bluuebunny/crossref_metadata_2025 huggingface dataset:
Childhood adversities in people at ultra-high risk (UHR) for psychosis: a systematic review and meta-analysis
Authors: Peh Oon Him , Rapisarda Attilio , Lee Jimmy
Published: January 2019

Childhood adversities have been reported to be more common among individuals at ultra-high risk (UHR) for psychosis. This paper systematically reviewed and meta-analysed (i) the severity and prevalence of childhood adversities (childhood trauma exposure, bullying victimisation and parental separation or loss) among the UHR, and (ii) the association between adversities and transition to psychosis (TTP). PsycINFO, PubMed and Embase databases were searched for studies reporting childhood adversities among UHR individuals. Only published articles were included. Risk of bias was assessed using Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guideline (von Elm et al., 2007) and the tool developed by Hoy et al. (2012). Seventeen case–control, cross-sectional and longitudinal studies were included. UHR individuals experienced significantly more severe trauma than controls, regardless of trauma subtype. UHR were 5.5, 2.5 and 3.1 times as likely to report emotional abuse, physical abuse and bullying victimisation, respectively. There was no association with parental separation. However, childhood trauma was not significantly associated with TTP (follow-up periods: 6 months to 15 years), suggesting that trauma alone may not be a sufficient risk factor. Sexual abuse was associated with TTP but this may have been driven by a single large study. Potential confounders and low rates of TTP among UHR are limitations of this review. This is the first meta-analysis that quantitatively summarises the associations between childhood adversities and TTP among UHR, and between specific abuse subtypes and TTP. Specific recommendations have been made to increase the quality of future research. PROSPERO registration no. CRD42017054884.
Processing of unfamiliar accents in monolingual and bilingual children: effects of type and amount of accent experience
Authors: LEVY Helena , KONIECZNY Lars , HANULÍKOVÁ Adriana
Published: January 2019

Substantial individual differences exist in regard to type and amount of experience with variable speech resulting from foreign or regional accents. Whereas prior experience helps with processing familiar accents, research on how experience with accented speech affects processing of unfamiliar accents is inconclusive, ranging from perceptual benefits to processing disadvantages. We examined how experience with accented speech modulates mono- and bilingual children's (mean age: 9;10) ease of speech comprehension for two unfamiliar accents in German, one foreign and one regional. More experience with regional accents helped children repeat sentences correctly in the regional condition and in the standard condition. More experience with foreign accents did not help in either accent condition. The results suggest that type and amount of accent experience co-determine processing ease of accented speech.
Help-seeking behaviour of problem gamblers: a narrative review
Authors: Loy Johanna K. , Grüne Bettina , Braun Barbara , Samuelsson Eva , Kraus Ludwig
Published: January 2019

Abstract. Background: There is evidence for low rates of help-seeking among problem gamblers. Identifying reasons for and barriers to seeking help is essential for improving help supply and gamblers’ treatment utilisation. The present study examines treatment utilisation of problem or pathological gamblers and reviews the evidence related to motives for and barriers to seeking help. Methods: The databases Medline, PsycInfo, and PubMed were searched for English-, Swedish- and German-language studies published between 2000 and 2017. Furthermore relevant references of included studies were analysed. Results: After exclusion of non-relevant publications 34 journal articles and seven reports covering the prevalence of help-seeking among gamblers or self-reported reasons for/barriers to help-seeking were maintained. The proportion of problem gamblers seeking help was less than 10 % in most studies. Problem severity was found positively associated with treatment attendance. Financial issues, negative emotions and crises were identified as main motives for seeking treatment. Main barriers to seeking treatment were shame, problem denial and lack of treatment availability. The results were similar across the examined studies. Conclusion: Low rates of treatment utilisation by problem gamblers strongly indicate that treatment providers and the society should strive to eliminate structural barriers that hinder gamblers to seek help. To better match problem gamblers´ needs, low-threshold early intervention, increasing knowledge of treatment options and efforts to reduce stigmatisation are important strategies to enhance access to help offers.
Correction: Loss of tuberous sclerosis complex 2 sensitizes tumors to nelfinavir–bortezomib therapy to intensify endoplasmic reticulum stress-induced cell death
Authors: Johnson Charlotte E. , Dunlop Elaine A. , Seifan Sara , McCann Henry D. , Hay Trevor , Parfitt Geraint J. , Jones Ashley T. , Giles Peter J. , Shen Ming H. , Sampson Julian R. , Errington Rachel J. , Davies D. Mark , Tee Andrew R.
Published: January 2019

This article was originally published under standard licence, but has now been made available under a CC BY 4.0 license. The PDF and HTML versions of the paper have been modified accordingly.
Cullin 5 is a novel candidate tumor suppressor in renal cell carcinoma involved in the maintenance of genome stability
Authors: Tapia-Laliena María Ángeles , Korzeniewski Nina , Peña-Llopis Samuel , Scholl Claudia , Fröhling Stefan , Hohenfellner Markus , Duensing Anette , Duensing Stefan
Published: January 2019

Clear cell renal cell carcinoma (ccRCC) is intimately associated with defects in ubiquitin-mediated protein degradation. Herein, we report that deficiency in the E3 ligase subunit cullin 5 (CUL5) promotes chromosomal instability and is an independent negative prognostic factor in ccRCC. CUL5 was initially identified in an RNA interference screen as a novel regulator of centrosome duplication control. We found that depletion of CUL5 rapidly promotes centriole overduplication and mitotic errors. Downregulation of CUL5 also caused an increase of DNA damage that was found to involve impaired DNA double-strand break repair. Using immunohistochemistry, CUL5 protein expression was found to be below detection level in the majority of RCCs. A re-analysis of the TCGA ccRCC cohort showed that a reduced CUL5 gene expression or CUL5 deletion were associated with a significantly worse overall patient survival. In conclusion, our results indicate that CUL5 functions as a novel tumor suppressor with prognostic relevance in ccRCC and is critically involved in the maintenance of genome stability.
Light limitation increases multidimensional trait evenness in phytoplankton populations
Authors: Fontana Simone , Thomas Mridul K , Reyes Marta , Pomati Francesco
Published: January 2019

