From little things big things grow: enhancement of an acoustic telemetry network to monitor broad-scale movements of marine species along Australia's east coast.

BACKGROUND: Acoustic telemetry has become a fundamental tool to monitor the movement of aquatic species. Advances in technology, in particular the development of batteries with lives of > 10 years, have increased our ability to track the long-term movement patterns of many species. However, logistics and financial constraints often dictate the locations and deployment duration of acoustic receivers. Consequently, there is often a compromise between optimal array design and affordability. Such constraints can hinder the ability to track marine animals over large spatial and temporal scales. Continental-scale receiver networks have increased the ability to study large-scale movements, but significant gaps in coverage often remain. METHODS: Since 2007, the Integrated Marine Observing System's Animal Tracking Facility (IMOS ATF) has maintained permanent receiver installations on the eastern Australian seaboard. In this study, we present the recent enhancement of the IMOS ATF acoustic tracking infrastructure in Queensland to collect data on large-scale movements of marine species in the northeast extent of the national array. Securing a relatively small initial investment for expanding receiver deployment and tagging activities in Queensland served as a catalyst, bringing together a diverse group of stakeholders (research institutes, universities, government departments, port corporations, industries, Indigenous ranger groups and tourism operators) to create an extensive collaborative network that could sustain the extended receiver coverage into the future. To fill gaps between existing installations and maximise the monitoring footprint, the new initiative has an atypical design, deploying many single receivers spread across 2,100 km of Queensland waters. RESULTS: The approach revealed previously unknown broad-scale movements for some species and highlights that clusters of receivers are not always required to enhance data collection. However, array designs using predominantly single receiver deployments are more vulnerable to data gaps when receivers are lost or fail, and therefore "redundancy" is a critical consideration when designing this type of array. CONCLUSION: Initial results suggest that our array enhancement, if sustained over many years, will uncover a range of previously unknown movements that will assist in addressing ecological, fisheries, and conservation questions for multiple species.

Ammonia for Determination of Cage-change Frequency in Antelope Ground Squirrels (Ammospermophilus leucurus).

Due to a lack of evidence-based standards for cage-change intervals for antelope ground squirrels (AGS, Ammospermophilus leucurus), we evaluated cage ammonia accumulation in our colony of adult, wild-caught AGS and identified factors that influenced ammonia levels. Intracage ammonia was measured daily in singly housed AGS in static caging that contained a running wheel and 1/2, 3/4, 1, or 2 quart (qt) of corncob bedding. Cages were changed when ammonia levels reached greater than 50 ppm, our upper acceptable limit for ammonia based on mouse studies of ammonia aversion and toxicity. We also measured average daily water consumption over 2 wk to examine any correlation between water use and ammonia accumulation. We hypothesized that the desert-dwelling AGS would not reach intracage ammonia levels of greater than 50 ppm in a 2-wk interval at any bedding volume. Our data showed that intracage ammonia was highly variable among individuals and was significantly associated with water consumption and bedding volumes. Seventeen percent of AGS on 1/2 qt of bedding and 18% on 3/4 qt of bedding reached greater than 50 ppm ammonia before 7 d. All AGS on 1 and 2 qt of bedding remained below 50 ppm ammonia for 1 wk. Even when maintained on 2 qt of bedding, not all AGS remained below 50 ppm ammonia for 2 wk. Therefore, we concluded that the most appropriate option was weekly cage change for singly housed AGS on 1 qt of bedding in static caging.

Low dose lofexidine for medically directed outpatient opioid tapering in adults with chronic pain: a prospective case series.

