TWIK-related acid-sensitive potassium channels TASK-1 and TASK-3 may participate in the process of the coexistence of asthma and OSA.

OBJECTIVE: To investigate the role of TWIK-related acid-sensitive potassium channels TASK-1 and TASK-3 in the mechanism of asthma combined with obstructive sleep apnea (OSA) in mice. METHOD: C57BL/6 mice were randomly divided into four groups: control group (NS-RA), asthma group (OVA-RA), OSA group (NS-IH), and asthma combined with OSA group (OVA-IH). After monitoring lung function in each group, the expression levels of TASK-1 and TASK-3 mRNA and protein in lung tissues were measured, and the correlation between the changes of both and lung function was analyzed. RESULTS: A total of 64 male mice were studied. Penh, serum IgE concentrations, and the percentage of eosinophils in bronchoalveolar lavage fluid (BALF) were higher in OVA-RA and OVA-IH mice compared with NS-RA (P < 0.05),while the above indexes were slightly elevated in NS-IH mice compared with NS-RA (P > 0.05), where the Penh and the percentage of eosinophils in BALF was higher in OVA-IH mice than NS-IH (P < 0.05).Increased TASK-3 mRNA expression (P < 0.05) as well as TASK-1 and TASK-3 protein expression (P > 0.05) in lung tissues of OVA-RA and NS-IH mice compared with NS-RA, and TASK-3 mRNA expression was slightly more in the OVA-IH group compared with NS-RA (P > 0.05), but less compared with OVA-RA (P < 0.05) or NS-IH (P > 0.05), while TASK-1 and TASK-3 protein expression was increased in the OVA-IH group compared with the remaining three groups, and TASK-3 protein expression was associated with lung function impairment was positively correlated with the degree of lung function impairment (P < 0.05). CONCLUSION: Task-1 and Task-3 may be involved in the pathogenesis of asthma with OSA by affecting lung function.

The mouse nicotinamide mononucleotide adenylyltransferase chaperones diverse pathological amyloid client proteins.

Molecular chaperones safeguard cellular protein homeostasis and obviate proteotoxicity. In the process of aging, as chaperone networks decline, aberrant protein amyloid aggregation accumulates in a mechanism that underpins neurodegeneration, leading to pathologies such as Alzheimer's disease and Parkinson's disease. Thus, it is important to identify and characterize chaperones for preventing such protein aggregation. In this work, we identified that the NAD+ synthase-nicotinamide mononucleotide adenylyltransferase (NMNAT) 3 from mouse (mN3) exhibits potent chaperone activity to antagonize aggregation of a wide spectrum of pathological amyloid client proteins including α-synuclein, Tau (K19), amyloid ß, and islet amyloid polypeptide. By combining NMR spectroscopy, cross-linking mass spectrometry, and computational modeling, we further reveal that mN3 uses different region of its amphiphilic surface near the active site to directly bind different amyloid client proteins. Our work demonstrates a client recognition mechanism of NMNAT via which it chaperones different amyloid client proteins against pathological aggregation and implies a potential protective role for NMNAT in different amyloid-associated diseases.

Cooperative activated hopping dynamics in binary glass-forming liquids: effects of the size ratio, composition, and interparticle interactions.

