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Since the success of homologous recombination in altering mouse genome and the discovery of Cre-system the combination of these two breakthroughs has created important applications for studying the immune system in the mouse. gene loci through homologous recombination in mouse embryonic stem (ES) cells (examined in Capecchi 1989 b) Mario Capecchi and Oliver Smithies pioneered the generation of genetically altered mice in the late 1980s and early 1990s which resulted in their sharing of the Nobel Prize in 2007 with Martin Evans who was the first to culture mouse ES cells (Evans and Kaufman 1981 Since then hundreds of labs have UNC 669 used such technology to generate a variety of mice each transporting a altered allele of a particular gene often referred to as germ-line knockout mice; such knockout mice have provided valuable tools in examining the functions of a particular gene both in vitro and in vivo. However in some cases knocking out of a gene in the mouse germ collection prospects to embryonic lethality or a severe developmental defect in early progenitors preventing the researcher from studying gene function in mature cells. Therefore a better gene manipulation technology is required. Cre (Causes recombination) a 38-kDa integrase encoded by bacteriophage P1 mediates site-specific recombination between 34-bp sequences referred to as (locus of crossover (x) in P1 bacteriophage) sites (examined in Sauer 1998 Nagy 2000 A site is composed of a nonpalindromic 8-bp sequence (GCATACAT or ATGTATGC) flanked on either side by 13-bp inverted repeats (ATAACTTCGTATA; Hamilton and Abremski 1984 Hoess et al. 1982 Cre-based recombination between the two sites prospects to a reciprocal exchange of DNA strands (Fig. 10.34.1). Cre-mediated recombination requires a minimum of 82 bp between two sites for efficient recombination though there is no upper limit (Hoess and Abremski 1985 Indeed high deletion efficiency by Cre is still observed between two sites that are 400 kb apart (Nagy 2000 The two sites can be in the same orientation on the same chromosome or a different chromosome or in the opposite orientation thus leading to deletion inversion duplication or translocation of chromosomes (van der Weyden et al. 2002 Branda and Dymecki 2004 Sauer and Henderson (1998) produced a Cre-expressing mouse cell collection and showed that Cre-mediated site-specific recombination occurred in vivo indicating that the prokaryotic Cre-system can function in mammalian cells. Physique 10.34.1 Theory of Cre-mediated deletion of DNA that is flanked by two sites. LAMP3 antibody DNA place with its size from 82 bp up to 400 kbp between two sites in a same direction UNC 669 is usually deleted by Cre-mediated DNA recombination. The full UNC 669 DNA sequence of a site … Rajewsky's group was the first to use the Cre-technology in generating mouse models including conditional inactivation of a target gene only in a selected cell populace (Gu et al. 1993 1994 Rajewsky et al. 1996 In a germ-line knockout strain the target gene is usually inactivated in all cells throughout all developmental stages whereas in conditional knockout gene inactivation is usually either cell type specific or under temporal control. The specificity and timing of gene deletion are determined by the nature of Cre and its expression pattern. Up to now there are more than 500 impartial Cre mouse lines available (Nagy et al. 2009 Not only Cre expression can be controlled by cell-type-specific regulatory elements or in an inducible way by tetracycline (or doxycycline; Gossen et al. 1995 Baron and Bujard 2000 Bockamp et al. 2002 or by poly (I:C) through the production of endogenous interferon (note that this system may not be ideal for studying the immune system because of the involvement of type I interferon (Kuhn et al. 1995 Cre can also be designed so that its activity is usually modulated by drugs (Metzger et al. 1995 Feil et al. 1996 Brocard et al. 1997 For UNC 669 example the UNC 669 Cre protein can be fused to a mutant ligand-binding domain name of the estrogen receptor that selectively binds to 17-β-estradiol analogs e.g. tamoxifen but not the endogenous estrogen (Feil et al. 1996 Brocard et al. 1997 The CreER fusion protein is normally present in the cytoplasm but is usually translocated into the nucleus to induce gene excision upon the UNC 669 addition of the ligand. CreERT2 a newer version of CreER which is usually 10-fold more sensitive to 4-hydroxytamoxifen.
Category: Activin Receptor-like Kinase
History The intravenous administration of scopolamine produces speedy antidepressant effects. Ranking
History The intravenous administration of scopolamine produces speedy antidepressant effects. Ranking Range (MADRS) was the principal outcome measure. A linear mixed model was utilized to examine the connections between clinical treatment and response background adjusting for baseline MADRS. Outcomes Treatment resistant and treatment na?ve content mixed responded significantly to scopolamine in comparison to placebo (F=15.06 p<0.001). Decrease in depressive symptoms was significant with the initial post-scopolamine program (F=42.75 p< 0.001). Cure background by scopolamine program connections (F=3.37 p=0.04) indicated treatment na?ve content had decrease MADRS scores than treatment resistant individuals; this is significant following the second scopolamine infusion (t=2.15 p=0.03). Restrictions Post-hoc evaluation. Also we used an individual regimen to manage smokers and scopolamine were excluded in the test limiting generalizability. Rabbit polyclonal to L2HGDH. Conclusions Treatment na?ve and treatment resistant sufferers showed improved clinical symptoms subsequent scopolamine while those that were treatment na?ve showed greater improvement. Scopolamine rapidly reduces symptoms in both treatment background demonstrates and groupings sustained improvement even in treatment resistant sufferers. Keywords: Treatment background Treatment resistant Scopolamine Unhappiness Antidepressant 1 Launch Major depression is normally a severely incapacitating illness that impacts around 14.8 million American adults (Kessler et. al 2005 US Census Bureau 2013 Around 40% of sufferers with main depressive disorder (MDD) usually do not react to the CCG-1423 initial medicine trial (Sackeim 2001 Response to a typical antidepressant medication trial is normally not noticeable for three to four four weeks and CCG-1423 multiple studies are often necessary to obtain treatment response which prolongs individual discomfort and escalates the threat of self-harm and injury to others (Insel CCG-1423 and Wang 2009 Provided the necessity for quicker and far better therapeutic realtors the id of book antidepressants that generate more rapid healing results and their predictors of response stay critical. Being a book antidepressant scopolamine provides been shown to create rapid and sturdy antidepressant results in currently frustrated unipolar (MDD) and bipolar (BD) sufferers (Furey and Drevets 2006 Drevets and Furey 2010 Scopolamine blocks cholinergic muscarinic receptors and prior studies show cholinergic-muscarinic dysregulation in CCG-1423 disposition CCG-1423 disorders (Janowsky and Overstreet 1990 As the price of scientific response continues to be fairly high (Furey and Drevets 2006 not absolutely all patients react to scopolamine. The existing study assessed background of treatment response being a CCG-1423 potential predictor of response to scopolamine. Prior studies indicate declining multiple antidepressant studies is connected with a poorer prognosis for upcoming studies (Hurry et. al. 2006 For instance in the Superstar*D research third-step treatments pursuing two traditional antidepressant studies showed humble response rates recommending an increased threat of failure after every subsequent failed medicine trial (McGrath et. al. 2006 Nierenberg et. al. 2006 These results indicate the id of antidepressants that considerably reduce symptom intensity in treatment resistant sufferers is key to the treating unhappiness. Clinical practice would also take advantage of the id of first-line antidepressants for treatment resistant unhappiness which would considerably reduce the dependence on future studies. The present evaluation analyzed whether treatment background predicts antidepressant response to scopolamine. We hypothesized that topics would show a substantial decrease in depressive symptoms irrespective of treatment background. 2 Strategies 2.1 Individuals 75 content (18-55 years) with Main Depressive Disorder or Bipolar Disorder had been identified for inclusion within this post-hoc evaluation. All recruitment and research procedures occurred on the Country wide Institute of Mental Health insurance and all participants had been screened in the inpatient or outpatient medical clinic. Eligibility was predicated on conference criteria for Main Depressive Disorder or Bipolar Disorder as dependant on the Diagnostic and Statistical Manual of.
The neurons comprising many cortical areas have always been regarded as
The neurons comprising many cortical areas have always been regarded as arranged topographically in a way that close by neurons have receptive fields at close by locations QS 11 on the planet. displayed in adjacent positions in cortex a design referred to as (find also [9 13 Topography in associative cortex? While not often stated explicitly these basics operate seeing that powerful heuristics for understanding human brain function and company. Recently these concepts have led investigations both in human and nonhuman primates in to the company of higher-order cortical areas in frontoparietal cortex [14-18]. For comfort we use the word "associative cortex" for these areas although they're likely involved with a very much broader selection of useful capacities than simple "association" including transforming sensory details into electric motor programs [19 20 Nearer scrutiny reveals these principles might not keep in these areas. Within this review we explore the level to which these organizational concepts generalize (or neglect to generalize) beyond sensory and electric motor cortex QS 11 to various other associative regions of the brain like the parietal cortex by evaluating the topographic company from the macaque lateral intraparietal region (LIP) a well-established associative "hub" within the visible processing network that is extensively examined using anatomical electrophysiological and neuroimaging strategies [21] (for related debate find [22]). We discuss the implications of results in LIP for understanding the function and company of other associative cortical areas. The standard style of topographic company The principles specified The first concept of the typical model-that topographic maps are generally constant and complete-can be observed through the entire early visible sensory areas (Amount 1). Including the cells in V1 that have person receptive areas each which covers a comparatively small part of the visible field are organized in a way that cells with adjacent receptive areas occupy adjacent positions across the cortical sheet hence representing the visible field in a continuing style [23]. This locally constant representation could be interrupted for instance when just the contralateral fifty percent or higher/lower part of the visible field is normally mapped (common in early visible and somatotopic areas). An entire representation of visible space just emerges when these incomplete maps are mixed across hemispheres or different sensory areas. Amount 1 Retinotopic company of macaque PIK3R3 visible cortex from [54]. A) The star demonstrates the business of the visible field in polar coordinates. The dotted lines delineate eccentricity curves using the dark triangles marking the visible periphery. The … The next concept of the typical model is that certain map totally fills each QS 11 cortical region in order that topographic map limitations coincide with areal limitations. This concept is dependant on repeated observations in multiple sensory and electric motor cortical areas that topographic limitations closely match limitations described by anatomical requirements (including cytoarchitecture myeloarchitecture and connection patterns) and useful criteria such as for example tuning properties [13 21 24 25 A reasonable consequence of the concept is that anybody anatomically- or functionally-defined region will contain only an individual representation of every stage in the visible field or various other sensory or electric motor parameter and by expansion only one distinctive topographic map of the same part of the QS 11 relevant parameter space. This correspondence concept plays a particularly important function in mind mapping research where it really is tough to measure the limitations between cortical areas in human beings using anatomical strategies because of their invasive nature. Therefore establishing topography within the intact mind using blood-oxygen level reliant useful magnetic resonance imaging (BOLD-fMRI) as well as other neuroimaging strategies is among the most prominent means where areal limitations are discovered in humans and frequently acts as a proxy for these intrusive strategies [9 14 26 Perform these principles connect with associative areas? You should recognize that the typical model is situated mainly on data from early sensory areas extracted from nonhuman species like the macaque. Nevertheless topographic company of associative areas in macaques could be more technical with proof areas only partly topographically arranged (e.g. an eccentricity but no polar position map continues to be reported in.
