Qiang Tian
Oct 1, 2004; 3:960-969
Research

Zika virus (ZIKV) is a neurotropic flavivirus that causes several diseases including birth defects such as microcephaly. Intrinsic immunity is known to be a frontline defense against viruses through host anti-viral restriction factors. Limited knowledge is available on intrinsic immunity against ZIKV in brains. Amyloid precursor protein (APP) is predominantly expressed in brains and implicated in the pathogenesis of Alzheimer's diseases. We have found that ZIKV interacts with APP, and viral infection increases APP expression via enhancing protein stability. Moreover, we identified the viral peptide, HGSQHSGMIVNDTGHETDENRAKVEITPNSPRAEATLGGFGSLGL, which is capable of en-hancing APP expression. We observed that aging brain tissues with APP had protective effects on ZIKV infection by reducing the availability of the viruses. Also, knockdown of APP expression or blocking ZIKV-APP interactions enhanced ZIKV replication in human neural progenitor/stem cells. Finally, intracranial infection of ZIKV in APP-null neonatal mice resulted in higher mortality and viral yields. Taken together, these findings suggest that APP is a restriction factor that protects against ZIKV by serving as a decoy receptor, and plays a protective role in ZIKV-mediated brain injuries.

Stop codon read-through (SCR) is a process of continuation of translation beyond a stop codon. This phenomenon, which occurs only in certain mRNAs under specific conditions, leads to a longer isoform with properties different from that of the canonical isoform. MTCH2, which encodes a mitochondrial protein that regulates mitochondrial metabolism, was selected as a potential read-through candidate based on evolutionary conservation observed in the proximal region of its 3' UTR. Here, we demonstrate translational read-through across two evolutionarily conserved, in-frame stop codons of MTCH2 using luminescence- and fluorescence-based assays, and by analyzing ribosome-profiling and mass spectrometry (MS) data. This phenomenon generates two isoforms, MTCH2x and MTCH2xx (single- and double-SCR products, respectively), in addition to the canonical isoform MTCH2, from the same mRNA. Our experiments revealed that a cis-acting 12-nucleotide sequence in the proximal 3' UTR of MTCH2 is the necessary signal for SCR. Functional characterization showed that MTCH2 and MTCH2x were localized to mitochondria with a long t1/2 (>36 h). However, MTCH2xx was found predominantly in the cytoplasm. This mislocalization and its unique C terminus led to increased degradation, as shown by greatly reduced t1/2 (<1 h). MTCH2 read-through–deficient cells, generated using CRISPR-Cas9, showed increased MTCH2 expression and, consistent with this, decreased mitochondrial membrane potential. Thus, double-SCR of MTCH2 regulates its own expression levels contributing toward the maintenance of normal mitochondrial membrane potential.

Reliable, specific polyclonal and monoclonal antibodies are important tools in research and medicine. However, the discovery of antibodies against their targets in their native forms is difficult. Here, we present a novel method for discovery of antibodies against membrane proteins in their native configuration in mammalian cells. The method involves the co-expression of an antibody library in a population of mammalian cells that express the target polypeptide within a natural membrane environment on the cell surface. Cells that secrete a single-chain fragment variable (scFv) that binds to the target membrane protein thereby become self-labeled, enabling enrichment and isolation by magnetic sorting and FRET-based flow sorting. Library sizes of up to 109 variants can be screened, thus allowing campaigns of naïve scFv libraries to be selected against membrane protein antigens in a Chinese hamster ovary cell system. We validate this method by screening a synthetic naïve human scFv library against Chinese hamster ovary cells expressing the oncogenic target epithelial cell adhesion molecule and identify a panel of three novel binders to this membrane protein, one with a dissociation constant (KD) as low as 0.8 nm. We further demonstrate that the identified antibodies have utility for killing epithelial cell adhesion molecule–positive cells when used as a targeting domain on chimeric antigen receptor T cells. Thus, we provide a new tool for identifying novel antibodies that act against membrane proteins, which could catalyze the discovery of new candidates for antibody-based therapies.

What will authorizing the return of US troops mean for Somalia? Explainer Video aboudiaf.drupal 17 June 2022

Ahmed Soliman examines what the reintroduction of US military means for Somalia.

He says the strategy remains to try and reduce al-Shabaab’s threat, suppress its ability to carry out operations, and target its senior leadership.