Slow dynamics in supercooled and glassy liquids is an important research topic in soft matter physics. Compared to the traditionally focused one-component systems, glassy dynamics in mixture systems adds in a rich set of new complexities, which are fundamentally interesting and also relevant for many technological applications. In this paper, we apply the recently developed self-consistent cooperative hopping theory (SCCHT) to systematically investigate the effects of the size ratio, composition and interparticle interactions on the cooperative activated hopping dynamics of matrix (in larger size) and penetrant (in smaller size) particles in varied binary sphere mixture model systems, with a specific focus on ultrahigh mixture packing fractions that mimic the deeply supercooled glass transition conditions for molecular/polymeric mixture materials. Analysis shows that in these high activation barrier cases, the long-range elastic distortion associated with a matrix particle hopping over its cage confinement always generates an elastic barrier of a nonnegligible magnitude, although the ratio between the elastic barrier and local barrier contribution is sensitively dependent on all three mixture-specific system factors considered in this work. SCCHT predicts two general scenarios of penetrant-matrix cooperative activated hopping dynamics: matrix/penetrant co-hopping (regime 1) or the penetrant mean barrier hopping time shorter than that of the matrix (regime 2). Increasing the penetrant-to-matrix size ratio or the penetrant-matrix cross-attraction strength is found to universally enlarge the composition window of regime 1. Diverse dynamical properties characterising different aspects of the cooperative activated hopping process, including the penetrant and matrix transient localization lengths, penetrant and matrix hopping jump distances, different types of local and elastic activated barriers, and matrix long-time diffusivity, relaxation time and dynamic fragility are quantitatively studied against a wide range of variations over the three system factors. Of particular interest is the universal "anti-plasticization" phenomenon achievable for sufficiently strong cross-attractive interactions. The prospects this work opens for the exploration of a wide variety of polymer-based mixture materials are briefly discussed at the end.

ROS-Sp1 axis is involved in thermochemotherapy-enhanced sensitivity of pancreatic cancer cells to gemcitabine.

Gemcitabine (GEM)-based chemotherapy represents the first choice for locally unresectable advanced pancreatic cancer, while the benefit is limited due to acquired chemoresistance or drug delivery insufficiency. Hyperthermia treatment potentially improves the clinical efficacy of GEM. However, the underlying mechanism is incompletely revealed. Our study aims to investigate the effect and involved mechanism of thermochemotherapy on cell survival. Pancreatic cancer cells PANC-1 and ASPC-1 were either treated with GEM or thermochemotherapy, then cell viability, apoptosis, migration, invasion, reactive oxygen species (ROS) production, and Sp1 expression were evaluated. The results showed that GEM dose and time-dependently affected cell viability, and 30 µM GEM achieved favorable effect in suppressing cancer cell growth. Meanwhile, hyperthermia preconditioning (43°C for 60 min) 24 h before GEM treatment yielded superior effect than other treatment sequence. GEM caused significant cell apoptosis and proapoptotic genes of both cancer cells, and thermochemotherapy further promoted apoptosis and genes transcription, accompanied by excessive ROS production. Thermochemotherapy was superior to GEM in suppressing cell migration and invasion of pancreatic cancer cells. Meanwhile, GEM significantly reduced Sp1 mRNA and protein and its downstream gene Cox-2, and thermochemotherapy further suppressed their expressions. ROS elimination with N-acetyl-l-cysteine notably neutralizes the suppressive effect of GEM and thermochemotherapy on cell growth and expressions of Sp1 and Cox-2. In conclusion, thermochemotherapy inhibited pancreatic cell viability, migration and invasion, and promoted cell apoptosis by inducing excessive ROS production, which subsequently suppressed Sp1 expression and the downstream Cox-2.

Bioinformatics analysis identifies the protective targets of omentin in mice with focal cerebral ischemia injury.

Omentin is known to play a protective role in ischemic stroke. However, its regulatory networks and downstream targets in the pathogenesis of IS are incompletely revealed now. In this study, the model of photochemical brain ischemia was constructed after omentin over-expression. 8 key differentially expressed genes (DEGs) were obtained and analyzed by transcriptome analysis. These DEGs were mainly related to the negative regulation of hormone secretion, cellular phosphate ion homeostasis, and other pathways. Moreover, the mRNA expression of predicted gene 3435 (Gm3435), ankyrin repeat domain 53 (Ankrd53), fibroblast growth factor 23 (Fgf23) and the Fgf23 protein expression were down-regulated after omentin over-expression in HT22 cells injured by oxygen-glucose deprivation (OGD). In conclusion, our findings identified 8 key DEGs regulated by omentin after IS. In vitro models, the Gm3435, Ankrd53, Fgf23 mRNA expression and the Fgf23 protein expression were further verified to consistent with the transcriptomics results.