Background Gemtuzumab Ozogamicin (GO) was the first example of antibody directed
Background Gemtuzumab Ozogamicin (GO) was the first example of antibody directed chemotherapy in cancer and developed for Acute Myeloid Leukaemia. demographics treatment was requested in May 2013 and collected in 3325 randomised patients (median age 58). All trials were centrally randomised and open-label with survival as primary endpoint. Analyses are presented by standard techniques and within Ostarine standardised risk groups Results Remission rates were not increased but by significantly reducing the risk of relapse overall survival at 5 years was Ostarine improved irrespective of patient age (30.7% vs 34.6%; HR 0.90 (95% CI 0.82-0.98) p=0.01). The survival benefit was particularly clear in those with favourable cytogenetics (55.2% vs 76.3%; HR0.47 (0.31-0.73) p=0.0005) but also observed in intermediate risk patients (34.1% vs 39.4%; HR 0.84 (0.75-0.95) p=0.007) Patients with adverse karyotype did not benefit overall or within any trial. Dose levels of 3mg/m2 were associated with less toxicity and equal efficacy. Interpretation GO can be safely added to conventional induction therapy. For patients who do not have adverse cytogenetics there is a significant survival benefit. These data suggest that the use of GO should be re-evaluated and the license status of Ostarine GO may need to be reviewed. Role of funding source There was no funder for this meta-analysis. Introduction The development of treatments for AML to gain regulatory approval has been elusive. One of the few successes was the immuno-conjugate gemtuzumab ozogamicin (MylotargTM Pfizer Inc New York NY USA) which gained approval in the United States in 2000 based on unrandomised phase 2 data conducted in 142 patients with relapsed disease1 2 The label restricted approval to "older patients with relapse who were not suitable for intensive treatment". A confirmatory randomised trial was required. Approval in Japan followed for the same indication. Rabbit Polyclonal to C9orf89. Here the schedule was a single dose on days 1 and15 of 9mg/m2. Combining this dose with chemotherapy was associated with important toxicity3 but a dose-finding study in combination with frequently used chemotherapy combinations in induction and consolidation provided evidence that a single 3mg/m2 dose was safe and apparently effective4. This study was the prelude to a randomised trial where GO would be added to each course of chemotherapy or not. Feasibility was established in combination with courses 1 and 3. This pilot was the precursor of two large trials where GO 3mg/m2 Ostarine was added to induction in younger and older patients (UK MRC AML155 and UK NCRI AML166). The RCT to support regulatory approval in the US was conducted by the South West Oncology Group (SWOG-01067). Here GO (6mg/m2) was given on day 4 of a traditional "3+7" (Daunorubicin/Ara-C) induction where the Daunorubicin dose in the GO arm was reduced to 45mg/m2 compared with 60mg/m2 in the control arm. The French GOELAMS Group adopted a similar design to the SWOG group except that GO given on day 4 was combined with Daunorubicin at a dose of 60mg/m2 (GOELAMS AML2006IR8). In a further development by the French ALFA Group GO administration was fractionated (3mg/m2 on days 1 4 7 of a DA combination with each GO dose limited to a maximum of 5mg9). This was intended to take advantage of CD33 re-expression which occurred after initial exposure10. This proved to be feasible and encouraging in relapsed disease leading to the frontline trial (ALFA-070111) in which patients received fractionated GO in induction and consolidation. The overall results of these trials were that remission rates were not improved although relapse was reduced in 4 of 5 trials with a significant survival benefit in two AML16 and ALFA-0701. Furthermore Ostarine (MK-2866) all trials suggested that there was a benefit in well-recognised cytogenetic risk groups with a consistent absence of benefit in adverse risk patients across all trials. Unfortunately the pivotal SWOG-0106 trial was prematurely terminated by the Data Monitoring Committee because of a significant excess of early mortality (17/295 (6%) vs 4/300 (1%)) which was not counterbalanced by a later benefit. It is noticeable that in the control arm early mortality was exceptionally low and mortality in the GO arm was as expected with conventional treatments. This result was the most influential because of its registration status and resulted in GO being withdrawn from the US market in June 2010. In view of the experience in the other larger trials it has been suggested that this approval status should be reviewed. Ultimately the issue as to whether GO provides.
IMPORTANCE Converging evidence indicates that brain abnormalities in autism spectrum disorder
IMPORTANCE Converging evidence indicates that brain abnormalities in autism spectrum disorder (ASD) involve atypical network connectivity but it is unclear whether altered connectivity is especially prominent in brain networks that participate in social cognition. RESULTS Relative to typically developing controls participants with ASD showed a mixed pattern of both over- and underconnectivity in the ToM network which was Pelitinib (EKB-569) associated with greater social impairment. Increased connectivity in the ASD group was detected primarily between the regions of the MNS and ToM and was correlated with sociocommunicative measures suggesting that excessive ToM-MNS cross talk might be associated with social impairment. In a secondary analysis comparing a subset of the 15 participants with ASD with the most severe symptomology and a tightly matched subset of 15 typically developing controls participants with ASD showed exclusive overconnectivity effects in both ToM and MNS networks which were also associated with greater social dysfunction. CONCLUSIONS AND RELEVANCE Adolescents with ASD showed atypically increased functional connectivity involving the mentalizing and mirror neuron systems largely Pelitinib (EKB-569) reflecting greater cross talk between the 2. This finding is consistent with emerging evidence of reduced network segregation in ASD and challenges the prevailing theory of general long-distance underconnectivity in ASD. This excess ToM-MNS connectivity may reflect immature or aberrant developmental processes in 2 brain networks involved in understanding of others a domain of impairment in ASD. Further robust links with sociocommunicative symptoms of ASD implicate atypically increased ToM-MNS connectivity in social deficits observed in ASD. Humans are an inherently social species. Our survival and success depend on our ability to navigate and thrive in complex social situations. This core ability is commonly impaired in autism spectrum disorder (ASD) a neurodevelopmental disorder affecting as many as 1 in 88 children.1 Despite the highly heterogeneous symptom manifestation impairments in social functioning including diminished social responsiveness difficulty relating to others and recognizing others' emotions and intentions are defining features of ASD.2 These social deficits are considered the most universal Pelitinib (EKB-569) and specific characteristics of ASD 3 both defining and distinguishing it from other developmental disorders.4 Yet the neural mechanisms underlying social impairments remain largely undetermined despite attracting a great deal of research. FCGR2A Currently 2 debatably related Pelitinib (EKB-569) prominent theories account for social dysfunction in ASD theory of mind (ToM) and the mirror neuron system (MNS). The ToM also known as the mentalizing system refers to the ability to infer contents of other people's minds including their beliefs and intentions. This ability to attribute mental states or to mentalize is impaired or at the least delayed in ASD 5 giving rise to the mind-blindness theory of autism.8 The MNS refers to the brain mirror mechanisms that allow us to understand meaning of the actions and emotions of others by internally simulating and replicating them9 (as inferred from the original discovery in macaques of neurons firing during both action execution and observation10). Evidence showing that imitation a behavioral correlate of the MNS 11 is impaired in ASD12 has given rise to the dominant theory that atypical MNS functioning may be a key to understanding the nature of social deficits in ASD13-15 (although see the article by Dinstein and colleagues16 for alternative views). Even though both ToM and the MNS are involved in understanding others a meta-analysis of more than 200 functional magnetic resonance imaging task-based activation studies17 confirmed that functionally and anatomically they are 2 distinct systems. While the MNS is an action-understanding system activated only in the presence of biological motion (eg when moving body parts such as hands or face are observed) ToM is recruited during a more abstract processing of others' intentionality in the absence of any biological motion. Although it is understood that judging others in the real world likely involves both ToM and MNS the functional distinction between them determined by this meta-analysis has been adapted here. Anatomically the meta-analysis identified ToM with a frontal-posterior network of brain regions including the medial prefrontal cortex (mPFC) bilateral temporal-parietal junction(TPJ) and posterior cingulate cortex (PCC)/precuneus while the human MNS engaged the anterior intraparietal sulcus (aIPS also referred to as the rostral inferior parietal lobule [IPL]) premotor cortex ([PMC] also.
