Impact of Zinc on Oxidative Signaling Pathways in the Development of Pulmonary Vasoconstriction Induced by Hypobaric Hypoxia

Hypobaric hypoxia is a condition that occurs at high altitudes (>2500 m) where the partial pressure of gases, particularly oxygen (PO₂), decreases. This condition triggers several physiological and molecular responses. One of the principal responses is pulmonary vascular contraction, which seeks to optimize gas exchange under this condition, known as hypoxic pulmonary vasoconstriction (HPV); however, when this physiological response is exacerbated, it contributes to the development of high-altitude pulmonary hypertension (HAPH). Increased levels of zinc (Zn²⁺) and oxidative stress (known as the “ROS hypothesis”) have been demonstrated in the vasoconstriction process. Therefore, the aim of this review is to determine the relationship between molecular pathways associated with altered Zn²⁺ levels and oxidative stress in HPV in hypobaric hypoxic conditions. The results indicate an increased level of Zn²⁺, which is related to increasing mitochondrial ROS (mtROS), alterations in nitric oxide (NO), metallothionein (MT), zinc-regulated, iron-regulated transporter-like protein (ZIP), and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-induced protein kinase C epsilon (PKCε) activation in the development of HPV. In conclusion, there is an association between elevated Zn²⁺ levels and oxidative stress in HPV under different models of hypoxia, which contribute to understanding the molecular mechanism involved in HPV to prevent the development of HAPH.     

Altered Distribution and Expression of Syndecan-1 and -4 as an Additional Hallmark in Psoriasis

Syndecans act as independent co-receptors to exert biological activities and their altered function is associated with many pathophysiological conditions. Here, syndecan-1 and -4 were examined in lesional skin of patients with psoriasis. Immunohistochemical staining confirmed altered syndecan-1 distribution and revealed absence of syndecan-4 expression in the epidermis. Fibronectin (FN)—known to influence inflammation and keratinocyte hyperproliferation via α5β1 integrin in psoriasis—was also decreased. Syndecan-1 and -4 expression was analyzed in freshly isolated lesional psoriatic human keratinocytes (PHK) characterized based on their proliferation and differentiation properties. mRNA levels of syndecan-1 were similar between healthy and PHK, while syndecan-4 was significantly decreased. Cell growth and release of the pro-inflammatory Tumor Necrosis Factor-alpha (TNFα) were selectively and significantly induced in PHKs plated on FN. Results from co-culture of healthy keratinocytes and psoriatic fibroblasts led to the speculation that at least one factor released by fibroblasts down-regulate syndecan-1 expression in PHK plated on FN. To assay if biological treatments for psoriasis target keratinocyte proliferation, gelatin-based patches enriched with inteleukin (IL)-17α or TNFα blockers were prepared and tested using a full-thickness healthy epidermal model (Phenion^®). Immunohistochemistry analysis showed that both blockers impacted the localisation of syndecan-1 within the refined epidermis. These results provide evidence that syndecans expression are modified in psoriasis, suggesting that they may represent markers of interest in this pathology.     

Enapotamab Vedotin,an AXL-Specific Antibody-Drug Conjugate,Demonstrates Antitumor Efficacy in Patient-Derived Xenograft Models of Soft Tissue Sarcoma

Doxorubicin (doxo) remains the standard of care for patients with advanced soft tissue sarcoma (STS), even though response rates to doxo are only around 14% to 18%. We evaluated enapotamab vedotin (EnaV), an AXL-specific antibody-drug conjugate (ADC), in a panel of STS patient-derived xenografts (PDX). Eight models representing multiple STS subtypes were selected from our STS PDX platform (n = 45) by AXL immunostaining on archived passages. Models were expanded by unilateral transplantation of tumor tissue into the left flank of 20 NMRI nu/nu mice. Once tumors were established, mice were randomized into an EnaV treatment group, or a group treated with isotype control ADC. Treatment efficacy was assessed by tumor volume evaluation, survival analysis, and histological evaluation of tumors, and associated with AXL expression. EnaV demonstrated significant tumor growth delay, regression, and/or prolonged survival compared to isotype control ADC in 5/8 STS PDX models investigated. Experimental passages of responding models were all found positive for AXL at varying levels, but no linear relationship could be identified between the level of expression and level of response to EnaV. One model was found negative for AXL on experimental passage and did not respond to EnaV. This study provides a preclinical rationale for the evaluation of AXL-targeting ADCs in the treatment of AXL-expressing sarcomas.     

Preparations for Y2K: Revisiting the Behavioral Component of the Third-Person Effect

Although the behavioral component was an integral part of the original formulation of the third-person effect hypothesis, little research has examined the impact of biased media effect perceptions on behaviors that assume others have already been affected. The present study examines how third-person perceptions (the belief that other people are particularly vulnerable to media messages) contributed to intentions to prepare for problems stemming from Y2K, also known as the "millennium bug." Analyses using data from 2 regional probability samples taken in late 1999 show that perceptions about the potential effects of news messages influenced public anxiety about the Y2K situation and beliefs that other people would overprepare for the new year. These 2 variables, in turn, predicted intentions to stockpile supplies of food, water, gasoline, and cash. The article discusses the implications of these findings for understanding the relationship between perceptions of media effects and an extended range of behaviors.     

Direct and Differential Effects of the Internet on Political and Civic Engagement

Given the significant rise in the number of Americans who turn to the Internet for political information, we examine the effects of these behaviors on political and civic engagement in an evolving media landscape. Specifically, we test hypotheses derived from competing models—the instrumental approach, which posits direct effects of Internet use and a psychological approach, which predicts contingent effects. Analyses of the 2004 American National Election Studies ( N = 1,212) reveal a pattern of direct effects of Internet use on basic information acquisition and use but contingent effects for concrete acts of civic or political engagement. These results provide an important window on the political impacts of contemporary Internet use and suggest that future reassessments of the Internet's role in public life should continue to probe for direct as well as differential effects.     

Transmission of 160-Gb/s Modified Manchester modulation over WDM system

The paper examines the performance of Modified Manchester (MM) modulation scheme over wavelength division multiplexing (WDM) in high-speed optical communication links. The MM as a new modulation technique has a narrow spectral width compared to conventional Manchester coding, which allows its implementation in WDM systems beneficial. In this study, the performance characteristics of MM and conventional Manchester modulation formats are assessed in WDM system at 10 Gb/s bitrate for each channel, for the least allowable channel spacing as well as tolerance to chromatic dispersion (CD). It is revealed from the results of simulation that MM performs meaningfully well in comparison with conventional Manchester in terms of tolerance against narrow optical filtering, spectral efficiency, which is improved by 32% and CD tolerance, which is improved by +100 ps/nm. Sixteen wavelength channels (16 × 10 Gb/s) are modulated to provide 160 Gb/s data capacity, which was transmitted successfully over 224 km standard single mode fibre (SSMF) using MM while the conventional Manchester only covered about 157 km.