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Objective: Activating brown adipose tissue (BAT) thermogenesis is a promising approach to combat obesity and metabolic disorders. The post-transcriptional regulation of BAT thermogenesis mediated by RNA-binding proteins (RBPs) is still not fully understood. This study explores the physiological role of novel RBPs in BAT differentiation and thermogenesis. Methods: We used multiple public datasets to screen out novel RBPs responsible for BAT differentiation and thermogenesis. In vitro loss- and gain-of-function experiments were performed in both C3H10T1/2 preadipocytes and mature brown adipocytes to determine the role of Y-box binding protein 3 (YBX3) in brown adipocyte differentiation and thermogenesis. Adeno-associated virus (AAV)-mediated BAT-specific knockdown or overexpression of Ybx3 was applied to investigate the function of YBX3 in vivo. Results: YBX3 is a brown adipocyte-enriched RBP induced by cold stimulation and β-adrenergic signaling. Both in vitro loss- and gain-of-function experiments demonstrate that YBX3 is essential for brown adipocyte differentiation and thermogenesis. BAT-specific loss of Ybx3 dampens thermogenesis and exacerbates diet-induced obesity in mice, while overexpression of Ybx3 promotes thermogenesis and confers protection against diet-induced metabolic dysfunction. Transcriptome analysis and mitochondrial stress test indicate that Ybx3 deficiency compromises the mitochondrial oxidative phosphorylation, leading to thermogenic failure. Mechanistically, YBX3 stabilizes the mRNA of Slc3a2 and Pparg, which facilitates branched-chain amino acid (BCAA) influx and catabolism and fuels brown adipocyte differentiation and thermogenesis. Conclusions: YBX3 facilitates BAT fueling BCAA to boost thermogenesis and energy expenditure, which protects against obesity and metabolic dysfunction. Thus, YBX3 could be a promising therapeutic target for obesity.

Abstract New therapeutic targets and drugs are urgently needed to halt the fibrosing process in idiopathic pulmonary fibrosis (IPF). SHR‐1906 is a novel fully humanized monoclonal antibody against the connective tissue growth factor, which plays an essential role in the genesis of IPF. We assessed the safety, tolerability, pharmacokinetics (PKs), and immunogenicity of single dose SHR‐1906 in healthy participants. This was a randomized, double‐blind, placebo‐controlled, dose‐escalation, phase I study. Twelve healthy participants for each dose level were enrolled to receive single ascending doses of SHR‐1906 intravenously (1.5, 6, 12, 20, 30, and 45 mg/kg) or placebo and followed for 71 days. The primary end points were safety and tolerability. Treatment‐related treatment‐emergent adverse events occurred in 25 participants (46.3%) in the SHR‐1906 group and 11 (61.1%) in the placebo group. No serious adverse events occurred. Over the dose range investigated, the geometric mean clearance was 0.14–0.63 mL/h/kg, the geometric mean volume of distribution at steady‐state was 47.4–75.5 mL/kg, and the terminal elimination half‐life was 51.9–349 h. SHR‐1906 showed nonlinear PKs. The peak concentration increased in a dose‐proportional manner, whereas the area under the concentration–time curve showed a greater than dose‐proportional increase. Anti‐drug antibodies of SHR‐1906 were detected in nine of 54 participants (16.7%). A single dose of SHR‐1906 up to 45 mg/kg demonstrated a favorable tolerability profile in healthy participants. The PKs and immunogenicity of SHR‐1906 were evaluated, supporting further clinical development.

Objectives: INS068 is a novel, soluble, and long-acting insulin analog. In this study, we evaluated the pharmacokinetics and relative bioavailability of two formulations of INS068 in healthy Chinese subjects: a reference formulation packaged in vials and administered via syringe (R), and a test formulation packaged and administered via pen injector (T).Methods: A randomized, open-label, two-period, two-sequence crossover study was conducted with 24 healthy Chinese subjects. Subjects were randomized and administered subcutaneously in the abdomen at 0.4 U/kg of test or reference INS068 injection according to an open crossover design. INS068 concentrations in the serum were measured using LC-MS/MS, and the pharmacokinetic parameters of maximum concentration (Cmax) and area under the concentration-time curve (AUC0–t and AUC0–∞) were used to evaluate relative bioavailability.Results: After a single dose at 0.4 U/kg, the median Tmax of INS068 was 12 h for both formulations, and the mean t1/2 for T and R was 13.0 h and 12.6 h, respectively. The geometric means of Cmax and AUC0–∞ were 3.99 nmol/L and 120 h·nmol/L for the T, and 4.05 nmol/L and 117 h·nmol/L for the R, respectively. The geometric mean ratios of Cmax, AUC0–t and AUC0–∞ of T over R were 98.7% (90% CI: 92.7%–105.2%), 102.6% (90% CI: 100.0%–105.3%) and 102.8% (90% CI: 100.1%–105.5%).Conclusion: The overall PK profile of the two formulations of INS068 injection was comparable in healthy subjects, and the pen injector of INS068 had adequate safety and tolerability, supporting it as a new formulation in a phase III study and bridging PK data from early phase clinical trials.Clinical Trial Registration:clinicaltrials.gov, identifier: NCT05336071

