Startup Logic in DH: Performativity and Sustainability

This paper argues that the logic of startup companies has penetrated the digital humanities, which has led the field to prioritize glossy veneer over sound construction (“skinning”), pursue grants for survival (“venture capitalists”), and conspicuously broadcast through social media to self-promote (“branding”). The result is a field centered on the performativity of a digital artifact, with little consideration of sustainability, contributing to the existing scholarly discourse, and a graveyard of abandoned projects once they have outlived their usefulness. It is a pattern with which I am well-familiar. In 2001, I left what would become a lucrative and successful Internet startup company to pursue graduate studies. There were myriad reasons—I disliked the rancor over finances; my schoolwork suffered; but most of all, I was disenchanted by the logic of startups, which stressed interface performativity over quality. Much to my dismay, I have discovered that the same logic has emerged in the digital humanities. This paper warns that this is untenable, both in the digital humanities and startup worlds. My company churned through projects in pursuit of angel investor funding, usually the result of a passable interface over a shoddy backend could collapse with the slightest breeze; sometimes our products were merely frontends with little else. Startup logic demands builds for funding gains and little else; sustainability isn’t prioritized because the goal is to be bought out by a larger company. Likewise, digital humanities, ruled by the same logic, highlights performativity over theoretical and critical engagement. The year 2001 also saw the Dot-com bubble burst; this paper warns that unless the model changes, a similar collapse may be in store for the digital humanities. Using the case of our building of a DH lab at the University of Utah, I explain how we attempted to circumvent startup logic from taking hold

The effects of peripheral and central high insulin on brain insulin signaling and amyloid-β in young and old APP/PS1 mice

Hyperinsulinemia is a risk factor for late-onset Alzheimer's disease (AD). In vitro experiments describe potential connections between insulin, insulin signaling, and amyloid-β (Aβ), but in vivo experiments are needed to validate these relationships under physiological conditions. First, we performed hyperinsulinemic-euglycemic clamps with concurrent hippocampal microdialysis in young, awake, behaving APP(swe)/PS1(dE9) transgenic mice. Both a postprandial and supraphysiological insulin clamp significantly increased interstitial fluid (ISF) and plasma Aβ compared with controls. We could detect no increase in brain, ISF, or CSF insulin or brain insulin signaling in response to peripheral hyperinsulinemia, despite detecting increased signaling in the muscle. Next, we delivered insulin directly into the hippocampus of young APP/PS1 mice via reverse microdialysis. Brain tissue insulin and insulin signaling was dose-dependently increased, but ISF Aβ was unchanged by central insulin administration. Finally, to determine whether peripheral and central high insulin has differential effects in the presence of significant amyloid pathology, we repeated these experiments in older APP/PS1 mice with significant amyloid plaque burden. Postprandial insulin clamps increased ISF and plasma Aβ, whereas direct delivery of insulin to the hippocampus significantly increased tissue insulin and insulin signaling, with no effect on Aβ in old mice. These results suggest that the brain is still responsive to insulin in the presence of amyloid pathology but increased insulin signaling does not acutely modulate Aβ in vivo before or after the onset of amyloid pathology. Peripheral hyperinsulinemia modestly increases ISF and plasma Aβ in young and old mice, independent of neuronal insulin signaling. SIGNIFICANCE STATEMENT The transportation of insulin from blood to brain is a saturable process relevant to understanding the link between hyperinsulinemia and AD. In vitro experiments have found direct connections between high insulin and extracellular Aβ, but these mechanisms presume that peripheral high insulin elevates brain insulin significantly. We found that physiological hyperinsulinemia in awake, behaving mice does not increase CNS insulin to an appreciable level yet modestly increases extracellular Aβ. We also found that the brain of aged APP/PS1 mice was not insulin resistant, contrary to the current state of the literature. These results further elucidate the relationship between insulin, the brain, and AD and its conflicting roles as both a risk factor and potential treatment

ttm-1 encodes CDF transporters that excrete zinc from intestinal cells of C. elegans and act in a parallel negative feedback circuit that promotes homeostasis