Spatiotemporal gait parameter fluctuations in older adults affected by mild cognitive impairment: comparisons among three cognitive dual-task tests.

BACKGROUNDS: Gait disorder is associated with cognitive functional impairment, and this disturbance is more pronouncedly when performing additional cognitive tasks. Our study aimed to characterize gait disorders in mild cognitive impairment (MCI) under three dual tasks and determine the association between gait performance and cognitive function. METHODS: A total of 260 participants were enrolled in this cross-sectional study and divided into MCI and cognitively normal control. Spatiotemporal and kinematic gait parameters (31 items) in single task and three dual tasks (serial 100-7, naming animals and words recall) were measured using a wearable sensor. Baseline characteristics of the two groups were balanced using propensity score matching. Important gait features were filtered using random forest method and LASSO regression and further described using logistic analysis. RESULTS: After matching, 106 participants with MCI and 106 normal controls were recruited. Top 5 gait features in random forest and 4 ~ 6 important features in LASSO regression were selected. Robust variables associating with cognitive function were temporal gait parameters. Participants with MCI exhibited decreased swing time and terminal swing, increased mid stance and variability of stride length compared with normal control. Subjects walked slower when performing an extra dual cognitive task. In the three dual tasks, words recall test exhibited more pronounced impact on gait regularity, velocity, and dual task cost than the other two cognitive tests. CONCLUSION: Gait assessment under dual task conditions, particularly in words recall test, using portable sensors could be useful as a complementary strategy for early detection of MCI.

Totally-green cellulosic fiber with prominent sustained antibacterial and antiviral properties for potential use in spunlaced non-woven fabric production.

The worldwide spread of COVID-19 has put a higher requirement for personal medical protective clothing, developing protective clothing with sustained antibacterial and antiviral performance is the priority for safe and sustaining application. For this purpose, we develop a novel cellulose based material with sustained antibacterial and antiviral properties. In the proposed method, the chitosan oligosaccharide (COS) was subjected to a guanylation reaction with dicyandiamide in the presence of Scandium (III) triflate; because of the relatively lower molecular weight and water solubility of the COS, GCOS (guanylated chitosan oligosaccharide) with high substitution degree (DS) could be successfully synthetized without acid application. In this instance, the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of the GCOS were only 1/8 and 1/4 of that of COS. The introduction of GCOS onto the fiber endowed the fiber with extremely high antibacterial and antiviral performance, showing 100% bacteriostatic rate against Staphylococcus aureus and Escherichia coli and 99.48% virus load reduction of bacteriophage MS2. More importantly, the GCOS modified cellulosic fibers (GCOS-CFs) exhibit excellent sustained antibacterial and antiviral properties; namely, 30 washing cycles had negligible effect on the bacteriostatic rate (100%) and inhibition rate of bacteriophage MS2 (99.0%). Moreover, the paper prepared from the GCOS-CFs still exhibited prominent antibacterial and antiviral activity; inferring that the sheeting forming, press, and drying process have almost no effect on the antibacterial and antiviral performances. The insensitive of antibacterial and antiviral activity to water washing (spunlace) and heat (drying) make the GCOS-CFs a potential material applicable in the spunlaced non-woven fabric production.

The Utility of the Ultrasound "Superimposed-Line" Sign at the Junction of the Vomer and Maxilla in First-Trimester Screening for Fetal Cleft Palate: A Case-Control Study.