BACKGROUND: In adults with chronic pain, mild-to-moderate withdrawal symptoms during medically directed opioid tapering in the outpatient setting may not be accompanied by hypertension or tachycardia. This clinical scenario could limit the use of lofexidine at dosages reported in clinical trials of opioid withdrawal precipitated by abrupt opioid discontinuation. Thus, the primary aim of this prospective case series is to describe the use of low dose lofexidine for opioid withdrawal in patients with chronic pain undergoing medically directed opioid tapering in an outpatient setting. METHODS: Six patients (white 5, Latino 1) admitted to an outpatient interdisciplinary pain rehabilitation program met inclusion and exclusion criteria. Patients self-selected to undergo medically directed opioid tapering, and the medication the patients were prescribed upon admission was used in the taper schedule. Upon initiation of the opioid taper, patients received 0.18 mg of lofexidine every 6 hours. RESULTS: Five of the six patients were women, and the median morphine milligram equivalents at baseline were 36.9. The median taper duration was 15 days, and the median duration of lofexidine administration was 14 days. Withdrawal scores were mild throughout the taper in four patients, and two patients with fibromyalgia experienced single episodes of moderately severe withdrawal symptoms at the median morphine milligram equivalent midpoint of the taper. No hypotension or sustained bradycardia were observed, and no adverse effects related to lofexidine were reported. CONCLUSION: The observations from this prospective case series suggest that low-dose lofexidine may be a feasible adjunct medication to attenuate withdrawal symptoms in adults with chronic pain undergoing outpatient opioid tapering.

The endocannabinoid system and retinoic acid signaling combine to influence bone growth.

Osteoporosis is an increasing burden on public health as the world-wide population ages and effective therapeutics are severely needed. Two pathways with high potential for osteoporosis treatment are the retinoic acid (RA) and endocannabinoid system (ECS) signaling pathways. We sought to elucidate the roles that these pathways play in bone development and maturation. Here, we use chemical treatments to modulate the RA and ECS pathways at distinct early, intermediate, and late times bone development in zebrafish. We further assessed osteoclast activity later in zebrafish and medaka. Finally, by combining sub-optimal doses of AR and ECS modulators, we show that enhancing RA signaling or reducing the ECS promote bone formation and decrease osteoclast abundance and activity. These data demonstrate that RA signaling and the ECS can be combined as sub-optimal doses to influence bone growth and may be key targets for potential therapeutics.

Experiences of Inuit in Canada who travel from remote settings for cancer care and impacts on decision making.

BACKGROUND: Inuit experience the highest cancer mortality rates from lung cancer in the world with increasing rates of other cancers in addition to other significant health burdens. Inuit who live in remote areas must often travel thousands of kilometers to large urban centres in southern Canada and negotiate complex and sometimes unwelcoming health care systems. There is an urgent need to improve Inuit access to and use of health care. Our study objective was to understand the experiences of Inuit in Canada who travel from a remote to an urban setting for cancer care, and the impacts on their opportunities to participate in decisions during their journey to receive cancer care. METHODS: We are an interdisciplinary team of Steering Committee and researcher partners ("the team") from Inuit-led and/or -specific organizations that span Nunavut and the Ontario cancer health systems. Guided by Inuit societal values, we used an integrated knowledge translation (KT) approach with qualitative methods. We conducted semi-structured interviews with Inuit participants and used process mapping and thematic analysis. RESULTS: We mapped the journey to receive cancer care and related the findings of client (n = 8) and medical escort (n = 6) ("participant") interviews in four themes: 1) It is hard to take part in decisions about getting health care; 2) No one explains the decisions you will need to make; 3) There is a duty to make decisions that support family and community; 4) The lack of knowledge impacts opportunities to engage in decision making. Participants described themselves as directed, with little or no support, and seeking opportunities to collaborate with others on the journey to receive cancer care. CONCLUSIONS: We describe the journey to receive cancer care as a "decision chain" which can be described as a series of events that lead to receiving cancer care. We identify points in the decision chain that could better prepare Inuit to participate in decisions related to their cancer care. We propose that there are opportunities to build further health care system capacity to support Inuit and enable their participation in decisions related to their cancer care while upholding and incorporating Inuit knowledge.

3D-Printable Fluoropolymer Gas Diffusion Layers for CO2 Electroreduction.

The electrosynthesis of value-added multicarbon products from CO2 is a promising strategy to shift chemical production away from fossil fuels. Particularly important is the rational design of gas diffusion electrode (GDE) assemblies to react selectively, at scale, and at high rates. However, the understanding of the gas diffusion layer (GDL) in these assemblies is limited for the CO2 reduction reaction (CO2 RR): particularly important, but incompletely understood, is how the GDL modulates product distributions of catalysts operating in high current density regimes > 300 mA cm-2 . Here, 3D-printable fluoropolymer GDLs with tunable microporosity and structure are reported and probe the effects of permeance, microstructural porosity, macrostructure, and surface morphology. Under a given choice of applied electrochemical potential and electrolyte, a 100× increase in the C2 H4 :CO ratio due to GDL surface morphology design over a homogeneously porous equivalent and a 1.8× increase in the C2 H4 partial current density due to a pyramidal macrostructure are observed. These findings offer routes to improve CO2 RR GDEs as a platform for 3D catalyst design.