Individual-level variation arising from responses to environmental gradients influences population and community dynamics. How such responses empirically relate to the mechanisms that govern species coexistence is, however, poorly understood. Previous results from lake phytoplankton communities suggested that the evenness of organismal traits in multiple dimensions increases with resource limitation, possibly due to resource partitioning at the individual level. Here we experimentally tested the emergence of this pattern by growing two phytoplankton species (Pseudokirchneriella subcapitata and Microcystis aeruginosa) under a gradient of light intensity, in monoculture and jointly. Under low light (resource) conditions, the populations diversified into a wide range of phenotypes, which were evenly distributed in multidimensional trait space (defined by four pigment-related trait dimensions), consistent with the observed field pattern. Our interpretation is that under conditions of light limitation, individual phytoplankton cells alter photosynthetic traits to reduce overlap in light acquisition, acquiring unexploited resources and thereby likely maximising individual success. Our results provide prime experimental evidence that resource limitation increases the evenness of conspecific and heterospecific microbial phenotypes along trait axes, advancing our understanding of trait-based coexistence.
Sanshool improves UVB-induced skin photodamage by targeting JAK2/STAT3-dependent autophagy
Authors: Hao Dan , Wen Xiang , Liu Lian , Wang Lian , Zhou Xianli , Li Yanmei , Zeng Xin , He Gu , Jiang Xian
Published: January 2019

Ultraviolet radiation is markedly increased because of pollution and the depletion of the stratospheric ozone layer. Excessive exposure to sunlight can negatively affect the skin, resulting in sunburn, photo-aging, or skin cancer. In this study, we first determined the photoprotective effect of sanshool, a major component in Zanthoxylum bungeanum, on UVB-irradiated responses in human dermal fibroblasts (HDFs) and nude mouse. We found that sanshool treatment can protect cells against the effects of UVB irradiation by (i) increasing cell viability, (ii) inhibiting MMP expression, and (iii) inducing autophagy. We also used the recombinant CSF2 or anti-CSF2 antibody co-cultured with human dermal fibroblasts (HDFs) and found that CSF2 contributes to sanshool-induced autophagy. Sanshool hindered the UVB-induced activation of JAK2-STAT3 signaling in HDFs, thereby inhibiting the expression of MMPs and activation of autophagic flux. Exposure of the dorsal skin of hairless mice to UVB radiation and subsequent topical application of sanshool delayed the progression of skin inflammation, leading to autophagy and inhibiting the activation of JAK2-STAT3 signaling. These results provide a basis for the study of the photoprotective effect of sanshool and suggest that it can be potentially used as an agent against UVB-induced skin damage in humans.
Reduction in murine acute GVHD severity by human gingival tissue-derived mesenchymal stem cells via the CD39 pathways
Authors: Ni Xuhao , Xia Yongxiang , Zhou Shun , Peng Hao , Wu Xiao , Lu Hao , Wang Han , Liu Rui , Blazar Bruce R. , Gu Jian , Lu Ling
Published: January 2019

Human gingival tissue-derived mesenchymal stem cells (GMSCs) present an accessible source of mesenchymal stem cells (MSCs) for treating autoimmune diseases. Here we show that human GMSCs can prevent and treat acute graft-versus-host disease (GVHD) in two different mouse models. Our results indicate that besides exhibiting suppressive function in vitro and in vivo, GMSCs may also regulate the conversion of Tregs to Th1 and/or Th17-like cells, as well as stabilize Foxp3 expression. Furthermore, GMSC-mediated prevention of acute GVHD was dependent on CD39 signaling that play an important role in the function and stability of Tregs. Finally, we also observed stronger protective ability of GMSCs with greater expansion ability compared with BMSCs or ASCs. These results indicate that human GMSCs have the potential to be used to treat GVHD.
Contribution of individual olfactory receptors to odor-induced attractive or aversive behavior in mice
Authors: Horio Nao , Murata Ken , Yoshikawa Keiichi , Yoshihara Yoshihiro , Touhara Kazushige
Published: January 2019

Odorants are recognized by multiple olfactory receptors (ORs) and induce innate behaviors like attraction or aversion via olfactory system in mice. However, a role of an individual OR is unclear. Muscone is recognized by a few ORs including MOR215–1 and MOR214–3, and attracts male mice. Odor preference tests using MOR215–1 knockout mice revealed that MOR215–1 and other OR(s), possibly including MOR214–3, are involved in the attraction. (Z)-5-tetradecen-1-ol (Z5–14:OH) activates ~3 ORs, including Olfr288, and evokes attraction at low levels but aversion at higher levels. Olfr288 knockout mice show no attraction but aversion, suggesting Olfr288 is involved in preference for Z5–14:OH, whereas activation of other low-affinity Z5–14:OH receptors evokes aversion. Each OR appears to send a signal to a neural circuit that possesses distinct valence, leading to a certain behavior. The final output behavior with multiple ORs stimulation is determined by summation (addition or competition) of valences coded by activated ORs.
Dispersible hydrogel force sensors reveal patterns of solid mechanical stress in multicellular spheroid cultures
Authors: Lee Wontae , Kalashnikov Nikita , Mok Stephanie , Halaoui Ruba , Kuzmin Elena , Putnam Andrew J. , Takayama Shuichi , Park Morag , McCaffrey Luke , Zhao Ruogang , Leask Richard L. , Moraes Christopher
Published: January 2019

