Alzheimer's disease linked Aß42 exerts product feedback inhibition on γ-secretase impairing downstream cell signaling.

Amyloid ß (Aß) peptides accumulating in the brain are proposed to trigger Alzheimer's disease (AD). However, molecular cascades underlying their toxicity are poorly defined. Here, we explored a novel hypothesis for Aß42 toxicity that arises from its proven affinity for γ-secretases. We hypothesized that the reported increases in Aß42, particularly in the endolysosomal compartment, promote the establishment of a product feedback inhibitory mechanism on γ-secretases, and thereby impair downstream signaling events. We conducted kinetic analyses of γ-secretase activity in cell-free systems in the presence of Aß, as well as cell-based and ex vivo assays in neuronal cell lines, neurons, and brain synaptosomes to assess the impact of Aß on γ-secretases. We show that human Aß42 peptides, but neither murine Aß42 nor human Aß17-42 (p3), inhibit γ-secretases and trigger accumulation of unprocessed substrates in neurons, including C-terminal fragments (CTFs) of APP, p75, and pan-cadherin. Moreover, Aß42 treatment dysregulated cellular homeostasis, as shown by the induction of p75-dependent neuronal death in two distinct cellular systems. Our findings raise the possibility that pathological elevations in Aß42 contribute to cellular toxicity via the γ-secretase inhibition, and provide a novel conceptual framework to address Aß toxicity in the context of γ-secretase-dependent homeostatic signaling.

No harmful effect of propranolol administered prior to fear memory extinction in rats and humans.

Exposure therapy is an evidence-based treatment option for anxiety-related disorders. Many patients also take medication that could, in principle, affect exposure therapy efficacy. Clinical and laboratory evidence indeed suggests that benzodiazepines may have detrimental effects. Large clinical trials with propranolol, a common beta-blocker, are currently lacking, but several preclinical studies do indicate impaired establishment of safety memories. Here, we investigated the effects of propranolol given prior to extinction training in 9 rat studies (N = 215) and one human study (N = 72). A Bayesian meta-analysis of our rat studies provided strong evidence against propranolol-induced extinction memory impairment during a drug-free test, and the human study found no significant difference with placebo. Two of the rat studies actually suggested a small beneficial effect of propranolol. Lastly, two rat studies with a benzodiazepine (midazolam) group provided some evidence for a harmful effect on extinction memory, i.e., impaired extinction retention. In conclusion, our midazolam findings are in line with prior literature (i.e., an extinction retention impairment), but this is not the case for the 10 studies with propranolol. Our data thus support caution regarding the use of benzodiazepines during exposure therapy, but argue against a harmful effect of propranolol on extinction learning.

Tocilizumab Reduces Lung Injury in a Rat Lung Ischemia and Reperfusion Model.

OBJECTIVE: In this study, the effect of tocilizumab (TCZ) on lung tissue in lung ischemia-reperfusion (I/R) injury in rats was investigated. MATERIAL AND METHODS: A total of 24 Wistar rats were divided into 4 equal groups, with 6 rats in each group: Left lung I/R was applied to I/R groups. In the I/R groups, the left lung hilum was clamped for 45 minutes, and then the clamp was removed and reperfused for 120 minutes. In the TCZ groups, 4 mg/kg and 8 mg/kg of TCZ were administered intraperitoneally to the rats 30 minutes before surgery. RESULTS: The tumor necrosis factor-alpha mean value was not statistically significant between the groups (P = .091). Statistically significant results were observed between group I/R-TCZ (8 mg/kg) and group I/R for catalase. (P = .005). Statistically significant results were observed between group I/R-TCZ (8 mg/kg) and group I/R for malondialdehyde. (P = .009). The difference in total ischemia score between group I/R-TCZ (4 mg/kg) and group I/R-TCZ (8 mg/kg) and group I/R was statistically significant (P < .001). In terms of alveolar hemorrhage, there was a statistically significant difference between group I/R-TCZ (4 mg/kg) and group I/R-TCZ (8 mg/kg) and group I/R (P = .01 and P = .002, respectively). There was a statistically significant difference between group I/R-TCZ (8 mg/kg) and group I/R in terms of neutrophil accumulation (P = .01). In terms of interstitial edema, there was a statistically significant difference between group I/R-TCZ (4 mg/kg) and group I/R-TCZ (8 mg/kg) and group I/R (P = .006 and P = .001, respectively). In terms of pulmonary edema, there was a statistically significant difference between group I/R-TCZ (4 mg/kg) and group I/R-TCZ (8 mg/kg) and group I/R (P = .01 and P = .009, respectively). CONCLUSION: Lung tissue may be affected by I/R injury and this damage can be reversed with the use of TCZ.