Identifying the nature and extent of public and donor concern about the commercialisation of biobanks for genomic research.

Various forms of private investment are considered necessary for the sustainability of biobanks, yet pose significant challenges to public trust. To manage this tension, it is vital to identify the concerns of relevant stakeholders to ensure effective and acceptable policy and practice. This research examines the aspects of commercialisation that are of most concern to the Australian public (n = 800) and patients who had donated their tissue to two large disease specific (cancer) public biobanks (n = 564). Overall, we found a commercialisation effect (higher support for public relative to private) in relation to funding, research location and access to stored biospecimens. The effect was strongest for research locations and access compared to funding. A latent class analysis revealed the pattern of concern differed, with the majority (34.1%) opposing all aspects of commercialisation, a minority supporting all (15.7%), one quarter (26.8%) opposing some (sharing and selling tissue) but not others (research locations and funding), and a group who were unsure about most aspects but opposed selling tissue (23.5%). Patient donors were found to be more accepting of and unsure about most aspects of commercialisation. Members of the (general) public who were motivated to participate in biobanking were more likely to oppose some aspects while supporting others, while those who indicated they would not donate to a biobank were more likely to oppose all aspects of commercialisation. The results suggest that approaches to policy, engagement and awareness raising need to be tailored for different publics and patient groups to increase participation.

Physical performance is enhanced in old mice fed a short term diet medicated with rapamycin, acarbose, and phenylbutyrate.

Loss of physical performance, as seen in humans by decreased grip strength and overall physical fitness, is generally accepted to be a consequence of aging. Treatments to delay or reduce these changes or increase resilience to them are generally not available. In this preliminary study, 20-month-old male and female C57BL/6 mice were given either a standard mouse diet or a formulated mouse diet containing rapamycin (14 ppm), acarbose (1000 ppm), and phenylbutyrate (1000 ppm), or a diet containing one half dose of each drug, for 3 months. At the end of the study, performance on a rotarod and grip strength test was compared. In general, mice fed the full dose drug cocktail diet performed better on these assays, with significant improvements in rotarod performance in females fed the full dose cocktail and in grip strength in males fed the full dose cocktail, and females fed the low dose cocktail. These observations provide support for the concept that short term treatment with a cocktail of drugs that targets multiple aging pathways can increase resilience to aging, and suggests that this prototype cocktail could be part of a clinical therapeutic strategy for delaying age-related loss of physical performance in people.

Selected cardiac abnormalities in Trypanosoma cruzi serologically positive, discordant, and negative working dogs along the Texas-Mexico border.

BACKGROUND: Chagas disease is increasingly recognized in the southern U.S., where triatomine vectors transmit Trypanosoma cruzi among wildlife and domestic dogs with occasional vector spillover to humans. As in humans, clinical outcome in dogs is variable, ranging from acute death to asymptomatic infections or chronic heart disease. In order to characterize cardiac manifestations of T. cruzi infections, we tracked a cohort of naturally-infected dogs and a matched cohort of uninfected dogs. We hypothesized that selected measures of cardiac disease (abnormal rate, abnormal rhythm, and elevated cardiac troponin I (cTnI; a biomarker of cardiac injury)) would occur more commonly in infected than uninfected dogs matched by age, breed, sex and location. In addition to the clearly positive and negative dogs, we specifically tracked dogs with discordant test results across three independent serological assays to gather clinical data that might elucidate the infection status of these animals and inform the utility of the different testing approaches. RESULTS: We placed an ambulatory ECG monitor (Holter) on 48 government working dogs and analyzed 39 successful recordings that met length and quality criteria from 17 T. cruzi-infected, 18 uninfected dogs and 4 dogs with discordant results. Overall, 76.5% of positive, 100.0% of discordant, and 11.1% of negative dogs showed > 1 ECG abnormality (p < 0.0001), and positive and discordant dogs had a higher mean number of different types of ECG abnormalities than negative dogs (p < 0.001-0.014). The most common cardiac abnormalities included supraventricular and ventricular arrhythmias and atrioventricular block. Positive dogs had higher serum concentrations of cTnI than both negative dogs (p = 0.044) and discordant dogs (p = 0.06). Based on dog handler reports, nearly all (4/5; 80%) dogs with reported performance decline or fatigue were T. cruzi-infected dogs. CONCLUSIONS: Further understanding cardiac manifestations in dogs naturally infected with T. cruzi is critical for prognostication, establishing a baseline for drug and vaccine studies, and better understanding of zoonotic risk.