There is more of a recognition now that the focus needs to be on restoring an effective security sector within Somalia and ensuring their forces are ready, but this also requires better coordination between the federal government and federal member states which it is hoped will happen in this new administration.

What challenges does the new president of Somalia face? Explainer Video aboudiaf.drupal 28 June 2022

Ahmed Soliman examines the challenges the new president Hassan Sheikh Mohamud faces in his first 100 days as president.

Key issues for the new administration are a deteriorating situation with regards to drought as close to half the population are facing food insecurity due to a fourth failed rainy season.

Combined with an inflation rate above ten per cent, many Somalis are at risk of famine and starvation. Many areas of the country are affected from the pastoralist regions to those which house IDP camps around the capital city and other towns, all being exacerbated by the war in Ukraine as Somalia was importing much of its wheat imports from Ukraine and Russia.

The Internet is full of cats—and in this case, malware-delivering fake cat websites used for very targeted search engine optimization.

Sylwia Struk
Dec 28, 2020; 0:RA119.001766v1-mcp.RA119.001766
Research

Chiara Pavanello
Dec 1, 2020; 61:1784-1788
Patient-Oriented and Epidemiological Research

Functions of the gut microbiome have a growing number of implications for host metabolic health, with diet being one of the most significant influences on microbiome composition. Compelling links between diet and the gut microbiome suggest key roles for various macronutrients, including lipids, yet how individual classes of dietary lipids interact with the microbiome remains largely unknown. Sphingolipids are bioactive components of most foods and are also produced by prominent gut microbes. This makes sphingolipids intriguing candidates for shaping diet–microbiome interactions. Here, we used a click chemistry–based approach to track the incorporation of bioorthogonal dietary omega-alkynyl sphinganine (sphinganine alkyne [SAA]) into the murine gut microbial community (Bioorthogonal labeling). We identified microbial and SAA-specific metabolic products through fluorescence-based sorting of SAA-containing microbes (Sort), 16S rRNA gene sequencing to identify the sphingolipid-interacting microbes (Seq), and comparative metabolomics to identify products of SAA assimilation by the microbiome (Spec). Together, this approach, termed Bioorthogonal labeling-Sort-Seq-Spec (BOSSS), revealed that SAA assimilation is nearly exclusively performed by gut Bacteroides, indicating that sphingolipid-producing bacteria play a major role in processing dietary sphinganine. Comparative metabolomics of cecal microbiota from SAA-treated mice revealed conversion of SAA to a suite of dihydroceramides, consistent with metabolic activities of Bacteroides and Bifidobacterium. Additionally, other sphingolipid-interacting microbes were identified with a focus on an uncharacterized ability of Bacteroides and Bifidobacterium to metabolize dietary sphingolipids. We conclude that BOSSS provides a platform to study the flux of virtually any alkyne-labeled metabolite in diet–microbiome interactions.

Familial LCAT deficiency (FLD) is a rare genetic disorder of HDL metabolism, caused by loss-of-function mutations in the LCAT gene and characterized by a variety of symptoms including corneal opacities and kidney failure. Renal disease represents the leading cause of morbidity and mortality in FLD cases. However, the prognosis is not known and the rate of deterioration of kidney function is variable and unpredictable from patient to patient. In this article, we present data from a follow-up of the large Italian cohort of FLD patients, who have been followed for an average of 12 years. We show that renal failure occurs at the median age of 46 years, with a median time to a second recurrence of 10 years. Additionally, we identify high plasma unesterified cholesterol level as a predicting factor for rapid deterioration of kidney function. In conclusion, this study highlights the severe consequences of FLD, underlines the need of correct early diagnosis and referral of patients to specialized centers, and highlights the urgency for effective treatments to prevent or slow renal disease in patients with LCAT deficiency.

