A recent article from Edutopia suggested that we’re rushing young children through childhood.

oscon: High Availability in MySQL - how to pick a solution that best matches your use case http://t.co/PItdw0maTj @h_ingo #oscon #tutorial

Teacher question: You wrote recently that it was a good idea to teach comprehension skills, but our school district says we shouldn’t, that it’s prior knowledge that matters. Do you know the baseball study? Have you read Natalie Wexler’s research? It is really difficult to trust research when everyone tells us something different. Shanahan's response:  I feel your pain.

The Public Investment Corporation has terminated the employment contract of Executive Head of Listed Investments Fidelis Madavo, it said in a statement on Monday.

Teacher question: You wrote recently that it was a good idea to teach comprehension skills, but our school district says we shouldn’t, that it’s prior knowledge that matters. Do you know the baseball study? Have you read Natalie Wexler’s research? It is really difficult to trust research when everyone tells us something different. Shanahan's response:  I feel your pain.

An organized kitchen doesn't have to be super minimal; it just has to function well. These editor-approved kitchen organizers help make the tools and ingredients in your kitchen more visible and accessible, so you can cook with more ease and joy!

Continue reading "Editors’ Picks: Kitchen Organizers" »

Stay up to date with the latest news, views and analysis as the number of coronavirus cases in SA increases.

Google’s (and now Alphabet’s) CEO opines in the FT (sub required) on why AI needs to be regulated, joining the chorus of tech leaders who have taken the apparent high road when it comes to regulation, even as governments around the world have shown next to no ability to actually regulate anything (well, I guess … Continue reading "Sundar Pichai in the FT: Please Regulate Us (And Good Luck with All That)"

A transit centre in north Edmonton was evacuated for about two hours Saturday morning due to a suspicious package.

RCMP say a 50-year-old man died and a 60-year-old man is in hospital following a crash involving a CP Rail train Friday morning.

Philadelphia Phillies star Bryce Harper believes Major League Baseball should relax its "dumb" rule preventing top players from competing in the Olympics.

So you've decided to hike Machu Picchu? Well great! There's no doubt that you're in for the experience of a lifetime. However, the truth of the matter is that now you've got some additional decisions to make. You see, there's more than one route to arrive to the world-famous Inca site, and even once you've arrived there are a few choices to make as well.

But don't fret! If you're looking to hike Machu Picchu, we've got the information you need to start planning your trip.

Hike Machu Picchu: Arriving to the Site

1. Classic Inca Trail

The Classic Inca Trail is a four-day trek stretching some 42 kilometers along an ancient road built by the Incas themselves. This is undoubtedly the most famous route to Machu Picchu, and it's the one way that offers the opportunity to enter the city through its storied Sun Gate. Frankly, we've got tons of information on the Inca Trail on other pages of our site, so we won't waste too much space being redundant here. Check out these pages for more information on the trail's itinerary as well as for access to an Inca Trail map.

2. One-Day Inca Trail

Whether you're crunched for time or simply don't feel physically up to four full days of trekking, don't fret--a small taste of the world-famous Inca Trail is still available to you! A number of tour companies offer an abridged version of the trek, either one full day of hiking or a shortened day followed by a night of camping and a dawn arrival at Machu Picchu. Besides the Inca Trail's famed destination, the one-day version of the trek also takes you past Wiñay Wayna, another favorite ruins along the trail. The bad news here is that you'll still need to reserve one of only a few hundred daily Inca Trail passes, meaning that, just like the full Inca Trail, you'll need to book this trek months in advance.

3. Lares Trail

Just north of the world-famous Sacred Valley sits the comparatively lesser-known Lares Valley, and whereas the former can be swarmed with tourists especially during the high season, life in the Lares Valley continues humming along relatively unchanged. So whether you're looking for a simpler, more culturally-immersive experience or if you just didn't book an Inca Trail pass in time, the Lares Trail is an excellent option! Lucky for you, we've already gathered plenty of information on the Lares Trail including the trek's daily itinerary and a side-by-side comparison of the Lares and Inca Trails if you're struggling to decide how to hike Machu Picchu.