Nationwide Exposure of U.S. Working Dogs to the Chagas Disease Parasite, Trypanosoma cruzi.

Trypanosoma cruzi is a zoonotic protozoan parasite vectored by triatomine insects that are endemic to the Americas, including the southern United States. Surveillance of domestic dogs for T. cruzi exposure allows for the determination of geographic regions of transmission that are relevant for human and animal health. The U.S. Department of Homeland Security (DHS) working dogs provide critical security and detection services across the country, and many train or work in the southern United States, where they are at risk for T. cruzi exposure. We sampled blood from 1,610 working dogs (predominantly Belgian Malinois, German shepherds, and Labrador retrievers) from six task forces (including the Transportation Security Administration, Customs and Border Protection, Secret Service, and more) and two canine training centers across 41 states from 2015 to 2018. Canine sera that were reactive on at least two independent serological assays were considered positive for anti-T.-cruzi antibodies. In addition, up to three independent polymerase chain reaction (PCR) assays were used to detect and type T. cruzi DNA. Overall seroprevalence was 7.5%, and four dogs (0.25%, n = 1,610) had detectable parasite DNA in the blood, comprising parasite discrete taxonomic units (DTUs) TcIV and a coinfection of TcI/TcIV. Dogs that worked within versus outside of the geographic range of established triatomines showed comparable seroprevalence (7.3% and 9.2%, respectively; P = 0.61). Determining the prevalence of T. cruzi in these working dogs and looking at spatially associated risk factors have practical implications for disease risk management and could assist with improved control measures to protect both animal and human health.

Structural changes to the uterus of the dwarf ornate wobbegong shark (Orectolobus ornatus) during pregnancy.

Embryos of the viviparous dwarf ornate wobbegong shark (Orectolobus ornatus) develop without a placenta, unattached to the uterine wall of their mother. Here, we present the first light microscopy study of the uterus of O. ornatus throughout pregnancy. At the beginning of pregnancy, the uterine luminal epithelium and underlying connective tissue become folded to form uterine ridges. By mid to late pregnancy, the luminal surface is extensively folded and long luminal uterine villi are abundant. Compared to the nonpregnant uterus, uterine vasculature is increased during pregnancy. Additionally, as pregnancy progresses the uterine epithelium is attenuated so that there is minimal uterine tissue separating large maternal blood vessels from the fluid that surrounds developing embryos. We conclude that the uterus of O. ornatus undergoes an extensive morphological transformation during pregnancy. These uterine modifications likely support developing embryos via embryonic respiratory gas exchange, waste removal, water balance, and mineral transfer.

Additive Manufacturing of Optical Quality Germania-Silica Glasses.

Direct ink writing (DIW) three-dimensional (3D) printing provides a revolutionary approach to fabricating components with gradients in material properties. Herein, we report a method for generating colloidal germania feedstock and germania-silica inks for the production of optical quality germania-silica (GeO2-SiO2) glasses by DIW, making available a new material composition for the development of multimaterial and functionally graded optical quality glasses and ceramics by additive manufacturing. Colloidal germania and silica particles are prepared by a base-catalyzed sol-gel method and converted to printable shear-thinning suspensions with desired viscoelastic properties for DIW. The volatile solvents are then evaporated, and the green bodies are calcined and sintered to produce transparent, crack-free glasses. Chemical and structural evolution of GeO2-SiO2 glasses is confirmed by nuclear magnetic resonance, X-ray diffraction, and Raman spectroscopy. UV-vis transmission and optical homogeneity measurements reveal comparable performance of the 3D printed GeO2-SiO2 glasses to glasses produced using conventional approaches and improved performance over 3D printed TiO2-SiO2 inks. Moreover, because GeO2-SiO2 inks are compatible with DIW technology, they offer exciting options for forming new materials with patterned compositions such as gradients in the refractive index that cannot be achieved with conventional manufacturing approaches.

