The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has caused the current worldwide pandemic and the associated coronavirus disease 2019 with potentially lethal outcome. Although ...effective vaccines strongly contributed to reduce disease severity, establishing a toolbox to control current and newly emerging coronaviruses of epidemic concern requires the development of novel therapeutic compounds, to treat severely infected individuals and to prevent virus transmission. Here we present a therapeutic strategy targeting the SARS-CoV-2 RNA genome using antisense oligonucleotides (ASOs). We demonstrate that selected locked nucleic acid gapmers have the potency to reduce the
intracellular viral load by up to 96%. Our promising results strongly support the case for further development of our preselected ASOs as therapeutic or prophylactic antiviral agents.
Lung cancer was a rare disease at the start of the last century, but exposures to new etiologic agents and an increasing lifespan have combined to make it one of the most prevalent forms of the ...disease in the 21st century. Furthermore, lung cancer remains the most common cause of cancer-related death. Pre-operative QoL and exercise capacity are poor in patients with lung cancer and become worse following (surgical) treatment. Moreover, post-operative recovery of QoL and exercise tolerance are only partial over extended periods of time. Therefore, in patients with lung cancer, there is a clear indication for comprehensive peri- and post-operative exercise-based rehabilitation. Indeed, exercise-based pulmonary rehabilitation could prove to be a powerful non-pharmacological intervention to improve exercise performance and health status, irrespective of change in pulmonary function. To date, the effects of exercise-based rehabilitation in patients with lung cancer have not been extensively studied but preliminary results from small-scale intervention studies suggest that lung cancer patients are good candidates for peri- and post-operative pulmonary rehabilitation programmes.
Large scale IT usage harms the environment during its life-cycle and this results in a threat to sustainability. This research provides an approach to help IT organizations recognize and prioritize ...appropriate measures. A green ontology consisting of suggestions to improve IT sustainability is introduced based on earlier work. Then, to be able to judge where sustainability impacts the IT of an organization, the dimensions Govern, Source, Make, and Return as derived from the Supply Chain Operations Relationship model are applied within a sustainability context. Furthermore, four maturity levels are defined for IT sustainability based on the available sustainable development literature: Cleaning up the waste, Preventing waste, Product reengineering, and IT as an opportunity. Finally, the resulting Maturity for IT Sustainability (MITS) model is presented which categorizes all ontology measures appropriately within the two MITS dimensions.
Abstract Purpose The aim of this study was to measure and improve the quality of target volume delineation by means of national consensus on target volume definition in early-stage rectal cancer. ...Methods and materials The CTV’s for eight patients were delineated by 11 radiation oncologists in 10 institutes according to local guidelines (phase 1). After observer variation analysis a workshop was organized to establish delineation guidelines and a digital atlas, with which the same observers re-delineated the dataset (phase 2). Variation in volume, most caudal and cranial slice and local surface distance variation were analyzed. Results The average delineated CTV volume decreased from 620 to 460 cc ( p < 0.001) in phase 2. Variation in the caudal CTV border was reduced significantly from 1.8 to 1.2 cm SD ( p = 0.01), while it remained 0.7 cm SD for the cranial border. The local surface distance variation (cm SD) reduced from 1.02 to 0.74 for anterior, 0.63 to 0.54 for lateral, 0.33 to 0.25 for posterior and 1.22 to 0.46 for the sphincter region, respectively. Conclusions The large variation in target volume delineation could significantly be reduced by use of consensus guidelines and a digital delineation atlas. Despite the significant reduction there is still a need for further improvement.
Fatigue is the most prevalent symptom among patients with sarcoidosis, and skeletal muscle dysfunction is a common clinical feature, making resistance training (RT) a recommended treatment strategy. ...Despite lacking knowledge regarding whether high-intensity RT will aggravate fatigue, low to moderate-intensity is routinely used even if the evidence for this protocol to improve muscle strength is inconclusive. This study aimed to investigate whether one single session of high-intensity RT induces a higher increase in fatigue than one single session of moderate-intensity RT. In this randomized crossover study, 41 patients with pulmonary sarcoidosis (age: 53 ± 11 yr) were recruited. They randomly performed one single session of high-intensity RT, 4 sets × 5 repetitions maximum (5RM), and one single session of moderate-intensity RT, 2 sets × 25 RM. Fatigue was assessed with the Visual Analogue Scale (0–100 mm) immediately before (T0), immediately after (T1) and 24 hours after (T2) each exercise session. Fatigue development from T0 to T1 was significantly lower after 5RM (−3 ± 18 mm) than after 25RM (5 ± 15 mm), p = 0.004. No difference was seen from T0 to T2 between 5RM (0 ± 17 mm) and 25RM (6 ± 18 mm), p = 0.147. The high-intensity 5RM session did not induce a larger increase in fatigue than the moderate-intensity 25RM session. RT appears feasible and safe in patients with pulmonary sarcoidosis irrespective of the intensity. Thus, the long-term effects of high-intensity RT on fatigue should be explored in a RT programme of longer duration.
