Hear about travel to the Auvergne region of France as the Amateur Traveler talks to Allison and Andrew Cornford-Matheson from CheeseWeb.eu as we talk about their visit to this central but overlooked area of France. 

Hear about travel to the countries of Kiribati, Tuvalu and Nauru in Micronesia as the Amateur Traveler talks to Stefan from Rapid Travel Chai about these small difficult to reach island nations. 

Perhaps you've read somewhere or other that there are over 3,000 traditional Peruvian festivals held throughout the year? It's a popular claim that pops up time and again in guidebooks and on websites, and though we ourselves haven't verified the number, it certainly wouldn't surprise us! Peru is a country that holds onto its traditions while increasingly embracing innovation as well, a perfect storm for festivals and fiestas of all types to flourish and to grow.

If you're planning to visit Peru, you might find yourself intrigued by the prospect of observing, or even participating in, one of these many different Peruvian festivals. If that's the case, you're in luck--we've taken the liberty to compile a list of some of our favorite Peruvian festivals, including one for each month of the year in hopes that you'll find something that corresponds with the dates of your trip. Keep in mind that this is very much just the tip of the iceberg--all of these Peruvian festivals are fantastic, but there are many more that we've had to leave out simply due to the nature of our list. If we haven't included any options that work out with your travel itinerary, don't fret--get to researching and we're sure you'll find the festival for you.

So without further ado, let's get to it! Here is our list of twelve awesome Peruvian festivals, one for each month of the year:

1. January--Trujillo Marinera Festival

Trujillo, a coastal city in northern Peru, is the traditional home of the marinera, an elegant couple's dance making use of handkerchiefs as props. Since 1986 it's been the official national capital of this dance, a status celebrated annually in a month-long marinera festival held throughout the city! The Festival de Marinera, as it's known in Spanish, features dance competitions, parades, and even exhibitions of the Peruvian Paso, a breed of horse also recognized as part of the cultural patrimony of the Trujillo region. One of our favorite Peruvian festivals, this one is a can't miss if you find yourself in the area during January.

2. February--Fiesta de la Candelaria

The Fiesta de la Candelaria is not only the largest and most famous festival in Peru, but also one of the largest in South America as a whole--in fact, throughout the continent, it's only dwarfed by the world-famous Carnival in Rio de Janeiro and the Carnaval de Ouro in Bolivia. The first of many religious Peruvian festivals on our list, the Fiesta de la Candelaria celebrates the Virgin of Candelaria, the patron saint of the town of Puno where the festivities are held. Music and dance are at the core of this festival, all of it performed by elaborately-costumed participants numbering well over 40,000. An incredible two week-long synthesis of indigenous and Catholic traditions, this is one of the most iconic Peruvian festivals.

3. March--Festival Internacional de la Vendimia

Depending upon where Easter falls during a given year, the month of March can either be very busy or very quiet as far as major Peruvian festivals are concerned. That said, we figured we may as well take a break from the religious festivals to focus on something else with a different sort of appeal--wine! The Ica Region of Peru is famous for a number of things, the Nazca Lines and the desert oasis of La Huacachina among them, but those in-the-know also recognize it as the finest wine-producing region in the country. This role has been celebrated annually in March since the 1950s during the Festival Internacional de la Vendimia, or the International Harvest Festival, in which a queen is famously chosen to ceremoniously stomp the first grapes of the season.

 4. April--Festividad del Señor del los Temblores del Cusco

El Señor de los Temblores, or the Lord of the Earthquakes, is the patron saint of Cusco and the celebratory focus of this major Holy Week celebration. The story goes that during an earthquake here in 1650, a canvas image of Jesus Christ was held to the sky as prayers were offered, causing the tremors to subside and saving the town from ruin. Since then, this statue commemorating the original image has become the focal point of an important annual celebration. Each Easter Monday at 7 PM, the statue is removed from Cusco's cathedral and paraded throughout the city. Amazingly, it's said that the statue was not originally black, but rather that its color is due to years of exposure to smoke from incense during religious ceremonies.