4. Vilcabamba Traverse Route

Warning--this option is neither for the faint of heart nor the out of shape! The Vilcabamba Traverse Route is one of the newest on the Peru trekking circuit, clocking in at nearly 100 kilometers over the course of a week of trekking. Though very difficult, the route is especially rewarding--think a variety of diverse biomes and the ruins of Choquequirao, often compared to Machu Picchu although less than 40% of the site has been excavated (pictured above). Though visited by only 5,000 or so brave trekkers last year, be warned--the local government is pushing a plan to build a cable car to the site! If you want to see the ruins in their current, undisturbed state, it would be best to go sooner than later.

Hike Machu Picchu: Once You're There

5. Huayna Picchu

Just because you've finally arrived at Machu Picchu doesn't mean your hiking experience has to end! The famous mountain soaring in the background of most iconic Machu Picchu photos is possible to hike, and the experience is certainly recommended. The views from the top are great, and on the way down you can even take a back route to the storied Temple of the Moon. For more information on Huayna Picchu, you can check out this past post on our site.

So that's it for today! If you're planning to hike Machu Picchu and have any questions you'd like to ask us, feel free to reach out in the comments section below. And, if you've already done one of these hikes, feel free to share your experience as well. We appreciate all of your comments!

Machu Picchu, Peru

Although it's one of the most well-known archaeological wonders of the world, Machu Picchu still holds plenty of secrets and is on our shortlist of must-see destinations on a Peru trip.

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Machu Picchu is an enigma, some would say a paradox because it is known as both the best known yet least known about of the Inca sites. Since its discovery on July 24, 1911, by North American Hiram Bingham, Machu Picchu has been considered one of the world's greatest architectural and archaeological monuments, due to its extraordinary magnificence and harmonious structure. Machu Picchu is definitely one of the most fascinating sites in Peru.

At 2,400 meters above sea level, in the province of Urubamba, department of Cusco, Machu Picchu surprises us because of the way its stone constructions are spread over a narrow and uneven mountain top, bordering a sheer 400 meter cliff side of the Urubamba River canyon.

Why and how was Machu Picchu built?

Machu Picchu is a citadel shrouded in mystery, and to this day archaeologists have not definitively uncovered the purpose of this city of stone. The site covers an area of about one square mile, and stands in a region that the Incas considered to be magical, due to the meeting of the Andes mountains with the mighty Amazon river. When 135 bodies were discovered while exploring the site, 109 of which were female, some believed that Machu Picchu could have been a monastery where acllas (young girls) were trained to serve the Inca and the Willac Uno (High Priest). Others said it may simply have been an advance settlement for further expansions planned by the Incas. Perhaps the mystery may never be fully explained.

The surprising perfection and beauty of Machu Picchu's walls, built by joining stone to stone without using any cement or adhesive whatsoever, has led to many theories developing around how the city was constructed as well. It is said that a bird by the name of Kak'aqllu knew the formula for softening rock but by command, perhaps by the ancient Inca gods, had its tongue torn out. Others say there was a magic plant that could dissolve and compress stone. Nonetheless, mysteries and myths aside, the obvious wisdom and skill of the city's ancient builders -- evidenced by Machu Picchu's many squares, aqueducts, watchtowers, observatories and its sun clock -- is quite clear.

Many people may be drawn to Peru by Machu Picchu, yet it is considered by many of our guests, to be just one of many of the ruins featuring on the "highlights reel"of their trip. See reviews to read more

How to get to Machu Picchu - One day or multi day trails

You can take a one day trip to Peru from Cuzco or Lima, and walk up to this citadel in the clouds high in the Andes, or you can take some time to get acclimatised and trek via several trails that lead to Machu Picchu, most taking around 4 to 5 days to complete. Alot of people begin their Peru trip with the intent of visiting Machu Picchu, but don't know how much more there is to see and do in and around Machu Picchu.

After all, if you are going to Peru to experience a South American trip of a lifetime, why not learn about all the activities and other ruins there are to discover.

