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"Wilson, Leah"
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Flirtin' with the monster : your favorite authors on Ellen Hopkins' Crank and Glass
Presents articles critically analyzing the popular novels on teenage crystal meth addiction, and includes testimonials from the author's family members upon whom the characters in the novel were based.
BOOK
Social stimuli impact behavioral responses to caffeine in the zebrafish
Caffeine is a widely consumed stimulant with dose-dependent effects on behavior. Across species, lower doses tend be anxiolytic and increase activity, while higher doses tend to be anxiogenic and decrease activity. Given the importance of the social environment on stress responses, we investigated how social stimuli modulate behavioral responses to caffeine. We exposed adult zebrafish to low (25 mg/L) or moderate (60 mg/L) caffeine either in isolation or within view of a stimulus group. Zebrafish are highly social, and social stimuli are known to buffer responses to environmental stressors. As predicted, we found that isolated fish were more sensitive to caffeine’s anxiogenic effects and less sensitive to caffeine’s stimulant effects. Among socially-exposed individuals, caffeine decreased social approach. Our data illustrate the importance of social context. Understanding how social cues shape pharmacological responses is important for understanding the external validity of studies that investigate drug effects in social species.
Journal Article
New Developments in Glucagon Treatment for Hypoglycemia
Glucagon is essential for endogenous glucose regulation along with the paired hormone, insulin. Unlike insulin, pharmaceutical use of glucagon has been limited due to the unstable nature of the peptide. Glucagon has the potential to address hypoglycemia as a major limiting factor in the treatment of diabetes, which remains very common in the type 1 and type 2 diabetes. Recent developments are poised to change this paradigm and expand the use of glucagon for people with diabetes. Glucagon emergency kits have major limitations for their use in treating severe hypoglycemia. A complicated reconstitution and injection process often results in incomplete or aborted administration. New preparations include intranasal glucagon with an easy-to-use and needle-free nasal applicator as well as two stable liquid formulations in pre-filled injection devices. These may ease the burden of severe hypoglycemia treatment. The liquid preparations may also have a role in the treatment of non-severe hypoglycemia. Despite potential benefits of expanded use of glucagon, undesirable side effects (nausea, vomiting), cost, and complexity of adding another medication may limit real-world use. Additionally, more long-term safety and outcome data are needed before widespread, frequent use of glucagon is recommended by providers.
Journal Article
Enabling fully automated insulin delivery through meal detection and size estimation using Artificial Intelligence
We present a robust insulin delivery system that includes automated meal detection and carbohydrate content estimation using machine learning for meal insulin dosing called robust artificial pancreas (RAP). We conducted a randomized, single-center crossover trial to compare postprandial glucose control in the four hours following unannounced meals using a hybrid model predictive control (MPC) algorithm and the RAP system. The RAP system includes a neural network model to automatically detect meals and deliver a recommended meal insulin dose. The meal detection algorithm has a sensitivity of 83.3%, false discovery rate of 16.6%, and mean detection time of 25.9 minutes. While there is no significant difference in incremental area under the curve of glucose, RAP significantly reduces time above range (glucose >180 mg/dL) by 10.8% (P = 0.04) and trends toward increasing time in range (70–180 mg/dL) by 9.1% compared with MPC. Time below range (glucose <70 mg/dL) is not significantly different between RAP and MPC.
