bluuebunny/crossref_metadata_2025 huggingface dataset:
Making Open Access Viable Economically
Authors: Hyde Andrew , Miller Russell A. , Towfigh Emanuel V.
Published: September 2020

The Editors-in-Chief have decided that we will provide our much-cherished readers with an editorial every so often as a way of sharing insights from the “machine room” where so much of the thinking and work is done to publish the German Law Journal. We want to let you in on the ideas that are on our minds, share with you our observations, and include you in the conversations we are having that might be of interest to you. We begin this tradition with this issue, Volume 21 – Number 6. Andrew Hyde, a member of the editorial team with which the Journal has partnered at Cambridge University Press, as well as Russell A. Miller and Emanuel V. Towfigh, two of the Journal’s co-Editors-in-Chief, open our From the Headquarters Essay with a piece on the Journal’s experiences with and its further plans for making open-access (OA) publishing economically viable. Related to that theme, we also want to share news with you about the introduction of a voluntary article processing charge this fall. Finally, we want to draw your attention to a videos and podcasts service we will start to produce to accompany the scholarship published in the Journal as a way of promoting our authors’ work and expanding access to their ideas. If you are interested only in these latter initiatives, you can also read the short section in the GLJ Instructions for Authors.
Neoproterozoic active margin in the northwestern Yangtze Block, South China: new clues from detrital zircon U–Pb geochronology and geochemistry of sedimentary rocks from the Hengdan Group
Authors: Hui Bo , Dong Yunpeng , Zhang Feifei , Sun Shengsi , He Shuai
Published: September 2020

The Yangtze Block in South China constitutes an important Precambrian landmass in the present East Asian continent. The Neoproterozoic sedimentary successions of the Hengdan Group in the NW Yangtze Block record essential information for deciphering the Neoproterozoic tectonics along the NW margin. However, its depositional age, provenance and tectonic properties remain uncertain. Here, a combined analysis of detrital zircon U–Pb dating and geochemistry is performed on representative samples from the Hengdan Group. Concordant dating results of samples from the bottom and upper parts constrain the maximum depositional age atc.720 Ma. Detrital zircon age patterns of samples reveal a uniformly pronounced age peak atc.915–720 Ma, which is consistent with the magmatic pulses in domains at the NW end of the Yangtze Block. In addition, these samples display left-sloping post-Archaean Australian shale (PAAS)-normalized rare-earth element patterns and variable trace element patterns, resembling sediments accumulated in a basin related to an active continental margin geodynamic setting. Provenance analysis reveals that the main sources featured intermediate to felsic components, which experienced rapid erosion and sedimentation. These integrated new investigations, along with previous compilations, indicate that the Hengdan Group might have been deposited in a fore-arc basin controlled by subduction beneath the Bikou Terrane. Thus, such interpretation further supports proposals for subduction-related tectonics along the western margin of the Yangtze Block during the early Neoproterozoic.
Perinatal anxiety and depressive symptoms and perception of child behavior and temperament in early motherhood
Authors: Miller Michelle L. , Williams Breanna M. , McCabe Jennifer E. , Williamson J. Austin , King Suzanne , Laplante David P. , Hart Kimberly J. , O’Hara Michael W.
Published: September 2020

The perinatal period is a vulnerable time for the development of psychopathology, particularly mood and anxiety disorders. In the study of maternal anxiety, important questions remain regarding the association between maternal anxiety symptoms and subsequent child outcomes. This study examined the association between depressive and anxiety symptoms, namely social anxiety, panic, and agoraphobia disorder symptoms during the perinatal period and maternal perception of child behavior, specifically different facets of development and temperament. Participants (N = 104) were recruited during pregnancy from a community sample. Participants completed clinician-administered and self-report measures of depressive and anxiety symptoms during the third trimester of pregnancy and at 16 months postpartum; child behavior and temperament outcomes were assessed at 16 months postpartum. Child development areas included gross and fine motor skills, language and problem-solving abilities, and personal/social skills. Child temperament domains included surgency, negative affectivity, and effortful control. Hierarchical multiple regression analyses demonstrated that elevated prenatal social anxiety symptoms significantly predicted more negative maternal report of child behavior across most measured domains. Elevated prenatal social anxiety and panic symptoms predicted more negative maternal report of child effortful control. Depressive and agoraphobia symptoms were not significant predictors of child outcomes. Elevated anxiety symptoms appear to have a distinct association with maternal report of child development and temperament. Considering the relative influence of anxiety symptoms, particularly social anxiety, on maternal report of child behavior and temperament can help to identify potential difficulties early on in mother–child interactions as well as inform interventions for women and their families.
Mortality Salience and Uncertainty Threat Among Younger vs. Older Adults
Authors: Ma-Kellams Christine , Harrison Ryan , Nguyen My Ngoc
Published: September 2020

Abstract. How do older versus younger individuals respond differently to existential threats? Although age brings emotional benefits that promote greater meaningfulness, it remains unclear how age influences reminders of death. Both terror management theory (TMT) and alternative frameworks (uncertainty management model – UMM, the meaning-making model – MMM) posit that individuals respond defensively to threat, but most of such studies focused on college-aged populations. Several TMT studies across the lifespan reached equivocal findings, and to our knowledge, no experiments have tested UMM/MMM across age groups. We tested how existential threats (i.e., mortality, uncertainty) predict defensive psychological distancing in younger/older adults. We found that older, but not younger, adults showed less defensiveness after existential threat.
Vom Honeymoon in die Realität
Authors: Müller Barbara
Published: September 2020