Popular activities on our Peru trips (including Machu Picchu):

1. Hiking the Lares or Classic Inca Trail
2. Exploring Machu Picchu - facts about Machu Picchu
3. Hiking in the Amazon jungle
4. Sea kayaking on Lake Titicaca
5. Staying with a local family on Amantani Island
6. Hiking Sacsayhuamán fortress
7. Hiking and cycle in the Sacred Valley of the Incas
8. Exploring Cuzco
9. Cycling through Andean villages and La Raya Pass
10. Hiking Amantani and Taquile Islands

[link to above pages Will]

You may be surprised at the number of activities you can do in Peru, in fact it's a surprise to alot of people that it is possible to enjoy these "non Machu Picchu focused" activities at all. Our philosophy is a little different to many tour companies, we believe that if you are going to travel all the way to a new country to experience a whole new culture, why not experience as many perspectives, local cultures and ruins as you can while you are there.

Obviously the most popular trail chosen by visitors wanting to visit Machu Picchu is the Inca Trail. Some people prefer the Lares trail because it offers a much more immersive experience in Peruvian village culture. If you wants to experience some of the traditions and village life the early Inca's enjoyed, you can stay with their descendants in one of the many villages along the Lares Trail.

If you want to hike the traditional route,  take a sneak peak below at some of what the Inca Trail has to offer.

Hike to Machu Picchu on the ancient Inca Trail

The Inca Trail between the Sacred Valley of the Urubamba River and the mysterious abandoned citadel of Machu Picchu is one of the world's classic treks. Climbing out of the river valley, crossing rugged mountain passes over 13,000 ft high, the trail winds through the Andes, passing numerous significant Inca ruins en route before descending through the Sun Gate to the silent stone city of Machu Picchu. To hike the Inca Trail is a thrilling experience and a great privilege. You need a permit from the Peruvian government to set foot on it, and there are strict limits on the number of permits issued each year.

But the Inca Trail is much more than a great hike. It is one small portion of an incredible network of such trails crossing high mountain ranges, bleak deserts, and raging Andean rivers, tying the Inca Empire together. At its peak expansion, Tahuantinsuyo (or The Four Corners as the empire was known) extended from what is now southern Colombia in the north, to central Chile in the south, covering a distance of about 5500 km (3400 mi). To rule such a vast domain, the emperor, or Inca, forged a remarkable communications system of approximately 18,600 miles of trails, paved through much of its length, stepped where need be, through tunnels where necessary, and using gossamer suspension bridges built of straw ropes to cross rivers unfordable in the wet season.

The roads served to move the conquering Inca armies, and were generally wide enough for a minimum of two warriors to travel abreast. A system of runners stationed at rest houses known as tambos sped messages along the roadways, much like the Pony Express mail of the old American West. The Inca, at his empire's capital in Cuzco, could receive news from far away Quito as rapidly as a letter crosses between the two cities in today's mail.

As remarkable as this highway system was in the days when it was built, used and maintained, it is an astounding testimony to its construction that so many segments remain serviceable today, after half a millennium of neglect. Clearly the Inca highway system ranks as one of the greatest engineering achievements of pre-industrial man.

The full Inca Trail is approximately 40km long. Spread over 4 days, this amounts to about five hours walking per day, although you can walk at your own pace - you are not forced to walk with your group the whole time. It is not a difficult walk, although there are a couple of high passes, and a steep climb on the second day, so a basic level of fitness is required.

Alternative Routes To Get To Machu Picchu other than the Inca Trail (link to another page how to get to machu picchu)

Lares Trail (link)

Inca Trail (link)

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History of Machu Picchu

Archaeological evidence uncovered around the site suggests that the area was first used for agricultural purposes back in 760 B.C.

The war of Vilcambamba Pachacutec in 1440 established the first settlement at the site. It was called the Tahuantinsuyo Empire which was later followed by the formation of the government of Manco Capac.

It is thought that Machu Picchu was first inhabited by 300-1000 inhabitants, who were of the highest Class or "llactas".