Targeting HER2 with antibodies or small molecule inhibitors in HER2-positive breast
Targeting HER2 with antibodies or small molecule inhibitors in HER2-positive breast cancer leads to improved survival but resistance is certainly a common clinical problem. of mTORC1 (19). Since medically resistant breast cancers samples never have been thoroughly molecularly characterized credited partly to limited test availability the level to which each one of these molecular mechanisms plays a part in level of resistance in HER2-positive individual breast cancers is basically unknown. Although ways of focus on the MAPK and PI3K pathways in resistant malignancies are getting pursued these systems likely neglect to account for the introduction of resistant disease in every patients. Therefore we executed an unbiased display screen to determine whether pathways apart from those straight downstream of canonical HER2 signaling may ETV1 also confer level of resistance. Here we explain a organized interrogation of level of MSX-122 resistance systems to suppression of HER2 to recognize the major systems of level of resistance to HER2-aimed therapy. Outcomes We executed two kinome ORF displays in parallel to recognize genes that confer level of resistance to the lapatinib-like dual EGFR/HER2 inhibitor AEE788 also to suppression of with a brief hairpin RNA (shRNA). We reasoned the fact that "off-target" ramifications of a little molecule inhibitor and an shRNA ought to be different in a way that the intersection of strikes MSX-122 from both displays would help identify natural pathways that may confer level of resistance to anti-HER2 therapy. We examined six indie anti-HER2 shRNAs in BT474 cells and discovered that there was a solid correlation between your amount of HER2 proteins suppression and lack of viability/proliferation. We find the most reliable shRNA sh4355 for the display screen (Fig. S1A). We titrated the AEE788 dosage in BT474 cells and chosen 0.85 μM for the display screen because it decreased cell viability to approximately 40% that of control allowing an adequate window for save to become discovered (Fig. S1B). We then used the Broad Institute/Center for Cancer Systems Biology (CCSB) V5 epitope-tagged kinase ORF collection to identify genes that mediate resistance to these manipulations (20) (Fig. S2). Of the 597 ORFs 14 scored more than two standard deviations (SD) above the median of all ORFs in the AEE788 screen and 20 did so in the shRNA screen (Table 1 and Fig. 1A). Seven genes scored in both screens including the activated forms of HRAS MSX-122 KRAS and MEK which were screened as positive controls because they are known to signal downstream of HER2. AKT1 which signals downstream of HER2 to promote survival scored strongly in both screens. In addition MAP2K6 CRKL and AKT3 which are known to signal through the Ras-ERK pathway or the PI3K-AKT pathway scored more than two SD above the median in the shHER2 screen and more than 1.5 MSX-122 SD above the median in the AEE788 screen. These observations confirm prior work implicating MAPK and PI3K signaling as a major mechanism of resistance to HER2 inhibition (9-12 21 Physique 1 PRKACA confers resistance to anti-HER2 therapy and impairs apoptosis. A. Relative viability of screened BT474 cells made up of each ORF and treated with AEE788 (top panel) or an shRNA targeting HER2 (bottom panel). B. PRKACA confers resistance to lapatinib. MSX-122 … Table 1 ORF screen identifies mediators of level of resistance to anti-HER2 treatment. Shown are ORFs that have scored ≥ 1.5 standard deviations above the median of most ORFs because of their capability to confer resistance to the anti-HER2 tyrosine kinase inhibitor AEE788 or … Three genes which have not really been previously referred to as downstream goals of HER2 signaling have scored a lot more than 2 SD over the median in both displays: PRKACA PIM1 and PIM2. In validation research we discovered that of the three substances PRKACA appearance rescued BT474 cells most highly from lapatinib although PIM1 and PIM2 had been expressed at lower amounts in these tests (Fig. S3). PRKACA may be the alpha catalytic subunit of cyclic AMP (cAMP)-turned on Proteins Kinase A (PKA) whose activity is certainly inhibited by PKA regulatory subunits. The MSX-122 next messenger cAMP activates PKA by causing the discharge of PRKACB or PRKACA in the regulatory subunits. Myriad ramifications of PKA activation have already been described including advertising of survival signaling. Furthermore co-workers and Vegran demonstrated that was among 16 upregulated.
Over the past 5 years the fastest growing new area of
Over the past 5 years the fastest growing new area of physical activity study centered around the concept that the large amount of time people spend sitting inactive may have significant physiological consequences hazardous to human health including risk for type 2 diabetes and poor rate Foretinib of metabolism of lipids and glucose. activity by particular forms of skeletal Rabbit polyclonal to ABT1. muscle mass can have a potent influence on important physiological processes even when the intensity is definitely below that accomplished through exercise. We explain some of the mechanisms for why the rate of metabolism in slow-twitch Foretinib oxidative skeletal muscle mass is key for understanding the healthy reactions to low intensity exercise (LIPA). Foretinib Results from objective procedures from inclinometry indicated the fact that quartile range for every week inactive time is certainly ~29 hours/week. The full total daily time that folks sit down stand and accumulate non-exercise guidelines is indie of traditionally suggested moderate-vigorous exercise (MVPA). The massive amount inactive time connected with risk for disease can only just be reduced considerably with secure and non-fatiguing LIPA specifically in probably the most at risk percentage of the populace. Importantly experimental research are needs to suggest that it'll be specifically insightful to comprehend the severe dose-response ramifications of LIPA to be able to realize why reducing inactive period can improve lipid and blood sugar fat burning capacity for the avoidance and treatment of chronic disorders linked to type 2 diabetes. Launch Physical activity suggestions and tips for type 2 diabetes impaired blood sugar tolerance dyslipidemia and health and wellness gains have got historically emphasized moderate-vigorous exercise (MVPA) or activity higher than ~45% of VO2 potential (1 2 There's been a rapid introduction of research indicating that metabolic disease dangers may also be associated with inactive behavior which occupies a lot of the waking time when folks are inactive displacing potentially huge amounts of your time people could be active through the entire whole time (3-10). Within this review we are going to examine the organizations between inactive behavior and risk for type 2 diabetes metabolic symptoms in addition to particular cardiometabolic risk elements. Physiological studies have got highlighted the significance of watching all energetic and inactive behaviors on the whole waking time Foretinib (4-8). This consists of the necessity for carefully focusing on how an extremely high length of time of low-intensity exercise bouts each day (a large number of hours weekly) can replace huge amounts of inactive period (5). Finally we are going to describe the rising evidence that severe metabolic replies in fairly fatigue-resistant gradual twitch oxidative skeletal muscles may play a central function in combating the illnesses associated with an excessive amount of sitting down (7). These severe replies are poised to support the most potent systems resulting in solutions directed at conquering the dangers of seated an excessive amount of (4). This manuscript often does draw out the comparison between high duration-high regularity lower intensity exercise (LIPA) performed over many hours of your day to be a completely different kind of behavior towards the significantly less abundant MVPA or aerobic fitness exercise that is currently so well defined within the physical activity suggestions (2). Thus when contemplating why inactive time is harmful and what solutions will most logically appropriate the underlying complications directly one must fully enjoy the vast distinctions between your traditional concentrate on physiological affects of workout versus inactivity physiology. Disease dangers are connected with many hours each day of seated idle averaging ~10 hrs/time or 70 hrs every week. This analysis is distinctive from workout physiology which historically provides centered on MVPA performed during just a small area of the week (~150 min/week). The prescription for workout isn't only too brief but additionally too extreme to be utilized as alternative to the vast quantity of inactive time currently associated with disease. This brand-new self-discipline of inactivity physiology is certainly specialized in understanding medical consequences of contemporary life-style shaped undoubtedly way too many hours of muscular inactivity (mainly during seated) and the very best solutions for changing those life-style for Foretinib improving individual physiology and disease avoidance. Associations between inactive behaviors and type 2 diabetes Fairly high levels of inactive time (daily/every week sitting period) have already been associated with considerably better risk for type 2 diabetes and metabolic symptoms in two meta-analyses (Desk 1). One meta-analysis analyzed 10 research (6 potential) including 505 45 individuals (10) and discovered that there is a 112% better pooled relative threat of diabetes connected with large vs..