Zusammenfassung. Der Übergang von der Rolle der Auszubildenden / Studierenden in die Rolle der examinierten Pflegefachkraft ist der Prozess einer professionellen Sozialisation. Duchscher (2012) nennt diesen Prozess eine Transition mit den Zeichen eines persönlichen und beruflichen Umbruchs und Wandels. Diese Transition ist verbunden mit Bewegungen auf allen Ebenen des Lebens: soziale Entwicklung, emotionale Befindlichkeit, geistige und intellektuelle Herausforderung und physische Kraft. Nicht zuletzt ist sie begleitet von Erwartungen, Hoffnungen und Wünschen und eingebunden in gesellschaftliche Anforderungen an die Pflege als Dienstleistungsberuf.
Im Alltag beraten
Authors: Müller Christoph
Published: September 2020

Zusammenfassung. Wer in der aufsuchenden Arbeit mit seelisch erkrankten Menschen arbeitet, der muss sich nicht nur seiner eigenen Haltung vergewissern. Dabei geht es vor allem darum, gemeinsam mit Menschen mit Eigensinn Perspektiven zu erarbeiten. Das Gezeiten-Modell eignet sich, in der eigenen Häuslichkeit betroffene Menschen beratend zu unterstützen.
The effects of different dietary fiber pectin structures on the gastrointestinal immune barrier: impact via gut microbiota and direct effects on immune cells
Authors: Beukema Martin , Faas Marijke M. , de Vos Paul
Published: September 2020

Pectins are dietary fibers with different structural characteristics. Specific pectin structures can influence the gastrointestinal immune barrier by directly interacting with immune cells or by impacting the intestinal microbiota. The impact of pectin strongly depends on the specific structural characteristics of pectin; for example, the degree of methyl-esterification, acetylation and rhamnogalacturonan I or rhamnogalacturonan II neutral side chains. Here, we review the interactions of specific pectin structures with the gastrointestinal immune barrier. The effects of pectin include strengthening the mucus layer, enhancing epithelial integrity, and activating or inhibiting dendritic cell and macrophage responses. The direct interaction of pectins with the gastrointestinal immune barrier may be governed through pattern recognition receptors, such as Toll-like receptors 2 and 4 or Galectin-3. In addition, specific pectins can stimulate the diversity and abundance of beneficial microbial communities. Furthermore, the gastrointestinal immune barrier may be enhanced by short-chain fatty acids. Moreover, pectins can enhance the intestinal immune barrier by favoring the adhesion of commensal bacteria and inhibiting the adhesion of pathogens to epithelial cells. Current data illustrate that pectin may be a powerful dietary fiber to manage and prevent several inflammatory conditions, but additional human studies with pectin molecules with well-defined structures are urgently needed.
Arthritis and the role of endogenous glucocorticoids
Authors: Macfarlane Eugenie , Seibel Markus J. , Zhou Hong
Published: September 2020

Rheumatoid arthritis and osteoarthritis, the most common forms of arthritis, are chronic, painful, and disabling conditions. Although both diseases differ in etiology, they manifest in progressive joint destruction characterized by pathological changes in the articular cartilage, bone, and synovium. While the potent anti-inflammatory properties of therapeutic (i.e., exogenous) glucocorticoids have been heavily researched and are widely used in clinical practice, the role of endogenous glucocorticoids in arthritis susceptibility and disease progression remains poorly understood. Current evidence from mouse models suggests that local endogenous glucocorticoid signaling is upregulated by the pro-inflammatory microenvironment in rheumatoid arthritis and by aging-related mechanisms in osteoarthritis. Furthermore, these models indicate that endogenous glucocorticoid signaling in macrophages, mast cells, and chondrocytes has anti-inflammatory effects, while signaling in fibroblast-like synoviocytes, myocytes, osteoblasts, and osteocytes has pro-inflammatory actions in rheumatoid arthritis. Conversely, in osteoarthritis, endogenous glucocorticoid signaling in both osteoblasts and chondrocytes has destructive actions. Together these studies provide insights into the role of endogenous glucocorticoids in the pathogenesis of both inflammatory and degenerative joint disease.
Cancer health disparities in racial/ethnic minorities in the United States
Authors: Zavala Valentina A. , Bracci Paige M. , Carethers John M. , Carvajal-Carmona Luis , Coggins Nicole B. , Cruz-Correa Marcia R. , Davis Melissa , de Smith Adam J. , Dutil Julie , Figueiredo Jane C. , Fox Rena , Graves Kristi D. , Gomez Scarlett Lin , Llera Andrea , Neuhausen Susan L. , Newman Lisa , Nguyen Tung , Palmer Julie R. , Palmer Nynikka R. , Pérez-Stable Eliseo J. , Piawah Sorbarikor , Rodriquez Erik J. , Sanabria-Salas María Carolina , Schmit Stephanie L. , Serrano-Gomez Silvia J. , Stern Mariana C. , Weitzel Jeffrey , Yang Jun J. , Zabaleta Jovanny , Ziv Elad , Fejerman Laura
Published: September 2020

