Nonlinear strict distance and similarity measures for intuitionistic fuzzy sets with applications to pattern classification and medical diagnosis.

In this paper, we propose a new type of nonlinear strict distance and similarity measures for intuitionistic fuzzy sets (IFSs). Our proposed methods not only have good properties, but also improve the drawbacks proposed by Mahanta and Panda (Int J Intell Syst 36(2):615-627, 2021) in which, for example, their distance value of [Formula: see text] is always equal to the maximum value 1 for any intuitionistic fuzzy number [Formula: see text]. To resolve these problems in Mahanta and Panda (Int J Intell Syst 36(2):615-627, 2021), we establish a nonlinear parametric distance measure for IFSs and prove that it satisfies the axiomatic definition of strict intuitionistic fuzzy distances and preserves all advantages of distance measures. In particular, our proposed distance measure can effectively distinguish different IFSs with high hesitancy. Meanwhile, we obtain that the dual similarity measure and the induced entropy of our proposed distance measure satisfy the axiomatic definitions of strict intuitionistic fuzzy similarity measure and intuitionistic fuzzy entropy. Finally, we apply our proposed distance and similarity measures to pattern classification, decision making on the choice of a proper antivirus face mask for COVID-19, and medical diagnosis problems, to illustrate the effectiveness of the new methods.

Discovery of ecnoglutide - A novel, long-acting, cAMP-biased glucagon-like peptide-1 (GLP-1) analog.

OBJECTIVE: Glucagon-like peptide (GLP)-1 is an incretin hormone that acts after food intake to stimulate insulin production, enhance satiety, and promote weight loss. Here we describe the discovery and characterization of ecnoglutide (XW003), a novel GLP-1 analog. METHODS: We engineered a series of GLP-1 peptide analogs with an alanine to valine substitution (Ala8Val) and a γGlu-2xAEEA linked C18 diacid fatty acid at various positions. Ecnoglutide was selected and characterized in GLP-1 receptor signaling assays in vitro, as well as in db/db mice and a diet induced obese (DIO) rat model. A Phase 1, double-blind, randomized, placebo-controlled, single (SAD) and multiple ascending dose (MAD) study was conducted to evaluate the safety, tolerability, and pharmacokinetics of subcutaneous ecnoglutide injection in healthy participants. SAD doses ranged from 0.03 to 1.0 mg; MAD doses ranged from 0.2 to 0.6 mg once weekly for 6 weeks (ClinicalTrials.gov Identifier: NCT04389775). RESULTS: In vitro, ecnoglutide potently induced cAMP (EC50 = 0.018 nM) but not GLP-1 receptor internalization (EC50 > 10 µM), suggesting a desirable signaling bias. In rodent models, ecnoglutide significantly reduced blood glucose, promoted insulin induction, and led to more pronounced body weight reduction compared to semaglutide. In a Phase 1 trial, ecnoglutide was generally safe and well tolerated as a once-weekly injection for up to 6 weeks. Adverse events included decreased appetite, nausea, and headache. The half-life at steady state ranged from 124 to 138 h, supporting once-weekly dosing. CONCLUSIONS: Ecnoglutide showed a favorable potency, pharmacokinetic, and tolerability profile, as well as a simplified manufacturing process. These results support the continued development of ecnoglutide for the treatment of type 2 diabetes and obesity.

Enhancing dentin bonding quality through Acetone wet-bonding technique: a promising approach.

Objective: This paper aimed to assess the impact of the acetone wet-bonding (AWB) technique on dentin bonding and to investigate its potential underlying mechanisms. Materials and Methods: Caries-free third molars were sliced, ground, etched, water-rinsed. Then the specimens were randomly allocated to four groups according to the following pretreatments: 1. water wet-bonding (WWB); 2. ethanol wet-bonding (EWB); 3. 50% (v/v) acetone aqueous solution (50%AWB); 4. 100% acetone solution (AWB). Singlebond universal adhesive was then applied and composite buildups were constructed. The microtensile bond strength (MTBS), failure modes and interface nanoleakage were respectively evaluated after 24 h of water storage, 10,000 times of thermocycling or 1-month collagenase ageing. In situ zymography and contact angle were also investigated. Results: Acetone pretreatment preserved MTBS after thermocycling or collagenase ageing (p < 0.05) without affecting the immediate MTBS (p > 0.05). Furthermore, AWB group manifested fewer nanoleakage than WWB group. More importantly, the contact angle of the dentin surfaces decreased significantly and collagenolytic activities within the hybrid layer were suppressed in AWB group. Conclusion: This study suggested that the AWB technique was effective in enhancing the dentin bond durability by increasing the wettability of dentin surface to dental adhesives, removing residual water in the hybrid layer, improving the penetration of adhesive monomer, and inhibiting the collagenolytic activities. Clinical significance: The lifespan of adhesive restorations would be increased by utilization of acetone wet-bonding technique.