Polycystin-1 is a novel protein predicted to be a large membrane-spanning glycoprotein with an extracellular N-terminus and an intracellular C-terminus, harboring several structural motifs. To study ...the subcellular localization, antibodies raised against various domains of polycystin-1 and against specific adhesion complex proteins were used for two-color immunofluorescence staining. In Madine Darby canine kidney (MDCK) cells, polycystin-1 was detected in the cytoplasm as well as co-localizing with desmosomes, but not with tight or adherens junctions. Using confocal laser scanning and immunoelectron microscopy we confirmed the desmosomal localization. By performing a calcium switch experiment, we demonstrated the sequential reassembly of tight junctions, subsequently adherens junctions and finally desmosomes. Polycystin-1 only stained the membrane after incorporation of desmoplakin into the desmosomes, suggesting that membrane-bound polycystin-1 may be important for cellular signaling or cell adhesion, but not for the assembly of adhesion complexes.
Polycystin-2 is a predicted integral membrane protein with non-selective cation channel activity. The protein is encoded by the PKD2 gene, which is mutated in approximately 15% of patients with ...autosomal dominant polycystic kidney disease (ADPKD). Polycystin-2 can interact with the transmembrane protein polycystin-1, the product of the PKD1 gene. However, endoplasmic reticulum (ER) localization was reported for (heterologously expressed) polycystin-2 in cultured cells and baso-lateral localization has been reported in renal tissues. Using two polyclonal antisera raised against polycystin-2 we demonstrated distinct expression of the endogenous protein in the Golgi apparatus and the plasma membrane of MDCK cells. In contrast, most of the heterologously expressed polycystin-2 (PC2-EGFP) remained in the ER, substantially overlapping with the staining pattern of protein-disulfide isomerase (PDI), a marker for the ER. Only in a small subset of these cells weak plasma membrane signals were observed. Membrane staining was also suggested by immunoelectron microscopy and was confirmed by subcellular fractionation on sucrose density gradients. The plasma membrane staining disappeared following extraction with a buffer containing Triton X-100, whereas signals for polycystin-1 and E-cadherin remained visible, suggesting that polycystin-2 is neither tightly bound to the Triton X-100 insoluble cytoskeleton, nor to these proteins. We conclude that endogenous polycystin-2 is transported via the Golgi apparatus to the plasma membrane and has a broader membrane localization than polycystin-1. These data suggest that polycystin-2 can move freely in certain regions of the membrane where it probably functions as a channel, activated by, or in complex with, polycystin-1.
Tuberous sclerosis (TSC) is an autosomal dominant multisystem disorder with loci assigned to chromosomes 9 and 16. Using pulsed-field gel electrophoresis (PFGE), we identified five TSC-associated ...deletions at 16p13.3. These were mapped to a 120 kb region that was cloned in cosmids and from which four genes were isolated. One gene, designated TSC2, was interrupted by all five PFGE deletions, and closer examination revealed several intragenic mutations, including one de novo deletion. In this case, Northern blot analysis identified a shortened transcript, while reduced expression was observed in another TSC family, confirming TSC2 as the chromosome 16 TSC gene. The 5.5 kb TSC2 transcript is widely expressed, and its protein product, tuberin, has a region of homology to the GTPase-activating protein GAP3.
Autosomal Dominant Polycystic Kidney Disease (ADPKD), a common inherited disease leading to progressive renal failure, can be caused by a mutation in either the PKD1 or PKD2 gene. Both genes encode ...for putative transmembrane proteins, polycystin-1 and polycystin-2, which show significant homology to each other and are believed to interact at their carboxy termini. To identify genes that code for related proteins we searched for homologous sequences in several databases and identified one partial cDNA and two genomic sequences with significant homology to both polycystin-1 and - 2. Further analysis revealed one novel gene, PKD2L2, located on chromosome band 5q31, and two recently described genes, PKD2L and PKDREJ, located on chromosome bands 10q31 and 22q13.3, respectively. PKD2L2 and PKD2L, which encode proteins of 613 and 805 amino acids, are approximately 65% similar to polycystin-2. The third gene, PKDREJ, encodes a putative 2253 amino acid protein and shows about 35% similarity to both polycystin-1 and polycystin-2. For all the genes expression was found in testis. Additional expression of PKD2L was observed in retina, brain, liver and spleen by RT-PCR. Analyses of five ADPKD families without clear linkage to either the PKD1 or PKD2 locus showed no linkage to any of the novel loci, excluding these genes as the cause of ADPKD in these families. Although these genes may not be involved in renal cystic diseases, their striking homology to PKD2 and PKD1 implies similar roles and may contribute to elucidating the function of both polycystin-1 and polycystin-2.
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