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Background Thymic epithelial tumors (TETs) are a heterogeneous group of rare malignancies which may be devastating, difficult to treat, and for which treatment options are limited. Herein, we investigated the comprehensive genomic alterations of TETs in a Chinese population for providing clinical management, especially targeted therapy. Methods Comprehensive genomic profiling (CGP) was performed with DNA targeted sequencing of cancer-associated genes (CSYS) from a cohort of 40 Chinese TET patients. TMB was measured by an in-house algorithm. MSI status was inferred based on the MANTIS (Microsatellite Analysis for Normal-Tumor InStability) score. The expression status of PD-L1 was estimated by immunohistochemistry. Results The mutational profiling of thymomas (Ts) and thymic neuroendocrine tumors (TNETs) showed scattered mutation distributions with no recurrently mutated genes. In contrast, thymic carcinomas (TCs) did show highly recurrent mutations including CDKN2A, CYLD, CDKN2B, and TP53. Among them, CDKN2A and CDKN2B mutations were the top potentially actionable alterations in TCs. PD-L1 expression was mainly present in Ts and TCs, and was predominant in males and smokers. Conclusions Our study provided a comprehensive genetic alteration view on the largest Chinese cohort of TETs to date. The results identified different genomic mutational profiles of Ts, TCs, and TNETs, and analyzed potential druggable biomarkers with clinical implications in Chinese TET patients, which provided the evidence for precision medicine of rare TET patients.

Radiation-induced lung injury (RILI) is a common serious complication and dose-limiting factor caused by radiotherapy for lung cancer. This study was to investigate radioprotective effects of grape seed proanthocyanidins (GSP) on normal lung as well as radiosensitizing effects on lung cancer. In vitro, we demonstrated radioprotective effects of GSP on normal alveolar epithelial cells (MLE-12 and BEAS/2B) and radiosensitizing effects on lung cancer cells (LLC and A549). In vivo, we confirmed these two-way effects in tumor-bearing mice. The results showed that GSP inhibited tumor growth, and played a synergistic killing effect with radiotherapy on lung cancer. Meanwhile, GSP reduced radiation damage to normal lung tissues. The two-way effects related to the differential regulation of the MAPK signaling pathway by GSP on normal lung and lung cancer. Moreover, GSP regulated secretion of cytokines IL-6 and IFN-γ and expression of p53 and Ki67 on normal lung and lung cancer. Our findings suggest that GSP is expected to be an ideal radioprotective drug for lung cancer patients who are treated with radiotherapy.

Diabetes mellitus (DM) is characterized by the irreversible destruction of insulin-secreting pancreatic β-islet cells and requires life-long exogenous insulin therapy. Umbilical cord Wharton's jelly-derived mesenchymal stem cells (WJ-MSCs) have been shown to improve islet function in animal models of diabetes. However, inadequate MSC homing to injured sites has limited their efficacy. Since efficient cell therapy heavily relies on appropriate homing to target tissues, increasing the specificity to the target organ and the extent of homing of the injected WJ-MSCs is paramount to successful clinical outcomes. Therefore, in this study, we synthesized Fe3O4@polydopamine nanoparticle (NP)-labeled MSCs and evaluated their therapeutic efficacy in a clinically relevant rat model of streptozotocin-induced diabetes using an external magnetic field. We found that NPs were successfully incorporated into WJ-MSCs and did not negatively affect stem cell properties. Magnetic targeting of WJ-MSCs contributed to long-term cell retention in pancreatic tissue and improved the islet function of diabetic rats, compared to injection of WJ-MSC alone. In addition, anti-inflammatory effects and the anti-apoptotic capacity of WJ-MSCs appeared to play a major role in the functional and structural recovery of the pancreas. Thus, therapy relying on the magnetic targeting of WJ-MSCs may serve as an effective approach for DM treatment.

The human RECQ4 gene encodes an ATP-dependent DNA helicase that contains a conserved superfamily II helicase domain located at the center of the polypeptide. RECQ4 is one of the five RECQ homologs in human cells, and its helicase domain is flanked by the unique amino and carboxyl termini with sequences distinct from other members of the RECQ helicases. Since the identification of the RECQ4 gene in 1998, multiple RECQ4 mutations have been linked to the pathogenesis of three clinical diseases, which are Rothmund-Thomson syndrome, Baller-Gerold syndrome, and RAPADILINO. Patients with these diseases show various developmental abnormalities. In addition, a subset of RECQ4 mutations are associated with high cancer risks, especially for osteosarcoma and/or lymphoma at early ages. The discovery of clinically relevant RECQ4 mutations leads to intriguing questions: how is the RECQ4 helicase responsible for preventing multiple clinical syndromes? What are the mechanisms by which the RECQ4 disease mutations cause tissue abnormalities and drive cancer formation? Furthermore, RECQ4 is highly overexpressed in many cancer types, raising the question whether RECQ4 acts not only as a tumor suppressor but also an oncogene that can be a potential new therapeutic target. Defining the molecular dysfunctions of different RECQ4 disease mutations is imperative to improving our understanding of the complexity of RECQ4 clinical phenotypes and the dynamic roles of RECQ4 in cancer development and prevention. We will review recent progress in examining the molecular and biochemical properties of the different domains of the RECQ4 protein. We will shed light on how the dynamic roles of RECQ4 in human cells may contribute to the complexity of RECQ4 clinical phenotypes.

Background: COVID-19 is a multi-systemic disease that is highly contagious and pathogenic. The long-term consequences of it are not yet clear, as is whether society and life can return to a healthy state. Long-term assessment of their health-related quality of life (HRQoL) is essential. This study aimed to investigate HRQoL and its risk factors in COVID-19 survivors at a follow-up of 6-month. Methods: A multicenter cross-sectional survey was conducted among 192 COVID-19 patients with confirmed age ≥ 18 years who were discharged from various hospitals in Wuhan from January to April 2020. The demographic characteristics, clinical characteristics, and laboratory results of the study subjects were obtained from the hospital's medical records. Survivors' HRQoL was assessed using the Short Form 36 (SF-36), cognition was assessed using the ascertain dementia eight-item informant questionnaire (AD8), and survivors' pulmonary function were examined. All participants in this study completed the survey and testing at Hubei Provincial Hospital of Chinese and Western Medicine. SF-36 scores were compared with the Chinese norm, and logistic regression and multivariate analysis were used to investigate the factors affecting HRQoL in COVID-19 survivors. Results: SF-36 showed significant differences in HRQoL between COVID-19 survivors and the general Chinese population ( P< 0.05).Multiple linear regression demonstrated that age was negatively correlated with physical functioning (PF), role-physical limitation (RP) and social functioning (SF) ( P

