The presence of large palaeo-landslides can hinder the construction of railway lines if they cause an alteration of the natural balance of the slope, significantly increasing the cost of the project. During the construction works in a section of the Madrid–Asturias high-speed railway line (Spain), a large-scale hillside instability affected 460 m of the section. The ground movement began 10 months after the start of the excavations and remained active throughout the observation period (2008–2010). Data provided by fieldwork, boreholes and instrumental monitoring have allowed the investigation of the geological units involved, together with the geometry and the kinematics of the mass movement. This landslide involves a Paleozoic basement with an estimated volume of 4 400 000 m³. It shows low displacement rates (<45 mm a^–1) and was accommodated on a single surface of rupture, which reaches more than 60 m depth. The kinematics is favoured by structural and lithological conditions, there being a strong rheological contrast in the lower part of the mobilized ground. This movement is linked to a large palaeo-landslide that was partially reactivated when excavations undermined the lower slopes of the hillside. Technical solutions for the stabilization have already caused an additional cost of 17% over the initial budget.

In 2015, the M_w 7.8 Gorkha earthquake struck Nepal, triggering thousands of landslides across the central and eastern Himalayas. These landslides had many adverse effects, including causing widespread damage to low-grade transport routes (e.g. tracks, footpaths) in rural regions that depend on tourism for survival. Langtang Valley is a glacial–periglacial landscape located 60 km north of Kathmandu. It is one of the most popular trekking regions in Nepal and has been severely affected by Gorkha earthquake-triggered and monsoon-triggered landsliding. Here, qualitative and quantitative observations from fieldwork and remote sensing are used to describe the materials and geomorphology of the landslides across Langtang Valley, and to quantify the extent to which coseismic and monsoon-triggered landslides have affected Langtang's trekking infrastructure. The dominant bedrock materials involved within Langtang landslides are found to be a range of gneisses and intruded leucogranites. In total, 64 landslides are found to have intersected trekking paths across Langtang, with coseismic and monsoon-triggered landslides having an impact on c. 3 km and 0.8 km of path respectively. It is observed that the practice of reconstructing paths through unstable landslide deposits is leaving the trekking infrastructure across Langtang increasingly vulnerable to future failure.

Dalton Buysse, Anna-Katharina Pfitzner, Matt West, Aurelien Roux, and Greg Odorizzi

The ESCRT-III protein complex executes reverse-topology membrane scission. The scission mechanism is unclear but is linked to remodeling of ESCRT-III complexes at the membrane surface. At endosomes, ESCRT-III mediates the budding of intralumenal vesicles (ILVs). In Saccharomyces cerevisiae, ESCRT-III activity at endosomes is regulated through an unknown mechanism by Doa4, an ubiquitin hydrolase that deubiquitylates transmembrane proteins sorted into ILVs. We report that the non-catalytic N-terminus of Doa4 binds Snf7, the predominant ESCRT-III subunit. Through this interaction, Doa4 overexpression alters Snf7 assembly status and inhibits ILV membrane scission. In vitro, the Doa4 N-terminus inhibits association of Snf7 with Vps2, which functions with Vps24 to arrest Snf7 polymerization and remodel Snf7 polymer structure. In vivo, Doa4 overexpression inhibits Snf7 interaction with Vps2 and also with the ATPase Vps4, which is recruited by Vps2 and Vps24 to remodel ESCRT-III complexes by catalyzing subunit turnover. Our data suggest a mechanism by which the deubiquitylation machinery regulates ILV biogenesis by interfering with ESCRT-III remodeling.

