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It is interesting that high iron is an independent inducer or cofactor of hepatocellular carcinoma (HCC) while the amount of iron is decreased in the liver tumor tissues. Due to the previous findings that iron deficiency promoted HCC metastasis, it is of significance to identify the underlying mechanism of iron deficiency in HCC. The tumor iron content and expressions of iron-metabolic molecules were observed in the primary liver cancers of rats and mice. The molecules that changed independently of iron were identified by comparing the expression profiles in the human HCC tissues and iron-deprived HCC cells. The downstream effects of these molecules on regulating intracellular iron content were investigated in vitro and further validated in vivo. Both in primary liver cancers of rats and mice, we confirmed the decreased iron content in tumor tissues and the altered expressions of iron-metabolic molecules, including transferrin receptor 1 (TfR1), six-transmembrane epithelial antigen of prostate 3 (STEAP3), divalent metal transporter 1 (DMT1), SLC46A1, ferroportin, hepcidin, and ferritin. Among these, STEAP3, DMT1, and SLC46A1 were altered free of iron deficiency. However, only silence or overexpression of SLC46A1 controlled the intracellular iron content of HCC cells. The interventions of STEAP3 or DMT1 could not change the intracellular iron content. Lentivirus-mediated regain of SLC46A1 expression restored the iron content in orthotopically implanted tumors, with correspondingly changes in the iron-metabolic molecules as iron increasing. Conclusion: Taken together, these results suggest that the loss of SLC46A1 expression leads to iron deficiency in liver tumor tissues, which would be an effective target to manage iron homeostasis in HCC.

Purpose The immunotherapy combined chemotherapy has been the standard treatment strategy for extensive-stage small lung cancer (ES-SCLC). The CREST trial reported consolidative thoracic radiotherapy (cTRT) improved overall survival (OS) for ES-SCLC with intrathoracic residual after chemotherapy. This study was aimed to evaluate the efficacy and safety of TRT for ES-SCLC after first line chemoimmunotherapy.Methods ES-SCLC patients who received immunotherapy in Zhejiang Cancer Hospital has been retrospectively analyzed between January 2020 and November 2021. Patients were assigned to receive either TRT or no TRT. Oligo-metastatic disease was defined as 3 or less discrete distant metastases with no more than 2 organs. Propensity score matching (PSM) was performed in two groups. The main outcome measures were progression-free survival (PFS), local recurrence-free survival (LRFS) and OS.Results 111 patients with ES-SCLC were enrolled in this study, the median OS was 14 months. 39 patients received TRT after chemoimmunotherapy (TRT group) and 72 patients did not receive TRT (no TRT group). TRT group improved OS (HR 0.58, 95% CI 0.34–0.99, p = 0.0445), PFS (HR 0.59, 95% CI 0.38–0.90, p = 0.0149) and LRFS (HR 0.3, 95% CI 0.16–0.56, p = 0.0001). Further sub-cohort analysis, TRT significantly improved LRFS in patients with oligo-metastasis and without liver metastasis. This trend persisted after PSM. However, OS in oligo-metastasis and non-liver metastasis subgroup was without significant difference.Conclusion TRT improved LRFS, PFS and OS for ES-SCLC with thoracic residual after chemoimmunotherapy with well tolerated toxicity.

Background This study examined the associations of diet quality assessed by Healthy Eating Index 2015 (HEI-2015), Alternative Healthy Eating Index 2010 (AHEI-2010), Mediterranean Diet (MedDiet) and overweight/obesity in children and adolescents. Methods This cross-sectional study used data of participants aged 2–19 years from National Health and Nutrition Examination Survey (NHANES) 2005–2018. The weighted logistic regression model was adopted to explore the association between diet quality scores and overweight, obesity in children and adolescents. Subgroup analysis was also performed based on sex. Results A total of 9,724 participants were included in children group (2–11 years old), and 5,934 were adolescent group (12–19 years old). All participants were divided into based on the BMI-for-age: underweight and normal, overweight and obesity groups. After adjusting for age, race, poverty-income ratio, maternal smoking during pregnancy and total energy, HEI-2015 and MedDiet scores were related to the risk of overweight in children, and only MedDiet scores remained associated with a decreased risk of obesity in children. MedDiet scores were associated with a decreased risk of overweight, obesity in adolescents, respectively, after adjusting age, sex, race, poverty-income ratio, cotinine, total energy and physical activity. The similar results in male participants were also found. Conclusion Higher MedDiet scores were associated with lower the risk of overweight and obesity, respectively, particularly for male children and adolescents. The higher HEI-2015 scores were also related to the risk of overweight in children.

There are three traditional surgical approaches to hemiarthroplasty (HA) for femoral neck fractures, respectively, the anterior approach (AA), the lateral approach (LA) and the posterior approach (PA). However, the optimum approach is still controversial, the purpose of this meta-analysis is to identify the merits and demerits of all three approaches. All clinical published studies in PubMed, Web of Science, Embase, and the Cochrane Library from January 2000 to April 2022 were searched which compared different surgical approaches and covered surgery-related outcomes and frequent complications. Five randomized controlled trials and 26 cohort studies for a total of 31 clinical trials were included in the meta-analysis. The dislocation of PA was significantly higher than LA (OR: 3.00 95% CI: 2.25–4.01 I2 = 27% P I2 = 0% P = 0.0005); PA was substantially more than LA in terms of risk of postoperative reoperation (P

Postoperative delirium (POD) is a frequent complication in geriatric patients with hip fractures, which is linked to poorer functional recovery, longer hospital stays, and higher short-and long-term mortality. Patients with increased age, preoperative cognitive impairment, comorbidities, perioperative polypharmacy, and delayed surgery are more prone to develop POD after hip fracture surgery. In this narrative review, we outlined the latest findings on postoperative delirium in geriatric patients with hip fractures, focusing on its pathophysiology, diagnosis, prevention, and treatment. Perioperative risk prediction, avoidance of certain medications, and orthogeriatric comprehensive care are all examples of effective interventions. Choices of anesthesia technique may not be associated with a significant difference in the incidence of postoperative delirium in geriatric patients with hip fractures. There are few pharmaceutical measures available for POD treatment. Dexmedetomidine and multimodal analgesia may be effective for managing postoperative delirium, and adverse complications should be considered when using antipsychotics. In conclusion, perioperative risk intervention based on orthogeriatric comprehensive care is the most effective strategy for preventing postoperative delirium in geriatric patients with hip fractures.

