Novel decay dynamics revealed for virus-mediated drug activation in cytomegalovirus infection

Human cytomegalovirus (CMV) infection is a substantial cause of morbidity and mortality in immunocompromised hosts and globally is one of the most important congenital infections. The nucleoside analogue ganciclovir (GCV), which requires initial phosphorylation by the viral UL97 kinase, is the mainstay for treatment. To date, CMV decay kinetics during GCV therapy have not been extensively investigated and its clinical implications not fully appreciated. We measured CMV DNA levels in the blood of 92 solid organ transplant recipients with CMV disease over the initial 21 days of ganciclovir therapy and identified four distinct decay patterns, including a new pattern exhibiting a transient viral rebound (Hump) following initial decline. Since current viral dynamics models were unable to account for this Hump profile, we developed a novel multi-level model, which includes the intracellular role of UL97 in the continued activation of ganciclovir, that successfully described all the decline patterns observed. Fitting the data allowed us to estimate ganciclovir effectiveness in vivo (mean 92%), infected cell half-life (mean 0.7 days), and other viral dynamics parameters that determine which of the four kinetic patterns will ensue. An important clinical implication of our results is that the virological efficacy of GCV operates over a broad dose range. The model also raises the possibility that GCV can drive replication to a new lower steady state but ultimately cannot fully eradicate it. This model is likely to be generalizable to other anti-CMV nucleoside analogs that require activation by viral enzymes such as UL97 or its homologues

Boundary Regulation Processes and Privacy Concerns With (Non-)Use of Voice-Based Assistants

An exemplar of human-machine communication, voice-based assistants (VBAs) embedded in smartphones and smart speakers simplify everyday tasks while collecting significant data about users and their environment. In recent years, devices using VBAs have continued to add new features and collect more data—in potentially invasive ways. Using Communication Privacy Management theory as a guiding framework, we analyze data from 11 focus groups with 65 US adult VBA users and nonusers. Findings highlight differences in attitudes and concerns toward VBAs broadly and provide insights into how attitudes are influenced by device features. We conclude with considerations for how to address boundary regulation challenges inherent in human-machine interactions

Phosphatidylethanolamine Methyltransferase Deficiency Exacerbates Acute Alcohol-Induced Liver Injury

Alcohol-associated liver disease (ALD) is a global burden of healthcare and remains a major cause of morbidity and mortality worldwide. ALD includes a spectrum of injuries that progresses from hepatic steatosis, alcoholic hepatitis to alcohol-associated cirrhosis and even hepatocellular carcinoma with continued alcohol misuse. The development of ALD depends on several factors, including genetics. The liver enzyme phosphatidylethanolamine methyltransferase (PEMT) catalyzes three sequential methyl transfers to phosphatidylethanolamine, generating phosphatidylcholine (PC). The PC generated with PEMT-mediated catalysis is preferentially used in very-low-density-lipoprotein (VLDL) assembly and is required for its normal biogenesis and secretion (1-3). Alcohol affects the methylation potential and impairs PEMT activity, which by inhibiting VLDL synthesis contributes to the development of hepatic steatosis. Polymorphisms in the human PEMT gene causing loss of function confer susceptibility to metabolic-associated steatohepatitis. Based on these considerations, we hypothesized that PEMT deletion would exacerbate alcohol-induced liver injury. Animal Handling and Diet: Male and female wildtype (WT) and PEMT knock out (KO) mice (12 weeks of age) were subjected to ethanol binge feeding model. The animals were gavaged with maltose dextrin or ethanol (5g/Kg BW) twice, 12 hours apart. The mice were euthanized eight hours after the second dose, where the blood and liver were collected for the following analyses: AST and ALT levels: Serum AST and ALT were analyzed using a VITROS 5.1 FS Chemistry System. Hepatic histopathology: Neutral-buffered formalin fixed liver sections stained with hematoxylin & eosin (H & E) and picrosirius red were imaged using a Keyence BZ-810 microscope. HPLC Analysis: Liver tissues were homogenized in 0.5N perchloric acid and subjected to HPLC analysis to determine S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) levels (3,4) The SAM:SAH ratio, or methylation index, was calculated, as detailed (3,4). Triglyceride Quantification: Lipids were extracted by Folch method (6) and triglyceride levels were quantified using the Thermo DNA Kit (3,4). Enzymatic Activity: Lysosomal acid lipase and proteasome activities were determined in liver homogenates, as detailed (7) Statistical Analyses: Data are expressed as mean values ± standard error (SE). Values not sharing a common subscript letter are statistically different, p \u3c 0.05. We found deletion of PEMT exacerbates acute alcohol-induced liver injury in both males and females as evidenced by: •Increased AST and ALT levels •Increased fat accumulation by histopathological assessment •Decreased SAM levels causing a reduction in the methylation potential •Increased hepatic triglycerides •Decreased lysosomal acid lipase activity •Decreased proteasome activityhttps://digitalcommons.unmc.edu/surp2022/1036/thumbnail.jp

Security, Privacy and Steganographic Analysis of FaceApp and TikTo

Article originally published in International Journal of Computer Science and SecuritySmartphone applications (Apps) can be addictive for users due to their uniqueness, ease-of-use, trendiness, and growing popularity. The addition of Artificial Intelligence (AI) into their functionality has rapidly gained popularity with smartphone users. Over the years, very few smartphone Apps have quickly gained immense popularity like FaceApp and TikTok. FaceApp boasts of using AI to transform photos of human faces using its powerful facial recognition capabilities. FaceApp has been the target of ensuing backlash against it driving the market for a number of other similar yet lesser-known clones into the top ranks of the App stores. TikTok offers video editing and sharing of short video clips whereby making them charming, funny, cringe-inducing, and addictive to the younger generation. FaceApp and TikTok have been the targets of the media, privacy watchdogs, and governments over worries of privacy, ethnicity filters, data misuse, anti-forensics, and security. In this paper, the authors forensically review FaceApp and TikTok Apps from the Android Play Store, for their data ownership, data management, privacy concerns, steganographic use, and overall security posture

The consumption of disposable income among female mall shoppers in Pietermaritzburg.