Perineural differentiation in neurotized nevi.

BACKGROUND: Perineuriomatous melanocytic nevi are rare and this may indicate the similar embryological source of melanocytes and peripheral nerves in the neural crest. Neurotized melanocytic nevi may resemble nerve sheath tumors histologically, and show schwannian differentiation. However, literature on whether neurotized nevi differentiate into perineural cells is controversial. We examined our cases of neurotized nevi for evidence of perineural differentiation. MATERIALS AND METHODS: A total of 100 benign nevi with large neurotized component (microscopically involved a low power field 4.2 mm in diameter) were prospectively evaluated in excisional biopsy samples. Immunohistochemical stainings for EMA, Claudin1, Glut1 and neurofilament were performed. RESULTS: Perineural differentiation was immunohistochemically detected in the neurotized component of the nevi in 61% of the cases with EMA and in all the cases with Glut1 and Claudin1. Axonal differentiation was not detected with neurofilament. The expression pattern, especially with Glut1, was usually in form of partial or complete staining surrounding the Meissner's corpuscle-like structure (MCLS). Also, a linear/curvilinear staining pattern was observed particularly with Claudin1. A diffuse staining pattern with EMA, Glut1 and Claudin1 was detected in a case with a microscopically distinct whorl structure, and in which spindle cells are separated from the superficial epithelioid melanocytes with an abrupt transition histologically. These findings of the case are compatible with previous reports of perineuromatous nevus. CONCLUSION: Perineural differentiation is not uncommon and immunohistochemically observed in all nevi with a relatively large component of neurotization. To prevent misdiagnosing desmoplastic melanoma and overtreating patients, it is crucial to be aware of perineuromatous nevi.

Re-visiting resource curse hypothesis in China through the lens of human capital and globalization.

The resource curse hypothesis has recently become an important research topic in environmental economics. However, there still needs to be consensus in the literature on whether natural resource rents (NRRs) support economic growth. Previous studies on China have mainly analyzed the resource curse hypothesis based on local or regional data. However, this study examines the issue based on national-level data using globalization and human capital as control variables. The dynamic Auto-Regressive Distributive Lag (DARDL) Simulations and the Kernel-based Regularized Least Squares (KRLS) techniques are employed for policy formulation for 1980-2019. The empirical assessments indicate that NRRs escalate economic growth, i.e., China's resource curse hypothesis is invalid. Further, empirical outcomes reveal that human capital and globalization encourage China's economic growth. The KRLS, a machine learning algorithm, also supports the findings of the DARDL approach. Finally, based on the empirical outcomes, several policy recommendations can be developed, such as more investment in the education sector and the use of NRRs for productive sectors of the economy.

Plain tobacco packaging: progress, challenges, learning and opportunities.

The aim of this paper is to overview progress made with respect to the adoption of plain (or standardised) packaging, key challenges faced, evaluative evidence and opportunities for extending this policy. It has been a decade since Australia became the first country to require tobacco products to be sold in plain packaging; after slow initial uptake, 16 countries have now fully implemented this policy. Since 2020, plain packaging laws have become more comprehensive in some countries, expanding coverage beyond traditional tobacco products to include heated tobacco, tobacco accessories (rolling papers) and other nicotine-containing products (e-cigarettes). Laws have also become more innovative: some now ban non-biodegradable filters, include provision for a periodic change of the pack colour or require both plain packaging and health-promoting pack inserts. The tobacco industry has and will continue to use multi-jurisdictional strategies to oppose this policy. Evaluations suggest that plain packaging has improved health outcomes and has not burdened retailers, although research is limited to early policy adopters and important gaps in the literature remain. While the power of packaging as a sales tool has diminished in markets with plain packaging, tobacco companies have exploited loopholes to continue to promote their products and have increasingly focused on filter innovations. Opportunities exist for governments to strengthen plain packaging laws.

