Sports365 plans to use the funds to build technological capacities, launch its own private label and increase manpower.

Sports365 is also supported by icons as Yuvraj Singh, Deepika Pallikal and Bhupathi's wife Lara Dutta and is partnering with foreign sports brands as their exclusive partners in India.

Fibroblasts are key effector cells in tissue remodeling. They remain persistently activated in fibrotic diseases, resulting in progressive deposition of extracellular matrix. Although fibroblast activation may be initiated by external factors, prolonged activation can induce an “autonomous,” self-maintaining profibrotic phenotype in fibroblasts. Accumulating evidence suggests that epigenetic alterations play a central role in establishing this persistently activated pathologic phenotype of fibroblasts. We demonstrated that in fibrotic skin of patients with systemic sclerosis (SSc), a prototypical idiopathic fibrotic disease, TGF-β induced the expression of DNA methyltransferase 3A (DNMT3A) and DNMT1 in fibroblasts in a SMAD-dependent manner to silence the expression of suppressor of cytokine signaling 3 (SOCS3) by promoter hypermethylation. Downregulation of SOCS3 facilitated activation of STAT3 to promote fibroblast-to-myofibroblast transition, collagen release, and fibrosis in vitro and in vivo. Reestablishment of the epigenetic control of STAT3 signaling by genetic or pharmacological inactivation of DNMT3A reversed the activated phenotype of SSc fibroblasts in tissue culture, inhibited TGF-β–dependent fibroblast activation, and ameliorated experimental fibrosis in murine models. These findings identify a pathway of epigenetic imprinting of fibroblasts in fibrotic disease with translational implications for the development of targeted therapies in fibrotic diseases.

Hydrocephalus is a pathologic condition associated with various brain diseases, including Alzheimer's disease (AD). Dysfunctional ependymal cells (EpCs) are believed to contribute to the development of hydrocephalus. It is thus of interest to investigate EpCs' development and function. Here, we report that vacuolar protein sorting-associated protein 35 (VPS35) is critical for EpC differentiation, ciliogenesis, and survival, and thus preventing neonatal hydrocephalus. VPS35 is abundantly expressed in EpCs. Mice with conditional knock-out (cKO) of Vps35 in embryonic (Vps35^GFAP-Cre and Vps35^Emx1-Cre) or postnatal (Vps35^Foxj1-CreER) EpC progenitors exhibit enlarged lateral ventricles (LVs) and hydrocephalus-like pathology. Further studies reveal marked reductions in EpCs and their cilia in both Vps35^GFAP-Cre and Vps35^Foxj1-CreER mutant mice. The reduced EpCs appear to be due to impairments in EpC differentiation and survival. Additionally, both Vps35^GFAP-Cre and Vps35^Foxj1-CreER neonatal pups exhibit increased cell proliferation and death largely in a region close to LV-EpCs. Many microglia close to the mutant LV-EpC region become activated. Depletion of the microglia by PLX3397, an antagonist of colony-stimulating factor 1 receptor (CSF1R), restores LV-EpCs and diminishes the pathology of neonatal hydrocephalus in Vps35^Foxj1-CreER mice. Taken together, these observations suggest unrecognized functions of Vps35 in EpC differentiation, ciliogenesis, and survival in neonatal LV, and reveal pathologic roles of locally activated microglia in EpC homeostasis and hydrocephalus development.

SIGNIFICANCE STATEMENT This study reports critical functions of vacuolar protein sorting-associated protein 35 (VPS35) not only in promoting ependymal cell (EpC) differentiation, ciliogenesis, and survival, but also in preventing local microglial activation. The dysfunctional EpCs and activated microglia are likely to induce hydrocephalus.

Antimicrobial peptides and proteins play critical roles in the host defense against invading pathogens. We recently discovered that recombinantly expressed human and mouse serum amyloid A1 (rhSAA1 and rmSAA1) proteins have potent antifungal activities against the major human fungal pathogen Candida albicans. At high concentrations, rhSAA1 disrupts C. albicans membrane integrity and induces rapid fungal cell death. In the current study, we find that rhSAA1 promotes cell aggregation and targets the C. albicans cell wall adhesin Als3. Inactivation of ALS3 in C. albicans leads to a striking decrease in cell aggregation and cell death upon rhSAA1 treatment, suggesting that Als3 plays a critical role in SAA1 sensing. We further demonstrate that deletion of the transcriptional regulators controlling the expression of ALS3, such as AHR1, BCR1, and EFG1 in C. albicans results in similar effects to that of the als3/als3 mutant upon rhSAA1 treatment. Global gene expression profiling indicates that rhSAA1 has a discernible impact on the expression of cell wall- and metabolism-related genes, suggesting that rhSAA1 treatment could lead to a nutrient starvation effect on C. albicans cells.

The Pakistan Navy in a joint raid with the Anti-Narcotics Force seized 100 kilogrammes of crystal meth worth around Rs3 billion.A Navy spokesman said that in an intelligence-based joint operation with the ANF, they seized 100 kilogrammes of crystal myth off Pasni, Balochistan. The drug was valued...