The microtubule-binding taxanes, docetaxel and cabazitaxel, are administered intravenously for the treatment of castration-resistant prostate cancer (CRPC) as the oral administration of these drugs is largely hampered by their low and highly variable bioavailabilities. Using a simple, rapid, and environmentally friendly microwave-assisted protocol, we have synthesized a number of 3,5-bis(styryl)pyrazoles 2a-l, thus allowing for their screening for antiproliferative activity in the androgen-independent PC3 prostate cancer cell line. Surprisingly, two of these structurally simple 3,5-bis(styryl)pyrazoles (2a and 2l) had concentrations which gave 50% of the maximal inhibition of cell proliferation (GI₅₀) in the low micromolar range in the PC3 cell line and were thus selected for extensive further biologic evaluation (apoptosis and cell cycle analysis, and effects on tubulin and microtubules). Our findings from these studies show that 3,5-bis[(1E)-2(2,6-dichlorophenyl)ethenyl]-1H-pyrazole 2l 1) caused significant effects on the cell cycle in PC3 cells, with the vast majority of treated cells in the G₂/M phase (89%); 2) induces cell death in PC3 cells even after the removal of the compound; 3) binds to tubulin [dissociation constant (K_d) 0.4 ± 0.1 μM] and inhibits tubulin polymerization in vitro; 4) had no effect upon the polymerization of the bacterial cell division protein FtsZ (a homolog of tubulin); 5) is competitive with paclitaxel for binding to tubulin but not with vinblastine, crocin, or colchicine; and 6) leads to microtubule depolymerization in PC3 cells. Taken together, these results suggest that 3,5-bis(styryl)pyrazoles warrant further investigation as lead compounds for the treatment of CRPC.

When we critically assess the reason for the current dominance of ⁶⁸Ga-labeled peptides and peptide-like ligands in radiopharmacy and nuclear medicine, we have to conclude that the major advantage of such radiopharmaceuticals is the apparent lack of suitable ¹⁸F-labeling technologies with proven clinical relevance. To prepare and to subsequently perform a clinical proof-of-concept study on the general suitability of silicon-fluoride-acceptor (SiFA)–conjugated radiopharmaceuticals, we developed inhibitors of the prostate-specific membrane antigen (PSMA) that are labeled by isotopic exchange (IE). To compensate for the pronounced lipophilicity of the SiFA unit, we used metal chelates, conjugated in close proximity to SiFA. Six different radiohybrid PSMA ligands (rhPSMA ligands) were evaluated and compared with the commonly used ¹⁸F-PSMA inhibitors ¹⁸F-DCFPyL and ¹⁸F-PSMA-1007. Methods: All inhibitors were synthesized by solid-phase peptide synthesis. Human serum albumin binding was measured by affinity high-performance liquid chromatography, whereas the lipophilicity of each tracer was determined by the n-octanol/buffer method. In vitro studies (IC₅₀, internalization) were performed on LNCaP cells. Biodistribution studies were conducted on LNCaP tumor–bearing male CB-17 SCID mice. Results: On the laboratory scale (starting activities, 0.2–9.0 GBq), labeling of ¹⁸F-rhPSMA-5 to -10 by IE was completed in < 20 min (radiochemical yields, 58% ± 9%; radiochemical purity, >97%) with molar activities of 12–60 GBq/μmol. All rhPSMAs showed low nanomolar affinity and high internalization by PSMA-expressing cells when compared with the reference radiopharmaceuticals, medium-to-low lipophilicity, and high human serum albumin binding. Biodistribution studies in LNCaP tumor–bearing mice revealed high tumor uptake, sufficiently fast clearance kinetics from blood, low hepatobiliary excretion, fast renal excretion, and very low uptake of ¹⁸F activity in bone. Conclusion: The novel ¹⁸F-rhPSMA radiopharmaceuticals developed under the radiohybrid concept show equal or better targeting characteristics than the established ¹⁸F-PSMA tracers ¹⁸F-DCFPyL and ¹⁸F-PSMA-1007. The unparalleled simplicity of production, the possibility to produce the identical ⁶⁸Ga-labeled ¹⁹F-⁶⁸Ga-rhPSMA tracers, and the possibility to extend this concept to true theranostic radiohybrid radiopharmaceuticals, such as F-Lu-rhPSMA, are unique features of these radiopharmaceuticals.