5. May--Fiesta de las Cruces

First of all, let's be clear: the Fiesta de las Cruces, or the Festival of the Crosses, is not a uniquely Peruvian celebration. However, the way the Peruvians celebrate it does make it one of the most important Peruvian festivals. You see, the Festival of the Crosses is not held in just one spot in the country. Rather, the festival is celebrated in towns and cities throughout Peru, each putting their own unique spin on things. Though the name may conjure up solemn images, don't worry--festivals throughout the Peruvian highlands include music, dancing, and even events such as bullfighting as part of the celebrations.

6. June--Inti Raymi

Inti Raymi, the ancient Inca Festival of the Sun, is one of the most traditional Peruvian festivals on our list, indigenous in design and untouched by Catholic tradition. Held annually on June 24th, Inti Raymi is meant to celebrate the Winter Solstice--remember that we're in the Southern Hemisphere here! Banned by the Spanish and the Catholic Church after 1535, the modern incarnation of the celebration began in 1944 based on the few historical records of the festivities that managed to survive. Since then it has grown in size and scope, and though sometimes derided as tourist pageantry by detractors, its historical and cultural significance definitely make it worth checking out among the many Peruvian festivals.

7. July--Fiesta de la Virgen del Carmen

Another fine example of traditional Andean culture blended with Catholicism, the Fiesta de la Virgen del Carmen is held annually around the 16th of July in the relatively small town of Paucartambo, some four hours outside of Cusco. This three or four day festival is nominally religious but also one of the biggest and wildest parties in Peru, drawing visitors from all over the country, many of whom pass the nights sleeping under the stars as there's simply not enough space in town! If you know what you're looking for, you'll actually notice some serious Peruvian history depicted in the festival's songs, costumes, and dance--for example, black-masked dancers represent African slaves imported to work the silver mines here during the colonial era.

8. August--Día de Santa Rosa de Lima

Santa Rosa de Lima was the first native-born American saint canonized by the Catholic Church, and her legacy is celebrated throughout the world. However, it should come as no surprise that the grandest festivities take place in her home country of Peru. On August 30th, the anniversary of her death, celebrations and memorials take place throughout the country, the most famous being in Santa Rosa de Quives just outside of the capital city itself.

9. September--Mistura Culinary Festival

As you should know by now, Peruvian cuisine is some of the world's best and Lima in particular features what is probably South America's most impressive culinary scene. And as if the food wasn't enticing enough year round, the prospect of eating your way through Peru becomes even more appealing each September when the Mistura Culinary Festival rolls around. Featuring over 200 restaurants and bars not to mention plenty of outdoor vendors and food carts, well over half a million visitors stop by to enjoy the festival's offerings over the course of some ten days in mid-September. Though certainly not one of the most traditional Peruvian festivals on our list, this is without a doubt the most delicious.

10. October--Procesión del Señor de los Milagros

The story might sound a bit familiar--an 18th Century earthquake destroyed a good part of town leaving only this iconic image of Jesus Christ standing. This was considered a miracle, the image became even more venerated, and with time the celebration of its feast day became the largest religious celebration in Peru featuring one of the longest processions of any religious gathering in the world. If you're just looking to have fun, this one probably isn't for you--however, this considerably more solemn celebration is one of the most important Peruvian festivals and we couldn't leave it off our list.

11. November--Puno Week

Perhaps the name Puno rings a bell? If so, you've got a good memory--this is the same city where our February festival choice of the Fiesta de la Candelaria took place! Puno Week takes place during the beginning of November and centers around November 5th, also known as Puno Day. The purpose of Puno Day, and by extension Puno Week, is to celebrate the legendary birth of one Manco Cápac, said to be the first Inca. This involves a very interesting reenactment of his arrival on the shores of Lake Titicaca bordering the city--and it's also just a great excuse to party the whole week long.

