33, and IgG4 concentrations were observed. Diagnostic performance of serum IFN-α and IL-33 concentrations as markers of type 1 AIP and/or IgG4-RD was comparable to that of serum IgG4 concentration, as calculated by the receiver operating characteristic curve analysis. Induction of remission by prednisolone treatment markedly decreased the serum concentration of these cytokines. We conclude that serum IFN-α and IL-33 concentrations can be useful as biomarkers for type 1 AIP and IgG4-RD.
GLN: a method to reveal unique properties of lasso type topology in proteins
Authors: Niemyska Wanda , Millett Kenneth C. , Sulkowska Joanna I.
Published: September 2020

Geometry and topology are the main factors that determine the functional properties of proteins. In this work, we show how to use the Gauss linking integral (GLN) in the form of a matrix diagram—for a pair of a loop and a tail—to study both the geometry and topology of proteins with closed loops e.g. lassos. We show that the GLN method is a significantly faster technique to detect entanglement in lasso proteins in comparison with other methods. Based on the GLN technique, we conduct comprehensive analysis of all proteins deposited in the PDB and compare it to the statistical properties of the polymers. We show how high and low GLN values correlate with the internal exibility of proteins, and how the GLN in the form of a matrix diagram can be used to study folding and unfolding routes. Finally, we discuss how the GLN method can be applied to study entanglement between two structures none of which are closed loops. Since this approach is much faster than other linking invariants, the next step will be evaluation of lassos in much longer molecules such as RNA or loops in a single chromosome.
The role of Serendipita indica and Lactobacilli mixtures on mitigating mycotoxins and heavy metals’ risks of contaminated sewage sludge and its composts
Authors: Youssef Nesrine H. , Al-Huqail Asma A. , Ali Hayssam M. , Abdelsalam Nader R. , Sabra Mayada A.
Published: September 2020

Accumulation of the Municipal Sewage Sludge (MSS) is considered as one of the most harmful renewable ecological and human health problems. MSS is a renewable resource that could be used as a soil organic amendment. This study aims to reduce the Heavy Metals (HMs) from the sludge content and sludge compost. Furthermore, this study is considered the first to assess the mycotoxins content in sludge and sludge compost via a new biological treatment using the fungus Serendipita indica or a mixture of lactic acid bacteria, thus providing safer nutrients for the soil amendment for a longer time and preserving human health. The HMs and mycotoxins were determined. The results exhibited that the biotic remediation of bio-solid waste and sewage sludge compost succeeded; a new bio-treated compost with a very low content of heavy metals and almost mycotoxins-free contents was availed. Also, the results indicated that the Lactobacilli mixture realized the best results in reducing heavy metals contents and mycotoxins. Afterward, S. indica. biotic remediation of bio-solid waste and sewage sludge compost minimized the health risk hazards affecting the human food chain, allowing for the different uses of sludge to be safer for the environment.