The synthesis of mitochondrial DNA (mtDNA) is a complex process that involves the formation and resolution of unusual nucleic acid structures, such as RNA:DNA hybrids. However, little is known about the enzymes that regulate these processes. RECQ4 is a DNA replication factor important for mtDNA maintenance, and here, we unveil a role of human RECQ4 in regulating the formation and resolution of mitochondrial RNA:DNA hybrids. Mitochondrial membrane protein p32 can block mtDNA synthesis by restricting RECQ4 mitochondrial localization via protein–protein interaction. We found that the interaction with p32 was disrupted not only by the previously reported cancer-associated RECQ4 mutation, del(A420-A463), but also by a clinical mutation of the adjacent residue, P466L. Surprisingly, although P466L mutant was present in the mitochondria at greater levels, unlike del(A420-A463) mutant, it failed to enhance mtDNA synthesis due to the accumulation of RNA:DNA hybrids throughout the mtDNA. Biochemical analysis revealed that P466L mutation enhanced RECQ4 annealing activity to generate RNA:DNA hybrids at the same time reduced its unwinding activity to resolve this structure. Hence, P466L mutation led to a reduced efficiency in completing mtDNA synthesis due to unresolved RNA:DNA hybrids across mtDNA.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age, accounting for 50-70% of anovulatory infertility cases. However, the etiology of PCOS at the molecular level remains unclear. Here, bioinformatics analysis was performed to identify differentially expressed genes (DEGs) between adipose tissue of PCOS patients and matched tissues from non-hyperandrogenic women. RT-qPCR, western blot, cell counting kit-8 (CCK-8), EdU (5-Ethynyl-2'-deoxyuridine) staining, LC3 staining, ROS (reactive oxygen species) detection, and apoptosis assays were conducted to explore the effects of sestrin 1 on KGN human granulosa-like tumor cells. Bioinformatics analysis indicated that DEGs in adipose tissue from PCOS patients were enriched in the p53 signaling pathway. Moreover, sestrin 1 was identified as a major target of the p53 gene. Downregulation of sestrin 1 inhibited proliferation of KGN cells by inhibiting autophagy. Additionally, sestrin 1 downregulation increased ROS generation and promoted apoptosis in KGN cells. By contrast, overexpression of sestrin 1 increased cell viability by increasing autophagy in KGN cells. Together, these results suggest that downregulation of sestrin 1 may be a potential novel treatment strategy for PCOS.

Lupus enteritis and Crohn's disease are two common immune diseases involving the gastrointestinal tract. There are many similar clinical manifestations, therefore it is very difficult to distinguish between them. The digestive system is involved anywhere from 8 to 40% of patients with systemic lupus erythematosus (SLE) and up to 53% of these go on to develop lupus enteritis. In patients with Crohn's disease, 6-40% were presented with oral mucosa ulceration, nodular erythema of skin, arthritis, eye disease and other extraintestinal manifestations. The concomitant of Crohn's disease and SLE is extremely rare; however, here we described a case of concomitant Crohn's disease and SLE characterized by recurrent intestinal obstruction. A systematic literature review of lupus concomitant with Crohn's disease was then conducted.

BACKGROUND Gastric carcinoma (GC) is one of the most aggressive primary digestive cancers. It has unsatisfactory therapeutic outcomes and is difficult to diagnose early. AIM To identify prognostic biomarkers for GC patients using comprehensive bioinformatics analyses. METHODS Differentially expressed genes (DEGs) were screened using gene expression data from The Cancer Genome Atlas and Gene Expression Omnibus databases for GC. Overlapping DEGs were analyzed using univariate and multivariate Cox regression analyses. A risk score model was then constructed and its prognostic value was validated utilizing an independent Gene Expression Omnibus dataset (GSE15459). Multiple databases were used to analyze each gene in the risk score model. High-risk score-associated pathways and therapeutic small molecule drugs were analyzed and predicted, respectively. RESULTS A total of 95 overlapping DEGs were found and a nine-gene signature (COL8A1, CTHRC1, COL5A2, AADAC, MAMDC2, SERPINE1, MAOA, COL1A2, and FNDC1) was constructed for the GC prognosis prediction. Receiver operating characteristic curve performance in the training dataset (The Cancer Genome Atlas-stomach adenocarcinoma) and validation dataset (GSE15459) demonstrated a robust prognostic value of the risk score model. Multiple database analyses for each gene provided evidence to further understand the nine-gene signature. Gene set enrichment analysis showed that the high-risk group was enriched in multiple cancer-related pathways. Moreover, several new small molecule drugs for potential treatment of GC were identified. CONCLUSION The nine-gene signature-derived risk score allows to predict GC prognosis and might prove useful for guiding therapeutic strategies for GC patients.

Citrus aurantium is rich in flavonoids, which may prevent osteosarcoma progression, but its related molecular mechanism remains unclear. Flavonoids were extracted from C. aurantium and purified by reparative HPLC. Each fraction was identified by using electrospray ionisation mass spectrometry (ESI-MS). Three main components (naringin, naringenin, and hesperetin) were isolated from C. aurantium. Naringenin inhibited the growth of MG-63 cells, whereas naringin and hesperetin had no inhibitory function on cell growth. ROS production was increased in naringin- and hesperetin-treated groups after one day of culture while the level was always lowest in the naringenin-treated group after three days of culture. 95 osteosarcoma patients who underwent surgery were assigned into two groups: naringenin group (NG, received 20 mg naringenin daily, n=47) and control group (CG, received 20 mg placebo daily, n=48). After an average of two-year follow-up, osteosarcoma volumes were smaller in the NG group than in the CG group (P>0.01). The rate of osteosarcoma recurrence was also lower in the NG group than in CG group. ROS levels were lower in the NG group than in the CG group. Thus, naringenin from Citrus aurantium inhibits osteosarcoma progression and local recurrence in the patients who underwent osteosarcoma surgery by improving antioxidant capability.