Longitudinal associations between multiple mental health problems and suicidal ideation among university students during the COVID-19 pandemic.

BACKGROUND: Recent research suggested that COVID-19-related multiple mental health problems were associated with an increased risk for suicidal ideations (SIs), but population-based data demonstrating these associations are scarce. This study aimed to estimate the cumulative effects of psychological risk factors on SIs during the outbreak and remission periods of COVID-19 using a cumulative risk model, as well as sex differences. METHODS: A total of 68,685 college students in China participated in the survey during two phases of the pandemic (T1 and T2). Mental health risks (acute stress, depression, anxiety, insomnia, and obsessive-compulsive symptoms) and sociodemographic characteristics were measured at T1, and SIs were assessed at T1 and T2. Hierarchical regression analysis was used to determine the combined effect of multiple mental health problems on SIs at T1 and T2. RESULTS: The prevalence of SIs increased from the early periods of the COVID-19 pandemic (7.6%) to the later periods (10.0%). Depression was a powerful risk factor for SIs during the COVID-19 pandemic. Individuals with >3 mental risks would be most likely to experience rapidly increasing SIs during the early periods of the COVID-19 pandemic. Sex exerted different effects on the cumulative risk model of SIs. CONCLUSIONS: Interventions, such as mental health education and improving utilization of student support services, should be implemented. There is a crucial need for early intervention and prevention efforts aimed at males with greater than three mental health problems.

Who is the hardest to wake up from sleep? An investigation of self-reported sleep inertia using a latent profile analysis.

Few studies have assessed the overall nature and profiles of subjective sleep inertia (SI) within the general population. This study was designed to identify subjective SI profiles and examine the associations between profiles of subjective SI with sociodemographic and sleep-related characteristics. A total of 11 colleges and universities were surveyed from May 30 to June 17, 2021, by convenience sampling. A total of 1,240 participants provided usable data regarding sociodemographic information, Sleep Inertia Questionnaire, and sleep-related characteristics via an online platform. Latent profile analysis was utilised to identify profiles of SI. Multinomial logistic regression was further performed to examine the predisposing factors of profiles of SI. Four profiles of SI were identified: (1) "Low SI", 20%; (2) "Mild SI", 31%; (3) "Moderate SI", 33%; and (4) "Severe SI", 16%. Compared to a Low SI profile, younger, individuals with an evening chronotype, and individuals who had <6 h sleep/night, experienced poor sleep quality, and moderate-to-severe sleep disturbance were at increased risk of experiencing severe SI. Individuals with more languid types tended to show more severe SI, while individuals reporting greater flexibility experienced less SI. This study is the first effort to examine the profiles of subjective SI using latent profile analysis and identified four profiles of SI in the general population. This effort may contribute to a greater understanding of SI, including the development of a screening tool and interventions to reduce SI.

An online participatory system for SWMM-based flood modeling and simulation.

In the context of the continuous development of urbanization and global climate change, urban flooding risk has become a well-publicized research issue. The Storm Water Management Model (SWMM) performs very well in urban rain-runoff simulations and is widely used to build flood models in specific areas. Because of the complicated and tedious processing work for urban flood modeling and simulation, multifield participants' cooperation is becoming a trend. To promote the research and application of flood modeling and simulation, some resource sharing-oriented systems and platforms have been proposed with the advantages of network technology. However, they still require a participatory environment that can help modeling participants overcome the difficulties of distributed cooperation in the process of SWMM-based flood modeling and simulation. Therefore, we designed and implemented an online participatory system to coordinate the effective collaboration of modeling participants in this process. By referring to the scenarios and specific participatory demands in the modeling process, the system provides a guiding framework that consists of multiple participatory activities and prepares a series of online auxiliary tools designed for these activities. Using the main urban area of Lishui City as the study area, it was confirmed that the process of SWMM-based flood modeling and simulation can be demonstrated collaboratively on the online participatory system developed in this study.