The valleys around these areas were important for their agricultural contribution, however after death of the Emperor Pachacutec, it lost it's importance, with the establishment of new sites like Ollaytantambo and Vilcambamba. The building of these new sites by his successors, in more accessible terrain made Machu Picchu less appealing.

From 1527 to 1532, two brothers Huáscar and Atahualpa fought against each other in a civil war over the Inca Empire. Their father, Inca Huayna Capac had given each brother a section of the empire to manage, one in Huáscar in Cuzco and Atahualpa in Quito. When Huayna Capac and his heir, Ninan Cuyuchi, died somewhere between 1525 and 1527, the two brothers Atahualpa and Huáscar went to war over who should rule.  The population who had come to live in the Machu Picchu area from rural or remote locations left after the war ended to return to where they came from. Later another brother, Manco Inca was sent into exile in Vilcambamba, and Machu Picchu was deserted.

Antonio Raimondi was an Italian geographer and scientist from Milan who visited Machu Picchu in 1851. In 1867 Augusto Berns arrived to mine the site.

Hiram Bingham re-discovered the ruins in 1911. He documented and publicised his "discovery".

Hiram Bingham

Part of the Going for gold promo for the BBC UK Homepage

The following article, Greg Gutfeld Levels Ilhan Omar With Epic Response To Her Claim That “White Privilege” Is Reason Charges Were Dropped Against General Flynn, was first published on 100PercentFedUp.com.

Yesterday, after 3 1/2 years of having his character and integrity called into question, President Trump's first NSA, General Michael Flynn was finally...

Continue reading: Greg Gutfeld Levels Ilhan Omar With Epic Response To Her Claim That “White Privilege” Is Reason Charges Were Dropped Against General Flynn ...

Telomeres are specific nucleoprotein structures that are located at the ends of linear eukaryotic chromosomes and play crucial roles in genomic stability. Telomere DNA consists of simple repeats of a short G-rich sequence: TTAGGG in mammals and TTTAGGG in most plants. In recent years, the mammalian telomeric G-rich repeats have been shown to form G-quadruplex (G4) structures, which are crucial for modulating telomere functions. Surprisingly, even though plant telomeres are essential for plant growth, development, and environmental adaptions, only few reports exist on plant telomeric G4 DNA (pTG4). Here, using bulk and single-molecule assays, including CD spectroscopy, and single-molecule FRET approaches, we comprehensively characterized the structure and dynamics of a typical plant telomeric sequence, d[GGG(TTTAGGG)3]. We found that this sequence can fold into mixed G4s in potassium, including parallel and antiparallel structures. We also directly detected intermediate dynamic transitions, including G-hairpin, parallel G-triplex, and antiparallel G-triplex structures. Moreover, we observed that pTG4 is unfolded by the AtRecQ2 helicase but not by AtRecQ3. The results of our work shed light on our understanding about the existence, topological structures, stability, intermediates, unwinding, and functions of pTG4.

Cone photoreceptors in the retina enable vision over a wide range of light intensities. However, the processes enabling cone vision in bright light (i.e. photopic vision) are not adequately understood. Chromophore regeneration of cone photopigments may require the retinal pigment epithelium (RPE) and/or retinal Müller glia. In the RPE, isomerization of all-trans-retinyl esters to 11-cis-retinol is mediated by the retinoid isomerohydrolase Rpe65. A putative alternative retinoid isomerase, dihydroceramide desaturase-1 (DES1), is expressed in RPE and Müller cells. The retinol-isomerase activities of Rpe65 and Des1 are inhibited by emixustat and fenretinide, respectively. Here, we tested the effects of these visual cycle inhibitors on immediate, early, and late phases of cone photopic vision. In zebrafish larvae raised under cyclic light conditions, fenretinide impaired late cone photopic vision, while the emixustat-treated zebrafish unexpectedly had normal vision. In contrast, emixustat-treated larvae raised under extensive dark-adaptation displayed significantly attenuated immediate photopic vision concomitant with significantly reduced 11-cis-retinaldehyde (11cRAL). Following 30 min of light, early photopic vision was recovered, despite 11cRAL levels remaining significantly reduced. Defects in immediate cone photopic vision were rescued in emixustat- or fenretinide-treated larvae following exogenous 9-cis-retinaldehyde supplementation. Genetic knockout of Des1 (degs1) or retinaldehyde-binding protein 1b (rlbp1b) did not eliminate photopic vision in zebrafish. Our findings define molecular and temporal requirements of the nonphotopic or photopic visual cycles for mediating vision in bright light.