Background: Low-risk patients with acute promyelocytic leukemia (APL) can be cured using only ATRA and arsenic trioxide (ATO), without chemotherapy(Lo-Coco F, et al. NEJM 2013) .Our group simplified the protocol by replacing iv ATO with oral arsenic, referred to as RIF, allowing for outpatient, oral and chemotherapy-free treatment for an increasing number of APL patients (Zhu HH, et al. NEJM 2014; 371:2239-41;Zhu HH, et al. Lancet Oncol 2018;19:871-879; Zhu HH, et al. Blood 2019;134:597-605). We also reported a promising single-center results using chemo-free postremission treatment for high-risk APL patients (Zhu HH, Blood 2018;131:2987-2989), which need to be confirmed in a well designed multi-center trial. Objective: To evaluate the efficacy of safety Realgar indigo formula plus retinoic acid as postremission treatment in an oral and chemo-free model for high-risk APL patients . Design, setting and participants: a prospective, multicenter, single-arm, phase II clinical trial conducted in the First Affiliated Hospital, Zhejiang University College of Medicine, China. Eligible patients (>18 years old) with newly diagnosed APL and achieved complete remission(CR) were enrolled since May 2019, with final follow-up in July 31,2021. Interventions: The consolidation therapy included realgar-Indigo naturalis formula (60 mg/kg daily in an oral divided dose) in a 4-week-on and4-week-off regimen for 4 cycles and ATRA (25 mg/m 2 daily in anoral divided dose) in a 2-week-on and 2-week-off regimen for 7 cycles. The primary endpoint was the 2-year DFS. Secondary endpoints included complete molecular remission (CMR) defined as the absence of detectable PML-RARA transcripts., event-free survival (EFS), OS, and safety. Main outcomes and measures: 38 eligible patients were enrolled including 18 males and 20 females and the median age was 41 years old (18-77 years). The median of WBC count is 25.39（10.2-113.9）×109/L[ >50×10 9/L n=10; (20-50)×10 9/L n=14，(10-20)×10 9/L n=14].All the patients achieved CMR during post-remission treatment phase (7 months). Until now, no molecular, hematologic recurrence,and central nervous system leukemia has happened with median follow-up of 13 months. What's more, this chemotherapy-free, completely oral regimen was well tolerated. C onclusions: These exciting results proved that RIF plus retinoic acid as postremission treatment of high-risk APL was effective, safe and convenient. The study is ongoing, and the effective of this regimen need to be evaluated by more patients and longer time. Figure 1. The overall survival(OS) and disease-free survival (DFS) of high-risk APL patients. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Background Primary central nervous system lymphoma (PCNSL) is a rare subtype of extranodal non-Hodgkin's lymphoma with poor prognosis. High-dose methotrexate (HD-MTX) is the cornerstone for treatment. However, there is no consensus on the best combination chemotherapy regimen. This study aimed to explore the efficacy and safety study of R2-MTX (Lenalidomide, Rituximab and Methotrexate) as a first-line induction regimen in the treatment of newly diagnosed PCNSLs. Methods This is a single-arm, prospective phase II study. Immunocompetent patients (18 to 75 years of age) with newly diagnosed PCNSLs were treated with 6 cycles of R2-MTX induction chemotherapy. Lenalidomide was dosed at 25mg daily (day 1-10); rituximab was dosed at 375mg/m2 (d0), MTX was dosed at 3.5g/m2 (d1). Every 21 days were as a course of treatment. Patients who did not reach CR after 6 courses of treatment were given salvage whole-brain radiotherapy (WBRT) to 30-36 Gy followed by a limited field to gross disease to 45 Gy. Then the patients received R2 maintenance (Rituximab 375mg/m 2 d1, lenalidomide 25mg d1-14, 29-42, 56 days per cycle) for 4 cycles. The primary endpoint is the objective response rate. Results 14 patients were enrolled from Feb 2020 to June 2021. Six (42.9%) patients were male and the median age was 59 (range 44-73). Ten (83.3%) patients were mediate or high-risk group (2-5 points) according to IELSG score. The last follow-up was July 15th 2021. Twelve patients were evaluable for response (one patient withdrew the consent; another patient was found with chronic lymphocytic leukemia). The overall response rate (ORR) was 91.7% (11/12). Nine patients achieved complete remission, and two patients achieved partial remission at the last follow-up. The median follow-up time was 11.3 (1.3-16.9) months. Only one patient did not respond and died for disease progression (Figure 1). The most common grade ≥3 adverse events (AEs) included elevated alanine transaminase (ALT) (16.7%), neutropenia (16.7%), thrombocytopenia (8.3%), infection (8.3%), and acute kidney injury (8.3%) (One patient with MTX overdose suffered from all these ≥3AEs). The most common grade 1-2 AEs were neutropenia (66.7%), anemia (58.3%), thrombocytopenia (16.7%) elevated ALT (41.7%). Conclusion R2-MTX regimen is an effective and well-tolerated combination treatment for newly diagnosed PCNSLs. More clinical data will be updated. Keyword(s): Primary Central Nervous System Lymphoma, Lymphoma therapy, Methotrexate, Rituximab, Methotrexate, Lenalidomide Trial registration: ClinicalTrials.gov NCT04934579. Conflict of Interest: The authors declare that they have no conflict of interest. Figure 1 Swimmer plots of all PCNSL patients evaluable for response. Each bar represents one patient; the length of the bars shows the time between the initiation of treatment and the last follow-up. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Background To investigate the prevalence and risk factors of premature thelarche (PT) in girls and gynecomastia (GM) in boys in Southern China. Methods We conducted a cross-sectional study of preschool children across 9 cities in Zhejiang province. A total of 6273 children in the age-group of 2–7 years were recruited from January 2014 to March 2015. Relevant information was collected from mothers through face-to-face interviews. Logistic regression models were used to examine the correlates of PT and GM. Odds ratios (ORs) with 95% confidence intervals (CIs) are reported. Results The prevalence of PT among girls was 4.8% and that of GM among boys was 0.8%. One hundred girls were diagnosed with PT before the age of 2 years; 69 (69.0%) of these girls experienced spontaneous resolution of PT. Twenty-four boys were diagnosed with GM before the age of 2 years; 10 (41.7%) of these experienced spontaneous resolution of GM. Children borne of mothers with early onset of menarche and those belonging to high-income families were at a higher risk of premature breast development. Greater consumption of eggs was associated with premature breast development in early childhood. Conclusions Socioeconomic status of family, early onset of menarche in mother, and consumption of eggs were strongly associated with premature breast development in early childhood.

// Hong Zhou 1, 2, 5, * , Jiawei Zhang 2, 3, * , Ying Gu 1, 2, 3, * , Xiaoxian Gan 3, 4 , Yichao Gan 1, 2 , Weiwei Zheng 1, 2 , Byung-Wook Kim 3 , Xiaohua Xu 1 , Xiaoya Lu 1, 2 , Qi Dong 2 , Shu Zheng 2 , Wendong Huang 3 , Rongzhen Xu 1, 2 1 Department of Hematology, Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China 2 Cancer Institute of Zhejiang University, Hangzhou 310009, China 3 Department of Diabetes Complications and Metabolism, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA 4 Zhejiang Academy of Medical Sciences, Hangzhou 310012, China 5 Hangzhou First People’s Hospital, Hangzhou 310006, China * These authors contributed equally to this work. Correspondence to: Rongzhen Xu, e-mail: zrxyk10@zju.edu.cn Wendong Huang, e-mail: whuang@coh.org Keywords: cancer cell, RNA giant nuclear body, nuclear RNA trafficking Received: August 25, 2015 Accepted: November 25, 2015 Published: December 15, 2015 ABSTRACT Constitutive synthesis of oncogenic mRNAs is essential for maintaining the uncontrolled growth of cancer cells. However, little is known about how these mRNAs are exported from the nucleus to the cytoplasm. Here, we report the identification of a RNA giant nuclear body (RNA-GNB) that is abundant in cancer cells but rare in normal cells. The RNA-GNB contains a RNA core surrounded by a protein shell. We identify 782 proteins from cancer-associated RNA-GNBs, 40% of which are involved in the nuclear mRNA trafficking. RNA-GNB is required for cell proliferation, and its abundance is positively associated with tumor burden and outcome of therapies. Our findings suggest that the RNA-GNB is a novel nuclear RNA trafficking organelle that may contribute to the nuclear mRNA exporting and proliferation of cancer cells.