Paramphistomosis, caused by the rumen fluke, Calicophoron daubneyi, is a parasitic infection of ruminant livestock which has seen a rapid rise in prevalence throughout Western Europe in recent years. Following ingestion of metacercariae (parasite cysts) by the mammalian host, newly-excysted juveniles (NEJs) emerge and invade the duodenal submucosa which causes significant pathology in heavy infections. The immature larvae then migrate upwards, along the gastrointestinal tract, and enter the rumen where they mature and begin to produce eggs. Despite their emergence, and sporadic outbreaks of acute disease, we know little about the molecular mechanisms used by C. daubneyi to establish infection, acquire nutrients and to avoid the host immune response. Here, transcriptome analysis of four intra-mammalian life-cycle stages, integrated with secretome analysis of the NEJ and adult parasites (responsible for acute and chronic disease respectively), revealed how the expression and secretion of selected families of virulence factors and immunomodulators are regulated in accordance with fluke development and migration. Our data show that whilst a family of cathepsins B with varying S2 sub-site residues (indicating distinct substrate specificities) are differentially secreted by NEJs and adult flukes, cathepsins L and F are secreted in low abundance by NEJs only. We found that C. daubneyi has an expanded family of aspartic peptidases, which is up-regulated in adult worms, although they are underrepresented in the secretome. The most abundant proteins in adult fluke secretions were helminth defence molecules (HDMs) that likely establish an immune environment permissive to fluke survival and/or neutralise pathogen-associated molecular patterns (PAMPs) such as bacterial lipopolysaccharide in the microbiome-rich rumen. The distinct collection of molecules secreted by C. daubneyi allowed the development of the first coproantigen-based ELISA for paramphistomosis which, importantly, did not recognise antigens from other helminths commonly found as co-infections with rumen fluke.

The F-box protein MORE AXILLARY GROWTH 2 (MAX2) is a central component in the signaling cascade of strigolactones (SLs) as well as of the smoke derived karrikins (KARs) and the so far unknown endogenous KAI2 ligand (KL). The two groups of molecules are involved in overlapping and unique developmental processes, and signal-specific outcomes are attributed to perception by the paralogous α/β-hydrolases DWARF14 (D14) for SL and KARRIKIN INSENSITIVE 2/ HYPOSENSITIVE TO LIGHT (KAI2/HTL) for KAR/KL. Additionally, depending on which receptor is activated, specific members of the SUPPRESSOR OF MAX2 1 (SMAX1) – LIKE (SMXL) family control KAR/KL and SL responses. As proteins that function in the same signal transduction pathway often occur in large protein complexes, we aimed at discovering new players of the MAX2, D14 and KAI2 protein network by tandem affinity purification using Arabidopsis cell cultures. When using MAX2 as a bait, various proteins were co-purified among which general components of the Skp1-Cullin-F-box complex and members of the CONSTITUTIVE PHOTOMORPHOGENIC 9 signalosome. Here, we report the identification of a novel interactor of MAX2, a type 5 serine/threonine protein phosphatase, designated PHYTOCHROME-ASSOCIATED PROTEIN PHOSPHATASE 5 (PAPP5). Quantitative affinity purification pointed at PAPP5 as being more present in KAI2 rather than D14 protein complexes. In agreement, mutant analysis suggests that PAPP5 modulates KAR/KL-dependent seed germination in suboptimal conditions and seedling development. Additionally, a phosphopeptide enrichment experiment revealed that PAPP5 might dephosphorylate MAX2 in vivo independently of the synthetic strigolactone analog, rac-GR24. Together, by analyzing the protein complexes to which MAX2, D14 and KAI2 belong, we revealed a new MAX2 interactor, PAPP5, that might act through dephosphorylation of MAX2 to control mainly KAR/KL- related phenotypes and, hence, provide another link with the light pathway.

Australian Prime Minister Anthony Albanese said Thursday his government will introduce legislation to ban children under 16 years of age from social media.

An emperor penguin is being cared for by wildlife experts after becoming the first member of its species to make the 2,200-mile trek from Antarctica to Australia.

Australian Defense Minister Peter Dutton called for alliances to protect the nations and people of the Indo-Pacific region.

March 20, 2024 — The Pawsey Supercomputing Research Centre invites Australian-based research groups to join the Pawsey Uptake Project call. This initiative will provide teams with access to dedicated Pawsey […]

The post Pawsey Invites Australian Researchers to Advance Scientific Innovation Through the Pawsey Uptake Project appeared first on HPCwire.