Charles Collot, Frank Merle and Pierre Raphaël
J. Amer. Math. Soc. 33 (2020), 527-607.
Abstract, references and article information

The respiratory epithelium comprises polarized cells at the interface between the environment and airway tissues. Polarized apical and basolateral protein secretions are a feature of airway epithelium homeostasis. Human respiratory syncytial virus (hRSV) is a major human pathogen that primarily targets the respiratory epithelium. However, the consequences of hRSV infection on epithelium secretome polarity and content remain poorly understood. To investigate the hRSV-associated apical and basolateral secretomes, a proteomics approach was combined with an ex vivo pediatric human airway epithelial (HAE) model of hRSV infection (data are available via ProteomeXchange and can be accessed at https://www.ebi.ac.uk/pride/ with identifier PXD013661). Following infection, a skewing of apical/basolateral abundance ratios was identified for several individual proteins. Novel modulators of neutrophil and lymphocyte activation (CXCL6, CSF3, SECTM1 or CXCL16), and antiviral proteins (BST2 or CEACAM1) were detected in infected, but not in uninfected cultures. Importantly, CXCL6, CXCL16, CSF3 were also detected in nasopharyngeal aspirates (NPA) from hRSV-infected infants but not healthy controls. Furthermore, the antiviral activity of CEACAM1 against RSV was confirmed in vitro using BEAS-2B cells. hRSV infection disrupted the polarity of the pediatric respiratory epithelial secretome and was associated with immune modulating proteins (CXCL6, CXCL16, CSF3) never linked with this virus before. In addition, the antiviral activity of CEACAM1 against hRSV had also never been previously characterized. This study, therefore, provides novel insights into RSV pathogenesis and endogenous antiviral responses in pediatric airway epithelium.

Telomeres are specific nucleoprotein structures that are located at the ends of linear eukaryotic chromosomes and play crucial roles in genomic stability. Telomere DNA consists of simple repeats of a short G-rich sequence: TTAGGG in mammals and TTTAGGG in most plants. In recent years, the mammalian telomeric G-rich repeats have been shown to form G-quadruplex (G4) structures, which are crucial for modulating telomere functions. Surprisingly, even though plant telomeres are essential for plant growth, development, and environmental adaptions, only few reports exist on plant telomeric G4 DNA (pTG4). Here, using bulk and single-molecule assays, including CD spectroscopy, and single-molecule FRET approaches, we comprehensively characterized the structure and dynamics of a typical plant telomeric sequence, d[GGG(TTTAGGG)3]. We found that this sequence can fold into mixed G4s in potassium, including parallel and antiparallel structures. We also directly detected intermediate dynamic transitions, including G-hairpin, parallel G-triplex, and antiparallel G-triplex structures. Moreover, we observed that pTG4 is unfolded by the AtRecQ2 helicase but not by AtRecQ3. The results of our work shed light on our understanding about the existence, topological structures, stability, intermediates, unwinding, and functions of pTG4.

