PRL-1/2 phosphatases control TRPM7 magnesium-dependent function to regulate cellular bioenergetics.

Phosphatases of regenerating liver (PRL-1, PRL-2, PRL-3; also known as PTP4A1, PTP4A2, PTP4A3, respectively) control intracellular magnesium levels by interacting with the CNNM magnesium transport regulators. Still, the exact mechanism governing magnesium transport by this protein complex is not well understood. Herein, we have developed a genetically encoded intracellular magnesium-specific reporter and demonstrate that the CNNM family inhibits the function of the TRPM7 magnesium channel. We show that the small GTPase ARL15 increases CNNM3/TRPM7 protein complex formation to reduce TRPM7 activity. Conversely, PRL-2 overexpression counteracts ARL15 binding to CNNM3 and enhances the function of TRPM7 by preventing the interaction between CNNM3 and TRPM7. Moreover, while TRPM7-induced cell signaling is promoted by PRL-1/2, it is reduced when CNNM3 is overexpressed. Lowering cellular magnesium levels reduces the interaction of CNNM3 with TRPM7 in a PRL-dependent manner, whereby knockdown of PRL-1/2 restores the protein complex formation. Cotargeting of TRPM7 and PRL-1/2 alters mitochondrial function and sensitizes cells to metabolic stress induced by magnesium depletion. These findings reveal the dynamic regulation of TRPM7 function in response to PRL-1/2 levels, to coordinate magnesium transport and reprogram cellular metabolism.

Resistant multiple sparse canonical correlation.

Canonical correlation analysis (CCA) is a multivariate technique that takes two datasets and forms the most highly correlated possible pairs of linear combinations between them. Each subsequent pair of linear combinations is orthogonal to the preceding pair, meaning that new information is gleaned from each pair. By looking at the magnitude of coefficient values, we can find out which variables can be grouped together, thus better understanding multiple interactions that are otherwise difficult to compute or grasp intuitively. CCA appears to have quite powerful applications to high-throughput data, as we can use it to discover, for example, relationships between gene expression and gene copy number variation. One of the biggest problems of CCA is that the number of variables (often upwards of 10,000) makes biological interpretation of linear combinations nearly impossible. To limit variable output, we have employed a method known as sparse canonical correlation analysis (SCCA), while adding estimation which is resistant to extreme observations or other types of deviant data. In this paper, we have demonstrated the success of resistant estimation in variable selection using SCCA. Additionally, we have used SCCA to find multiple canonical pairs for extended knowledge about the datasets at hand. Again, using resistant estimators provided more accurate estimates than standard estimators in the multiple canonical correlation setting. R code is available and documented at https://github.com/hardin47/rmscca.

The role of subcutaneous fat and BMI in predicting surgical outcomes and patient reported outcomes in robotic-assisted total hip arthroplasty.

Background: The purpose of this study was to assess if subcutaneous fat (SCF) or BMI is a predictor of surgical complications and patient reported outcomes in patients undergoing robotic-assisted total hip arthroplasty (THA). Methods: Patients who underwent robotic-assisted primary THAs at one institution between 2018 and 2020 were included in this retrospective cohort study. Prior to surgery, computed tomography (CT) was used to measure SCF in the posterolateral quadrant of the hip. SCF was measured 3 centimeters (cm) proximal to the greater trochanter (PGT) and 3 cm inferior to the distal tip of the greater trochanter (DGT).Measurements were normalized to the size of the patient's bony anatomy by dividing the subcutaneous fat area measurement by the transverse diameter of the femur 10 cm inferior to the tip of the greater trochanter. Patients were divided into quintiles determined by SCF distribution around the mean (groups 1-5) and BMI (BMI<25, BMI 25-29.9, BMI 30-34.9, BMI 35-39.9, and >40). Ninety day outcomes and PROMIS (Patient Reported Outcome Measures Information System) scores were acquired from the Michigan Arthroplasty Registry Collaborative Quality Initiative (MARCQI) database preoperatively, at 14-112 days post-operative and at the latest follow up. Results: There were 175 patients identified with a mean age of 63.83 years (range 27-89) and a mean BMI of 30.73kg/m2 (range 18.2-48.4). Interclass correlation coefficient was greater than 0.9 in all PGT, DGT, and GT measurements. Analysis of Variance (ANOVA) found there was a significantly shorter time from incision to closure in quintiles 1 and 3 when compared to the SCF quintile 5 (p<0.05) and that there was a significantly shorter time from incision to closure in BMI categories 1, 2, and 3 when compared to BMI category 5 (BMI > 40). There were no differences between SCF and BMI as predictive of length of stay, transfusion status, infection, or PROMIS scores. Conclusion: It can be concluded that hip SCF on axial CT images can reliably measure SCF and is predictive of time from incision to closure, but it does not show a significant difference in predicting the length of stay, infection, or PROMIS scores when compared to BMI.

The Effects of Exercise on Appetite-Regulating Hormone Concentrations over a 36-h Fast in Healthy Young Adults: A Randomized Crossover Study.

Hunger and satiety are controlled by several physiological mechanisms, including pancreatic and gastrointestinal hormones. While the influence of exercise and fasting have been described individually, in relation to these hormones, there is a paucity of work showing the effects of the two modalities (fasting and exercise) combined. Twenty healthy adults (11 males, 9 females) completed both conditions of this study, each consisting of a 36-h water-only fast. One of the fasts began with treadmill exercise, and the differences between the conditions on various appetite hormones were measured every 12 h. The difference in the area under the curve between conditions for ghrelin was 211.8 ± 73.1 pg/mL (F = 8.40, p < 0.0105), and, for GLP-1, it was -1867.9 ± 850.4 pg/mL (F = 4.82, p < 0.0422). No significant differences were noted for areas under the curve between conditions for leptin, PP, PYY, insulin, or GIP. Initiating a fast with exercise lowers ghrelin concentrations and elevates GLP-1 concentrations. Given that ghrelin elicits feelings of hunger and GLP-1 signals feelings of satiety, adding exercise to the beginning of a fast may reduce some of the biological drive of hunger, which could make fasting more tolerable, leading to better adherence and more significant health outcomes.

Iliopsoas Irritation as Presentation of Head-Neck Corrosion After Total Hip Arthroplasty: A Case Series.

Corrosion of modular components at the femoral neck remains a complication of total hip arthroplasty (THA). The authors have found the iliopsoas sign (pain on resisted flexion of the hip) to be suggestive of femoral component corrosion. These cases represented 8 of 120 revision hip arthroplasties (7%) performed at the authors' institution. After the revisions, all iliopsoas tendonitis symptoms resolved. Based on the authors' experience and the recent literature, they recommend that the iliopsoas sign or presentation of a sterile iliopsoas abscess in a previously well-functioning THA be concern for corrosion of the femoral component of the total hip.