Understanding how forces orchestrate tissue formation requires technologies to map internal tissue stress at cellular length scales. Here, we develop ultrasoft mechanosensors that visibly deform under less than 10 Pascals of cell-generated stress. By incorporating these mechanosensors into multicellular spheroids, we capture the patterns of internal stress that arise during spheroid formation. We experimentally demonstrate the spontaneous generation of a tensional ‘skin’, only a few cell layers thick, at the spheroid surface, which correlates with activation of mechanobiological signalling pathways, and balances a compressive stress profile within the tissue. These stresses develop through cell-driven mechanical compaction at the tissue periphery, and suggest that the tissue formation process plays a critically important role in specifying mechanobiological function. The broad applicability of this technique should ultimately provide a quantitative basis to design tissues that leverage the mechanical activity of constituent cells to evolve towards a desired form and function.
Achieving three-dimensional lithium sulfide growth in lithium-sulfur batteries using high-donor-number anions
Authors: Chu Hyunwon , Noh Hyungjun , Kim Yun-Jung , Yuk Seongmin , Lee Ju-Hyuk , Lee Jinhong , Kwack Hobeom , Kim YunKyoung , Yang Doo-Kyung , Kim Hee-Tak
Published: January 2019

Uncontrolled growth of insulating lithium sulfide leads to passivation of sulfur cathodes, which limits high sulfur utilization in lithium-sulfur batteries. Sulfur utilization can be augmented in electrolytes based on solvents with high Gutmann Donor Number; however, violent lithium metal corrosion is a drawback. Here we report that particulate lithium sulfide growth can be achieved using a salt anion with a high donor number, such as bromide or triflate. The use of bromide leads to ~95 % sulfur utilization by suppressing electrode passivation. More importantly, the electrolytes with high-donor-number salt anions are notably compatible with lithium metal electrodes. The approach enables a high sulfur-loaded cell with areal capacity higher than 4 mA h cm−2 and high sulfur utilization ( > 90 %). This work offers a simple but practical strategy to modulate lithium sulfide growth, while conserving stability for high-performance lithium-sulfur batteries.
Supplementary stocking selects for domesticated genotypes
Authors: Hagen Ingerid J. , Jensen Arne J. , Bolstad Geir H. , Diserud Ola H. , Hindar Kjetil , Lo Håvard , Karlsson Sten
Published: January 2019

Stocking of hatchery produced fish is common practise to mitigate declines in natural populations and may have unwanted genetic consequences. Here we describe a novel phenomenon arising where broodstock used for stocking may be introgressed with farmed individuals. We test how stocking affects introgression in a wild population of Atlantic salmon (Salmo salar) by quantifying how the number of adult offspring recaptured in a stocked river depend on parental introgression. We found that hatchery conditions favour farmed genotypes such that introgressed broodstock produce up to four times the number of adult offspring compared to non-introgressed broodstock, leading to increased introgression in the recipient spawning population. Our results provide the first empirical evidence that stocking can unintentionally favour introgressed individuals and through selection for domesticated genotypes compromise the fitness of stocked wild populations.
Improved state-level influenza nowcasting in the United States leveraging Internet-based data and network approaches
Authors: Lu Fred S. , Hattab Mohammad W. , Clemente Cesar Leonardo , Biggerstaff Matthew , Santillana Mauricio
Published: January 2019

In the presence of health threats, precision public health approaches aim to provide targeted, timely, and population-specific interventions. Accurate surveillance methodologies that can estimate infectious disease activity ahead of official healthcare-based reports, at relevant spatial resolutions, are important for achieving this goal. Here we introduce a methodological framework which dynamically combines two distinct influenza tracking techniques, using an ensemble machine learning approach, to achieve improved state-level influenza activity estimates in the United States. The two predictive techniques behind the ensemble utilize (1) a self-correcting statistical method combining influenza-related Google search frequencies, information from electronic health records, and historical flu trends within each state, and (2) a network-based approach leveraging spatio-temporal synchronicities observed in historical influenza activity across states. The ensemble considerably outperforms each component method in addition to previously proposed state-specific methods for influenza tracking, with higher correlations and lower prediction errors.
Author Correction: Molecular basis for the inhibition of the methyl-lysine binding function of 53BP1 by TIRR
Authors: Wang Jiaxu , Yuan Zenglin , Cui Yaqi , Xie Rong , Yang Guang , Kassab Muzaffer A. , Wang Mengxi , Ma Yinliang , Wu Chen , Yu Xiaochun , Liu Xiuhua
Published: January 2019

The original version of this Article contained an error in the author affiliations. Xiaochun Yu was incorrectly associated with College of Life Sciences, Hebei University, Baoding 071000 Hebei, China.This has now been corrected in both the PDF and HTML versions of the Article.
Pseudodoping of a metallic two-dimensional material by the supporting substrate
Authors: Shao Bin , Eich Andreas , Sanders Charlotte , Ngankeu Arlette S. , Bianchi Marco , Hofmann Philip , Khajetoorians Alexander A. , Wehling Tim O.
Published: January 2019

Charge transfers resulting from weak bondings between two-dimensional materials and the supporting substrates are often tacitly associated with their work function differences. In this context, two-dimensional materials could be normally doped at relatively low levels. Here, we demonstrate how even weak hybridization with substrates can lead to an apparent heavy doping, using the example of monolayer 1H-TaS2 grown on Au(111). Ab-initio calculations show that sizable changes in Fermi areas can arise, while the transferred charge between substrate and two-dimensional material is much smaller than the variation of Fermi areas suggests. This mechanism, which we refer to as pseudodoping, is associated with non-linear energy-dependent shifts of electronic spectra, which our scanning tunneling spectroscopy experiments reveal for clean and defective TaS2 monolayer on Au(111). The influence of pseudodoping on the formation of many-body states in two-dimensional metallic materials is analyzed, shedding light on utilizing pseudodoping to control electronic phase diagrams.
Quantum absorption refrigerator with trapped ions
Authors: Maslennikov Gleb , Ding Shiqian , Hablützel Roland , Gan Jaren , Roulet Alexandre , Nimmrichter Stefan , Dai Jibo , Scarani Valerio , Matsukevich Dzmitry
Published: January 2019