Highly Sensitive and Single-Use Biosensing System Based on a GP Electrode for Analysis of Adiponectin, an Obesity Biomarker.

This study presents a disposable, novel, and sensitive biosensing system to determine adiponectin, an obesity biomarker, in real human serum. The graphite paper (GP) working electrode is a new material for impedimetric biosensors. In the literature, there is no study in which this electrode is used in impedance-based biosensors for adiponectin detection. Sensitive and useful techniques, such as electrochemical impedance spectroscopy and cyclic voltammetry, were utilized for investigation of the modification of the GP electrode surface and optimization and characterization of the constructed biosensor. The single frequency impedance technique was used to study the interactions between antiadiponectin and adiponectin. The morphology of the electrode surface for each immobilization step was examined with scanning electron microscopy. All experimental parameters were optimized to fabricate a rapid and sensitive biosensing system. The designed biosensor presents excellent performance with a wide detection range (0.05-25 pg mL-1) and a low limit of detection (0.0033 pg mL-1) for adiponectin determination. Also, it has been demonstrated that the biosensor sensitively allows for the detection of adiponectin in human serum. The affinity of the designed immunosensor toward other proteins and components was examined in the presence of the target protein (adiponectin), leptin (100 pg mL-1), creatine kinase (50 pg mL-1), parathyroid hormone (50 pg mL-1), and d-glucose (0.5 M). The selectivity of the adiponectin biosensor resulted in high capacity to neglect the interference effect. The constructed biosensor showed good linearity, long-term storage life (10 weeks), high reusability (18 times regenerability), and high ability to detect adiponectin concentrations at picogram levels.

A novel and disposable GP- based impedimetric biosensor using electropolymerization process with PGA for highly sensitive determination of leptin: Early diagnosis of childhood obesity.

This study presents a novel, single-use electrochemical biosensor for the leptin biomarker, which may have potential use for early diagnosis of childhood obesity. The graphite paper working electrode was used for the first time in impedimetric biosensors. All immobilization procedure, investigation of the optimal parameters and characterization of biosensors were followed and evaluated using Electrochemical Impedance Spectroscopy (EIS) and Cyclic Voltammetry (CV). The Scanning Electron Microscope (SEM) was utilized to visualize the morphology of the electrode surface during the immobilization steps of the immunosensor. Moreover, the characterization of the interactions between anti-leptin and leptin was investigated by using Single Frequency Technique (SFI). The applicability of the designed biosensor for real serum samples was tested for clinical use. It was observed that the biosensor allows high sensitivity in the analyte detection (leptin) in real serum samples. Moreover, it was suggested that the developed biosensor presents advantages such as long shelf life (5% loss of activity after 8 weeks and 60% loss after 10 weeks), ability to determine analyte concentrations at picogram level (0.2 pg mL-1 -20 pg mL-1), low limit of detection (0.00813 pg mL- 1), reproducibility, reusability (12 times) and high sensitivity.

The Acute Effects of Different Intensity Whole-Body Vibration Exposure on Muscle Tone and Strength of the Lower Legs, and Hamstring Flexibility: A Pilot Study.