Synaptic protein interaction networks encode experience by assuming stimulus-specific and brain-region-specific states.

A core network of widely expressed proteins within the glutamatergic post-synapse mediates activity-dependent synaptic plasticity throughout the brain, but the specific proteomic composition of synapses differs between brain regions. Here, we address the question, how does proteomic composition affect activity-dependent protein-protein interaction networks (PINs) downstream of synaptic activity? Using quantitative multiplex co-immunoprecipitation, we compare the PIN response of in vivo or ex vivo neurons derived from different brain regions to activation by different agonists or different forms of eyeblink conditioning. We report that PINs discriminate between incoming stimuli using differential kinetics of overlapping and non-overlapping PIN parameters. Further, these "molecular logic rules" differ by brain region. We conclude that although the PIN of the glutamatergic post-synapse is expressed widely throughout the brain, its activity-dependent dynamics show remarkable stimulus-specific and brain-region-specific diversity. This diversity may help explain the challenges in developing molecule-specific drug therapies for neurological disorders.

Sleep disturbance predicts suicidal ideation during COVID-19 pandemic: A two-wave longitudinal survey.

BACKGROUND: This study aimed to examine the cross-sectional and longitudinal associations between sleep disturbance and suicidal ideation (SI) in a large cohort of adolescents experiencing the Coronavirus disease 2019 (COVID-19) crisis in China. METHODS: One two-wave longitudinal web-based survey of sleep, SI, and depression was conducted among 67,905 college students (mean age = 20.23 years, SD = 1.63 years; 31.3% male) during the COVID-19 outbreak (Time1, T1: Feb 3rd to 10th, 2020) and initial remission period (Time2, T2: March 24th to April 3rd, 2020). RESULTS: At T1 and T2, 8.5% and 9.7% of students reported sleep disturbance, 7.6% and 10.0% reported SI, respectively. The prevalence rates of SI at T1 and T2 increased significantly with sleep disturbance and short sleep duration. After adjusting for demographics, pandemic related factors, and depression at T1, sleep disturbance and short sleep duration at T1 were significantly associated with increased risk for SI at T2. Furthermore, sleep disturbance and short sleep duration predicted the new onset and persistence of SI. CONCLUSION: These findings suggested that sleep disturbance predicts the development and persistence of SI. Early assessment and treatment of sleep disturbance may be an important strategy for prevention and intervention of SI in individuals after exposure to the special public health emergency of COVID-19.

Psychological impact on COVID-19 patients during the outbreak in China: A case-control study.

BACKGROUND: The coronavirus disease 2019 (COVID-19) has caused widespread panic due to its highly infectious and pandemic transmission. We aimed to evaluate the psychological impact of the COVID-19 outbreak on infected subjects in China. METHODS: This case-control, survey-based study assessed the psychological status of COVID-19 patients and non-infected controls from February 10 to March 18, 2020, in China. Sex, age, education years, marital status, jobs, annual household income, living status, and geographic origin were matched between the two groups. The main outcome measures included anxiety, depression, insomnia, help-seeking behaviors, and treatment for mental problems. RESULTS: A total of 326 patients and 1304 (1:4 ratio) matched non-infected controls were enrolled. Compared with controls, patients had higher scores on the Beck Anxiety Inventory (BAI), Patient Health Questionnaire-9 (PHQ-9), and Insomnia Severity Index (ISI) (all p<0.01). Patients had higher rate of any mental problems (62.6% vs 42.5%, p<0.01), anxiety (27.3% vs 12.2%, p<0.01), depression (26.7% vs 14.6%, p<0.01), suicidal ideation (16.0% vs 10.7%, p<0.01), and insomnia (57.7% vs 36.7%, p<0.01). Among the subjects with mental problems, the proportion of seeking help (15.2% vs 6.9%, p<0.01) and receiving treatment (11.3% vs 4.3%, p<0.01) was higher in patients than controls. CONCLUSIONS: Our study showed a higher prevalence of mental problems in COVID-19 patients compared to controls, suggesting a great psychological impact of COVID-19 infection. Our findings highlighted the urgent need for psychological assistance for COVID-19 patients.