Zinc is an essential metal involved in a wide range of biological processes, and aberrant zinc metabolism is implicated in human diseases. The gastrointestinal tract of animals is a critical site of zinc metabolism that is responsible for dietary zinc uptake and distribution to the body. However, the role of the gastrointestinal tract in zinc excretion remains unclear. Zinc transporters are key regulators of zinc metabolism that mediate the movement of zinc ions across membranes. Here, we identified a comprehensive list of 14 predicted Cation Diffusion Facilitator (CDF) family zinc transporters in Caenorhabditis elegans and demonstrated that zinc is excreted from intestinal cells by one of these CDF proteins, TTM-1B. The ttm-1 locus encodes two transcripts, ttm-1a and ttm-1b, that use different transcription start sites. ttm-1b expression was induced by high levels of zinc specifically in intestinal cells, whereas ttm-1a was not induced by zinc. TTM-1B was localized to the apical plasma membrane of intestinal cells, and analyses of loss-of-function mutant animals indicated that TTM-1B promotes zinc excretion into the intestinal lumen. Zinc excretion mediated by TTM-1B contributes to zinc detoxification. These observations indicate that ttm-1 is a component of a negative feedback circuit, since high levels of cytoplasmic zinc increase ttm-1b transcript levels and TTM-1B protein functions to reduce the level of cytoplasmic zinc. We showed that TTM-1 isoforms function in tandem with CDF-2, which is also induced by high levels of cytoplasmic zinc and reduces cytoplasmic zinc levels by sequestering zinc in lysosome-related organelles. These findings define a parallel negative feedback circuit that promotes zinc homeostasis and advance the understanding of the physiological roles of the gastrointestinal tract in zinc metabolism in animals

Mortality risk associated with underweight : a census-linked cohort of 31,578 individuals with up to 32 years of follow-up

BACKGROUND: In contrast to obesity, information on the health risks of underweight is sparse. We examined the long-term association between underweight and mortality by considering factors possibly influencing this relationship. METHODS: We included 31,578 individuals aged 25-74 years, who participated in population based health studies between 1977 and 1993 and were followed-up for survival until 2008 by record linkage with the Swiss National Cohort (SNC). Body Mass Index (BMI) was calculated from measured (53% of study population) or self-reported height and weight. Underweight was defined as BMI < 18.5 kg/m2. Cox regression models were used to determine mortality Hazard Ratios (HR) of underweight vs. normal weight (BMI 18.5- < 25.0 kg/m2). Covariates were study, sex, smoking, healthy eating proxy, sports frequency, and educational level. RESULTS: Underweight individuals represented 3.0% of the total study population (n = 945), and were mostly women (89.9%). Compared to normal weight, underweight was associated with increased all-cause mortality (HR: 1.37; 95% CI: 1.14-1.65). Increased risk was apparent in both sexes, regardless of smoking status, and mainly driven by excess death from external causes (HR: 3.18; 1.96-5.17), but not cancer, cardiovascular or respiratory diseases. The HR were 1.16 (0.88-1.53) in studies with measured BMI and 1.59 (1.24-2.05) with self-reported BMI. CONCLUSIONS: The increased risk of dying of underweight people was mainly due to an increased mortality risk from external causes. Using self-reported BMI may lead to an overestimation of mortality risk associated with underweight

Structural basis for L27 domain‐mediated assembly of signaling and cell polarity complexes

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/102252/1/emboj7600294.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/102252/2/emboj7600294-sup-0001.pd

GIV/Girdin is a central hub for profibrogenic signalling networks during liver fibrosis.

Progressive liver fibrosis is characterized by the deposition of collagen by activated hepatic stellate cells (HSCs). Activation of HSCs is a multiple receptor-driven process in which profibrotic signals are enhanced and antifibrotic pathways are suppressed. Here we report the discovery of a signalling platform comprising G protein subunit, Gαi and GIV, its guanine exchange factor (GEF), which serves as a central hub within the fibrogenic signalling network initiated by diverse classes of receptors. GIV is expressed in the liver after fibrogenic injury and is required for HSC activation. Once expressed, GIV enhances the profibrotic (PI3K-Akt-FoxO1 and TGFβ-SMAD) and inhibits the antifibrotic (cAMP-PKA-pCREB) pathways to skew the signalling network in favour of fibrosis, all via activation of Gαi. We also provide evidence that GIV may serve as a biomarker for progression of fibrosis after liver injury and a therapeutic target for arresting and/or reversing HSC activation during liver fibrosis

Deficiency of plasminogen activator inhibitor‐2 results in accelerated tumor growth

BackgroundUpregulation of the plasminogen activation system, including urokinase plasminogen activator (uPA), has been observed in many malignancies, suggesting that co‐opting the PA system is a common method by which tumor cells accomplish extracellular matrix proteolysis. PAI‐2, a serine protease inhibitor, produced from the SERPINB2 gene, inhibits circulating and extracellular matrix‐tethered uPA. Decreased SERPINB2 expression has been associated with increased tumor invasiveness and metastasis for several types of cancer. PAI‐2 deficiency has not been reported in humans and PAI‐2‐deficient (SerpinB2−/−) mice exhibit no apparent abnormalities.ObjectivesWe investigated the role of PAI‐2 deficiency on tumor growth and metastasis.MethodsTo explore the long‐term impact of PAI‐2 deficiency, a cohort of SerpinB2−/− mice were aged to >18 months, with spontaneous malignancies observed in 4/9 animals, all of apparently vascular origin. To further investigate the role of PAI‐2 deficiency in malignancy, SerpinB2−/− and wild‐type control mice were injected with either B16 melanoma or Lewis lung carcinoma tumor cells, with markedly accelerated tumor growth observed in SerpinB2−/− mice for both cell lines. To determine the relative contributions of PAI‐2 from hematopoietic or nonhematopoietically derived sources, bone marrow transplants between wild‐type C57BL/6J and SerpinB2−/− mice were performed.Results and ConclusionsOur results suggest that PAI‐2 deficiency increases susceptibility to spontaneous tumorigenesis in the mouse, and demonstrate that SerpinB2 expression derived from a nonhematopoietic compartment is a key host factor in the regulation of tumor growth in both the B16 melanoma and Lewis lung carcinoma models.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/163438/2/jth15054_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/163438/1/jth15054.pd