INTRODUCTION: The current retrospective case-control study evaluates the diagnostic value of screening for a fetal cleft palate by using the ultra-sound-based observation of the "superimposed-line" sign appearing at the junction of the vomer and maxilla in the first trimester of pregnancy. METHODS: Retrospective analyses were performed of ultrasonographic images of nuchal translucency obtained during the first trimester of pregnancy (11-13+6 weeks) from 45 fetuses with a cleft palate later confirmed following parturition or induced labor (cases) and 4,500 normal fetuses confirmed after parturition (controls). Ultrasonographic features of the "superimposed-line" sign were observed and recorded, and between-group comparisons were performed. RESULTS: The "superimposed-line" sign was absent in 39 cases (86.67%), including 4 (8.89%) with simple secondary hard palate cleft and 35 (77.78%) with secondary hard palate cleft complicated by a primary cleft palate. The "superimposed-line" sign was shown in 6 cases (13.33%), including 2 (4.44%) with a simple secondary soft palate cleft, 1 (2.22%) with a simple secondary bifid uvula, and 3 (6.67%) with a simple primary cleft palate. Among the 4,500 controls, 31 fetuses showed an absence of the "superimposed-line" sign (0.69%) and 4,469 showed the "superimposed-line" sign (99.31%). The between-group difference was significant (p < 0.05). The sensitivity, specificity, positive predictive value, and negative predictive values of the "superimposed-line" sign in the first trimester of pregnancy for predicting fetal cleft palate were 86.67% (39/45), 99.31% (4,469/4,500), 55.71% (39/70), and 99.86% (4,469/4,475), respectively. CONCLUSION: The "superimposed-line" sign did not appear in fetuses with secondary hard palate cleft and primary cleft palate only when a secondary hard palate cleft is present. The sign appeared in normal fetuses and those with a simple primary cleft palate, simple secondary soft palate cleft, or a simple secondary bifid uvula. Based on these results, we propose that the "superimposed-line" sign in the mid-sagittal plane of the fetal face in the first trimester of pregnancy (11-13+6 weeks) is an important tool in screening for fetal cleft palate, especially secondary hard palate cleft.

Balancing Accuracy and Speed in Gaze-Touch Grid Menu Selection in AR via Mapping Sub-Menus to a Hand-Held Device.

Eye gaze can be a potentially fast and ergonomic method for target selection in augmented reality (AR). However, the eye-tracking accuracy of current consumer-level AR systems is limited. While state-of-the-art AR target selection techniques based on eye gaze and touch (gaze-touch), which follow the "eye gaze pre-selects, touch refines and confirms" mechanism, can significantly enhance selection accuracy, their selection speeds are usually compromised. To balance accuracy and speed in gaze-touch grid menu selection in AR, we propose the Hand-Held Sub-Menu (HHSM) technique.tou HHSM divides a grid menu into several sub-menus and maps the sub-menu pointed to by eye gaze onto the touchscreen of a hand-held device. To select a target item, the user first selects the sub-menu containing it via eye gaze and then confirms the selection on the touchscreen via a single touch action. We derived the HHSM technique's design space and investigated it through a series of empirical studies. Through an empirical study involving 24 participants recruited from a local university, we found that HHSM can effectively balance accuracy and speed in gaze-touch grid menu selection in AR. The error rate was approximately 2%, and the completion time per selection was around 0.93 s when participants used two thumbs to interact with the touchscreen, and approximately 1.1 s when they used only one finger.

Analysis of CircRNA Expression in Peripheral Blood of Holstein Cows in Response to Heat Stress.

The present study aimed to identify key circRNAs and pathways associated with heat stress in blood samples of Holstein cows, which will provide new insights into the molecular mechanisms driving heat stress in cows. Hence, we evaluated changes in milk yield, rectal temperature, and respiratory rate of experimental cows between heat stress (summer) and non-heat stress (spring) conditions with two comparisons, including Sum1 vs. Spr1 (same lactation stage, different individuals, 15 cows per group) and Sum1 vs. Spr2 (same individual, different lactation stages, 15 cows per group). Compared to both Spr1 and Spr2, cows in the Sum1 group had a significantly lower milk yield, while rectal temperature and respiratory rate were significantly higher (p < 0.05), indicating that cows in the Sum1 group were experiencing heat stress. In each group, five animals were chosen randomly to undergo RNA-seq. The results reveal that 140 and 205 differentially expressed (DE) circRNAs were screened in the first and second comparisons, respectively. According to the gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, these DE circRNAs were mainly enriched in five signaling pathways, including choline metabolism, the PI3K/AKT signaling pathway, the HIF-1 signaling pathway, the longevity-regulating pathway, and autophagy. Then, we obtained the top 10 hub source genes of circRNAs according to the protein-protein interaction networks. Among them, ciRNA1282 (HIF1A), circRNA4205 (NR3C1), and circRNA12923 (ROCK1) were enriched in multiple pathways and identified as binding multiple miRNAs. These key circRNAs may play an important role in the heat stress responses of dairy cows. These results provide valuable information on the involvement of key circRNAs and their expression pattern in the heat stress response of cows.