CONTEXT: The research on the change in properties of the lower leg muscles by different intensity sinusoidal vertical whole-body vibration (SV-WBV) exposures has not yet been investigated. OBJECTIVE: The purpose of this study was to determine effect of a 20-minute different intensity SV-WBV application to the ankle plantar flexor and dorsiflexor muscles properties and hamstring flexibility. DESIGN: Prospective preintervention-postintervention design. SETTING: Physiotherapy department. PARTICIPANTS: A total of 50 recreationally active college-aged individuals with no history of a lower leg injury volunteered. INTERVENTIONS: The SV-WBV was applied throughout the session with an amplitude of 2 to 4 mm and a frequency of 25 Hz in moderate-intensity vibration group and 40 Hz in a vigorous-intensity vibration group. MAIN OUTCOME MEASURES: The gastrocnemius and tibialis anterior muscle tone was assessed with MyotonPRO, and the strength evaluation was made on the same lower leg muscles using hand-held dynamometer. The sit and reach test was used for the lower leg flexibility evaluation. RESULTS: The gastrocnemius muscle tone decreased on the right side (d = 0.643, P = .01) and increased on the left (d = 0.593, P = .04) when vigorous-intensity vibration was applied. Bilateral gastrocnemius muscle strength did not change in both groups (P > .05). Without differences between groups, bilateral tibialis anterior muscle strength increased in both groups (P < .01). Bilateral gastrocnemius and tibialis anterior muscle tone did not change in the moderate-intensity vibration group (P > .05). Flexibility increased in both groups (P < .01); however, there was no statistically significant difference between the groups (d = 0.169, P = .55). CONCLUSIONS: According to study results, if SV-WBV is to be used in hamstring flexibility or ankle dorsiflexor muscle strengthening, both vibration exposures should be preferred. Different vibration programs could be proposed to increase ankle plantar flexor muscle strength in the acute results. Vigorous-intensity vibration exposure is effective in altering ankle plantar flexor muscle tone, but it is important to be aware of the differences between the lower legs.

Re-estimating the interconnectedness between the demand of energy consumption, income, and sustainability indices.

In this study, we analyze the time-varying causality linkages between energy consumption, economic growth, and environmental degradation in 33 Organization for Economic Co-operation and Development countries, spanning the period 2000 to 2013. The curve causality approach provides evidence of a significant environmental Kuznets curve in 25 countries in the case of the ecological footprint and in 23 countries in the case of the Environmental Performance Index. However, out of them, only Italy, Slovakia, and South Korea have traditional environmental Kuznets curve, in the form of an inverted U-shaped curve. For the remaining countries, different forms of curves are valid. In particular, an N-shaped curve appears to be valid between income and environmental degradation for nearly half of the sample, i.e., for Austria, Belgium, Chile, Estonia, Finland, France, Germany, Hungary, Luxembourg, Netherlands, Sweden, Switzerland, New Zealand, Turkey, and the USA. Additionally, bidirectional causality relationships are confirmed among all covariates in most countries. In view of the results, some crucial policy implications would be suggested, such as sustainable development that aims to make a balance between economic growth and environmental protection.

Highly sensitive and cost-effective ITO-based immunosensor system modified by 11-CUTMS: Analysis of SOX2 protein in real human serum.

In this study it is aimed to construct an immunosensor system for detection of Sex-determining region Y-box 2 (SOX2) antigen by using Indium tin oxide- polyethylene terephthalate (ITO-PET) as working electrode. Firstly, ITO-PET electrode surfaces were hydroxylated by using NH4OH/H2O2/H2O and were incubated with 11-cyanoundecyltrimethoxysilane (11-CUTMS), respectively. After silanization process, anti- SOX2 was immobilized on modified ITO-PET electrodes. All immobilization processes were examined with Electrochemical impedance spectroscopy (EIS) and Cyclic voltammetry (CV). The basic parameters such as 11-CUTMS and anti-SOX2 concentrations, anti-SOX2 and SOX2 incubation period were optimized. The immunosensor prepared under optimal conditions gave a response for a wide concentration range of SOX2 protein (0.02 pg mL-1-2 pg mL-1) and the limit of detection was determined as low as 0.013 pg mL-1. And also, the immunosensor had good repeatability, reproducibility, reusability and long shelf life. Scanning Electron Microscope (SEM) method was utilized to observe the morphologies of the electrode surfaces belonging to all steps. Lastly, seven different real human serum were analyzed with the constructed immunosensor and Enzyme-Linked ImmunoSorbent Assay (ELISA). The results found with these methods were analogised with each other.

A revisit of the environmental Kuznets curve hypothesis for Turkey: new evidence from bootstrap rolling window causality.

This study aims at analyzing the Environmental Kuznets Curve (EKC) hypothesis for Turkey, spanning the period of 1961-2013. Unlike previous studies, instead of carbon emissions, the ecological footprint is used as a proxy for environmental degradation. Moreover, a bootstrap time-varying causality approach is used to detect the possible changes in causal relations and to obtain the parameters across subsample periods. The results clearly indicate that there are feedback relationships between economic growth and the ecological footprint in some subsample periods. In addition, the impact of economic growth on environmental degradation is positive and has a slowly increasing trend in all subsample periods. Therefore, the EKC hypothesis is not confirmed for the Turkish economy. Based on these results, some crucial policy implications are suggested.

