Oculocerebrorenal syndrome of Lowe (OCRL) controls leukemic T-cell survival by preventing excessive PI(4,5)P2 hydrolysis in the plasma membrane.

T-cell acute lymphoblastic leukemia (T-ALL) is one of the deadliest and most aggressive hematological malignancies, but its pathological mechanism in controlling cell survival is not fully understood. Oculocerebrorenal syndrome of Lowe is a rare X-linked recessive disorder characterized by cataracts, intellectual disability, and proteinuria. This disease has been shown to be caused by mutation of oculocerebrorenal syndrome of Lowe 1 (OCRL1; OCRL), encoding a phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] 5-phosphatase involved in regulating membrane trafficking; however, its function in cancer cells is unclear. Here, we uncovered that OCRL1 is overexpressed in T-ALL cells, and knockdown of OCRL1 results in cell death, indicating the essential role of OCRL in controlling T-ALL cell survival. We show OCRL is primarily localized in the Golgi and can translocate to plasma membrane (PM) upon ligand stimulation. We found OCRL interacts with oxysterol-binding protein-related protein 4L, which facilitates OCRL translocation from the Golgi to the PM upon cluster of differentiation 3 stimulation. Thus, OCRL represses the activity of oxysterol-binding protein-related protein 4L to prevent excessive PI(4,5)P2 hydrolysis by phosphoinositide phospholipase C ß3 and uncontrolled Ca2+ release from the endoplasmic reticulum. We propose OCRL1 deletion leads to accumulation of PI(4,5)P2 in the PM, disrupting the normal Ca2+ oscillation pattern in the cytosol and leading to mitochondrial Ca2+ overloading, ultimately causing T-ALL cell mitochondrial dysfunction and cell death. These results highlight a critical role for OCRL in maintaining moderate PI(4,5)P2 availability in T-ALL cells. Our findings also raise the possibility of targeting OCRL1 to treat T-ALL disease.

[FreeArcs Knife: a Novel Stereotactic Radiosurgery System].

This paper describes the design of an innovative linear accelerator image-guided radiosurgery (IGRS) device, which is based on a composite twofold rotary gantry structure. The paper discusses five aspects of the innovative device: its overall composition, the safety net space created by the accelerator radiation head as it rotates around the patient's longitudinal axis, the non-coplanar spherical coverage in the direction of the incidence angle for quasi-4π delivery, the structural features of the composite twofold rotary gantry, and the processes of treatment planning and implementation. It elaborates on the device's manufacturing feasibility, safety, effectiveness, accuracy, and efficiency. The conclusion is that this innovative device design holds significant development value and market promotion potential.

Diagnostic value of a new axial loading MRI device in patients with suspected lumbar spinal stenosis.

OBJECTIVES: This study was carried out to investigate a new device for axial loading MRI (alMRI) in the diagnosis of lumbar spinal stenosis (LSS). METHODS: A total of 87 patients with suspected LSS sequentially underwent conventional MRI and alMRI using a new device with pneumatic shoulder-hip compression mode. Four quantitative parameters of dural sac cross-sectional area (DSCA), sagittal vertebral canal diameter (SVCD), disc height (DH), and ligamentum flavum thickness (LFT) at L3-4, L4-5, and L5-S1 in both examinations were measured and compared. Eight qualitative indicators were compared as valuable diagnostic information. Image quality, examinee comfort, test-retest repeatability, and observer reliability were also assessed. RESULTS: Using the new device, all 87 patients successfully completed alMRI with no statistically significant differences in image quality and examinee comfort from conventional MRI. Statistically significant changes were observed in DSCA, SVCD, DH, and LFT after loading (p < 0.01). SVCD, DH, LFT, and DSCA changes were all positively correlated (r = 0.80, 0.72, 0.37, p < 0.01). Eight qualitative indicators increased from 501 to 669 after axial loading, for a total increase of 168 (33.5%). Nineteen patients (21.8%, 19/87) developed absolute stenosis after axial loading and 10 of them (11.5%, 10/87) also had a significant reduction in DSCA (> 15 mm2). The test-retest repeatability and observer reliability were good to excellent. CONCLUSION: The new device is stable for performing alMRI and can exacerbate the severity of spinal stenosis, providing more valuable information for diagnosing LSS and reducing missed diagnoses. KEY POINTS: • The new axial loading MRI (alMRI) device could detect a higher frequency of patients with lumbar spinal stenosis (LSS). • The new device with pneumatic shoulder-hip compression mode was used to investigate its applicability in alMRI and diagnostic value for LSS. • The new device is stable for performing alMRI and can provide more valuable information for diagnosing LSS.

The Preparation of Golgi Apparatus-Targeted Polymer Dots Encapsulated with Carbon Nanodots of Bright Near-Infrared Fluorescence for Long-Term Bioimaging.

As a vital organelle in eukaryotic cells, the Golgi apparatus is responsible for processing and transporting proteins in cells. Precisely monitoring the status of the Golgi apparatus with targeted fluorescence imaging technology is of enormous importance but remains a dramatically challenging task. In this study, we demonstrate the construction of the first Golgi apparatus-targeted near-infrared (NIR) fluorescent nanoprobe, termed Golgi-Pdots. As a starting point of our investigation, hydrophobic carbon nanodots (CNDs) with bright NIR fluorescence at 674 nm (fluorescence quantum yield: 12.18%), a narrow emission band of 23 nm, and excellent stability were easily prepared from Magnolia Denudata flowers using an ultrasonic method. Incorporating the CNDs into a polymer matrix modified with Golgi-targeting molecules allowed for the production of the water-soluble Golgi-Pdots, which showed high colloidal stability and similar optical properties compared with pristine CNDs. Further studies revealed that the Golgi-Pdots showed good biocompatibility and Golgi apparatus-targeting capability. Based on these fascinating merits, utilizing Golgi-Pdots for the long-term tracking of the Golgi apparatus inside live cells was immensely successful.

