bluuebunny/crossref_metadata_2025_split huggingface dataset:
FMO rewires metabolism to promote longevity through tryptophan and one carbon metabolism
Authors: Choi Hyo Sub , Bhat Ajay , Howington Marshall B. , Schaller Megan L. , Cox Rebecca , Huang Shijiao , Beydoun Safa , Miller Hillary A. , Tuckowski Angela M. , Mecano Joy , Dean Elizabeth S. , Jensen Lindy , Beard Daniel A. , Evans Charles R. , Leiser Scott F. 
Published: June 2021

AbstractFlavin containing monooxygenases (FMOs) are promiscuous enzymes known for metabolizing a wide range of exogenous compounds. In C. elegans, fmo-2 expression increases lifespan and healthspan downstream of multiple longevity-promoting pathways through an unknown mechanism. Here, we report that, contrary to its classification as a xenobiotic enzyme, fmo-2 expression leads to rewiring of endogenous metabolism principally through changes in one carbon metabolism (OCM). Using computer modeling, we identify decreased methylation as the major OCM flux modified by FMO-2 that is sufficient to recapitulate its longevity benefits. We further find that tryptophan is decreased in multiple mammalian FMO overexpression models and is a validated substrate for FMO enzymes. Our resulting model connects a single enzyme to two previously unconnected key metabolic pathways and provides a framework for the metabolic interconnectivity of longevity-promoting pathways such as dietary restriction. FMOs are well-conserved enzymes that are also induced by lifespan-extending interventions in mice, supporting a conserved and critical role in promoting health and longevity through metabolic remodeling.
Tumor PD-L1 selectively suppresses type I interferon in myeloid cells to suppress CTL recruitment to promote lung metastasis
Authors: Klement John D. , Redd Priscilla S. , Lu Chunwan , Merting Alyssa D. , Poschel Dakota B. , Yang Dafeng , Zhou Gang , Munn David H. , Liu Kebin 
Published: June 2021

AbstractThe mechanism underlying tumor cell PD-L1 (tPD-L1) induction of immune suppression through T cell PD-1 is well-known, but the mechanism underlying tPD-L1 induction of immune suppression via an intermediate cell is incompletely understood. We report here that tPD-L1 does not suppress cytotoxic T lymphocyte (CTL) activation and lytic function when only tumor cells and CTLs are present. Strikingly, knocking out PD-L1 in tumor cells has no effect on primary tumor growth, but significantly decreases lung metastasis in a CTL-dependent manner. Depletion of myeloid cells impaired tPD-L1 promotion of lung metastasis. Single-cell RNA sequencing revealed that tPD-L1 engages myeloid PD-1 (mPD-1) to antagonize type I interferon (IFN-I) and STAT1 signaling to repressCxcl9andCxcl10expression to impair CTL recruitment to lung metastases. Human patient response to PD-1 blockade immunotherapy correlates with IFN-I response in myeloid cells. Our data determines that the tPD-L1/mPD-1/IFN-I/STAT1/Cxcl9/10 axis controls CTL tumor infiltration in lung metastasis.
Lamellipodia-like actin networks in cells lacking WAVE Regulatory Complex
Authors: Kage Frieda , Döring Hermann , Mietkowska Magdalena , Schaks Matthias , Grüner Franziska , Stahnke Stephanie , Steffen Anika , Müsken Mathias , Stradal Theresia E. B. , Rottner Klemens 
Published: June 2021

SummaryCell migration frequently involves the formation of lamellipodia induced by Rac GTPases mediating activation of WAVE Regulatory Complex (WRC) driving Arp2/3 complex-dependent actin assembly. Previous genome editing studies solidified the view of an essential, linear pathway employing aforementioned components. Using disruption of the WRC subunit Nap1 and its paralogue Hem1 followed by serum and growth factor stimulation or expression of active GTPases now revealed a pathway to formation of Arp2/3 complex-dependent, lamellipodia-like structures (LLS) that require both Rac and Cdc42, but not WRC. These observations were independent of WRC subunit eliminated and coincided with the lack of recruitment of Ena/VASP family actin polymerases. Moreover, aside from the latter, induced LLS contained all common lamellipodial regulators tested, including cortactin, the Ena/VASP ligand lamellipodin or FMNL subfamily formins. Our studies thus establish the existence of a signaling axis to Arp2/3 complex-dependent actin remodeling at the cell periphery operating without WRC and Ena/VASP.
Telomere transcription in MLL-rearranged acute leukemia: increased levels of TERRA associate with lymphoid lineage and are independent of telomere length and ploidy
Authors: Caslini Corrado , Serna Amparo 
Published: June 2021