In recent years substantial efforts have been expended in extending thermodynamics to single quantum systems. Quantum effects have emerged as a resource that can improve the performance of heat machines. However in the fully quantum regime their implementation still remains a challenge. Here, we report an experimental realization of a quantum absorption refrigerator in a system of three trapped ions, with three of its normal modes of motion coupled by a trilinear Hamiltonian such that heat transfer between two modes refrigerates the third. We investigate the dynamics and steady-state properties of the refrigerator and compare its cooling capability when only thermal states are involved to the case when squeezing is employed as a quantum resource. We also study the performance of such a refrigerator in the single shot regime made possible by coherence and demonstrate cooling below both the steady-state energy and a benchmark set by classical thermodynamics.
Reducing aggregation caused quenching effect through co-assembly of PAH chromophores and molecular barriers
Authors: Huang Yinjuan , Xing Jie , Gong Qiuyu , Chen Li-Chuan , Liu Guangfeng , Yao Changjiang , Wang Zongrui , Zhang Hao-Li , Chen Zhong , Zhang Qichun
Published: January 2019

The features of well-conjugated and planar aromatic structures make π-conjugated luminescent materials suffer from aggregation caused quenching (ACQ) effect when used in solid or aggregated states, which greatly impedes their applications in optoelectronic devices and biological applications. Herein, we reduce the ACQ effect by demonstrating a facile and low cost method to co-assemble polycyclic aromatic hydrocarbon (PAH) chromophores and octafluoronaphthalene together. Significantly, the solid photoluminescence quantum yield (PLQYs) for the as-resulted four micro/nanococrystals are enhanced by 254%, 235%, 474 and 582%, respectively. Protection from hydrophilic polymer chains (P123 (PEO20-PPO70-PEO20)) endows the cocrystals with superb dispersibility in water. More importantly, profiting from the above-mentioned highly improved properties, nano-cocrystals present good biocompatibility and considerable cell imaging performance. This research provides a simple method to enhance the emission, biocompatibility and cellular permeability of common chromophores, which may open more avenues for the applications of originally non- or poor fluorescent PAHs.
Aminoacyl sulfonamide assembly in SB-203208 biosynthesis
Authors: Hu Zhijuan , Awakawa Takayoshi , Ma Zhongjun , Abe Ikuro
Published: January 2019

Sulfonamide is present in many important drugs, due to its unique chemical and biological properties. In contrast, naturally occurring sulfonamides are rare, and their biosynthetic knowledge are scarce. Here we identify the biosynthetic gene cluster of sulfonamide antibiotics, altemicidin, SB-203207, and SB-203208, from Streptomyces sp. NCIMB40513. The heterologous gene expression and biochemical analyses reveal unique aminoacyl transfer reactions, including the tRNA synthetase-like enzyme SbzA-catalyzed L-isoleucine transfer and the GNAT enzyme SbzC-catalyzed β-methylphenylalanine transfer. Furthermore, we elucidate the biogenesis of 2-sulfamoylacetic acid from L-cysteine, by the collaboration of the cupin dioxygenase SbzM and the aldehyde dehydrogenase SbzJ. Remarkably, SbzM catalyzes the two-step oxidation and decarboxylation of L-cysteine, and the subsequent intramolecular amino group rearrangement leads to N-S bond formation. This detailed analysis of the aminoacyl sulfonamide antibiotics biosynthetic machineries paves the way toward investigations of sulfonamide biosynthesis and its engineering.
Prostaglandin E2 mediates sensory nerve regulation of bone homeostasis
Authors: Chen Hao , Hu Bo , Lv Xiao , Zhu Shouan , Zhen Gehua , Wan Mei , Jain Amit , Gao Bo , Chai Yu , Yang Mi , Wang Xiao , Deng Ruoxian , Wang Lei , Cao Yong , Ni Shuangfei , Liu Shen , Yuan Wen , Chen Huajiang , Dong Xinzhong , Guan Yun , Yang Huilin , Cao Xu
Published: January 2019