Hereditary spastic paraplegia (HSP) is a group of neurodegenerative diseases with genetic and clinical heterogeneity characterized by spasticity and weakness of the lower limbs. It includes four genetic inheritance forms: autosomal dominant inheritance (AD), autosomal recessive inheritance (AR), X-linked inheritance, and mitochondrial inheritance. To date, more than 82 gene loci have been found to cause HSP, and SPG15 (ZFYVE26) is one of the most common autosomal recessive hereditary spastic paraplegias (ARHSPs) with a thin corpus callosum (TCC), presents with early cognitive impairment and slowly progressive leg weakness. Here, we reported a homozygous pathogenic variant in ZFYVE26. A 19-year-old Chinese girl was admitted to our hospital presenting with a 2-year progressive bilateral leg spasticity and weakness; early cognitive impairment; corpus callosum dysplasia; chronic neurogenic injury of the medulla oblongata supplied muscles; and bilateral upper and lower limbs on electromyogram (EMG). Based on these clinical and electrophysiological features, HSP was suspected. Exome sequencing of the family was performed by high-throughput sequencing, and an analysis of the patient showed a ZFYVE26 NM_015346: c.7111dupA p.(M2371Nfs*51) homozygous mutation. This case reported a new ZFYVE26 pathogenic variant, which was different from the SPG15 gene mutation reported earlier.

Summary: Branched-chain amino acids (BCAAs) provide nutrient signals for cell survival and growth. How BCAAs affect CD8+ T cell functions remains unexplored. Herein, we report that accumulation of BCAAs in CD8+ T cells due to the impairment of BCAA degradation in 2C-type serine/threonine protein phosphatase (PP2Cm)-deficient mice leads to hyper-activity of CD8+ T cells and enhanced anti-tumor immunity. CD8+ T cells from PP2Cm−/− mice upregulate glucose transporter Glut1 expression in a FoxO1-dependent manner with more glucose uptake, as well as increased glycolysis and oxidative phosphorylation. Moreover, BCAA supplementation recapitulates CD8+ T cell hyper-functions and synergizes with anti-PD-1, in line with a better prognosis in NSCLC patients containing high BCAAs when receiving anti-PD-1 therapy. Our finding thus reveals that accumulation of BCAAs promotes effector function and anti-tumor immunity of CD8+ T cells through reprogramming glucose metabolism, making BCAAs alternative supplementary components to increase the clinical efficacy of anti-PD-1 immunotherapy against tumors.

BackgroundMyotonic dystrophy type 1 (DM1) is the most common and dominant inherited neuromuscular dystrophy disease in adults, involving multiple organs, including the brain. Although structural measurements showed that DM1 is predominantly associated with white-matter damage, they failed to reveal the dysfunction of the white-matter. Recent studies have demonstrated that the functional activity of white-matter is of great significance and has given us insights into revealing the mechanisms of brain disorders.Materials and methodsUsing resting-state fMRI data, we adopted a clustering analysis to identify the white-matter functional networks and calculated functional connectivity between these networks in 16 DM1 patients and 18 healthy controls (HCs). A two-sample t-test was conducted between the two groups. Partial correlation analyzes were performed between the altered white-matter FC and clinical MMSE or HAMD scores.ResultsWe identified 13 white-matter functional networks by clustering analysis. These white-matter functional networks can be divided into a three-layer network (superficial, middle, and deep) according to their spatial distribution. Compared to HCs, DM1 patients showed increased FC within intra-layer white-matter and inter-layer white-matter networks. For intra-layer networks, the increased FC was mainly located in the inferior longitudinal fasciculus, prefrontal cortex, and corpus callosum networks. For inter-layer networks, the increased FC of DM1 patients is mainly located in the superior corona radiata and deep networks.ConclusionResults demonstrated the abnormalities of white-matter functional connectivity in DM1 located in both intra-layer and inter-layer white-matter networks and suggested that the pathophysiology mechanism of DM1 may be related to the white-matter functional dysconnectivity. Furthermore, it may facilitate the treatment development of DM1.

Non-alcoholic fatty liver disease (NAFLD), hallmarked by liver steatosis, is becoming a global concern, but effective and safe drugs for NAFLD are still lacking at present. Parathyroid hormone (PTH), the only FDA-approved anabolic treatment for osteoporosis, is important in calcium-phosphate homeostasis. However, little is known about its potential therapeutic effects on other diseases. Here, we report that intermittent administration of PTH ameliorated non-alcoholic liver steatosis in diet-induced obese (DIO) mice and db/db mice, as well as fasting-induced hepatic steatosis. In vitro, PTH inhibits palmitic acid-induced intracellular lipid accumulation in a parathyroid hormone 1 receptor (PTH1R)-dependent manner. Mechanistically, PTH upregulates the expression of genes involved in lipid β-oxidation and suppresses the expression of genes related to lipid uptake and de novo lipogenesis by activating the cAMP/PKA/CREB pathway. Taken together, our current finding proposes a new therapeutic role of PTH on NAFLD.

