Markus Tiedge
Nov 1, 1997; 46:1733-1742
Original Article

Norikazu Maeda
Sep 1, 2001; 50:2094-2099
Pathophysiology

Incretin hormone dysregulation contributes to reduced insulin secretion and hyperglycemia in patients with type 2 diabetes mellitus (T2DM). Resistance to glucose-dependent insulinotropic polypeptide (GIP) action may occur through desensitization or downregulation of β-cell GIP receptors (GIP-R). Studies in rodents and cell lines show GIP-R expression can be regulated through peroxisome proliferator–activated receptor (PPAR) response elements (PPREs). Whether this occurs in humans is unknown. To test this, we conducted a randomized, double-blind, placebo-controlled trial of pioglitazone therapy on GIP-mediated insulin secretion and adipocyte GIP-R expression in subjects with well-controlled T2DM. Insulin sensitivity improved, but the insulinotropic effect of infused GIP was unchanged following 12 weeks of pioglitazone treatment. In parallel, we observed increased GIP-R mRNA expression in subcutaneous abdominal adipocytes from subjects treated with pioglitazone. Treatment of cultured human adipocytes with troglitazone increased PPAR binding to GIP-R PPREs. These results show PPAR agonists regulate GIP-R expression through PPREs in human adipocytes, but suggest this mechanism is not important for regulation of the insulinotropic effect of GIP in subjects with T2DM. Because GIP has antilipolytic and lipogenic effects in adipocytes, the increased GIP-R expression may mediate accretion of fat in patients with T2DM treated with PPAR agonists.

Insulin-mediated microvascular recruitment (IMVR) regulates delivery of insulin and glucose to insulin-sensitive tissues. We have previously proposed that perivascular adipose tissue (PVAT) controls vascular function through outside-to-inside communication and through vessel-to-vessel, or "vasocrine," signaling. However, direct experimental evidence supporting a role of local PVAT in regulating IMVR and insulin sensitivity in vivo is lacking. Here, we studied muscles with and without PVAT in mice using combined contrast-enhanced ultrasonography and intravital microscopy to measure IMVR and gracilis artery diameter at baseline and during the hyperinsulinemic-euglycemic clamp. We show, using microsurgical removal of PVAT from the muscle microcirculation, that local PVAT depots regulate insulin-stimulated muscle perfusion and glucose uptake in vivo. We discovered direct microvascular connections between PVAT and the distal muscle microcirculation, or adipomuscular arterioles, the removal of which abolished IMVR. Local removal of intramuscular PVAT altered protein clusters in the connected muscle, including upregulation of a cluster featuring Hsp90ab1 and Hsp70 and downregulation of a cluster of mitochondrial protein components of complexes III, IV, and V. These data highlight the importance of PVAT in vascular and metabolic physiology and are likely relevant for obesity and diabetes.

Since its launch in 2015, the Express Entry system has changed how economic immigration to Canada happens and how it fits into public and political debates. And while it has proven successful in cutting through application backlogs, some challenges remain. This report looks at how and why this points-based system was introduced, what its impact has been, and how it could be further finetuned.

London : J. & A. Churchill, 1879.

London : Chemist and Druggist, 1898.

London (No. 4, Hanover Street) : Published ... for the proprietor by T.G. March ; [London] (Threadneedle Street) : Sold also by F. G. Moon ; [London] (Strand) : [Sold also by] Ackermann & Co., April 10, 1842 ([London?] : Printed by R. Lloyd)

Zhixiang Lin, Mahdi Zamanighomi, Timothy Daley, Shining Ma, Wing Hung Wong.

Source: Statistical Science, Volume 35, Number 1, 2--13.

Abstract:
Unsupervised methods, including clustering methods, are essential to the analysis of single-cell genomic data. Model-based clustering methods are under-explored in the area of single-cell genomics, and have the advantage of quantifying the uncertainty of the clustering result. Here we develop a model-based approach for the integrative analysis of single-cell chromatin accessibility and gene expression data. We show that combining these two types of data, we can achieve a better separation of the underlying cell types. An efficient Markov chain Monte Carlo algorithm is also developed.

