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151.
Jamie A. G. Hamilton Miyoung Y. Lee Rae Hunter Raira S. Ank Jamie Y. Story Ganesh Talekar Talia Sisroe Dov B. Ballak Andrew Fedanov Christopher C. Porter Elan Z. Eisenmesser Charles A. Dinarello Sunil S. Raikar James DeGregori Curtis J. Henry 《Aging cell》2021,20(2)
Aging‐associated declines in innate and adaptive immune responses are well documented and pose a risk for the growing aging population, which is predicted to comprise greater than 40 percent of the world''s population by 2050. Efforts have been made to improve immunity in aged populations; however, safe and effective protocols to accomplish this goal have not been universally established. Aging‐associated chronic inflammation is postulated to compromise immunity in aged mice and humans. Interleukin‐37 (IL‐37) is a potent anti‐inflammatory cytokine, and we present data demonstrating that IL‐37 gene expression levels in human monocytes significantly decline with age. Furthermore, we demonstrate that transgenic expression of interleukin‐37 (IL‐37) in aged mice reduces or prevents aging‐associated chronic inflammation, splenomegaly, and accumulation of myeloid cells (macrophages and dendritic cells) in the bone marrow and spleen. Additionally, we show that IL‐37 expression decreases the surface expression of programmed cell death protein 1 (PD‐1) and augments cytokine production from aged T‐cells. Improved T‐cell function coincided with a youthful restoration of Pdcd1, Lat, and Stat4 gene expression levels in CD4+ T‐cells and Lat in CD8+ T‐cells when aged mice were treated with recombinant IL‐37 (rIL‐37) but not control immunoglobin (Control Ig). Importantly, IL‐37‐mediated rejuvenation of aged endogenous T‐cells was also observed in aged chimeric antigen receptor (CAR) T‐cells, where improved function significantly extended the survival of mice transplanted with leukemia cells. Collectively, these data demonstrate the potency of IL‐37 in boosting the function of aged T‐cells and highlight its therapeutic potential to overcome aging‐associated immunosenescence. 相似文献
152.
Volkow ND Fowler JS Wang GJ Telang F Logan J Wong C Ma J Pradhan K Benveniste H Swanson JM 《PloS one》2008,3(4):e2017
The use of stimulants (methylphenidate and amphetamine) as cognitive enhancers by the general public is increasing and is controversial. It is still unclear how they work or why they improve performance in some individuals but impair it in others. To test the hypothesis that stimulants enhance signal to noise ratio of neuronal activity and thereby reduce cerebral activity by increasing efficiency, we measured the effects of methylphenidate on brain glucose utilization in healthy adults. We measured brain glucose metabolism (using Positron Emission Tomography and 2-deoxy-2[18F]fluoro-D-glucose) in 23 healthy adults who were tested at baseline and while performing an accuracy-controlled cognitive task (numerical calculations) given with and without methylphenidate (20 mg, oral). Sixteen subjects underwent a fourth scan with methylphenidate but without cognitive stimulation. Compared to placebo methylphenidate significantly reduced the amount of glucose utilized by the brain when performing the cognitive task but methylphenidate did not affect brain metabolism when given without cognitive stimulation. Whole brain metabolism when the cognitive task was given with placebo increased 21% whereas with methylphenidate it increased 11% (50% less). This reflected both a decrease in magnitude of activation and in the regions activated by the task. Methylphenidate's reduction of the metabolic increases in regions from the default network (implicated in mind-wandering) was associated with improvement in performance only in subjects who activated these regions when the cognitive task was given with placebo. These results corroborate prior findings that stimulant medications reduced the magnitude of regional activation to a task and in addition document a "focusing" of the activation. This effect may be beneficial when neuronal resources are diverted (i.e., mind-wandering) or impaired (i.e., attention deficit hyperactivity disorder), but it could be detrimental when brain activity is already optimally focused. This would explain why methylphenidate has beneficial effects in some individuals and contexts and detrimental effects in others. 相似文献
153.
Isabelle M. C?té Emily S. Darling Christopher J. Brown 《Proceedings. Biological sciences / The Royal Society》2016,283(1824)
Interactions between multiple ecosystem stressors are expected to jeopardize biological processes, functions and biodiversity. The scientific community has declared stressor interactions—notably synergies—a key issue for conservation and management. Here, we review ecological literature over the past four decades to evaluate trends in the reporting of ecological interactions (synergies, antagonisms and additive effects) and highlight the implications and importance to conservation. Despite increasing popularity, and ever-finer terminologies, we find that synergies are (still) not the most prevalent type of interaction, and that conservation practitioners need to appreciate and manage for all interaction outcomes, including antagonistic and additive effects. However, it will not be possible to identify the effect of every interaction on every organism''s physiology and every ecosystem function because the number of stressors, and their potential interactions, are growing rapidly. Predicting the type of interactions may be possible in the near-future, using meta-analyses, conservation-oriented experiments and adaptive monitoring. Pending a general framework for predicting interactions, conservation management should enact interventions that are robust to uncertainty in interaction type and that continue to bolster biological resilience in a stressful world. 相似文献
154.
155.