Whether sensory nerve can sense bone density or metabolic activity to control bone homeostasis is unknown. Here we found prostaglandin E2 (PGE2) secreted by osteoblastic cells activates PGE2 receptor 4 (EP4) in sensory nerves to regulate bone formation by inhibiting sympathetic activity through the central nervous system. PGE2 secreted by osteoblasts increases when bone density decreases as demonstrated in osteoporotic animal models. Ablation of sensory nerves erodes the skeletal integrity. Specifically, knockout of the EP4 gene in the sensory nerves or cyclooxygenase-2 (COX2) in the osteoblastic cells significantly reduces bone volume in adult mice. Sympathetic tone is increased in sensory denervation models, and propranolol, a β2-adrenergic antagonist, rescues bone loss. Furthermore, injection of SW033291, a small molecule to increase PGE2 level locally, significantly boostes bone formation, whereas the effect is obstructed in EP4 knockout mice. Thus, we show that PGE2 mediates sensory nerve to control bone homeostasis and promote regeneration.
Author Correction: Genome-wide association study of classical Hodgkin lymphoma identifies key regulators of disease susceptibility
Authors: Sud Amit , Thomsen Hauke , Law Philip J. , Försti Asta , da Silva Filho Miguel Inacio , Holroyd Amy , Broderick Peter , Orlando Giulia , Lenive Oleg , Wright Lauren , Cooke Rosie , Easton Douglas , Pharoah Paul , Dunning Alison , Peto Julian , Canzian Federico , Eeles Rosalind , Kote-Jarai Zsofia , Muir Kenneth , Pashayan Nora ,   The PRACTICAL consortium, Henderson Brian E. , Haiman Christopher A. , Benlloch Sara , Schumacher Fredrick R. , Olama Ali Amin Al , Berndt Sonja I. , Conti David V. , Wiklund Fredrik , Chanock Stephen , Stevens Victoria L. , Tangen Catherine M. , Batra Jyotsna , Clements Judith , Gronberg Henrik , Schleutker Johanna , Albanes Demetrius , Weinstein Stephanie , Wolk Alicja , West Catharine , Mucci Lorelei , Cancel-Tassin Géraldine , Koutros Stella , Sorensen Karina Dalsgaard , Maehle Lovise , Neal David E. , Travis Ruth C. , Hamilton Robert J. , Ingles Sue Ann , Rosenstein Barry , Lu Yong-Jie , Giles Graham G. , Kibel Adam S. , Vega Ana , Kogevinas Manolis , Penney Kathryn L. , Park Jong Y. , Stanford Janet L. , Cybulski Cezary , Nordestgaard Børge G. , Brenner Hermann , Maier Christiane , Kim Jeri , John Esther M. , Teixeira Manuel R. , Neuhausen Susan L. , De Ruyck Kim , Razack Azad , Newcomb Lisa F. , Lessel Davor , Kaneva Radka , Usmani Nawaid , Claessens Frank , Townsend Paul A. , Gago-Dominguez Manuela , Roobol Monique J. , Menegaux Florence , Hoffmann Per , Nöthen Markus M. , Jöckel Karl-Heinz , von Strandmann Elke Pogge , Lightfoot Tracy , Kane Eleanor , Roman Eve , Lake Annette , Montgomery Dorothy , Jarrett Ruth F. , Swerdlow Anthony J. , Engert Andreas , Orr Nick , Hemminki Kari , Houlston Richard S.
Published: January 2019

The original version of this Article contained an error in the spelling of a member of the PRACTICAL Consortium, Manuela Gago-Dominguez, which was incorrectly given as Manuela Gago Dominguez. This has now been corrected in both the PDF and HTML versions of the Article.
Author Correction: Large-scale transcriptome-wide association study identifies new prostate cancer risk regions
Authors: Mancuso Nicholas , Gayther Simon , Gusev Alexander , Zheng Wei , Penney Kathryn L. ,   The PRACTICAL consortium, Henderson Brian E. , Benlloch Sara , Schumacher Fredrick R. , Olama Ali Amin Al , Muir Kenneth , Berndt Sonja I. , Conti David V. , Wiklund Fredrik , Chanock Stephen , Stevens Victoria L. , Tangen Catherine M. , Batra Jyotsna , Clements Judith , Gronberg Henrik , Pashayan Nora , Schleutker Johanna , Albanes Demetrius , Weinstein Stephanie , Wolk Alicja , West Catharine , Mucci Lorelei , Cancel-Tassin Géraldine , Koutros Stella , Sorensen Karina Dalsgaard , Maehle Lovise , Neal David E. , Hamdy Freddie C. , Donovan Jenny L. , Travis Ruth C. , Hamilton Robert J. , Ingles Sue Ann , Rosenstein Barry , Lu Yong-Jie , Giles Graham G. , Kibel Adam S. , Vega Ana , Kogevinas Manolis , Park Jong Y. , Stanford Janet L. , Cybulski Cezary , Nordestgaard Børge G. , Brenner Hermann , Maier Christiane , Kim Jeri , John Esther M. , Teixeira Manuel R. , Neuhausen Susan L. , De Ruyck Kim , Razack Azad , Newcomb Lisa F. , Lessel Davor , Kaneva Radka , Usmani Nawaid , Claessens Frank , Townsend Paul A. , Gago-Dominguez Manuela , Roobol Monique J. , Menegaux Florence , Khaw Kay-Tee , Cannon-Albright Lisa , Pandha Hardev , Thibodeau Stephen N. , Hunter David J. , Kraft Peter , Kote-Jarai Zsofia , Eeles Rosalind , Freedman Matthew , Haiman Christopher , Pasaniuc Bogdan
Published: January 2019

The original version of this Article contained an error in the spelling of a member of the PRACTICAL Consortium, Manuela Gago-Dominguez, which was incorrectly given as Manuela Gago Dominguez. This has now been corrected in both the PDF and HTML versions of the Article. Furthermore, In the original HTML version of this Article, the order of authors within the author list was incorrect. The consortium PRACTICAL consortium was incorrectly listed after Bogdan Pasaniuc and should have been listed after Kathryn L. Penney. This error has been corrected in the HTML version of the Article; the PDF version was correct at the time of publication.
Mature IgDlow/- B cells maintain tolerance by promoting regulatory T cell homeostasis
Authors: Ray Avijit , Khalil Mohamed I. , Pulakanti Kirthi L. , Burns Robert T. , Gurski Cody J. , Basu Sreemanti , Wang Demin , Rao Sridhar , Dittel Bonnie N.
Published: January 2019

A number of different B cell subsets have been shown to exhibit regulatory activity using a variety of mechanisms to attenuate inflammatory diseases. Here we show, using anti-CD20-mediated partial B cell depletion in mice, that a population of mature B cells distinguishable by IgDlow/-expression maintains tolerance by, at least in part, promoting CD4+Foxp3+regulatory T cell homeostatic expansion via glucocorticoid-induced tumor necrosis factor receptor ligand, or GITRL. Cell surface phenotyping, transcriptome analysis and developmental study data show that B cells expressing IgD at a low level (BDL) are a novel population of mature B cells that emerge in the spleen from the transitional-2 stage paralleling the differentiation of follicular B cells. The cell surface phenotype and regulatory function of BDLare highly suggestive that they are a new B cell subset. Human splenic and peripheral blood IgDlow/-B cells also exhibit BDLregulatory activity, rendering them of therapeutic interest.
CD73 expression on effector T cells sustained by TGF-β facilitates tumor resistance to anti-4-1BB/CD137 therapy
Authors: Chen Siqi , Fan Jie , Zhang Minghui , Qin Lei , Dominguez Donye , Long Alan , Wang Gaoxiang , Ma Renqiang , Li Huabin , Zhang Yi , Fang Deyu , Sosman Jeffrey , Zhang Bin
Published: January 2019