12. December--Santuranticuy

As we wind down our list, a few things should by now be obvious: the first is that Peruvians love their festivals, and the second is that many of these Peruvian festivals feature religious--and here that means Catholic--themes. The final entry on our list is of course no exception--Santuranticuy is held exclusively in the city of Cusco each year on Christmas Eve, December 24th, and is essentially a massive outdoor marketplace set up to celebrate the holiday. The festival's name, which means "sale of saints," is quite appropriate, as the primary draw here are dolls, sculptures, and figurines used to decorate the nacimientos, or Catholic nativity scenes, found in many Peruvian homes during the Christmas season. However, even if you aren't religious, you're sure to find something of interest at this most shopper-friendly of Peruvian festivals.

When someone mentions “Peru,” images of bucolic mountain pastures, ancient Incan ruins, and verdant Amazonian jungle are probably the first thing that pop into your mind. But this beautiful South American nation boasts miles and miles of gorgeous Pacific coastline, and it is also home to some amazing beaches. Let’s take a look at some of best beaches Peru has to offer.

Cabo Blanco: Arguably the most famous beach along Peru’s 2,500 kilometers of coastline, Cabo Blanco is routinely hailed as one the best surf spots in the world. When Peruvian surfer Gordo Barreda was scouting the area for great waves, he randomly paid a visit to the village, where he stumbled upon the now famous Peruvian Pipeline. A hollow, powerful left-hanging wave, it is arguably one of the best places to catch a wave on the continent’s entire Pacific coastline. Even before Barreda’s famous discovery, this fishing hamlet long enchanted visitors with its small-town charm and thriving fishing industry. In the 1950s and 1960s, fishermen routinely made the trek to Cabo Blanco in search of the area’s legendary large marlin. The famous writer Ernest Hemmingway spent several months here during the filming of the movie adaptation of his novel “The Old Man and the Sea.” During his stay, he reportedly caught a 700-pound marlin.

Mancora: Once a quaint fishing village, Mancora has exploded onto Peru’s backpacker scene as a major hub in the last decade or so. Located right in the middle of Peru’s sunniest and warmest region, you can relax on beautiful beaches during the day and then party the night away. Mancora is great for travelers on a budget, and cheap hostels abound.

Vichayito: If you want great beaches without a slew of rowdy partiers, Vichayito is an excellent option. Situated about 7 kilometers to the south of Mancora, this is an ideal spot for families. The water is ideal for swimming and kite surfing, and the beaches are clean and quiet.

Punta Hermosa: Just an hour drive from Peru’s capital, Punta Hermosa is popular with Limeños looking for a summer retreat from the city. While not as spectacular as the beaches of Paracas or Mancora, Punta Hermosa’s proximity to Lima makes it a great option for looking for a quick weekend escape from the city.

Asia: Peru’s most opulent beach, Asia is all about glitz and glamour. The upper echelons of Peruvian society have luxurious summer homes at this beach resort town, making it a hub of wealth. The beaches are great, but what really make Asia stand out are its high-end restaurants, luxury shopping center, and dazzling nightclubs.

Paracas: The Paracas National Reserve boasts some of Peru’s most dramatic desert landscape. Here, enormous sand dunes and dramatic sandstone rock formations meet the azure waters of the Pacific. The reserve, which consists of a total of 335,000 hectares of tropical desert on the Paracas Peninsula, is intended to preserve the area’s rich marine ecosystem as well as protect its unique cultural heritage (the site was of great significance to the Paracas, a pre-Colombian indigenous group that inhabited the area between roughly 800 BC and 1000 BC). There are no formal hotels within the reserve, though there are many sites popular with beach campers.

If you are looking for more luxurious accommodations, they can certainly also be found. Though beach destinations to the north of the country often attract the majority of tourist attention, it is Paracas where you will find the most luxurious beach vacations Peru has to offer. Just a few miles from the park’s entrance, you will find Hotel Paracas, a Luxury Collection Resort complete with 5-star accommodations, three pools, and a luxury spa.