Preparation and Characterization of Instant Casein Phosphopeptide by Supercritical Fluid Assisted Atomization.

Casein phosphopeptide (CPP) has been widely used as micronutrient supplementation for certain populations. However, its solubility performance is far from satisfying. In this work, instant CPP powders with micropore structures were fabricated by supercritical fluid-assisted atomization (SAA) using supercritical CO2 fluid (SC-CO2) as an atomizing agent. The effects of the processing parameters (temperature, time, and pressure) on SC-CO2 absorption rate and dissolution rate were systematically evaluated and studied. The viscosity of the CPP solution increased with increased pressure of SC-CO2 as pressure increased its solubility. The processing conditions are optimized as follows: 40 °C, 40 min, and 8.27 MPa, with an SC-CO2 absorption rate of about 8 wt.%. The dissolution time of the SAA-CPP powders was significantly decreased from 1800 s to 54 s at room temperature, due to the micropore structures and almost 10 times increase in the specific surface area of SAA-CPP. The bioactivities of the instant SAA-CPP, especially the calcium-binding capacity, were also evaluated and showed no observable difference. Among the four CPPs prepared in different ways in this work, SAA-CPP had better dissolution performance. The results show that SAA technology is a promising way to prepare instant polypeptide powders.

Insomnia and other sleep-related problems during the remission period of the COVID-19 pandemic: A large-scale survey among college students in China.

This study aimed to evaluate the sleep-related problems and predictors of probable clinical insomnia among college students during the COVID-19 remission period in China. 146,102 college students from 22 colleges/universities in Guangdong province participated in this study from 1th to 15th June, 2020. Self-administered questionnaires were used to assess demographic characteristics. Sleep-related problems, depression and anxiety symptoms were measured by Youth Self-Rating Insomnia Scale, Patient Health Questionnaire-9 and Generalized Anxiety Disorder Scale-7, respectively. The prevalence of difficulty in initiating sleep, difficulty in maintaining sleep, early morning awakening, sleep insufficiency, unrefreshing sleep and daytime functioning impairment were 7.2%, 3.4%, 3.5%, 9.6%, 14.6%, and 7.6%, respectively. 16.9% students had varying degrees of insomnia and 6.3% were considered as displaying probable clinical insomnia. Moreover, being urban residents, having a history of physical or mental illness, and probable clinical depression or anxiety were significant risk factors of probable clinical insomnia, while college senior degree and 7-8 hours' sleep duration per day was the protective factor for probable clinical insomnia. Unrefreshing sleep was the most prominent sleep problem among college students during COVID-19 remission in China. Good sleep hygiene practices are strongly suggested to develop in the time of prolonged home isolation.

Geographic modeling and simulation systems for geographic research in the new era: Some thoughts on their development and construction.

Regionality, comprehensiveness, and complexity are regarded as the basic characteristics of geography. The exploration of their core connotations is an essential way to achieve breakthroughs in geography in the new era. This paper focuses on the important method in geographic research: Geographic modeling and simulation. First, we clarify the research requirements of the said three characteristics of geography and its potential to address geo-problems in the new era. Then, the supporting capabilities of the existing geographic modeling and simulation systems for geographic research are summarized from three perspectives: Model resources, modeling processes, and operational architecture. Finally, we discern avenues for future research of geographic modeling and simulation systems for the study of regional, comprehensive and complex characteristics of geography. Based on these analyses, we propose implementation architecture of geographic modeling and simulation systems and discuss the module composition and functional realization, which could provide theoretical and technical support for geographic modeling and simulation systems to better serve the development of geography in the new era.

Is returning to school during the COVID-19 pandemic stressful? A study on immediate mental health status of Chinese college students.