Agonist antibodies (Ab) directed against costimulatory molecules on the surface of antigen-primed T cells are in various stages of pre-clinical and clinical trials, albeit with limited therapeutic benefit as single agents. The underlying mechanisms of action remain incompletely understood. Here, we demonstrate an inhibitory role of ecto-enzyme CD73 for agonistic anti-4-1BB/CD137 Ab therapy. In particular, anti-4-1BB treatment preferentially drives CD73−effector T cell response for tumor inhibition. Anti-CD73 neutralizing Ab further improves anti-4-1BB therapy associated with enhanced anti-tumor T cell immunity. However, the TGF-β-rich tumor milieu confers resistance to anti-4-1BB therapy by sustaining CD73 expression primarily on infiltrating CD8+T cells across several tumor models. TGF-β blockade results in downregulation of CD73 expression on infiltrating T cells and sensitizes resistant tumors to agonistic anti-4-1BB therapy. Thus, our findings identify a mechanism of action for more effective clinical targeting of 4-1BB or likely other costimulatory molecules.
Strigolactone perception and deactivation by a hydrolase receptor DWARF14
Authors: Seto Yoshiya , Yasui Rei , Kameoka Hiromu , Tamiru Muluneh , Cao Mengmeng , Terauchi Ryohei , Sakurada Akane , Hirano Rena , Kisugi Takaya , Hanada Atsushi , Umehara Mikihisa , Seo Eunjoo , Akiyama Kohki , Burke Jason , Takeda-Kamiya Noriko , Li Weiqiang , Hirano Yoshinori , Hakoshima Toshio , Mashiguchi Kiyoshi , Noel Joseph P. , Kyozuka Junko , Yamaguchi Shinjiro
Published: January 2019

The perception mechanism for the strigolactone (SL) class of plant hormones has been a subject of debate because their receptor, DWARF14 (D14), is an α/β-hydrolase that can cleave SLs. Here we show via time-course analyses of SL binding and hydrolysis by Arabidopsis thaliana D14, that the level of uncleaved SL strongly correlates with the induction of the active signaling state. In addition, we show that an AtD14D218A catalytic mutant that lacks enzymatic activity is still able to complement the atd14 mutant phenotype in an SL-dependent manner. We conclude that the intact SL molecules trigger the D14 active signaling state, and we also describe that D14 deactivates bioactive SLs by the hydrolytic degradation after signal transmission. Together, these results reveal that D14 is a dual-functional receptor, responsible for both the perception and deactivation of bioactive SLs.
Intergenerational inheritance of high fat diet-induced cardiac lipotoxicity in Drosophila
Authors: Guida Maria Clara , Birse Ryan Tyge , Dall’Agnese Alessandra , Toto Paula Coutinho , Diop Soda Balla , Mai Antonello , Adams Peter D. , Puri Pier Lorenzo , Bodmer Rolf
Published: January 2019

Obesity is strongly correlated with lipotoxic cardiomyopathy, heart failure and thus mortality. The incidence of obesity has reached alarming proportions worldwide, and increasing evidence suggests that the parents’ nutritional status may predispose their offspring to lipotoxic cardiomyopathy. However, to date, mechanisms underlying intergenerational heart disease risks have yet to be elucidated. Here we report that cardiac dysfunction induced by high-fat-diet (HFD) persists for two subsequent generations in Drosophila and is associated with reduced expression of two key metabolic regulators, adipose triglyceride lipase (ATGL/bmm) and transcriptional cofactor PGC-1. We provide evidence that targeted expression of ATGL/bmm in the offspring of HFD-fed parents protects them, and the subsequent generation, from cardio-lipotoxicity. Furthermore, we find that intergenerational inheritance of lipotoxic cardiomyopathy correlates with elevated systemic H3K27 trimethylation. Lowering H3K27 trimethylation genetically or pharmacologically in the offspring of HFD-fed parents prevents cardiac pathology. This suggests that metabolic homeostasis is epigenetically regulated across generations.
Pharmacologic ATF6 activation confers global protection in widespread disease models by reprograming cellular proteostasis
Authors: Blackwood Erik A. , Azizi Khalid , Thuerauf Donna J. , Paxman Ryan J. , Plate Lars , Kelly Jeffery W. , Wiseman R. Luke , Glembotski Christopher C.
Published: January 2019

Pharmacologic activation of stress-responsive signaling pathways provides a promising approach for ameliorating imbalances in proteostasis associated with diverse diseases. However, this approach has not been employed in vivo. Here we show, using a mouse model of myocardial ischemia/reperfusion, that selective pharmacologic activation of the ATF6 arm of the unfolded protein response (UPR) during reperfusion, a typical clinical intervention point after myocardial infarction, transcriptionally reprograms proteostasis, ameliorates damage and preserves heart function. These effects were lost upon cardiac myocyte-specific Atf6 deletion in the heart, demonstrating the critical role played by ATF6 in mediating pharmacologically activated proteostasis-based protection of the heart. Pharmacological activation of ATF6 is also protective in renal and cerebral ischemia/reperfusion models, demonstrating its widespread utility. Thus, pharmacologic activation of ATF6 represents a proteostasis-based therapeutic strategy for ameliorating ischemia/reperfusion damage, underscoring its unique translational potential for treating a wide range of pathologies caused by imbalanced proteostasis.
Virucidal nano-perforator of viral membrane trapping viral RNAs in the endosome
Authors: Kong Byoungjae , Moon Seokoh , Kim Yuna , Heo Paul , Jung Younghun , Yu Seok-Hyeon , Chung Jinhyo , Ban Choongjin , Kim Yong Ho , Kim Paul , Hwang Beom Jeung , Chung Woo-Jae , Shin Yeon-Kyun , Seong Baik Lin , Kweon Dae-Hyuk
Published: January 2019