Marcona: For those really looking to get off of Peru’s beaten tourist trail, we recommend a visit to the rugged, windswept beaches of Marcona, located roughly 8 hours south of Lima. The waters here can be quite cold year-round thanks to the Humboldt current, which brings water up from Antarctica along the Pacific coast of Chile and southern Peru. But the cold temperatures mean that waters are teeming with marine life. With any bit of luck, visitors might catch a glimpse of one of the zone’s enormous seal colonies. The beaches are known for their dramatic rock formations and rough surf, but they are a great place for those looking for options totally free of tourists.

So they you have it, our pick of the best Peruvian beaches. Happy adventuring in Peru!

Vancouver resident Hugo Huynh says he's never seen the man who got out of a minivan outside his home early Monday morning and uprooted the young tree.

The incident happened in the West Point Grey neighbourhood around 3:30 p.m. on Wednesday, police said.

Pyruvate kinase muscle isoform 2 (PKM2) is a key glycolytic enzyme involved in ATP generation and critical for cancer metabolism. PKM2 is expressed in many human cancers and is regulated by complex mechanisms that promote tumor growth and proliferation. Therefore, it is considered an attractive therapeutic target for modulating tumor metabolism. Various stimuli allosterically regulate PKM2 by cycling it between highly active and less active states. Several small molecules activate PKM2 by binding to its intersubunit interface. Serine and cysteine serve as an activator and inhibitor of PKM2, respectively, by binding to its amino acid (AA)-binding pocket, which therefore represents a potential druggable site. Despite binding similarly to PKM2, how cysteine and serine differentially regulate this enzyme remains elusive. Using kinetic analyses, fluorescence binding, X-ray crystallography, and gel filtration experiments with asparagine, aspartate, and valine as PKM2 ligands, we examined whether the differences in the side-chain polarity of these AAs trigger distinct allosteric responses in PKM2. We found that Asn (polar) and Asp (charged) activate PKM2 and that Val (hydrophobic) inhibits it. The results also indicate that both Asn and Asp can restore the activity of Val-inhibited PKM2. AA-bound crystal structures of PKM2 displayed distinctive interactions within the binding pocket, causing unique allosteric effects in the enzyme. These structure-function analyses of AA-mediated PKM2 regulation shed light on the chemical requirements in the development of mechanism-based small-molecule modulators targeting the AA-binding pocket of PKM2 and provide broader insights into the regulatory mechanisms of complex allosteric enzymes.

3-Mercaptopyruvate sulfur transferase (MPST) catalyzes the desulfuration of 3-mercaptopyruvate (3-MP) and transfers sulfane sulfur from an enzyme-bound persulfide intermediate to thiophilic acceptors such as thioredoxin and cysteine. Hydrogen sulfide (H2S), a signaling molecule implicated in many physiological processes, can be released from the persulfide product of the MPST reaction. Two splice variants of MPST, differing by 20 amino acids at the N terminus, give rise to the cytosolic MPST1 and mitochondrial MPST2 isoforms. Here, we characterized the poorly-studied MPST1 variant and demonstrated that substitutions in its Ser–His–Asp triad, proposed to serve a general acid–base role, minimally affect catalytic activity. We estimated the 3-MP concentration in murine liver, kidney, and brain tissues, finding that it ranges from 0.4 μmol·kg−1 in brain to 1.4 μmol·kg−1 in kidney. We also show that N-acetylcysteine, a widely-used antioxidant, is a poor substrate for MPST and is unlikely to function as a thiophilic acceptor. Thioredoxin exhibits substrate inhibition, increasing the KM for 3-MP ∼15-fold compared with other sulfur acceptors. Kinetic simulations at physiologically-relevant substrate concentrations predicted that the proportion of sulfur transfer to thioredoxin increases ∼3.5-fold as its concentration decreases from 10 to 1 μm, whereas the total MPST reaction rate increases ∼7-fold. The simulations also predicted that cysteine is a quantitatively-significant sulfane sulfur acceptor, revealing MPST's potential to generate low-molecular-weight persulfides. We conclude that the MPST1 and MPST2 isoforms are kinetically indistinguishable and that thioredoxin modulates the MPST-catalyzed reaction in a physiologically-relevant concentration range.