The first formed tooth serves as a signalling centre to induce the formation of the dental row in zebrafish.

The diversity of teeth patterns in actinopterygians is impressive with tooth rows in many locations in the oral and pharyngeal regions. The first-formed tooth has been hypothesized to serve as an initiator controlling the formation of the subsequent teeth. In zebrafish, the existence of the first tooth (named 4 V1) is puzzling as its replacement is induced before the opening of the mouth. Functionally, it has been shown that 4 V1 formation requires fibroblast growth factor (FGF) and retinoic acid (RA) signalling. Here, we show that the ablation of 4 V1 prevents the development of the dental row demonstrating its dependency over it. If endogenous levels of FGF and RA are restored after 4 V1 ablation, embryonic dentition starts again by de novo formation of a first tooth, followed by the dental row. Similarly, induction of anterior ectopic teeth induces subsequent tooth formation, demonstrating that the initiator tooth is necessary and sufficient for dental row formation, probably via FGF ligands released by 4 V1 to induce the formation of subsequent teeth. Our results show that by modifying the formation of the initiator tooth it is possible to control the formation of a dental row. This could help to explain the diversity of tooth patterns observed in actinopterygians and more broadly, how diverse traits evolved through molecular fine-tuning.

Captive parturition and neonatal growth of the dwarf ornate wobbegong (Orectolobus ornatus de Vis, 1883).

Neonatal predation in multispecies aquarium exhibits can prevent detection of captive breeding by wobbegong sharks. We used ultrasonography and isolation strategies to prevent neonatal predation and maximize survival/growth of the dwarf ornate wobbegong (Orectolobus ornatus de Vis, 1883). We captured seven free-living wobbegongs (two males and five females) and subjected each animal to a health assessment which led to the euthanasia of one female with a retained hook. Ultrasonography showed that females were pregnant, one was preovulatory, and one was in a resting phase. Two females (one pregnant) and one male were placed in isolation in each of two tanks. In October 2006, 25 neonates were born overnight with the two litters placed into separate neonate tanks. Over the ∼6.5-month monitoring period, four neonates with reduced body condition died without premonitory signs resulting in a 63.0% annual survival rate. Finite growth rates did not differ between sexes or litters and averaged (±SE) 12.2 (1.5) cm/year and 156.4 (26.4) g/year. At the cessation of monitoring, total length had increased by ∼30%, whereas total weight had almost doubled with neonatal body condition in line with free-living wobbegongs. Our efficacious, six-step manipulative, the approach should be applicable with all wobbegongs given their reproductive similarities, but we recommend that efforts focus on the dwarf ornate, tasselled and Japanese wobbegongs because all are small in size and have bred in aquaria. Ultimately, this approach should produce self-sustaining aquarium populations, place less reliance on the wild acquisition and provide animals for other aquaria, population restocking, or scientific research.

Class IIa HDACs do not influence beta-cell function under normal or high glucose conditions.

Inhibiting Class IIa Histone Deacetylase (HDAC) function is a promising approach to therapeutically enhance skeletal and cardiac muscle metabolic health in several chronic diseases including type 2 diabetes. However, the importance of Class IIa HDACs in the beta-cell remains unknown. As beta-cell function is vital to maintaining glycaemia it is essential that the importance of Class IIa HDACs in the beta-cell is determined. Here we used the INS-1E cell line cultured in normal glucose (11.1 mM) or hyperglycaemic (20 mM) conditions for 48 hrs to represent cells in a normal and diabetic environment respectively. Cells cultured in high glucose showed significantly reduced insulin secretory function and increased apoptotic signalling compared to cells cultured in normal glucose. Class IIa HDACS, HDAC-4 and -5, were not regulated at the transcript or protein level under normal or hyperglycaemic conditions suggesting that they may not play a role in beta-cell dysfunction. Furthermore, overexpression of wild-type HDAC-4 and -5 or dominant negative HDAC-4 and -5 did not alter insulin secretion, insulin mRNA expression or apoptotic signalling under normal or hyperglycaemic conditions. This suggests that Class IIa Histone Deacetylases do not play an important physiological role in the beta-cell under normal or diabetic conditions. Thus, Class IIa Histone Deacetylase inhibitors are not likely to have a detrimental effect on beta-cells supporting the use of these inhibitors to treat metabolic diseases such as type 2 diabetes.