Abstract Background Differences of genotypes between male and female have been studied in Parkinson’s disease (PD), but limited research has focused on the comparison between sexes with LRRK2 G2385 variant. Objective The aim of this study was to explore sex effects in the same genetic subtype and role of leucine-rich repeat kinase 2 (LRRK2) G2385R variants in the same sex in PD. Methods 613 PD patients were recruited from the Movement Disorders Clinic in Ruijin Hospital. We did not include healthy controls in this study. The data collected includes demographic information, disease history, scores of motor and non-motor symptoms scales, midbrain transcranial sonography and DNA. Binary logistic regression analysis was performed to evaluate the association between clinical features and sex in LRRK2 G2385R carriers and non-carriers, as well as the association between the clinical features and LRRK2 G2385R variants in male and female sex. Results Sex distribution is similar in LRRK2 G2385R carriers and non-carriers. In male sex, LRRK2 G2385R carriers showed lower risk in cognitive impairment compared with non-carriers (OR = 0.301, p = 0.003, 95%CI 0.135–0.668). In female sex, LRRK2 G2385R carriers showed lower risk in autonomic dysfunction compared with non-carrier (OR = 0.401, p = 0.040, 95%CI 0.167–0.960). In LRRK2 G2385R non-carriers, female sex showed lower risk of impairment in activity of daily living (OR = 0.610, p = 0.021, 95%CI 0.400–0.928), excessive daytime sleepiness (OR = 0.555, p = 0.007, 95%CI 0.361–0.853), substantia nigra hyperechogenicity (OR = 0.448, p = 0.019, 95%CI 0.228–0.878), autonomic dysfunction frequency (OR = 0.626, p = 0.016, 95%CI 0.428–0.917) and higher risk in mood disorders (OR = 1.691, p = 0.022, 95%CI 1.078–2.654) compared with male. In LRRK2 G2385R carriers, female sex showed a lower risk of autonomic dysfunction (OR = 0.294, p = 0.024, 95%CI 0.102–0.849) compared with male. Conclusion In contrast to male PD patients, a more benign disease course was observed in female in both LRRK2 G2385R carriers and non-carriers. However, sex differences were less notable in PD with LRRK2 G2385R variants.

AIM: To investigate the significance of ultrasound elastography for evaluating stiffness of the human lens nucleus in volunteers with different ages. METHODS: A total of 90 volunteers (lens transparency, uncorrected visual acuity ≥0.5, intraocular pressure: 14-19 mm Hg) were divided into 3 groups according to age: Group A (30 people, median age: 82±3.5y, mean axial lengths 23.7±0.5 mm); Group B (30 people, median age: 46±2.1y, mean axial lengths 23.9±0.4 mm); and Group C (30 people, median age: 22±3.5y, mean axial lengths 24.0±0.4 mm). Lens nuclear stiffness was measured by Free-hand qualitative elastography by independent operators. Strain gray scale and color-coded elastography maps were recorded. In each case, three consecutive detections were performed and strain ratio was used for statistical analysis. RESULTS: Elastography analysis showed excellent diagnostic performance for lens sclerosis. Lens strain ratio was lowest (0.03±0.01)% in Group A and highest (2.03±0.43)% in Group C. Lens strain ratio was moderate (0.64±0.10)% in Group B. There were significant differences between these three groups (P

Molecular subtypes of breast cancer are important references to personalized clinical treatment. For cost and labor savings, only one of the patient’s paraffin blocks is usually selected for subsequent immunohistochemistry (IHC) to obtain molecular subtypes. Inevitable block sampling error is risky due to the tumor heterogeneity and could result in a delay in treatment. Molecular subtype prediction from conventional H&E pathological whole slide images (WSI) using the AI method is useful and critical to assist pathologists to pre-screen proper paraffin block for IHC. It is a challenging task since only WSI-level labels of molecular subtypes from IHC can be obtained without detailed local region information. Gigapixel WSIs are divided into a huge amount of patches to be computationally feasible for deep learning, while with coarse slide-level labels, patch-based methods may suffer from abundant noise patches, such as folds, overstained regions, or non-tumor tissues. A weakly supervised learning framework based on discriminative patch selection and multi-instance learning was proposed for breast cancer molecular subtype prediction from H&E WSIs. Firstly, co-teaching strategy using two networks was adopted to learn molecular subtype representations and filter out some noise patches. Then, a balanced sampling strategy was used to handle the imbalance in subtypes in the dataset. In addition, a noise patch filtering algorithm that used local outlier factor based on cluster centers was proposed to further select discriminative patches. Finally, a loss function integrating local patch with global slide constraint information was used to fine-tune MIL framework on obtained discriminative patches and further improve the prediction performance of molecular subtyping. The experimental results confirmed the effectiveness of the proposed AI method and our models outperformed even senior pathologists, which has the potential to assist pathologists to pre-screen paraffin blocks for IHC in clinic.