Identification, characterization, and localization of a novel kidney polycystin-1-polycystin-2 complex 总被引:9,自引:0,他引:9
Newby LJ Streets AJ Zhao Y Harris PC Ward CJ Ong AC 《The Journal of biological chemistry》2002,277(23):20763-20773
The functions of the two proteins defective in autosomal dominant polycystic kidney disease, polycystin-1 and polycystin-2, have not been fully clarified, but it has been hypothesized that they may heterodimerize to form a "polycystin complex" involved in cell adhesion. In this paper, we demonstrate for the first time the existence of a native polycystin complex in mouse kidney tubular cells transgenic for PKD1, non-transgenic kidney cells, and normal adult human kidney. Polycystin-1 is heavily N-glycosylated, and several glycosylated forms of polycystin-1 differing in their sensitivity to endoglycosidase H (Endo H) were found; in contrast, native polycystin-2 was fully Endo H-sensitive. Using highly specific antibodies to both proteins, we show that polycystin-2 associates selectively with two species of full-length polycystin-1, one Endo H-sensitive and the other Endo H-resistant; importantly, the latter could be further enriched in plasma membrane fractions and co-immunoprecipitated with polycystin-2. Finally, a subpopulation of this complex co-localized to the lateral cell borders of PKD1 transgenic kidney cells. These results demonstrate that polycystin-1 and polycystin-2 interact in vivo to form a stable heterodimeric complex and suggest that disruption of this complex is likely to be of primary relevance to the pathogenesis of cyst formation in autosomal dominant polycystic kidney disease. 相似文献
156.
Stephen?R.F. Twigg Deborah Lloyd Dagan Jenkins Nursel?E. El?ioglu Christopher?D.O. Cooper Nouriya Al-Sannaa Ali Annagür Gabriele Gillessen-Kaesbach Irina Hüning Samantha?J.L. Knight Judith?A. Goodship Bernard?D. Keavney Philip?L. Beales Opher Gileadi Simon?J. McGowan Andrew?O.M. Wilkie 《American journal of human genetics》2012,91(5):897-905
Carpenter syndrome is an autosomal-recessive multiple-congenital-malformation disorder characterized by multisuture craniosynostosis and polysyndactyly of the hands and feet; many other clinical features occur, and the most frequent include obesity, umbilical hernia, cryptorchidism, and congenital heart disease. Mutations of RAB23, encoding a small GTPase that regulates vesicular transport, are present in the majority of cases. Here, we describe a disorder caused by mutations in multiple epidermal-growth-factor-like-domains 8 (MEGF8), which exhibits substantial clinical overlap with Carpenter syndrome but is frequently associated with abnormal left-right patterning. We describe five affected individuals with similar dysmorphic facies, and three of them had either complete situs inversus, dextrocardia, or transposition of the great arteries; similar cardiac abnormalities were previously identified in a mouse mutant for the orthologous Megf8. The mutant alleles comprise one nonsense, three missense, and two splice-site mutations; we demonstrate in zebrafish that, in contrast to the wild-type protein, the proteins containing all three missense alterations provide only weak rescue of an early gastrulation phenotype induced by Megf8 knockdown. We conclude that mutations in MEGF8 cause a Carpenter syndrome subtype frequently associated with defective left-right patterning, probably through perturbation of signaling by hedgehog and nodal family members. We did not observe any subject with biallelic loss-of function mutations, suggesting that some residual MEGF8 function might be necessary for survival and might influence the phenotypes observed. 相似文献
157.
Jennifer Greaves Kimon Lemonidis Oforiwa A. Gorleku Carlos Cruchaga Christopher Grefen Luke H. Chamberlain 《The Journal of biological chemistry》2012,287(44):37330-37339
Recently, mutations in the DNAJC5 gene encoding cysteine-string protein α (CSPα) were identified to cause the neurodegenerative disorder adult-onset neuronal ceroid lipofuscinosis. The disease-causing mutations (L115R or ΔL116) occur within the cysteine-string domain, a region of the protein that is post-translationally modified by extensive palmitoylation. Here we demonstrate that L115R and ΔL116 mutant proteins are mistargeted in neuroendocrine cells and form SDS-resistant aggregates, concordant with the properties of other mutant proteins linked to neurodegenerative disorders. The mutant aggregates are membrane-associated and incorporate palmitate. Indeed, co-expression of palmitoyltransferase enzymes promoted the aggregation of the CSPα mutants, and chemical depalmitoylation solubilized the aggregates, demonstrating that aggregation is induced and maintained by palmitoylation. In agreement with these observations, SDS-resistant CSPα aggregates were present in brain samples from patients carrying the L115R mutation and were depleted by chemical depalmitoylation. In summary, this study identifies a novel interplay between genetic mutations and palmitoylation in driving aggregation of CSPα mutant proteins. We propose that this palmitoylation-induced aggregation of mutant CSPα proteins may underlie the development of adult-onset neuronal ceroid lipofuscinosis in affected families. 相似文献
158.
Melinda ChuaKelvin Chan Trevor J. HockingPeter A. Williams Christopher J. PerryTimothy C. Baldwin 《Carbohydrate polymers》2012,87(3):2202-2210
Here we present a comparison of commonly used methodologies for the extraction and quantification of konjac glucomannan (KGM). Compositional analysis showed that the purified konjac flour (PKF) produced using a modified extraction procedure contained 92% glucomannan, with a weight average molecular weight (Mw), polydispersity index (PDI) and degree of acetylation (DA) of 9.5 ± 0.6 × 105 g mol−1, 1.2 and 2.8 wt.%. These data, plus Fourier-transform infrared spectral (FTIR) and zero shear viscosity analyses of the extract (PKF) were all consistent with the literature. Comparison of three existing methodologies for the quantitative analysis of the KGM content of the PKF, namely 3,5-dinitrosalicylic acid (3,5-DNS), phenol-sulphuric acid and enzymatic colorimetric assays; indicated that the 3,5-DNS colorimetric assay was the most reproducible and accurate method, with a linear correlation coefficient of 0.997 for samples ranging from 0.5 to 12.5 mg/ml, and recoveries between 97% and 103% across three spiking levels (250, 500 and 750 μg/g) of starch. These data provide the basis of improved good laboratory practice (GLP) for the commercial extraction and analysis of this multifunctional natural polymer. 相似文献
159.
Paul Christopher Webster 《CMAJ》2012,184(12):E633-E634
160.