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VDAC1 is a target for pharmacologically induced insulin hypersecretion in β cells
No full textβ cells are dysfunctional in type 2 diabetes (T2D) and congenital hyperinsulinism (HI), but the mechanisms linking hypersecretion to β cell failure are poorly understood. Here, we use proteomics and functional assays in human and mouse β cell lines to identify VDAC1 as a target for the small molecule hypersecretion inducer SW016789. By enhancing membrane depolarization, SW016789 acutely increases Ca2+ influx, eventually driving β cell dysfunction. Time-course transcriptomics analysis reveals a distinct hypersecretory response signature compared to classical endoplasmic reticulum (ER) stress, highlighting ER-associated degradation (ERAD) as a key adaptive pathway. While SW016789 reduces ERAD substrate OS-9 levels, broader ERAD component changes are limited in cell lines. However, immunostaining of the T2D human pancreas shows altered distributions of the ratios of the core ERAD components SEL1L, HRD1, and DERL3 in β cells. This work provides a detailed mechanistic characterization of a hypersecretion-specific stress response, revealing potential therapeutic targets, including VDAC1 and ERAD, for modulating β cell function and survival in disease
Synthesizing Stable Matrices from the HS-5 Bone Marrow Stromal Cell Line
No full textBACKGROUND:
Our lab is focused on investigating the physical and biochemical mechanisms through which the bone marrow extracellular matrix (ECM) regulates musculoskeletal and hematopoietic homeostasis. Previously, we showed that primary cells from young and aging bone produce matrices which recapitulate aging-related remodeling of the bone marrow microenvironment. Among these changes is a significant depletion of CCN matricellular proteins. However, isolating the impact of CCNs from the variety of aging-associated changes requires producing ECMs from immortalized bone marrow stromal cell lines, in which individual CCNs may be deleted without disturbing other matrix components. However, matrices produced by immortalized stromal lines are highly susceptible to damage by decellularization.
METHODS:
A 9-day matrix production protocol was performed with HS-5 bone marrow stromal cells maintained on a variety of commercially available substrates/surfaces. Briefly, the procedure consisted of ascorbic acid induction on day 5 and decellularization on day 8, followed by ECM collection and analysis/imaging with Coomassie Blue stain. Substrates evaluated included tissue culture plastic (TCP), Cell-Tak, Collagen, PDL, CellBind, Silane, Supra, UpCell; with and without fibronectin coating.
RESULTS:
While HS-5 cells readily produced matrix on several substrates, plates coated with Collagen I, further supplemented with fibronectin, most consistently supported the preparation of a well-anchored matrix, which remained intact following decellularization.
CONCLUSION AND POTENTIAL IMPACT:
Producing stable ECMs from HS-5 bone stromal cells will allow our lab to specifically modify and study proteins of interest, including CCN1 and CCN2, which have been suggested to play important roles related to the aging-associated remodeling of the bone marrow niche. When coated with fibronectin, UpCell (Corning) supported stable matrix anchoring, while also allowing for detachment from the culture surface, suggesting potential applications in manufacturing of orthobiologic implants
In Vitro Comparison of the Effectiveness of Different Attachment Shapes and Locations on Extrusion of the Upper Left Lateral Incisor Using Thermoplastic Aligners
No full textObjectives: The aim of this study was to compare the effectiveness of different attachment shapes and locations on the extrusion of the upper left lateral incisor (UL2) using thermoplastic aligners.
Materials and methods: Seven typodonts were digitally printed with hemi-ellipsoid or rectangular attachments in the incisal, middle or cervical third of the UL2. Five clear aligners were fabricated for each typodont; each was tested twice. Forces and moments were measured with an orthodontic force tester during 0.2 mm simulated extrusion of the UL2. Analysis of variance (ANOVA) was used to determine the effects of group, tooth, and the group-by-tooth interaction on the outcomes. A two-sided 5% significance level was used for all tests.
Results: Altering attachment shape and location had a statistically significant effect on the forces and moments generated in each trial (p 0.05). The rectangular middle attachment generated the highest extrusive force (Fz = 7.498 N), followed by hemi-ellipsoid cervical (Fz = 6.338 N) and rectangular incisal (Fz = 5.948 N).