Mucosal healing is a key treatment goal for inflammatory bowel disease, and adequate epithelial regeneration is required for an intact gut epithelium. However, the underlying mechanism for mucosal healing is unclear. Long noncoding RNAs (lncRNAs) have been reported to be involved in the development of inflammatory bowel disease. Here, we report that a lncRNA named Gm31629 decreased in intestinal epithelial cells in response to inflammatory stimulation. Gm31629 deficiency led to exacerbated intestinal inflammation and delayed epithelial regeneration in dextran sulfate sodium–induced (DSS-induced) colitis model. Mechanistically, Gm31629 promoted E2F pathways and cell proliferation by stabilizing Y-box protein 1 (YB-1), thus facilitating epithelial regeneration. Genetic overexpression of Gm31629 protected against DSS-induced colitis in vivo. Theaflavin 3-gallate, a natural compound mimicking Gm31629, alleviated DSS-induced epithelial inflammation and mucosal damage. These results demonstrate an essential role of lncRNA Gm31629 in linking intestinal inflammation and epithelial cell proliferation, providing a potential therapeutic approach to inflammatory bowel disease.

Tuberculosis (TB) is an airborne infection caused by Mycobacterium tuberculosis that usually affects the lungs. Timely treatment of active TB, diagnosis and prevention of latent TB are very important. However, extrapulmonary TB affects almost any tissues around the eye and orbit, and it then requires a high degree of suspicion to accurately diagnose. Diagnostic delays are common and may lead to morbidity. For ophthalmologists and infectious disease specialists, it is important to work together to accurately diagnose and treat ocular tuberculosis (OTB) to prevent vision loss. This review reports the latest advanced diagnostic methods for active TB and latent TB as well as various known manifestations of OTB. Important elements of diagnosis and treatment are also reviewed.

Abstract MicroRNAs (miRNAs) play important roles in cell proliferation, differentiation, and survival and may be useful for acute myeloid leukemia (AML) diagnosis and prognosis. In this study, we defined a novel miRNA, hsa-miR-12462, through small RNA sequencing of the bone marrow (BM) cells from 128 AML patients. Overexpression of hsa-miR-12462 in AML cells (U937 and HL-60) significantly decreased their growth rate when compared with those of the wild-type and MOCK controls. In a xenograft mouse model, tumor weight and size in the mice bearing the U937 cells with hsa-miR-12462 overexpression were significantly reduced when compared with those bearing the mock cells. The AML cells overexpressing hsa-miR-12462 had increased sensitivity to cytarabine chemotherapy. Combining the data from the MiRDB, an online microRNA database ( http://mirdb.org ), with the RNA-sequencing results, SLC9A1 was predicted to be one of the targets of hsa-miR-12462. hsa-miR-12462 was further confirmed to bind exclusively to the 3′UTR of SLC9A1 in U937 cells, leading to downregulation of SLC9A1. In summary, a higher level of hsa-miR-12462 in AML cells is associated with increased sensitivity to cytarabine chemotherapy via downregulation of SLC9A1.

"AIM: To investigate the significance of ultrasound elastography for evaluating stiffness of the human lens nucleus in patients with anisometropia. METHODS: A total of 14 patients (28 eyes) with anisometropia were enrolled. The difference in refractive status between two eyes ≥-4.0 diopters (D) and the difference in axial length (AL) of the eyes was ≥3 mm. There were 5 males and 9 females with an average age of 62±3.3y. The test data of the long AL eye of each patient was included in group A (14 eyes), and test data of the eye with relative short AL was included in group B. Lens nuclear stiffness was measured with free-hand qualitative elastography by independent operators. Strain gray scale and color-coded elastography maps were recorded. In each case, three consecutive measurements were performed and strain ratio was used for statistical analysis. Photograph and sectional view of the lens were analyzed and archived by anterior segment image. RESULTS: In the long AL group, the strain rate in the nucleus of the lens was 0.16%±0.08%; in the short AL group, the strain rate in the nucleus of the lens was 0.54%±0.16%. Independent sample t-test analyses showed that the long AL group lens had a significantly smaller nuclear strain rate than the relatively short AL group, P

Abstract Background Progressive supranuclear palsy (PSP) is a rare movement disorder with poor prognosis. This retrospective study aimed to characterize the natural history of PSP and to find predictors of shorter survival and faster decline of activity of daily living. Method All patients recruited fulfilled the movement disorder society (MDS) clinical diagnostic criteria for PSP (MDS-PSP criteria) for probable and possible PSP with median 12 years. Data were obtained including age, sex, date of onset, age at onset (AAO), symptoms reported at first visit and follow-up, date of death and date of institutionalization. Magnetic resonance imaging was collected at the first visit. Endpoints were death and institutionalization. Kaplan-Meier method and Cox proportional hazard model were used to explore factors associated with early death and institutionalization. Results Fifty-nine patients fulfilling MDS-PSP criteria were enrolled in our study. Nineteen patients (32.2%) had died and 31 patients (52.5%) were institutionalized by the end of the follow-up. Predictors associated with poorer survival were late-onset PSP and decreased M/P area ratio. Predictors associated with earlier institutionalization were older AAO and decreased M/P area ratio. Conclusion Older AAO and decreased M/P area ratio were predictors for earlier dearth and institutionalization in PSP. The neuroimaging biomarker M/P area ratio was a predictor for prognosis in PSP.