Dementia increases the risk of death in stroke patients: A retrospective cohort-based risk score model study.

BACKGROUND: The relationship between dementia and the mortality of stroke is a significant concern for patients and careers. However, there are few research about it in China and a lack of reliable data on the risk of dementia. We aim to analyze and compare the risk of death in stroke patients with and without dementia. Further investigation into the predictive value of dementia for stroke death. METHODS: All patients with stroke who were identified among residents of Ningxia, between January 1, 2014 to December 31, 2021, set death or May 22, 2022 as the observation endpoint. All patients were screened by 1:4 propensity score matching (PSM). The association between dementia and all-cause mortality was evaluated using Cox regression with survival time. Evaluation of the predictive value of dementia using decision curve analysis (DCA) and clinical impact curve (CIC) curves. RESULT: Mortality of stroke with dementia is 45.4% and without dementia is 13.8%, further calculated one-year mortality is higher in the patients with dementia than without dementia (17.3%vs. 5.4%, p < 0.001). Stroke patients with dementia had a 3.74 times higher risk of death (95% CI = 3.29,4.26) and had a shorter survival time than those without dementia. Dementia was an independent predictor of death in all models (hazard ratio [HR]=3.77,95%CI: 3.31-4.30, p < 0.001). DCA and CIC curves indicated that dementia has a high value in predicting the risk of death in stroke patients. CONCLUSION: Dementia is an independent risk factor for death and reduces survival time in stroke patients.

Structural basis of the interplay between α-synuclein and Tau in regulating pathological amyloid aggregation.

Amyloid aggregation of pathological proteins is closely associated with a variety of neurodegenerative diseases, and α-synuclein (α-syn) deposition and Tau tangles are considered hallmarks of Parkinson's disease and Alzheimer's disease, respectively. Intriguingly, α-syn and Tau have been found to co-deposit in the brains of individuals with dementia and parkinsonism, suggesting a potential role of cross-talk between these two proteins in neurodegenerative pathologies. Here we show that monomeric α-syn and the two variants of Tau, Tau23 and K19, synergistically promote amyloid fibrillation, leading to their co-aggregation in vitro NMR spectroscopy experiments revealed that α-syn uses its highly negatively charged C terminus to directly interact with Tau23 and K19. Deletion of the C terminus effectively abolished its binding to Tau23 and K19 as well as its synergistic effect on promoting their fibrillation. Moreover, an S129D substitution of α-syn, mimicking C-terminal phosphorylation of Ser129 in α-syn, which is commonly observed in the brains of Parkinson's disease patients with elevated α-syn phosphorylation levels, significantly enhanced the activity of α-syn in facilitating Tau23 and K19 aggregation. These results reveal the molecular basis underlying the direct interaction between α-syn and Tau. We proposed that this interplay might contribute to pathological aggregation of α-syn and Tau in neurodegenerative diseases.

Chicoric acid attenuates hyperglycemia-induced endothelial dysfunction through AMPK-dependent inhibition of oxidative/nitrative stresses.