BackgroundNon-small cell lung cancer (NSCLC) driven by MET exon 14 skipping (METex14) occurs in 3-4% of NSCLC cases and defines a subset of patients with distinct characteristics. While MET targeted therapy has led to strong clinical results in METex14 patients, acquired drug resistance seemed to be unavoidable during treatment. Limited information is available regarding acquired resistance during MET targeted therapy, nor has there been any report on such patient-derived xenografts (PDXs) model facilitating the research.MethodsWe describe a patient case harboring METex14 who exhibited drug resistance after treatment with crizotinib. Subcutaneous xenografts were generated from pretreatment and post-resistance patient specimens. PDX mice were then treated with MET inhibitors (crizotinib and tepotinib) and EGFR-MET bispecific antibodies (EMB-01 and amivantamab) to evaluate their drug response in vivo. DNA and RNA sequencing analysis was performed on patient tumor specimens and matching xenografts.ResultsPDXs preserved most of the histological and molecular profiles of the parental tumors. Drug resistance to MET targeted therapy was confirmed in PDX models through in vivo drug analysis. Newly acquired MET D1228H mutations and EGFR amplificated were detected in patient-resistant tumor specimens. Although the mutations were not detected in the PDX, EGFR overexpression was observed in RNA sequencing analysis indicating possible off-target resistance through the EGFR bypass signaling pathway. As expected, EGFR-MET bispecific antibodies overcome drug resistant in the PDX model.ConclusionsWe detected a novel MET splice site deletion mutation that could lead to METex14. We also established and characterized a pair of METex14 NSCLC PDXs, including the first crizotinib resistant METex14 PDX. And dual inhibition of MET and EGFR might be a therapeutic strategy for EGFR-driven drug resistance METex14 lung cancer.

Non-small cell lung cancer (NSCLC) driven byWe describe a patient case harboringPDXs preserved most of the histological and molecular profiles of the parental tumors. Drug resistance to MET targeted therapy was confirmed in PDX models throughWe detected a novel MET splice site deletion mutation that could lead to

As the traditional conservative remedy for endometrial carcinoma (EC), progesterone has great limitations due to its poor performance, and a new strategy is urgently needed. Our previous work revealed that the antipsychotic drug chlorpromazine (CPZ) has stronger antitumor activity on EC than progesterone does, which may provide a promising conservative alternative for EC patients. Unfortunately, the severe extrapyramidal symptoms (EPSs) at concentrations (5 mg/kg) that are required for anticarcinoma activity limited its repurposing. Therefore, a series of novel CPZ derivatives were designed and synthesized to avoid EPS and retain its antitumor activity. Among them, 11·2HCl and 18 displayed greater inhibitory activity by modulating SOS1. Notably, even at a dose of 100 mg/kg, 11·2HCl/18 had little effect on the extrapyramidal system. In conclusion, 11·2HCl and 18 greatly repressed the malignant features of endometrial carcinoma and decreased extrapyramidal side effects compared with the original drug CPZ.

Background Non-small cell lung cancer (NSCLC) driven by MET exon 14 skipping (METex14) occurs in 3-4% of NSCLC cases and defines a subset of patients with distinct characteristics. MET targeted therapy has led to strong clinical responses, however little is known about aquired resistance to drugs in these patients. Patient derived xenograft (PDX) models are recognized as excellent preclinical models to facilitate the understanding of the mechanisms underlying drug resistance. Methods We describe a patient case harboring METex14 who exhibited drug resistance after treatment with crizotinib. Subcutaneous xenografts were generated from pretreatment and post-resistance patient specimens. PDX mice were then treated with MET inhibitors (crizotinib and tepotinib) to evaluate their drug response. DNA and RNA sequencing analysis was performed on patient tumor specimens and matching xenografts. Results PDXs preserved most of the histological and molecular profiles of the parental tumors. Drug resistance to MET targeted therapy was confirmed in PDX models through in vivo drug analysis. Newly aquired MET D1228N mutations and EGFR amplificated were detected in patient-resistant tumor specimens. Although the mutations were not detected in the PDX, EGFR overexpression was observed in RNA sequencing analysis indicating possible off target resistance through the EGFR bypass signaling pathway. Conclusions We established and characterized a pair of METex14 NSCLC patient-derived xenografts (PDXs), including the first crizotinib resistant METex14 PDX. This model will be a powerful tool for testing hypotheses of drug resistance mechanisms and investigations into novel therapeutic strategies.

The integrin receptor protein talin plays vital roles in intracellular chemical and mechanical activities, and it is implicated in the high invasion and poor prognosis of non-small cell lung cancer (NSCLC). To better understand the mechanism underlying the function of talin in NSCLC invasion and metastasis, a few newly designed tension probe based on Förster resonance energy transfer was used for real-time observation of tension changes in A549 cells. High NSCLC cell aggressiveness was found to be accompanied with inward talin and outward glial fibrillary acidic protein (GFAP) tensions, which are closely associated with microfilament (MF) force and intracellular osmotic potential. The increased osmotic pressure resulted from the production of intracellular protein nanoparticles and the related ion influx. Furthermore, integrin activation was found to adjust the talin and GFAP tensions. Disruption of the interaction between talin and MFs blocked the mechanical source of talin, reducing both talin tension and osmotic pressure and thus inhibiting NSCLC cell invasion and migration. Consequently, our study demonstrates that talin is involved in NSCLC invasion and migration via its inward tension and that the integrin pathway is correlated closely with protein-nanoparticle-induced outward osmotic pressure.

The structured DNA-binding domain (DBD) of p53 is a well-known client protein of the chaperone Hsp90. The p53 DBD contains a single zinc ion, coordinated by the side chains of Cys176, His179, Cys238, and Cys242; zinc coordination plays a structural role to stabilize the DBD and is required for its DNA binding. The ambiguous nature of the p53-Hsp90 interaction, together with the stabilizing role of the zinc in the structure of the DBD, prompted us to examine the interaction of Hsp90 with zinc-free p53 DBD. NMR spectroscopy and native gel electrophoresis did not show any apparent preference for the interaction of the destabilized zinc-free form of p53 DBD with Hsp90. Intriguingly, however, at lower protein concentrations, closer to physiological concentrations, the addition of Hsp90, but not other chaperones such as Hsp70, Hsp40, p23, and HOP, appears to slow or prevent the aggregation of zinc-free p53 DBD. This result suggests that part of the function of the Hsp90-p53 interaction in the cell may be to stabilize the apoprotein in the absence of zinc.