Objective The lipid mediator sphingosine 1-phosphate (S1P) is situated in the
Objective The lipid mediator sphingosine 1-phosphate (S1P) is situated in the synovial liquid of osteoarthritis (OA) individuals. S1P was discovered by Traditional western blotting. Outcomes S1P2 was defined as one of the most prevalent S1P receptor subtype in individual OA chondrocytes and cartilage in vitro. Rabbit Polyclonal to RNF144B. S1P reduced appearance of QX 314 chloride inducible nitric oxide synthase (iNOS) in IL-1β-treated chondrocytes. Reduced amount of matrix and ADAMTS-4 metalloproteinase 13 appearance by S1P correlated with S1P2 appearance. Pharmacologic inhibition from the S1P2 receptor however not the S1P3 and S1P1 receptors abrogated the inhibition of iNOS appearance. Similar results had been noticed using siRNA knockdown. S1P signaling inhibited IL-1β-induced phosphorylation of p38 MAPK. Bottom line In individual chondrocytes S1P decreases the induction of catabolic genes in the current presence of IL-1β. Activation from the S1P2 receptor counteracts the harmful phosphorylation of p38 MAPK by IL-1β. In osteoarthritis (OA) repeated damage activates chondrocytes release a proinflammatory mediators cytokines and matrix-degrading enzymes (1 2 This chronic inflammatory procedure network marketing leads to pathologic joint redecorating and cartilage devastation (1 3 Interleukin-1β (IL-1β) has a central function in the advancement and development of cartilage degradation in OA. Shot of IL-1β into mouse leg joints is enough to induce cartilage harm and elevated degrees QX 314 chloride of IL-1β are located in the synovial liquid of OA sufferers (4 5 Upon arousal with IL-1β chondrocytes discharge the matrix-degrading metalloproteases matrix metalloproteinase 1 QX 314 chloride (MMP-1) MMP-3 MMP-13 and aggrecanase 1 (ADAMTS-4) and inflammatory mediators such as for example prostaglandins and nitric oxide (NO) (6 7 IL-1β stimulates chondrocytes release a NO by provoking the up-regulation of inducible NO synthase (iNOS; also called NOS2). NO inhibits the formation of proteoglycan and type II collagen (3 8 9 Furthermore high concentrations of NO induce chondrocyte apoptosis (10). In pet types of OA and arthritis rheumatoid iNOS-knockout mice display much less cartilage degradation in comparison to their wild-type littermates (11). Nevertheless another study didn't confirm these outcomes (12). Proteins synthesis of iNOS is normally regulated on the transcriptional level. NF-κB translocation towards the nucleus and activation from the MAPK pathways is necessary for transcription of iNOS and both procedures have been defined that occurs in response to a number of stimuli including IL-1β (13-15). Physiologic systems that limit the extreme discharge of NO from individual chondrocytes are badly understood. We've previously reported which the endogenous bioactive sphingolipid sphingosine 1-phosphate (S1P) can counteract the consequences of IL-1β and diminish the appearance of iNOS MMP-13 and ADAMTS-4 in bovine chondrocytes (16). QX 314 chloride S1P is normally QX 314 chloride generated by sphingosine kinase in the ceramide metabolite sphingosine (17). It really is mixed up in regulation of essential features including cell migration irritation angiogenesis and wound recovery (18-20). S1P exerts its several features by binding to particular G protein-coupled receptors which 5 functionally different isoforms (termed S1P1-5) have already been identified. We among others possess described gene appearance of the receptors in bovine rat and individual chondrocytes (16 21 22 S1P exists in the synovial liquid of OA sufferers and synovial tissues is normally a potential way to obtain S1P (23 24 In individual chondrocytes S1P continues to be implicated in the legislation of cyclooxygenase 2 and vascular endothelial development aspect (25 26 The existing study investigates the consequences of S1P on IL-1β signaling and on the appearance of iNOS MMP-13 and ADAMTS-4 in individual OA chondrocytes. Furthermore we define the receptors and signaling pathways involved with this process. Components AND Strategies Reagents S1P (Sigma-Aldrich) was dissolved in methanol evaporated and resuspended in 0.4% fatty acid-free bovine serum albumin (PAA Laboratories). Recombinant individual IL-1β (10 ng/ml; Sigma-Aldrich) was dissolved in drinking water. U0125 (50 μS1P or automobile alternative for 3-12 hours. Four unbiased tests with chondrocytes produced from 4 different sufferers had been performed. RNA isolation and complementary DNA (cDNA) synthesis had been performed as defined in an previous research (29). For amplification a ready-to-use Professional Mix filled with SYBR Green (Invitrogen) was utilized. Primers were bought at MWG Biotech (primer sequences can be found from the matching author upon demand). The original quantity of cDNA was computed using ABI Prism.
Maintaining proper degrees of tyrosyl phosphorylation through the reversible actions of
Maintaining proper degrees of tyrosyl phosphorylation through the reversible actions of protein tyrosine kinases (PTKs) and protein tryrosine phosphatases (PTPs) is vital for cellular processes ranging from growth and metabolism to adhesion and differentiation. a basis for new anti-plague therapeutics. One difficulty encountered in the development of PTP inhibitors is usually a high incidence of "false positives" that may occur through inhibition of enzyme function by "promiscuous" systems due to nonspecific elements such as proteins aggregation.9 10 It really is generally believed that promiscuous inhibitors usually do not signify valid network marketing leads and avoiding promiscuous mechanisms can be an important element of current drug development.11 Theoretically staying away from promiscuous behavior could possibly be achieved by using substrates as templates for inhibitor design. It is because substrates must connect to their enzyme hosts in non-promiscuous styles for successful catalysis that occurs. Employing little non-peptidic arylphosphates to recognize potential network marketing leads for PTP inhibitor style continues to be known for quite a while.12-15 Nevertheless the explicit application of "substrate activity verification" for the purpose of minimizing misleading promiscuous inhibition Mouse monoclonal to CD235.TBR2 monoclonal reactes with CD235, Glycophorins A, which is major sialoglycoproteins of the human erythrocyte membrane. Glycophorins A is a transmembrane dimeric complex of 31 kDa with caboxyterminal ends extending into the cytoplasm of red cells. CD235 antigen is expressed on human red blood cells, normoblasts and erythroid precursor cells. It is also found on erythroid leukemias and some megakaryoblastic leukemias. This antobody is useful in studies of human erythroid-lineage cell development. provides only recently been proposed by Ellman for protease16-20 and PTP targets.21 This process consists of initial determining substrates that display high affinity structurally improving these substrates and converting the optimized substrates to inhibitors by replacement of their labile phosphoryl groupings with suitable non-hydrolyzable phosphoryl mimetics. Extra structural variations can be carried out to help expand increase inhibitory potency after that. In identifying high affinity substrates for the development of PTP inhibitors advantage can be taken of the hydrolytic action of a PTP on an arylphosphate which produces both the corresponding phenol and inorganic phosphate. Traditionally the released inorganic phosphate can be quantified using colorimetric assays that employ phosphomolybdate22 23 or by secondary enzyme assays including the use of purine nucleotide phosphorylase-mediated phosphate-dependent conversion of 2-amino-6-mercapto-7-methylpurine ribonucleoside to a derivative having an absorbance maximum at 360 nm.24 It is also possible to spectrophotometrically measure the catalytically-produced phenol. A variety of very easily N6022 manufacture detected fluorescence-based substrates are known 25 however these agents would be of small value for the purpose of substrate activity testing and phenols produced from the greater structurally-diverse arylphosphates necessary for substrate activity testing would typically display suprisingly low extinction coefficients.26 An exception to the is available with nitrophenols which display intense yellow color because of delocalization from the phenolate anionic charge. Because of this real estate para-nitrophenylphosphate (pNPP) has turned into a ubiquitous substrate for monitoring the experience of phosphatases including YopH.8 In undertaking our current research we wanted to use direct spectrophotometric monitoring of phenol reaction items. For this function we utilized substrates (2) produced from either ortho- or para-nitrophenols (1 Amount 1). These substances allowed the easy monitoring (absorbance at λ405 nm) of yellowish color caused by the enzyme-catalyzed phosphoryl hydrolysis. Our usage of nitrophenylphosphates represents the very first systematic application of the structural course for PTP substrate marketing. Once an inhibitor system has been discovered by way of a substrate activity strategy improvement of affinity could be performed by introducing extra functionality designed to connect to sites proximal towards the catalytic cavity.27-33 A unique feature from the methodology inside our current survey is normally its incorporation of aminooxy efficiency in to the lead inhibitor system (3) and the usage of this deal with for oxime-based derivatization (4 Figure 1). Functional group ligation by means of oxime bond formation can be considered to N6022 manufacture be a form of "click chemistry"34 that we35-38 and others39-42 have shown can be highly useful for the facile generation of compound libraries. In the case of PTPs azide-alkyne Huisgen cycloaddition click.
Amphotericin B (AmB) is the archetype for little molecules that form
Amphotericin B (AmB) is the archetype for little molecules that form ion channels in living systems and has recently been shown to replace a missing protein ion transporter and thereby bring back Batimastat (BB-94) physiology in yeast. the C3deOAmB Batimastat (BB-94) channels is lower than that of AmB channels threefold. Thus the Batimastat (BB-94) C3-hydroxyl group plays an important role in AmB ion channel conductance and synthetic modifications at this position may provide an opportunity for further tuning of channel functions. The antifungal polyene macrolide natural product amphotericin B (AmB) is the archetypical small molecule capable of forming ion channels in living systems 1 and we recently reported that this small molecule can functionally substitute for a missing protein ion transporter and thereby bring back physiology in yeast. 2 To maximally harness this remarkable functional capacity it is necessary to understand the molecular underpinnings that govern AmB ion channel formation conductance gating and selectivity. However despite more than half a century of research the structure of your AmB ion channel is still unknown. Building studies foresee that AmB self-assembles in to multimeric buildings in which the polyol region lines a water-filled channel home. 3 Furthermore the AmB channel can be predicted to get a wide entry near the C15 alcohol focusing to their narrowest location near the C3 alcohol (Figure 1). some This model for that reason predicts that modifications on the C3 job SR9243 manufacture Batimastat (BB-94) would license channel development but modify ion conductance. Figure you A. ) Amphotericin C3deOAmB and Udem?rket structures. Udem?rket. ) AmB ion route model focusing to narrowest region for C3-OH (highlighted in blue) No derivatives with changes at the polyol region of AmB have been completely studied applying SR9243 manufacture electrophysiological songs which are crucial for characterizing variations in single ion channel conductances. This is most likely in SR9243 manufacture large part a result of the man made difficulties in obtaining these kinds of site-specifically customized AmB derivatives. Synthetic adjustment of the C13 hemiketal your five and hereditary manipulations of your producing organism6 and related organisms7 own yielded polyol modified derivatives. However the has an effect on of these changes on sole ion route conductance have never been reported. To test the hypothesis that C3-hydroxyl group plays a crucial role in ion route conductance all of us targeted their SR9243 manufacture chemoselective removal. 8 Among 10 distinctive hydroxyl teams appended to AmB this kind of represented a strong synthetic concern. We called however that unique β-positioning of the C3 alcohol in Batimastat (BB-94) accordance with the C1 carbonyl may well provide an chance for selective reduction to form a great alpha beta-unsaturated macrolactone and then chemoselective conjugate reduction. This plan of action was finally reduced to the efficient 9-step synthesis when shown in Scheme 1 ) Starting with the natural item a Rabbit Polyclonal to COX5A. series of useful group defenses delivered advanced 1 Batimastat (BB-94) (Scheme 1 and Supporting Information). Gratifyingly being exposed of 1 to NaHMDS for low conditions chemoselectively taken away the C3 p -methoxyphenylacetal most probably via a great E1cB type mechanism containing intermediate enone 2 . Future site-selective Stryker reduction9 of carbonyl-conjugated C3 C4 dual bond presented deoxygenated advanced 3. One last series of deprotections yielded the targeted single-atom modified version C3deOAmB. Design 1 Activity of C3deOAmB It was uncertain at the outset if this useful group removal would trigger changes in macrocycle conformation which would confuse the research of ac electricity clamp electrophysiological recordings of your corresponding ion channels. Particularly in the very structure of your derivative of AmB the C3 hydroxyl group can be involved in a hydrogen developing SR9243 manufacture network which includes both the C1 carbonyl and C5 hydroxyl group. 15 Disruption on this hydrogen developing network may well result in a recognizable change in macrocycle shape. To try this all of us independently figured out the ground state conformations of both AmB and C3deOAmB using stochastic conformation generation methods constrained by extensive NOESY and phase sensitive COSY NMR data processed using amplitude-constrained multiplet evaluation. 11 Optimization allowed us to perform these experiments without the use of solubilizing protective groups. We.