BACKGROUND: Endothelial dysfunction is a driving force during the development and progression of cardiovascular complications in diabetes. Targeting endothelial injury may be an attractive avenue for the management of diabetic vascular disorders. Chicoric acid is reported to confer antioxidant and anti-inflammatory properties in various diseases including diabetes. However, the role and mechanism of chicoric acid in hyperglycemia-induced endothelial damage are not well understood. METHODS: In the present study, human umbilical vein endothelial cells (HUVECs) were incubated with high glucose/high fat (HG + HF) to induce endothelial cell injury. RESULTS: We found that exposure of HUVECs to HG + HF medium promoted the release of cytochrome c (cytc) from mitochondrion into the cytoplasm, stimulated the cleavage of caspase-3 and poly ADP-ribose-polymerase (PARP), then inducing cell apoptosis, the effects that were prevented by administration of chicoric acid. Besides, we found that chicoric acid diminished HG + HF-induced phosphorylation and degradation of IκBα, and subsequent p65 NFκB nuclear translocation, thereby contributing to its anti-inflammatory effects in HUVECs. We also confirmed that chicoric acid mitigated oxidative/nitrative stresses under HG + HF conditions. Studies aimed at exploring the underlying mechanisms found that chicoric acid activated the AMP-activated protein kinase (AMPK) signaling pathway to attenuate HG + HF-triggered injury in HUVECs as AMPK inhibitor Compound C or silencing of AMPKα1 abolished the beneficial effects of chicoric acid in HUVECs. CONCLUSION: Collectively, chicoric acid is likely protected against diabetes-induced endothelial dysfunction by activation of the AMPK signaling pathway. Chicoric acid could be a novel candidate for the treatment of the diabetes-associated vascular endothelial injury.

Fighting Food Allergy by Inducing Oral Tolerance: Facts and Fiction.

The prevalence of food allergy (FA) is increasing, and there is an urgent need to take effective measures against it. One important measure is the avoidance diet, which shows a disadvantage, especially in case of accidental exposure. Oral tolerance restoration sheds new light on the control of FA. Oral tolerance is naturally a state of systemic unresponsiveness of the gastrointestinal tract to food antigens and its restoration can be a clinical therapy for FA. Its immune basis lies on the intestinal mucosal immune system and factors, such as gut microbiota and food processing methods, are also important. This review presents recent advances in oral tolerance and its closely related factors.

The functional impairment of different subtypes and occupational states in euthymic patients with bipolar disorder.

BACKGROUND: The aim was to explore the associations between clinical symptoms, demographic variables, social and neurocognitive functioning in euthymic patients with bipolar disorder (BD) stratified by subgroups of DSM-IV BD (type I (BD-I) and type II (BD-II)) and occupational status (employed/unemployed), and to highlight the significance of occupational status when assessing social and neurocognitive functioning in euthymic BD patients. METHODS: A total of 81 euthymic BD patients were participated in the study. The severity of the depressive and manic/hypomanic symptoms was measured using the 17-item Hamilton Depression Rating Scale (HDRS-17) and the Young Mania Rating Scale (YMRS), respectively. Social functioning and neurocognitive functioning were evaluated by the Functioning Assessment Short Test (FAST) and neurocognitive measures, respectively. RESULTS: Employed BD patients displayed greater social functioning (autonomy, occupational functioning, interpersonal relationship domain) and better verbal learning performance and speed of processing than unemployed BD patients. The correlation between neurocognitive functioning and social functioning was stronger in the employed group than in the unemployed group. There were no significant differences in neurocognitive and social functioning between the BD-I and BD-II groups, and the correlation between neurocognitive functioning and social functioning was similar between the BD-I and BD-II groups. CONCLUSION: Employed BD patients may present greater occupational functioning and interpersonal relationships, as well as better verbal learning performance and speed of processing.

The Impact of Integrin ß2 on Granulocyte/Macrophage Progenitor Proliferation.