Intracellular mechanical tension plays a vital role in maintaining neuronal function and is generated steerablely by motor proteins along microfilaments (MFs) and microtubules (MTs). To explore the interaction between these subcellular tensions and elucidate their underlying mechanisms, we constructed MF- and MT-dependent tension probes using the Förster resonance energy transfer technique. Hypotonic stress activated MF and MT tensions in calcium-dependent manner, which antagonized outward expansion of cells synergistically; conversely, hypertonic stress attenuated MF and MT tensions in a calcium-independent manner and their interaction is antagonistical. In response to ischemia/hypoxia-related factors, glutamic acid upregulated MF and MT tensions synergistically, similarly to calcium signaling. Energy depletion elicited by ammonium ions increased MT tension, but not MF tension. Oxygen free radical stimulus had no effect on MT and MT tensions. However, MT tension was involved in the antagonism of MF tension in response to energy depletion and oxygen free radicals. Our findings suggest that intracellular MF and MT tensions can interact synergistically or antagonistically in neuronal cells, which is indispensable in ischemia/hypoxia -induced neuron dysfunction.

The existence of sports anemia, induced by strenuous or long-term exercise and characterized by decreases of red blood cells (RBCs), hemoglobin and iron content, remains to be doubtful. To observe the effects of endurance exercise on RBCs and explain the underlying reason, we designed this study by observing RBCs parameters and iron metabolism in 8-weeks training rats and effects of iron supplement or protein supplement on RBCs. Results showed that erythrocyte counts, hematocrit, mean corpuscular volume and hemoglobin content decreased while RBC distribution width increased in exercised rats at later stage during 8 weeks training. But the contents of serum iron and ferritin decreased only at 1-week and 2-week and returned to normal at 4-week and 8-week. Same as iron content, apparent iron absorption rate was declined at early stage but restored to normal level at 8-week, as well as serum adrenaline, cortisol and insulin levels. Instead, the contents of total protein and albumin in serum were decreased at later stage during 8-weeks training. Furthermore, we observed that protein supplement ameliorated RBCs parameters in rats exposed to 8 weeks swimming exercise, but iron supplement had no effects on RBCs, though it obviously increased iron content of serum and the liver. Based on these results, we drew a conclusion that transient changes of iron metabolism, which may be induced by stress hormone changes, was not the reason for RBCs decrease in endurance exercises but hemoglobin reduction, induced by defects in protein supplement, impeded development of RBCs.

In vivo tumor growth is characterized by a necrotic core generated by oxygen and nutrients gradients, which is replicated by in vitro three-dimensional (3D) tumor spheroids but not traditional two-dimensional cell monolayers. Gap junctions provide direct communication between adjacent cells and play a critical role in cancer development, but their effects are still debatable. In this study, we found that connexin 43 (Cx43) reduced the area of necrotic core in colon cancer 3D spheroids, thus providing a growth advantage. This impact is dependent on gap junction channel functions, as the channel blocker carbenoxolone or connexin channel death mutant reverses this effect. Additionally, enhanced glucose uptake was detected in Cx43-overexpressing spheroids, along with upregulated mTOR, downregulated AMPK signaling, increased ATP content, and enhanced oxygen consumption rate. Furthermore, the xenograft mouse model confirmed the growth advantage of Cx43 in vivo. RNAseq data and clinical information from The Cancer Genome Atlas (TCGA) database indicated a more heterogeneous expression pattern of Cx43 in colon cancer compared to normal colon tissue, and higher Cx43 level is associated with worse clinical outcomes. Our data suggest a novel function of connexin in tumor growth, that gap junctions may provide nutrients transmitting routes in lieu of vasculature to meet the increasing metabolic requirement of solid tumors.

Medroxyprogesterone acetate (MPA) is the main conservative treatment for endometrial cancer (EC) patients desirable to preserve fertility and those who cannot suffer from surgery. Considering the high incidence of progestin resistance and recurrence of MPA treatment, we reproposed antipsychotics chlorpromazine (CPZ) as a new strategy for both progestin-sensitive and -resistant endometrial cancer. Cytobiology experiments indicated that CPZ could significantly suppress proliferation, migration/invasion and induce apoptosis in Ishikawa (ISK) and KLE EC cell lines. And xenograft mouse models were constructed to validate the antitumor effect and toxicity of CPZ in-vivo. CPZ inhibited the growth at a low dose of 3mg/kg and the mice exhibited no signs of toxicity. Next, concomitant treatment and sequential treatment with CPZ and MPA were proceeded to analysis the synergistic effect in EC cells. Concomitant treatment only performed a limited synergistic effect on apoptosis in ISK and KLE cells. Nevertheless, sequential treatment showed favorable synergistic effects in progestin-resistant KLE cells. Finally, a stable MPA-resistant cell line shRNA was established to explore the mechanism of CPZ reversing progestin resistance. Immunoblot data showed that CPZ inhibited the activation of PI3K/AKT signal in ISK and KLE cells and upregulated PRB expression in progestin-resistant cells, by which CPZ overcame progestin resistance to MPA. Thus, CPZ might act as a candidate drug for conservative treatment and sequential treatment with CPZ and MPA could be a suitable therapeutic option for progestin resistant patients.

The nonideal characteristics of the entire channel of satellite navigation signals from generation, propagation to reception will cause signal distortions, resulting in pseudorange biases. Such kind of biases cannot be eliminated by differential technologies and has become a core error source in high-accuracy applications. We study the theoretical model and implementation method of a pseudorange-bias-free linear channel. The ideal channel transfer function equation under the unbiased pseudorange requirement is first derived from the equivalent baseband model. Based on two corresponding criteria and the simulation of the influence of different amplitude- and phase-frequency responses, a digital phase compensation method based on an all-pass filter is proposed to eliminate pseudorange biases. Then the significant effects of the two phase equalizers are validated by a simulation example of the BPSK(10) signal. Finally, the real BDS3 PRN32 and PRN33 satellite B1C signals collected by a 40-m high-gain dish antenna are utilized to invert the channel transfer characteristics and processed by our software receiver. The measurement results demonstrate that the phase equalizers constructed according to either the linear phase criterion or the linear phase plus even-symmetric phase criterion can effectively reduce the pseudorange bias. The model and method provide a reference for payload and receiver optimization and are suitable for various signal structures and applications.

Increasing populations are found to bear mild hepatic iron overload (HIO) due to unhealthy lifestyles, metabolic diseases, etc., whether this mild but chronic HIO induces hepatic inflammation is unknown. In the present study, mice receiving a 12-months 0.3% dextran-iron diet show mild HIO with no detectable oxidative damages in the liver but have infiltrated macrophages and increased IL-6, TNFα, AST and ALT since 6-months. The HNF4α/miR-122/CCL2 pathway, identified by our previous studies to induce macrophages infiltration, is initiated by chronic mild HIO. After excluding the role of DNA methylation, a modified transcription factor microarray is applied to find that transcription factor YY1 is responsible for HIO-decreased HNF4α expression. Then the E3 ubiquitin ligase TRIP12 is identified by an immunoprecipitation coupled LC-MS/MS and proved to bind and ubiquitinate YY1, leading to its degradation. The overexpression or silence of YY1 in the liver regulates the HNF4α/miR-122/CCL2 pathway. More importantly, YY1 overexpression alleviates chronic mild HIO induced hepatic inflammatory responses. In conclusion, these results elucidate an oxidative-stress-independent, TRIP12/YY1/HNF4α/miR-122/CCL2 pathway of chronic mild HIO inducing hepatic inflammation, implying that effective measures in addition to antioxidants are needed for individuals at the risk of chronic mild HIO.

