Regulation of cAMP responses by the G12/13 pathway converges on adenylyl cyclase VII

Regulation of intracellular cyclic adenosine 3’, 5’-monophosphate (cAMP) by multiple pathways enables differential function of this ubiquitous second messenger in a context dependent manner. Modulation of Gs-stimulated intracellular cAMP has long been known to be modulated by the Gi and Gq/Ca2+ pathways. Recently, the G13 pathway was also shown to facilitate cAMP responses in murine macrophage cells. We report here that this synergistic regulation of cAMP synthesis by the Gs and G13 pathways is mediated by a specific isoform of adenylyl cyclase, AC7. Furthermore, this signaling paradigm exists in several hematopoietic lineages and can be recapitulated by exogenous expression of AC7 in HEK 293 cells. Mechanistic characterization of this synergistic interaction indicates that it occurs downstream of receptor activation and it can be mediated by the alpha subunit of either G12 or G13. Our results demonstrate that AC7 is a specific downstream effector of the G12/13 pathway

Panel: OASIS in the mirror: reflections on the impacts and research of IFIP WG 8.2

What has IFIP contributed to the field of information systems and organizations through the activities of Working Group 8.2, its central working group in information systems? What has WG 8.2 delivered to its constituents? What have the results and impacts of the WG 8.2 been on the larger community? This panel will not shy away from controversy as it discusses the history, contributions, and unrealized potential of research spawned by this working group over the past 30 years.The past and the future of information systems: 1976-2006 and beyondRed de Universidades con Carreras en Informática (RedUNCI

Nucleosynthetic vanadium isotope heterogeneity of the early solar system recorded in chondritic meteorites

Author Posting. © The Author(s), 2018. This is the author's version of the work. It is posted here under a nonexclusive, irrevocable, paid-up, worldwide license granted to WHOI. It is made available for personal use, not for redistribution. The definitive version was published in Earth and Planetary Science Letters 505 (2019): 131-140, doi:10.1016/j.epsl.2018.10.029.Vanadium (V) isotopes have been hypothesized to record irradiation processes in the early solar system through production of the minor 50V isotope. However, because V only possesses two stable isotopes it is difficult to distinguish irradiation from other processes such as stable isotope fractionation and nucleosynthetic heterogeneity that could also cause V isotope variation. Here we perform the first detailed investigation of V isotopes in ordinary and carbonaceous chondrites to investigate the origin of any variation. We also perform a three-laboratory inter-calibration for chondrites, which confirms that the different chemical separation protocols do not induce V isotope analytical artifacts as long as samples are measured using medium resolution multiple collector inductively coupled plasma mass spectrometry (MCICPMS). Vanadium isotope compositions (51V/50V) of carbonaceous chondrites correlate with previously reported nucleosynthetically derived excesses in 54Cr. Both 51V and 54Cr are the most neutron-rich of their respective elements, which may suggest that pre-solar grains rich in r-process isotopes is the primary cause of the V-Cr isotope correlation. Vanadium isotope ratios of ordinary chondrite groups and Earth form a weaker correlation with 54Cr that has a different slope than observed for carbonaceous chondrites. The offset between carbonaceous and non-carbonaceous meteorites in V-Cr isotope space is similar to differences also reported for chromium, titanium, oxygen, molybdenum and ruthenium isotopes, which has been inferred to reflect the presence in the early solar system of two physically separated reservoirs. The V isotope composition of Earth is heavier than any meteorite measured to date. Therefore, V isotopes support models of Earth accretion in which a significant portion of Earth was formed from material that is not present in our meteorite collections.This study was funded by NASA Emerging Worlds grant NNX16AD36G to SGN

ESTABLISHING TRAINING PARAMETERS FOR A DEEP NEURAL NETWORK TO ASSESS 2D, FRONTAL PLANE KINEMATICS

The purpose of this study was to establish the optimal training parameters to assess frontal plane, 2D kinematics using DeepLabCut. DeepLabCut is an open-source platform that allows the user to train neural networks for customized feature detection in 2D videos. Deep neural networks were trained using frontal plane videos from 41 participants who completed single- and double-leg drop landings. Networks were trained with an increasing number of training iterations (25-250k) and training frames (200-800). Our results indicate that a minimum of 175k training iterations and 400 training frames were adequate for stable network performance (training/test errors= 2.8/3.7 pixels)

Potent selective inhibitors of protein kinase C

AbstractA series of potent, selective inhibitors of protein kinase C has been derived from the structural lead provided by the microbial broth products, staurosporine and K252a. Our inhibitors block PCK in intact cells (platelets and T cells), and prevent the proliferation of mononuclear cells in response to interleukin 2 (IL2)