Previously, we reported that although the HSPC frequency in bone marrow cells (BMC) was comparable between ß2-/- and ß2+/+ mice, transplantation of ß2-/- BMC into lethally irradiated CD45.1 recipient resulted in more myeloid cell production than ß2+/+ BMC. The objective of this study is to address if integrin ß2 deficiency skews granulocyte/macrophage progenitor (GMP) proliferation. FACS analysis demonstrated that GMP frequency and cell number were higher and megakaryocyte/erythrocyte progenitor frequency and cell number were lower in ß2-/- mice than ß2+/+ mice. However, the common myeloid progenitors (CMP) frequency and cell number were similar between the two groups. The increased GMP number was due to GMP proliferation as evidenced by the percentage of BrdU-incorporating GMP. Whole genome transcriptome analysis identified increased FcεRIα expression in ß2-/- CMP compared to ß2+/+ CMP. FcεRIα expression on ß2-/- GMP was detected increased in ß2-/- mice by qRT-PCR and FACS. Although transplantation of FcεRIαhi GMP or FcεRIαlo GMP into lethally irradiated CD45.1 recipient resulted in comparable myeloid cell production, transplantation of ß2 deficient FcεRIαhi GMP generated more myeloid cells than ß2+/+ FcεRIαhi GMP. GATA2 expression was increased in ß2-/- GMP. Using a luciferase reporter assay, we demonstrated that mutation of the GATA2 binding site in the FcεRIα promoter region diminished FcεRIα transcription. In vitro, the addition of IgE, the ligand of FcεRIα, promoted GMP expansion, which was abrogated by inhibition of JNK phosphorylation. Integrin ß2 deficiency promoted GMP proliferation and myeloid cell production, which was mediated via FcεRIα/IgE-induced JNK phosphorylation in GMP. Stem Cells 2019;37:430-440.

Identification of genomic alterations in oesophageal squamous cell cancer.

Oesophageal cancer is one of the most aggressive cancers and is the sixth leading cause of cancer death worldwide. Approximately 70% of global oesophageal cancer cases occur in China, with oesophageal squamous cell carcinoma (ESCC) being the histopathological form in the vast majority of cases (>90%). Currently, there are limited clinical approaches for the early diagnosis and treatment of ESCC, resulting in a 10% five-year survival rate for patients. However, the full repertoire of genomic events leading to the pathogenesis of ESCC remains unclear. Here we describe a comprehensive genomic analysis of 158 ESCC cases, as part of the International Cancer Genome Consortium research project. We conducted whole-genome sequencing in 17 ESCC cases and whole-exome sequencing in 71 cases, of which 53 cases, plus an additional 70 ESCC cases not used in the whole-genome and whole-exome sequencing, were subjected to array comparative genomic hybridization analysis. We identified eight significantly mutated genes, of which six are well known tumour-associated genes (TP53, RB1, CDKN2A, PIK3CA, NOTCH1, NFE2L2), and two have not previously been described in ESCC (ADAM29 and FAM135B). Notably, FAM135B is identified as a novel cancer-implicated gene as assayed for its ability to promote malignancy of ESCC cells. Additionally, MIR548K, a microRNA encoded in the amplified 11q13.3-13.4 region, is characterized as a novel oncogene, and functional assays demonstrate that MIR548K enhances malignant phenotypes of ESCC cells. Moreover, we have found that several important histone regulator genes (MLL2 (also called KMT2D), ASH1L, MLL3 (KMT2C), SETD1B, CREBBP and EP300) are frequently altered in ESCC. Pathway assessment reveals that somatic aberrations are mainly involved in the Wnt, cell cycle and Notch pathways. Genomic analyses suggest that ESCC and head and neck squamous cell carcinoma share some common pathogenic mechanisms, and ESCC development is associated with alcohol drinking. This study has explored novel biological markers and tumorigenic pathways that would greatly improve therapeutic strategies for ESCC.

GEN-27 exhibits anti-inflammatory effects by suppressing the activation of NLRP3 inflammasome and NF-κB pathway.