There are well-established disparities in cancer incidence and outcomes by race/ethnicity that result from the interplay between structural, socioeconomic, socio-environmental, behavioural and biological factors. However, large research studies designed to investigate factors contributing to cancer aetiology and progression have mainly focused on populations of European origin. The limitations in clinicopathological and genetic data, as well as the reduced availability of biospecimens from diverse populations, contribute to the knowledge gap and have the potential to widen cancer health disparities. In this review, we summarise reported disparities and associated factors in the United States of America (USA) for the most common cancers (breast, prostate, lung and colon), and for a subset of other cancers that highlight the complexity of disparities (gastric, liver, pancreas and leukaemia). We focus on populations commonly identified and referred to as racial/ethnic minorities in the USA—African Americans/Blacks, American Indians and Alaska Natives, Asians, Native Hawaiians/other Pacific Islanders and Hispanics/Latinos. We conclude that even though substantial progress has been made in understanding the factors underlying cancer health disparities, marked inequities persist. Additional efforts are needed to include participants from diverse populations in the research of cancer aetiology, biology and treatment. Furthermore, to eliminate cancer health disparities, it will be necessary to facilitate access to, and utilisation of, health services to all individuals, and to address structural inequities, including racism, that disproportionally affect racial/ethnic minorities in the USA.
Bisphosphonates and risk of cancers: a systematic review and meta-analysis
Authors: Li Yuan-Yuan , Gao Li-Jie , Zhang Yu-Xue , Liu Shu-Juan , Cheng Shuo , Liu Yu-Peng , Jia Cun-Xian
Published: September 2020

Background

It is unclear whether bisphosphonates are associated with risk of cancers. Therefore, this meta-analysis aimed to evaluate the effect of bisphosphonates on overall cancers.

Methods

A search in Pubmed, Embase, Cochrane Library and Web of Science databases was conducted, from the inception date of each resource to September 26, 2019. The summarised effect estimates with 95% CIs were calculated using a random-effect model. Heterogeneity and publication bias were explored.

Results

Thirty-four articles were included in this study (4,508,261 participants; 403,196 cases). The results revealed that bisphosphonates significantly decreased the risk of colorectal cancer (RR = 0.89, 95% CI: 0.81–0.98), breast cancer (RR = 0.87, 95% CI: 0.82–0.93) and endometrial cancer (RR = 0.75, 95% CI: 0.61–0.94), but no significant association was observed in all-cause cancer. Furthermore, nitrogen-containing bisphosphonates only had protective effects both on breast cancer (RR = 0.94, 95% CI: 0.90–0.99) and endometrial cancer (RR = 0.70, 95% CI: 0.54–0.92). Non-nitrogen-containing bisphosphonates tended to increase the risk of liver cancer (RR = 2.14, 95% CI: 1.23–3.72) and pancreas cancer (RR = 1.75, 95% CI: 1.32–2.33).

Conclusion

Bisphosphonates are significantly associated with risk reduction of colorectal, breast and endometrial cancer, especially nitrogen-containing bisphosphonates. It should be noted that non-nitrogen-containing bisphosphonates might increase the risk of liver and pancreas cancer. Large prospective cohort studies are needed to find the causal association between bisphosphonates and risk of cancers.
CHIP ubiquitylates NOXA and induces its lysosomal degradation in response to DNA damage
Authors: Albert Marie-Christine , Brinkmann Kerstin , Pokrzywa Wojciech , Günther Saskia Diana , Krönke Martin , Hoppe Thorsten , Kashkar Hamid
Published: September 2020

The BH3-only protein NOXA is a regulator of mitochondrial apoptosis by specifically antagonizing the anti-apoptotic protein MCL-1. Here we show that the E3 ubiquitin ligase CHIP controls NOXA stability after DNA damage. Our findings reveal that CHIP and MCL-1 are binding partners of NOXA and differentially define the fate of NOXA. Whereas NOXA is initially targeted to mitochondria upon MCL-1-binding, CHIP mediates ubiquitylation of cytosolic NOXA and promotes lysosomal degradation of NOXA, which is not bound by MCL-1. Our data indicate that MCL-1 defines NOXA abundance and its pro-apoptotic activity. Increased NOXA levels beyond this threshold are effectively removed by lysosomal protein degradation triggered via CHIP-mediated ubiquitylation. Together, these results shed new light on regulatory circuits controlling DNA damage response and identified the E3 ligase CHIP as a new molecular guardian, which restricts the cytosolic accumulation of NOXA upon genotoxic stress.
UBAC2 promotes bladder cancer proliferation through BCRC-3/miRNA-182-5p/p27 axis
Authors: Gu Chaohui , Zhao Keyuan , Zhou Naichun , Liu Feng , Xie Fei , Yu Shunli , Feng Yongjie , Chen Long , Yang Jinjian , Tian Fengyan , Jiang Guosong
Published: September 2020

Emerging evidences have demonstrated that ubiquitin-associated domain-containing protein 2 (UBAC2) is closely related to the occurrence and development of malignant tumors. However, the functions and underlying molecular mechanisms of UBAC2 in bladder cancer (BC) development have not been defined. In this study, we found that both UBAC2 mRNA and protein levels were upregulated in BC tissues and cell lines, and knockdown of UBAC2 inhibited BC cells proliferation both in vitro and in vivo. Meanwhile, Kaplan–Meier survival plots of 406 BC cases from TCGA database showed that higher expression of UBAC2 in BC patients was associated with lower survival rate. Mechanistic studies revealed that knockdown of UBAC2 increased the expression of p27 by posttranscriptional regulation. Our previous study indicated that circular RNA BCRC-3 (BCRC-3) promoted the expression of p27 through interacting with miR-182-5p, and reversed miR-182-5p-induced inhibition of p27 3′UTR activity. In the present study, we found that UBAC2 could bind to BCRC-3, and subsequently affected the interaction of BCRC-3 with miR-182-5p to inhibit the expression of p27. Furthermore, knockdown of BCRC-3 partly reversed the upregulation of p27 expression induced by knockdown of UBAC2. Our findings highlight a novel mechanism of UBAC2 in regulating p27 through affecting the function of BCRC-3, and provide a research basis for the diagnostic and therapeutic application of BC.
Upregulation of CPT1A is essential for the tumor-promoting effect of adipocytes in colon cancer
Authors: Xiong Xiaopeng , Wen Yang-An , Fairchild Rachelle , Zaytseva Yekaterina Y. , Weiss Heidi L. , Evers B. Mark , Gao Tianyan
Published: September 2020