Cancer-suppressing transcription factor p53 is regulated by a wide variety of cellular factors, including many chaperones. The DNA-binding domain (DBD) of p53 is known to interact with the chaperone Hsp90, but the role of other members of the chaperone network, including co-chaperones such as p23, is unknown. Using a combination of nuclear magnetic resonance (NMR) titration, isothermal titration calorimetry, fluorescence anisotropy, and native agarose gel electrophoresis, we have identified a direct interaction between the p53 DBD and Hsp90 co-chaperone p23 that occurs in the absence of Hsp90. The affinity is relatively weak and largely determined by electrostatic interactions between the acidic C-terminal disordered tail of p23 and the two DNA-binding regions of the p53 DBD. We show by NMR and native agarose gel electrophoresis that a p53-specific double-stranded DNA sequence competes successfully with p23 for binding to the p53 DBD. The Hsp90 independence of the interaction between p23 and p53 DBD, together with the competition of p23 versus DNA for p53, raises the intriguing possibility that p23, like other small charged proteins, may affect p53 in hitherto unknown ways.

Aims Macrophages, as an important member of immune system, engulf and digest pathogens in innate immunity and help initiate adaptive immunity. However, macrophages also involve in occurrence and development of many diseases, such as obesity and type 2 diabetes. Here, we aimed to reveal how activated macrophages cause insulin resistance in skeletal muscle in vitro through simulating body environment. Main methods We established RAW264.7 macrophages and C2C12 myotubes co-incubation model in vitro using Transwell filter to simulate body environment and investigated effects of RAW264.7 cells on insulin-regulated glucose metabolism in C2C12 myotubes. Immunofluorescence, Immunoblot and glucose uptake tests were used to assess metabolic changes in C2C12 myotubes. ELISA test detected secretions of tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6) from RAW264.7 cells. In addition, RNA interference and inhibitor treatment were used. Key findings Activated RAW264.7 cells attenuated insulin response in C2C12 myotubes. Activated RAW264.7 cells secreted a lot of TNF-α and IL-6. We found that TNFα, but not IL-6, caused insulin resistance of skeletal muscle in a dose-dependent manner. The results further indicated that activation of TNF-α downstream proteins, inhibitor of nuclear factor κ-B kinase (IKK) and the jun-N-terminal kinase 1 (JNK1) led to phosphorylation of insulin receptor substrate 1 (IRS-1) at Ser residues and insulin resistance in C2C12 myotubes. Significance Our research provided further and direct demonstration on activated macrophage-induced insulin resistance in skeletal muscle, suggesting TNF-α might become a therapeutic target to ameliorate and treat type 2 diabetes.

User scheduling in mmWave multi-user multiple-input multiple output (MU-MIMO) systems involves the joint optimization of user selection and beam pair selection due to its hybrid beamforming architecture. Most of the existing solutions are based on ideal channel state information (CSI). How to choose the users to be scheduled and their beams for operation in the case of non-ideal CSI is still challenging. In this study, we propose a blind beam search assisted user scheduling (BSUS) algorithm operating in the absence of ideal CSI. The proposed method consists of two steps. In the first step, the beam information acquired in the initial beam training is used to identify the channels’ orthogonality and classify the users into groups. In the second step, a scheduled user is chosen from each group to maximize the equivalent channel energy. Subsequently, the selection of beam pairs for communication is simplified owing to the information acquired in initial beam training. Simulation results show that the proposed scheme can achieve 93.6% of the maximal sum rate, and maintain a low computational complexity.

Background Iron is finely regulated due to its vital roles in organisms and the peroxidase reactivity if excess. Solute Carrier Family 46 Member 1 (SLC46A1), also named PCFT or HCP1, is the main importer of heme‑iron in the intestine, but has a high abundance in the liver. Since the liver has a central role in iron homeostasis, whether SLC46A1 regulates hepatic iron metabolism is of interest to be identified. Methods The recombinant adeno-associated virus vectors were used to hepatic-specifically inhibit SLC46A1 expression to observe its effects on hepatic iron metabolism. Then the abilities of SLC46A1 in importing heme and folate, and consequent alterations of iron content in hepatocytes were determined. Furthermore, effects of iron on SLC46A1 expression were investigated both in vitro and in vivo. Results The hepatocyte-specific inhibition of SLC46A1 decreases iron content in the liver and increases iron content in serum. Expressions of iron-related molecules, transferrin receptor 1, hepcidin and ferroportin, are correspondingly altered. Interestingly, free heme concentration in serum is increased, indicating a decreased import of heme by the liver. In hepatocytes, SLC46A1 is capable of importing hemin, increasing intracellular iron content. The import of hemin by SLC46A1 is unaffected by its other substrate, folate. Instead, hemin treatment decreases SLC46A1 expression, reducing the import of folate. In addition, SLC46A1 itself shows to be iron-responsive both in vivo and in vitro, making it available for regulating iron metabolism. Conclusion The results elucidate that SLC46A1 regulates iron metabolism in the liver through a folate-independent manner of importing heme. The iron-responsive characters of SLC46A1 give us a new clue to link heme or iron overload with folate deficiency diseases.

SUMMARYThe nucleus is the most prominent organelle in eukaryotic cells, and its deformation depends on interactions between the nuclear lamina (NL) and cytoskeleton structural tensions. The structural tensions can be quantified at a pico-Newton (pN) level using a genetically encoded optical probe. In living cells, NL tensions countered the 4.26pN resting strain imposed competitively by cytoskeletal tension. The depolymerization of microfilaments or microtubules drove an aberrant increase in outward osmotic pressure through the production of mass protein-nanoparticles. The osmotic pressure also served as a directional converter of inward cytoskeletal force, and contributed to the outward expansion of NL via the passive pull of intermediate filaments (IFs). The NL, but not IFs, can remotely detect extracellular osmosis pressure alterations, which are closely associated with highly polarized microfilament and microtubule structures and their directional force activities. The oxidative-induced increase of NL tension results from intracellular hyper-osmosis, associated closely with protein-nanoparticles production elicited by cofilin and stathmin activation. These data reveal that intracellular steerable forces interact direction-dependently to control NL tension in terms of their magnitude and vectors.