APP deficiency results in resistance to obesity but impairs glucose tolerance upon high fat feeding.

The amyloid precursor protein (APP) generates a number of peptides when processed through different cleavage mechanisms, including the amyloid beta peptide that is implicated in the development of Alzheimer's disease. It is well established that APP via its cleaved peptides regulates aspects of neuronal metabolism. Emerging evidence suggests that amyloidogenic processing of APP can lead to altered systemic metabolism, similar to that observed in metabolic disease states. In the present study, we investigated the effect of APP deficiency on obesity-induced alterations in systemic metabolism. Compared with WT littermates, APP-deficient mice were resistant to diet-induced obesity, which was linked to higher energy expenditure and lipid oxidation throughout the dark phase and was associated with increased spontaneous physical activity. Consistent with this lean phenotype, APP-deficient mice fed a high-fat diet (HFD) had normal insulin tolerance. However, despite normal insulin action, these mice were glucose intolerant, similar to WT mice fed a HFD. This was associated with reduced plasma insulin in the early phase of the glucose tolerance test. Analysis of the pancreas showed that APP was required to maintain normal islet and ß-cell mass under high fat feeding conditions. These studies show that, in addition to regulating aspects of neuronal metabolism, APP is an important regulator of whole body energy expenditure and glucose homeostasis under high fat feeding conditions.

The Role of Herbivory in Structuring Tropical Seagrass Ecosystem Service Delivery.

Seagrass meadows support key ecosystem services, via provision of food directly for herbivores, and indirectly to their predators. The importance of herbivores in seagrass meadows has been well-documented, but the links between food webs and ecosystem services in seagrass meadows have not previously been made explicit. Herbivores interact with ecosystem services - including carbon sequestration, cultural values, and coastal protection. Interactions can be positive or negative and depend on a range of factors including the herbivore identity and the grazing type and intensity. There can be unintended consequences from management actions based on a poor understanding of trade-offs that occur with complex seagrass-herbivore interactions. Tropical seagrass meadows support a diversity of grazers spanning the meso-, macro-, and megaherbivore scales. We present a conceptual model to describe how multiple ecosystem services are influenced by herbivore pressure in tropical seagrass meadows. Our model suggests that a balanced ecosystem, incorporating both seagrass and herbivore diversity, is likely to sustain the broadest range of ecosystem services. Our framework suggests the pathway to achieve desired ecosystem services outcomes requires knowledge on four key areas: (1) how size classes of herbivores interact to structure seagrass; (2) desired community and management values; (3) seagrass responses to top-down and bottom-up controls; (4) the pathway from intermediate to final ecosystem services and human benefits. We suggest research should be directed to these areas. Herbivory is a major structuring influence in tropical seagrass systems and needs to be considered for effective management of these critical habitats and their services.

Metformin, beta-cell development, and novel processes following beta-cell ablation in zebrafish.

PURPOSE: Type 1 and 2 diabetes are characterized by a loss of insulin-producing beta-cells. Current treatments help maintain blood glucose levels but cannot provide a cure. As such, a vital target for the cure of diabetes is a way to restore beta-cell mass. The drug metformin can protect cultured beta-cells/islets from hyperglycemia-induced dysfunction and death. Further, treatment of pregnant mice with metformin results in an enhanced beta-cell fraction in the embryos; however, whether this occurs via a direct effect is unknown. METHODS: We utilized the external embryogenesis of the zebrafish to determine the direct effect of metformin treatment on the pancreas of the developing embryo and following beta-cell ablation. RESULTS: During development metformin did not alter beta-cell or alpha-cell mass but had a small effect to increase delta-cell mass as measured by in situ hybridization. Further metformin significantly increased beta-cell number. Following beta-cell ablation, both glucagon and somatostatin expression were upregulated (>2-fold). Additionally, while metformin showed no effect to alter beta-cell mass or number, somatostatin expression was further increased (>5-fold). CONCLUSIONS: We showed that direct exposure to metformin during embryogenesis does not increase insulin-expressing area but does increase beta-cell number. Further, we identified novel consequences of beta-cell ablation to alter the expression of other pancreatic hormones that were enhanced by metformin. Therefore, this study provides a greater understanding of the beta-cell development/regenerative processes and the effect of metformin, bringing us closer to identifying how to increase beta-cells in humans.