Chris Englund
Jan 5, 2005; 25:247-251
BRIEF COMMUNICATION

Jessica A. Gorski
Aug 1, 2002; 22:6309-6314
BRIEF COMMUNICATION

Lennart Mucke
Jun 1, 2000; 20:4050-4058
Cellular

Sensory systems integrate multiple stimulus features to generate coherent percepts. Spectral surround suppression, the phenomenon by which sound-evoked responses of auditory neurons are suppressed by stimuli outside their receptive field, is an example of this integration taking place in the auditory system. While this form of global integration is commonly observed in auditory cortical neurons, and potentially used by the nervous system to separate signals from noise, the mechanisms that underlie this suppression of activity are not well understood. We evaluated the contributions to spectral surround suppression of the two most common inhibitory cell types in the cortex, parvalbumin-expressing (PV+) and somatostatin-expressing (SOM⁺) interneurons, in mice of both sexes. We found that inactivating SOM⁺ cells, but not PV+ cells, significantly reduces sustained spectral surround suppression in excitatory cells, indicating a dominant causal role for SOM⁺ cells in the integration of information across multiple frequencies. The similarity of these results to those from other sensory cortices provides evidence of common mechanisms across the cerebral cortex for generating global percepts from separate features.

SIGNIFICANCE STATEMENT To generate coherent percepts, sensory systems integrate simultaneously occurring features of a stimulus, yet the mechanisms by which this integration occurs are not fully understood. Our results show that neurochemically distinct neuronal subtypes in the primary auditory cortex have different contributions to the integration of different frequency components of an acoustic stimulus. Together with findings from other sensory cortices, our results provide evidence of a common mechanism for cortical computations used for global integration of stimulus features.

Interview with Mr Luis de Guindos, Vice-President of the European Central Bank, and Expresso, conducted by Mr João Silvestre on 15 April 2020.

Happy birthday Vijay Deverakonda: Tollywood's 'Dear Comrade' who auctioned his first Filmfare Award for charity  The New Indian Express

Sound of hope  The New Indian Express

Most studies on corticoid treatment of respiratory syncytial virus (RSV) respiratory diseases have revealed no beneficial effect. The mechanism by which RSV respiratory-infected patients are insensitive to the antiinflammatory effect of corticosteroids is unknown.

This study helps to understand how a respiratory syncytial viral infection may alter the normal antiinflammatory response to cortisol and the insensitivity to glucocorticoid treatment. The increase expression of β glucocorticoid receptor could be a marker of disease severity. (Read the full article)

Rapid and reliable tools for the diagnosis of neonatal sepsis are still unavailable. No single biomarker studied has yielded conclusive results. Genome-wide expression profiles (GWEPs) have been successfully determined for the diagnosis of sepsis in pediatric and adult populations.

GWEPs are described for the first time in very low birth weight infants with proven bacterial sepsis. Our results suggest that GWEPs could be used for early discrimination of septic newborn versus nonseptic infants. (Read the full article)

QPX7728 is an ultra-broad-spectrum boronic acid beta-lactamase inhibitor with potent inhibition of key serine and metallo beta-lactamases observed in biochemical assays. Microbiological studies using characterized strains were used to provide a comprehensive characterization of the spectrum of beta-lactamase inhibition by QPX7728. The MIC of multiple IV only (ceftazidime, piperacillin, cefepime, ceftolozane and meropenem) and orally bioavailable (ceftibuten, cefpodoxime, tebipenem) antibiotics alone and in combination with QPX7728 (4 μg/ml), as well as comparator agents, were determined against the panels of laboratory strains of P. aeruginosa and K. pneumoniae expressing over 55 diverse serine and metallo beta-lactamases. QPX7728 significantly enhanced the potency of antibiotics against the strains expressing Class A extended spectrum beta-lactamases (CTX-M, SHV, TEM, VEB, PER) and carbapenemases (KPC, SME, NMC-A, BKC-1), consistent with beta-lactamase inhibition demonstrated in biochemical assays. It also inhibits both plasmidic (CMY, FOX, MIR, DHA) and chromosomally encoded (P99, PDC, ADC) Class C beta-lactamases and Class D enzymes including carbapenemases such as OXA-48 from Enterobacteriaceae and OXA enzymes from Acinetobacter baumannii (OXA-23/24/72/58). QPX7728 is also a potent inhibitor of many class B metallo beta-lactamases (NDM, VIM, CcrA1, IMP, GIM but not SPM or L1). Addition of QPX7728 (4 μg/ml) reduced the MICs in a majority of strains to the level observed for the vector alone control, indicative of complete beta-lactamase inhibition. The ultra-broad-spectrum beta-lactamase inhibition profile makes QPX7728 a viable candidate for further development.

Newly appointed provisional liquidator of SA Express is in the process of investigating affairs of the state-owned regional airline.

The Indian Express will host its second online Express Adda with Dr Guleria, also internationally renowned pulmonologist, on Monday, May 4.

Indian Railways Catering and Tourism Corporation’s premier luxury train, the Maharajas Express, is all set to run its first Indian Panorama journey of the 2012-13 season tomorrow. The train will depart from the Safdarjung Railway Station tomorrow at 2200 hours. All guests have been...