Membrane-disrupting agents that selectively target virus versus host membranes could potentially inhibit a broad-spectrum of enveloped viruses, but currently such antivirals are lacking. Here, we develop a nanodisc incorporated with a decoy virus receptor that inhibits virus infection. Mechanistically, nanodiscs carrying the viral receptor sialic acid bind to influenza virions and are co-endocytosed into host cells. At low pH in the endosome, the nanodiscs rupture the viral envelope, trapping viral RNAs inside the endolysosome for enzymatic decomposition. In contrast, liposomes containing a decoy receptor show weak antiviral activity due to the lack of membrane disruption. The nanodiscs inhibit influenza virus infection and reduce morbidity and mortality in a mouse model. Our results suggest a new class of antivirals applicable to other enveloped viruses that cause irreversible physical damage specifically to virus envelope by viruses’ own fusion machine. In conclusion, the lipid nanostructure provides another dimension for antiviral activity of decoy molecules.
The conservation value of human-modified landscapes for the world’s primates
Authors: Galán-Acedo Carmen , Arroyo-Rodríguez Víctor , Andresen Ellen , Verde Arregoitia Luis , Vega Ernesto , Peres Carlos A. , Ewers Robert M.
Published: January 2019

Land-use change pushes biodiversity into human-modified landscapes, where native ecosystems are surrounded by anthropic land covers (ALCs). Yet, the ability of species to use these emerging covers remains poorly understood. We quantified the use of ALCs by primates worldwide, and analyzed species’ attributes that predict such use. Most species use secondary forests and tree plantations, while only few use human settlements. ALCs are used for foraging by at least 86 species with an important conservation outcome: those that tolerate heavily modified ALCs are 26% more likely to have stable or increasing populations than the global average for all primates. There is no phylogenetic signal in ALCs use. Compared to all primates on Earth, species using ALCs are less often threatened with extinction, but more often diurnal, medium or large-bodied, not strictly arboreal, and habitat generalists. These findings provide valuable quantitative information for improving management practices for primate conservation worldwide.
Chromium-ruthenium oxide solid solution electrocatalyst for highly efficient oxygen evolution reaction in acidic media
Authors: Lin Yichao , Tian Ziqi , Zhang Linjuan , Ma Jingyuan , Jiang Zheng , Deibert Benjamin J. , Ge Ruixiang , Chen Liang
Published: January 2019

The development of active, acid-stable and low-cost electrocatalysts for oxygen evolution reaction is urgent and challenging. Herein we report an Iridium-free and low ruthenium-content oxide material (Cr0.6Ru0.4O2) derived from metal-organic framework with remarkable oxygen evolution reaction performance in acidic condition. It shows a record low overpotential of 178 mV at 10 mA cm−2 and maintains the excellent performance throughout the 10 h chronopotentiometry test at a constant current of 10 mA cm−2 in 0.5 M H2SO4 solution. Density functional theory calculations further revealed the intrinsic mechanism for the exceptional oxygen evolution reaction performance, highlighting the influence of chromium promoter on the enhancement in both activity and stability.
Partial proteasomal degradation of Lola triggers the male-to-female switch of a dimorphic courtship circuit
Authors: Sato Kosei , Ito Hiroki , Yokoyama Atsushi , Toba Gakuta , Yamamoto Daisuke
Published: January 2019

InDrosophila, some neurons develop sex-specific neurites that contribute to dimorphic circuits for sex-specific behavior. As opposed to the idea that the sexual dichotomy in transcriptional profiles produced by a sex-specific factor underlies such sex differences, we discovered that the sex-specific cleavage confers the activity as a sexual-fate inducer on the pleiotropic transcription factor Longitudinals lacking (Lola). Surprisingly, Fruitless, another transcription factor with a master regulator role for courtship circuitry formation, directly binds to Lola to protect its cleavage in males. We also show that Lola cleavage involves E3 ubiquitin ligase Cullin1 and 26S proteasome. Our work adds a new dimension to the study of sex-specific behavior and its circuit basis by unveiling a mechanistic link between proteolysis and the sexually dimorphic patterning of circuits. Our findings may also provide new insights into potential causes of the sex-biased incidence of some neuropsychiatric diseases and inspire novel therapeutic approaches to such disorders.
Anti-CRISPR-mediated control of gene editing and synthetic circuits in eukaryotic cells
Authors: Nakamura Muneaki , Srinivasan Prashanth , Chavez Michael , Carter Matthew A. , Dominguez Antonia A. , La Russa Marie , Lau Matthew B. , Abbott Timothy R. , Xu Xiaoshu , Zhao Dehua , Gao Yuchen , Kipniss Nathan H. , Smolke Christina D. , Bondy-Denomy Joseph , Qi Lei S.
Published: January 2019