Reactive oxygen and nitrogen species have been implicated in many biological processes and diseases, including immune responses, cardiovascular dysfunction, neurodegeneration, and cancer. These chemical species are short-lived in biological settings, and detecting them in these conditions and diseases requires the use of molecular probes that form stable, easily detectable, products. The chemical mechanisms and limitations of many of the currently used probes are not well-understood, hampering their effective applications. Boronates have emerged as a class of probes for the detection of nucleophilic two-electron oxidants. Here, we report the results of an oxygen-18–labeling MS study to identify the origin of oxygen atoms in the oxidation products of phenylboronate targeted to mitochondria. We demonstrate that boronate oxidation by hydrogen peroxide, peroxymonocarbonate, hypochlorite, or peroxynitrite involves the incorporation of oxygen atoms from these oxidants. We therefore conclude that boronates can be used as probes to track isotopically labeled oxidants. This suggests that the detection of specific products formed from these redox probes could enable precise identification of oxidants formed in biological systems. We discuss the implications of these results for understanding the mechanism of conversion of the boronate-based redox probes to oxidant-specific products.

Fumie Tazaki talks about creating the first image of a black hole and its shadow, which relied on Fourier transforms. About the work to make the image, she says, "Our collaboration has 200 members and we did it with all of our efforts."

In-form American sprinter, Michael Rodgers, ran a world-leading 9.94 seconds and there were no Caribbean

Cătălin I. Cârstea, Gen Nakamura and Lauri Oksanen
Trans. Amer. Math. Soc. 373 (2020), 3423-3443.
Abstract, references and article information

Moacir Aloisio, Silas L. Carvalho and César R. de Oliveira
Proc. Amer. Math. Soc. 148 (2020), 2509-2523.
Abstract, references and article information

Telomeres are specific nucleoprotein structures that are located at the ends of linear eukaryotic chromosomes and play crucial roles in genomic stability. Telomere DNA consists of simple repeats of a short G-rich sequence: TTAGGG in mammals and TTTAGGG in most plants. In recent years, the mammalian telomeric G-rich repeats have been shown to form G-quadruplex (G4) structures, which are crucial for modulating telomere functions. Surprisingly, even though plant telomeres are essential for plant growth, development, and environmental adaptions, only few reports exist on plant telomeric G4 DNA (pTG4). Here, using bulk and single-molecule assays, including CD spectroscopy, and single-molecule FRET approaches, we comprehensively characterized the structure and dynamics of a typical plant telomeric sequence, d[GGG(TTTAGGG)3]. We found that this sequence can fold into mixed G4s in potassium, including parallel and antiparallel structures. We also directly detected intermediate dynamic transitions, including G-hairpin, parallel G-triplex, and antiparallel G-triplex structures. Moreover, we observed that pTG4 is unfolded by the AtRecQ2 helicase but not by AtRecQ3. The results of our work shed light on our understanding about the existence, topological structures, stability, intermediates, unwinding, and functions of pTG4.

(NOAA Headquarters) While the global average number of tropical cyclones each year has not budged from 86 over the last four decades, climate change has been influencing the locations of where these deadly storms occur, according to new NOAA-led research published in Proceedings of the National Academy of Science.

Quentin Perraud
Apr 1, 2020; 19:589-607
Research

Karl A. T. Makepeace
Apr 1, 2020; 19:624-639
Research

Prediction of post-operative pulmonary function in lung cancer patients before tumor resection is essential for patient selection for surgery and is conventionally done with a non-imaging segment counting method (SC) or a two-dimensional planar lung perfusion scintigraphy (PS). The purpose of this study was to compare quantitative analysis of PS to single photon emission computed tomography/computed tomography (SPECT/CT) and to estimate the accuracy of SC, PS and SPECT/CT in predicting post-operative pulmonary function in patients undergoing lobectomy. Methods: Seventy-five non-small cell lung cancer (NSCLC) patients planned for lobectomy were prospectively enrolled (68% males, average age 68.1±8 years ). All patients completed pre-operative forced expiratory volume capacity (FEV1), diffusing capacity of the lung for carbon monoxide (DLCO), Tc99m-MAA lung perfusion scintigraphy with PS and SPECT/CT quantification. A subgroup of 60 patients underwent video-assisted thoracoscopic (VATS) lobectomy and measurement of post-operative FEV1 and DLCO. Relative uptake of the lung lobes estimated by PS and SPECT/CT were compared. Predicted post-operative FEV1 and DLCO were derived from SC, PS and SPECT/CT. Prediction results were compared between the different methods and the true post-operative measurements in patients who underwent lobectomy. Results: Relative uptake measurements differed significantly between PS and SPECT/CT in right lung lobes, with a mean difference of -8.2±3.8, 18.0±5.0 and -11.5±6.1 for right upper, middle and lower lobes respectively (p<0.001). The differences between the methods in the left lung lobes were minor with a mean difference of -0.4±4.4 (p>0.05) and -2.0±4.0 (p<0.001) for left upper and lower lobes respectively. No significant difference and strong correlation (R=0.6-0.76, p<0.001) were found between predicted post-operative lung function values according to SC, PS, SPECT/CT and the actual post-operative FEV1 and DLCO. Conclusion: Although lobar quantification parameters differed significantly between PS and SPECT/CT, no significant differences were found between the predicted post-operative lung function results derived from these methods and the actual post-operative results. The additional time and effort of SPECT/CT quantification may not have an added value in patient selection for surgery. SPECT/CT may be advantageous in patients planned for right lobectomies but further research is warranted.