Translationally controlled tumor protein (TCTP) is an abundant protein that is highly conserved in eukaryotes. However, its primary function is still not clear. Human TCTP interacts with the metazoan-specific eukaryotic elongation factor 1Bδ (eEF1Bδ) and inhibits its guanine nucleotide exchange factor (GEF) activity, but the structural mechanism remains unknown. The interaction between TCTP and eEF1Bδ was investigated by NMR titration, structure determination, paramagnetic relaxation enhancement, site-directed mutagenesis, isothermal titration calorimetry, and HADDOCK docking. We first demonstrated that the catalytic GEF domain of eEF1Bδ is not responsible for binding to TCTP but rather a previously unnoticed central acidic region (CAR) domain in eEF1Bδ. The mutagenesis data and the structural model of the TCTP-eEF1Bδ CAR domain complex revealed the key binding residues. These residues are highly conserved in eukaryotic TCTPs and in eEF1B GEFs, including the eukaryotically conserved eEF1Bα, implying the interaction may be conserved in all eukaryotes. Interactions were confirmed between TCTP and the eEF1Bα CAR domain for human, fission yeast, and unicellular photosynthetic microalgal proteins, suggesting that involvement in protein translation through the conserved interaction with eEF1B represents a primary function of TCTP.

Double-stranded RNA-dependent protein kinase (PKR), an intracellular pathogen recognition receptor, is involved both in insulin resistance in peripheral tissues and in downregulation of pancreatic β-cell function in a kinase-dependent manner, indicating PKR as a core component in the progression of type 2 diabetes. PKR also acts as an adaptor protein via its protein-binding domain. Here, the PKR protein-binding function promoted β-cell proliferation without its kinase activity, which is associated with enhanced physical interaction with tumor necrosis factor receptor-associated factor 2 (TRAF2) and TRAF6. In addition, the transcription of the nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB)-dependent survival gene c-Myc was upregulated significantly and is necessary for proliferation. Upregulation of the PKR protein-binding function induced the NF-κB pathway, as observed by dose-dependent degradation of IκBα, induced nuclear translocation of p65 and elevated NF-κB-dependent reporter gene expression. NF-κB-dependent reporter activity and β-cell proliferation both were suppressed by TRAF2-siRNA, but not by TRAF6-siRNA. TRAF2-siRNA blocked the ubiquitination of receptor-interacting serine/threonine-protein kinase 1 (RIP1) induced by PKR protein binding. Furthermore, RIP1-siRNA inhibited β-cell proliferation. Proinflammatory cytokines (TNFα) and glucolipitoxicity also promoted the physical interaction of PKR with TRAF2. Collectively, these data indicate a pivotal role for PKR’s protein-binding function on the proliferation of pancreatic β cells through TRAF2/RIP1/NF-κB/c-Myc pathways. Therapeutic opportunities for type 2 diabetes may arise when its kinase catalytic function, but not its protein-binding function, is downregulated.

In an overloaded MU-MIMO system with hybrid beamforming that supports a very large number of users, user scheduling is necessary as the base station (BS) cannot simultaneously serve such a large number of users. Since hybrid beamforming provides a new resource to schedule, i.e. beams, user pairing becomes a joint optimization on user selection and beam selection, which is computationally demanding. In this paper, a low-complexity two-stage user scheduling scheme considering both the inter-user channel correlation and the channel energy is proposed. The idea is motivated by the fact that both the orthogonality between the user channels and the channel energy can affect the system achievable sum rate in a MU-MIMO system. Therefore, we propose to firstly sort the users from the perspective of channel orthogonality, and then carry out user and beam selection within a narrowed range for channel energy maximization. Simulation results validate the proposed scheduling strategy not only has a significant advantage in reducing computational complexity, but also achieves higher sum rate than other non-exhaustive schemes.

Hsp70 is a highly conserved chaperone that in addition to providing essential cellular functions and aiding in cell survival following exposure to a variety of stresses is also a key modulator of prion propagation. Hsp70 is composed of a nucleotide-binding domain (NBD) and substrate-binding domain (SBD). The key functions of Hsp70 are tightly regulated through an allosteric communication network that coordinates ATPase activity with substrate-binding activity. How Hsp70 conformational changes relate to functional change that results in heat shock and prion-related phenotypes is poorly understood. Here, we utilised the yeast [PSI +] system, coupled with SBD-targeted mutagenesis, to investigate how allosteric changes within key structural regions of the Hsp70 SBD result in functional changes in the protein that translate to phenotypic defects in prion propagation and ability to grow at elevated temperatures. We find that variants mutated within the β6 and β7 region of the SBD are defective in prion propagation and heat-shock phenotypes, due to conformational changes within the SBD. Structural analysis of the mutants identifies a potential NBD:SBD interface and key residues that may play important roles in signal transduction between domains. As a consequence of disrupting the β6/β7 region and the SBD overall, Hsp70 exhibits a variety of functional changes including dysregulation of ATPase activity, reduction in ability to refold proteins and changes to interaction affinity with specific co-chaperones and protein substrates. Our findings relate specific structural changes in Hsp70 to specific changes in functional properties that underpin important phenotypic changes in vivo. A thorough understanding of the molecular mechanisms of Hsp70 regulation and how specific modifications result in phenotypic change is essential for the development of new drugs targeting Hsp70 for therapeutic purposes.

ObjectivesThe clinical and epidemiological profiles of Guillain-Barré syndrome (GBS) in southern China have yet to be fully recognised. We aimed to investigate the subtypes of GBS in southern China, compare the clinical features of demyelinating form with that of axonal form and test whether preceding infections and age have influence on the clinical phenotype, disease course and severity of GBS.MethodsMedical records of patients with a diagnosis of GBS admitted to 31 tertiary hospitals, located in 14 provinces in southern China, from 1 January 2013 to 30 September 2016, were collected and retrospectively reviewed.ResultsFinally. 1056 patients, including 887 classic GBS and 169 variants, were enrolled. The 661 classic patients with available electromyographic data were grouped as having acute inflammatory demyelinating polyneuropathy (AIDP, 49.0%), acute motor axonal neuropathy (AMAN, 18.8%), inexcitable (0.9%) and equivocal (31.3%). In contrast to AIDP, patients with AMAN were characterised by earlier nadir (P=0.000), higher Hughes score at nadir (P=0.003) and at discharge (P=0.000). Preceding upper respiratory infections were identified in 369 (34.9%) patients, who were more inclined to develop AIDP (P=0.000) and Miller-Fisher syndrome (P=0.027), whereas gastrointestinal infection were found in 89 (8.4%) patients, who were more prone to develop AMAN (P=0.000), with more severe illness (P=0.001) and longer hospital stay (P=0.009). Children (≤15 years) and the elderly (≥56 years) were more severe at nadir, the elderly had the longest hospital stay (P=0.023).ConclusionAIDP is the predominant form in southern China, which is different from data of northern China. The different subtypes, preceding infection and age of onset can partially determine the disease progression, severity and short-term recovery speed of GBS.Clinical trial registrationChiCTR-RRC-17014152.