BACKGROUND: As the COVID-19 pandemic has posed substantial impacts on individual's daily routine and psychological state. For the first time at great scale, Chinese college students had their educational activities moved online in spring 2020. Due to this unexpected isolation and unconventional learning method, their mental health following returning to school is worth investigating. METHODS: Between June 1 and June 15, 2020, a total of 8,921 returning college students' mental health status were assessed using instruments designed for psychiatric disorders, namely the 9-Item Patient Heath Questionnaire (PHQ-9), 7-Item Generalized Anxiety Disorder Scale (GAD-7), 6-Item Impact of Event Scale (IES-6), Youth Self Rating Insomnia Scale (YSIS), and self-developed questionnaire. RESULTS: Our results showed that 8.7%, 4.2%, 10.5%, and 6.1% of the participants experienced depression, anxiety, acute stress, and insomnia, respectively, with a total of 19.8% reporting having at least one psychiatric symptom following their return to school. Sophomore and Senior year, and presence of previous psychiatric conditions contribute to the increased occurrence of psychiatric issues. The level of impact by COVID-19 on one's daily functioning is also positively associated with poor mental health. CONCLUSIONS: Our findings suggested no significant increase in the prevalence of psychiatric symptoms, following the first batch of students' return to school. These findings aim to complement the current understanding of the psychiatric impact of COVID-19 on students and assist school principals to plan their return-to-school approaches in a mental-health sensitive way.

TAT delivery of a PTEN peptide inhibitor has direct cardioprotective effects and improves outcomes in rodent models of cardiac arrest.

We have recently shown that pharmacologic inhibition of PTEN significantly increases cardiac arrest survival in a mouse model, however, this protection required pretreatment 30 min before the arrest. To improve the onset of PTEN inhibition during cardiac arrest treatment, we have designed a TAT fused cell-permeable peptide (TAT-PTEN9c) based on the C-terminal PDZ binding motif of PTEN for rapid tissue delivery and protection. Western blot analysis demonstrated that TAT-PTEN9c peptide significantly enhanced Akt activation in mouse cardiomyocytes in a concentration- and time-dependent manner. Mice were subjected to 8 min asystolic arrest followed by CPR, and 30 mice with successful CPR were then randomly assigned to receive either saline or TAT-PTEN9c treatment. Survival was significantly increased in TAT-PTEN9c-treated mice compared with that of saline control at 4 h after CPR. The treated mice had increased Akt phosphorylation at 30 min resuscitation with significantly decreased sorbitol content in heart or brain tissues and reduced release of taurine and glutamate in blood, suggesting improved glucose metabolism. In an isolated rat heart Langendorff model, direct effects of TAT-PTEN9c on cardiac function were measured for 20 min following 20 min global ischemia. Rate pressure product was reduced by >20% for both TAT vehicle and nontreatment groups following arrest. Cardiac contractile function was completely recovered with TAT-PTEN9c treatment given at the start of reperfusion. We conclude that TAT-PTEN9c enhances Akt activation and decreases glucose shunting to the polyol pathway in critical organs, thereby preventing osmotic injury and early cardiovascular collapse and death.NEW & NOTEWORTHY We have designed a cell-permeable peptide, TAT-PTEN9c, to improve cardiac arrest survival. It blocked endogenous PTEN binding to its adaptor and enhanced Akt signaling in mouse cardiomyocytes. It improved mouse survival after cardiac arrest, which is related to improved glucose metabolism and reduced glucose shunting to sorbitol in critical organs.

ZEB1 activated-VPS9D1-AS1 promotes the tumorigenesis and progression of prostate cancer by sponging miR-4739 to upregulate MEF2D.