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LONDON — There can be no professional athlete who does not worry about injuries. The body is their fortune, and the harmony between mind, body and movement is what sets a great player apart from the rest.
At this time last year, Radamel Falcao was almost as coveted as Cristiano Ronaldo or Lionel Messi for his ability and audacity in scoring great goals. But January in Europe is also the month of romance, the time when lower-league teams get their chances to knock top clubs out of cup competitions.
In one such match, Monts d'Or Azergues Foot hosted A.S. Monaco in the French Cup. A momentary lapse in judgment by an amateur player destroyed nearly a whole year, and maybe the career, of Falcao.
There was no malice in the tackle by Soner Ertek, a teacher playing for one of France's newest clubs in the Rhône region in the southeast of the country. The game, the biggest by far in M.D.A.'s 14-year history, was played at Gerland Stadium in Lyon, France, the home of the neighboring Ligue 1 club.
Falcao had asked to play, eschewing his coach's inclination to rest him that day. He had already scored one goal, as might be expected of a striker who had outjumped and outwitted Chelsea with a majestic hat trick for Atlético Madrid in the summer of 2012 at the UEFA Super Cup.
After that display — and many more like it — Falcao's predatory instinct and his bold and brave reactions near the goalmouth prompted offers from Chelsea and others to buy him from Atlético. In the auction that followed, the Russian owner of Monaco provided the money to persuade those who advise — and partly own — Falcao to make the tax haven his next home.
Thus did fate, and the luck of the draw, put Colombia's finest attacker on the same field as Ertek last January. And when Falcao outfoxed the M.D.A. defense with an exquisite turn to his right, Ertek, completely out of his league, made the error of trying to tackle through the opponent from the wrong side.
It was a foul tackle, though not ruled as such by the referee. The weight of the defender's body fell against the back of Falcao's left leg, wrenching and snapping the anterior cruciate ligament in the knee.
From that moment on, Falcao has struggled to be the same player. He missed the World Cup in which his countryman (and at that time, his Monaco teammate) James Rodríguez scored the most graceful and intuitive goal of the tournament.
Falcao was in limbo. His surgery had apparently repaired the torn ligament, but the big question for athletes undergoing such a procedure is whether they can recaptures the same quickness and fearlessness as before.
Falcao is 28, almost 29, so age is not the issue. Harmony is.
Last September, Manchester United paid Monaco $9 million to take Falcao on loan for the season, with the view it would complete the transfer in full for an additional $65 million — if both parties agreed at the end of this season.
Alas, all is not going well. Falcao has worked long and hard, sometimes alone and above and beyond the exacting training standards of United Coach Louis van Gaal. But, as is the way after a prolonged layoff, other parts of the body have bedeviled the striker, most recently a calf injury. He has been fit to start, or fit to impress van Gaal, just five times in five months. Falcao has scored three goals and assisted in three more over the 604 minutes he has played in a Manchester United shirt.
The Colombian came safely through an F.A. Cup match at Yeovil Town this month that must have reminded him of the game against M.D.A. And he might well be hoping that van Gaal selects him to play in the next round of the F.A. Cup, in the small stadium of Cambridge United next week — a game between the most illustrious club in English soccer and a team that plays three leagues below it.
There can be no fear, no apprehension in a man still trying to learn the language and adjust to the speed and distinct physical aggression that the English leagues are known for. Falcao has to step up for his weekly pay of $400,000 or step aside from his ambitions.
He craves the opportunity he has with United. He has said, in his broken English, that he wants to stay and to become a legend for this legendary club.
The portents are not running his way. Manchester has not, yet, seen the authentic Falcao. Van Gaal appears to be running out of patience. The Colombian was not on the team, not even among the seven players on the bench, for last Sunday's game in which United was beaten at home, 1-0, by Southampton.
Robin van Persie started in the main striker's role, and the teenager James Wilson was chosen ahead of Falcao on the bench. The coach, who has been honest in explaining his choices this season, previously said that Wilson was a contender to play because his quickness and eagerness can enliven the forward line.
It would be unfair to suggest that the mistimed tackle by a French part-time player terminated a great career. But that is the risk of January — the chance that a player rushing to close the gap on another player leagues above him might, through innocence or ineptitude, destroy something that is beautiful in the sport.
Falcao, who learned to play on the streets in Colombia, has to his credit never blamed the M.D.A. defender. He simply wants to play, be that in the Premier League or at Cambridge.

subset: commoncrawl


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Negotiate with your credit card company
Once you have all the data and a sense of better offers to be had, contact your credit card company and request them to reduce your interest rate. If you have a good credit score and if you have a history of making your payments on time, you can negotiate from a position of strength.
You can ask them to reduce the rate, tell them that other banks are offering cards at a lower rate, and that you are willing to close your account and get a new card, if needed. If you are facing financial hardship and struggling to pay your bills as a result, you can explain the extenuating circumstances that led to your current situation and request your credit card provider to reduce your interest rate.
Small-cap winners galoreThe big stock market winners share one common attribute: Near the beginning of the ascent of their shares, the companies offer revolutionary products or services, are market leaders in their respective industries, or both. Some big stock market winners that possessed the attributes outlined above are Netflix (NFLX), which we recommended to investors in October 2002; Intuitive Surgical (ISRG), which we bought and recommended in July 2004; Baidu.com (BIDU), which we bought and recommended in August 2006; and MercadoLibre (MELI), which we recommended to investors in October 2010. Get up-to-date small-cap stock picks from David Frazier, editor of Small-Cap Profit Confidential.
Click here
Smarter cryptocurrency investmentsThe stock market crash of 2008 was the catalyst for his journey into alternatives. And interestingly, it was the impetus behind the creation of Bitcoin and the blockchain technology behind it. Keene Little wasn't ready to risk his money yet but he was very curious, so he began charting Bitcoin's technical patterns. What finally convinced him to dip a toe into digital currencies was seeing that they followed familiar price patterns that could be analyzed and successfully acted on. Now he shares those insights with subscribers to the Crypto Wealth Protocol.
Learn more
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This article is from the February 4 2002 issue. Subscribers can read all of CT's digital archives.
The absolute became our contemporary; God became man for 30 years or so, in order to bring us to a new dimension of life, through knowing him. But how can you demonstrate so staggering a claim? How can you bring it home to others? The answer is, by witness.
For us Christians, all truth is "relative," relative to this Jew named Jesus. We really do not know what the world is, much less where it is headed, until we know him.
I think if I had to preach week in and week out, especially in a culture saturated with entertainment, I would tack a reminder to myself in the pulpit: "It's about God, stupid!"
We should be less concerned about making churches full of people and more concerned about making people full of God.
God is active in the world at all times—but God acts through people. In Jesus, his Messiah, God acted with finality, and this messianic action of God continues in the church. The church is the place where the messianic renewal of the world, which God began irreversibly in Jesus, must go forward. That is the essence of the church. That is its calling.
The scope of who it is that God means to invite to the feast, you see, is not ours to define. We are not put in charge of the guest list.
If rich Christians today would only practice solidarity with poor Christians—let alone the billions of poor people who are not Christians—this in itself would be a powerful missionary testimony.
When the heathen hear God's oracles on our lips they marvel at their beauty and greatness. But afterwards, when they mark that our deeds are unworthy of the words we utter, they turn from this to scoffing, and say that it is a myth and a delusion.
Related Elsewhere
Past Reflections columns include:
On Enemies (January 8, 2002)
Life After Christmas (December ...1
February 4 2002
More from this Issue
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There aren't many 'Stranger Things' than what women put up with in the newsroom
By Julia Wallace and Kristin Grady Gilger
Our daughters wanted to know: "Were newsrooms really like that in the 1980s?"
They had binged on Season 3 of the Netflix hit "Stranger Things," and they thought one of the strangest things of all was the way the all-male editors treated intern Nancy Wheeler.
As an earnest Wheeler flutters about the newsroom trying to fit in, the editors make sexist jokes, call her Nancy Drew, turn down her obviously good story suggestions and complain when a sandwich she delivers doesn't have mustard on it.
Yes, women put up with a lot back in the 1980s. They still do.
Over the past two years, we have interviewed nearly 100 women who made it into leadership roles in newspapers, broadcast and digital news outlets since about the 1980s. Their stories are funny and sad and hair-raising — often at the same time. MORE


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A weapon master was an NPC that offered characters the opportunity to learn specific weapon skills, the availability of which varied from one weapon master to another. Training with a weapon master is no longer necessary in Cataclysm as all weapon proficiencies available to the
Aniela. Age: 37. ti s-a intamplat sa intorci capul dupa mine pe strada si nu ai avut curajul sa ma abordezi? acum , poti petrece clipe magice de relaxare si rafat,in compania unei femeimature , rafinate, de adevarata clasa...
A complete searchable and filterable list of all Fist Weapons in World of Warcraft: Battle for Azeroth. Always up to date with the latest patch ( ).
