Loss-of-function of ALDH3B2 transdifferentiates human pancreatic duct cells into beta-like cells.

Replenishment of pancreatic beta cells is a key to the cure for diabetes. Beta cells regeneration is achieved predominantly by self-replication especially in rodents, but it was also shown that pancreatic duct cells can transdifferentiate into beta cells. How pancreatic duct cells undergo transdifferentiated and whether we could manipulate the transdifferentiation to replenish beta cell mass is not well understood. Using a genome-wide CRISPR screen, we discovered that loss-of-function of ALDH3B2 is sufficient to transdifferentiate human pancreatic duct cells into functional beta-like cells. The transdifferentiated cells have significant increase in beta cell marker genes expression, secrete insulin in response to glucose, and reduce blood glucose when transplanted into diabetic mice. Our study identifies a novel gene that could potentially be targeted in human pancreatic duct cells to replenish beta cell mass for diabetes therapy.

Protective Renalase Deficiency in ß-Cells Shapes Immune Metabolism and Function in Autoimmune Diabetes.

Type 1 diabetes (T1D) is caused by the immune-mediated loss of pancreatic ß-cells that produce insulin. The latest advances in stem cell (SC) ß-cell differentiation methods have made a cell replacement therapy for T1D feasible. However, recurring autoimmunity would rapidly destroy transplanted SC ß-cells. A promising strategy to overcome immune rejection is to genetically engineer SC ß-cells. We previously identified Renalase (Rnls) as a novel target for ß-cell protection. Here we show that Rnls deletion endows ß-cells with the capacity to modulate the metabolism and function of immune cells within the local graft microenvironment. We used flow cytometry and single-cell RNA sequencing to characterize ß-cell graft-infiltrating immune cells in a mouse model for T1D. Loss of Rnls within transplanted ß-cells affected both the composition and the transcriptional profile of infiltrating immune cells in favor of an anti-inflammatory profile with decreased antigen-presenting capacity. We propose that changes in ß-cell metabolism mediate local immune regulation and that this feature could be exploited for therapeutic goals. ARTICLE HIGHLIGHTS: Protective Renalase (Rnls) deficiency impacts ß-cell metabolism. Rnls-deficient ß-cell grafts do not exclude immune infiltration. Rnls deficiency in transplanted ß-cells broadly modifies local immune function. Immune cell in Rnls mutant ß-cell grafts adopt a noninflammatory phenotype.

Physiological Responses to Speed-Matched Running on Non-Motorized Assault AirRunner versus Traditional Treadmills in Active Females: A Pilot Study.

Treadmills are utilized as a training tool to improve aerobic fitness, but precise understanding of intensity and the corresponding physiological strain is critical for optimizing exercise prescription and associated adaptations. Running on non-motorized, curved treadmills may result in greater oxygen uptake (VO2), increased heart rate (HR), and increased rating of perceived exertion (RPE) compared to traditional motorized treadmills. The purpose of this study was to investigate the physiological responses on non-motorized versus traditional motorized treadmills during speed-matched running. Participants were 4 college-aged, recreationally active females. HR, VO2, respiratory exchange ratio (RER), and RPE were monitored during 3 speed-matched stages of incremental exercise in two conditions: the non-motorized Assault AirRunner and a traditional motorized treadmill, as well as for 5 minutes post-exercise. VO2, RER, and HR were greater in the Assault condition (ESVO2 = 0.998, ESRER = 0.839, ESHR = 0.972, p < 0.05). While not significant between groups, RPE showed a greater increase with increasing speeds in the Assault condition (ES = 0.728), as did RER (ES = 0.800, p < 0.05). Cumulative excess-post exercise oxygen consumption (EPOC) during a five-minute period post-exercise was also greater in the Assault condition, and HR and RER remained higher five minutes post-exercise in the Assault condition (ESEPOC = 0.738, ESHR = 1.600, ESRER = 2.075, p < 0.05). The Assault AirRunner elicited greater physiological responses (VO2, carbohydrate usage, and HR) in response to speed-matched running in comparison to a traditional motorized treadmill in active college-aged females. Collectively, aerobic exercise conducted on the Assault AirRunner has a greater physiological and perceived intensity and need to be taken into consideration when designing and implementing training programs or testing.