AbstractTelomere transcription into telomeric repeat-containing RNA (TERRA) is an integral component of all aspects of chromosome end protection consisting of telomerase- or recombination-dependent telomere elongation, telomere capping, and preservation of (sub)telomeric heterochromatin structure. The chromatin modifier and transcriptional regulator MLL associates with telomeres and regulates TERRA transcription in telomere length homeostasis and response to telomere dysfunction. MLL fusion proteins (MLL-FPs), the product of MLL rearrangements in leukemia, are also associated with telomeric chromatin. However, an effect on telomere transcription in MLL-rearranged (MLL-r) leukemia has not yet been evaluated. Here, we show increased UUAGGG repeat-containing RNA levels in MLL-r acute lymphoblastic leukemia (ALL) when compared to myeloid and non-MLL-r ALL leukemia. MLL rearrangements do not affect telomere length and increased levels of UUAGGG repeatcontaining RNA correlate with mean telomere length and reflect increased levels of TERRA. Also, increased TERRA levels in MLL-r ALL occur in the presence of telomerase activity and are independent of ploidy, an underestimated source of variation on the overall transcriptome size in a cell. This MLL rearrangement-dependent and lymphoid lineage-associated increase in levels of TERRA supports a sustained telomere transcription by MLL-FPs that correlates with marked genomic stability previously reported in pediatric MLL-r ALL.
Stem cell-free therapy for glaucoma to preserve vision
Authors: Kumar Ajay , Siqi Xiong , Zhou Minwen , Chen Wen , Yang Enzhi , Price Andrew , Le Liang , Zhang Ying , Florens Laurence , Washburn Michael , Kumar Akshay , Li Yunshu , Xu Yi , Lathrop Kira , Davoli Katherine , Chen Yuanyuan , Schuman Joel S. , Xie Ting , Du Yiqin 
Published: June 2021

AbstractGlaucoma is the leading cause of irreversible blindness with trabecular meshwork (TM) dysfunction resulting in elevated intraocular pressure and retinal ganglion cell (RGC) damage leading to vision loss. In this study, we discovered that secretome, derived from human TM stem cells, via minimal invasive periocular injection, can reduce intraocular pressure, restore TM homeostasis, protect RGC, and restore RGC function in both steroid-induced and genetic myocilin mutant mouse models of glaucoma. The secretome upregulated the COX2-PGE2 axis via mitochondrial TMEM177 and led to activation of endogenous stem cells and TM regeneration. Inhibition of COX2 abolished the protective effect of secretome on TM cells. Secretome treatment also enhanced RGC survival and function. Proteomic analysis revealed that the secretome is enriched with proteins involved in extracellular matrix modulation leading to the remodeling of TM to restore homeostasis. This study highlights the feasibility of stem cell-free therapy for glaucoma with minimal invasive administration and the involvement of multiple novel pathways for a cumulative regenerative effect on the TM to protect RGC.Brief summaryThis study describes a cell-free treatment using stem cell secretome in two animal models of glaucoma and explores the potential mechanisms
Cryo-EM reveals new species-specific proteins and symmetry elements in the Legionella pneumophila Dot/Icm T4SS
Authors: Sheedlo Michael J. , Durie Clarissa L. , Chung Jeong Min , Chang Louise , Swanson Michele , Borden Lacy D. , Ohi Melanie D. 
Published: June 2021