Progress of solute carrier SLC family in nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease is closely related to obesity and type 2 diabetes mellitus, and is one of the components of metabolic syndrome. Due to the complexity of its pathogenesis, there is no effective drug treatment to date. Solute carrier transporters are associated with a variety of metabolic diseases and are abundantly expressed in the liver. They participate in the transport of a variety of nutrients and metabolites, regulate nutrient supply, metabolic transformation, energy balance and oxidative stress, and modulate the physiological functions of liver. Particularly, it is important that some of these SLC transporters have become new targets for drug development. In this review, we summarize the role of SLC in the transport of nutrients and liver metabolites and its correlation with NAFLD, and reveal the potential of SLC as a target for the development of new drugs for NAFLD treatment so as to provide a new choice for the treatment of the disease.

[In-machine Fault Monitoring Mechanism and Maintainability Improvement of Varian Linear Accelerator].

Through repaired the RF driver momentary oscillation stop of Varian 2300CD linear accelerator, systematically and comprehensively expounds the three state machine mode of control system and the in-machine fault monitoring mechanism involved in maintainability of Varian high energy accelerator. It proposes an improved solution to bring RF driver output into interlock system, by doing so it can avoid the control computer breakdown and improve maintainability.

[Dose Monitoring and Maintain of Varian High Energy Linear Accelerators].

The paper analyzes the dose monitoring and control system of Varian C-series high energy linear accelerators systematically from twofold view of machine physics and electromechanical structure. It dissects the structure characteristics of chamber and implementation method of beam steering. It expounds the complete methods of quality control adjustment and troubleshooting.

No causal relationship between serum urate and neurodegenerative diseases: A Mendelian randomization study.

OBJECTIVE: Observational studies have shown that increased serum urate is associated with a lower risk of neurodegenerative diseases (NDs), but the causality remains unclear. We employed a two-sample Mendelian randomization (MR) approach to assess the causal relationship between serum urate and four common subtypes of NDs, including Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). METHODS: Serum urate data came from the CKDGen Consortium. GWAS data for PD, AD, ALS, and MS were obtained from four databases in the primary analysis and then acquired statistics from the FinnGen consortium for replication and meta-analysis. Inverse variance weighted (IVW), weighted median (WM), and MR-Egger regression methods were applied in the MR analyses. Pleiotropic effects, heterogeneity, and leave-one-out analyses were evaluated to validate the results. RESULTS: There was no evidence for the effect of serum urate on PD (OR: 1.00, 95 % CI: 0.90-1.11, P = 0.97), AD (OR: 1.02, 95 % CI: 1.00-1.04, P = 0.06), ALS (OR: 1.05, 95 % CI: 0.97-1.13, P = 0.22), and MS (OR: 1.01, 95 % CI: 0.89-1.14, P = 0.90) risk when combined with the FinnGen consortium, neither was any evidence of pleiotropy detected between the instrumental variables (IVs). CONCLUSION: The MR analysis suggested that serum urate may not be causally associated with a risk of PD, AD, ALS, and MS.

Axial loading lumbar magnetic resonance imaging with a new device in asymptomatic individuals.

Background: Axial loading magnetic resonance imaging (MRI) of lumbar spine is of great significance in the diagnosis of lumbar diseases. However, the axial loading device used in clinic is unique and has some defects. Therefore, we aimed to investigate the effect and examinee comfort of a new device for axial loading lumbar MRI in asymptomatic volunteers. Methods: A new axial loading MRI device for the lumbar spine was developed. A total of 30 asymptomatic individuals underwent conventional lumbar MRI and axial loading lumbar MRI sequentially. The dural sac cross-sectional area (DSCA), sagittal vertebral canal diameter (SVCD), and disc height (DH) at L3-4, L4-5, and L5-S1 before and after axial loading were compared by two experienced radiologists. Examinee comfort during the two examinations was assessed. Results: All 30 volunteers completed the examinations with the new device. No difference in examinee comfort was found between conventional and axial loading MRI. After axial loading, the DSCA, SVCD, and DH showed the largest decreases at L4-5 followed by L5-S1 and L3-4, with the decreases in DSCA and SVCD at L4-5 being significant (P<0.05). Definite imaging-diagnosable disc herniation or bulging was shown at three intervertebral disc levels of three participants. Conclusions: The new device could effectively implement axial loading of the lumbar spine without causing obvious discomfort for the examinee. The present study has demonstrated that significant changes occur in the lumbar spine of asymptomatic individuals after axial loading.

A genome-wide scan of selective sweeps in two broiler chicken lines divergently selected for abdominal fat content.

BACKGROUND: Genomic regions controlling abdominal fatness (AF) were studied in the Northeast Agricultural University broiler line divergently selected for AF. In this study, the chicken 60KSNP chip and extended haplotype homozygosity (EHH) test were used to detect genome-wide signatures of AF. RESULTS: A total of 5357 and 5593 core regions were detected in the lean and fat lines, and 51 and 57 reached a significant level (P<0.01), respectively. A number of genes in the significant core regions, including RB1, BBS7, MAOA, MAOB, EHBP1, LRP2BP, LRP1B, MYO7A, MYO9A and PRPSAP1, were detected. These genes may be important for AF deposition in chickens. CONCLUSIONS: We provide a genome-wide map of selection signatures in the chicken genome, and make a contribution to the better understanding the mechanisms of selection for AF content in chickens. The selection for low AF in commercial breeding using this information will accelerate the breeding progress.