Colon tumors grow in an adipose tissue-enriched microenvironment. Locally advanced colon cancers often invade into surrounding adipose tissue with a direct contact with adipocytes. We have previously shown that adipocytes promote tumor growth by modulating cellular metabolism. Here we demonstrate that carnitine palmitoyltransferase I (CPT1A), a key enzyme controlling fatty acid oxidation (FAO), was upregulated in colon cancer cells upon exposure to adipocytes or fatty acids. In addition, CPT1A expression was increased in invasive tumor cells within the adipose tissue compared to tumors without direct contact with adipocytes. Silencing CPT1A abolished the protective effect provided by fatty acids against nutrient deprivation and reduced tumor organoid formation in 3D culture and the expression of genes associated with cancer stem cells downstream of Wnt/β-catenin. Mechanistically, CPT1A-dependent FAO promoted the acetylation and nuclear translocation of β-catenin. Furthermore, knockdown of CPT1A blocked the tumor-promoting effect of adipocytes in vivo and inhibited xenograft tumor initiation. Taken together, our findings identify CPT1A-depedent FAO as an essential metabolic pathway that enables the interaction between adipocytes and colon cancer cells.
Bromodomain-containing protein 9 promotes the growth and metastasis of human hepatocellular carcinoma by activating the TUFT1/AKT pathway
Authors: Dou Changwei , Sun Liankang , Wang Liang , Cheng Jian , Wu Weiding , Zhang Chengwu , Xu Qiuran , Tu Kangsheng , Liu Jie
Published: September 2020

Bromodomain-containing protein 9 (BRD9) has a critical role in human squamous cell lung cancer, acute myeloid leukemia, and malignant rhabdoid tumors. However, the expression and biological role of BRD9 in hepatocellular carcinoma (HCC) is poorly understood. In this study, BRD9 expression was found to be elevated in HCC through data mining of public databases. Next, we confirmed that the expression of BRD9 was increased in HCC tissues compared with that in adjacent non-tumor tissues. The upregulated level of BRD9 was also observed in HCC cells in comparison to LO2 cells. The increased BRD9 expression was correlated with unfavorable clinicopathological features. A high level of BRD9 predicted a poorer overall survival and disease-free survival of HCC patients. Functionally, BRD9 overexpression facilitated the proliferation, migration, invasion, and epithelial–mesenchymal transition (EMT) of Hep3B cells. Conversely, either BRD9 depletion or pharmacological inhibition of BRD9 resulted in the reduced proliferation and invasiveness of HCCLM3 cells. In addition, the BRD9 knockdown restrained the growth and metastasis of HCCLM3 cells in vivo. Mechanistically, BRD9 positively regulated TUFT1 expression and AKT activation in HCC cells. ChIP-qPCR analysis indicated that BRD9 promoted the binding of P300 acetyltransferase to the TUFT1 promoter and epigenetically regulated TUFT1 expression by increasing H3K27Ac in the promoter. Notably, either TUFT1 knockdown or AKT inhibitor (MK2206) abrogated the promoting effects of BRD9 on the proliferation, migration, invasion, and EMT of Hep3B cells. The forced expression of TUFT1 abolished the effects of BRD9 knockdown on the growth and metastasis of HCCLM3 cells. Altogether, these data indicate that BRD9 promotes the growth and metastasis of HCC cells by activating the TUFT1/AKT pathway and may serve as a promising biomarker and therapeutic target for HCC.
MFG-E8 accelerates wound healing in diabetes by regulating “NLRP3 inflammasome-neutrophil extracellular traps” axis
Authors: Huang Wei , Jiao Jinyu , Liu Ju , Huang Meng , Hu Yanyan , Ran Wenzhuo , Yan Li , Xiong Yin , Li Mei , Quan Ziyao , Rao Yahua , Chen Jiayi , Huang Yan , Zhang Dongxin
Published: September 2020

Sustained activation of NLRP3 inflammasome and release of neutrophil extracellular traps (NETs) impair wound healing of diabetic foot ulcers (DFUs). Our previous study reported that milk fat globule epidermal growth factor VIII (MFG-E8) attenuates tissue damage in systemic lupus erythematosus. However, the functional effect of MFG-E8 on “NLRP3 inflammasome-NETs” inflammatory loop in wound healing of diabetes is not completely elucidated. In this study, neutrophils from DFU patients are susceptible to undergo NETosis, releasing more NETs. The circulating levels of NET components neutrophil elastase and proteinase 3 and inflammatory cytokines IL-1β and IL-18 were significantly elevated in DFU patients compared with healthy controls or diabetic patients, in spite of higher levels of MFG-E8 in DFU patients. In Mfge8−/− diabetic mice, skin wound displayed exaggerated inflammatory response, including leukocyte infiltration, excessive activation of NLRP3 inflammasome (release of higher IL-1β, IL-18, and TNF-α), largely lodged NETs, resulting in poor angiogenesis and wound closure. When stimulated with high-dose glucose or IL-18, MFG-E8-deficient neutrophils release more NETs than WT neutrophils. After administration of recombinant MFG-E8, IL-18-primed NETosis of WT or Mfge8−/− neutrophils was significantly inhibited. Furthermore, NET and mCRAMP (component of NETs, the murine equivalent of cathelicidin LL-37 in human)-mediated activation of NLRP3 inflammasome and production of IL-1β/IL-18 were significantly elevated in Mfge8−/− macrophages compared with WT macrophages, which were also significantly dampened by the administration of rmMFG-E8. Therefore, our study demonstrated that as inhibitor of the “NLRP3 inflammasome-NETs” inflammatory loop, exogenous rMFG-E8 improves angiogenesis and accelerates wound healing, highlighting possible therapeutic potential for DFUs.
Circuit-specific hippocampal ΔFosB underlies resilience to stress-induced social avoidance
Authors: Eagle Andrew L. , Manning Claire E. , Williams Elizabeth S. , Bastle Ryan M. , Gajewski Paula A. , Garrison Amber , Wirtz Alexis J. , Akguen Seda , Brandel-Ankrapp Katie , Endege Wilson , Boyce Frederick M. , Ohnishi Yoshinori N. , Mazei-Robison Michelle , Maze Ian , Neve Rachel L. , Robison Alfred J.
Published: September 2020