AbstractLegionella pneumophila is an opportunistic pathogen that causes the potentially fatal pneumonia known as Legionnaires’ Disease. The pathology associated with infection depends on bacterial delivery of effector proteins into the host via the membrane spanning Dot/Icm type IV secretion system (T4SS). We have determined sub-3.0 Å resolution maps of the Dot/Icm T4SS core complex by single particle cryo-EM. The high-resolution structural analysis has allowed us to identify proteins encoded outside the Dot/Icm genetic locus that contribute to the core T4SS structure. We can also now define two distinct areas of symmetry mismatch, one that connects the C18 periplasmic ring (PR) and the C13 outer membrane cap (OMC) and one that connects the C13 OMC with a 16-fold symmetric dome. Unexpectedly the connection between the PR and OMC is DotH, with five copies sandwiched between the OMC and PR to accommodate the symmetry mismatch. Finally, we observe multiple conformations in the reconstructions that indicate flexibility within the structure. We hypothesize this conformational flexibility is likely to facilitate the Dot/Icm T4SS’s ability to translocate a remarkably large set of ∼300 putative substrates across the inner and outer membranes of the bacterial cell.
The structural basis for regulation of the glutathione transporter Ycf1 by regulatory domain phosphorylation
Authors: Khandelwal Nitesh Kumar , Millan Cinthia R. , Zangari Samantha I. , Avila Samantha , Williams Dewight , Thaker Tarjani M. , Tomasiak Thomas M. 
Published: June 2021

AbstractYeast Cadmium Factor-1 (Ycf1) sequesters heavy metals and glutathione into the vacuole to counter cell stress. Ycf1 belongs to the ATP binding cassette C-subfamily (ABCC) of transporters, many of which are regulated by phosphorylation on intrinsically disordered domains. The regulatory mechanism of phosphorylation is still poorly understood. Here, we report two cryo-EM structures of Ycf1 at 3.4Å and 4.0Å in distinct inward-facing open conformations capturing a previously unobserved ordered state of the intrinsically disordered regulatory domain (R-domain). R-domain phosphorylation is clearly evident and induces a topology promoting electrostatic and hydrophobic interactions with Nucleotide Binding Domain 1 (NBD1) and the lasso domain. These interactions stay constant between the structures and are related by rigid body movements of the NBD1/R-domain complex. Biochemical data further show R-domain phosphorylation reorganizes the Ycf1 architecture and is required for maximal ATPase activity. Together, we provide long-sought after insights into how R-domains control ABCC transporter activity.
Diversity of response and effect traits provides complementary information about avian community dynamics linked to ecological function
Authors: Hordley Lisbeth A. , Gillings Simon , Petchey Owen L. , Tobias Joseph A. , Oliver Thomas H. 
Published: June 2021

AbstractFunctional diversity metrics based on species traits are widely used to investigate ecosystem functioning. In theory, such metrics have different implications depending on whether they are calculated from traits mediating responses to environmental change (response traits) or those regulating function (effect traits), yet trait choice in diversity metrics is rarely scrutinized.Here, we compile effect and response traits for British bird species supplying two key ecological services—seed dispersal and insect predation—to assess the relationship between functional diversity and both mean and stability of community abundance over time.As predicted, functional diversity correlates with stability in community abundance of seed dispersers when calculated using response traits. However, we found a negative relationship between functional diversity and mean community abundance of seed dispersers when calculated using effect traits. Subsequently, when combining all traits together, we found inconsistent results with functional diversity correlating with reduced stability in insectivores, but greater stability in seed dispersers.Our findings suggest that trait choice should be considered more carefully when applying such metrics in ecosystem management.A freePlain Language Summarycan be found within the Supporting Information of this article.
Fear effects and group size interact to shape herbivory on coral reefs
Authors: Bauman Andrew G. , Hoey Andrew S. , Dunshea Glenn , Fong Jenny , Chan Ian Z. W. , Todd Peter A. 
Published: June 2021

AbstractFear of predators (‘fear effects’) is an important determinant of foraging decisions by consumers across a range of ecosystems. Group size is one of the main behavioural mechanisms for mitigating fear effects while also providing foraging benefits to group members. Within coral reef ecosystems, fear effects have been shown to influence the feeding rates of herbivorous fishes, a key functional group that prevents macroalgal overgrowth. Yet, how fear effects and group size interact to shape macroalgal removal on coral reefs remains unclear.Here, we conducted field‐based experiments using models of a common piscivorous fish, the leopard coral grouperPlectropomus leopardusand a series of macroalgalSargassum ilicifoliumassays positioned at increasing distances from the models (1, 2, 3 and 4 m) on two coral reefs in Singapore to investigate how acute fear effects shape the intensity of herbivory, and whether these effects were influenced by variation in the group size of herbivorous fishes feeding on the assays.We found acute fear effects strongly influenced the foraging behaviour of herbivorous fishes over small spatial scales. Rates ofSargassumbiomass removal, feeding rates and the total number of individual feeding events were all lower near the predator model. These effects dissipated rapidly with increasing distance from the predator model and were undetectable at a distance of 4 m. We also found generally larger group sizes of herbivorous fishes further from the predator model, presumably reflecting decreased risk. Furthermore, the number of individual bites/event increased significantly with increasing group size for two common browsing fishes,Siganus virgatusandSiganus javus.Our findings highlight that acute fear effects influence the distribution and intensity of herbivory over small spatial scales. Fear effects also interacted with herbivore group size resulting in changes in the number of individual feeding events and bite rates that collectively shape the realized ecosystem function of macroalgal removal on coral reefs. Group size is an important context‐dependent factor that should be considered when examining fear effects on coral reefs.A freePlain Language Summarycan be found within the Supporting Information of this article.
Water availability influences thermal safety margins for leaves
Authors: Cook Alicia M. , Berry Neil , Milner Kirsty V. , Leigh Andrea 
Published: June 2021