Pyruvate kinase muscle isoform 2 (PKM2) is a key glycolytic enzyme involved in ATP generation and critical for cancer metabolism. PKM2 is expressed in many human cancers and is regulated by complex mechanisms that promote tumor growth and proliferation. Therefore, it is considered an attractive therapeutic target for modulating tumor metabolism. Various stimuli allosterically regulate PKM2 by cycling it between highly active and less active states. Several small molecules activate PKM2 by binding to its intersubunit interface. Serine and cysteine serve as an activator and inhibitor of PKM2, respectively, by binding to its amino acid (AA)-binding pocket, which therefore represents a potential druggable site. Despite binding similarly to PKM2, how cysteine and serine differentially regulate this enzyme remains elusive. Using kinetic analyses, fluorescence binding, X-ray crystallography, and gel filtration experiments with asparagine, aspartate, and valine as PKM2 ligands, we examined whether the differences in the side-chain polarity of these AAs trigger distinct allosteric responses in PKM2. We found that Asn (polar) and Asp (charged) activate PKM2 and that Val (hydrophobic) inhibits it. The results also indicate that both Asn and Asp can restore the activity of Val-inhibited PKM2. AA-bound crystal structures of PKM2 displayed distinctive interactions within the binding pocket, causing unique allosteric effects in the enzyme. These structure-function analyses of AA-mediated PKM2 regulation shed light on the chemical requirements in the development of mechanism-based small-molecule modulators targeting the AA-binding pocket of PKM2 and provide broader insights into the regulatory mechanisms of complex allosteric enzymes.

A. A. Vladimirov
Trans. Moscow Math. Soc. 80 (2020), 211-219.
Abstract, references and article information

A decade of precarity for young workers has changed perceptions and expectations around the labour movement. Can digital offer a set of tools to boost engagement?

Pyruvate kinase muscle isoform 2 (PKM2) is a key glycolytic enzyme involved in ATP generation and critical for cancer metabolism. PKM2 is expressed in many human cancers and is regulated by complex mechanisms that promote tumor growth and proliferation. Therefore, it is considered an attractive therapeutic target for modulating tumor metabolism. Various stimuli allosterically regulate PKM2 by cycling it between highly active and less active states. Several small molecules activate PKM2 by binding to its intersubunit interface. Serine and cysteine serve as an activator and inhibitor of PKM2, respectively, by binding to its amino acid (AA)-binding pocket, which therefore represents a potential druggable site. Despite binding similarly to PKM2, how cysteine and serine differentially regulate this enzyme remains elusive. Using kinetic analyses, fluorescence binding, X-ray crystallography, and gel filtration experiments with asparagine, aspartate, and valine as PKM2 ligands, we examined whether the differences in the side-chain polarity of these AAs trigger distinct allosteric responses in PKM2. We found that Asn (polar) and Asp (charged) activate PKM2 and that Val (hydrophobic) inhibits it. The results also indicate that both Asn and Asp can restore the activity of Val-inhibited PKM2. AA-bound crystal structures of PKM2 displayed distinctive interactions within the binding pocket, causing unique allosteric effects in the enzyme. These structure-function analyses of AA-mediated PKM2 regulation shed light on the chemical requirements in the development of mechanism-based small-molecule modulators targeting the AA-binding pocket of PKM2 and provide broader insights into the regulatory mechanisms of complex allosteric enzymes.