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HCS365

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HCS320

Mumbai: Brookfield Asset Management Inc., a Canadian asset management company that manages investments worth $181 billion, is set to acquire all of Unitech Corporate Parks Plc (UCP), a London Stock Exchange-listed, India-focused real estate investment firm, paying `3,000 crore. A definitive agreement to this end is likely to be signed this week in London, said four persons directly involved in the deal. None of them wanted to be named. “We do not comment on market speculation,” said Brookfield Asset Management in an email response. Routhu Nagaraju, executive vice-President at Unitech Ltd, said, “UCP has announced that it will sell six projects and the process has not seen anything adverse. It […]

ABSTRACT

Clostridioides difficile is an important nosocomial pathogen that causes approximately 500,000 cases of C. difficile infection (CDI) and 29,000 deaths annually in the United States. Antibiotic use is a major risk factor for CDI because broad-spectrum antimicrobials disrupt the indigenous gut microbiota, decreasing colonization resistance against C. difficile. Vancomycin is the standard of care for the treatment of CDI, likely contributing to the high recurrence rates due to the continued disruption of the gut microbiota. Thus, there is an urgent need for the development of novel therapeutics that can prevent and treat CDI and precisely target the pathogen without disrupting the gut microbiota. Here, we show that the endogenous type I-B CRISPR-Cas system in C. difficile can be repurposed as an antimicrobial agent by the expression of a self-targeting CRISPR that redirects endogenous CRISPR-Cas3 activity against the bacterial chromosome. We demonstrate that a recombinant bacteriophage expressing bacterial genome-targeting CRISPR RNAs is significantly more effective than its wild-type parent bacteriophage at killing C. difficile both in vitro and in a mouse model of CDI. We also report that conversion of the phage from temperate to obligately lytic is feasible and contributes to the therapeutic suitability of intrinsic C. difficile phages, despite the specific challenges encountered in the disease phenotypes of phage-treated animals. Our findings suggest that phage-delivered programmable CRISPR therapeutics have the potential to leverage the specificity and apparent safety of phage therapies and improve their potency and reliability for eradicating specific bacterial species within complex communities, offering a novel mechanism to treat pathogenic and/or multidrug-resistant organisms.

IMPORTANCE Clostridioides difficile is a bacterial pathogen responsible for significant morbidity and mortality across the globe. Current therapies based on broad-spectrum antibiotics have some clinical success, but approximately 30% of patients have relapses, presumably due to the continued perturbation to the gut microbiota. Here, we show that phages can be engineered with type I CRISPR-Cas systems and modified to reduce lysogeny and to enable the specific and efficient targeting and killing of C. difficile in vitro and in vivo. Additional genetic engineering to disrupt phage modulation of toxin expression by lysogeny or other mechanisms would be required to advance a CRISPR-enhanced phage antimicrobial for C. difficile toward clinical application. These findings provide evidence into how phage can be combined with CRISPR-based targeting to develop novel therapies and modulate microbiomes associated with health and disease.

ABSTRACT

Hepatitis C virus (HCV) infects millions of people worldwide, causing chronic liver disease that can lead to cirrhosis, hepatocellular carcinoma, and liver transplant. In the last several years, the advent of direct-acting antivirals, including NS3/4A protease inhibitors (PIs), has remarkably improved treatment outcomes of HCV-infected patients. However, selection of resistance-associated substitutions and polymorphisms among genotypes can lead to drug resistance and in some cases treatment failure. A proactive strategy to combat resistance is to constrain PIs within evolutionarily conserved regions in the protease active site. Designing PIs using the substrate envelope is a rational strategy to decrease the susceptibility to resistance by using the constraints of substrate recognition. We successfully designed two series of HCV NS3/4A PIs to leverage unexploited areas in the substrate envelope to improve potency, specifically against resistance-associated substitutions at D168. Our design strategy achieved better resistance profiles over both the FDA-approved NS3/4A PI grazoprevir and the parent compound against the clinically relevant D168A substitution. Crystallographic structural analysis and inhibition assays confirmed that optimally filling the substrate envelope is critical to improve inhibitor potency while avoiding resistance. Specifically, inhibitors that enhanced hydrophobic packing in the S4 pocket and avoided an energetically frustrated pocket performed the best. Thus, the HCV substrate envelope proved to be a powerful tool to design robust PIs, offering a strategy that can be translated to other targets for rational design of inhibitors with improved potency and resistance profiles.

IMPORTANCE Despite significant progress, hepatitis C virus (HCV) continues to be a major health problem with millions of people infected worldwide and thousands dying annually due to resulting complications. Recent antiviral combinations can achieve >95% cure, but late diagnosis, low access to treatment, and treatment failure due to drug resistance continue to be roadblocks against eradication of the virus. We report the rational design of two series of HCV NS3/4A protease inhibitors with improved resistance profiles by exploiting evolutionarily constrained regions of the active site using the substrate envelope model. Optimally filling the S4 pocket is critical to avoid resistance and improve potency. Our results provide drug design strategies to avoid resistance that are applicable to other quickly evolving viral drug targets.