Abstract Objective To describe the clinical and genetic features of two patients with different phenotypes due to various Dynactin 1 (DCTN1) gene mutations and further explore the phenotype–genotype relationship. Methods Patient 1 is a 23‐year‐old man with congenital foot deformity and life‐long distal muscle weakness and atrophy. Patient 2 is a 48‐year‐old woman with adult‐onset progressive weakness, lower limbs atrophy, and pyramid bundle signs. Electrophysiology test showed normal nerve conduction velocity of both patients and neurogenic changes in needle electromyography. Open sural nerve biopsy for Patient 1 showed slight loss of myelinated nerve fibers. Both patients were performed with whole‐exome sequencing followed by functional study of identified variants. Results Two mutations in DCTN1 gene were identified in Patient 1 (c.626dupC) and Patient 2 (c.3823C>T), respectively. In vitro, the wild type mostly located in cytoplasm and colocalized with α‐tubulin. However, c.626dupC tended to be trapped into nuclear and the c.3823C>T formed cytoplasmic aggregates, both losing colocalization with α‐tubulin. Western blotting showed a truncated mutant with less molecular weight of c.626dupC was expressed. Interpretation We identify two novel DCTN1 mutations causing different phenotypes: (1) early‐onset distal hereditary motor neuropathy plus congenital foot malformation and (2) amyotrophic lateral sclerosis, respectively. We provide the initial evidence that foot developmental deficiency probably arises from subcellular localizing abnormality of Dynactin 1, revealing DCTN1‐related spectrum is still expanding.

Abstract Background CSF1R-related leukoencephalopathy, also known as hereditary diffuse leukoencephalopathy with spheroids (HDLS), is a rare white-matter encephalopathy characterized by motor and neuropsychiatric symptoms due to colony-stimulating factor 1 receptor (CSF1R) gene mutation. Few of CSF1R mutations have been functionally testified and the pathogenesis remains unknown. Methods In order to investigate clinical and pathological characteristics of patients with CSF1R-related leukoencephalopathy and explore the potential impact of CSF1R mutations, we analyzed clinical manifestations of 15 patients from 10 unrelated families and performed brain biopsy in 2 cases. Next generation sequencing was conducted for 10 probands to confirm the diagnosis. Sanger sequencing, segregation analysis and phenotypic reevaluation were utilized to substantiate findings. Functional examination of identified mutations was further explored. Results Clinical and neuroimaging characteristics were summarized. The average age at onset was 35.9 ± 6.4 years (range 24–46 years old). Younger age of onset was observed in female than male (34.2 vs. 39.2 years). The most common initial symptoms were speech dysfunction, cognitive decline and parkinsonian symptoms. One patient also had marked peripheral neuropathy. Brain biopsy of two cases showed typical pathological changes, including myelin loss, axonal spheroids, phosphorylated neurofilament and activated macrophages. Electron microscopy disclosed increased mitochondrial vacuolation and disorganized neurofilaments in ballooned axons. A total of 7 pathogenic variants (4 novel, 3 documented) were identified with autophosphorylation deficiency, among which c.2342C > T remained partial function of autophosphorylation. Western blotting disclosed the significantly lower level of c.2026C > T (p.R676*) than wild type. The level of microtubule associated protein 1 light chain 3-II (LC3-II), a classical marker of autophagy, was significantly lower in mutants expressed cells than wild type group by western blotting and immunofluorescence staining. Conclusions Our findings support the loss-of-function and haploinsufficiency hypothesis in pathogenesis. Autophagy abnormality may play a role in the disease. Repairing or promoting the phosphorylation level of mutant CSF1R may shed light on therapeutic targets in the future. However, whether peripheral polyneuropathy potentially belongs to CSF1R-related spectrum deserves further study with longer follow-up and more patients enrolled. Trial registration ChiCTR, ChiCTR1800015295. Registered 21 March 2018.

This study is aimed at investigating the characteristics of the spontaneous brain activity in patients with myotonic dystrophy type 1 (DM1). A total of 18 patients with DM1 and 18 healthy controls (HCs) were examined by resting-state functional MRI. Combined methods include amplitude of low-frequency fluctuations (ALFFs), the fractional amplitude of low-frequency fluctuations (fALFFs), and Wavelet transform-based ALFFs (Wavelet-ALFFs) with standardization, percent amplitude of fluctuation (PerAF) with/without standardization were applied to evaluate the spontaneous brain activity of patients with DM1. Compared with HCs, patients with DM1 showed decreased ALFFs and Wavelet-ALFFs in the bilateral precuneus (PCUN), angular gyrus (ANG), inferior parietal, but supramarginal and angular gyri (IPL), posterior cingulate gyrus (PCG), superior frontal gyrus, medial (SFGmed), middle occipital gyrus (MOG), which were mainly distributed in the brain regions of default mode network (DMN). Decreased ALFFs and Wavelet-ALFFs were also seen in bilateral middle frontal gyrus (MFG), inferior frontal gyrus, opercular part (IFGoperc), which were the main components of the executive control network (ECN). Patients with DM1 also showed decreased fALFFs in SFGmed.R, the right anterior cingulate and paracingulate gyri (ACGR), bilateral MFG. Reduced PerAF in bilateral PCUN, ANG, PCG, MOG, and IPLL as well as decreased PerAF without standardization in PCUNR and bilateral PCG also existed in patients with DM1. In conclusion, patients with DM1 had decreased activity in DMN and ECN with increased fluctuations in the temporal cortex and cerebellum. Decreased brain activity in DMN was the most repeatable and reliable with PCUN and PCG being the most specific imaging biomarker of brain dysfunction in patients with DM1.