Background & Aims Hepatic fibrosis, featured by the accumulation of excessive extracellular matrix in liver tissue, is associated with metabolic disease and cancer. Inhalation exposure to airborne particulate matter in fine ranges (PM 2.5 ) correlates with pulmonary dysfunction, cardiovascular disease, and metabolic syndrome. In this study, we investigated the effect and mechanism of PM 2.5 exposure on hepatic fibrogenesis. Methods Both inhalation exposure of mice and in vitro exposure of specialized cells to PM 2.5 were performed to elucidate the effect of PM 2.5 exposure on hepatic fibrosis. Histological examinations, gene expression analyses, and genetic animal models were utilized to determine the effect and mechanism by which PM 2.5 exposure promotes hepatic fibrosis. Results Inhalation exposure to concentrated ambient PM 2.5 induces hepatic fibrosis in mice under the normal chow or high-fat diet. Mice after PM 2.5 exposure displayed increased expression of collagens in liver tissues. Exposure to PM 2.5 led to activation of the transforming growth factor β-SMAD3 signaling, suppression of peroxisome proliferator-activated receptor γ, and expression of collagens in hepatic stellate cells. NADPH oxidase plays a critical role in PM 2.5 -induced liver fibrogenesis. Conclusions Exposure to PM 2.5 exerts discernible effects on promoting hepatic fibrogenesis. NADPH oxidase mediates the effects of PM 2.5 exposure on promoting hepatic fibrosis.

As phospho-eIF4E (p-eIF4E), unlike total eIF4E (t-eIF4E) essential for normal cells, is specifically required by cancer cells, it is an attractive, yet unrealized, target for anti-tumor intervention. Here we identify a small molecule, homoharringtonine (HHT), that antagonizes p-eIF4E function and eradicates acute myeloid leukemia (AML) expressing high level of p-eIF4E in vitro and in vivo. HHT selectively reduces p-eIF4E levels of leukemia cells without affecting t-eIF4E. HHT targets the phosphorylated serine 209 residue of p-eIF4E and induces p-eIF4E oligomerization, which enhances its interaction with the small ubiquitin-like protein modifier (SUMO)-conjugating enzyme UBC9, resulting in proteasome-dependent degradation of p-eIF4E via SUMO2/3-mediated SUMOylation. These results suggest that the phosphorylated serine 209 residue of p-eIF4E might be a potential target for developing small molecule-based new therapies for leukemia.

This study’s aim was to investigate the post-effect of an air quality improvement on systemic inflammation and circulating microparticles in asthmatic patients during, and 2 months after, the Beijing Olympics 2008. We measured the levels of circulating inflammatory cytokines and microparticles in the peripheral blood from asthma patients and healthy controls during (phase 1), and 2 months after (phase 2) the Beijing 2008 Olympic Games. The concentrations of circulating cytokines (including TNFα, IL-6, IL-8, and IL-10) were still seen reduced in phase 2 when compared with those in phase 1. The number of circulating endothelial cell-derived microparticles was significantly lower during the phase 2 than that during phase 1 in asthma patients. The level of plasma lipopolysaccharide-binding protein (LBP) was significantly decreased in asthmatics in phase 2. The level of norepinephrine was significantly higher in phase 2 than that in phase 1 in plasma from both asthma patients and healthy subjects. There were no significant differences in the gene profile for the toll-like receptor (TLR) signaling from peripheral blood mononuclear cells. In vitro, microvesicles from patients with asthma impaired the relaxation to bradykinin and contraction to acetylcholine, whereas microparticles from healthy subjects did not. These data suggested that reduction in systemic pro-inflammatory responses and circulating LBP and increased level of norepinephrine in asthma patients persisted even after 2 months of the air pollution intervention. These changes were independent of the TLR signaling pathway. Circulating microparticles might be associated with airway smooth muscle dysfunction.

The spatiotemporal structure of the climatology of multiple tropopauses (MTs) is presented in this paper by using the temperature profiles from the Global Positioning System radio occultation measurements from the Constellation Observing System for Meteorology, Ionosphere, and Climate (COSMIC) mission between January 2007 and December 2012. Various climatological characteristics about MTs are studied, including the relationship between the occurrence of double tropopauses (DTs) and jet streams, the interannual variation and the trends of the occurrence of DTs, the seasonal and geographical variations of the occurrence of MTs, and the meridional distributions of the features of MTs in different seasons. Our results agree well with those of earlier studies based on other data sets. In addition, we find some new MT features. A global increase of the occurrence of DTs of about 0.15% ± 0.09% yr−1 (0.13% ± 0.09% yr−1) is found between 2007 and 2012 including (excluding) the sampling errors, respectively. There is an increasing trend of the occurrence of DTs in the extratropics, especially in the subtropics in both hemispheres, and a decreasing trend in the tropics. We also find that the maximum seasonal variation of the occurrence of DTs is located between 30°N and 40°N, which is much stronger than that in the Southern Hemisphere. The occurrence of DTs is much lower from the winter of 2009 to the spring of 2010 than during the same time period of other years.

SummaryMitochondrial DNA (mtDNA) encodes proteins that are important for ATP biogenesis. Therefore, changes in mtDNA copy number will have profound consequences on cell survival and proliferation. RECQ4 DNA helicase participates in both nuclear DNA and mtDNA synthesis. However, the mechanism that balances the distribution of RECQ4 in the nucleus and mitochondria is unknown. Here, we show that RECQ4 forms protein complexes with Protein Phosphatase 2A (PP2A), nucleophosmin (NPM), and mitochondrial p32 in different cellular compartments. Critically, the interaction with p32 negatively controls the transport of both RECQ4 and its chromatin-associated replication factor, MCM10, from the nucleus to mitochondria. Amino acids that are deleted in the most common cancer-associated RECQ4 mutation are required for the interaction with p32. Hence, this RECQ4 mutant, which is no longer regulated by p32 and is enriched in the mitochondria, interacts with the mitochondrial replication helicase PEO1 and induces abnormally high levels of mtDNA synthesis.

The aim of this work was to develop a method to provide rapid results for humans with internal radioactive contamination. The authors hypothesized that valuable information could be obtained from gas proportional counter techniques by screening urine samples from potentially exposed individuals rapidly. Recommended gross alpha and beta activity screening methods generally employ gas proportional counting techniques. Based on International Standards Organization (ISO) methods, improvements were made in the evaporation process to develop a method to provide rapid results, adequate sensitivity, and minimum sample preparation and operator intervention for humans with internal radioactive contamination. The method described by an American National Standards Institute publication was used to calibrate the gas proportional counter, and urine samples from patients with or without radionuclide treatment were measured to validate the method. By improving the evaporation process, the time required to perform the assay was reduced dramatically. Compared with the reference data, the results of the validation samples were very satisfactory with respect to gross-alpha and gross-beta activities. The gas flow proportional counting method described here has the potential for radioactivity monitoring in the body. This method was easy, efficient, and fast, and its application is of great utility in determining whether a sample should be analyzed by a more complicated method, for example radiochemical and/or γ-spectroscopy. In the future, it may be used commonly in medical examination and nuclear emergency treatment.Health Phys. 106(5):000-000; 2014.

The myosin heavy chain isoform MHC-α has 3-fold higher ATPase activity than MHC-β. After myocardial infarction (MI), MHC-α expression is profoundly downregulated and MHC-β expression is reciprocally upregulated. This shift, which is attributed to low thyroid hormone (TH), contributes to myocardial systolic dysfunction. We investigated the effect of post-MI exercise training on MHC isoforms, TH, and cardiac function. MI was surgically induced in 7-week-old rats by ligation of the coronary artery. The survivors were assigned to 3 groups (n = 10/group): Sham (no MI, no exercise), MISed (MI, no exercise), and MIEx (MI, exercise). Treadmill exercise training began 1 week post-MI and lasted for 8 weeks. Echocardiogram measurements were taken on the day prior to initiation of exercise training and at the end of exercise training. Tissue and blood samples were collected at the end of the experiment. MHC isoform gene and protein expression and TH were measured. Our results illustrated that MHC-α gene expression was higher and MHC-β gene expression was lower in the MIEx group than in the MISed group. Resting serum TH concentrations (T3 and T4) were similar between the 2 MI groups. The MIEx group had higher fractional shortening than the MISed group. In conclusion, post-MI exercise training beneficially altered MHC isoforms and improved cardiac function without changing TH.

