To date, a compromise between resolution and print speed has rendered most high-resolution additive manufacturing technologies unscalable with limited applications. By combining a reduction lens optics system for single-digit-micrometer resolution, an in-line camera system for contrast-based sharpness optimization, and continuous liquid interface production (CLIP) technology for high scalability, we introduce a single-digit-micrometer-resolution CLIP-based 3D printer that can create millimeter-scale 3D prints with single-digit-micrometer-resolution features in just a few minutes. A simulation model is developed in parallel to probe the fundamental governing principles in optics, chemical kinetics, and mass transport in the 3D printing process. A print strategy with tunable parameters informed by the simulation model is adopted to achieve both the optimal resolution and the maximum print speed. Together, the high-resolution 3D CLIP printer has opened the door to various applications including, but not limited to, biomedical, MEMS, and microelectronics.
Geisler et al. show that GABAtransaminase catalyzes GABA synthesis in the liver of obese mice, resulting in hyperinsulinemia, insulin resistance, and hyperphagia. In people with obesity, liver GABA-transaminase expression is positively associated with hyperinsulinemia. Thus, GABAtransaminase inhibitors may be effective at restoring glucose homeostasis in obese, hyperinsulinemic, insulinresistant individuals.
Mice are a valuable model for elegant studies of complex, systems-dependent diseases, including pulmonary diseases. Current tools to assess lung function in mice are either terminal or lack accuracy. We set out to develop a low-cost, accurate, head-out variable-pressure plethysmography system to allow for repeated, non-terminal measurements of lung function in mice. Current head-out plethysmography systems are limited by air leaks that prevent accurate measures of volume and flow. We designed an inflatable cuff that encompasses the mouse's neck preventing air leak. We wrote corresponding software to collect and analyze the data, remove movement artifacts, and automatically calibrate each dataset. This software calculates inspiratory/expiratory volume, inspiratory/expiratory time, breaths per minute, mid-expiratory flow, and end-inspiratory pause. To validate the use, we established that our plethysmography system accurately measured tidal breathing, the bronchoconstrictive response to methacholine, sex and age associated changes in breathing, and breathing changes associated with house dust mite sensitization. Our estimates of volume, flow, and timing of breaths are in line with published estimates, we observed dose-dependent decreases in volume and flow in response to methacholine (P < 0.05), increased lung volume and decreased breathing rate with aging (P < 0.05), and that house dust mite sensitization decreased volume and flow (P <0.05) while exacerbating the methacholine induced increases in inspiratory and expiratory time (P < 0.05). We describe an accurate, sensitive, low-cost, head-out plethysmography system that allows for longitudinal studies of pulmonary disease in mice.
With a growing population, a reliable food supply is increasingly important. Heat stress reduces livestock meat and milk production. Genetic selection of highproducing animals increases endogenous heat production, while climate change increases exogenous heat exposure. Both sources of heat exacerbate the risk of heat-induced depression of production. Rodents are valuable models to understand mechanisms conserved across species. Heat exposure suppresses feed intake across homeothermic species including rodents and production animal species. We assessed the response to early-mid lactation or late-gestation heat exposure on milk production and mammary gland development/ function, respectively. Using pair-fed controls we experimentally isolated the feed intake-dependent and -independent effects of heat stress on mammary function and mass. Heat exposure (35°C, relative humidity 50%) decreased daily feed intake. When heat exposure occurred during lactation, hypophagia accounted for approximately 50% of the heat stress-induced hypogalactia. Heat exposure during middle to late gestation suppressed feed intake, which was fully responsible for the lowered mammary gland weight of dams at parturition. However, the impaired mammary gland function in heat-exposed dams measured by metabolic rate and lactogenesis could not be explained by depressed feed consumption. In conclusion, mice recapitulate the depressed milk production and mammary gland development observed in dairy species while providing insight regarding the role of feed intake. This opens the potential to apply genetic, experimental, and pharmacological models unique to mice to identify the mechanism by which heat is limiting animal production.
Hepatic lipid accumulation is a hallmark of type II diabetes (T2D) and associated with hyperinsulinemia, insulin resistance, and hyperphagia. Hepatic synthesis of GABA, catalyzed by GABAtransaminase (GABA-T), is upregulated in obese mice. To assess the role of hepatic GABA production in obesity-induced metabolic and energy dysregulation, we treated mice with two pharmacologic GABA-T inhibitors and knocked down hepatic GABA-T expression using an antisense oligonucleotide. Hepatic GABA-T inhibition and knockdown decreased basal hyperinsulinemia and hyperglycemia, and improved glucose intolerance. GABA-T knockdown improved insulin sensitivity assessed by hyperinsulinemiceuglycemic clamps in obese mice. Hepatic GABA-T knockdown also decreased food intake and induced weight loss without altering energy expenditure in obese mice. Data from people with obesity support the notion that hepatic GABA production and transport are associated with serum insulin, HOMA-IR, T2D, and BMI. These results support a key role for hepatocyte GABA production in the dysfunctional glucoregulation and feeding behavior associated with obesity.However, in the liver, GABA-T mediates GABA synthesis 12 . We have proposed that hepatic lipids activate reversed GABA shunt activity in hepatocytes, and that hepatic GABA and glucose production are metabolically linked ). It remains completely untested whether manipulating this GABA shunt can prevent hepatic steatosis derived metabolic disease. Thus, GABA-T represents a promising target to decrease hyperinsulinemia and insulin resistance by limiting hepatic GABA production. Accordingly, in the current manuscript, we employed two novel models to limit hepatic GABA production: 1) pharmacologic inhibition of GABA-T activity, and 2) antisense oligonucleotide (ASO) mediated knockdown of hepatic specific GABA-T expression. Using these models for the first time we assessed systemic glucose homeostasis to strengthen the causative role between hepatic GABA production and hyperinsulinemia / insulin resistance. We also assessed food intake and energy expenditure to understand the role of hepatic GABA production in the dysregulation of energy homeostasis in obesity. Results GABA-Transaminase Inhibition Improves Glucose Homeostasis in ObesityTo directly assess the effect of GABA-T in obesity-induced metabolic dysfunction we treated high fat diet-induced obese mice with one of two irreversible GABA-T inhibitors, ethanolamine-Osulphate (EOS) or vigabatrin (8 mg/day). Both reduce hepatic GABA-T activity by over 90% within two days 13 . Through 5 days of treatment, body weight remained similar among EOS, vigabatrin, and saline injected mice (Fig. 1A). Four days of EOS or vigabatrin treatment decreased serum insulin and glucose concentrations and increased the glucose:insulin ratio relative to pre-treatment ( Figs. 1B-1D). Two-weeks washout from EOS or vigabatrin resulted in a return of serum insulin and the glucose:insulin ratio to pretreatment levels (Figs. 1B-1D). EOS treatment (5 days) decreased serum glucagon relat...
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