Alpha 1-Antitrypsin Does Not Inhibit Human Monocyte Caspase-1

BackgroundAlpha 1-antitrypsin (A1AT) is a 52 kDa serine protease inhibitor produced largely by hepatocytes but also by mononuclear phagocytes. A1AT chiefly inhibits neutrophil elastase and proteinase-3 but has also been reported to have immune modulatory functions including the ability to inhibit caspases. Its clinical availability for infusion suggests that A1AT therapy might modulate caspase related inflammation. Here we tested the ability of A1AT to modulate caspase-1 function in human mononuclear phagocytes.MethodsPurified plasma derived A1AT was added to active caspase-1 in a cell-free system (THP-1 lysates) as well as added exogenously to cell-culture models and human whole blood models of caspase-1 activation. Functional caspase-1 activity was quantified by the cleavage of the caspase-1 specific fluorogenic tetrapeptide substrate (WEHD-afc) and the release of processed IL-18 and IL-1β.ResultsTHP-1 cell lysates generated spontaneous activation of caspase-1 both by WEHD-afc cleavage and the generation of p20 caspase-1. A1AT added to this cell free system was unable to inhibit caspase-1 activity. Release of processed IL-18 by THP-1 cells was also unaffected by the addition of exogenous A1AT prior to stimulation with LPS/ATP, a standard caspase-1 activating signal. Importantly, the A1AT exhibited potent neutrophil elastase inhibitory capacity. Furthermore, A1AT complexed to NE (and hence conformationally modified) also did not affect THP-1 cell caspase-1 activation. Finally, exogenous A1AT did not inhibit the ability of human whole blood samples to process and release IL-1β.ConclusionsA1AT does not inhibit human monocyte caspase-1.     

Circadian resonance in the development of two sympatric species of Camponotus ants

Circadian clocks provide adaptive advantage to their owners by timing their behavioural and physiological processes in accordance with the external environment. Here we report the results of our study aimed at investigating the effect of the interaction between circadian timing system and environmental light/dark (LD) cycles on pre-adult development time of two sympatric species of Componotus ants, the night active Componotus compressus, and the day active C. paria—both species develop in dark underground nests, under fairly constant conditions of humidity and temperature. We estimated pre-adult developmental durations in these ants under three different LD cycles (T20 = 10 h of light and 10 h of darkness, T24 = 12 h of light and 12 h of darkness, and T28 = 14 h of light and 14 h of darkness). We find that both species exhibit significantly faster pre-adult development under T24 compared to T20 and T28. Given that faster development in insects is considered as an adaptive strategy these results can be taken to suggest that Camponotus ants accrue greater fitness advantage under T24 compared to T20 and T28 LD cycles, possibly due to “circadian resonance” between circadian timing system and environmental LD cycle. Thus our study reveals that boreal species of ants could serve as a case for the study of adaptive significance of circadian organization.     

MicroRNA-487a-3p functions as a new tumor suppressor in prostate cancer by targeting CCND1

Prostate cancer (PCa) is one of the major health problems of the aging male. The roles of dysregulated microRNAs in PCa remain unclear. In this study, we mined the public published data and found that miR-487a-3p was significantly downregulated in 38 pairs of clinical prostate tumor tissues compared with the normal tissues. We further verified this result by in situ hybridization on tissue chip and quantitative real-time polymerase chain reaction (qRT-PCR) in PCa/normal cells. miR-487a-3p targeting of cyclin D1 (CCND1) was identified using bioinformatics, qRT-PCR and western blot analyses. The cellular proliferation, cell cycle, migration, and invasion were assessed by cell counting kit-8, flow cytometry analysis and transwell assay. We discovered that overexpression of miR-487a-3p suppressed PCa cell growth, migration, invasion by directly targeting CCND1. Knockdown of CCND1 in PCa cells showed similar results. Meanwhile, the expression level of CCND1 was significantly upregulated in the PCa tissues and cell lines, which presented negative correlation with the expression of miR-487a-3p. More important, we demonstrated significantly reduced growth of xenograft tumors of stable miR-487a-3p-overexpressed human PCa cells in nude mice. Taken together, for the first time, our results revealed that miR-487a-3p as a tumor suppressor of PCa could target CCND1. Our finding might reveal miR-487a-3p could be potentially contributed to the pathogenesis and a clinical biomarker or the new potential therapeutic target of PCa.     

Change in BMI Accurately Predicted by Social Exposure to Acquaintances

Research has mostly focused on obesity and not on processes of BMI change more generally, although these may be key factors that lead to obesity. Studies have suggested that obesity is affected by social ties. However these studies used survey based data collection techniques that may be biased toward select only close friends and relatives. In this study, mobile phone sensing techniques were used to routinely capture social interaction data in an undergraduate dorm. By automating the capture of social interaction data, the limitations of self-reported social exposure data are avoided. This study attempts to understand and develop a model that best describes the change in BMI using social interaction data.We evaluated a cohort of 42 college students in a co-located university dorm, automatically captured via mobile phones and survey based health-related information. We determined the most predictive variables for change in BMI using the least absolute shrinkage and selection operator (LASSO) method. The selected variables, with gender, healthy diet category, and ability to manage stress, were used to build multiple linear regression models that estimate the effect of exposure and individual factors on change in BMI. We identified the best model using Akaike Information Criterion (AIC) and R².This study found a model that explains 68% (p<0.0001) of the variation in change in BMI. The model combined social interaction data, especially from acquaintances, and personal health-related information to explain change in BMI.This is the first study taking into account both interactions with different levels of social interaction and personal health-related information. Social interactions with acquaintances accounted for more than half the variation in change in BMI. This suggests the importance of not only individual health information but also the significance of social interactions with people we are exposed to, even people we may not consider as close friends.     