Background: Exposure to particulate matter ≤ 2.5 μm in diameter (PM2.5) increases blood pressure (BP) in humans and animal models. Abnormal activation of the sympathetic nervous system may have a role in the acute BP response to PM2.5 exposure. The mechanisms responsible for sympathetic nervous system activation and its role in chronic sustenance of hypertension in response to PM2.5 exposure are currently unknown. Objectives: We investigated whether central nervous system inflammation may be implicated in chronic PM2.5 exposure-induced increases in BP and sympathetic nervous system activation. Methods: C57BL/6J mice were exposed to concentrated ambient PM2.5 (CAPs) for 6 months, and we analyzed BP using radioactive telemetric transmitters. We assessed sympathetic tone by measuring low-frequency BP variability (LF-BPV) and urinary norepinephrine excretion. We also tested the effects of acute pharmacologic inhibitors of the sympathetic nervous system and parasympathetic nervous system. Results: Long-term CAPs exposure significantly increased basal BP, paralleled by increases in LF-BPV and urinary norepinephrine excretion. The increased basal BP was attenuated by the centrally acting α2a agonist guanfacine, suggesting a role of increased sympathetic tone in CAPs exposure–induced hypertension. The increase in sympathetic tone was accompanied by an inflammatory response in the arcuate nucleus of the hypothalamus, evidenced by increased expression of pro-inflammatory genes and inhibitor kappaB kinase (IKK)/nuclear factor–kappaB (NF-κB) pathway activation. Conclusion: Long-term CAPs exposure increases BP through sympathetic nervous system activation, which may involve hypothalamic inflammation. Citation: Ying Z, Xu X, Bai Y, Zhong J, Chen M, Liang Y, Zhao J, Liu D, Morishita M, Sun Q, Spino C, Brook RD, Harkema JR, Rajagopalan S. 2014. Long-term exposure to concentrated ambient PM2.5 increases mouse blood pressure through abnormal activation of the sympathetic nervous system: a role for hypothalamic inflammation. Environ Health Perspect 122:79–86; http://dx.doi.org/10.1289/ehp.1307151

Background: Epidemiologic and experimental studies support an association between PM2.5 exposure and insulin resistance (IR). Innate immune cell activation has been suggested to play a role in the pathogenesis of these effects. Objectives: We sought to evaluate the role of CC-chemokine receptor 2 (CCR2) in PM2.5-mediated inflammation and IR. Methods: Wild-type C57BL/6 and CCR2–/– male mice were fed a high-fat diet and exposed to either concentrated ambient PM2.5 or filtered air for 17 weeks via a whole-body exposure system. We evaluated glucose tolerance and insulin sensitivity. At euthanasia, blood, spleen, and visceral adipose tissue (VAT) were collected, and inflammatory cells were measured using flow cytometry. We used standard immunoblots, immunohistochemical methods, and quantitative PCR (polymerase chain reaction) to assess pathways of interest involving insulin signaling, inflammation, and lipid and glucose metabolism in various organs. Vascular function was assessed using myography. Results: PM2.5 exposure resulted in whole-body IR and increased hepatic lipid accumulation in the liver, which was attenuated in CCR2–/– mice by inhibiting SREBP1c-mediated transcriptional programming, decreasing fatty acid uptake, and suppressing p38 MAPK activity. Abnormal phosphorylation levels of AKT, AMPK in VAT, and adipose tissue macrophage content in wild-type mice were not present in CCR2–/– mice. However, the impaired whole-body glucose tolerance and reduced GLUT-4 in skeletal muscle in response to PM2.5 was not corrected by CCR2 deficiency. Conclusions: PM2.5 mediates IR by regulating VAT inflammation, hepatic lipid metabolism, and glucose utilization in skeletal muscle via both CCR2-dependent and -independent pathways. These findings provide new mechanistic links between air pollution and metabolic abnormalities underlying IR. Citation: Liu C, Xu X, Bai Y, Wang TY, Rao X, Wang A, Sun L, Ying Z, Gushchina L, Maiseyeu A, Morishita M, Sun Q, Harkema JR, Rajagopalan S. 2014. Air pollution–mediated susceptibility to inflammation and insulin resistance: influence of CCR2 pathways in mice. Environ Health Perspect 122:17–26; http://dx.doi.org/10.1289/ehp.1306841

Epidemiological studies suggest that fine particulate matter (PM2.5) may increase the risk for developing diabetes mellitus (DM). To evaluate possible mechanisms explaining these associations, we investigated if sub-acute ambient-level exposures can impair insulin sensitivity. Twenty-five healthy adults living in rural Michigan were transported to an urban location for 5 consecutive days (exposure-block) of daily 4- to 5-hour-long ambient air pollution exposures. Health outcomes, including the homeostasis model assessment of insulin resistance (HOMA-IR) the primary outcome of insulin sensitivity, were measured at 3 time points in relation to exposure-blocks: 7 days prior to start; on the last exposure-day; and 7 days after completion. PM2.5 was monitored at the urban exposure site and at community monitors near subjects’ residences. We calculated 3 “sub-acute” exposure periods (approximately 5-days-long) starting retrospective from the time of health outcome measurements (PM2.5 ranges: 9.7±3.9 to 11.2±3.9 µg•m−3). A 10 µg•m−3 increase in sub-acute PM2.5 exposures was associated with increased HOMA-IR (+0.7, 95% confidence interval (CI) 0.1 to 1.3; p=0.023) and reduced heart rate variability (standard deviation of normal-to-normal intervals [−13.1 msec, 95%CI −25.3 to −0.9; p=0.035]). No alterations in other outcomes (inflammatory markers, vascular function) occurred in relation to PM2.5 exposures. Our findings suggest that ambient PM2.5, even at low levels, may reduce metabolic insulin sensitivity supporting the plausibility that air pollution could potentiate the development of DM.

Background & Aims: Air pollution is a global challenge to public health. Epidemiological studies have linked exposure to ambient particulate matter with aerodynamic diameters

Background Chronic exposure to fine ambient particulate matter (PM2.5) induces insulin resistance. CC-chemokine receptor 2 (CCR2) appears to be essential in diet-induced insulin resistance implicating an important role for systemic cellular inflammation in the process. We have previously suggested that CCR2 is important in PM2.5 exposure-mediated inflammation leading to insulin resistance under high fat diet situation. The present study assessed the importance of CCR2 in PM2.5 exposure-induced insulin resistance in the context of normal diet. Methods and Results C57BL/6 and CCR2-/- mice were subjected to exposure to concentrated ambient PM2.5 or filtered air for 6 months. In C57BL/6 mice, concentrated ambient PM2.5 exposure induced whole-body insulin resistance, macrophage infiltration into the adipose tissue, and upregulation of phosphoenolpyruvate carboxykinase (PEPCK) in the liver. While CCR2 deficiency reduced adipose macrophage content in the PM2.5-exposed animals, it did not improve systemic insulin resistance. This lack of improvement in insulin resistance was paralleled by increased hepatic expression of genes in PEPCK and inflammation. Conclusion CCR2 deletion failed to attenuate PM2.5 exposure-induced insulin resistance in mice fed on normal diet. The present study indicates that PM2.5 may dysregulate glucose metabolism directly without exerting proinflammatory effects. Electronic supplementary material The online version of this article (doi:10.1186/s12989-017-0187-3) contains supplementary material, which is available to authorized users.