¹⁸F-prostate-specific membrane antigen (PSMA)-1007 is excreted mainly through the liver. We benchmarked the performance of ¹⁸F-PSMA-1007 against 3 renally excreted PSMA tracers. Methods: Among 668 patients, we selected 27 in whom PET/CT results obtained with ⁶⁸Ga-PSMA-11, ¹⁸F-DCFPyL (2-(3-(1-carboxy-5-[(6-[¹⁸F]fluoro-pyridine-3-carbonyl)-amino]-pentyl)-ureido)-pentanedioic acid), or ¹⁸F-JK-PSMA-7 (JK, Juelich-Koeln) were interpreted as equivocal or negative or as oligometastatic disease (PET-1). Within 3 wk, a second PET scan with ¹⁸F-PSMA-1007 was performed (PET-2). The confidence in the interpretation of PSMA-positive locoregional findings was scored on a 5-point scale, first in routine diagnostics (reader 1) and then by an independent second evaluation (reader 2). Discordant PSMA-positive skeletal findings were examined by contrast-enhanced MRI. Results: For both readers, ¹⁸F-PSMA-1007 facilitated the interpretability of 27 locoregional lesions. In PET-2, the clinical readout led to a significantly lower number of equivocal locoregional lesions (P = 0.024), and reader 2 reported a significantly higher rate of suspected lesions that were falsely interpreted as probably benign in PET-1 (P = 0.023). Exclusively in PET-2, we observed a total of 15 PSMA-positive spots in the bone marrow of 6 patients (22%). None of the 15 discordant spots had a morphologic correlate on the corresponding CT scan or on the subsequent MRI scan. Thus, ¹⁸F-PSMA-1007 exhibits a significantly higher rate of unspecific medullary spots (P = 0.0006). Conclusion: ¹⁸F-PSMA-1007 may increase confidence in interpreting small locoregional lesions adjacent to the urinary tract but may decrease the interpretability of skeletal lesions.

Background

Advances in information communications technology (ICT) provide opportunities for enhanced diabetes care. Knowledge of the more acceptable communication modalities in patients of different ages will help to inform the direction of future innovations.

ABSTRACTThe Standard Days Method (SDM), a modern fertility awareness-based family planning method, has been introduced in 30 countries since its development in 2001. It is still unclear to what extent the SDM was mainstreamed within the family planning method mix, particularly in low- and middle-income country (LMIC) settings, where the SDM had been introduced by donors and implementing partners. This review of implementation science publications on the SDM in LMICs first looked at community pilot studies of the SDM to determine the acceptability of the method; correct use and efficacy rates; demographics of users; and changes to contraceptive prevalence rates and family planning behaviors, especially among men and couples. Then, we examined the status of the SDM in the 16 countries that had attempted to scale up the method within national family planning protocols, training, and service delivery. At the community level, evidence demonstrated a high level of acceptability of the method; efficacy rates comparable to the initial clinical trials; diversity in demographic characteristics of users, including first-time or recently discontinued users of family planning; increased male engagement in family planning; and improved couple's communication. Nationally, few countries had scaled up the SDM due to uneven stakeholder engagement, lackluster political will, and competing resource priorities. Results of this review could help policy makers determine the added value of the SDM in the contraceptive method mix and identify potential barriers to its implementation moving forward.

OBJECTIVE

To report U.S. national population-based rates and trends in diabetic ketoacidosis (DKA) and hyperglycemic hyperosmolar state (HHS) among adults, in both the emergency department (ED) and inpatient settings.

OBJECTIVE

We aimed to evaluate trends in bone mineral density (BMD) and the prevalence of osteoporosis/osteopenia in U.S. adults with prediabetes and normal glucose regulation (NGR) and further investigate the association among prediabetes, osteopenia/osteoporosis, and fracture.

Balamuthia mandrillaris is an under-reported, pathogenic free-living amoeba that causes Balamuthia amoebic encephalitis (BAE) and cutaneous skin infections. Although cutaneous infections are not typically lethal, BAE with or without cutaneous involvement is usually fatal. This is due to the lack of drugs that are both efficacious and can cross the blood-brain barrier. We aimed to discover new leads for drug discovery by screening the open-source Medicines for Malaria Venture (MMV) Malaria Box and MMV Pathogen Box, with 800 compounds total. From an initial single point screen at 1 and 10 μM, we identified 54 hits that significantly inhibited the growth of B. mandrillaris in vitro. Hits were reconfirmed in quantitative dose-response assays and 23 compounds (42.6%) were confirmed with activity greater than miltefosine, the current standard of care.