Chronic stress is a key risk factor for mood disorders like depression, but the stress-induced changes in brain circuit function and gene expression underlying depression symptoms are not completely understood, hindering development of novel treatments. Because of its projections to brain regions regulating reward and anxiety, the ventral hippocampus is uniquely poised to translate the experience of stress into altered brain function and pathological mood, though the cellular and molecular mechanisms of this process are not fully understood. Here, we use a novel method of circuit-specific gene editing to show that the transcription factor ΔFosB drives projection-specific activity of ventral hippocampus glutamatergic neurons causing behaviorally diverse responses to stress. We establish molecular, cellular, and circuit-level mechanisms for depression- and anxiety-like behavior in response to stress and use circuit-specific gene expression profiling to uncover novel downstream targets as potential sites of therapeutic intervention in depression.
Low dimensional nanostructures of fast ion conducting lithium nitride
Authors: Tapia-Ruiz Nuria , Gordon Alexandra G. , Jewell Catherine M. , Edwards Hannah K. , Dunnill Charles W. , Blackman James M. , Snape Colin P. , Brown Paul D. , MacLaren Ian , Baldoni Matteo , Besley Elena , Titman Jeremy J. , Gregory Duncan H.
Published: September 2020

As the only stable binary compound formed between an alkali metal and nitrogen, lithium nitride possesses remarkable properties and is a model material for energy applications involving the transport of lithium ions. Following a materials design principle drawn from broad structural analogies to hexagonal graphene and boron nitride, we demonstrate that such low dimensional structures can also be formed from an s-block element and nitrogen. Both one- and two-dimensional nanostructures of lithium nitride, Li3N, can be grown despite the absence of an equivalent van der Waals gap. Lithium-ion diffusion is enhanced compared to the bulk compound, yielding materials with exceptional ionic mobility. Li3N demonstrates the conceptual assembly of ionic inorganic nanostructures from monolayers without the requirement of a van der Waals gap. Computational studies reveal an electronic structure mediated by the number of Li-N layers, with a transition from a bulk narrow-bandgap semiconductor to a metal at the nanoscale.
Femtosecond laser programmed artificial musculoskeletal systems
Authors: Ma Zhuo-Chen , Zhang Yong-Lai , Han Bing , Hu Xin-Yu , Li Chun-He , Chen Qi-Dai , Sun Hong-Bo
Published: September 2020

Natural musculoskeletal systems have been widely recognized as an advanced robotic model for designing robust yet flexible microbots. However, the development of artificial musculoskeletal systems at micro-nanoscale currently remains a big challenge, since it requires precise assembly of two or more materials of distinct properties into complex 3D micro/nanostructures. In this study, we report femtosecond laser programmed artificial musculoskeletal systems for prototyping 3D microbots, using relatively stiff SU-8 as the skeleton and pH-responsive protein (bovine serum albumin, BSA) as the smart muscle. To realize the programmable integration of the two materials into a 3D configuration, a successive on-chip two-photon polymerization (TPP) strategy that enables structuring two photosensitive materials sequentially within a predesigned configuration was proposed. As a proof-of-concept, we demonstrate a pH-responsive spider microbot and a 3D smart micro-gripper that enables controllable grabbing and releasing. Our strategy provides a universal protocol for directly printing 3D microbots composed of multiple materials.
Computational screen-out strategy for electrically pumped organic laser materials
Authors: Ou Qi , Peng Qian , Shuai Zhigang
Published: September 2020

Electrically pumped organic lasing is one of the most challenging issues in organic optoelectronics. We present a systematic theoretical investigation to screen out electrical pumping lasing molecules over a wide range of organic materials. With the electronic structure information obtained from time-dependent density functional theory, we calculate multiple photophysical parameters of a set of optical pumping organic laser molecules in our self-developed molecular material property prediction package (MOMAP) to judge whether the electrically pumped lasing conditions can be satisfied, namely, to avoid reabsorption from excitons and/or polarons, and the accumulation of triplet excitons. In addition, a large oscillator strength of S1 and weak intermolecular π–π interaction are preferred. With these criteria, we are able to conclude that BP3T, BSBCz, and CzPVSBF compounds are promising candidates for electrically pumped lasing, and the proposed computational strategy could serve as a general protocol for molecular design of organic lasing materials.
Integration of molecular profiles in a longitudinal wellness profiling cohort
Authors: Tebani Abdellah , Gummesson Anders , Zhong Wen , Koistinen Ina Schuppe , Lakshmikanth Tadepally , Olsson Lisa M. , Boulund Fredrik , Neiman Maja , Stenlund Hans , Hellström Cecilia , Karlsson Max J. , Arif Muhammad , Dodig-Crnković Tea , Mardinoglu Adil , Lee Sunjae , Zhang Cheng , Chen Yang , Olin Axel , Mikes Jaromir , Danielsson Hanna , von Feilitzen Kalle , Jansson Per-Anders , Angerås Oskar , Huss Mikael , Kjellqvist Sanela , Odeberg Jacob , Edfors Fredrik , Tremaroli Valentina , Forsström Björn , Schwenk Jochen M. , Nilsson Peter , Moritz Thomas , Bäckhed Fredrik , Engstrand Lars , Brodin Petter , Bergström Göran , Uhlen Mathias , Fagerberg Linn
Published: September 2020

