Closing a loophole? One of the key features, and one of the most contentious provisions, of the Charities (Protection and Social Investment) Bill 2015 (“the Bill”) is the new power it will grant the Charity Commission (“the Commission”) to issue of...

The Fourth Rail Package, which was introduced between June and December 2016, is a set of six items of EU legislation designed to increase the reliability and competitiveness of European railways in accordance with the EU’s liberalisation agen...

O2 and Virgin media sign a £31.4 billion merger agreement to form a telecom giant in the UK. The new company will boast 46 million total subscribers and revenue of £11 billion. The joint venture plans on making a £10 billion investment in the United Kingdom in five years. Earlier this week on Thursday, Spain’s Telefonica (EBR: TFA) and UK’s Liberty Global (NASDAQ: LBTYA) announced to have signed a £31.4 billion...

In response to Government guidance on maintaining educational provision for the children of key workers, the FCA and PRA have published guidance regarding individuals in th...

In her time at the Mail & Guardian, Patel was responsible for bringing stability to the newsroom and in the process assembled one of the best newsrooms in South Africa.

The post Khadija Patel resigns as Mail & Guardian editor-in-chief appeared first on The Mail & Guardian.

Re-examining the design of rural road projects will make them more effective in improving the lives of the people living nearby.

Carefully designed social programs offer the best chance to avoid corruption, inefficiency and other governance problems. 

Islamabad: Chairman of the United International Group, Mian Shahid said Friday that the current economic meltdown because of coronavirus may impact the business volumes of the industry, which are yet to be ascertained.Speaking on the development, Mian Shahid said that we have planned to generate...

ADB and the Government of Mongolia today signed $40 million in loans and a $2 million Japan Fund for Poverty Reduction grant to support the modernization of government-owned irrigation networks and vegetable production in Mongolia.

ADB today signed a $60 million loan deal (in Chinese Yuan equivalent) with Maxwealth Financial Leasing Co., Ltd. to improve municipal and industrial wastewater treatment capacity and standards in the People’s Republic of China...

Resolver Replacement Reference Design

MUMBAI: Indian real estate market witnessed a significant change in the last decade mainly backed by opening up of FDI in the sector and shift in preference to high-rises over traditional low-rise structures, according to a report. The opening up of the sector to foreign direct investment in 2005 initiated the entry of new avenues for funding, and capital inflow witnessed a spike, property consultant CBRE said in its report titled ‘Inflection Point: Ten years of organised real estate in India (2005-2014)’. Restrictive legislations till 2004 provided limited scope of funds for the sector. However, opening up of the sector to FDI in 2005 opened up new avenues for investment, […]

STAMFORD, CT -- HARMAN International Industries, Inc. (NYSE:HAR), the premium global audio and infotainment group, announced today that 19 of its audio products have been selected as winners in the prestigious Red Dot Award: Product Design 2014 competition.

You heard it here first: in 2018, HARMAN received a record-breaking 53 product design and technology awards, bringing our six-year-total to more than 300 awards for 190 different products.   This unprecedented number is a direct reflection of our...

Today’s companies see the importance of design as more consumers demand elegance alongside flawless functionality and exceptional user experience. As a company that has created countless ingenious product designs in different markets all over the ...

CES 2020, LAS VEGAS – JANUARY 6, 2020 – Today, JBL is introducing its first headphone series inspired by touring musicians, the JBL CLUB. Equipped with Legendary JBL Pro Sound, Personi-Fi™ and native voice assistants, the JBL CLUB series – CLUB ONE, CLUB...

Huemen, HARMAN’s in-house design agency, brings home 25 iF World Design Awards

Nouvelles lignes de basse percutantes et solos de guitare à tomber : les enceintes JBL Link Portable et Link Music viennent de sortir. Avec leur son signature 360 JBL, le Wi-Fi et le Bluetooth, Chromecast et Google Assistant intégrés, les enceintes sont aussi belles qu’intelligentes.

Music and driving are a powerful combination, and JBL automotive sound is designed to connect consumers to their vehicles at an emotional level. From Italy-based creative agency Garage Italia to leading auto manufacturers who leverage JBL’s audio ...

We’re thrilled to announce that HARMAN’s QLED Auto solution has been recognized in the User Experience category in Fast Company’s 2019 Innovation by Design Awards.

Stamford, CT – 12 March, 2020 – HARMAN International, a wholly-owned subsidiary of Samsung Electronics Co. Ltd., focused on connected technologies for automotive, consumer and enterprise markets, and its Huemen design team have received 25 iF Design...

Rethinking Design for Man & Machine: Q&A with Huemen’s Stephanie Tuttle Design has an instrumental role in delivering powerful experiences. HARMAN’s mission to unlocking and elevating experiences for a wide range of stakeholders, from automakers and...