Applying CRISPR Screen in Diabetes Research.

The CRISPR/Cas9 genome editing system has been one of the greatest scientific discoveries in the last decade. The highly efficient and precise editing ability of this technology is of great therapeutic value and benefits the basic sciences as an advantageous research tool. In recent years, forward genetic screens using CRISPR technology have been widely adopted, with genome-wide or pathway-focused screens leading to important and novel discoveries. CRISPR screens have been used primarily in cancer biology, virology, and basic cell biology, but they have rarely been applied to diabetes research. A potential reason for this is that diabetes-related research can be more complicated, often involving cross talk between multiple organs or cell types. Nevertheless, many questions can still be reduced to the study of a single cell type if assays are carefully designed. Here we review the application of CRISPR screen technology and provide perspective on how it can be used in diabetes research.

Examining Neuromuscular Control of the Vastus Medialis Oblique and Vastus Lateralis Muscles During Fundamental Dance Movements.

Elite dancers have a higher rate of injury than college athletes. This may be due, in part, to improper alignment during dance movements. Electromyography (EMG) can be an important indicator of such activity. This study aimed to examine how turnout (maximal hip external rotation) impacts activation of the vastus medialis oblique (VMO) and vastus lateralis (VL) muscles during fundamental dance movements. Thirty female collegiate dancers were recruited from intermediate and advanced ballet and modern technique classes. Surface EMG was used to examine activation of the VMO and VL during maximal isokinetic knee extension in demi-pliés and sautés in parallel and turned-out positions. The mean VMO:VL ratio was determined as a percentage of the highest repetition of maximal extension. The ratio was significantly lower during parallel sautés (0.921 ± 0.258) in comparison to turned-out sautés (1.008 ± 0.384; p = 0.033) and parallel pliés (1.185 ± 0.509; p = 0.002). No significant relationships were found between the VMO:VL ratio and injury history or predominant style of dance. Further investigation is warranted to examine the relationships between VMO:VL activation, patellofemoral alignment, and risk of pathology during simple and complex dance movements.

Effects of a combined protein and antioxidant supplement on recovery of muscle function and soreness following eccentric exercise.

BACKGROUND: An acute bout of eccentric contractions (ECC) cause muscle fiber damage, inflammation, impaired muscle function (MF) and muscle soreness (MS). Individually, protein (PRO) and antioxidant (AO) supplementation may improve some aspects of recovery from ECC, though have yet to be combined. We sought to determine if combined PRO and AO supplementation (PRO + AO) improves MS and MF following damaging ECC over PRO alone. METHODS: Sixty sedentary college-aged males participated in a randomized, single-blind, parallel design study of peak isometric torque (PIMT), peak isokinetic torque (PIKT), thigh circumference (TC), and muscle soreness (MS) of knee extensor muscles measured at baseline, immediately after and 1, 2, 6, and 24 h after completion of 100 maximal ECC. Immediately, 6 h, and 22 h post-ECC, participants consumed either: carbohydrate control (CHO; n = 14), PRO (n = 16), or PRO + AO (n = 17). RESULTS: At baseline MS, TC, MF, macro- and micro-nutrient intakes, and total work during the ECC were not different between groups (p > 0.05). PIMT and PIKT (both -25%∆), TC (~1%∆) and MS (~35%∆) all changed with time (p < 0.05). We observed a group by time effect for PIKT (PRO + AO and PRO > CHO, p < 0.05). At 24 h post ECC, there was a trend towards improved relative PIMT (~11%) and PIKT (~17%) for PRO + AO (~17%) and PRO (~11%) compared to CHO. An interaction indicated PRO + AO had lowest MS over time (PRO + AO > PRO & CHO, p < 0.05). CONCLUSIONS: Our results suggest PRO facilitates recovery of muscle function within 24 h following ECC, and addition of AO ameliorates MS more than PRO or CHO alone.