Drosophila Sirt2/mammalian SIRT3 deacetylates ATP synthase β and regulates complex V activity

Adenosine triphosphate (ATP) synthase β, the catalytic subunit of mitochondrial complex V, synthesizes ATP. We show that ATP synthase β is deacetylated by a human nicotinamide adenine dinucleotide (NAD⁺)–dependent protein deacetylase, sirtuin 3, and its Drosophila melanogaster homologue, dSirt2. dsirt2 mutant flies displayed increased acetylation of specific Lys residues in ATP synthase β and decreased complex V activity. Overexpression of dSirt2 increased complex V activity. Substitution of Lys 259 and Lys 480 with Arg in human ATP synthase β, mimicking deacetylation, increased complex V activity, whereas substitution with Gln, mimicking acetylation, decreased activity. Mass spectrometry and proteomic experiments from wild-type and dsirt2 mitochondria identified the Drosophila mitochondrial acetylome and revealed dSirt2 as an important regulator of mitochondrial energy metabolism. Additionally, we unravel a ceramide–NAD⁺–sirtuin axis wherein increased ceramide, a sphingolipid known to induce stress responses, resulted in depletion of NAD⁺ and consequent decrease in sirtuin activity. These results provide insight into sirtuin-mediated regulation of complex V and reveal a novel link between ceramide and Drosophila acetylome.     

A New GaAs Metal-Semiconductor-Metal Photodetector Based on Hybrid Plasmonic Structure to Improve the Optical and Electrical Responses

In this article, a new hybrid plasmonic based metal-semiconductor-metal photodetector (MSM-PD) is proposed. A subwavelength slit, the metal nanoscale gratings, and the metal pads which are extended into the absorption layer are used in a basic hybrid plasmonic structure to enhance the absorption coefficient. The finite-difference time-domain (FDTD) method is used to simulate the new structure. The absorption coefficient of the hybrid plasmonic MSM-PD becomes 42 times greater than that of the conventional plasmonic MSM-PD made of only subwavelength slit, which is known as the reference structure. This result is equivalently about 1.5 times greater than that of a recently reported structure. It is also demonstrated that the quantum efficiency of the proposed structure is 10 times more, if compared with the reference one. Moreover, considering the incident light modulation frequency, the frequency response of the hybrid plasmonic MSM-PD is improved, where the cutoff frequency is increased 22 times greater than that of the reference MSM-PD.     

The Effect of Cellular Stress on T and B Cell Memory Pathways in Immunized and Unimmunized BALB/c Mice

Immunological memory is a fundamental function of vaccination. The antigenic breakdown products of the vaccine may not persist, and undefined tonic stimulation has been proposed to maintain the specific memory. We have suggested that cellular stress agents to which the immune cells are constantly exposed may be responsible for tonic stimulation. Here we have studied four stress agents: sodium arsenite, an oxidative agent; Gramicidin, eliciting K⁺ efflux and calcium influx; dithiocarbamate, a metal ionophore; and aluminum hydroxide (alum), an immunological adjuvant. The aims of this study are to extend these investigations to T and B cell responses of unimmunized and ovalbumin (OVA)-immunized BALB/c mice, and furthermore, to ascertain whether stress is involved in optimal expression of memory B cells, as demonstrated in CD4⁺ T cells. Examination of the homeostatic pathway defined by IL-15/IL-15R (IL-15 receptor) interaction and the inflammasome pathway defined by the IL-1-IL-1R interaction between dendritic cells (DC) and CD4⁺ T cells suggests that both pathways are involved in the development of optimal expression of CD4⁺CD45RO⁺ memory T cells in unimmunized and OVA-immunized BALB/c mice. Furthermore, significant direct correlation was found between CD4⁺CD44⁺ memory T cells and both IL-15 of the homeostatic and IL-1β of the inflammasome pathways. However, CD19⁺CD27⁺ memory B cells in vivo seem to utilize only the IL-15/IL-15R homeostatic pathway, although the proliferative responses are enhanced by the stress agents. Altogether, stress agents may up-regulate unimmunized and OVA-immunized CD4⁺CD44⁺ memory T cells by the homeostatic and inflammasome pathways. However, the CD19⁺CD27⁺ memory B cells utilize only the homeostatic pathway.     

Exploring the evolutionary dynamics of Rhizobium plasmids through bipartite network analysis

The genus Rhizobium usually has a multipartite genome architecture with a chromosome and several plasmids, making these bacteria a perfect candidate for plasmid biology studies. As there are no universally shared genes among typical plasmids, network analyses can complement traditional phylogenetics in a broad-scale study of plasmid evolution. Here, we present an exhaustive analysis of 216 plasmids from 49 complete genomes of Rhizobium by constructing a bipartite network that consists of two classes of nodes, the plasmids and homologous protein families that connect them. Dissection of the network using a hierarchical clustering strategy reveals extensive variety, with 34 homologous plasmid clusters. Four large clusters including one cluster of symbiotic plasmids and two clusters of chromids carrying some truly essential genes are widely distributed among Rhizobium. In contrast, the other clusters are quite small and rare. Symbiotic clusters and rare accessory clusters are exogenetic and do not appear to have co-evolved with the common accessory clusters; the latter ones have a large coding potential and functional complementarity for different lifestyles in Rhizobium. The bipartite network also provides preliminary evidence of Rhizobium plasmid variation and formation including genetic exchange, plasmid fusion and fission, exogenetic plasmid transfer, host plant selection, and environmental adaptation.