Evidence accumulates that the transcription factor nuclear factor E2-related factor 2 (Nrf2) has an essential role in cancer development and chemoresistance, thus pointing to its potential as an ...anticancer target and undermining its suitability in chemoprevention. Through the induction of cytoprotective and proteasomal genes, Nrf2 confers apoptosis protection in tumor cells, and inhibiting Nrf2 would therefore be an efficient strategy in anticancer therapy. In the present study, pancreatic carcinoma cell lines (Panc1, Colo357 and MiaPaca2) and H6c7 pancreatic duct cells were analyzed for the Nrf2-inhibitory effect of the coffee alkaloid trigonelline (trig), as well as for its impact on Nrf2-dependent proteasome activity and resistance to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and anticancer drug-induced apoptosis. Chemoresistant Panc1 and Colo357 cells exhibit high constitutive Nrf2 activity, whereas chemosensitive MiaPaca2 and H6c7 cells display little basal but strong tert-butylhydroquinone (tBHQ)-inducible Nrf2 activity and drug resistance. Trig efficiently decreased basal and tBHQ-induced Nrf2 activity in all cell lines, an effect relying on a reduced nuclear accumulation of the Nrf2 protein. Along with Nrf2 inhibition, trig blocked the Nrf2-dependent expression of proteasomal genes (for example, s5a/psmd4 and α5/psma5) and reduced proteasome activity in all cell lines tested. These blocking effects were absent after treatment with Nrf2 siRNA, a condition in which proteasomal gene expression and proteasome activity were already decreased, whereas siRNA against the related transcription factor Nrf1 did not affect proteasome activity and the inhibitory effect of trig. Depending on both Nrf2 and proteasomal gene expression, the sensitivity of all cell lines to anticancer drugs and TRAIL-induced apoptosis was enhanced by trig. Moreover, greater antitumor responses toward anticancer drug treatment were observed in tumor-bearing mice when receiving trig. In conclusion, representing an efficient Nrf2 inhibitor capable of blocking Nrf2-dependent proteasome activity and thereby apoptosis protection in pancreatic cancer cells, trig might be beneficial in improving anticancer therapy.
White flight Kruse, Kevin M
2013., 20130711, 2013, 2005, 2007, 2007-08-14, Letnik:
50
eBook
During the civil rights era, Atlanta thought of itself as "The City Too Busy to Hate," a rare place in the South where the races lived and thrived together. Over the course of the 1960s and 1970s, ...however, so many whites fled the city for the suburbs that Atlanta earned a new nickname: "The City Too Busy Moving to Hate."
In this reappraisal of racial politics in modern America, Kevin Kruse explains the causes and consequences of "white flight" in Atlanta and elsewhere. Seeking to understand segregationists on their own terms,White Flightmoves past simple stereotypes to explore the meaning of white resistance. In the end, Kruse finds that segregationist resistance, which failed to stop the civil rights movement, nevertheless managed to preserve the world of segregation and even perfect it in subtler and stronger forms.
Challenging the conventional wisdom that white flight meant nothing more than a literal movement of whites to the suburbs, this book argues that it represented a more important transformation in the political ideology of those involved. In a provocative revision of postwar American history, Kruse demonstrates that traditional elements of modern conservatism, such as hostility to the federal government and faith in free enterprise, underwent important transformations during the postwar struggle over segregation. Likewise, white resistance gave birth to several new conservative causes, like the tax revolt, tuition vouchers, and privatization of public services. Tracing the journey of southern conservatives from white supremacy to white suburbia, Kruse locates the origins of modern American politics.
Some images inside the book are unavailable due to digital copyright restrictions.
The Spaces of the Modern City Gyan Prakash, Kevin M. Kruse / Gyan Prakash, Kevin M. Kruse
2021, 2008, 2021-06-08, 20080101, Letnik:
2
eBook
By United Nations estimates, 60 percent of the world's population will be urban by 2030. With the increasing speed of urbanization, especially in the developing world, scholars are now rethinking ...standard concepts and histories of modern cities. The Spaces of the Modern City historicizes the contemporary discussion of urbanism, highlighting the local and global breadth of the city landscape. This interdisciplinary collection examines how the city develops in the interactions of space and imagination. The essays focus on issues such as street design in Vienna, the motion picture industry in Los Angeles, architecture in Marseilles and Algiers, and the kaleidoscopic paradox of post- apartheid Johannesburg. They explore the nature of spatial politics, examining the disparate worlds of eighteenth-century Baghdad, nineteenth-century Morelia, Cold War-era West Berlin, and postwar Los Angeles. They also show the meaning of everyday spaces to urban life, illuminating issues such as crime in metropolitan London, youth culture in Dakar, "memory projects" in Tokyo, and Bombay cinema. Informed by a range of theoretical writings, this collection offers a fresh and truly global perspective on the nature of the modern city. The contributors are Sheila Crane, Belinda Davis, Mamadou Diouf, Philip J. Ethington, David Frisby, Christina M. Jiménez, Dina Rizk Khoury, Ranjani Mazumdar, Frank Mort, Martin Murray, Jordan Sand, and Sarah Schrank.