Decreasing survival benefit from cardiac transplantation for outpatients as the waiting list lengthens

AbstractMany patients are accepted for cardiac transplantation during a period of clinical instability associated with a high risk of death, even though most can be discharged home to await transplantation. As the waiting lists lengthen, priority is awarded solely on the basis of the waiting time of outpatients, who now usually undergo transplantation after they have already survived a major period of jeopardy. To determine the impact of the current waiting times and priority system on the previously expected benefit offered by transplantation, 1-year actuarial survival without transplantation was recalculated after each month without transplantation for 214 potential candidates with an ejection fraction of 0.17 ± 0.05 discharged on tailored medical therapy after evaluation. These data were compared with the 1-year survival data of 88 outpatients who underwent transplantation.Actuarial survival after 1 year was 67% on tailored therapy compared with 88% after transplantation (p = 0.009). Death without transplantation was sudden in 43 of 51 patients, resulting from hemodynamic decompensation in 8. For outpatients already surviving 6 months without transplantation, actuarial survival over the next 12 months was 83% without transplantation. Thus, the expected improvement in survival after transplantation would be only 5% over the subsequent year for patients waiting 6 months, which is the waiting time for many outpatients. Such patients should be reevaluated to determine whether transplantation remains indicated during the next year

Insights into Pathophysiology from Medication-induced Tremor

Background: Medication-induced tremor (MIT) is common in clinical practice and there are many medications/drugs that can cause or exacerbate tremors. MIT typically occurs by enhancement of physiological tremor (EPT), but not all drugs cause tremor in this way. In this manuscript, we review how some common examples of MIT have informed us about the pathophysiology of tremor. Methods: We performed a PubMed literature search for published articles dealing with MIT and attempted to identify articles that especially dealt with the medication’s mechanism of inducing tremor. Results: There is a paucity of literature that deals with the mechanisms of MIT, with most manuscripts only describing the frequency and clinical settings where MIT is observed. That being said, MIT emanates from multiple mechanisms depending on the drug and it often takes an individualized approach to manage MIT in a given patient. Discussion: MIT has provided some insight into the mechanisms of tremors we see in clinical practice. The exact mechanism of MIT is unknown for most medications that cause tremor, but it is assumed that in most cases physiological tremor is influenced by these medications. Some medications (epinephrine) that cause EPT likely lead to tremor by peripheral mechanisms in the muscle (β-adrenergic agonists), but others may influence the central component (amitriptyline). Other drugs can cause tremor, presumably by blockade of dopamine receptors in the basal ganglia (dopamine-blocking agents), by secondary effects such as causing hyperthyroidism (amiodarone), or by other mechanisms. We will attempt to discuss what is known and unknown about the pathophysiology of the most common MITs

Urinary total arsenic and arsenic methylation capacity in pregnancy and gestational diabetes mellitus: A case-control study

Previous studies suggest arsenic exposure may increase the risk of gestational diabetes mellitus (GDM). However, prior assessments of total arsenic concentrations have not distinguished between toxic and nontoxic species. Our study aimed to investigate the relationships between inorganic arsenic exposure, arsenic methylation capacity, and GDM. Sixty-four cases of GDM and 237 controls were analyzed for urinary concentrations of inorganic arsenic species and their metabolites (arsenite (As3), arsenate (As5), monomethylarsonic acid (MMA), and dimethylarsinic acid (DMA)), and organic forms of arsenic. Inorganic arsenic exposure was defined as the sum of inorganic and methylated arsenic species (iSumAs). Methylation capacity indices were calculated as the percentage of inorganic arsenic species [iAs% = (As3 + As5)/iSumAs, MMA% = MMA/iSumAs, and DMA% = DMA/iSumAs]. Multivariable logistic regression was performed to evaluate the association between inorganic arsenic exposure, methylation capacity indices, and GDM. We did not observe evidence of a positive association between iSumAs and GDM. However, women with GDM had an increased odds of inefficient methylation capacity when comparing the highest and lowest tertiles of iAs% (adjusted odds ratio (aOR) = 1.48, 95% CI 0.58–3.77) and MMA% (aOR = 1.95 (95% CI 0.81–4.70) and a reduced odds of efficient methylation capacity as indicated by DMA% (aOR = 0.62 (95% CI 0.25–1.52), though the confidence intervals included the null value. While the observed associations with arsenic methylation indices were imprecise and warrant cautious interpretation, the direction and magnitude of the relative measures reflected a pattern of lower detoxification of inorganic arsenic exposures among women with GDM