AIM: To discuss the protective effects of betaine-homocysteine methyl transferase(BHMT)on oxidative damaged human lens epithelial cells(HLEC)induced by homocysteine.METHODS: HLEC were cultured in vitro and then randomly divided into 3 groups. Normal group:normal cultured HLEC; control group: normal cultured HLEC transfected with empty vector; BHMT gene overexpression group(OE): HLEC transfected with BHMT gene overexpression. All groups were cultured in 10% FCS DMEM +5mmol/L Hcy for 16h. After cultured, BHMT mRNA expression was measured by qRT-PCR and Western blot, the cell proliferation was detected by EdU Assay Kit,The level of ROS and GSH of HLEC were measured by Flow Cytometer and Visible Spectrophotometers. The expression level of of protein(GRP78, Nrf2, Caspase-12)was measured by western blotting. RESULTS: After cultured 16h, cell proliferation ability in OE group was increased by 30.0% compared with NC group(PPPCONCLUSION: BHMT in vitro can prevent the oxidative damage of HLEC by high homocysteine, clear the ROS and decrease the ER stress reaction. Apoptosis of lens epithelial cells was inhibited. BHMT plays an important protective role in oxidative damaged HLEC induced by Hcy.

Abstract Objective GDP‐mannose pyrophosphorylase B (GMPPB) related phenotype spectrum ranges widely from congenital myasthenic syndrome (CMS), limb‐girdle muscular dystrophy type 2T (LGMD 2T) to severe congenital muscle‐eye‐brain syndrome. Our study investigates the clinicopathologic features of a patient with novel GMPPB mutations and explores the pathogenetic mechanism. Methods The patient was a 22‐year‐old woman with chronic proximal limb weakness for 9 years without cognitive deterioration. Weakness became worse after fatigue. Elevated serum creatine kinase and decrements on repetitive nerve stimulation test were recorded. MRI showed fatty infiltration in muscles of lower limbs and shoulder girdle on T1 sequence. Open muscle biopsy and genetic analysis were performed. Results Muscle biopsy showed myogenic changes. Two missense mutations in GMPPB gene (c.803T>C and c.1060G>A) were identified in the patient. Western blotting and immunostaining showed GMPPB and α‐dystroglycan deficiency in the patient's muscle. In vitro, mutant GMPPB forming cytoplasmic aggregates completely colocalized with microtubule‐associated protein 1 light chain 3‐II (LC3‐II), a classical marker of autophagosome. Degradation of GMPPB was accompanied by an upregulation of LC3‐II, which could be restored by lysosomal inhibitor leupeptin. Interpretation We identified two novel GMPPB mutations causing overlap phenotype between LGMD 2T and CMS. We provided the initial evidence that mutant GMPPB colocalizes with autophagosome at subcellular level. GMPPB mutants degraded by autophagy‐lysosome pathway is associated with LGMD 2T. This study shed the light into the enzyme replacement which could become one of the therapeutic targets in the future study.

L-Methionine (L-Met) is a sulfur-containing amino acid, which is one of the eight essential amino acids to human body. In this work, the fermentative production of L-Met with genetically engineered Escherichia coli W3110-BL in a 5-L fermentor was enhanced through supplement of Ca2+ into the fermentation medium. With the addition of 30 g/L calcium carbonate (CaCO3), the titer of L-Met and yield against glucose reached 1.48 g/L and 0.09 mol/mol glucose, 57.45% higher than those of the control, respectively. The flux balance analysis (FBA) revealed that addition of CaCO3 strengthened the tricarboxylic acid cycle and increased the intracellular ATP concentration by 39.28%. The re-distribution of carbon, ATP, and cofactors flux may collaborate to improve L-Met biosynthesis with E. coli W3110-BL. The regulation of citrate synthase and oxidative phosphorylation pathway was proposed to be important for overproduction of L-Met. These foundations provide helpful reference in the following metabolic modification or fermentation control for further improvement of L-Met biosynthesis.

Abstract Background Chinese guidelines for management of Parkinson’s disease (PD) have been issued and updated regularly since 2006. We undertook a cross-sectional survey to evaluate the impact of the latest edition (2014) on current approaches to the management of PD based on previous pilot works. Methods Seven hundred and seventeen participants, divided into 3 groups (GPs, Neurologists, and Specialists), recruited from 138 randomly chosen hospitals from 30 cities across China, participated by completing the questionnaire describing their current approaches before and after the guidelines were issued. Results Considerable discrepancies in management were apparent across the three categories, with different selection of first-choice medication for PD patients. There were also variations in management of concurrent psychiatric symptoms and dementia. Notably, over 50% of participants reported improvements in PD recognition and management by following the guidelines. Conclusions The increasing use of Chinese clinical practice guidelines for PD management is having a positive impact on the optimization of care, which in turn offers important economic benefits.