Herpesviruses infect the majority of the human population and can cause significant morbidity and mortality. Herpes simplex virus (HSV) type 1 causes cold sores and herpes simplex keratitis, whereas ...HSV-2 is responsible for genital herpes. Human cytomegalovirus (HCMV) is the most common viral cause of congenital defects and is responsible for serious disease in immuno-compromised individuals. Epstein-Barr virus (EBV) is associated with infectious mononucleosis and a broad range of malignancies, including Burkitt's lymphoma, nasopharyngeal carcinoma, Hodgkin's disease, and post-transplant lymphomas. Herpesviruses persist in their host for life by establishing a latent infection that is interrupted by periodic reactivation events during which replication occurs. Current antiviral drug treatments target the clinical manifestations of this productive stage, but they are ineffective at eliminating these viruses from the infected host. Here, we set out to combat both productive and latent herpesvirus infections by exploiting the CRISPR/Cas9 system to target viral genetic elements important for virus fitness. We show effective abrogation of HCMV and HSV-1 replication by targeting gRNAs to essential viral genes. Simultaneous targeting of HSV-1 with multiple gRNAs completely abolished the production of infectious particles from human cells. Using the same approach, EBV can be almost completely cleared from latently infected EBV-transformed human tumor cells. Our studies indicate that the CRISPR/Cas9 system can be effectively targeted to herpesvirus genomes as a potent prophylactic and therapeutic anti-viral strategy that may be used to impair viral replication and clear latent virus infection.
Direct Prebiotic Pathway to DNA Nucleosides Teichert, Jennifer S.; Kruse, Florian M.; Trapp, Oliver
Angewandte Chemie International Edition,
July 15, 2019, Letnik:
58, Številka:
29
Journal Article
Recenzirano
It is assumed that RNA played a key role in the origin of life, and the transition to more complex but more stable DNA for continuous information storage and replication requires the development of a ...ribonucleotide reductase to obtain the deoxyribonucleotides from ribonucleotides. This step, as well as an alternative path from abiotic molecules to DNA‐based life is completely unknown. Shown here is the formation of deoxyribonucleosides under relevant prebiotic conditions in water in high regio‐ and stereoselectivity, from all canonical purine and pyrimidine bases, by condensation with acetaldehyde and sugar‐forming precursors. Thus, a continuous path to deoxyribonucleosides, starting from simple, prebiotically available molecules has been discovered. Furthermore, the deoxyapionucleosides (DApiNA) were identified as a potential DNA progenitor. The results suggest that the DNA world evolved much earlier than previously assumed.
Path‐breaking: A path to deoxyribonucleosides starting from simple, prebiotically available molecules was found. Deoxyribonucleosides are formed under prebiotic conditions (in water!) in high regio‐ and stereoselectivity from all canonical purine and pyrimidine bases by condensation with acetaldehyde and sugar‐forming precursors.
Rigorous rehabilitation after anterior cruciate ligament (ACL) reconstruction is necessary for a successful surgical outcome. A large number of clinical trials continue to assess aspects of this ...rehabilitation process. Prior systematic reviews evaluated fifty-four Level-I and II clinical trials published through 2005.
Eighty-five articles from 2006 to 2010 were identified utilizing multiple search engines. Twenty-nine Level-I or II studies met inclusion criteria and were evaluated with use of the CONSORT (Consolidated Standards of Reporting Trials) criteria. Topics included in this review are postoperative bracing, accelerated strengthening, home-based rehabilitation, proprioception and neuromuscular training, and six miscellaneous topics investigated in single trials.
Bracing following ACL reconstruction remains neither necessary nor beneficial and adds to the cost of the procedure. Early return to sports needs further research. Home-based rehabilitation can be successful. Although neuromuscular interventions are not likely to be harmful to patients, they are also not likely to yield large improvements in outcomes or help patients return to sports faster. Thus, they should not be performed to the exclusion of strengthening and range-of-motion exercises. Vibration training may lead to faster and more complete proprioceptive recovery but further evidence is needed.
Several new modalities for rehabilitation after ACL reconstruction may be helpful but should not be performed to the exclusion of range-of-motion, strengthening, and functional exercises. Accelerated rehabilitation does not appear to be harmful but further investigation of rehabilitation timing is warranted.
Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.
In this paper, we present an experimental investigation of pool boiling heat transfer on multiscale (micro/nano) functionalized metallic surfaces. Heat transfer enhancement in metallic surfaces is ...very important for large scale high heat flux applications like in the nuclear power industry. The multiscale structures were fabricated via a femtosecond laser surface process (FLSP) technique, which forms self-organized mound-like microstructures covered by layers of nanoparticles. Using a pool boiling experimental setup with deionized water as the working fluid, both the heat transfer coefficients and critical heat flux were investigated. A polished reference sample was found to have a critical heat flux of 91 W/cm
at 40 °C of superheat and a maximum heat transfer coefficient of 23,000 W/m
K. The processed samples were found to have a maximum critical heat flux of 142 W/cm
at 29 °C and a maximum heat transfer coefficient of 67,400 W/m
K. It was found that the enhancement of the critical heat flux was directly related to the wetting and wicking ability of the surface which acts to replenish the evaporating liquid and delay critical heat flux. The heat transfer coefficients were also found to increase when the surface area ratio was increased as well as the microstructure peak-to-valley height. Enhanced nucleate boiling is the main heat transfer mechanism, and is attributed to an increase in surface area and nucleation site density.
Ultrasound of the lung and quantification of B lines was recently introduced as a novel tool to detect overhydration. In the present study, we aimed to evaluate a four-region protocol of lung ...ultrasound to determine the pulmonary fluid status in ventilated patients in the intensive care unit.
Fifty patients underwent both lung ultrasound and transpulmonary thermodilution measurement with the PiCCO system. An ultrasound score based on number of single and confluent B lines per intercostal space was used to quantify pulmonary overhydration. To check for reproducibility, two different intensivists who were blinded as to the ultrasound pictures reassessed and classified them using the same scoring system. The results were compared with those obtained using other methods of evaluating hydration status, including extravascular lung water index (EVLWI) and intrathoracic blood volume index calculated with data from transpulmonary thermodilution measurements. Moreover, chest radiographs were assessed regarding signs of pulmonary overhydration and categorized based on a numeric rating scale.
Lung water assessment by ultrasound using a simplified protocol showed excellent correlation with EVLWI over a broad range of lung hydration grades and ventilator settings. Correlation of chest radiography and EVLWI was less accurate. No correlation whatsoever was found with central venous pressure measurement.
Lung ultrasound is a useful, non-invasive tool in predicting hydration status in mechanically ventilated patients. The four-region protocol that we used is time-saving, correlates well with transpulmonary thermodilution measurements and performs markedly better than chest radiography.
Background
Postoperative wound complications are common following surgical procedures. Negative‐pressure wound therapy (NPWT) is well recognized for the management of open wounds and has been applied ...recently to closed surgical incisions. The evidence base to support this intervention is limited. The aim of this study was to assess whether NPWT reduces postoperative wound complications when applied to closed surgical incisions.
Methods
This was a systematic review and meta‐analysis of randomized clinical trials of NPWT compared with standard postoperative dressings on closed surgical incisions.
Results
Ten studies met the inclusion criteria, reporting on 1311 incisions in 1089 patients. NPWT was associated with a significant reduction in wound infection (relative risk (RR) 0·54, 95 per cent c.i. 0·33 to 0·89) and seroma formation (RR 0·48, 0·27 to 0·84) compared with standard care. The reduction in wound dehiscence was not significant. The numbers needed to treat were three (seroma), 17 (dehiscence) and 25 (infection). Methodological heterogeneity across studies led to downgrading of the quality of evidence to moderate for infection and seroma, and low for dehiscence.
Conclusion
Compared with standard postoperative dressings, NPWT significantly reduced the rate of wound infection and seroma when applied to closed surgical wounds. Heterogeneity between the included studies means that no general recommendations can be made yet.
Good for closed wounds too
Video
Ever since the discovery of nucleic acids 150 years ago,1 major achievements have been made in understanding and decrypting the fascinating scientific questions of the genetic code.2 However, the ...most fundamental question about the origin and the evolution of the genetic code remains a mystery. How did nature manage to build up such intriguingly complex molecules able to encode structure and function from simple building blocks? What conditions were required? How could the precursors survive the unhostile environment of early Earth? Over the past decades, promising synthetic concepts were proposed providing clarity in the field of prebiotic nucleic acid research. In this Minireview, we show the current status and various approaches to answer these fascinating questions.
Unlocking life's mysteries: Achievements in the field of prebiotic RNA and DNA nucleoside and nucleotide synthesis are highlighted under consideration of plausible reaction conditions, starting from simple building blocks.
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