Palo Alto, CA – Aha™ by HARMAN today announced that the new 2014 Mazda3 to be launched in Japan, the United States, and a number of additional North American and Asian Countries this fall will offer access to the Aha free service with the ability to select presets from more than 40,000* audio and information stations from Japan and other countries.

CES 2015, LAS VEGAS – HARMAN, the premium global audio, infotainment and enterprise automation group (NYSE:HAR), proudly introduce yurbuds® powered by JBL®, the number one selling sport earphone in the nation, is officially debuting yurbuds® products with JBL® Signature Sound in the US. JBL® is known industry-wide for its supreme quality, so coupling that with yurbuds® ergonomics, guaranteed never to hurt or fall out, you have a headphone like no other on the market.

May 25 - A bed sensor developed by an Israeli team is proving to be an effective and more reliable alternative to conventional patient monitoring technology. The sensor is designed to unobtrusively monitor a patient's vital signs from beneath their mattress and is less prone to sending out false alarms to nursing staff. Tara Cleary reports.

CES 2019, LAS VEGAS – JANUARY 7, 2019 – Today’s discerning audio consumer is seeking sophisticated design and innovative technology that seamlessly blends with their daily lives. When it comes to a multi-room speaker system that means: ease of use, form...

One of the world’s largest and most prestigious design competitions, the iF World Design Awards have been recognizing excellence in design for the past 65 years. HARMAN has often been among the companies selected by the competition’s panel of design...

Just like our individual identity makes us unique, brand identity helps a business set itself apart from its competitors in the market. An organization’s brand design shapes a company and its products. We recently caught up with one of our savvy lead...

CES 2020 – LAS VEGAS, NV – JANUARY 6, 2020 – Harman Kardon adds to its most iconic speaker series with the SoundSticks 4. In 2000, when the original SoundSticks was introduced, it quickly became one of the most sought-after desktop sound systems. The...

Weird blasts of radio waves from space called fast radio bursts have been baffling astronomers since they were discovered, but after finding one in our galaxy we may finally know what creates them

A study of brain cells in a dish adds to growing evidence that Alzheimer’s disease can be caused by herpes viruses, but antiviral treatment may help stop it

Payne Capital Management's Courtney Dominguez says the high level of investor pessimism indicates the markets may have bottomed. She says savings could make their way into stocks.

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Long noncoding RNAs (lncRNA) have been found to play critical roles in tumorigenesis and the development of various cancers, including hepatocellular carcinoma (HCC). Metastasis associated with lung adenocarcinoma transcript-1 (MALAT1) has been identified as an oncogene and prognostic biomarker in HCC. Here, we demonstrated that MALAT1 expression was obviously high in sorafenib-resistant HCC cells. Furthermore, knockdown of MALAT1 increased sorafenib sensitivity in nonresponsive HCC cells, whereas forced expression of MALAT1 conferred sorafenib resistance to responsive HCC cells in vitro. In addition, loss/gain-of-function assays revealed that MALAT1 promoted cell proliferation, migration, and epithelial–mesenchymal transition in HCC cells. Mechanistically, MALAT1 regulated Aurora-A expression by sponging miR-140-5p, thus promoting sorafenib resistance in HCC cells. Moreover, MALAT1 inhibition enhanced the antitumor efficacy of sorafenib in vivo. Clinically, we found that MALAT1 expression was negatively correlated with miR-140-5p expression but positively correlated with Aurora-A expression in patients with HCC and that upregulated MALAT1 was closely correlated with poor survival outcomes in patients with HCC. These findings indicated that MALAT1 may be a novel target for prognosis prediction and therapeutic strategies in patients with HCC treated with sorafenib.

Cholesterol/sphingolipid-rich membrane domains, known as lipid rafts or membrane rafts, play a critical role in the compartmentalization of signaling pathways. Physical segregation of proteins in lipid rafts may modulate the accessibility of proteins to regulatory or effector molecules. Thus, lipid rafts serve as sorting platforms and hubs for signal transduction proteins. Cancer cells contain higher levels of intracellular cholesterol and lipid rafts than their normal non-tumorigenic counterparts. Many signal transduction processes involved in cancer development (insulin-like growth factor system and phosphatidylinositol 3-kinase-AKT) and metastasis [cluster of differentiation (CD)44] are dependent on or modulated by lipid rafts. Additional proteins playing an important role in several malignant cancers (e.g., transmembrane glycoprotein mucin 1) are also being detected in association with lipid rafts, suggesting a major role of lipid rafts in tumor progression. Conversely, lipid rafts also serve as scaffolds for the recruitment and clustering of Fas/CD95 death receptors and downstream signaling molecules leading to cell death-promoting raft platforms. The partition of death receptors and downstream signaling molecules in aggregated lipid rafts has led to the formation of the so-called cluster of apoptotic signaling molecule-enriched rafts, or CASMER, which leads to apoptosis amplification and can be pharmacologically modulated. These death-promoting rafts can be viewed as a linchpin from which apoptotic signals are launched. In this review, we discuss the involvement of lipid rafts in major signaling processes in cancer cells, including cell survival, cell death, and metastasis, and we consider the potential of lipid raft modulation as a promising target in cancer therapy.