Myeloid sarcoma is a type of malignant neoplasm composed of myeloblasts that locates extramedullary. The present study reports the case of a 31-year-old female who presented with upper abdominal pain, melena, vomiting and jaundice. The abdominal computed tomography revealed a mass in gastric antrum area and possible infiltration of the duodenum, gallbladder and head of the pancreas, with possible retroperitoneal lymph node metastasis. The tumor grew quickly and led to serious obstructive jaundice. New masses developed in the bilateral orbits and left breast within 2 months of admission. The pathological results of the gastroscopic biopsy and the fine-needle biopsy of the breast revealed myeloid sarcoma. Transhepatic cholangial drainage, radiotherapy and chemotherapy were administered, but the disease reoccurred and became resistant to chemotherapy, so salvage allogenetic peripheral blood stem cell transplantation was performed. The disease relapsed at 5 months post-transplantation, and chemotherapy and donor lymphocytes transfusions were then administered. The patient declined further treatment and succumbed to disease on May 19, 2015. The present study could improve the understanding of myeloid sarcoma and provide a reference for standardized and individualized treatments for this disease.

Internalized stigma in people living with HIV is associated with negative outcomes including sexual risk behaviors and depression. Little research has focused on internalized stigma in men who have sex with men living with HIV (MSMLWH) in China. We measured internalized stigma and examined its potential predictors in a sample of 277 MSMLWH from two infectious disease specialist hospitals in Beijing, China. Descriptive analysis showed an intermediate high level of internalized stigma in these men. Multiple linear regression revealed that higher levels of stereotypes, negative affect, older age, lower levels of mastery, and limited information and emotional support were significant predictors of internalized stigma. Cognitive reconstruction interventions should be developed to change negative stereotypes and reduce internalized stigma, and information and emotional support should be provided to develop mastery, foster coping skills for internalized stigma, and alleviate negative affect. MSMLWH of older ages need more attention in stigma reduction programs.

Objective: To evaluate the effects of tetrandrine citrate, a novel tetrandrine salt with high water solubility, on the growth of imatinib (IM)-resistant chronic myeloid leukemia (CML) in vitro and in vivo, and reveal action molecular mechanisms. Methods: Cell viability in vitro was measured using methyl thiazolyl tetrazolium (MTT) assay. CML cell growth in vivo was assessed using a xenograft model in nude mice. Bcr-Abl and β-catenin protein levels were determined using Western blotting. Bcr-Abl messenger RNA (mRNA) was measured by reverse transcription polymerase chain reaction (RT-PCR). Flow cytometry (FCM) was used to determine cell cycle status. Results: Tetrandrine citrate inhibited the growth of IM-resistant K562 cells, primary leukemia cells, and primitive CD34+ leukemia cells, and their inhibition concentration that inhibited 50% of target cells (IC50) ranged from 1.20 to 2.97 μg/ml. In contrast, tetrandrine citrate did not affect normal blood cells under the same conditions, and IC50 values were about 10.12–13.11 μg/ml. Oral administration of tetrandrine citrate caused complete regression of IM-resistant K562 xenografts in nude mice without overt toxicity. Western blot results revealed that treatment of IM-resistant K562 cells with tetrandrine citrate resulted in a significant decrease of both p210Bcr-Abl and β-catenin proteins, but IM did not affect the Bcr-Abl protein levels. Proteasome inhibitor, MG132, did not prevent tetrandrine-mediated decrease of the p210Bcr-Abl protein. RT-PCR results showed that tetrandrine treatment caused a decrease of Bcr-Abl mRNA. FCM analysis indicated that tetrandrine induced gap 1 (G1) arrest in CML cells. Conclusions: Tetrandrine citrate is a novel orally active tetrandrine salt with potent anti-tumor activity against IM-resistant K562 cells and CML cells. Tetrandrine citrate-induced growth inhibition of leukemia cells may be involved in the depletion of p210Bcr-Abl mRNA and β-catenin protein.

We have discovered a role for natural autoantibodies in central nervous system repair, remyelination and axon protection. These natural human antibodies are of the immunoglobulin M (IgM) isotype, and they bind to the surface of neural cells. The epitope of the antibody includes sialic acid because treatment with sialidase disrupts the binding. A fully human recombinant form of one of these IgMs, rHIgM12, has the same properties as the serum-derived IgM. rHIgM12 enhanced polarized axonal outgrowth from primary neurons when presented as a substrate in vitro and improved motor functions in chronically Theiler’s virus-infected SJL mice, a model of MS. rHIgM12 bound to neuronal surfaces and induced cholesterol and ganglioside (GM1) clustering, indicating that rHIgM12 functions through a mechanism of axonal membrane stabilization. Our work demonstrates that a natural human neuron-binding IgM can regulate membrane domain dynamics. This antibody has the potential to improve neurologic disease.

Multiple sclerosis is a progressive neurological disorder that results in the degradation of myelin sheaths that insulate axons in the central nervous system. Therefore promotion of myelin repair is a major thrust of multiple sclerosis treatment research. Two mouse monoclonal natural autoantibodies, O1 and O4, promote myelin repair in several mouse models of multiple sclerosis. Natural autoantibodies are generally polyreactive and predominantly of the IgM isotype. The prevailing paradigm is that because they are polyreactive, these antibodies bind antigens with low affinities. Despite their wide use in neuroscience and glial cell research, however, the affinities and kinetic constants of O1 and O4 antibodies have not been measured to date. In this work, we developed a membrane biosensing platform based on surface plasmon resonance in gold nanohole arrays with a series of surface modification techniques to form myelin-mimicking lipid bilayer membranes to measure both the association and dissociation rate constants for O1 and O4 antibodies binding to their myelin lipid antigens. The ratio of rate constants shows that O1 and O4 bind to galactocerebroside and sulfated galactocerebroside, respectively, with unusually small apparent dissociation constants (K(D) ≈ 0.9 nM) for natural autoantibodies. This is approximately one to 2 orders of magnitude lower than typically observed for the highest affinity natural autoantibodies. We propose that the unusually high affinity of O1 and O4 to their targets in myelin contributes to the mechanism by which they signal oligodendrocytes and induce central nervous system repair.