M. Com. University of KwaZulu-Natal, Pietermaritzburg 2014.The growing significance of the female market gives marketers impetus to tap into this promising market. Much can be gleaned from the consumption habits of women. Numerous studies conducted provide statistics of consumer spending amongst women. However, in order to effectively target women in the Pietermaritzburg region, a study of women‟s spending specific to this area will prove most useful. Additionally, because of the dynamic nature of the economic environment, current research on markets proves invaluable. Emergent trends show that consumers are likely to be found in shopping centres. Given the inclination of urban consumers to shop in malls, this research study focuses specifically on female mall shoppers. Consequently, the current study seeks to determine the disposable income and spending habits of female mall shoppers in Pietermaritzburg. Specifically, the main purpose of the study is to determine the amount of disposable income available to female mall shoppers in Pietermaritzburg; which categories of product and service they spend this disposable income on; and to ascertain if there is a difference in this spending among race groups. Data was collected by questionnaire and analysed using chi squared and Kruskal Wallis tests to identify if there are differences in the disposable income and the amount spent on various products and services with respect to race groups of the female shoppers. In sum, the findings suggest that the disposable income available to the female mall shopper in Pietermaritzburg is significantly higher than the national average; and that there is a distinct difference in the median amounts of money spent on different categories of product and in the median monthly household income with respect to race. These findings can be useful to forward thinking marketers, who may use this information to tap into the female market in Pietermaritzburg. Overall, these findings lead to important managerial implications for targeting female mall shoppers in Pietermaritzburg

Intellectual Biography: Dorothy Smith

Drawing from Smith\u27s own works and other scholars\u27 analysis of her theories, we create a comprehensive review of the work of Dorothy Smith, including insights from her personal and academic backgrounds and her major contributions to the field of sociology. Specifically, we examine standpoint theory and institutional ethnography with particular attention to influences from Smith\u27s own life experiences. In addition, we recognize Smith\u27s transformation of sociology to represent those who are excluded by traditional theories and methods. These academic contributions continue to influence scholars around the world both within and beyond the field of sociology

Contemporary climate analogs project north-south polarization of urban water-energy nexus across US cities under warming climate

Despite the coupled nature of water and electricity demand, the two utilities are often managed by different entities with minimal interaction. Neglecting the water-energy demand nexus leads to to suboptimal management decisions, particularly under climate change. Here, we leverage state-of-the-art machine learning and contemporary climate analogs to project the city-level coupled water and electricity demand of 46 major U.S. cities into the future. The results show that many U.S. cities may experience an increase in electricity (water) demand of up to 20% (15%) due to climate change under a high emissions scenario, with a clear north-south gradient. In the absence of appropriate mitigation strategies, these changes will likely stress current infrastructure, limiting the effectiveness of the ongoing grid decarbonization efforts. In the event that cities are unable to match the increasing demand, there may be increased occurrence of supply shortages, leading to blackouts with disproportionate impacts on vulnerable populations. As such, reliable projections of future water and electricity demand under climate change are critical not only for preventing further exacerbation of the existing environmental injustices but also for more effective design and execution of climate change mitigation and adaptation plans

Strengthening children's privacy literacy through contextual integrity

Researchers and policymakers advocate teaching children about digital privacy, but privacy literacy has not been theorized for children. Drawing on interviews with 30 families, including 40 children, we analyze children’s perspectives on password management in three contexts -family life, friendship, and education- and develop a new approach to privacy literacy grounded in Nissenbaum’s contextual integrity framework. Contextual integrity equates privacy with appropriate flows of information, and we show how children’s perceptions of the appropriateness of disclosing a password varied across contexts. We explain why privacy literacy should focus on norms rather than rules and discuss how adults can use learning moments to strengthen children’s privacy literacy. We argue that equipping children to make privacy-related decisions serves them better than instructing them to follow privacy-related rules

Evaluation of the Ion Channel Assembly in a Eukaryotic Cell-Free System Focusing on Two-Pore Domain Potassium Channels K2P

Oligomeric ion channels are abundant in nature. However, the recombinant expression in cell culture-based systems remains tedious and challenging due to negative side effects, limiting the understanding of their role in health and disease. Accordingly, in this work, we demonstrate the cell-free synthesis (CFS) as an alternative platform to study the assembly of two-pore domain potassium channels (K2P) within endogenous endoplasmic reticulum-derived microsomes. Exploiting the open nature of CFS, we investigate the cotranslational translocation of TREK-2 into the microsomes and suggest a cotranslational assembly with typical single-channel behavior in planar lipid-bilayer electrophysiology. The heteromeric assembly of K2P channels is a contentious matter, accordingly we prove the successful assembly of TREK-2 with TWIK-1 using a biomolecular fluorescence complementation assay, Western blot analysis and autoradiography. The results demonstrate that TREK-2 homodimer assembly is the initial step, followed by heterodimer formation with the nascent TWIK-1, providing evidence of the intergroup heterodimerization of TREK-2 and TWIK-1 in eukaryotic CFS. Since K2P channels are involved in various pathophysiological conditions, including pain and nociception, CFS paves the way for in-depth functional studies and related pharmacological interventions. This study highlights the versatility of the eukaryotic CFS platform for investigating ion channel assembly in a native-like environment