Numerous recent works highlight the limited utility of established tumor cell lines in recapitulating the heterogeneity of tumors in patients. More realistic preclinical cancer models are thought to be provided by transplantable, patient-derived tumor xenografts (PDX). Inter- and intra-tumor heterogeneity of PDX, however, present several challenges in developing optimal quantitative pipelines to assess response to therapy. The objective of this work was to develop and optimize image metrics of FDG-PET to assess response to combination docetaxel/carboplatin therapy in a co-clinical trial involving triple negative breast cancer (TNBC) PDX. We characterize the reproducibility of SUV metrics to assess response to therapy and optimize a preclinical PERCIST (µPERCIST) paradigm to complement clinical standards. Considerations in this effort included variability in tumor growth rate and tumor size; solid tumor vs. tumor heterogeneity and necrotic phenotype; and optimal selection of tumor slice versus whole tumor. A test-retest protocol was implemented to optimize the reproducibility of FDG-PET SUV thresholds, SUVpeak metrics, and µPERCIST parameters. In assessing response to therapy, FDG-PET imaging was performed at baseline and +4 days following therapy. The reproducibility, accuracy, variability, and performance of imaging metrics to assess response to therapy were determined. We defined an index—"Quantitative Response Assessment Score (QRAS)"—to integrate parameters of prediction and precision, and thus aid in selecting optimal image metrics of response to therapy. Our data suggests that a threshold value of 25% (SUV25) of SUVmax was highly reproducible (<9% variability). Concordance and reproducibility of µPERCIST were maximized at α=0.7 and β=2.8 and exhibited high correlation to SUV25 measures of tumor uptake. QRAS scores favor SUV25 followed by SUVP14 as optimal metrics of response to therapy. Additional studies are warranted to fully characterize the utility of SUV25 and µPERCIST SUVP14 as image metrics of response to therapy across a wide range of therapeutic regiments and PDX models.

Background: The management for totally thyroidectomized differentiated thyroid cancer (TT-DTC) patients with unexplained hyperthyroglobulinemia remains indeterminate due to evidence scarcity. This multicenter study aimed at prospectively evaluating the response to radioiodine (¹³¹I) adjuvant therapy (RAT) and its potential role in risk stratification and causal clarification. Methods: TT-DTC patients with stimulated serum thyroglobulin (Tgoff) levels > 10 ng/mL but no structurally evident disease were consecutively enrolled in five tertiary care institutions. After the administration of 5.55 GBq of ¹³¹I, the risk of presence of persistent/recurrent/metastatic DTC (prmDTC) was compared to that before RAT. The causes of hyperthyroglobulinemia were explored and the response to RAT was assessed 6-12 months post RAT. The change in suppressed thyroglobulin (Tgon) level was reported. Results: A cohort of 254 subjects with a median Tgoff of 27.1 ng/mL was enrolled for the analyses. Immediately after RAT, low-, intermediate-, and high-risk were identified in 5.9%, 88.6%, and 5.5% patients, respectively, with no significant difference in risk stratification compared with that before RAT (P = 0.952). During the follow-up (median, 10.6 months), hyperthyroglobulinemia was ultimately attributed to thyroid remnant, biochemical disease, and structural/functional disease in 17.3%, 54.3%, and 28.3% of subjects, respectively. In addition, excellent, indeterminate, biochemical incomplete, and structural/functional incomplete responses were achieved in 18.1%, 27.2%, 36.2%, and 18.5% of patients, respectively. Notably, distribution for either cause of hyperthyroglobulinemia or response to RAT was comparable among the three postoperative risk groups. Tgon levels in patients who merely received RAT declined significantly over time. Conclusion: Our study demonstrated that over 90% of TT-DTC patients with unexplained hyperthyroglobulinemia are stratified as intermediate-high risk, and RAT using 5.55 GBq of ¹³¹I reveals biochemical/functional/structural disease and yields non-structural/functional incomplete response in more than 80% patients, suggesting TT-DTC patients with unexplained hyperthyroglobulinemia as explicit candidates for RAT.