Abstract Background The differential diagnosis of Parkinson’s disease (PD) and multiple system atrophy (MSA) remains a challenge, especially in the early stage. Here, we assessed the value of transcranial sonography (TCS) to discriminate non-tremor dominant (non-TD) PD from MSA with predominant parkinsonism (MSA-P). Methods Eighty-six MSA-P patients and 147 age and gender-matched non-TD PD patients who had appropriate temporal acoustic bone windows were included in this study. All the patients were followed up for at least 2 years to confirm the initial diagnosis. Patients with at least one substantia nigra (SN) echogenic size ≥18 mm2 were classified as hyperechogenic, those with at least one SN echogenic size ≥25 mm2 was defined as markedly hyperechogenic. Results The frequency of SN hyperechogenicity in non-TD PD patients was significantly higher than that in MSA-P patients (74.1% vs. 38.4%, p

AIM: To investigate the effect of tumor necrosis factor receptor associated factor 6(TRAF6)on proliferation, apoptosis and invasion of retinoblastoma Y79 cells. METHODS: The Y79 cells were divided into three groups: blank control group, negative control group and TRAF6 siRNA group. After TRAF6 siRNA transfection, the levels of TRAF6 mRNA and protein in Y79 cells were examined by RT-PCR and Western blotting. MTT assay was used to detect cell proliferation. Flow cytometry was employed to detect changes in cell cycle and apoptosis. Cell invasiveness was detected by the Transwell method. RESULTS: Expression of TRAF6 mRNA and protein in the TRAF6 siRNA group significantly decreased compared with the negative and blank control groups. Following the silencing of TRAF6, cell proliferation was inhibited and the apoptosis rate increased; the cell cycle was arrested at G0/G1 phase; the number of cells in S phase was reduced, while the invasion ability of cancer cells decreased. CONCLUSION: Silencing TRAF6 may inhibit the proliferation of Y79 cells, promote cell apoptosis, arrest the cell cycle at G0/G1 phase and decrease the invasive ability. Thus, TRAF6 may be a potential target in therapy for retinoblastoma.

AIM: To study the clinical effect of Conbercept and Ranibizumab for macular edema(ME)with meta-analysis. METHODS:We searched Pubmed, EMBASE, Cochrane Library Central Register of Controlled Trials(CENTRAL), Google scholar, ClinicalTrials.gov, CNKI, VIP and wanfang database for studies which published between January 1 2012 and July 1 2017, on the comparison of conbercept with ranibizumab for the clinical effect of secondary macular edema. The primary endpoints were visual acuity(VA)and central macular thickness in this study to assess the efficiency of the drugs. Review Manager 5.3 and Stata 12.0 were used for data analysis with the pooled odds ratios(OR), mean difference and 95% confidence interval(CI). RESULTS: Eleven RCTs involving 812 patients met inclusion criteria and included in this meta-analysis, including 414 eyes in conbercept group and 398 eyes in ranibizumab group. Macular edema in this study were secondary to age-related macular degeneration, diabetic retinopathy and retinal vein occlusion. No significant differences in improvement of vision acuity(P=0.09)or reduction of CMT(P>0.05)were noted at the end of 3mo between two groups. Compared to ranibizumab, conbercept showed a better effectiveness in macular edema alleviation in the end of 6mo in the present study(OR=-58.50, 95%CI: -108.04 to -8.95; P=0.02). CONCLUSION: Despite evidence from the meta-analysis of the RCTs suggesting a strong difference of the effectiveness for macular edema between conbercept and ranibizumab, more clinical trials are still needed to confirm our results because of the heterogeneity in the collected data.

AIM: To compare of lens oxidative damage induced by vitrectomy and/or hyperoxia in rabbit. METHODS: Sixteen New Zealand rabbits (2.4-2.5 kg) were randomly divided into two groups (Group A, n=12; Group B, n=4). In Group A, the right eyes were treated with vitrectomy and systemic hyperoxia (oxygen concentration: 80%-85%, 1 ATA, 4h/d) (Group A-right), and the left eyes were treated with hyperoxia without vitrectomy surgery (Group A-left). Four rabbits in group B (eight eyes) were untreated as the controls. Lens transparency was monitored with a slit lamp and recorded before and after vitrectomy. After hyperoxic treatment for 6mo, the eyeballs were removed and the lens cortices (containing the capsules) and nuclei were separated for further morphological and biochemical evaluation. RESULTS: Six months after treatments, there were no significant morphological changes in the lenses in any experimental group when observed with a slit lamp. However, the levels of water-soluble proteins and ascorbate, and the activities of catalase and Na+-K+-ATPase were significantly reduced, whereas the levels of malondialdehyde and transforming growth factor β2 (TGF-β2) were significantly elevated, in both the cortices and nuclei of eyes treated with vitrectomy and hyperoxia. The increase in protein-glutathione mixed disulfides and the reduction in water-soluble proteins were more obvious in the lens nuclei. The levels of ascorbate in the vitreous fluid were also reduced after vitrectomy, whereas TGF-β2 increased after vitrectomy and hyperoxia. Systemic hyperoxia exposure increased these effects. CONCLUSION: Removal of the intact vitreous gel with vitrectomy and exposing the lens to increased oxygen from the retina induce lens oxidation and aggregation. Thus, an intact vitreous gel structure may protect the lens from oxidative insult and maintain lens transparency.