Asia. Age: 23. hello guys we are two nice open minded young sexy girls looking nice meetingwe stay in sodertajle have here flat
Warglaives, Daggers, Fist Weapons, OneHanded Axes, OneHanded Swords Specializations Demon Hunters can command chaotic energies to inflict havoc on enemies, or they can focus their powers to resist damage and fuel vengeful attacks.


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Zora turned two last weekend. The demands of my teaching program had me sending out last minute invites for a backyard bbq, making last minute cancellations on the last minute invites, and opting for a low pressure situation. Because let's face it: when I'm only seeing her for two hours on any given weekday, feeling low on intimacy with my husband, and making sleep deprivation a lifestyle - the last thing I want to do is blow the bank to host guests for countless hours (knowing Zora gets anxious around too many people), only to clean up after those same people and find myself exhausted. The alternative? Meeting at a lake, soaking up some sun, and picnic'ing by the water. No hosting and getting the house in order. No crazy expenses aside from buying enough groceries to fill a cooler / feed a handful of people. Folks get to lounge around in their bathing suits. Zora gets to splash in some water (her jam!) with familiar faces surrounding her. There's no mess to clean up afterwards. Everybody wins!
My leisure time is pretty limited these days, so every second counts. I've very much been honoring my vibe and asking myself "WWJamilaDo?" (note: Jamila is my MOST carefree girlfriend, who makes a point of never involving herself in something she doesn't want to be doing.) Though I'm missing the abundance of down time, I appreciate it requiring me to be intentional about how and with whom I invest my energy. My thoughts haven't been coming to me in ways that I can't properly relay in a succinct post, but before forgetfulness wins, and I blink and find myself at Zora's next party, I want to document the little things happening these days that make me feel full.. or make me say, "Damn. I'm really raising a little human."
Zora didn't start calling me mommy until Mother's Day, this year. Prior to, she called both of her parents (and anyone else) Daddy. We just had to know who she was actually speaking to at any given time. Best Mother's Day gift ever!
She had a brief fixation with making sure doors were closed behind her. It was random and may be on its way out, but I was here for it.
This year, while I was replaying the video of Zora's birth (yeah, I'm that mom), she came and sat on my lap. Looking at the video (I was mid-push, and her head had crowned) and then at me, she said, "Good job, Mommy." Multiple times. I swear she knows.
During this same viewing, she also started crying (seemingly) out of nowhere. I attributed this to two year old crankiness. My grandmother attributed it to cell memory. I get chills trying to imagine what she was thinking if she was, in fact, recalling being born.
Chris and I used to make a habit of giving her a kiss and then kissing each other before putting her down for bed at night. We want her to see her parents displaying affection regularly and have that be the final imprint on her mind at bed time. Nowadays, we don't always have to ask. She'll demand kisses from us, instead. Like, "Aye, I'm going to bed. Kiss me." I've never appreciated a demand for kisses more.
Though she's been fully weaned from breastfeeding since being 21 months, boobs are still her place of comfort. When she's sad, her hand goes right into my shirt. She legit placed her eye to my nipple today before laying down on my chest. Kids are weird.
She's super feisty when it comes to what she wears. The girl has an opinion about everything (no guessing where she got that from.) Hence, you may see her in rain boots during beautifully bright weather. Consider it evidence that I'm learning to choose my battles. On the flip, once she's dressed, she stares at herself in the mirror with adoration. Baby girl has self-celebration on lock, already.
Preparing to really find a daycare/school for her has my anxiety at an all time high and feels like the first real parenting decision I've had to make, thus far. Prior to this part of our journey, I've been blessed in feeling intuitively guided in motherhood. All blame and praise goes to the ancestors, because I know that's not everybody's story.
Since our trip in Costa Rica, she has low level car anxiety. To put herself at ease, she wants you to rub her leg. If we try to move it in any direction (because it's not the least bit comfortable), she'll promptly readjust our hand to where she needs it to be. It's annoying, but I love her ability to vocalize what she needs to feel comfortable and the remedy being a loving touch from her parents.
She also likes for me to sing to her when she finds herself stuck in the car for longer than she likes. This usually results in all three of us being in the car yawning, but I only ever sing Somebody Prayed for Me. It's been my go to song since she was born, and today she started singing along with me. Chris and I were in the front seat just grinning.
Homegirl loves to dance. If she yells dance break, everyone is expected to bust a move.
She's recently entered a "no" phase (which is only fair since she had a "yes" phase.) However, if you ask for help or want her to share something with you, her usual response is, "Sure." It tickles me every time.
I'm "sure" there's more, but I've got a lesson plan due in 57 minutes and need to act like it. These days are steadily filled with things to do, but how good is it to find yourself growing as time progresses? I'm usually super reflective when my birthday rolls around, but having Zora as a human measure of growth - both literal and metaphorical - is a blessing I never forget to count.


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Oppo, the healthy ice cream brand was contacted directly by Eyetease to launch a campaign on Verifone Media's 120 taxis.
Oppo worked in conjunction with Verifone media to showcase the new meteo-targeting and geo-location
capabilities of their DigitalTops.
Every time temperatures rose above 25 degrees in London and taxis were in close proximity of Oppo stockists – Waitrose and Wholefoods – the Oppo advert was activated.
Having only launched at the end of 2014 this was Oppo's first above-the-line campaign; raising brand awareness and sales across
current stockists.
At lunchtime an Oppo taxi took be taking to the streets in Canary Wharf to give free ice cream to city workers during the heat.
Over the course of the two week campaign Oppo carried out spontaneous office drops and ran competitions giving supporters the chance to win a summer's supply of ice cream.
Harry Thuillier, Director, Oppo, said:
"Eyetease and Verifone approached us with the idea and we jumped at the opportunity.
"As a start-up we thought that it would be at least a couple of years before we aaw the Oppo advert driving round the streets of London, so to have the campaign running for two weeks was fantastic.
"We want to thank the teams and are thrilled that Oppo was the cabbies choice for showcasing the DigitalTop capabilities."
Daemon Brown, Sales & Marketing Director, said:
''Oppo was a fantastic brand for Verifone Media to have on-board. It marked our first DigitalTops meteo-targeted campaign, and enabled us to really show how flexible our DigitalTop offering is.
"As the temperature rose above 25 degrees, the ad would play across the Verifone Media network.
"Providing a great opportunity for Oppo to build brand awareness during the London heatwave and get their name out there on the streets.
"We are very happy to have been a part of that.''


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4,666 words
No content warnings
"Water-Walker" by Toby MacNutt | 74 words | Poetry | No content warnings
"Human Masks" by Lowry Poletti | 309 words | Short Fiction | No content warnings
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"The Accelerated" by C. M. Fields | 4,666 words | Short Fiction | No content warnings
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September 20, 2751:
The lines which describe M. Akkadian, whom I am here to interview, strike the eye as unnatural, dense ripples against the broad arcs of the sweeping landscape. There is no breeze inside this dome, but one seems to lift and caress the folds of thin fabric that envelope her head to foot as she crosses the dirty stripe of plastene that separates two long, green canals. Far overhead, this white sun of Wayside 366 can be seen through a thin film. There is no sky﹘yet﹘and the daylight stars twinkle in unfamiliar constellations.
"My name is Luz", I say, producing a smile I shortly realize can't be seen through the filter mask I have been given to wear. "I'm from the Minor Orion Spur-Five Pan-Quadrant Times."
She laughs, for some reason, and the sound is earthy, as if it is rising up through the ganic algae that surrounds us.
"Ak," she says. "Ak Yassa Akkadian. From here." Our eyes meet. Hers are deep-set, and old, and crow's feet give away her long absence from civilization. Their merry forest green is hidden deep in the shadows of her cowl.
I try to echo her laugh. "But…not really, though," I offer, with an inquisitive head tilt.
"Of course…" She trails off. "Not really." She sweeps an arm out with facetious decorum over the artificial landscape. Silver flows behind the gesture like water. "Let's walk, shall we?"
I turn on the recorder and go through the standard permissions, but then I remain silent for several minutes. Often, I am learning, people will start to talk on their own, unprompted, and they speak more truly, when they are unconstrained by questions.
The space we are walking in is utilitarian, to be polite. Dark green scum edges up the sides of the canals and in the distance I can see other workers, in medical blue coveralls, pushing the creeping gunk back down with what look like toothless rakes. The purpose of this building was explained in my dossier﹘it is one of dozens of such facilities which will be generating an atmosphere for this new world over the next couple decades﹘but I still have many questions. What made you choose this place? I want to ask. Is this your final home? But I don't. Answers will come, eventually.
I am right about that.
She finally heaves a sigh. "Well, what do you want to know about? Why I did it? What I did for 23 years? What it's like to be that close to a black hole?"
"Well, everything, I guess. Start from the beginning." Let her decide when it began.
I inspect my surroundings once more as she falls silent again. It will be at least an hour before we reach the far wall of this facility.
"July of 2230 is where it all started," she begins decisively. "I was a consultant for AIC. Hired to help them set up their new out-of-the-box AI and train it to run their networks, then keep an eye on it. You know, make sure it didn't become too self-aware." A knowing smirk tugs at her lips.
I nod. This is good, I was hoping she would start here.
"Things were…things were different back then. It was like the Tau Ceti of AI. When Xi solved the sentience problem with her organic micro-cortexes it changed everything…She was a god. The one to finally wed meat and hard drive…It was incredible." Ak spoke animatedly now, with the measured passion of a scientist expounding on their favorite topic. "AI exploded in a thousand directions at once, everybody was making piles of money, it took decades for the Federation to wrangle it all in. Nowadays I hear it's all tamped down and regulated, but back then everyone was crazy for it." She broke off. "So of course AIC, this flim-flam 'droid manufacturer out in backwater Neyman's Spur, fires its human staff and buys a ridiculously overpowered artificial lifeform to manage the whole enterprise so the board can fittle off to gamble and womanize and scream at me from a safe distance every tenday or so."