The value of interim ¹⁸F-fluorodeoxyglucose positron emission tomography (iPET) guided treatment decisions in patients with diffuse large B-cell lymphoma (DLBCL) has been the subject of much debate. This investigation focuses on a comparison of the Deauville score and the deltaSUV_max (SUV_max) approach – two methods to assess early metabolic response to standard chemotherapy in DLBCL. Methods: Of 609 DLBCL patients participating in the Positron Emission Tomography-guided Therapy of Aggressive non-Hodgkin Lymphomas (PETAL) trial, iPET scans of 596 patients originally evaluated using the SUV_max method were available for post-hoc assessment of the Deauville score. A commonly used definition of an unfavorable iPET result according to the Deauville score is an uptake greater than that of the liver, whereas an unfavorable iPET scan with regard to the SUV_max approach is characterized as a relative reduction of the maximum standardized uptake value between baseline and iPET staging of less than or equal to 66%. We investigated the two methods’ correlation and concordance by Spearman’s rank correlation coefficient and the agreement in classification, respectively. We further used Kaplan-Meier curves and Cox regression to assess differences in survival between patient subgroups defined by the pre-specified cut-offs. Time-dependent receiver operating curve analysis provided information on the methods’ respective discrimination performance. Results: Deauville score and SUV_max approach differed in their iPET-based prognosis. The SUV_max approach outperformed the Deauville score in terms of discrimination performance – most likely due to a high number of false-positive decisions by the Deauville score. Cut-off-independent discrimination performance remained low for both methods, but cut-off-related analyses showed promising results. Both favored the SUV_max approach, e.g. for the segregation by iPET response, where the event-free survival hazard ratio was 3.14 (95% confidence interval (CI): 2.22 – 4.46) for SUV_max and 1.70 (95% CI: 1.29 – 2.24) for the Deauville score. Conclusion: When considering treatment intensification, the currently used Deauville score cut-off of an uptake above that of the liver seems to be inappropriate and associated with potential harm for DLBCL patients. The SUV_max criterion of a relative reduction of the maximum standardized uptake value of less than or equal to 66% should be considered as an alternative.

Pyruvate kinase M2 (PKM2) links metabolic and inflammatory dysfunction in atherosclerotic coronary artery disease; however, its role in oxidized LDL (Ox-LDL)-induced macrophage foam cell formation and inflammation is unknown and therefore was studied. In recombinant mouse granulocyte-macrophage colony-stimulating factor-differentiated murine bone marrow-derived macrophages, early (1–6 h) Ox-LDL treatment induced PKM2 tyrosine 105 phosphorylation and promotes its nuclear localization. PKM2 regulates aerobic glycolysis and inflammation because PKM2 shRNA or Shikonin abrogated Ox-LDL-induced hypoxia-inducible factor-1α target genes lactate dehydrogenase, glucose transporter member 1, interleukin 1β (IL-1β) mRNA expression, lactate, and secretory IL-1β production. PKM2 inhibition significantly increased Ox-LDL-induced ABCA1 and ABCG1 protein expression and NBD-cholesterol efflux to apoA1 and HDL. PKM2 shRNA significantly inhibited Ox-LDL-induced CD36, FASN protein expression, DiI-Ox-LDL binding and uptake, and cellular total cholesterol, free cholesterol, and cholesteryl ester content. Therefore, PKM2 regulates lipid uptake and efflux. DASA-58, a PKM2 activator, downregulated LXR-α, ABCA1, and ABCG1, and augmented FASN and CD36 protein expression. Peritoneal macrophages showed similar results. Ox-LDL induced PKM2- SREBP-1 interaction and FASN expression in a PKM2-dependent manner. Therefore, this study suggests a role for PKM2 in Ox-LDL-induced aerobic glycolysis, inflammation, and macrophage foam cell formation.