The impact of internet use on air pollution: Evidence from emerging countries.

The goal of this study is to analyze the impact of Internet use, employed as a proxy for information and communications technologies (ICTs), on CO2 emissions. Using a panel of 20 emerging economies spanning the period 1990 to 2015, this paper finds that increased Internet access results in lower levels of air pollution. Moreover, panel causality test results highlight a unidirectional causality running from Internet use to CO2 emissions. This result also has crucial policy implications for the governments in emerging markets. For instance, increased investment in the ICT sector could be a plausible channel to reduce air pollution level.

Graphene oxide based electrochemical label free immunosensor for rapid and highly sensitive determination of tumor marker HSP70.

In this study, it is aimed to design a label free immunosensor for determination of HSP70 (heat shock protein 70). Glassy carbon electrode was used as a working electrode. Graphene oxide was covered on the working electrode surface. AntiHSP70 as a biorecognition element of the biosensor was covalently immobilized onto the graphene oxide layer by using EDC/NHS chemistry. The immobilization of antiHSP70 and binding of HSP70 protein onto the electrode surface were monitored by cyclic voltammetry and electrochemical impedance spectroscopy. Single frequency technique was also utilized to monitor binding characterization of HSP70 and antiHSP70. Surface morphology was defined by using scanning electron microscopy. All important fabrication steps of the biosensor were optimized to prepare an ultrasensitive biosensor. Under optimum conditions, analytical studies such as linearity, repeatability, and reproducibility were also experienced. A linear detection range of HSP70 was determined between 12 and 144fg/mL. Moreover, Kramer's Kronig transform was applied on impedance data. Finally, the biosensor was applied with real human blood serum samples and hopeful results were obtained.

Thermal, viscoelastic and mechanical properties' optimization of polyphenylene sulfide via optimal processing parameters using the Taguchi method.

Thermal, viscoelastic and mechanical properties of polyphenylene sulfide (PPS) were optimized as a function of extrusion and injection molding parameters. For this purpose, design of experiments approach utilizing Taguchi's L27 (37) orthogonal arrays was used. Effect of the parameters on desired properties was determined using the analysis of variance. Differential scanning calorimeter (DSC) tests were performed for the analysis of thermal properties such as melting temperature (Tm) and melting enthalpy (ΔHM). Dynamic mechanical analysis (DMA) tests were performed for the analysis of viscoelastic properties such as damping factor (tan δ) and glass transition temperature (Tg). Tensile tests were performed for the analysis of mechanical properties such as tensile strength and modulus. With optimized process parameters, verification DSC, DMA and tensile tests were performed for thermal, viscoelastic and mechanical properties, respectively. The Taguchi method showed that 'barrel temperature' and its level of '340°C' were seen to be the most effective parameter and its level; respectively. It was suggested that PPS can be reinforced for further improvement after optimized thermal, viscoelastic and mechanical properties.

Introducing a new method for evaluation of the interaction between an antigen and an antibody: single frequency impedance analysis for biosensing systems.

This paper illustrates the application of an antibody, anti-parathyroid hormone (anti-PTH), as a bioreceptor in a biosensor system for the first time, and demonstrates how this biosensor can be used in parathyroid hormone (PTH) determination. The interaction between the biosensor and parathyroid hormone was firstly investigated by a novel electrochemical method, single frequency impedance analysis. The biosensor was based on the gold electrode modified by cysteine self-assembled monolayers. Anti-PTH was covalently immobilized onto cysteine layer by using an EDC/NHS couple. The immobilization of anti-PTH was monitored by cyclic voltammetry and electrochemical impedance spectroscopy techniques. The performance of the biosensor was evaluated in terms of linearity, sensitivity, repeatability and reproducibility, after a few important optimization studies were carried out. In particular, parathyroid hormone was detected within a linear range of 10-60 fg/mL. Kramers-Kronig transform was also performed on the impedance data. The specificity of the biosensor was also evaluated. The biosensor was validated by using a complementary reference technique. Lastly the developed biosensor was used to monitor PTH levels in artificial serum samples.