Abstract

One application of plant physiological heat tolerance measurements is the assessment of vulnerability to increasing environmental temperatures under climatic change. A thermal safety margin (TSM), the difference between physiological tolerance and environmental temperature, is a common metric for the assessment of plant thermal vulnerability. However, there are biological and methodological aspects to consider when evaluating thermal vulnerability that have the potential to substantially alter the assessments. Two such aspects include the leaf to air temperature relationship and the scale at which air temperature data are collected.

We grew plants of a desert species, Myoporum montanum, in situ under water‐stressed and well‐watered conditions, and measured their leaf temperatures and photosynthetic heat tolerance (T50 threshold) every third day over 12 days in summer. Thermal safety margins were calculated based on leaf temperatures and compared to those calculated with local and regional air temperatures.

We found that heat tolerance and the thermal vulnerability assessment of a plant changed with water status. When water was readily available, plants maintained wide leaf temperature safety margins and displayed partial homeothermy. When cooling via transpiration was limited, increasing leaf temperature corresponded with occurrences of leaf poikilo‐ and megathermy, higher heat tolerance and narrower safety margins.

Our study shows high physiological heat thresholds are not necessarily reflective of wide safety margins, but instead can indicate a greater vulnerability and increased risk of heat stress exposure. Calculating TSMs using air temperatures can also substantially alter margin widths. Where possible, the use of leaf temperatures in assessments of thermal vulnerability will lead to more meaningful vulnerability assessments. We recommend considering the source and temporal pairing of temperature measurements as well as plant water status, when measuring and interpreting plant TSMs.

A free Plain Language Summary can be found within the Supporting Information of this article.
Effects of climate‐change‐driven gradual and acute temperature changes on shark and ray species
Authors: Osgood Geoffrey J. , White Easton R. , Baum Julia K. 
Published: June 2021

Abstract

Climate change is altering distributions and abundances of marine species through both gradual and acute changes in temperature and productivity. Due to their high mobility and metabolic rates, elasmobranchs (sharks and rays) are likely to redistribute across latitudes and depths as they thermoregulate, but little is known about their responses to these climatic changes, which could vary widely across this diverse group of species.

Here, we assessed how species with differing mobility and ecology responded to gradual changes in daily sea surface temperature (SST) and acute temperature anomalies, caused by the El Niño–Southern Oscillation (ENSO), at Cocos Island, Costa Rica, the site of multiple marine heatwaves.

We used generalized linear mixed models to analyse 34,342 records of relative abundance or frequency of occurrence for seven shark and ray species collected in 27 years (1993–2019) by a dive company. We compared effect sizes for SST and the Oceanic Niño Index across the different species, which vary widely in body size and mobility.

Large, mobile species responded strongly but inconsistently to temperature. For scalloped hammerhead sharks Sphyrna lewini, a 1℃ rise in SST reduced counts by over 14%, and dropped the occurrence of their large schools by almost one‐fifth (19.4%). Mobula ray occurrence also declined substantially with a few degrees rise in SST, whereas tiger shark Galeocerdo cuvier occurrence sharply increased. These species also had divergent responses to the ENSO: S. lewini and G. cuvier were sighted with greater frequency during La Niña events, and their abundance dropped considerably during El Niño events—over a twofold decline between a strong La Niña and strong El Niño for S. lewini. In contrast, Mobula rays showed little response to ENSO. The smaller and sedentary Triaenodon obesus exhibited the weakest response of all species to both SST and the ENSO, reflecting its lower metabolic rates and mobility.