Currently, the expansion of the novel human respiratory coronavirus (known as SARS-CoV-2 [severe acute respiratory syndrome coronavirus 2], COVID-2019 [coronavirus disease 2019], or 2019-nCoV [2019 novel coronavirus]) has stressed the need for therapeutic alternatives to alleviate and stop this new epidemic. The previous epidemics of infections by high-morbidity human coronaviruses, such as SARS-CoV in 2003 and the Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012, prompted the characterization of compounds that could be potentially active against the currently emerging novel coronavirus, SARS-CoV-2. The most promising compound is remdesivir (GS-5734), a nucleotide analog prodrug currently in clinical trials for treating Ebola virus infections. Remdesivir inhibited the replication of SARS-CoV and MERS-CoV in tissue cultures, and it displayed efficacy in nonhuman animal models. In addition, a combination of the human immunodeficiency virus type 1 (HIV-1) protease inhibitors lopinavir/ritonavir and interferon beta (LPV/RTV–IFN-β) was shown to be effective in patients infected with SARS-CoV. LPV/RTV–IFN-β also improved clinical parameters in marmosets and mice infected with MERS-CoV. Remarkably, the therapeutic efficacy of remdesivir appeared to be superior to that of LPV/RTV–IFN-β against MERS-CoV in a transgenic humanized mouse model. The relatively high mortality rates associated with these three novel human coronavirus infections, SARS-CoV, MERS-CoV, and SARS-CoV-2, have suggested that proinflammatory responses might play a role in the pathogenesis. It remains unknown whether the generated inflammatory state should be targeted. Therapeutics that target the coronavirus alone might not be able to reverse highly pathogenic infections. This minireview aims to provide a summary of therapeutic compounds that have shown potential in fighting SARS-CoV-2 infections.

Chromosomal resistance islands containing the methicillin resistance gene mecD (McRI_mecD) have been reported in Macrococcus caseolyticus. Here, we identified novel macrolide resistance genes in Macrococcus canis on similar elements, called McRI_msr. These elements were also integrated into the 3' end of the 30S ribosomal protein S9 gene (rpsI), delimited by characteristic attachment (att) sites, and carried a related site-specific integrase gene (int) at the 5' end. They carried novel macrolide resistance genes belonging to the msr family of ABC subfamily F (ABC-F)-type ribosomal protection protein [msr(F) and msr(H)] and the macrolide efflux mef family [mef(D)]. Highly related mef(D)-msr(F) fragments were found on diverse McRI_msr elements in M. canis, M. caseolyticus, and Staphylococcus aureus. Another McRI_msr-like element identified in an M. canis strain lacked the classical att site at the 3' end and carried the msr(H) gene but no neighboring mef gene. The expression of the novel resistance genes in S. aureus resulted in a low-to-moderate increase in the MIC of erythromycin but not streptogramin B. In the mef(D)-msr(F) operon, the msr(F) gene was shown to be the crucial determinant for macrolide resistance. The detection of circular forms of McRI_msr and the mef(D)-msr(F) fragment suggested mobility of both the island and the resistance gene subunit. The discovery of McRI_msr in different Macrococcus species and S. aureus indicates that these islands have a potential for dissemination of antibiotic resistance within the Staphylococcaceae family.

Since 2018, the FDA has required that U.S. clinical trial results be reported to clinicaltrials.gov within a year of trial completion, but this mandate is often ignored. A recent study found that less than half of U.S. trials submitted results to the site by the deadline. Industry-led trials were the most likely to be reported on time.

Chuyên môi giới - đầu tư bất động sản phân khúc đa dạng:

• Nhà, đất thổ cư đẹp 
• Đất nền dự án 
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Khu vực môi giới tốt nhất: Sơn Trà (Đà Nẵng), Điện Bàn (Quảng Nam), Quy Nhơn (Bình Định), Thừa Thiên Huế

Danh sách dự án BĐS đã thực hiện: Dự án Apec Mandala Wyndham Huế, dự án Nhơn Hội New City, dự án Ngọc Dương Riverside, dự án Mường Thanh Sơn Trà Đà Nẵng...

 

Along with the recovery of market, property investment also rebounds with new trends. Here are three new trends of property investment that become more and more popular in 2015.

Found footage from many hours of trawling through night-drive ghost sighting videos on YouTube while on lockdown. The Golden Filter’s Stephen Hindman takes us on a haunted night-drive in the video for ‘But Please’, a new track released under his Isolating alias. ‘But Please’ appears on his new EP for Optimo Music Digital Danceforce, System. […]

The post Isolating finds himself on a haunted night-drive in ‘But Please’ appeared first on FACT Magazine.