Repurposed CRISPR-Cas molecules provide a useful tool set for broad applications of genomic editing and regulation of gene expression in prokaryotes and eukaryotes. Recent discovery of phage-derived proteins, anti-CRISPRs, which serve to abrogate natural CRISPR anti-phage activity, potentially expands the ability to build synthetic CRISPR-mediated circuits. Here, we characterize a panel of anti-CRISPR molecules for expanded applications to counteract CRISPR-mediated gene activation and repression of reporter and endogenous genes in various cell types. We demonstrate that cells pre-engineered with anti-CRISPR molecules become resistant to gene editing, thus providing a means to generate “write-protected” cells that prevent future gene editing. We further show that anti-CRISPRs can be used to control CRISPR-based gene regulation circuits, including implementation of a pulse generator circuit in mammalian cells. Our work suggests that anti-CRISPR proteins should serve as widely applicable tools for synthetic systems regulating the behavior of eukaryotic cells.
A macrophage-based screen identifies antibacterial compounds selective for intracellular Salmonella Typhimurium
Authors: Ellis Michael J. , Tsai Caressa N. , Johnson Jarrod W. , French Shawn , Elhenawy Wael , Porwollik Steffen , Andrews-Polymenis Helene , McClelland Michael , Magolan Jakob , Coombes Brian K. , Brown Eric D.
Published: January 2019

Salmonella Typhimurium (S. Tm) establishes systemic infection in susceptible hosts by evading the innate immune response and replicating within host phagocytes. Here, we sought to identify inhibitors of intracellular S. Tm replication by conducting parallel chemical screens against S. Tm growing in macrophage-mimicking media and within macrophages. We identify several compounds that inhibit Salmonella growth in the intracellular environment and in acidic, ion-limited media. We report on the antimicrobial activity of the psychoactive drug metergoline, which is specific against intracellular S. Tm. Screening an S. Tm deletion library in the presence of metergoline reveals hypersensitization of outer membrane mutants to metergoline activity. Metergoline disrupts the proton motive force at the bacterial cytoplasmic membrane and extends animal survival during a systemic S. Tm infection. This work highlights the predictive nature of intracellular screens for in vivo efficacy, and identifies metergoline as a novel antimicrobial active against Salmonella.
Insulin inhibits glucagon release by SGLT2-induced stimulation of somatostatin secretion
Authors: Vergari Elisa , Knudsen Jakob G. , Ramracheya Reshma , Salehi Albert , Zhang Quan , Adam Julie , Asterholm Ingrid Wernstedt , Benrick Anna , Briant Linford J. B. , Chibalina Margarita V. , Gribble Fiona M. , Hamilton Alexander , Hastoy Benoit , Reimann Frank , Rorsman Nils J. G. , Spiliotis Ioannis I. , Tarasov Andrei , Wu Yanling , Ashcroft Frances M. , Rorsman Patrik
Published: January 2019

Hypoglycaemia (low plasma glucose) is a serious and potentially fatal complication of insulin-treated diabetes. In healthy individuals, hypoglycaemia triggers glucagon secretion, which restores normal plasma glucose levels by stimulation of hepatic glucose production. This counterregulatory mechanism is impaired in diabetes. Here we show in mice that therapeutic concentrations of insulin inhibit glucagon secretion by an indirect (paracrine) mechanism mediated by stimulation of intra-islet somatostatin release. Insulin’s capacity to inhibit glucagon secretion is lost following genetic ablation of insulin receptors in the somatostatin-secreting δ-cells, when insulin-induced somatostatin secretion is suppressed by dapagliflozin (an inhibitor of sodium-glucose co-tranporter-2; SGLT2) or when the action of secreted somatostatin is prevented by somatostatin receptor (SSTR) antagonists. Administration of these compounds in vivo antagonises insulin’s hypoglycaemic effect. We extend these data to isolated human islets. We propose that SSTR or SGLT2 antagonists should be considered as adjuncts to insulin in diabetes therapy.
Controlling the fluorescence and room-temperature phosphorescence behaviour of carbon nanodots with inorganic crystalline nanocomposites
Authors: Green David C. , Holden Mark A. , Levenstein Mark A. , Zhang Shuheng , Johnson Benjamin R. G. , Gala de Pablo Julia , Ward Andrew , Botchway Stanley W. , Meldrum Fiona C.
Published: January 2019

There is a significant drive to identify alternative materials that exhibit room temperature phosphorescence for technologies including bio-imaging, photodynamic therapy and organic light-emitting diodes. Ideally, these materials should be non-toxic and cheap, and it will be possible to control their photoluminescent properties. This was achieved here by embedding carbon nanodots within crystalline particles of alkaline earth carbonates, sulphates and oxalates. The resultant nanocomposites are luminescent and exhibit a bright, sub-second lifetime afterglow. Importantly, the excited state lifetimes, and steady-state and afterglow colours can all be systematically controlled by varying the cations and anions in the host inorganic phase, due to the influence of the cation size and material density on emissive and non-emissive electronic transitions. This simple strategy provides a flexible route for generating materials with specific, phosphorescent properties and is an exciting alternative to approaches relying on the synthesis of custom-made luminescent organic molecules.
A new carbon phase with direct bandgap and high carrier mobility as electron transport material for perovskite solar cells
Authors: Sun Ping-Ping , Bai Lichun , Kripalani Devesh R. , Zhou Kun
Published: January 2019

Rapid development of perovskite solar cells is challenged by the fact that current semiconductors hardly act as efficient electron transport materials that can feature both high electron mobility and a well-matched energy level to that of the perovskite. Here we show that T-carbon, a newly emerging carbon allotrope, could be an ideal candidate to meet this challenge. By using first-principles calculations and deformation potential theory, it is found that T-carbon is a semiconductor with a direct bandgap of 2.273 eV, and the energy level in the conduction band is lower than that of perovskite by 0.5 eV, showing a larger force of electron injection. Moreover, the calculated electron mobility can reach up to 2.36 × 103 cm2 s–1 V–1, superior to conventional electron transport materials such as TiO2, ZnO and SnO2, which will facilitate more efficient electron separation and more rapid diffusion away from their locus of generation within the perovskite absorbers. Furthermore, the bandgap of T-carbon is highly sensitive to strain, thus providing a convenient method to tune the carrier transport capability. Overall, T-carbon satisfies the requirements for a potential efficient electron transport material and could therefore be capable of accelerating the development of perovskite solar cells.