VanMoof is releasing a new generation of its electric bike. In many ways, the VanMoof S3 and its smaller version the VanMoof X3 are refined versions of the VanMoof Electrified S2 and X2. It features an updated motor, hydraulic brakes and a familiar design. If you’re not familiar with VanMoof bikes, the company has been […]

Backblaze today announced that its B2 Cloud Storage service is now API-compatible with Amazon’s S3 storage service. Backblaze started as an affordable cloud backup service, but over the last few years, the company has also taken its storage expertise and launched the developer-centric B2 Cloud Storage service, which promises to be significantly cheaper than similar […]

Backblaze today announced that its B2 Cloud Storage service is now API-compatible with Amazon’s S3 storage service. Backblaze started as an affordable cloud backup service, but over the last few years, the company has also taken its storage expertise and launched the developer-centric B2 Cloud Storage service, which promises to be significantly cheaper than similar […]

The Audi S3 feels smart, comfortable, sporty and grown-up, but also great fun says RAY MASSEY. The stop-start system also switches off the engine to save fuel.

गैजेट डेस्क. यूएस की कंपनी क्रॉसएयर ने बीते दिनों भारत में अपनी नया हेडफोन लॉन्च किया है। इस हेडफोन का मॉडल नंबर HS35 स्टीरियो है। ये वायर्ड गेमिंग हेडफोन है। इसे कार्बन, ब्लू, रेड और ग्रीन कलर्स में खरीदा जा सकता है। कंपनी की ऑफिशियल वेबसाइट पर इसकी कीमत 40 डॉलर यानी करीब 2800 रुपए है। कंपनी अपनी साउंड प्रोडक्ट के साथ 'नेवर मिस ए बीट' का स्लोगन देती है। यही वजह है कि इसकी साउंड क्वालिटी जबरदस्त है। इस हेडफोन में और क्या खूबियां है, वीडियो में देखते हैं...

Grannell, Craig

Delorme, Rick, author

Reis, George

Sikora, Piotr, author

Felke-Morris, Terry

Felke-Morris, Terry

You can apply CSS3 transitions to the z-index property, but it may work in a way you don't expect.

In August, due to a twitter discussion with Molly, and of course while partying on a Saturday night, Dave Gregory and I were looking at whether the Flexible box layout module (still a working draft) is getting close to ready for prime time yet. Our hope was that it will solve some of the frustrations [...]

As you may have read, outside of gradients, you can’t change a background-image with CSS transitions. Or can you? At InControl Conference last week, Greg Rewis spoke about Transitions, Transforms and Animations. A question was asked about showing one background-image on load and transitioning to another in a subsequent pseudo-state. You can always change the [...]

This morning I awakened with a question in my twitter stream from @deebeefunky. He was frustrated by the fact that when he sets a blur on box-shadow, it shows on two sides of the box. He wants it to show on only one side. Of course, that got me thinking. I did come up with [...]

Future CSS implementations should allow for some form of responsive images via CSS alone. This is an early idea for how that might be done. However, a significant drawback is that it would not prevent both “mobile optimised” and larger size images from being requested at larger screen resolutions.

Note that the CSS presented here is not supported in any browsers at the time of writing.

This method relies on the use of @media queries, CSS3 generated content, and the CSS3 extension to the attr() function.

The principles are basically the same as those underpinning Filament Group’s work on Responsive Images. The source image is “mobile optimised” and the urls of larger size images are included using HTML data-* attributes.

<img src="image.jpg"
     data-src-600px="image-600px.jpg"
     data-src-800px="image-800px.jpg"
     alt="">

Using CSS @media queries you can target devices above certain widths. Within each media query block, images with larger alternatives can be targeted using an attribute selector.

CSS3 generated content allows you to replace the content of any element using the content property. At the moment, only Opera 10+ supports it. In CSS 2.1, the content property is limited to use with the :before and :after pseudo-elements.

By combining the content property with the CSS3 extension to attr(), you will be able to specify that an attribute’s value is interpreted as the URL part of a url() expression. In this case, it means you will be able to replace an image’s content with the image found at the destination URL stored in a custom HTML data-* attribute.

@media (min-device-width:600px) {
  img[data-src-600px] {
    content: attr(data-src-600px, url);
  }
}

@media (min-device-width:800px) {
  img[data-src-800px] {
    content: attr(data-src-800px, url);
  }
}

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Issues

Unfortunately, there are a number of issues with this technique.

1. It doesn’t prevent multiple assets being downloaded at larger screen widths because network activity kicks in before CSS is applied. That means, for example, that desktop environments would make 2 HTTP requests for an image and have to load more assets than if they had been served only the larger image in the source.
2. It makes the assumption that wider screens are tied to better internet connections.
3. It forces authors to create and maintain multiple image sizes for each image.
4. At present, using the context menu (or drag and drop) to copy the image will result in the source file being copied and not the replacement image.
5. It doesn’t account for devices with different pixel densities.

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