Galectins are carbohydrate-binding proteins overexpressed in bladder cancer (BCa) cells. Dendritic galactose moieties have a high affinity for galectin-expressing tumor cells. We radiolabeled a dendritic galactose carbohydrate with fluorine-18 – ¹⁸F-labeled galactodendritic unit 4 – and examined its potential in imaging urothelial malignancies. Methods: The ¹⁸F-labeled 1st generation galactodendritic unit 4 was obtained from its tosylate precursor. We conducted in vivo studies in galectin-expressing UMUC3 orthotopic BCa model to determine the ability of ¹⁸F-labeled galactodendritic unit 4 to image BCa. Results: Intravesical administration of ¹⁸F-labeled galactodendritic unit 4 allowed specific accumulation of the carbohydrate radiotracer in galectin-1 overexpressing UMUC3 orthotopic tumors when imaged with PET. The ¹⁸F-labeled galactodendritic unit 4 was not found to accumulate in non-tumor murine bladders. Conclusion: The ¹⁸F-labeled galactodendritic unit 4 and similar analogs may be clinically relevant and exploitable for PET imaging of galectin-1 overexpressing bladder tumors.

An experimental and computational approach for identification of protein-protein interactions by ex vivo chemical crosslinking and mass spectrometry (CLMS) has been developed that takes advantage of the specific characteristics of cyanurbiotindipropionylsuccinimide (CBDPS), an affinity-tagged isotopically coded mass spectrometry (MS)-cleavable crosslinking reagent. Utilizing this reagent in combination with a crosslinker-specific data-dependent acquisition strategy based on MS2 scans, and a software pipeline designed for integrating crosslinker-specific mass spectral information led to demonstrated improvements in the application of the CLMS technique, in terms of the detection, acquisition, and identification of crosslinker-modified peptides. This approach was evaluated on intact yeast mitochondria, and the results showed that hundreds of unique protein-protein interactions could be identified on an organelle proteome-wide scale. Both known and previously unknown protein-protein interactions were identified. These interactions were assessed based on their known sub-compartmental localizations. Additionally, the identified crosslinking distance constraints are in good agreement with existing structural models of protein complexes involved in the mitochondrial electron transport chain.

Bacteria secrete siderophores to access iron, a key nutrient poorly bioavailable and the source of strong competition between microorganisms in most biotopes. Many bacteria also use siderophores produced by other microorganisms (exosiderophores) in a piracy strategy. Pseudomonas aeruginosa, an opportunistic pathogen, produces two siderophores, pyoverdine and pyochelin, and is also able to use a panel of exosiderophores. We first investigated expression of the various iron-uptake pathways of P. aeruginosa in three different growth media using proteomic and RT-qPCR approaches and observed three different phenotypic patterns, indicating complex phenotypic plasticity in the expression of the various iron-uptake pathways. We then investigated the phenotypic plasticity of iron-uptake pathway expression in the presence of various exosiderophores (present individually or as a mixture) under planktonic growth conditions, as well as in an epithelial cell infection assay. In all growth conditions tested, catechol-type exosiderophores were clearly more efficient in inducing the expression of their corresponding transporters than the others, showing that bacteria opt for the use of catechol siderophores to access iron when they are present in the environment. In parallel, expression of the proteins of the pyochelin pathway was significantly repressed under most conditions tested, as well as that of proteins of the pyoverdine pathway, but to a lesser extent. There was no effect on the expression of the heme and ferrous uptake pathways. Overall, these data provide precise insights on how P. aeruginosa adjusts the expression of its various iron-uptake pathways (phenotypic plasticity and switching) to match varying levels of iron and competition.