ABSTRACT

Bacterial flagella are rotating nanomachines required for motility. Flagellar gene expression and protein secretion are coordinated for efficient flagellar biogenesis. Polar flagellates, unlike peritrichous bacteria, commonly order flagellar rod and hook gene transcription as a separate step after production of the MS ring, C ring, and flagellar type III secretion system (fT3SS) core proteins that form a competent fT3SS. Conserved regulatory mechanisms in diverse polar flagellates to create this polar flagellar transcriptional program have not been thoroughly assimilated. Using in silico and genetic analyses and our previous findings in Campylobacter jejuni as a foundation, we observed a large subset of Gram-negative bacteria with the FlhF/FlhG regulatory system for polar flagellation to possess flagellum-associated two-component signal transduction systems (TCSs). We present data supporting a general theme in polar flagellates whereby MS ring, rotor, and fT3SS proteins contribute to a regulatory checkpoint during polar flagellar biogenesis. We demonstrate that Vibrio cholerae and Pseudomonas aeruginosa require the formation of this regulatory checkpoint for the TCSs to directly activate subsequent rod and hook gene transcription, which are hallmarks of the polar flagellar transcriptional program. By reprogramming transcription in V. cholerae to more closely follow the peritrichous flagellar transcriptional program, we discovered a link between the polar flagellar transcription program and the activity of FlhF/FlhG flagellar biogenesis regulators in which the transcriptional program allows polar flagellates to continue to produce flagella for motility when FlhF or FlhG activity may be altered. Our findings integrate flagellar transcriptional and biogenesis regulatory processes involved in polar flagellation in many species.

IMPORTANCE Relative to peritrichous bacteria, polar flagellates possess regulatory systems that order flagellar gene transcription differently and produce flagella in specific numbers only at poles. How transcriptional and flagellar biogenesis regulatory systems are interlinked to promote the correct synthesis of polar flagella in diverse species has largely been unexplored. We found evidence for many Gram-negative polar flagellates encoding two-component signal transduction systems with activity linked to the formation of flagellar type III secretion systems to enable production of flagellar rod and hook proteins at a discrete, subsequent stage during flagellar assembly. This polar flagellar transcriptional program assists, in some manner, the FlhF/FlhG flagellar biogenesis regulatory system, which forms specific flagellation patterns in polar flagellates in maintaining flagellation and motility when activity of FlhF or FlhG might be altered. Our work provides insight into the multiple regulatory processes required for polar flagellation.

ABSTRACT

Bacillus subtilis contains two known cyclic di-GMP (c-di-GMP)-dependent receptors, YdaK and DgrA, as well as three diguanylate cyclases (DGCs): soluble DgcP and membrane-integral DgcK and DgcW. DgrA regulates motility, while YdaK is responsible for the formation of a putative exopolysaccharide, dependent on the activity of DgcK. Using single-molecule tracking, we show that a majority of DgcK molecules are statically positioned in the cell membrane but significantly less so in the absence of YdaK but more so upon overproduction of YdaK. The soluble domains of DgcK and of YdaK show a direct interaction in vitro, which depends on an intact I-site within the degenerated GGDEF domain of YdaK. These experiments suggest a direct handover of a second messenger at a single subcellular site. Interestingly, all three DGC proteins contribute toward downregulation of motility via the PilZ protein DgrA. Deletion of dgrA also affects the mobility of DgcK within the membrane and also that of DgcP, which arrests less often at the membrane in the absence of DgrA. Both, DgcK and DgcP interact with DgrA in vitro, showing that divergent as well as convergent direct connections exist between cyclases and their effector proteins. Automated determination of molecule numbers in live cells revealed that DgcK and DgcP are present at very low copy numbers of 6 or 25 per cell, respectively, such that for DgcK, a part of the cell population does not contain any DgcK molecule, rendering signaling via c-di-GMP extremely efficient.

IMPORTANCE Second messengers are free to diffuse through the cells and to activate all responsive elements. Cyclic di-GMP (c-di-GMP) signaling plays an important role in the determination of the life style transition between motility and sessility/biofilm formation but involves numerous distinct synthetases (diguanylate cyclases [DGCs]) or receptor pathways that appear to act in an independent manner. Using Bacillus subtilis as a model organism, we show that for two c-di-GMP pathways, DGCs and receptor molecules operate via direct interactions, where a synthesized dinucleotide appears to be directly used for the protein-protein interaction. We show that very few DGC molecules exist within cells; in the case of exopolysaccharide (EPS) formation via membrane protein DgcK, the DGC molecules act at a single site, setting up a single signaling pool within the cell membrane. Using single-molecule tracking, we show that the soluble DGC DgcP arrests at the cell membrane, interacting with its receptor, DgrA, which slows down motility. DgrA also directly binds to DgcK, showing that divergent as well as convergent modules exist in B. subtilis. Thus, local-pool signal transduction operates extremely efficiently and specifically.