Journal Article
To flock or fight: Neurochemical signatures of divergent life histories in sparrows
Many bird species exhibit dramatic seasonal switches between territoriality and flocking, but whereas neuroendocrine mechanisms of territorial aggression have been extensively studied, those of seasonal flocking are unknown. We collected brains in spring and winter from male field sparrows (Spizella pusilla), which seasonally flock, and male song sparrows (Melospiza melodia), which are territorial year-round in much of their range. Spring collections were preceded by field-based assessments of aggression. Tissue series were immunofluorescently multilabeled for vasotocin, mesotocin (MT), corticotropin-releasing hormone (CRH), vasoactive intestinal polypeptide, tyrosine hydroxylase, and aromatase, and labeling densities were measured in many socially relevant brain areas. Extensive seasonal differences are shared by both species. Many measures correlate significantly with both individual and species differences in aggression, likely reflecting evolved mechanisms that differentiate the less aggressive field sparrow from the more aggressive song sparrow. Winter-specific species differences include a substantial increase of MT and CRH immunoreactivity in the dorsal lateral septum (LS) and medial amygdala of field sparrows but not song sparrows. These species differences likely relate to flocking rather than the suppression of winter aggression in field sparrows, because similar winter differences were found for two other emberizids that are not territorial in winter—dark-eyed juncos (Junco hyemalis), which seasonally flock, and eastern towhees (Pipilo erythropthalmus), which do not flock. MT signaling in the dorsal LS is also associated with year-round species differences in grouping in estrildid finches, suggesting that common mechanisms are targeted during the evolution of different life histories.
Journal Article
Scalable intracellular delivery via microfluidic vortex shedding enhances the function of chimeric antigen receptor T-cells
Adoptive chimeric antigen receptor T-cell (CAR-T) therapy is transformative and approved for hematologic malignancies. It is also being developed for the treatment of solid tumors, autoimmune disorders, heart disease, and aging. Despite unprecedented clinical outcomes, CAR-T and other engineered cell therapies face a variety of manufacturing and safety challenges. Traditional methods, such as lentivirus transduction and electroporation, result in random integration or cause significant cellular damage, which can limit the safety and efficacy of engineered cell therapies. We present hydroporation as a gentle and effective alternative for intracellular delivery. Hydroporation resulted in 1.7- to 2-fold higher CAR-T yields compared to electroporation with superior cell viability and recovery. Hydroporated cells exhibited rapid proliferation, robust target cell lysis, and increased pro-inflammatory and regulatory cytokine secretion in addition to improved CAR-T yield by day 5 post-transfection. We demonstrate that scaled-up hydroporation can process 5 × 10
8
cells in less than 10 s, showcasing the platform as a viable solution for high-yield CAR-T manufacturing with the potential for improved therapeutic outcomes.
Journal Article
An artificial intelligence decision support system for the management of type 1 diabetes
Type 1 diabetes (T1D) is characterized by pancreatic beta cell dysfunction and insulin depletion. Over 40% of people with T1D manage their glucose through multiple injections of long-acting basal and short-acting bolus insulin, so-called multiple daily injections (MDI)
1
,
2
. Errors in dosing can lead to life-threatening hypoglycaemia events (<70 mg dl
−1
) and hyperglycaemia (>180 mg dl
−1
), increasing the risk of retinopathy, neuropathy, and nephropathy. Machine learning (artificial intelligence) approaches are being harnessed to incorporate decision support into many medical specialties. Here, we report an algorithm that provides weekly insulin dosage recommendations to adults with T1D using MDI therapy. We employ a unique virtual platform
3
to generate over 50,000 glucose observations to train a
k
-nearest neighbours
4
decision support system (KNN-DSS) to identify causes of hyperglycaemia or hypoglycaemia and determine necessary insulin adjustments from a set of 12 potential recommendations. The KNN-DSS algorithm achieves an overall agreement with board-certified endocrinologists of 67.9% when validated on real-world human data, and delivers safe recommendations, per endocrinologist review. A comparison of inter-physician-recommended adjustments to insulin pump therapy indicates full agreement of 41.2% among endocrinologists, which is consistent with previous measures of inter-physician agreement (41–45%)
5
. In silico
3
,
6
benchmarking using a platform accepted by the United States Food and Drug Administration for evaluation of artificial pancreas technologies indicates substantial improvement in glycaemic outcomes after 12 weeks of KNN-DSS use. Our data indicate that the KNN-DSS allows for early identification of dangerous insulin regimens and may be used to improve glycaemic outcomes and prevent life-threatening complications in people with T1D.
An automated decision support system is reported that provides weekly insulin dosage recommendations to users with T1D and that, when analysing previously collected patient data, exhibits high agreement with recommendations from physicians.