Background: The aim of this study was to assess the efficacy and safety of vinorelbine and cisplatin (NP chemotherapy) alone or in combination with Aidi injection for the treatment of advanced nonsmall cell lung cancer (NSCLC). Methods: Pertinent publications were identified in PubMed, EMBASE, Cochrane Library, CNKI, CQVIP, and Wanfang databases, up to December 8, 2015. After quality assessment of all included randomized controlled trials evaluating Aidi injection combined with NP chemotherapy for the treatment of advanced NSCLC, a meta-analysis was performed by Review Manager 5.2 and STATA 12.0 for statistical analyses. Results: Twelve studies including 509 and 503 cases in the experimental and control groups, respectively, were finally analyzed. The meta-analysis revealed that when cisplatin dose ranging from 20 to 40 mg/m 2 , combination of Aidi injection and NP chemotherapy was statistically different compared with NP chemotherapy alone in enhancing efficiency (relative risk [RR] = 1.24, 95% confidence interval [CI] [1.05-1.47], P = 0.010) and reducing the incidence of Grade II or above nausea and vomiting (RR = 0.49, 95% CI [0.30-0.80], P = 0.005). Meanwhile, with cisplatin ranging from 80 to 120 mg/m 2 , no significant differences in efficiency (RR = 1.11, 95% CI [0.87-1.42], P = 0.390) and Grade II or above nausea and vomiting (RR = 0.88, 95% CI [0.71-1.10], P = 0.260) were obtained. In addition, Aidi injection combined with NP chemotherapy was superior to NP chemotherapy alone in improving the quality of life, alleviating Grade II or above leukopenia and thrombocytopenia. Conclusions: Aidi injection combined with NP chemotherapy can enhance efficiency, improve the quality of life, and decrease adverse effects in patients with advanced NSCLC.

AIM:To investigate the effect of photodynamic therapy(PDT)combined with intravitreal injection of ranibizumab on circumscribed choroidal hemangioma(CCH). METHODS:A retrospective study was performed for 6 eyes(6 cases)diagnosed as CCH. Before treatment, OCT examination showed macular cystoid edema and retinal neurepithelium layer detachment in all patients. All patients underwent photodynamic therapy, then intravitreal injection of ranibizumab 0.5mg(0.05mL)were administered at 48h after PDT. The best corrected visual acuity(BCVA), examination of the ocular fundus, fundus photography, fluorescence fundus angiography(FFA), indocyanine green angiography(ICGA), eye B ultrasonic and optical coherence tomography(OCT)were performed respectively at 1, 3 and 6mo after treatment. RESULTS:The patients were followed up for 4 to 10mo, the final vision of follow-up increased than before, it was raised 7 lines. The images of ICGA revealed hypofluorescence or no leakage in focal area. Eye B ultrasonic showed that hemangioma shrunk or faded. The images of ICGA revealed macular region retinal reattached well and edema disappeared completely. Mean flow-up was 6mo postoperative. There had no evidence of recurrence. CONCLUSION:For CCH patients, hemangioma got smaller obviously by PDT. Intravitreal ranibizumab injection promote effusion absorption under the retina. Combining use of the two therapies could improve visual acuity in a short-term.

Background: Hyperglycemia is associated with poor clinical outcomes and mortality in several patients. However, studies evaluating hyperglycemia variation in tumor patients receiving total parenteral nutrition (TPN) are scarce. The aim of this study was to assess the relationship between glycemia and tumor kinds with TPN by monitoring glycemic variation in tumor patients. Methods: This retrospective clinical trial selected 312 patients with various cancer types, whose unique nutrition treatment was TPN during the monitoring period. All patients had blood glucose (BG) values assessed at least six times daily during the TPN infusion. The glycemic variation before and after TPN was set as the indicator to evaluate the factors influencing BG. Results: The clinical trial lasted 7.5 ± 3.0 days adjusted for age, gender, family cancer history and blood types. There were six cancer types: Hepatic carcinoma (HC, 21.8%), rectal carcinoma (17.3%), colon carcinoma (CC, 14.7%), gastric carcinoma (29.8%), pancreatic carcinoma (11.5%), and duodenal carcinoma (DC, 4.8%). The patients were divided into diabetes and nondiabetes groups. No statistical differences in TPN glucose content between diabetes and nondiabetes groups were found; however, the tumor types affected by BG values were obvious. With increasing BG values, DC, HC and CC were more represented than other tumor types in this sequence in diabetic individuals, as well as in the nondiabetic group. BG was inclined to be more easily influenced in the nondiabetes group. Other factors did not impact BG values, including gender, body mass index, and TPN infusion duration time. Conclusions: When tumor patients are treated with TPN, BG levels should be monitored according to different types of tumors, besides differentiating diabetes or nondiabetes patients. Special BG control is needed for DC, HC and CC in both diabetic and nondiabetic patients. If BG overtly increases, positive measurements are needed to control BG values. The ClinicalTrials.gov ID is NCT02024321.