Formation of magnetite and iron-rich carbonates by thermophilic iron-reducing bacteria

Laboratory experiments were performed to study the formation of iron minerals by a thermophilic (45 - 75 degree(s)C) fermentative iron-reducing bacterial culture (TOR39) obtained from the deep subsurface. Using amorphous Fe(III) oxyhydroxide as an electron acceptor and glucose as an electron donor, TOR39 produced magnetite and iron-rich carbonates at conditions consistent, on a thermodynamic basis, with Eh (-200 mV to -415 mV) and pH (6.2 to 7.7) values determined for these experiments. Analyses of the precipitating solid phases by X-ray diffraction showed that the starting amorphous Fe(III) oxyhydroxide was nearly completely converted to magnetite and Fe-rich carbonate after 20 days of incubation. Increasing bicarbonate concentration in the chemical milieu resulted in increased proportions of siderite relative to magnetite and the addition of MgCl2 caused the formation of magnesium-rich carbonate in addition to siderite. The results suggest that the TOR39 bacterial culture may have the capacity to form magnetite and iron-rich carbonates in a variety of geochemical conditions. These results may have significant implications for studying the past biogenic activities in the Martian meteorite ALH84001

Development and first evaluation of an attractant impregnated adhesive tape against blood-sucking flies

Stable flies are one of the most important arthropod pests of livestock that reduce cattle weight gain and milk production leading to annual economic losses in excess of $2 billion to the US cattle industry. The host-seeking behavior is primarily mediated by associated odors from stable fly larval development environments and host animals. The present paper reports the development and evaluation of attractant-impregnated adhesive tapes to reduce stable fly attacks on cattle. Laboratory bioassays showed that only m-cresol impregnated adhesive tapes caught significantly more stable flies (16 ± 1) than the control tape without attractant added (7 ± 1), with a 77% fly recapture rate. Attractantimpregnated adhesive tapes deployed in cattle feedlots showed significant impacts in reducing fly population, with a total of one million stable flies captured over a period of three weeks (mean catches from 57 596 to 102 088 stable flies per trap per week). It further relieved cattle stress with a significant reduction of biting fly avoidance behavior, (6 ± 0.4 cows observed with tail wagging in control vs. 3 ± 0.4 from the trap-deployed). The efficacy of the developed tapes lasted up to 1-week longevity, although 70% of mcresol was released starting from the second day. The m-cresol impregnated adhesive tape provided an 80% reduction in cattle stress due to stable fly attack. This is the first report of a technology developed by integrating an attractant compound into an adhesive material on a plastic film with demonstrated effectiveness in trapping biting flies that attack livestock animals

Development and first evaluation of an attractant impregnated adhesive tape against blood-sucking flies

Stable flies are one of the most important arthropod pests of livestock that reduce cattle weight gain and milk production leading to annual economic losses in excess of $2 billion to the US cattle industry. The host-seeking behavior is primarily mediated by associated odors from stable fly larval development environments and host animals. The present paper reports the development and evaluation of attractant-impregnated adhesive tapes to reduce stable fly attacks on cattle. Laboratory bioassays showed that only m-cresol impregnated adhesive tapes caught significantly more stable flies (16 ± 1) than the control tape without attractant added (7 ± 1), with a 77% fly recapture rate. Attractantimpregnated adhesive tapes deployed in cattle feedlots showed significant impacts in reducing fly population, with a total of one million stable flies captured over a period of three weeks (mean catches from 57 596 to 102 088 stable flies per trap per week). It further relieved cattle stress with a significant reduction of biting fly avoidance behavior, (6 ± 0.4 cows observed with tail wagging in control vs. 3 ± 0.4 from the trap-deployed). The efficacy of the developed tapes lasted up to 1-week longevity, although 70% of mcresol was released starting from the second day. The m-cresol impregnated adhesive tape provided an 80% reduction in cattle stress due to stable fly attack. This is the first report of a technology developed by integrating an attractant compound into an adhesive material on a plastic film with demonstrated effectiveness in trapping biting flies that attack livestock animals