Double-stranded RNA-dependent protein kinase (PKR) is revealed to participate in the development of insulin resistance in peripheral tissues in type 2 diabetes (T2DM). Meanwhile, PKR is also characterized as a critical regulator of cell proliferation. To date, no study has focused on the impact of PKR on the proliferation of pancreatic β-cells. Here, we adopted insulinoma cell lines and mice islet β-cells to investigate: (1) the effects of glucolipotoxicity and pro-inflammatory cytokines on PKR activation; (2) the effects of PKR on proliferation of pancreatic β-cells and its underlying mechanisms; (3) the actions of PKR on pro-proliferative effects of IGF-I and its underlying pathway. Our results provided the first evidence that PKR can be activated by glucolipitoxicity and pro-inflammatory cytokines in pancreatic β-cells, and activated PKR significantly inhibited cell proliferation by arresting cell cycle at G1 phase. Reductions in cyclin D1 and D2 as well as increases in p27 and p53 were associated with the anti-proliferative effects of PKR, and proteasome-dependent degradation took part in the reduction of cyclin D1 and D2. Besides, PKR activation abrogated the pro-proliferative effects of IGF-I by activating JNK and disrupting IRS1/PI3K/Akt signaling pathway. These findings indicate that the anti-proliferative actions of PKR on pancreatic β-cells may contribute to the pathogenesis of T2DM.

// Xin Zhou 1 , Dewu Han 1 , Ruiling Xu 1 , Huiwen Wu 1,2 , Chongxiao Qu 3 , Feng Wang 1 , Xiangyu Wang 4 and Yuanchang Zhao 1 1 Department of Pathophysiology, Basic Medical Science, Shanxi Medical University, Taiyuan, Shanxi, China 2 Science & technology center of Fenyang College, Shanxi Medical University, Fenyang, Shanxi, China 3 Department of Pathology, Shanxi Provincial People’s Hospital, Taiyuan, Shanxi, China 4 Department of Oral Medicine, Shanxi Medical University, Taiyuan, Shanxi, China Correspondence to: Dewu Han, email: // Keywords : glycine, non-alcoholic steatohepatitis, intestinal endotoxin, endoplasmic reticulum stress, oxidative stress, Pathology Section Received : July 14, 2016 Accepted : October 12, 2016 Published : October 23, 2016 Abstract We set out to explore the hypothesis that glycine attenuates non-alcoholic steatohepatitis (NASH) in rats and the possible mechanism by which is it does. Male Sprague-Dawley (SD) rats were fed a diet containing high fat and high sucrose (HSHF) for 24 weeks to induce NASH. Blood and liver tissues were sampled at selected time points throughout the study. Compared with control animals, the content of alanine transaminase (ALT), triglycerides (TGs), and free fatty acids (FFAs) in plasma and the TG and FFA content in the liver was increased from week 4 to 24. The level of TNF α and MCP-1 in plasma, the content of TNF α in the liver, the insulin resistance index, inflammatory cell infiltration, hepatocyte apoptosis, reactive oxygen species (ROS) generation, and endoplasmic stress-associated protein expression were unaltered at 4 weeks. However, these levels were significantly elevated in HSHF fed rats at 12 weeks. At the same time, the level of endotoxin progressively increased from 0.08 ± 0.02 endotoxin EU/ml at week 4 to 0.7 ± 0.19 EU/ml at week 24. Moreover, these rats had elevated blood endotoxin levels, which were positively associated with their NASH indexes. Liver histology progressively worsened over the course of the study. However, we found that with concomitant treatment with glycine, the level of endotoxin decreased, while NASH indexes significantly decreased and liver status markedly improved,. These data support the hypothesis that glycine protects against NASH in rats by decreasing the levels of intestinal endotoxin, alleviating endoplasmic reticulum and oxidative stress.

Cases of sporadic Alzheimer’s disease (SAD) are the predominant form of the age-related dementia. New evidence suggests that metabolic syndrome (MS), a metabolic disorder, is an initiating factor of some SAD cases. A high-sugar high-fat diet could cause MS, we aimed to investigate whether it could directly lead to SAD. The characteristic molecules of AD (hippocampus Aβ and Tau) were tested by using ELISA and western blotting to confirm the happening hallmarks of AD in brain. MS and inflammation related biochemical indicators were measured using immunological method. Proteins associated with the insulin resistance signal pathway (JNK, PI-3K, AKT, GSK-3β, GLUT3) were evaluated using western blotting method. The levels of reactive oxygen species (ROS) were measured by immunofluorescence method. Expressions of hippocampus Aβ, phosphorylation-Tau (p-Tau), inflammatory factors and p-JNK, Gsk-3βwere higher in the model rats than those in the control rats and expressions of p-PI3K, p-AKT and GLUT3 were reversed. The MS model animals, which can induce the characteristics symptoms of AD, and therefore it may be preliminarily considered that the AD pertains to the MS-related diseases.

Arsenic trioxide (ATO) has shown anticancer activity against a variety of solid tumor models through induction of apoptosis, promotion of cellular differentiation, and inhibition of cellular invasive ability. The present study investigated the role of ceramide in regulating the invasive activity of hepatoma carcinoma HCCLM3 cells during ATO treatment. We found that ATO treatment inhibited HCCLM3 cell invasion and downregulated matrix metalloproteinase-9 (MMP-9) protein levels in a concentration-dependent manner. ATO also dose dependently induced the generation and accumulation of ceramide in HCCLM3 cells. Blockage of intracellular ceramide production through the inhibition of de novo ceramide synthesis or the hydrolysis of sphingomyelin increased the invasive ability and upregulated MMP-9 protein levels. The findings of this study indicated that ATO induced ceramide production through de novo ceramide synthesis and the hydrolysis of sphingomyelin and suggested that ceramide accumulation in response to ATO stimuli may play an important role in cancer therapy.