Climate change will continue to impact elasmobranchs, even for smaller and more localized species, with the potential to impact the effectiveness of marine protected areas (MPAs). Our results compel further work on the diversity of elasmobranch responses to environmental change.
‘Black African’ identification and the COVID‐19 pandemic in Britain: A site for sociological, ethical and policy debate
Authors: Aspinall Peter J. 
Published: June 2021

AbstractThis paper is a narrative review of the use of collective terminology in relation to race and health in Britain, with particular reference to the ‘Black African’ community. ‘Black Africans’ have been categorised in the 1991–2011 censuses with added free‐text in 2021 in response to user demand. However, the UK government is increasingly reporting data for the ‘Black’ pan‐ethnicity, especially in the even more generalised ‘BAME’ (‘Black, Asian and Minority Ethnic’) acronym in COVID‐19 pandemic reports. The consequences of this practice are addressed. Firstly, with respect to ethical challenges, Black Africans find their conscription by government into the term BAME offensive and do not accept it as a self‐descriptor. This labelling, which subsumes Black Africans’ self‐assigned ethnicity in the census, and consequent misrecognition may be interpreted as a micro‐aggression (a term coined in the 1970s but used here to denote microinvalidation), as suggested in the current black activism of the ‘Black Lives Matter movement’. Secondly, ONS has warned that concealed heterogeneity renders the pan‐ethnicities unreliably crude, making them scientifically inaccurate. Analysts are recommended to present ethnic group data for the full census classification where possible for reasons of validity and respect for the patient as arbiter of their ethnic group.
Protective effects of ginsenoside Rc against acute cold exposure‐induced myocardial injury in rats
Authors: Xue Yan , Yu Xiaofeng , Zhang Xiuhang , Yu Ping , Li Yuangeng , Fu Wenwen , Yu Jiaao , Sui Dayun 
Published: June 2021

AbstractGinsenoside Rc is one of the cardinal bioactive components of Panax ginseng. The present study aimed to investigate whether ginsenoside Rc exerted protective effects against acute cold exposure‐induced myocardial injury in rats. Forty rats were randomly assigned into four groups: Control, model, ginsenoside Rc 10 mg/kg, and 20 mg/kg groups. Rats were intragastrically administrated with ginsenoside Rc (10, 20 mg/kg) or vehicle daily for 7 days. On the seventh day, all rats except the control group were exposed to low temperature. Cardiac function, myocardial enzyme activities, hemorheology, and inflammatory response were detected. Histopathological examination and apoptosis of cardiac tissues were performed. The expressions of silent information regulator 1 (SIRT1), B‐cell lymphoma (Bcl‐2), Bcl‐2‐associated X (Bax), procaspase‐3, and the mRNA (messenger RNA) level of SIRT1 were measured by western blot and real‐time quantitative polymerase chain reaction (PCR) analysis. Ginsenoside Rc significantly improved cardiac function, diminished the activities of lactate dehydrogenase (LDH), aspartate aminotransferase, and creatine kinase isoenzyme (CK‐MB), and regulated abnormal hemorheology in acute cold‐exposed rats (p < 0.05 or p < 0.01). Furthermore, ginsenoside Rc could attenuate myocardial histological changes and structural abnormalities, decrease apoptotic cells and reduce the mRNA levels and activity of tumor necrosis factor‐α (TNF‐α), interleukin‐1β (IL‐1β), and IL‐6 (p < 0.01). In addition, ginsenoside Rc upregulated the expressions of SIRT1, Bcl‐2, and procaspase‐3 and downregulated that of Bax (p < 0.01). The changes in both the mRNA and protein expression levels of SIRT1 were similar. The results of the current study suggested that ginsenoside Rc could alleviate acute cold exposure‐induced myocardial injury in rats by inhibiting cardiomyocyte apoptosis via regulating SIRT1 expression and attenuating the inflammatory responses.Practical ApplicationThe current study indicated that ginsenoside Rc could alleviate acute cold exposure‐induced myocardial injury in rats. Ginsenoside Rc could be potentially used as a bioactive ingredient in processed functional food products or food supplements to prevent from acute cold exposure‐induced myocardial injury.