An important aspect of precision medicine is to probe the stability in molecular profiles among healthy individuals over time. Here, we sample a longitudinal wellness cohort with 100 healthy individuals and analyze blood molecular profiles including proteomics, transcriptomics, lipidomics, metabolomics, autoantibodies and immune cell profiling, complemented with gut microbiota composition and routine clinical chemistry. Overall, our results show high variation between individuals across different molecular readouts, while the intra-individual baseline variation is low. The analyses show that each individual has a unique and stable plasma protein profile throughout the study period and that many individuals also show distinct profiles with regards to the other omics datasets, with strong underlying connections between the blood proteome and the clinical chemistry parameters. In conclusion, the results support an individual-based definition of health and show that comprehensive omics profiling in a longitudinal manner is a path forward for precision medicine.
Chiroptical spectroscopy of a freely diffusing single nanoparticle
Authors: Sachs Johannes , Günther Jan-Philipp , Mark Andrew G. , Fischer Peer
Published: September 2020

Chiral plasmonic nanoparticles can exhibit strong chiroptical signals compared to the corresponding molecular response. Observations are, however, generally restricted to measurements on stationary single particles with a fixed orientation, which complicates the spectral analysis. Here, we report the spectroscopic observation of a freely diffusing single chiral nanoparticle in solution. By acquiring time-resolved circular differential scattering signals we show that the spectral interpretation is significantly simplified. We experimentally demonstrate the equivalence between time-averaged chiral spectra observed for an individual nanostructure and the corresponding ensemble spectra, and thereby demonstrate the ergodic principle for chiroptical spectroscopy. We also show how it is possible for an achiral particle to yield an instantaneous chiroptical response, whereas the time-averaged signals are an unequivocal measure of chirality. Time-resolved chiroptical spectroscopy on a freely moving chiral nanoparticle advances the field of single-particle spectroscopy, and is a means to obtain the true signature of the nanoparticle’s chirality.
Collectively stabilizing and orienting posterior migratory forces disperses cell clusters in vivo
Authors: Lin B. , Luo J. , Lehmann R.
Published: September 2020

Individual cells detach from cohesive ensembles during development and can inappropriately separate in disease. Although much is known about how cells separate from epithelia, it remains unclear how cells disperse from clusters lacking apical–basal polarity, a hallmark of advanced epithelial cancers. Here, using live imaging of the developmental migration program of Drosophila primordial germ cells (PGCs), we show that cluster dispersal is accomplished by stabilizing and orienting migratory forces. PGCs utilize a G protein coupled receptor (GPCR), Tre1, to guide front-back migratory polarity radially from the cluster toward the endoderm. Posteriorly positioned myosin-dependent contractile forces pull on cell–cell contacts until cells release. Tre1 mutant cells migrate randomly with transient enrichment of the force machinery but fail to separate, indicating a temporal contractile force threshold for detachment. E-cadherin is retained on the cell surface during cell separation and augmenting cell–cell adhesion does not impede detachment. Notably, coordinated migration improves cluster dispersal efficiency by stabilizing cell–cell interfaces and facilitating symmetric pulling. We demonstrate that guidance of inherent migratory forces is sufficient to disperse cell clusters under physiological settings and present a paradigm for how such events could occur across development and disease.
A less cloudy picture of the inter-model spread in future global warming projections
Authors: Hu Xiaoming , Fan Hanjie , Cai Ming , Sejas Sergio A. , Taylor Patrick , Yang Song
Published: September 2020

Model warming projections, forced by increasing greenhouse gases, have a large inter-model spread in both their geographical warming patterns and global mean values. The inter-model warming pattern spread (WPS) limits our ability to foresee the severity of regional impacts on nature and society. This paper focuses on uncovering the feedbacks responsible for the WPS. Here, we identify two dominant WPS modes whose global mean values also explain 98.7% of the global warming spread (GWS). We show that the ice-albedo feedback spread explains uncertainties in polar regions while the water vapor feedback spread explains uncertainties elsewhere. Other processes, including the cloud feedback, contribute less to the WPS as their spreads tend to cancel each other out in a model-dependent manner. Our findings suggest that the WPS and GWS could be significantly reduced by narrowing the inter-model spreads of ice-albedo and water vapor feedbacks, and better understanding the spatial coupling between feedbacks.
Haloarchaea swim slowly for optimal chemotactic efficiency in low nutrient environments
Authors: Thornton Katie L. , Butler Jaimi K. , Davis Seth J. , Baxter Bonnie K. , Wilson Laurence G.
Published: September 2020