Primary objective: Global ischemia reportedly results in intense ERK activation followed by its inactivation and mild reactivation. This study examined the molecular mechanisms underlying inhibition of the ERK pathway following cerebral ischemia in the rat hippocampus.Methods: Forebrain ischemia was induced by four-vessel occlusion and protein activity was assessed using co-immunoprecipitation and immunoblotting analysis.Results: Reperfusion post-ischemia induced an up-regulation in Spry2 activity through Src-Spry2 interactions, contributing to suppression of the Ras/Raf/MEK/ERK signalling cascade. The NMDA receptor antagonist, ketamine, and the Src family protein kinase inhibitor, PP2, both potently blocked the ischemia-induced up-regulation of Spry2, indicating that NMDA receptors and Src family tyrosine kinases are essential for Spry2 activity.Conclusions: Cerebral ischemia induces a Src-mediated up-regulation of Spry2 in a NMDA receptor-dependent manner, serving as an attenuation signal in the ERK cas...

Hsp70 chaperone proteins play crucial roles in the cell. Extensive structural and functional studies have been performed for bacterial and mammalian Hsp70s. Ssa1 from Saccharomyces cerevisiae is a member of the Hsp70 family. In vivo and biochemical studies on Ssa1 have revealed that it regulates prion propagation and the cell cycle. However, no structural data has been obtained for Ssa1 up to now. Here we report the almost complete (96 %) (1)H, (13)C, (15)N backbone and side chain NMR assignment of the 18.8 kDa Ssa1 substrate binding domain. The construct includes residues 382-554, which corresponds to the entire substrate binding domain and two following α-helices in homologous structures. The secondary structure predicted from the assigned chemical shifts is consistent with that of homologous Hsp70 substrate binding domains.

This paper presents the parameters design, modeling and performance analysis of the Sigma-Delta Modulator (SDM) for chromatography application. Chromatograph instruments often have rigid requirements to the output analog signal in signal processing. In order to ensure the high resolution, it requires not only the noise is very small and the signal distortion is not existence. The rate of signal to noise of SDM usually should be higher than 106dB. Specially, the frequency of chromatography signal is very low, often lower than 2Hz. It is different from other applications. In this paper, the main parameters of SDM for chromatography are designed and the topology of modulator is optimized. Finally, simulations are conducted by simulink modeling. Results show that the proposed SDM is stable and suitable for chromatography application.

Background Ceramide accumulation is considered a contributing factor to neuronal dysfunction and damage. However, the underlying mechanisms that occur following ischemic insult are still unclear. Methods In the present study, we established cerebral ischemia models using four-vessel occlusion and oxygen-glucose deprivation methods. The hippocampus neural cells were subjected to immunohistochemistry and immunofluorescence staining for ceramide and neutral sphingomyelinase 2 (nSMase2) levels; immunoprecipitation and immunoblot analysis for nSMase2, receptor for activated C kinase 1 (RACK1), embryonic ectoderm development (EED), p38 mitogen-activated protein kinase (p38MAPK) and phosphorylated p38MAPK expression; SMase assay for nSMase and acid sphingomyelinase (aSMase) activity; real-time reverse transcription polymerase chain reaction for cytokine expression; and Nissl, microtubule-associated protein 2 and terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate nick-end labeling staining. Results We found considerable production of ceramide in astrocytes, but not in neurons, during early cerebral ischemia. This was accompanied by the induction of nSMase (but not aSMase) activity in the rat hippocampi. The inhibition of nSMase2 activity effectively reduced ceramide accumulation in astrocytes and alleviated neuronal damage to some extent. Meanwhile, the expression levels of proinflammatory cytokines, including tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β) and IL-6, were found to be upregulated, which may have played an import role in neuronal damage mediated by the nSMase2/ceramide pathway. Although enhanced binding of nSMase2 with RACK1 and EED were also observed after cerebral ischemia, nSMase2 activity was not blocked by the TNF-α receptor inhibitor through RACK1/EED signaling. p38MAPK, but not protein kinase Cζ or protein phosphatase 2B, was able to induce nSMase2 activation after ischemia. p38MAPK can be induced by A2B adenosine receptor (A2BAR) activity. Conclusions These results indicate that the inhibition of ceramide production in astrocytes by targeting A2BAR/p38MAPK/nSMase2 signaling may represent a viable approach for attenuating inflammatory responses and neuronal damage after cerebral ischemia.

The c-Jun N-terminal kinase (JNK) undergoes complete inactivation following the intense activation induced by cerebral ischemia and reperfusion in rat hippocampi. This study examines the molecular mechanism underlying JNK dephosphorylation and inactivation evoked by dual-specificity phosphates following cerebral ischemia. The results revealed upregulation of dual-specificity phosphatase M3/6 (DUSP8) activity at 4 h of reperfusion in rat hippocampi. This was accompanied by the dephosphorylation of JNK. The M3/6 inhibitor, anisomycin, was found to enhance JNK activity following postischemic reperfusion, suggesting that M3/6 is closely associated with JNK inactivation following cerebral ischemia. Cerebral ischemia also induced an increase in heat shock protein (HSP70) levels, which is involved in the upregulation of soluble cytoplasmic M3/6 levels. The inhibition of HSP70 using quercetin resulted in an elevation of JNK activity by decreasing the cytoplasmic solubility of M3/6. The findings of the current study suggest that M3/6 is implicated in the inactivation of JNK in response to cerebral ischemia, which requires the molecular chaperone HSP70 to facilitate the correction of folding defects.

Background The inactivation of c-Jun N-terminal kinase (JNK) is associated with anti-apoptotic and anti-inflammatory effects in cerebral ischemia, which can be induced by an imbalance between upstream phosphatases and kinases. Result Mitogen-activated protein kinase phosphatase 7 (MKP-7) was upregulated significantly at 4 h of reperfusion postischemia in rat hippocampi. By administration of cycloheximide or siRNA against mitogen-activated protein kinase phosphatase 7 (MKP-7) in a rat model of ischemia/reperfusion, an obvious enhancement of JNK activity was observed in 4 h of reperfusion following ischemia, suggesting MKP-7 was involved in JNK inactivation after ischemia. The subcellular localization of MKP-7 altered after ischemia, and the inhibition of MKP-7 nuclear export by Leptomycin B up-regulated JNK activity. Although PI3K/Akt inhibition could block downregulation of JNK activity through SEK1 and MKK-7 activation, PI3K/Akt activity was not associated with the regulation of JNK by MKP-7. Conclusions MKP-7, independently of PI3K/Akt pathway, played a key role in downregulation of JNK activity after ischemia in the rat hippocampus, and the export of MKP-7 from the nucleus was involved in downregulation of cytoplasmic JNK activity in response to ischemic stimuli.