The respiratory epithelium comprises polarized cells at the interface between the environment and airway tissues. Polarized apical and basolateral protein secretions are a feature of airway epithelium homeostasis. Human respiratory syncytial virus (hRSV) is a major human pathogen that primarily targets the respiratory epithelium. However, the consequences of hRSV infection on epithelium secretome polarity and content remain poorly understood. To investigate the hRSV-associated apical and basolateral secretomes, a proteomics approach was combined with an ex vivo pediatric human airway epithelial (HAE) model of hRSV infection (data are available via ProteomeXchange and can be accessed at https://www.ebi.ac.uk/pride/ with identifier PXD013661). Following infection, a skewing of apical/basolateral abundance ratios was identified for several individual proteins. Novel modulators of neutrophil and lymphocyte activation (CXCL6, CSF3, SECTM1 or CXCL16), and antiviral proteins (BST2 or CEACAM1) were detected in infected, but not in uninfected cultures. Importantly, CXCL6, CXCL16, CSF3 were also detected in nasopharyngeal aspirates (NPA) from hRSV-infected infants but not healthy controls. Furthermore, the antiviral activity of CEACAM1 against RSV was confirmed in vitro using BEAS-2B cells. hRSV infection disrupted the polarity of the pediatric respiratory epithelial secretome and was associated with immune modulating proteins (CXCL6, CXCL16, CSF3) never linked with this virus before. In addition, the antiviral activity of CEACAM1 against hRSV had also never been previously characterized. This study, therefore, provides novel insights into RSV pathogenesis and endogenous antiviral responses in pediatric airway epithelium.

Inês Magro dos Reis
Apr 14, 2020; 0:jlr.RA120000632v1-jlr.RA120000632
Research Articles

For the second week running hosting duties are taken by Henry Burrell, who is joined by Techworld.com editor Charlotte Jee to discuss the impact of Brexit on the UK's startups. Producer Chris then jumps in to discuss the Pokemon Go launch in the UK and a debate breaks out over whether it is for adults (13:00) Finally, online editor at Computerworld UK Scott Carey brings the latest news around driverless cars, from Tesla's recent struggles and how it may affect the industry in general (25:00)  

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Oh boy what a meaty session we have for you as Christina Mercer, Somrata Sarkar, David Price and Henry Burrell tackle three whopics (whopping topics) head on.

Somrata takes us into the sometimes scary thoughts of our own digital afterlives. Should we be worried that we'll end up as misrepresentative chat bots one day? Who will have the authority to police the companies that harvest our data?

Then Christina explains the knife edge America is on when it comes to net neutrality. Despite recent hope, there's still a chance the web across the pond will be ruthlessly metered and segmented.

Finally David asks us if we've checked our unused email accounts recently, as there might be a lot of desperate noodle companies in there begging you to stay on their mailing lists.

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Here it is folks, the insane 100th episode we have been planned for weeks (ahem). What better way to spend just over 50 minutes than with 100 tech topics covering over two years, one taken from each of the last 99 episodes of the pod plus the bonus round at the end.

Henry Burrell leads Tamlin Magee, Charlotte Jee, Scott Carey, Karen Khan and Christina Mercer down the tech rabbit hole in a game show-style quick fire test of our tech brains. In this game, everyone is a winner. Naw.

Thanks a lot for listening - here's to the next 100.

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