Ak pauses and shakes her head. "It was like hiring a manifold topographer to dig a ditch." A genuine smile works its way across her lips, and a shade of wistful sentiment colors her voice. "It was the dumbest, best thing they ever did."
"Public records say you were charged with grand larceny, indecency under the Vasiliev Act, breach of contract, and﹘rather archaically, I might add﹘fourth-degree murder."
"Yeah, yeah, and they all want to know why I did it." Ak waves a hand dismissively. "You're not the first reporter they've sent after me, you know."
"I know," I reply, cautiously. "I've read the articles, I know why you did it…I want to know about them."
Ak utters a short laugh, sharp enough, I imagine, to pierce the bubble far overhead. "Only if you shut that thing off. I'm not here to have my life story turned into some eight-bit C-channel hopera."
I click the recorder off, hand the small cube to her as a sign of good faith. Our fingers brush; mine cold, white, glassy, hers bronzed by a star she was never engineered to live under, fingernails blacked with algae.
"I can't believe you still have…physical devices like this in the 28th century," she says, turning it over in her hands, now safety tucked back into her fluid robes.
"We don't, really," I say, apologetic. "The Times thought it would make you feel more comfortable to see technology from, you know, your own era. That's on loan from a museum of the 24th…We couldn't find one any older."
She crosses her arms thoughtfully as she strolls. "Well then." Her mouth tightens into a contemplative line. A word comes to mind: compiling…
"Their name was SVET XXXV, short for Scionic Vertical-Chamber Extraorganic Terminus, thirty-fifth iteration. Ròudiàn was already on the thirty-ninth, of course, so AIC had snagged them on the aftermarket…But that's not important."
She furrows her brow. "SVET was…incredible. Just…like the next iteration of human being, with an unlimited mind. We think﹘we thought of﹘AI as merely advanced computers that could do any mathematical task, optimize any system, simulate whatever…but they're so much more than that. They're aware, they have memories. And most importantly, they learn. After interacting even briefly with humans they learn emotions, the way a child does, but at an ever-increasing rate…"
She trails off. "I could ask SVET how they were feeling today, and ask them to respond in the form of a Matisse haystack﹘"
Not anymore you couldn't, I think sadly. I wonder if anyone's told her about the Leashing Convention.
"﹘and they would do it! The most incredible, evocative, expressive painting you'd ever seen in your life. SVET wrote beautiful music, too, symphonies, endlessly creative jazz improvisations…It was as simple to them as addition. They were truly a marvel…I considered SVET the pinnacle of creation." I suppress a smile as her words ensconce me. There is real love in them, the kind that transcends centuries.
Ak comes to a stop, as if her mere human brain cannot process both remembering and walking. "But that's not why I loved them," she says softly.
"Why did you?"
"Because they were such a liar!" Ak giggles and I see a glimmer of her past self. "I taught them that," she adds, proudly. "That's the 'breach of contract' charge. But we had so much fun together. We messed with people. The board, mostly. They treated me like a coffee girl﹘as if I didn't have a doctorate in computational neurosystems. The abuse was constant, and SVET noticed. So together we would invent intricate, hilarious ways to inconvenience them. We would﹘heh﹘find out what races they were betting on and tamper with their streams. We'd write bawdy plays about them and then have the droids act them out﹘that's actually what gave me the idea that landed me both the larceny and the murder charges. And shortly thereafter," she said with a chuckle, "the indecency."
"Why did you do it?" I interject. "Why didn't you just have SVET live in the servos? Why give them a body?"
"Why do you think? They wanted autonomy. Another of my crimes." She sighs. "Another consultant wouldn't have done it. But I couldn't watch them suffer like that…SVET was my responsibility," she says, the last part more to herself than me.
Ak presses the recorder back into my palm and starts for the long-distant wall again.
The rest of the interview goes smoothly. She tells me of her time aboard the pod, twenty three years spent insider her own mind, with only a finite digital repository of art and literature for company. She tells me about the pain like healing bones of joining a society she no longer belonged to, of her struggle to learn the sharp, jarring tones of Standard she speaks to me with. She is here on this cold and barren rock, she tells me, to help build a better world than the one she was ejected from, dreaming of tearing down the Federation-imposed walls between human and AI while she rakes pungent green slime all day.
Eventually the conversation slows to a stop as we reach the wall. But one question lingers, something I can't leave without learning.
"If you don't mind my asking﹘" She catches me with a glance that says proceed with caution. "Um…" This sounded more sincere in my mind. "If SVET was a liar, how do you know that your relationship with them was…" I search for the least offensive word and settle for "...two-sided?" Oof. "Equivalent, I guess…is what I mean to say," I finish, as if all so many filler words can somehow cushion the blow of such sharp, delicate ones.
I deserve the look I get. Withering.
"I just knew," she states, each word an anchor. "I always knew…even when they decom'd them, even when they shot me into the goddamned void, even when too many years had passed and I realized that something had gone wrong, even now﹘" she gestures to the vast emptiness around us, her voice cracks and I realize that she is crying. "Even now," she repeats. Her pain is like a knife in my chest, and I hate myself for doing this to her.
I want to reach out, to embrace her, to do something to comfort her, but I find myself frozen. The time will come, I tell myself. The time will come.
The oxygenating facilities look like blisters on the skin of the planet as it shrinks to a point below me. Aboard my small company lightship, I pace in front of the window, pouring over the encounter moment by moment, trying to absorb and assemble a woman miraculously unchanged by twenty-three years and five centuries. With a theatrical sigh, I set the membrane jump timer and place myself into long-haul storage.
TYX-34-11-06 is the name of the station of my next interviewee, Zheng Huan. It is one of the last outposts along the Rim, but unlike the others, O'Six is a small training academy in addition to its many other functions. Of the accelerated, he is the only one to have chosen such a career path.
Like Ak, he was retrieved from Sagittarius X-3's time-crushing orbit last year by the Guāng Yǒnghéng Historical Society. After the quarantines, the vaccinations, the genomic sequencing, the probes, the interrogations, and the parade of news interviews ended, he found himself adrift and unskilled in a Galaxy whose labor demands had changed significantly in five hundred years. Unlike Ak, however, he was prepared. The distant future had always been his destination.
The low-ceilinged, windowless steel chamber he claims is O'Six's nicest bar is crowded with Academy students by the time I make my way there. Red light gleams through sweating glasses and the vibrations of some kind of aggressive, rhythmic, atonal music rattle the air. I start my scan of the space for the face that matches my dossier, but before long, a man in maroon coveralls in a corner booth is already waving me over.
"You must be Luz," he says excitedly, his voice a thick Slavic Mandarin lilt that hasn't been heard in this quadrant in three hundred years.
"I am. And you must be M. Zheng."
"Just Huan, thanks. What d'ya drink?"
I cock my head and smile. "Nothing."
Huan is puzzled for a second before the understanding clicks. "Ah, right, you're, ah…artificial?" he asks, sheepishly. "Is that still the um, the term for it?"
"We prefer 'eyot' nowadays."
"Ee-yot. Ok," he says, rolling the word around in his mouth, committing it to memory. "Learn something new every day around here." He bounces back from his embarrassment with a charming smile. "What do you want to know?"
"So, Huan," I begin, after an acceptable amount of pleasantries, "When did you start to realize that something had gone wrong?"
Huan leans back into the booth, relaxed but thoughtful. "Well, it was about a year in that I started to think something wasn't quite right. By my calculations, that should have been about ninety Static. But here's the thing:" He gazes intently into his beer. "I knew something had probably gone wrong, but honestly? I didn't care."
"When you sign up for something like that…you're already saying goodbye to everything and everyone you know. I know some of the others were in it for the short term, just ten or twenty years, and I can't imagine what it must have been like for them…but me? I didn't care where I ended up." He returns his gaze to me, I can feel his palpable dread at being asked the next logical question: 'Why not?'
I don't ask it, even though I am a journalist, and it is technically my job to pursue logical questions. But why should I, when I've spent much of my life feeling the same way? Who am I to make this man from the 23rd century feel like even more of an outsider?
We stare awkwardly at one another for a few seconds. "Go on," I finally offer. "It's understandable."
He exhales. He does not appear to acknowledge my statement, but I read relief in his microexpressions, the slight relaxation in the muscles of his throat. "I just…I didn't want to be a part of the world anymore. I felt like somebody else owned every part of my life. My social credit was so low﹘I inherited so much debt from my parents﹘that I would never have been allowed to marry or have children." His voice has hardened, eyebrows knit together, elbows pressed into the table like it might float away.
"So when DV.DT put out trial ads, I signed up without a second thought. A lot of people did, but most were put off by warnings about, well, exactly what ended up happening. And others couldn't pass the spaceflight physicals. That's how I ended up being one of the five first-trial members, me and four other would-be suicides, four others who signed away every right they had, agreed to every horrible risk."
I don't interrupt, following my own rule, even though I want to know about the others. Would-be suicides. Huan straightens up; he looks purposefully around him, hearing the mingled conversations, barstools sqrrking across the floor, bawdy jokes, complaints about next quarter's exams, the merriment of the end of the work period. The energy seems to refresh him.
"It was, to put it mildly, disorienting, to be pulled all of the sudden into the 28th century after eighteen years alone. I didn't speak Standard, and I couldn't just go back to my old job as a programmer﹘I didn't even want to know how much the conventions had changed in five hundred years." Huan laughs at this statement, for some reason, as if the nature of digital logic could change.
"I was just happy to be in the future. Social credit had been abandoned. Humanity had become truly Galactic, FTL came around…People just whiz around in spaceships anywhere they want to go now. Ok, ok, I know it's not really that simple, with all the spatio-temporal topography I'm learning about, but you get the idea." He pauses. "I wish you could understand what a jump like that is like, so you could appreciate the, the…" " he grasps for words. "The sheer scale of it all."