Archaea have evolved to survive in some of the most extreme environments on earth. Life in extreme, nutrient-poor conditions gives the opportunity to probe fundamental energy limitations on movement and response to stimuli, two essential markers of living systems. Here we use three-dimensional holographic microscopy and computer simulations to reveal that halophilic archaea achieve chemotaxis with power requirements one hundred-fold lower than common eubacterial model systems. Their swimming direction is stabilised by their flagella (archaella), enhancing directional persistence in a manner similar to that displayed by eubacteria, albeit with a different motility apparatus. Our experiments and simulations reveal that the cells are capable of slow but deterministic chemotaxis up a chemical gradient, in a biased random walk at the thermodynamic limit.
Chromatin modifier MTA1 regulates mitotic transition and tumorigenesis by orchestrating mitotic mRNA processing
Authors: Liu Jian , Li Chunxiao , Wang Jinsong , Xu Dongkui , Wang Haijuan , Wang Ting , Li Lina , Li Hui , Nan Peng , Zhang Jingyao , Wang Yang , Huang Changzhi , Chen Dong , Zhang Yi , Wen Tao , Zhan Qimin , Ma Fei , Qian Haili
Published: September 2020

Dysregulated alternative splicing (AS) driving carcinogenetic mitosis remains poorly understood. Here, we demonstrate that cancer metastasis-associated antigen 1 (MTA1), a well-known oncogenic chromatin modifier, broadly interacts and co-expresses with RBPs across cancers, contributing to cancerous mitosis-related AS. Using developed fCLIP-seq technology, we show that MTA1 binds abundant transcripts, preferentially at splicing-responsible motifs, influencing the abundance and AS pattern of target transcripts. MTA1 regulates the mRNA level and guides the AS of a series of mitosis regulators. MTA1 deletion abrogated the dynamic AS switches of variants for ATRX and MYBL2 at mitotic stage, which are relevant to mitosis-related tumorigenesis. MTA1 dysfunction causes defective mitotic arrest, leads to aberrant chromosome segregation, and results in chromosomal instability (CIN), eventually contributing to tumorigenesis. Currently, little is known about the RNA splicing during mitosis; here, we uncover that MTA1 binds transcripts and orchestrates dynamic splicing of mitosis regulators in tumorigenesis.
The precursor of PI(3,4,5)P3 alleviates aging by activating daf-18(Pten) and independent of daf-16
Authors: Shi Dawei , Xia Xian , Cui Aoyuan , Xiong Zhongxiang , Yan Yizhen , Luo Jing , Chen Guoyu , Zeng Yingying , Cai Donghong , Hou Lei , McDermott Joseph , Li Yu , Zhang Hong , Han Jing-Dong J.
Published: September 2020

Aging is characterized by the loss of homeostasis and the general decline of physiological functions, accompanied by various degenerative diseases and increased rates of mortality. Aging targeting small molecule screens have been performed many times, however, few have focused on endogenous metabolic intermediates—metabolites. Here, using C. elegans lifespan assays, we conducted a worm metabolite screen and identified an eukaryotes conserved metabolite, myo-inositol (MI), to extend lifespan, increase mobility and reduce fat content. Genetic analysis of enzymes in MI metabolic pathway suggest that MI alleviates aging through its derivative PI(4,5)P2. MI and PI(4,5)P2 are precursors of PI(3,4,5)P3, which is negatively related to longevity. The longevity effect of MI is dependent on the tumor suppressor gene, daf-18 (homologous to mouse Pten), independent of its classical pathway downstream genes, akt or daf-16. Furthermore, we found MI effects on aging and lifespan act through mitophagy regulator PTEN induced kinase-1 (pink-1) and mitophagy. MI’s anti-aging effect is also conserved in mouse, indicating a conserved mechanism in mammals.
Collagen promotes anti-PD-1/PD-L1 resistance in cancer through LAIR1-dependent CD8+ T cell exhaustion
Authors: Peng David H. , Rodriguez Bertha Leticia , Diao Lixia , Chen Limo , Wang Jing , Byers Lauren A. , Wei Ying , Chapman Harold A. , Yamauchi Mitsuo , Behrens Carmen , Raso Gabriela , Soto Luisa Maren Solis , Cuentes Edwin Roger Parra , Wistuba Ignacio I. , Kurie Jonathan M. , Gibbons Don L.
Published: September 2020

Tumor extracellular matrix has been associated with drug resistance and immune suppression. Here, proteomic and RNA profiling reveal increased collagen levels in lung tumors resistant to PD-1/PD-L1 blockade. Additionally, elevated collagen correlates with decreased total CD8+T cells and increased exhausted CD8+T cell subpopulations in murine and human lung tumors. Collagen-induced T cell exhaustion occurs through the receptor LAIR1, which is upregulated following CD18 interaction with collagen, and induces T cell exhaustion through SHP-1. Reduction in tumor collagen deposition through LOXL2 suppression increases T cell infiltration, diminishes exhausted T cells, and abrogates resistance to anti-PD-L1. Abrogating LAIR1 immunosuppression through LAIR2 overexpression or SHP-1 inhibition sensitizes resistant lung tumors to anti-PD-1. Clinically, increased collagen, LAIR1, and TIM-3 expression in melanoma patients treated with PD-1 blockade predict poorer survival and response. Our study identifies collagen and LAIR1 as potential markers for immunotherapy resistance and validates multiple promising therapeutic combinations.
Resolution of R-loops by INO80 promotes DNA replication and maintains cancer cell proliferation and viability
Authors: Prendergast Lisa , McClurg Urszula L. , Hristova Rossitsa , Berlinguer-Palmini Rolando , Greener Sarah , Veitch Katie , Hernandez Inmaculada , Pasero Philippe , Rico Daniel , Higgins Jonathan M. G. , Gospodinov Anastas , Papamichos-Chronakis Manolis
Published: September 2020