Many studies have linked ambient fine particulate matter (aerodynamic diameters less than 2.5 μm, PM₂.₅) air pollution to increased morbidity and mortality of cardiovascular diseases in the general population, but the biologic mechanisms of these associations are yet to be elucidated. In this study, we aimed to evaluate the relationship between daily variations in exposure to PM₂.₅ and inflammatory responses in mice during and for 2 months after the Beijing Olympic Games. Male C57BL/6 mice were exposed to Beijing PM₂.₅ or filtered air (FA) in 2008 during the 2 months of Beijing Olympic and Paralympic Games, and for 2 months after the end of the Games. During the Games, circulating monocyte chemoattractant protein 1 and interleukin 6 were increased significantly in the PM₂.₅ exposure group, when compared with the FA control group, although there were no significant inter-group differences in tumor necrosis factor-α or interferon-γ, or in macrophages, neutrophils or lymphocytes in the spleen or thymus between these 2 groups. However, macrophages were significantly increased in the lung and visceral fat with increasing PM₂.₅. After the Olympic Games, there were no significant PM₂.₅-associated differences for macrophages, neutrophils or lymphocytes in the thymus, but macrophages were significantly elevated in the lung, spleen, subcutaneous and visceral fat with increasing PM₂.₅, and the numbers of macrophages were even higher after than those during the Games. Moreover, the number of neutrophils was markedly higher in the spleen for the PM₂.₅-exposed- than the FA-group. These data suggest that short-term increases in exposure to ambient PM₂.₅ leads to increased systemic inflammatory responses, primarily macrophages and neutrophils in the lung, spleen, and visceral adipose tissue. Short-term air quality improvements were significantly associated with reduced overall inflammatory responses.

Although statin therapy is a cornerstone of current low density lipoprotein (LDL)-lowering strategies, there is a need for additional therapies to incrementally lower plasma LDL cholesterol. In this study, we investigated the effect of several methylenedioxyphenol derivatives in regulating LDL cholesterol through induction of LDL receptor (LDLR). INV-403, a modified methylenedioxyphenol derivative, increased LDLR mRNA and protein expression in HepG2 cells in a dose- and time-dependent fashion. These effects were apparent even under conditions of HMG-CoA reductase inhibition. Electrophoresis migration shift assays demonstrated that INV-403 activates SREBP2 but not SREBP1c, with immunoblot analysis showing an increased expression of the mature form of SREBP2. Knockdown of SREBP2 reduced the effect of INV-403 on LDLR expression. The activation of SREBP2 by INV-403 is partly mediated by Akt/GSK3β pathways through inhibition of phosphorylation-dependent degradation by ubiquitin-proteosome pathway. Treatment of C57Bl/6j mice with INV-403 for two weeks increased hepatic SREBP2 levels (mature form) and upregulated LDLR with concomitant lowering of plasma LDL levels. Transient expression of a LDLR promoter-reporter construct, a SRE-mutant LDLR promoter construct, and a SRE-only construct in HepG2 cells revealed an effect predominantly through a SRE-dependent mechanism. INV-403 lowered plasma LDL cholesterol levels through LDLR upregulation. These results indicate a role for small molecule approaches other than statins for lowering LDL cholesterol.

Despite increasing knowledge of allantoin as a phytochemical involved in rice, relatively little is known about its distribution and function in rice grains. In this study, allantoin was quantified in 15 Chinese rice grains, and its contents varied with grain fraction, cultivar, and genotype. Bran always had the highest allantoin level, followed by brown rice and milled rice. Hull contained the lowest allantoin content. Allantoin in japonica bran ranged from 70 to 171 μg/g but rarely exceeded 100 μg/g in indica bran. There was a positive relationship between allantoin level in grains and seedling survival in seedbeds under low temperature or water deficit. Exogenous allantoin stimulated plant growth, increased soluble sugar and free proline contents, and decreased malondialdehyde content in rice seedlings. However, allantoin did not show any antioxidant activity through free radical-scavenging capacity, reducing power, linoleic acid peroxidation inhibition, and chelating activity. The results suggest that allantoin in rice grains may play some roles in providing plant stress protection but not serving as a beneficial health antioxidant.

Background— Dipeptidyl-peptidase 4 (DPP-4) inhibitors are increasingly used to accomplish glycemic targets in patients with type II diabetes mellitus. Because DPP-4 is expressed in inflammatory cells, we hypothesized that its inhibition will exert favorable effects in atherosclerosis. Methods and Results— Male LDLR −/− mice (6 weeks) were fed a high-fat diet or normal chow diet for 4 weeks and then randomized to vehicle or alogliptin, a high-affinity DPP-4 inhibitor (40 mg · kg −1 · d −1 ), for 12 weeks. Metabolic parameters, blood pressure, vascular function, atherosclerosis burden, and indexes of inflammation were obtained in target tissues, including the vasculature, adipose, and bone marrow, with assessment of global and cell-specific inflammatory pathways. In vitro and in vivo assays of DPP-4 inhibition (DPP-4i) on monocyte activation/migration were conducted in both human and murine cells and in a short-term ApoE −/− mouse model. DPP-4i improved markers of insulin resistance and reduced blood pressure. DPP-4i reduced visceral adipose tissue macrophage content (adipose tissue macrophages; CD11b + , CD11c + , Ly6C hi ) concomitant with upregulation of CD163. DPP-4 was highly expressed in bone marrow–derived CD11b + cells, with DPP-4i downregulating proinflammatory genes in these cells. DPP-4i decreased aortic plaque with a striking reduction in plaque macrophages. DPP-4i prevented monocyte migration and actin polymerization in in vitro assays via Rac-dependent mechanisms and prevented in vivo migration of labeled monocytes to the aorta in response to exogenous tumor necrosis factor-α and DPP-4. Conclusion— DPP-4i exerts antiatherosclerotic effects and reduces inflammation via inhibition of monocyte activation/chemotaxis. These findings have important implications for the use of this class of drugs in atherosclerosis.

Mouse and human IgMs support neurite extension from primary cerebellar granule neurons. In this study using primary hippocampal and cortical neurons, we demonstrate that a recombinant human IgM, rHIgM12, promotes axon outgrowth by coupling membrane domains (lipid rafts) to microtubules. rHIgM12 binds to the surface of neuron and induces clustering of cholesterol and ganglioside GM1. After cell binding and membrane fractionation, rHIgM12 gets segregated into two pools, one associated with lipid raft fractions and the other with the detergent-insoluble cytoskeleton-containing pellet. Membrane-bound rHIgM12 co-localized with microtubules and co-immuno precipitated with β3-tubulin. rHIgM12-membrane interaction also enhanced the tyrosination of α-tubulin indicating a stabilization of new neurites. When presented as a substrate, rHIgM12 induced axon outgrowth from primary neurons. We now demonstrate that a recombinant human mAb can induce signals in neurons that regulate membrane lipids and microtubule dynamics required for axon extension. We propose that the pentameric structure of the IgM is critical to cross-link membrane lipids and proteins resulting in signaling cascades.

