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.

[The influence of using simplified model for beamlet dose calculations in IMRT treatment planning and the approaches to diminish the influence].

Simplified dose calculation model with high computation efficiency is often used to generate the dose matrices for beamlets in the inverse planning of the intensity modulate radiation therapy. It is likely that this simplification could degrade the quality of the final treatment plans. This paper is aimed at testing the influence of such simplification in dose calculations of beamlets and accordingly proposing methods to avoid severe degradation of the plans. Two simulation instances were adopted. The primary dose calculation model without involvment of scattering effect was used to generate the dose matrices of beamlets. The differential convolution superposition dose calculation model that well accounts for scattering effect was used to calculate the final dose distributions for given intensity profiles. It is found that the simplification in dose matrices of beamlets degrades the dose levels in the edge area of the targets, however, the degradation could be diminished or even avoided by adding a suitable margin around the targets or by using the multiple-shifted-beamlet-matrices (MSBM) method that was proposed in our previous paper.

Polymorphism of heart fatty acid-binding protein gene associatied with fatness traits in the chicken.

Fatty acid-binding proteins (FABP) belong to a superfamily of lipid binding proteins that exhibit a high affinity for long chain fatty acids and appear to function in metabolism and intracellular transportation of lipids. The current study was designed to investigate the effects of heart (H)-FABP gene on chicken growth and body composition traits. The Northeast Agricultural University divergent broiler lines for abdominal fat and a broiler X silkie F2 population were used in this study. Body weight and body composition traits were measured in the populations. Primers were designed according to the chicken H-FABP gene sequence. Polymorphisms between parental lines were detected by DNA sequencing. PCR-RFLP and PCR-fragment length polymorphism methods were developed to genotype the populations. The results showed that the H-FABP gene polymorphisms in the two populations were associated with abdominal fat percentage. It implied that H-FABP gene can be a candidate locus or linked to a major gene(s) that affects abdominal fat content in the chicken.

Correlation analysis between single-nucleotide polymorphism of malate dehydrogenase gene 5'-flanking region and growth and body composition traits in chicken.

Malate dehydrogenase (MD) is a key enzyme that plays an important role in energy metabolism. It catalyzes the oxidative decarboxylation of L-malate to yield CO2 and pyruvate, while simultaneously generating NADPH from NADP+. The NADPH generated can be utilized in de novo synthesis of palmitate, which is the precursor molecule for the formation of other long-chain fatty acids. And high levels of MD will also activate muscle development. The current study was designed to investigate the effects of MD gene on growth and body-composition traits in chicken. The eighth generation population of Northeast Agricultural University broiler lines divergently selected for its abdominal fat and Northeast Agricultural University F2 resource population were used in the research. Polymorphisms were detected by DNA sequencing and PCR-RFLP method was then developed to screen the population. A single mutation at the position of the 235 bp (Accession No. U49693) of MD 5'-flanking region was found. The correlation analysis between the polymorphism of the MD gene and growth and body composition traits was carried out using the appropriate statistic model. Least-square analysis showed that the BB genotype birds had much higher pectoralis major weight and percentage of pectoralis major than AA genotype birds (P<0.05). The abdominal fat weight, percentage of abdominal fat, the liver weight and percentage of liver weight of the AA genotype birds were much higher than those of BB genotype birds (P<0.05). These results indicate that MD gene is the major gene or is linked to the major gene that affects the growth and body composition traits in chicken.

[The field shape optimization in conformal radiation therapy by MLC rotation].

Conformal radiation therapy using multi-leaf collimator (MLC) is considered as a conventional technology in the hospital nowadays. However the stepped leaf edge caused by the finite width of the leaves could influence the conformality that could be achievable. In this paper, the effect produced by rotating the collimator angle on the conformality was investigated. A method, in which multiple MLC fields of various rotation angles are applied, has been proposed to have the targets be more uniformly irradiated and thus to eliminate the cold spots on the targets and hot spots in normal tissues. By simulation, it has been shown that the multiple MLC field method can eliminate the stepped leaf edges and improve the conformality significantly, moreover, the PTV can receive a more uniform delivery with cold spot eliminated.

[Cloning and sequencing of the introns of UCP gene and construction of molecular phylogenetic tree in chicken].

The UCP genes were the newly discovered genes that can increase the energy expenditure and involve in the metabolism of fat and regulation of energy. Four pairs of primers in chicken UCP exon region were designed to amplify the introns of chicken UCP gene according to the splice ways of the mouse UCP2 gene (Accession No.AF096288). The sequence results showed that the chicken UCP gene also had five GT-AG type introns. The molecular phylogenetic tree was constructed based on the sequence of cds, intron 2 and intron 3 region, respectively. The phylogenetic tree based on the UCP cds region was consistent with the species phylogenetic tree. This result implicated that UCP gene can be regarded as the useful gene for the study of animal phylogenesis. On the contrast, the phylogenetic tree based on the intron 2 and intron 3 region was different from the species phylogenetic tree, which showed that the evolution of intron and cds region is different.

[SSSR fingerprinting in broiler selected for very low density lipoprotein (VLDL)].