Kleptoparasitism, in which a bird harasses another to steal its food, might introduce avian flu to the continent, currently the only one without the severe H5N1 strain

Using sound recordings, the team identified the largest known population of the night parrot, a secretive species known as the "Holy Grail of birdwatching"

Most adult king penguins weigh between 31 and 37 pounds. At nine months old, a 51.8-pound Pesto is already looming over his parents

This brief chapter of art history is often overlooked. Now, an exhibition in New York City makes a strong argument for the integral role played by four artists in the city of Siena

The Art Gallery of New South Wales is showcasing works full of the Surrealist artist's signature motifs—such as apples, pipes and bowler hats—in addition to lesser-known pieces

The Manhattan district attorney's office has obtained an arrest warrant for Edoardo Almagià, who has been accused of working with looters and dealing stolen artifacts for years

The viral king penguin chick at Sea Life Melbourne Aquarium is beginning to lose his youthful down, a process that will give him his distinctive and waterproof adult plumage

It's not clear how the juvenile male ended up so far north, but experts suggest he was motivated by his appetite

Renaissance paintings, medieval archives, cloistered orchards—how one Italian scientist is uncovering secrets that could help combat a growing agricultural crisis

CME Group, the world's leading derivatives marketplace, today announced its new CBL Australian Carbon Credit Unit (ACCU) futures have launched and are available for trading. A total of five...

Australia's prime minister on Thursday vowed to ban children under 16 from social media, saying the pervasive influence of platforms like Facebook and TikTok was "doing real harm to our kids".

An update about the flood damage in Eastern Australia

On 12 December, OM Australia settled on their first-ever permanent base after renting for over 20 years.

Teens in Europe are gathered this week to connect with Jesus and each other. A month ago, teenagers in Australia had this experience.

A former Afghan fighter discovers Jesus Christ in the Qur’an.

A team of researchers at Penn State College of Medicine and collaborators from five different institutes has created a 3D atlas of developing mice brains, providing a more dynamic understanding of how the mammalian brain develops. This atlas provides a common reference and anatomical framework to help researchers understand brain development and study neurodevelopmental disorders.

Thousands of people queued up in the city of Geelong, south of Melbourne in Australia, to catch a glimpse of what's once-in-a-decade occurrence -- the blooming 'corpse flower'.

The newly identified ‘Chonkus’ strain of cyanobacteria, discovered in Italy's volcanic waters, may be a natural ally in carbon sequestration. With its CO₂-absorbing properties and ability to thrive in extreme environments, Chonkus shows promise in industrial carbon storage and bio-manufacturing, potentially lowering costs while contributing to climate action.

Wicket-keeper batter Alex Carey was tipped by former Australia T20I captain Aaron Finch to play a big role during the Border-Gavaskar Trophy.

Australia captain Pat Cummins had attended a Coldplay concert during his nation's series-deciding third ODI against Pakistan.

Don Meij started as a delivery driver for Dominos almost 40 years back, and eventually became the CEO.

Thousands of people queued up in the city of Geelong, south of Melbourne in Australia, to catch a glimpse of what's once-in-a-decade occurrence -- the blooming 'corpse flower'.

October is National Italian American Heritage Month, a month dedicated to celebrating the distinguished cultural contributions of Americans with Italian lineage. According to the United States Census Bureau, as of 2019, more than 16 million Americans of Italian descent reside in the United States, making up the seventh largest ethnic group in the country. “Italian […]

U.S. Senator Chriss Coons and Ambassador to Australia Carolina Kennedy recently visited New Castle's historic sites.

Amid the massive row over his alleged racist remark against Union minister HD Kumaraswamy, Karnataka minister BZ Zameer Ahmed Khan has said he called the JDS leader "Kaalia" out of affection and that he was ready to apologise

North Rhine-Westphalia is fDi's top large region for FDI Strategy, with the Basque Country topping the table for mid-sized regions and Ireland South East first among small regions. 

Maserati Shamal restomod project in the works Restomod will use Biturbo Coupe body and Ghibli S twin-turbocharged V-6 Production to be limited to 33 units The Maserati Shamal launched in 1990 didn't see much success, despite featuring a body penned by the legendary Marcello Gandini, and a twin-turbocharged V-8 under the hood. It was devised when...

Utilities in Australia are looking to the sky when it comes to avoiding costly network failures and bushfires, enlisting the expertise of investors such as Canada’s Aethon Aerial Solutions to monitor power lines.

Dutch company Starware has defied the challenges of COVID-19 and established a subsidiary in Melbourne, Victoria.