Studies have revealed that the adult mammalian brain has the capacity to regenerate some neurons after cerebral ischemia. And this perspective on neurogenesis adds to the conceptual framework for strategies for the repair of ischemia-induced brain injury, that is, if the effect of ischemia-induced neurogenesis is enhanced, then the recovery of brain function after stroke can be promoted. Neurogenesis is a multistep process that requires the proliferation of neural stem/progenitor cells, migration and that new cells differentiate, survive and integrate into existing neural networks. For that to occur, the same concerted action of various factors is needed, especially transcription factors which regulate the expression of many moleculars and interact with them to promote neurogenesis. This review article gives a brief overview of some transcription factors (NF-κB, Hes, STAT3, AP-1, CREB, HIF1, Pax6, Tcf/Lef, Gli, Sox2, Olig2, Dlx2, TLX, Bmi-1) in ischemia-induced neurogenesis.

Extracellular-signal-regulated kinase (ERK) undergoes rapid inactivation following the intense activation evoked by cerebral ischemia and reperfusion. However, the precise mechanism of this inactivation has not been elucidated. To investigate how phosphatases regulate the ERK cascade following ischemia, the PP2A inhibitors cantharidin and okadaic acid were administrated to the CA1 subregion of the rat hippocampus. The resulting sustained ERK activity implies that PP2A is a major phosphatase contributing to the rapid inactivation, but not activation, of ERK following cerebral ischemia. The increase in PP2A activity induced by ceramide has a weak effect on the activation of Raf via dephosphorylation of Ser259 in response to ischemia. In contrast, ketamine (Keta) and cyclosporine A (CsA), two chemicals that block calcium signal in ischemia, decrease ERK activity by blocking Raf dephosphorylation of Ser259. We also observed that activation of an upstream protein, Ras-GRF, leads to calcium/calmodulin-dependent activation of the ERK signaling cascade in response to ischemic stimuli. In addition, the activity of cyclic AMP response element-binding protein (CREB) and estrogen receptor α (ERα), target proteins of ERK and protective elements against ischemic lesion, parallels the activity of ERK. These data indicate that PP2A plays a significant role in blocking the protective effect induced by the ERK kinase pathway and that fast inactivation of ERK is the result of cross talk between calcium/calmodulin-dependent, positively regulated signal cascades and a ceramide-dependent negative signaling pathway. © 2008 Wiley-Liss, Inc.

Production of reactive oxygen species (ROS) results in up-regulation of the extracellular signal-regulated kinase (ERK) cascade in response to numerous stimuli. Cerebral ischemia induces calcium-dependent kinase activation followed by ROS production. Here, we examined how ROS mediates the activation of ERK following cerebral ischemia in the rat hippocampus. We found that alpha-tocopherol, a free radical scavenger, attenuated the initial, robust activation of ERK by inhibiting Raf-1 dephosphorylation at Ser259. Alpha-tocopherol also down-regulated the second and mild activation of ERK through inhibition of Src-dependent phosphorylation of Raf-1 at Tyr340/341. Our results suggest that ROS production mediates the biphasic activation of ERK through different signaling cascades following post-ischemic reperfusion. Mediation of these signaling pathways involves changes in Raf-1 phosphorylation at different sites.

Extracellular signal-regulated kinases (ERKs) can be activated by calcium signals. In this study, we investigated whether calcium-dependent kinases were involved in ERKs cascade activation after global cerebral ischemia.Cerebral ischemia was induced by four-vessel occlusion, and the calcium-dependent proteins were detected by immunoblot.Lethal-simulated ischemia significantly resulted in ERKs activation in N-methyl-D-aspartate (NMDA) receptor-dependent manner, accompanying with differential upregulation of Src kinase and Ca2+/calmodulin-dependent protein kinase II (CaMKII) activities. With the inhibition of Src family tyrosine kinases or CaMKII by administration of PP2 or KN62, the phosphorylation of ERKs was impaired dramatically during post-ischemia recovery. However, ischemic challenge also repressed ERKs activity when Src kinase was excessively activated.Src family tyrosine kinases and CaMKII might be involved in the activation of ERKs mediated by NMDA receptor in response to acute ischemic stimuli in vivo, but the intense activation of Src kinase resulted from ischemia may play a reverse role in the ERKs cascade.

Aim We sought develop and characterize a diet-induced model of metabolic syndrome and its related diseases. Methods The experimental animals (Spague-Dawley rats) were randomly divided into two groups, and each group was fed a different feed for 48 weeks as follows: 1) standard control diet (SC), and 2) a high sucrose and high fat diet (HSHF). The blood, small intestine, liver, pancreas, and adipose tissues were sampled for analysis and characterization. Results Typical metabolic syndrome (MS), non-alcoholic fatty liver disease (NAFLD), and type II diabetes (T2DM) were common in the HSHF group after a 48 week feeding period. The rats fed HSHF exhibited signs of obesity, dyslipidemia, hyperglycaemia, glucose intolerance, and insulin resistance (IR). At the same time, these animals had significantly increased levels of circulating LPS, TNFα, and IL-6 and increased ALP in their intestinal tissue homogenates. These animals also showed a significant reduction in the expression of occluding protein. The HSHF rats showed fatty degeneration, inflammation, fibrosis, cirrhosis, and lipid accumulation when their liver pathologies were examined. The HSHF rats also displayed increased islet diameters from 12 to 24 weeks, while reduced islet diameters occurred from 36 to 48 weeks with inflammatory cell infiltration and islet fat deposition. The morphometry of adipocytes in HSHF rats showed hypertrophy and inflammatory cell infiltration. HSHF CD68 analysis showed macrophage infiltration and significant increases in fat and pancreas size. HSHF Tunel analysis showed significant increases in liver and pancreas cell apoptosis. Conclusions This work demonstrated the following: 1) a characteristic rat model of metabolic syndrome (MS) can be induced by a high sucrose and high fat diet, 2) this model can be used to research metabolic syndrome and its related diseases, such as NAFLD and T2DM, and 3) intestinal endotoxemia (IETM) may play an important role in the pathogenesis of MS and related diseases, such as NAFLD and T2DM.

A distortion-tolerant reconstruction algorithm for sweep fingerprint sequences oriented to portable devices is proposed. The performance of this algorithm on simulated and real data is presented. Some performance results are included to illustrate the efficiency of this algorithm compared to two state-of-the-art reconstruction methods.

The term-based vector space model is a prominent technique for retrieving textual information. In this paper we examine the usefulness of phrases as terms in vector-based document classification. We focus on statistical techniques to extract both adjacent and window phrases from documents. We discover that the positive effect of adding phrase terms is very limited, if we have already achieved good performance using single-word terms, even when SVD/LSI is used as the dimensionality reduction method.