Prostate cancer (PCa) is a destructive malignancy with a bad prognosis. LncRNA VPS9D1-AS1 has recently been delineated as an oncogene in some kinds of tumor, whereas, the function of VPS9D1-AS1 in PCa remains to be clarified. In this study, we researched its underlying role in PCa. The expression of VPS9D1-AS1 was conspicuously upregulated in PCa tissues and cells. And absence of VPS9D1-AS1 inhibited cell proliferation, migration and invasion, and promoted cell apoptosis in PCa. In addition, VPS9D1-AS1 overexpression led to opposite results. Furthermore, VPS9D1-AS1/MEF2D could sponge with miR-4739. VPS9D1-AS1/MEF2D and miR-4739 were inversely correlated in tumor cells. And the expression of miR-4739 is markedly downregulated in PCa, meanwhile, that of MEF2D exhibited the opposite tendency. However, MEF2D was positively regulated by VPS9D1-AS1. Moreover, MEF2D upregulation offset the suppressive effects of VPS9D1-AS1 deficiency on cell proliferation, migration and invasion in PCa. Additionally, ZEB1 contained the binding sites of VPS9D1-AS1 promoter, and there existed positive relation between them. Taken together, above results illustrated that ZEB1 activated-VPS9D1-AS1 promotes the tumorigenesis and progression of PCa by sponging miR-4739 to upregulate MEF2D, which offering a new useful reference for studying the development process of PCa.

Prostate carcinoma cell-derived exosomal MicroRNA-26a modulates the metastasis and tumor growth of prostate carcinoma.

Prostate carcinoma may develop into metastatic castration-resistant prostate carcinoma (mCRPC) after endocrine therapy. Exosomal microRNAs play an important role in the regulation of tumor microenvironment. Our study aimed to investigate the effect of exosomal miR-26a on tumor phenotype of prostate carcinoma. Low-grade prostate carcinoma cell line (LNCAP) and mCRPC cell line (PC-3) were treated as experimental subjects according to their miR-26a expressions. Wound healing, transwell and colony-forming unit assays were performed after miR-26a mimic/inhibitor transfection. Then, exosomes were isolated from LNCAP and PC-3 cells, and the levels of exosomal miR-26a were determined. After co-culture of LNCAP (PC-3) cells with PC-3 (LNCAP) exosomes, changes in malignant behaviors were measured. Moreover, LNCAP/PC-3 exosomes were injected into xenograft tumor mice to determine effects of the exosomes on tumorigenicity of LNCAP and PC-3 cells. MiR-26a showed a potently inhibitory effect on cell proliferation, migration and invasion of LNCAP and PC-3 cells. LNCAP exosomes had a higher miR-26a level, compared with PC-3 exosomes. Overexpression of miR-26a attenuated the enhanced malignant behavior of LNCAP cells induced by PC-3 exosomes, and miR-26a inhibition could reverse the inhibitory effects of LNCAP exosomes on PC-3 cells. Exosomal miR-26a could significantly alter the expressions of epithelial-mesenchymal transition (EMT)-related factors. Moreover, LNCAP exosomes suppressed the tumorigenicity of PC-3 cells, while PC-3 exosomes could promote the tumorigenicity of LNCAP cells. Our data suggest that exosomal miR-26a derived from prostate carcinoma cells had a suppressive effect on the metastasis and tumor growth of prostate carcinoma.

Long noncoding RNA BDNF-AS is associated with clinical outcomes and has functional role in human prostate cancer.

BACKGROUND: The underlying molecular mechanisms of prostate cancer (CaP) are largely unknown. We investigated the expression, prognostic value and functional role of long non-coding RNA (lncRNA) brain-derived neurotrophin factor antisense (BDNF-AS) in CaP. METHODS: Clinical tumor samples were excised from patients with CaP. Their endogenous BDNF-AS expression levels were evaluated by qRT-PCR. Correlations between CaP patients' endogenous BDNF-AS expression and their clinicopathological factors, overall survival were statistically analyzed. BDNF-AS expression levels were also probed in immortal CaP cell lines. In LNCaP and PC-3 cells, BDNF-AS was ectopically overexpressed through lentiviral transduction. The functions of BDNF-AS upregulation on CaP cell development were evaluated both in vitro and in vivo. RESULTS: BDNF-AS was downregulated in human CaP tumors. Low BDNF-AS expression was correlated with CaP patients' poor prognosis and shorter overall survival. BDNF-AS was also found to be lowly expressed in CaP cell lines. In LNCaP and PC-3 cells, lentivirus-driven BDNF-AS overexpression exerted significantly tumor-suppressing effects on hindering cancer cell proliferation and invasion in vitro, and explant growth in vivo. CONCLUSION: Downregulated BDNF-AS in CaP patients could be a potential prognostic biomarker for predicating poor prognosis and survival. Upregulating BDNF-AS may be a novel molecular intervening target for CaP treatment.