ABSTRACT

Human noroviruses (HuNoV) are a leading cause of viral gastroenteritis worldwide and a significant cause of morbidity and mortality in all age groups. The recent finding that HuNoV can be propagated in B cells and mucosa-derived intestinal epithelial organoids (IEOs) has transformed our ability to dissect the life cycle of noroviruses. Using transcriptome sequencing (RNA-Seq) of HuNoV-infected intestinal epithelial cells (IECs), we have found that replication of HuNoV in IECs results in interferon (IFN)-induced transcriptional responses and that HuNoV replication in IECs is sensitive to IFN. This contrasts with previous studies that suggested that the innate immune response may play no role in the restriction of HuNoV replication in immortalized cells. We demonstrated that inhibition of Janus kinase 1 (JAK1)/JAK2 enhanced HuNoV replication in IECs. Surprisingly, targeted inhibition of cellular RNA polymerase II-mediated transcription was not detrimental to HuNoV replication but instead enhanced replication to a greater degree than blocking of JAK signaling directly. Furthermore, we demonstrated for the first time that IECs generated from genetically modified intestinal organoids, engineered to be deficient in the interferon response, were more permissive to HuNoV infection. Taking the results together, our work revealed that IFN-induced transcriptional responses restrict HuNoV replication in IECs and demonstrated that inhibition of these responses mediated by modifications of the culture conditions can greatly enhance the robustness of the norovirus culture system.

IMPORTANCE Noroviruses are a major cause of gastroenteritis worldwide, and yet the challenges associated with their growth in culture have greatly hampered the development of therapeutic approaches and have limited our understanding of the cellular pathways that control infection. Here, we show that human intestinal epithelial cells, which represent the first point of entry of human noroviruses into the host, limit virus replication by induction of innate responses. Furthermore, we show that modulating the ability of intestinal epithelial cells to induce transcriptional responses to HuNoV infection can significantly enhance human norovirus replication in culture. Collectively, our findings provide new insights into the biological pathways that control norovirus infection but also identify mechanisms that enhance the robustness of norovirus culture.

ABSTRACT

A bioinformatics approach was employed to identify transcriptome alterations in the peripheral blood mononuclear cells of well-characterized human subjects who were diagnosed with early disseminated Lyme disease (LD) based on stringent microbiological and clinical criteria. Transcriptomes were assessed at the time of presentation and also at approximately 1 month (early convalescence) and 6 months (late convalescence) after initiation of an appropriate antibiotic regimen. Comparative transcriptomics identified 335 transcripts, representing 233 unique genes, with significant alterations of at least 2-fold expression in acute- or convalescent-phase blood samples from LD subjects relative to healthy donors. Acute-phase blood samples from LD subjects had the largest number of differentially expressed transcripts (187 induced, 54 repressed). This transcriptional profile, which was dominated by interferon-regulated genes, was sustained during early convalescence. 6 months after antibiotic treatment the transcriptome of LD subjects was indistinguishable from that of healthy controls based on two separate methods of analysis. Return of the LD expression profile to levels found in control subjects was concordant with disease outcome; 82% of subjects with LD experienced at least one symptom at the baseline visit compared to 43% at the early convalescence time point and only a single patient (9%) at the 6-month convalescence time point. Using the random forest machine learning algorithm, we developed an efficient computational framework to identify sets of 20 classifier genes that discriminated LD from other bacterial and viral infections. These novel LD biomarkers not only differentiated subjects with acute disseminated LD from healthy controls with 96% accuracy but also distinguished between subjects with acute and resolved (late convalescent) disease with 97% accuracy.

IMPORTANCE Lyme disease (LD), caused by Borrelia burgdorferi, is the most common tick-borne infectious disease in the United States. We examined gene expression patterns in the blood of individuals with early disseminated LD at the time of diagnosis (acute) and also at approximately 1 month and 6 months following antibiotic treatment. A distinct acute LD profile was observed that was sustained during early convalescence (1 month) but returned to control levels 6 months after treatment. Using a computer learning algorithm, we identified sets of 20 classifier genes that discriminate LD from other bacterial and viral infections. In addition, these novel LD biomarkers are highly accurate in distinguishing patients with acute LD from healthy subjects and in discriminating between individuals with active and resolved infection. This computational approach offers the potential for more accurate diagnosis of early disseminated Lyme disease. It may also allow improved monitoring of treatment efficacy and disease resolution.