Prolonged inflammation and deregulated cytokine production are associated with diversified inflammatory diseases. Genistein (GEN), the active and predominant isoflavonoid in dietary soybean, possesses anti-inflammatory activity. Our study aimed to assess the anti-inflammatory effects of GEN-27, a derivative of GEN, as well as explore the potential molecular mechanisms using lipopolysaccharide (LPS)-induced RAW264.7 cells. In our study, we demonstrated that GEN-27 administration (1, 5, or 10 µM) dose-dependently inhibited nitrite and nitric oxide (NO) levels in LPS-stimulated RAW264.7 cells. Also, GEN-27 suppressed the release of LPS-induced pro-inflammatory cytokines including tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), IL-6, and IL-18. Moreover, GEN-27 attenuated LPS-induced inducible NO synthase (iNOS), and cyclooxygenase-2 (COX-2) expressions at messenger RNA and protein levels, and reversed the promoter activity of iNOS in RAW264.7 cells. Mechanistically, GEN-27 abated LPS-induced reactive oxygen species production, as well as mitigated LPS-induced increase of caspase 1 activity and the protein levels of NOD-like receptor 3 (NLRP3), anti-apoptosis-associated speck-like protein-containing a CRAD (ASC), and caspase 1 in RAW264.7 cells in a dose-dependent manner. Similarly, GEN-27 dose-dependently weakened adenosine triphosphate-induced NLRP3 and IL-1ß in RAW264.7 cells. In addition, GEN-27 treatment significantly suppressed LPS-induced phosphorylation of nuclear factor-κB (NF-κB) p65 and alleviated LPS-induced increase of transcriptional activity of NF-κB in RAW264.7 cells. In summary, these results revealed that GEN-27 exhibited anti-inflammatory effects by suppressing the activation of NLRP3 inflammasome and NF-κB pathway, suggesting that GEN-27 may be served as a promising therapeutic agent for the prevention and therapy of inflammatory-associated diseases.

The Association Between Child Abuse and Emotional and Behavioral Problems in Chinese School-Aged Boys With Attention Deficit Hyperactivity Disorder.

The aim of our study was to investigate the relationship between child abuse and emotional and behavioral problems in Chinese school-aged boys with attention deficit hyperactivity disorder (ADHD). Forty-eight school-aged boys with ADHD and 77 male healthy controls completed the final assessments that included the Child Behavior Checklist, the Barratt Impulsiveness Scale Version 11, the Screen for Child Anxiety Related Disorders, the Depression Self-Rating Scale for Children, and the Childhood Trauma Questionnaire, Short Form. Our findings showed that child abuse could associate with the behavioral problems in ADHD. Regression analysis further showed that child abuse (especially emotional abuse and physical abuse), adverse living conditions, and school anxiety significantly could be contributors to behavioral problems in boys with ADHD. Our study indicated that child abuse may be associated with the behavioral problems in Chinese school-aged boys with ADHD.

Zea mays Fe deficiency-related 4 (ZmFDR4) functions as an iron transporter in the plastids of monocots.

Iron (Fe)-homeostasis in the plastids is closely associated with Fe transport proteins that prevent Fe from occurring in its toxic free ionic forms. However, the number of known protein families related to Fe transport in the plastids (about five) and the function of iron in non-green plastids is limited. In the present study, we report the functional characterization of Zea mays Fe deficiency-related 4 (ZmFDR4), which was isolated from a differentially expressed clone of a cDNA library of Fe deficiency-induced maize roots. ZmFDR4 is homologous to the bacterial FliP superfamily, coexisted in both algae and terrestrial plants, and capable of restoring the normal growth of the yeast mutant fet3fet4, which possesses defective Fe uptake systems. ZmFDR4 mRNA is ubiquitous in maize and is inducible by iron deficiency in wheat. Transient expression of the 35S:ZmFDR4-eGFP fusion protein in rice protoplasts indicated that ZmFDR4 maybe localizes to the plastids envelope and thylakoid. In 35S:c-Myc-ZmFDR4 transgenic tobacco, immunohistochemistry and immunoblotting confirmed that ZmFDR4 is targeted to both the chloroplast envelope and thylakoid. Meanwhile, ultrastructure analysis indicates that ZmFDR4 promotes the density of plastids and accumulation of starch grains. Moreover, Bathophenanthroline disulfonate (BPDS) colorimetry and inductively coupled plasma mass spectrometry (ICP-MS) indicate that ZmFDR4 is related to Fe uptake by plastids and increases seed Fe content. Finally, 35S:c-Myc-ZmFDR4 transgenic tobacco show enhanced photosynthetic efficiency. Therefore, the results of the present study demonstrate that ZmFDR4 functions as an iron transporter in monocot plastids and provide insight into the process of Fe uptake by plastids.