Infants born to mothers with obesity have a greater risk for childhood obesity and metabolic diseases; however, the underlying biological mechanisms remain poorly understood. We used a Japanese macaque model to investigate whether maternal obesity combined with a western-style diet (WSD) impairs offspring muscle insulin action. Adult females were fed a control or WSD prior to and during pregnancy through lactation, and offspring subsequently weaned to a control or WSD. Muscle glucose uptake and signaling were measured ex vivo in fetal (n=5-8/group) and juvenile offspring (n=8/group). In vivo signaling was evaluated after an insulin bolus just prior to weaning (n=4-5/group). Maternal WSD reduced insulin-stimulated glucose uptake and impaired insulin signaling at the level of Akt phosphorylation in fetal muscle. In juvenile offspring, insulin-stimulated glucose uptake was similarly reduced by both maternal and post-weaning WSD and corresponded to modest reductions in insulin-stimulated Akt phosphorylation relative to controls. We conclude that maternal WSD leads to a persistent decrease in offspring muscle insulin-stimulated glucose uptake even in the absence of increased offspring adiposity or markers of systemic insulin resistance. Switching offspring to a healthy diet did not reverse the effects of maternal WSD on muscle insulin action suggesting earlier interventions may be warranted.

The reality is setting in for Astros star second baseman Jose Altuve, who's shared a clubhouse with close friend Marwin Gonzalez for the previous seven springs. They became confidants on and off the field, which is what makes this spring so strange.

The 2019 MLB season feels so close now. Spring Training has begun. Players are taking the field. So it's time to rank the best of the best.

Neoadjuvant chemotherapy for breast cancer is a new strategy that was introduced towards the end of the 20th century with the aim of reducing tumour size - rendering an otherwise inoperable tumour operable, allowing more conservative surgery, and hopefully improving overall survival. Although data indicate that the first rationale remains valid,...

Excessive fructose consumption is closely linked to the pathogenesis of metabolic disease. Carbohydrate response element-binding protein (ChREBP) is a transcription factor essential for fructose tolerance in mice. However, the functional significance of liver ChREBP in fructose metabolism remains unclear. Here, we show that liver ChREBP protects mice against fructose-induced hepatotoxicity by regulating liver glycogen metabolism and ATP homeostasis. Liver-specific ablation of ChREBP did not compromise fructose tolerance, but rather caused severe transaminitis and hepatomegaly with massive glycogen overload in mice fed a high-fructose diet, while no obvious inflammation, cell death, or fibrosis was detected in the liver. In addition, liver ATP contents were significantly decreased by ChREBP deficiency in the fed state, which was rendered more pronounced by fructose feeding. Mechanistically, liver contents of glucose-6-phosphate (G6P), an allosteric activator of glycogen synthase, were markedly increased in the absence of liver ChREBP, while fasting-induced glycogen breakdown was not compromised. Furthermore, hepatic overexpression of LPK, a ChREBP target gene in glycolysis, could effectively rescue glycogen overload and ATP reduction, as well as mitigate fructose-induced hepatotoxicity in ChREBP-deficient mice. Taken together, our findings establish a critical role of liver ChREBP in coping with hepatic fructose stress and protecting from hepatotoxicity by regulating LPK.

Technological forecasting.

A Paris : Germer-Bailliere ; A Londres : J.-B. Bailliere, 1835.

Paris : O. Doin, 1878.

Paris : G. Steinheil, 1894.

Paris : Société d’éditions scientifiques, 1895.

Paris : J.-B. Baillière, 1880.

London : printed for B. and J. White, 1797.

[Paris] : [publisher not identified], 1895.

Paris : Trouvé, 1822.

Londres : Paris, 1840.

Paris : G. Steinheil, 1892.

Toulon : chez l'auteur, 1812.

The justices agreed to decide whether the Eighth Amendment requires a trial court to find that a juvenile is permanently incorrigible before imposing a sentence of life without parole.

A Paris (rue du Cloître Notre Dame no. 4) : chez Tessari & Cie., [1829]

2019

French translation of the press release about the Basel Committee publishing a discussion paper on "The regulatory treatment of sovereign exposures" (7 December 2017)

French translation of the BIS press release about the BIS Quarterly Review, December 2018

Laurent Duvernay-Tardif and the Kansas City Chiefs have agreed to a restructured deal for the Canadian offensive lineman.

A Quebec-born Super Bowl champion is making the move from the offensive line to the medical front line.