Microarray technology has facilitated many powerful high-throughput studies in the fields of genetics and proteomics, among others. However, preparation of microarrays composed of cell-derived membranes with embedded receptors has proven difficult. Here we describe a new method for forming microarrays composed of synthetic lipid vesicles and natural cell membranes. The method is based upon assembly of vesicles and natural membranes into recessed micro- and nanowells and using a polydimethylsiloxane (PDMS) block as a "squeegee." This method is used to assemble phospholipid vesicles into arrays with micrometer and nanoscale dimensions. Native myelin and neuronal lipid raft arrays are also formed in 30 min or less. We show the natural membrane arrays can be used for sensing lipid-protein interactions by detecting cholera toxin binding to ganglioside GM1 in neuronal lipid rafts. In multicomponent arrays myelin can be distinguished from neuronal rafts by antibody binding to cell-specific surface antigens. Finally, myelin arrays formed in gold nanowells are used for surface plasmon resonance sensing. This assembly approach is simple, broadly applicable, and opens up new avenues of research not easily accomplished with standard microarray technology.

Repair of the central nervous system (CNS) constitutes an integral part of treating neurological disease and plays a crucial role in restoring CNS architecture and function. Distinct strategies have been developed to reconstruct the damaged neural tissue, with many tested preclinically in animal models. We review cell replacement-based repair strategies. By taking spinal cord injury, cerebral ischaemia and degenerative CNS disorders as examples for CNS repair, we discuss progress and potential problems in utilizing embryonic stem cells and adult neural/non-neural stem cells to repair cell loss in the CNS. Nevertheless, CNS repair is not simply a matter of cell transplantation. The major challenge is to induce regenerating neural cells to integrate into the neural network and compensate for damaged neural function. The neural cells confront an environment very different from that of the developmental stage in which these cells differentiate to form interwoven networks. During the repair process, one of the challenges is neurodegeneration, which can develop from interrupted innervations to/from the targets, chronic inflammation, ischaemia, aging or idiopathic neural toxicity. Neurodegeneration, which occurs on the basis of a characteristic vascular and neural web, usually presents as a chronically progressive process with unknown aetiology. Currently, there is no effective treatment to stop or slow down neurodegeneration. Pathological changes from patients with Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis indicate a broken homeostasis in the CNS. We discuss how the blood-brain barrier and neural networks are formed to maintain CNS homeostasis and their contribution to neurodegeneration in diseased conditions. Another challenge is that some inhibitors produced by CNS injury do not facilitate the regenerating neural cells to incorporate into a pre-existing network. We review glial responses to CNS injury. Of note, the reactive astrocytes not only encompass the lesions/pathogens but may also form glial scars to impede regenerating axons from traversing the lesions. In addition, myelin debris can prevent axon growth. Myelination enables saltatory transduction of electrical impulses along axonal calibers and actually provides trophic support to stabilize the axons. Therefore, repair strategies should be designed to promote axonal growth, myelination and modulate astrocytic responses. Finally, we discuss recent progress in developing human monoclonal IgMs that regulate CNS homeostasis and promote neural regeneration.

A high-fat diet (HFD) is associated with adipose inflammation, which contributes to key components of metabolic syndrome, including obesity and insulin resistance. The increased visceral adipose tissue mass associated with obesity is the result of hyperplasia and hypertrophy of adipocytes. To investigate the effects of exercise on HFD-induced metabolic disorders, male C57BL/6 mice were divided into four groups: SED (sedentary)-ND (normal diet), EX (exercise)-ND, SED-HFD, and EX-HFD. Exercise was performed on a motorized treadmill at 15 m/min, 40 min/day, and 5 day/wk for 8 wk. Exercise resulted in a decrease in abdominal fat contents and inflammation, improvements in glucose tolerance and insulin resistance, and enhancement of vascular constriction and relaxation responses. Exercise with or without HFD increased putative brown adipocyte progenitor cells in brown adipose tissue compared with groups with the same diet, with an increase in brown adipocyte-specific gene expression in brown and white adipose tissue. Exercise training enhanced in vitro differentiation of the preadipocytes from brown adipose depots into brown adipocytes and enhanced the expression of uncoupling protein 1. These findings suggest that exercise ameliorates high-fat diet-induced metabolic disorders and vascular dysfunction, and increases adipose progenitor cell population in brown adipose tissue, which might thereby contribute to enhanced functional brown adipose.

An increase in oxidative stress and decrease in antioxidant enzymes have been suggested to be involved in the pathophysiology of myocardial infarction (MI). In this study in rats, treadmill exercise training and losartan treatment began 1 week post-myocardial infarction (MI) and lasted 8 weeks. We evaluated the changes in the mRNA and protein expressions for the enzymatic antioxidants superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase after exercise and losartan treatment post-MI. Our results demonstrated that GPx and catalase mRNA levels were comparable among all the groups, while the mRNA level for manganese SOD (MnSOD) was significantly increased in exercise training with/without losartan treatment compared with the sedentary post-MI group. Moreover, the mRNA level for gp91(phox) was dramatically decreased by a combination of exercise and losartan treatment. The protein levels for MnSOD were significantly elevated by exercise training in combination with losartan treatment. The protein levels for catalase were significantly increased in response to exercise, and further augmented by exercise together with losartan treatment. Thiobarbituric acid-reactive substances in plasma were significantly increased in the post-MI rats, but were decreased by exercise or losartan treatment, indicating that both exercise and losartan may reduce lipid oxidative damage. In addition, catalase and SOD enzymatic activities were significantly enhanced by exercise combined with losartan treatment. Our results suggest that exercise training improves catalase and MnSOD expression and attenuates oxidative stress. These effects are potentiated when combining exercise with angiotensin II receptor blockade.

Objective: Our aim was to characterize the changes in messenger RNA (mRNA) abundance, protein, and activity levels of the enzymatic antioxidants, superoxide dismutase (SOD), glutathione peroxidase, and catalase by exercise training combined with l-arginine after myocardial infarction (MI). Methods: l-Arginine (1 g[middle dot]kg-1[middle dot]d-1) and NG-nitro-l-arginine methyl ester (l-NAME; 10 mg[middle dot]kg-1[middle dot]d-1) were administered in drinking water for 8 wk. Sprague-Dawley rats were randomized to the following groups: sham-operated control (Sham); MI sedentary (Sed); MI exercise (Ex); MI sedentary + l-arginine (Sed + LA); MI exercise + l-arginine (Ex + LA); MI sedentary + l-NAME (Sed + l-NAME); and MI exercise + l-NAME (Ex + l-NAME). Results: The glutathione peroxidase, catalase, and gp91phox mRNA levels were comparable among all the groups. The SOD mRNA level was significantly increased in the Ex group (5.43 +/- 0.87) compared with the Sed group (1.74 +/- 0.29), whereas this effect was pronouncedly down-regulated by the l-NAME intervention (2.51 +/- 1.17, P < 0.05). The protein levels of SOD in the Sed and Ex groups were both significantly decreased with the administration of l-NAME. The protein levels of catalase were significantly higher in the Ex and Ex + LA groups than that in the Sed, Sed + LA, and l-NAME-treated groups. The collagen volume fraction was significantly lowered by the exercise and/or l-arginine treatment when compared with the Sed group. Fractional shortening was significantly preserved in the trained groups compared with their corresponding sedentary groups with or without drug treatments. However, the beneficial effect was not further improved by l-arginine treatment. Conclusions: Our results suggest that exercise training exerts antioxidative effects and attenuates myocardial fibrosis in the MI rats. These improvements, in turn, alleviate cardiac stiffness and preserve post-MI cardiac function. In addition, l-arginine appears to have no additive effect on cardiac function or expression of enzymatic antioxidants