SSR fingerprints were analyzed in three generations of fat line (FL) and lean line (LL) of broiler chickens. Changes in gene frequencies of every locus were evaluated. Thus the relationship between SSR markers and VLDL (a trait representing fat mass of broiler), which is the basis for early selection of LL broiler, was examined. Fourteen microsatellite locus were successfully amplified with 4 of 5 primers used. The results of chi2 test for the gene frequencies of every locus show that one locus was significantly different in generation 1(P<0.05), two in generation 2 and 4 in generation 3.

Comparison of apparent diffusion coefficient and T2 relaxation time variation patterns in assessment of age and disc level related intervertebral disc changes.

PURPOSE: To compare the variation patterns of ADC and T2 values in different age and intervertebral disc (IVD) levels, thus to identify their sensitivities in assessing age and disc level related IVDs changes. MATERIALS AND METHODS: The T2 and ADC values were recorded from 345 IVDs of 69 volunteers. Kendall's correlation analysis was used to identify the relationship between age and T2/ADC mean values respectively. The one-way analysis of variance (ANOVA) with post hoc analysis was then applied to test the differences of T2 and ADC values among different IVD levels and age groups, followed by linear regression analysis between age (<45 and >45 years) and T2/ADC mean values. This study was approved by the Ethics Committee of the Chinese Academy of Medical Sciences and the Peking Union Medical College Hospital. RESULTS: Significant negative correlation was observed between age and T2/ADC mean values. The T2 and ADC values showed significant differences among IVD levels and among age groups except for T2 values in age group 1 (25-34 years) and group 2 (35-44 years), and for ADC values at L1-2 level. Both T2 and ADC values showed significant differences between young (age<45 years) and elderly group (age>45 years) at each IVD level. A linear relationship was observed between age and T2/ADC mean values in the elderly group as well as in the young group for the ADC mean values, while no such tendency was identified in the young group for the T2 mean values. CONCLUSIONS: ADC values may be a more sensitive parameter than T2 in assessing age and disc level related intervertebral disc changes.

Selection signature analysis implicates the PC1/PCSK1 region for chicken abdominal fat content.

We conducted a selection signature analysis using the chicken 60k SNP chip in two chicken lines that had been divergently selected for abdominal fat content (AFC) for 11 generations. The selection signature analysis used multiple signals of selection, including long-range allele frequency differences between the lean and fat lines, long-range heterozygosity changes, linkage disequilibrium, haplotype frequencies, and extended haplotype homozygosity. Multiple signals of selection identified ten signatures on chromosomes 1, 2, 4, 5, 11, 15, 20, 26 and Z. The 0.73 Mb PC1/PCSK1 region of the Z chromosome at 55.43-56.16 Mb was the most heavily selected region. This region had 26 SNP markers and seven genes, Mar-03, SLC12A2, FBN2, ERAP1, CAST, PC1/PCSK1 and ELL2, where PC1/PCSK1 are the chicken/human names for the same gene. The lean and fat lines had two main haplotypes with completely opposite SNP alleles for the 26 SNP markers and were virtually line-specific, and had a recombinant haplotype with nearly equal frequency (0.193 and 0.196) in both lines. Other haplotypes in this region had negligible frequencies. Nine other regions with selection signatures were PAH-IGF1, TRPC4, GJD4-CCNY, NDST4, NOVA1, GALNT9, the ESRP2-GALR1 region with five genes, the SYCP2-CADH4 with six genes, and the TULP1-KIF21B with 14 genes. Genome-wide association analysis showed that nearly all regions with evidence of selection signature had SNP effects with genome-wide significance (P<10(-6)) on abdominal fat weight and percentage. The results of this study provide specific gene targets for the control of chicken AFC and a potential model of AFC in human obesity.

[Antitumour study with combined IL-2 gene therapy and radiation for head and neck squamous cell carcinoma].

OBJECTIVE: To assess the efficacy of combination therapy with IL-2 gene transfer and radiation in an immunocompetent murine model that parallel more closely the clinical therapy of head and neck Squamous cell carcinoma(HNSCC). METHOD: Tumors were established in the floor of mouth in C3H/HeJ mice with SCC VII cell line. Lipid-DNA complexed (lipoplexes) by using polycationic liposome-Mediated transduction for HNSCC were transducted in tumor-bearing mouse by direct intratumoral gene transfer. The local tumor radiation with 2 Gy were done in second day. Tumor size were measured before and after the treatment as compared to different single treatment groups and the controls. After tumors were subcultured, the supernatants were collected for IL-2 expression by enzyme-linked immunosorbent assay (ELISA). Natural killer (NK) cell activity and cytotoxic T-lymphocyte (CTL) activity were also assayed by LDH method. CD4+ and CD8+ T-lymphcyte in tumour tissues were examined by immunohistochemistry. RESULT: HNSCC tumor growth was significantly inhibited after a combined IL-2 gene and radiation therapy as compared to the controls. Increased secreted levels of IL-2 protein expression were found in combined and single IL-2 gene treated groups. The combination and IL-2 gene treated groups produced greater activation of CTL and NK than the other groups. The significant CD4+ and CD8+ T lymphocyte infiltration was distributed in tumor tissues after IL-2 gene therapy. CONCLUSION: Combined IL-2 gene therapy and radiation could significantly inhibited HNSCC tumor growth in the murine model and efficiently induced antitumor immunity of the host.