Season 5 of Respawn Entertainment’s hero-based battle royale kicks off next week and it looks like they’re doing more than just blowing up the map. This new Apex Legends trailer shows off what appears to be a horde mode PvE quest initiated by the newest Legend of the bunch: Loba. It looks like you’ll be […]

If you're 13 to 24 years old and love to make movies, you'll want to enter the Windsor Youth Short Film Showcase next week. Organizer Gemma Eva says the project is meant to spotlight local "Gen-Z filmmakers."

Crawling on his belly through a sewer pipe beneath the streets of Warsaw, Poland, with a battle raging overhead, 16-year-old Lucjan Krause could scarcely have imagined he would survive the fighting, let alone go on to build a globally admired atomic physics program at the University of Windsor. Now 92 and still in full command […]

The US Army has built a prototype device that allows wearers to go glove-free in freezing conditions. It works by heating the forearm, which helps keep the fingertips warm

Always forgetting birthdays? Terrible at staying in touch? New tech promises to turn you into the best buddy ever. We put it to the test

TfL as in Transport for London. Greeeeeaaat.

Being at home this long, or really, just in one place for this long, has led me to see how much waste I produce. Spoiler alert: it’s a lot more than I thought. But I’m not here to shame anyone, in fact, quite the opposite. I think there are plenty of small ways we can cut down our carbon footprint, from driving less (check), to not using a washing machine or dryer (also, sadly, check), but gardening is what I’ve been doing, and is something that I’d recommend everyone give a shot now that we all have a little more times on our hands.

GETTING STARTED

Composting is a natural way to recycle all of the organic materials in your house through decomposition. Compost can improve your soil’s water retention, which saves you money on your water bills, and helps keep excess garbage out of landfills, too. To get started you need two things. The first is a compost bin for your kitchen. This is great whether you want to start a compost at home or if you have a compost center you can bring them to. You want something sleek, designy, yet simple because after all, it’s really just a trash can. This is an excellent one.

Read more at The Daily Beast.

Rafael Nadal revealed this week he was doubtful there will be further tennis in 2020.

The International Astronomical Union has concluded a review of satellite mega constellations such as SpaceX's Starlink satellites and found they will have a major impact on large telescopes, but not naked eye astronomy

Brown dwarfs, which are halfway between huge planets and small stars, have extremely powerful winds whipping around them at speeds of about 650 metres per second

A new automated lab bench combs through known chemical reactions to figure out how best to synthesize compounds

Failed to get friends list and several more Pokemon GO friends list errors are once again impacting players on iOS and Android.

Manny gives fashion advice. Chris learns that he doesn’t know how to Kindle. And Anna Marie orders avatar tuna. Is it a slow news week?

As Anna prepares her statement, Alice introduces us to a new form of missile delivery. Chris plays really old games instead of the other old...

Anna Marie ponders the limits of her love. Kelley rules Ireland. Johnathan usurps Ireland. Then Chris cheats goes off to play Suikoden II.

It’s a cozy foursome on the RPGCast this week. Discussing the highs and lows of their now playing. But in the end, we are left wondering, what the heck is a “nursenary?”

ON one of those Greenock afternoons when rain and sun fight for the day’s naming rights a statistic becomes flesh and blood. At the side of a four-lane highway bearing the weight of the town’s rush-hour traffic a young wheelchair-user approaches.

C&A, Adidas/Reebok, Esprit and M&S round out top five as average scores increase year on year, but Max Mara, Pepe Jeans and Tom Ford fall flat

The H&M Group, C&A, Adidas/Reebok, Esprit, Marks & Spencer and Patagonia are the world’s most transparent major fashion brands, according to the 2020 fashion transparency index from the campaign group Fashion Revolution.

The annual report, now in its fifth year, ranks the amount of information companies disclose about social and environmental policies, processes and effects within their operations and supply chains.

From Stay at Home T-shirts to NHS baseball caps, here’s a selection from small labels donating some or all of their profits to charities helping healthcare workers and the Covid-19 response

Some labels are showing how fashion can put the planet first. To celebrate Earth Day, here are a few of our favourites

Researchers have uncovered how bats can carry the Middle East respiratory syndrome (MERS) coronavirus without getting sick -- research that could shed light on how coronaviruses make the jump to humans and other animals.

People who attended religious services at least once a week were significantly less likely to die from 'deaths of despair,' including deaths related to suicide, drug overdose, and alcohol poisoning, according to new research.