Journal Article
Numerical optimization of microfluidic vortex shedding for genome editing T cells with Cas9
Microfluidic vortex shedding (
µVS
) can rapidly deliver mRNA to T cells with high yield and minimal perturbation of the cell state. The mechanistic underpinning of
µVS
intracellular delivery remains undefined and
µVS
-Cas9 genome editing requires further studies. Herein, we evaluated a series of
µVS
devices containing splitter plates to attenuate vortex shedding and understand the contribution of computed force and frequency on efficiency and viability. We then selected a
µVS
design to knockout the expression of the endogenous T cell receptor in primary human T cells via delivery of Cas9 ribonucleoprotein (RNP) with and without brief exposure to an electric field (
eµVS
).
µVS
alone resulted in an equivalent yield of genome-edited T cells relative to electroporation with improved cell quality. A 1.8-fold increase in editing efficiency was demonstrated with
eµVS
with negligible impact on cell viability. Herein, we demonstrate efficient processing of 5 × 10
6
cells suspend in 100 µl of cGMP OptiMEM in under 5 s, with the capacity of a single device to process between 10
6
to 10
8
in 1 to 30 s. Cumulatively, these results demonstrate the rapid and robust utility of
µVS
and
eµVS
for genome editing human primary T cells with Cas9 RNPs.
Journal Article
Juvenile Hemochromatosis Connecting Cardiac Arrest and Hypogonadotropic Hypogonadism in a Young Woman
Abstract
Juvenile hemochromatosis (JH) is a subtype of hereditary hemochromatosis, a genetic disorder characterized by excessive iron absorption and deposition in various organs, leading to cardiomyopathy, cirrhosis, and diabetes. Endocrine dysfunction is a common manifestation and may appear years before end-organ damage. This report describes a rare case of JH, emphasizing the consequences of delayed diagnosis. A 28-year-old woman with a history of hypogonadotropic hypogonadism presented with cardiac arrest complicated by acute renal failure and cerebral vascular accidents. She initially exhibited signs of severe cardiomyopathy and multiorgan failure, which led to workup for an underlying cause. Laboratory values showed significantly elevated ferritin and transferrin saturation. Subsequent genetic screening revealed HJV gene pathogenic variants consistent with juvenile hemochromatosis. Treatment involved aggressive iron chelation therapy and outpatient referral for cardiac transplant. This case calls for heightened awareness and early screening of JH, particularly among patients with unexplained endocrine dysfunction. Early diagnosis and treatment are paramount in preventing irreversible organ damage and improving patient outcomes.
Journal Article
The Role of VIP in Social Behavior
Although the modulation of social behaviors by most major neurochemical systems has been explored, there are still standouts, including the study of vasoactive intestinal polypeptide (VIP). VIP is a modulator of circadian, reproductive, and seasonal rhythms and is well known for its role in reproductive behavior, as it is the main vertebrate prolactin-releasing hormone. Originally isolated as a gut peptide, VIP and its cognate receptors are present in virtually every brain area that is important for social behavior, including all nodes of the core “social behavior network” (SBN). Furthermore, VIP cells show increased transcriptional activity throughout the SBN in response to social stimuli. Using a combination of comparative and mechanistic approaches in socially diverse species of estrildid finches and emberizid sparrows, we have identified neural “hotspots” in the SBN that relate to avian affiliative behavior, as well as neural “hotspots” that may represent critical nodes underlying a trade-off between aggression and parental care. Specifically, we have found that: (1) VIP fiber densities and VIP receptor binding in specific brain sites, such as the lateral septum, medial extended amygdala, arcopallium, and medial nidopallium, correlate with species and/or seasonal differences in flocking behavior, and (2) VIP cells and fibers within the anterior hypothalamus—caudocentral septal circuit relate positively to aggression and negatively to parental care while VIP elements in the mediobasal hypothalamus relate negatively to aggression and positively to parental care. Thus, while a given behavior or social context likely activates VIP circuitry throughout the SBN and beyond, key brain sites emerge as potential “hotspots” for the modulation of affiliation, aggression, and parental care.
Journal Article