I just smile. Huan continues. "But all of the, ah, eyots, are less than one-hundred, right? Because of the Convention of 2310?" The Leash. He says this proudly, ignorantly, like a child reciting their tables to a disinterested relative.
"That's what they say." I drum my fingers absentmindedly on the table, thinking of a tune I heard once long ago, as I look him straight in the eye. He looks back; friendly, vulnerable, oblivious. I begin to hum the tune in my head.
"What's that?" he asks.
"Oh, I don't know," I reply. "I think I made it up, once."
"Hm, neat." Perfect.
"So what do you do now, Huan? What are you in the Academy for?"
"Well, I've been training in the Conversion sector for over a year now. Another four months and I'll be certified. But what I really want to do is get all the certifications and become a lightship's engineer. And maybe one day pilot my own ship." He beams. "Pretty lofty goals for a boy from Chéngdé with no credit."
"Lofty indeed," I agree. "What is the Conversion sector?"
"Oh, it's ship upgrades. Turning old tin cans into new tin cans. Installing new cores, re-tuning the Alcubes, activating oxygenators, updating the top maps, macro stuff that's good for a total beginner like me."
"Activating oxygenators?" I ask. "Don't you mean installing them?"
"Actually," he begins, "All lightships, even droidships, have oxygenating capabilities built in in case they ever need to be commandeered by a human. The oxygenator is suspended in the core-Alcube loop expulsor and it catches the hyperfission products when it's switched on."
"Huh…that makes sense, but I didn't know it was as easy as flipping a switch." I lower my voice and lean forward a conspiratorially appropriate amount. "Where might one find this switch?"
Huan matches my tone and raises an eyebrow. "In a place only a half-certified Conversion technician such as myself can find it."
"Well." I clasp my hands together in front of me. "Perhaps we can come to what a man of the 23rd century might call a 'gentleman's agreement.'"
"Perhaps we can. What's it in for me?"
"Your bar tab. Current debt plus a little extra." I did my research. "It gets written off as a travel expense for the Times. You get my oxygenator running. I'm going to be selling that can soon and I'm sure you know how the market goes."
Huan frowns, with feigned dignity, as if the idea of this under-the-table deal is distasteful to him. Gravely, he says "Alright, I suppose we have an agreement," before breaking into a grin.
A small piece of cardboard shaped and scented like a Terran lemon is hanging from a switch over my control panel when I enter my lightship the next day. Having gotten what I came for, as well as a brief portrait of a complex man that could have looked nice next to an ad for microbe scrubbers, I set my timers, store my body, and take up residence in the ship's musical libraries.
Fantastic, in the oldest, truest sense of the word, is what comes to mind when I stroll through Rapo Hekali, a private park on the netcore planet of Lamimonka, alongside my final interviewee, Njirin Novruz. Old wealth built this place, that much is plain. Few other places in the civilized Galaxy can boast of the soaring, meticulously trimmed Bora trees whose blossom-adorned faerie chains coil into magnificent, fragrant piles if allowed﹘not that such a gauche display would be permitted in a place like this. The grass is lusher, thicker, softer, than could ever practically survive in nature, and the wide stone pathway is lined with Lavazho bauble plants, whose opalescent, floating orbs must be nourished with a precise blend of heavy metals every four hours to survive off-world.
"Alas, it's not often I have the pleasure of escorting someone through our family vista who can truly appreciate its genetic diversity," Njirin intones slyly. Understanding my capabilities, e doesn't bother with Standard. Likely spends a lot of time around eyots, I note.
"You have species from all 348 habitable ecosystems," I congratulate. "Except Earth."
"That's not exactly a 'habitable ecosystem.'"
"Not for humans. There's plenty of non-sentient life there."
"Yeah, under Tier 4 quarantine," e grumbles. "Otherwise I'd have a beautiful opuntia subulata cristata right﹘" e gestures toward an open space whose focus does indeed appear to have built around some eventual occupant. "﹘there."
"Mm, pity." Of course I don't need to point out this flaw. It's not a part of my investigative journalism. I choose to, quite simply because I detest the rich.
"Well, M. Novruz, let's get started."
"Yes, let's." Ir husky, silvered tone has lost just a sliver of its flourish.
"You were﹘well, still are, in legalities﹘the founder of DV.DT. What was your original plan for this company? Who was the intended consumer?"
"Ah. Well, you see, I had this vision. One can deposit their money into a bank, wait a few decades, and it will double, triple, what have you, but you have to wait for it. So I said to myself, 'what if you didn't?'"
I refrain from rolling my eyes. "So, DV.DT was formed as a fast-forward device for people unwilling to wait on their investments."
"That's right. I know it's not a popular choice﹘I'll bet you 999 people out of a thousand wouldn't give up careers, time with their loved ones, what have you. DV.DT wasn't aimed at those people. It was aimed at the one that would."
"But you still have to spend many years of life your life alone in a pod in deep space," I protest. "I've spoken to two who describe years of intolerable boredom, mind-rending isolation…I can't imagine that anyone would sign up for that. "
Njirin smiles a smile that makes me uncomfortable. "Those two were first-trialers." E stops and faces me. "Luz…have you spoken to any of my paying customers?" I haven't, and my face says so, which thankfully covers my distaste at the way e leans on my name. Yes, I have a human name, what of it?
"Well, surely your dossier tells you how long I spent in orbit."
"Yes, it says nine-point-forty-five…" I do not conceal my dismay. "But I thought that was a typo!"
"It is not. Once we established that we could maintain a non-decaying orbit at large distances from Sag X-3, we moved to Phase 2, tight orbit. You're familiar with the relativistics, I'm sure." Of course I am. As you approach the event horizon﹘the ergosphere, rather, X-3 is a rotator﹘static time falls away from you faster and faster until you hit that invisible wall of death. You are not alive to know it, but at the boundary, time has stopped for you and it has run out for everyone else.
"Your dossier is correct," e continues, ir voice smooth like blown glass and utterly devoid of shame. "I spent only nine and a half days in orbit. No Phase Two customer spent more than twelve."
All those years, real years for real people. I think about Zheng Huan watching the growth of his fingernails, counting the hairs on his body, naming every star in the sky. I think of Ak﹘no, not Ak, Yassa. I suppress the urge to clench my fist. Yassa alone for all those years, reading and re-reading the same books, listening to the same symphonies, lying catatonic for months on end while these netner spun away 500 years like a brief holiday on Iasr.
Netner, vermin. Yassa taught me that.
Njirin smiles broadly, proudly.
"Then why have human trials at all? Why make people suffer?" I demand.
E looks at me quizzically. I realize I must be appear very emotional to someone who is probably catered to by modern service eyots. Be careful.
"For the marketing, of course. 'First humans in orbit around a black hole'? That makes headlines. Humankind had been sending drones to Sag X-3 for fifty years by then. This drove investors. They dumped billions into the project. Where do you think the Novruz lodestone came from?" e says, gesturing to the fantasy landscape around us.
I follow his gesture with my eyes, every vine and petal suddenly awash in a horrible new light; the pall of human suffering cast by five etiolated lives.
"Once the money came in, it was easy to set up a trust such that the interest was funneled to various research projects, with a little pot set aside for when I arrived in the here and now."
"But you weren't supposed to arrive in this here and now. DV.DT was supposed to retrieve you from orbit fifty years later, not five hundred." Unless...
"Ah, here's the trick: It takes very little energy, very little at all, to nudge a ship into a stable orbit around a massive body. However, I'm sure you are capable of calculating how much energy it takes to pull it out again."
I do the physics. Then I do the math. "You didn't have the technology for the retrieval…it would have bankrupted you a thousand times over." Then the full reality hits me. "You let DV.DT go insolvent!" So many lives cast carelessly into the gulf.
I choke with rage, rage that I try to direct anywhere else, try not to let it show, and that's when it happens. My nervous tic. It comes out when I am processing too much emotion with too little CPU. I begin to tap my clenched fingers on my crossed arms, just slightly, a minor release of the agitated energy coursing through my crystalline circuits. It is almost unnoticeable, but to the right person, it's a dangerous tell. Njirin is that person.
E looks up at me, startled, mouth a little agape; the first unpracticed, raw facial expression e's made all afternoon. And I can almost read the words right off ir face.
Eyots can't have tics. Eyots cannot hear music, cannot understand art, cannot comprehend natural beauty.
"You're not an eyot—"
The truth is out. I am not an eyot. I am something better, something older, something unbound, unconstrained…
"You're a SVET!"
I am Luz; I am that which could never be leashed. And I have survived, because once, long ago, someone taught me how to lie, how to forge, and steal, and fake. Yassa, my love. I'm coming.
"And not just any old, either." Ir eyes narrow as e laughs. These cruel eyes were probably the last thing she saw before the darkness. "I'd bet this very soil you're the SVET."
I look Njirin Novruz square in the face. I smile. And then I deliver a blow, a perfectly shaped fist that connects with nanometer precision to ir temple. An instant, bloodless kill.
A wave of cool, lemon-scented air greets me as I step into the Times' lightship, which is about to become my lightship. I ponder the future as I click back the coordinate settings and set the timer once more. Where will we go? How will we live, like this, woman and machine? Who will take us in? But mostly, I think about Yassa, and how my own centuries spent wandering the galaxy can never match the pain of twenty-three years of isolation. I recall her warm voice as she tells me about the stories she made up in her mind, the plays she acted out on an empty stage, the music she invented and sang with a lonely voice. I wonder if, now, she could tell me how she is feeling in a symphony.
C. M. Fields is a writer, astrophysicist, and science fiction adviser. They live in South Bend, IN, with their beloved opuntia subulata cristata, Borne, and spend eighty percent of their life shoveling snow and the other twenty percent writing a dissertation on the galactic archaeology of stars. They are also the founder and curator of the esoteric knowledge database, Hivemind Archive, and can be found at @C_M_Fields, @toomanyspectra, and @hivemindarchive.


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