Conclusions: Varying direct attachment shape and location on the UL2 during extrusion has a significant effect on the forces and moments generated by thermoplastic aligners. The rectangular attachment located in the middle third generated the most effective extrusive force and least unwanted moment. For anchorage teeth, hemi-ellipsoid attachments located in the cervical third were found to be the most effective in minimising the reciprocal intrusive forces and unwanted moments
Hypothalamic Neural Circuits Regulating Energy Expenditure
No full textThe hypothalamus plays a central role in regulating energy expenditure and maintaining energy homeostasis, crucial for an organism's survival. Located in the ventral diencephalon, it is a dynamic and adaptable brain region capable of rapid responses to environmental changes, exhibiting high anatomical and cellular plasticity and integrates a myriad of sensory information, internal physiological cues, and humoral factors to accurately interpret the nutritional state and adjust food intake, thermogenesis, and energy homeostasis. Key hypothalamic nuclei contain distinct neuron populations that respond to hormonal, nutrient, and neural inputs and communicate extensively with peripheral organs like the gastrointestinal tract, liver, pancreas, and adipose tissues to regulate energy production, storage, mobilization, and utilization. The hypothalamus has evolved to enhance energy storage for survival in famine and scarce environments but contribute to obesity in modern contexts of caloric abundance. It acts as a master regulator of whole-body energy homeostasis, rapidly adapting to ensure energy supplies for cellular functions. Understanding hypothalamic function, pertaining to energy expenditure, is crucial for developing targeted interventions to address metabolic disorders, offering new insights into the neural control of metabolic states and potential therapeutic strategies
Engaging Patients with Headache in the Veterans Health Administration (VHA): ACTIvated Veterans Engagement Group (ACTIVE) to Improve Delivery of Patient-Centered Headache Services
No full textIn 2018, the Veterans Health Administration (VHA) established the original 19 Headache Centers of Excellence (HCoE) program, and an evaluation center. This study utilized a Veteran engagement group method to elicit input from Veteran patients living with chronic headache on daily needs, social determinants of health, and preferences and suggestions for headache programs, services, and research priorities. Four engagement groups were conducted between July 13th and August 22nd of 2022 with Veterans who experience headache and received care at a VHA HCoE. Engagement groups were audio-recorded, de-identified, transcribed, and analyzed using rapid qualitative content matrix analysis. Participants also completed a baseline survey on demographics, technology use, headache history, and health. Patients perceived care coordination, social support, gender specific preferences and access to complementary and integrative therapies to be important aspects of headache care delivered by HCoEs. Participants expressed strong interest in effective, interactive peer support groups to share and learn from each other's experiences with headaches and treatments. Findings underscore the demand for coordinated, interdisciplinary headache care integrating complementary health approaches and addressing gender-specific needs
The Impact of Covid-19 on Implantable Cardioverter Defibrillator Implantation in Heart Failure Patients with Reduced Ejection Fraction
No full textThe Impact of Covid-19 on Implantable Cardioverter Defibrillator Implantation in Heart Failure Patients with Reduced Ejection Fraction
Emily Ryan, Rebecca Sparks-Thissen, Adrian Singson
Background: Discrepancies in the utilization of implantable cardioverter defibrillators (ICD) in heart failure with reduced ejection fraction (HFrEF) patients is well documented. However, there is little real-world evidence investigating the impact of the Covid-19 pandemic on the utilization of ICDs in HFrEF patients.
Study Objective/Hypothesis: The objective of this study was to assess how the Covid-19 pandemic impacted the odds of receiving an ICD implant in adult HFrEF patients.
Methods: This study used data from the IU School of Medicine-Evansville RWEdataLab (CRC/Sidus Insights) Cardiology database, nationally sourced from de-identified electronic health record systems. Patients were filtered by adult age, HFrEF ICD-10 diagnosis codes, and presence or absence of ICD implant CPT codes. The pre-Covid and post-Covid periods were from June through November of 2018-2019 and 2022-2023, respectively. Patient groups were compared based on an initial HFrEF diagnosis and presence or absence of ICD implant during pre- and post-COVID periods.
Results: Men and women were more likely to receive an ICD pre-Covid than post-Covid (OR 1.279, 95% CI (1.06-1.54) and OR 1.475, 95% CI (1.12-1.94), respectively). Men and women aged 71-80 received an ICD pre-Covid more than their post-Covid counterparts (OR 1.69, 95% CI (1.13-2.25) and OR 2.129, 95% CI (1.39-3.26)). More post-Covid men received an ICD than post-Covid women (OR 1.34, 95% CI (1.03-1.75)). Although there was no significant difference between all adult pre-Covid males versus females, males aged 81-90 received an ICD more than females (OR 1.707, 95% CI (1.21-2.40)).
Conclusions: This study shows that Covid-19 reduced the odds of ICD utilization in HFrEF patients, especially older females. Future directions include investigating explanations for this healthcare inequity, including delayed medical procedures and increased mortality due to the pandemic. Further research should identify sources of age and gender disparities and minimize care inequities for older female HFrEF patients