ΔN-ASPP2, a novel isoform of the ASPP2 tumor suppressor, promotes cellular survival.

ASPP2 is a tumor suppressor that works, at least in part, through enhancing p53-dependent apoptosis. We now describe a new ASPP2 isoform, ΔN-ASPP2, generated from an internal transcription start site that encodes an N-terminally truncated protein missing a predicted 254 amino acids. ΔN-ASPP2 suppresses p53 target gene transactivation, promoter occupancy, and endogenous p53 target gene expression in response to DNA damage. Moreover, ΔN-ASPP2 promotes progression through the cell cycle, as well as resistance to genotoxic stress-induced growth inhibition and apoptosis. Additionally, we found that ΔN-ASPP2 expression is increased in human breast tumors as compared to adjacent normal breast tissue; in contrast, ASPP2 is suppressed in the majority of these breast tumors. Together, our results provide insight into how this new ASPP2 isoform may play a role in regulating the ASPP2-p53 axis.

Diagnostic application of next-generation sequencing in ZMYM2-FGFR1 8p11 myeloproliferative syndrome: A case report.

The 8p11 myeloproliferative syndrome (EMS), also known as 8p11 myeloproliferative neoplasm (8p11 MPN), is a collection of rare hematologic malignancies that are associated with fusion genes involving the tyrosine kinase receptor gene FGFR1 in chromosome 8p11. The entity is an aggressive disease with a high rate of transformation to acute myeloid leukemia (AML) and pathologically characterized by its associated eosinophilia. In this study, we reported a distinctive EMS case featuring an in-frame ZMYM2-FGFR1 fusion gene identified by next-generation sequencing technology (NGS). This patient exhibited not only typical EMS signs including elevated white blood cells in peripheral blood and hypercellular bone marrow with marked leukocytosis, but also exceptional characteristics including erythrocytosis in blood and bone marrow basophilia. Moreover, we detected 2 novel genomic mutations in 2 known leukemogenic genes, IKZF1 and ASXL1. Whether these 2 mutations play a part in EMS pathogenesis or contribute to its specific presentations clinically remain to be determined. In summary, we present a unique EMS case involving a ZMYM2-FGFR1 fusion with distinctive hematologic characteristics.

RNA interference of GluN1 inhibits neuronal rhythmogenesis in the adult inferior olive.

RNA interference (RNAi) to knockdown N-methyl-D-aspartate receptor (NMDAR) function is being investigated to address disorders associated with pathological brain rhythms. A motivating finding has been that pharmacological block of NMDARs inhibited oscillations in neuronal membrane potential that entrain rhythmic bursts of action potentials. To determine whether transient effects of NMDAR antagonist drugs to inhibit neuronal rhythmicity can be stably induced with genetic specificity, we examined the effects of RNAi of GluN1 protein on the subthreshold oscillations (STOs) of neurons in the inferior olive (IO), a pacemaking nucleus necessary for motor and cognitive timing. Western blot of dissociated neurons demonstrated 90% knockdown of GluN1 after a strong in vivo transduction by a dual-microRNA lentiviral vector. GluN1 RNAi in whole-cell-patched IO neurons blocked both membrane depolarization and STOs typically induced by NMDAR activation for up to 54 days without affecting input resistance, membrane capacitance, action potential firing, high-threshold Ca(2+) spikes, the hyperpolarization-activated current Ih, or the activation of the low-threshold Ca(2+) current I(T). Although an off-target effect on Cav3 expression was ruled out also by BlastN query, we found that GluN1 RNAi chronically eliminated I(T)-dependent STOs at resting membrane potential, well below the activation threshold of the NMDAR channel. In the context of a recent report showing that NMDAR activation induces STOs as it strengthens electrical coupling, the long-term block of STOs by GluN1 RNAi may relate to the loss of an essential support mechanism. Lentivector-mediated RNAi of GluN1 provides a novel technique for future investigations of NMDAR involvement in electrical oscillations and behavior.