Collisions between the DNA replication machinery and co-transcriptional R-loops can impede DNA synthesis and are a major source of genomic instability in cancer cells. How cancer cells deal with R-loops to proliferate is poorly understood. Here we show that the ATP-dependent chromatin remodelling INO80 complex promotes resolution of R-loops to prevent replication-associated DNA damage in cancer cells. Depletion of INO80 in prostate cancer PC3 cells leads to increased R-loops. Overexpression of the RNA:DNA endonuclease RNAse H1 rescues the DNA synthesis defects and suppresses DNA damage caused by INO80 depletion. R-loops co-localize with and promote recruitment of INO80 to chromatin. Artificial tethering of INO80 to a LacO locus enabled turnover of R-loops in cis. Finally, counteracting R-loops by INO80 promotes proliferation and averts DNA damage-induced death in cancer cells. Our work suggests that INO80-dependent resolution of R-loops promotes DNA replication in the presence of transcription, thus enabling unlimited proliferation in cancers.
Modulating mechanical stability of heterodimerization between engineered orthogonal helical domains
Authors: Yu Miao , Zhao Zhihai , Chen Zibo , Le Shimin , Yan Jie
Published: September 2020

Mechanically stable specific heterodimerization between small protein domains have a wide scope of applications, from using as a molecular anchorage in single-molecule force spectroscopy studies of protein mechanics, to serving as force-bearing protein linker for modulation of mechanotransduction of cells, and potentially acting as a molecular crosslinker for functional materials. Here, we explore the possibility to develop heterodimerization system with a range of mechanical stability from a set of recently engineered helix-heterotetramers whose mechanical properties have yet to be characterized. We demonstrate this possibility using two randomly chosen helix-heterotetramers, showing that their mechanical properties can be modulated by changing the stretching geometry and the number of interacting helices. These helix-heterotetramers and their derivatives are sufficiently stable over physiological temperature range. Using it as mechanically stable anchorage, we demonstrate the applications in single-molecule manipulation studies of the temperature dependent unfolding and refolding of a titin immunoglobulin domain and α-actinin spectrin repeats.
Canadian permafrost stores large pools of ammonium and optically distinct dissolved organic matter
Authors: Fouché J. , Christiansen C. T. , Lafrenière M. J. , Grogan P. , Lamoureux S. F.
Published: September 2020

Permafrost degradation may lead to mobilization of carbon and nutrients and enhance microbial processing rates of previously frozen organic matter. Although the pool size and chemical composition of dissolved organic matter (DOM) are fundamental determinants of the carbon cycle in Arctic watersheds, its source within the seasonally thawing active layer and the underlying permafrost remains largely uncharacterized. Here, we used 25 soil cores that extended down into the permafrost from nine sites across Arctic Canada to quantify dissolved organic carbon (DOC) and nitrogen stocks, and to characterize DOM optical properties. Organic permafrost stores 5–7 times more DOC and ammonium than the active layer and mineral permafrost. Furthermore, the permafrost layers contain substantial low molecular weight DOM with low aromaticity suggesting high biodegradability. We conclude that soil organic matter stoichiometry and cryogenic processes determine permafrost DOM chemistry, and that thawing will mobilize large amounts of labile DOC and ammonium into Arctic watersheds.
Uncovering the cytochrome P450-catalyzed methylenedioxy bridge formation in streptovaricins biosynthesis
Authors: Sun Guo , Hu Chaoqun , Mei Qing , Luo Minghe , Chen Xu , Li Zhengyuan , Liu Yuanzhen , Deng Zixin , Zhang Zhengyu , Sun Yuhui
Published: September 2020

Streptovaricin C is a naphthalenic ansamycin antibiotic structurally similar to rifamycins with potential anti-MRSA bioactivities. However, the formation mechanism of the most fascinating and bioactivity-related methylenedioxy bridge (MDB) moiety in streptovaricins is unclear. Based on genetic and biochemical evidences, we herein clarify that the P450 enzyme StvP2 catalyzes the MDB formation in streptovaricins, with an atypical substrate inhibition kinetics. Furthermore, X-ray crystal structures in complex with substrate and structure-based mutagenesis reveal the intrinsic details of the enzymatic reaction. The mechanism of MDB formation is proposed to be an intramolecular nucleophilic substitution resulting from the hydroxylation by the heme core and the keto-enol tautomerization via a crucial catalytic triad (Asp89-His92-Arg72) in StvP2. In addition, in vitro reconstitution uncovers that C6-O-methylation and C4-O-acetylation of streptovaricins are necessary prerequisites for the MDB formation. This work provides insight for the MDB formation and adds evidence in support of the functional versatility of P450 enzymes.
Spatial ultrasound modulation by digitally controlling microbubble arrays
Authors: Ma Zhichao , Melde Kai , Athanassiadis Athanasios G. , Schau Michael , Richter Harald , Qiu Tian , Fischer Peer
Published: September 2020

Acoustic waves, capable of transmitting through optically opaque objects, have been widely used in biomedical imaging, industrial sensing and particle manipulation. High-fidelity wave front shaping is essential to further improve performance in these applications. An acoustic analog to the successful spatial light modulator (SLM) in optics would be highly desirable. To date there have been no techniques shown that provide effective and dynamic modulation of a sound wave and which also support scale-up to a high number of individually addressable pixels. In the present study, we introduce a dynamic spatial ultrasound modulator (SUM), which dynamically reshapes incident plane waves into complex acoustic images. Its transmission function is set with a digitally generated pattern of microbubbles controlled by a complementary metal–oxide–semiconductor (CMOS) chip, which results in a binary amplitude acoustic hologram. We employ this device to project sequentially changing acoustic images and demonstrate the first dynamic parallel assembly of microparticles using a SUM.