Indian luxury train, The Maharaja’s Express, is making quite an impression in the US as owner and operator IRCTC is hosting multiple events promoting the Maharaja Express in Las Vegas, Los Angeles (November 26) and San Francisco (November 30). The train has been bestowed with several honors...

Popular Indian luxury train, The Maharaja’s Express, has been awarded World’s Leading Luxury Train 2012 at the World Travel Awards 2012 held in New Delhi yesterday. The train was one of the contenders for the coveted title of the best luxury train in the world which included the...

IRCC conducted its 131st Express Entry draw, and has issued Invitations to Apply for 3,600 candidates on November 27th.  Features of the DrawHere the minimum score in the Comprehensive Ranking System stood at 471, which is lesser by one point…

Canada conducted its new draw in the Express Entry, and issued 3,200 Invitations to Apply to the candidates on December 11th.  In it the least Comprehensive Ranking System score was 472, which is one point increase comparing to the 131st Express…

The immigration authorities in Ontario held their largest draw on December 11th4wsqor 2019, and issued 667 Notifications of Interest to such candidates who had a profile in Express Entry Pool. This was the first draw in the Skilled Trades stream after…

The immigration authorities in Canada conducted their 133rd Express Entry draw, within eight days of the earlier draw, and issued 3,200 Invitations to Apply, to the promising candidates, on December 19. The DetailsThere was a decline of three points…

Saskatchewan has invited 595 candidates belonging to Express Entry and Occupations In-Demand categories to seek the provincial nomination for permanent residence in Canada.Making a Fine ProgressOn December 20 a draw was held for The Saskatchewan Immigrant…

There were several twists and turns in the Express Entry system of Canada for the candidates and the observers in 2019.  Canada issued 85,300 invitations to apply for permanent residence issued.Interesting FeaturesThis was the record top second,…

There is an increase in the Settlement funds requirement for fresh immigrants in the Express Entry reaching Canada in 2020. Funds requirements for single applicants increased to $12,960 in 2020. In 2019 they were $12,669. Also, there was an increase…

On January 8th Canada held its First Draw in 2020 and Invited 3,400 Express Entry Candidates to get the PR. In this draw the minimum score of the Comprehensive Ranking System increased by four points to 473 in comparison to the earlier…

On January 9th, Ontario conducted a draw for the first time after May 2019 in the French-Speaking Skilled Worker stream that is linked to Express Entry. The draw in Ontario Immigrant Nominee Program issued 242 Notifications of Interest.The qualifying…

We present the facts of Express Entry as an option for candidates who have credentials that are similar to the credentials of Meghan and Harry. Their qualifying for permanent residence in Canada is a matter of discussion. There is news about the potential…

Canadian Immigration authorities are beginning the issuing process at a great pace. In an Express Entry draw conducted on January 22, 2020, they issued 3,400 Invitations to Apply. The CRS score had a decline of two points in comparison to the draw held…

150 invitations were issued to Express Entry candidates to apply and seek the Alberta provincial nomination on January 9. The Candidates having a 350 CRS score received these NOIs.Through the Alberta Express Entry Stream the Alberta Immigrant Nominee…

The latest details of the recently launched Maharajas’ Express winter itineraries are the new update on the Indian Luxury Trains website. Maharajas’ Express, dubbed as India’s answer to the Orient Express, has announced its winter itineraries across the choicest of...

Maharajas Express, a luxury tourist train in India, will now offer an additional journey. The new itinerary which is named Royal Sojourn will cover destinations such as Delhi, Jaipur, Kota, Sawai Madhopur and Agra. This new journey will be in addition to the already existing three itineraries...

Maharajas Express added another feather in its cap as it bagged the first runner up award in the Specialist Train Operators Category awarded by the Conde Nast Traveller Readers' Travel Award. The first prize was grabbed by the Hiram Bingham Express, a luxury train by Orient Express Group....

Maharajas’ Express, launched amid much fanfare in 2010 and touted to be the India’s answer to the Orient Express of the West may not continue its service in the coming year. The train was a joint venture between IRCTC and Cox and Kings India. Whereas the IRCTC owned the train, Cox and...

There's good news at last for those looking forward to a unique luxury rail ride on board Maharajas Express. Maharajas Express is back on track. Maharajas Express may still take the guests on “a journey like no other” uptill April, 2012. Hon’ble judge of the High Court of...

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DevExpress ASP.NET File Manager versions 10.2 through 13.2.8 suffer from a directory traversal vulnerability.

NICE Recording eXpress versions 6.0.x, 6.1.x, 6.2.x, 6.3.x, and 6.5.x suffer from cross site scripting, root backdoor, unauthenticated access, fail authorization, insecure cookie handling, and remote SQL injection vulnerabilities.