Novel genomic island modifies DNA with 7-deazaguanine derivatives

The discovery of ∼20-kb gene clusters containing a family of paralogs of tRNA guanosine transglycosylase genes, called tgtA5, alongside 7-cyano-7-deazaguanine (preQ[subscript 0]) synthesis and DNA metabolism genes, led to the hypothesis that 7-deazaguanine derivatives are inserted in DNA. This was established by detecting 2’-deoxy-preQ[subscript 0] and 2’-deoxy-7-amido-7-deazaguanosine in enzymatic hydrolysates of DNA extracted from the pathogenic, Gram-negative bacteria Salmonella enterica serovar Montevideo. These modifications were absent in the closely related S. enterica serovar Typhimurium LT2 and from a mutant of S. Montevideo, each lacking the gene cluster. This led us to rename the genes of the S. Montevideo cluster as dpdA-K for 7-deazapurine in DNA. Similar gene clusters were analyzed in ∼150 phylogenetically diverse bacteria, and the modifications were detected in DNA from other organisms containing these clusters, including Kineococcus radiotolerans, Comamonas testosteroni, and Sphingopyxis alaskensis. Comparative genomic analysis shows that, in Enterobacteriaceae, the cluster is a genomic island integrated at the leuX locus, and the phylogenetic analysis of the TgtA5 family is consistent with widespread horizontal gene transfer. Comparison of transformation efficiencies of modified or unmodified plasmids into isogenic S. Montevideo strains containing or lacking the cluster strongly suggests a restriction–modification role for the cluster in Enterobacteriaceae. Another preQ[subscript 0] derivative, 2’-deoxy-7-formamidino-7-deazaguanosine, was found in the Escherichia coli bacteriophage 9g, as predicted from the presence of homologs of genes involved in the synthesis of the archaeosine tRNA modification. These results illustrate a deep and unexpected evolutionary connection between DNA and tRNA metabolism.Deutsche ForschungsgemeinschaftSingapore-MIT Alliance in Research and Technology (SMART

The Global Ecosystem Dynamics Investigation: High-resolution laser ranging of the Earth’s forests and topography

Obtaining accurate and widespread measurements of the vertical structure of the Earths forests has been a longsought goal for the ecological community. Such observations are critical for accurately assessing the existing biomass of forests, and how changes in this biomass caused by human activities or variations in climate may impact atmospheric CO2 concentrations. Additionally, the three-dimensional structure of forests is a key component of habitat quality and biodiversity at local to regional scales. The Global Ecosystem Dynamics Investigation (GEDI) was launched to the International Space Station in late 2018 to provide high-quality measurements of forest vertical structure in temperate and tropical forests between 51.6 N & S latitude. The GEDI instrument is a geodetic-class laser altimeter/waveform lidar comprised of 3 lasers that produce 8 transects of structural information. Over its two-year nominal lifetime GEDI is anticipated to provide over 10 billion waveforms at a footprint resolution of 25 m. These data will be used to derive a variety of footprint and gridded products, including canopy height, canopy foliar profiles, Leaf Area Index (LAI), sub-canopy topography and biomass. Additionally, data from GEDI are used to demonstrate the efficacy of its measurements for prognostic ecosystem modeling, habit and biodiversity studies, and for fusion using radar and other remote sensing instruments. GEDI science and technology are unique: no other space-based mission has been created that is specifically optimized for retrieving vegetation vertical structure. As such, GEDI promises to advance our understanding of the importance of canopy vertical variations within an ecological paradigm based on structure, composition and function

Efficacy and safety of the human anti-IL-1beta monoclonal antibody canakinumab in rheumatoid arthritis: results of a 12-week, phase II, dose-finding study

<p>Abstract</p> <p>Background</p> <p>Canakinumab is a fully human anti-interleukin IL-1beta monoclonal antibody, being investigated for the treatment of rheumatoid arthritis (RA). This multicenter, phase II, randomized, double-blind, placebo-controlled, parallel-group, dose-finding study investigated the efficacy and safety of canakinumab in patients with active RA despite ongoing therapy at stable doses of methotrexate.</p> <p>Methods</p> <p>Patients were randomized to receive one of four regimens, in addition to methotrexate, for 12 weeks: canakinumab 150 mg subcutaneously (SC) every 4 weeks (q4wk), canakinumab 300 mg SC (2 injections of 150 mg SC) every 2 weeks, a 600 mg intravenous loading dose of canakinumab followed by 300 mg SC every 2 weeks', or placebo SC every 2 weeks.</p> <p>Results</p> <p>Among 274 patients with evaluable efficacy data, the percentage of responders according to American College of Rheumatology 50 criteria (the primary endpoint, based on a 28-joint count) was significantly higher with canakinumab 150 mg SC q4wk than with placebo (26.5% vs. 11.4%, respectively; p = 0.028). Compared to placebo, this dosage of canakinumab was also associated with significantly more favorable responses at week 12 with respect to secondary endpoints including the Disease Activity Score 28, scores on the Health Assessment Questionnaire and Functional Assessment of Chronic Illness Therapy-Fatigue, swollen 28-joint count, and patient's and physician's global assessments of disease activity. No safety concerns were raised with canakinumab therapy, particularly with regard to infections. Few injection-site reactions occurred.</p> <p>Conclusion</p> <p>The addition of canakinumab 150 mg SC q4wk improves therapeutic responses among patients who have active RA despite stable treatment with methotrexate.</p> <p>Trial Registration</p> <p>(ClinicalTrials.gov identifier: <a href="http://www.clinicaltrials.gov/ct2/show/NCT00784628">NCT00784628</a>)</p

Interseasonal RSV infections in Switzerland - rapid establishment of a clinician-led national reporting system (RSV EpiCH).

In anticipation of an interseasonal respiratory syncytial virus (RSV) epidemic, a clinician-led reporting system was rapidly established to capture RSV infections in Swiss hospitals, starting in January 2021. Here, we present details of the reporting system and first results to June 2021. An unusual epidemiology was observed with an interseasonal surge of RSV infections associated with COVID-19-related non-pharmacological interventions. These data allowed real-time adjustment of RSV prophylaxis guidelines and consequently underscore the need for and continuation of systematic nationwide RSV surveillance

Aberrant methylation of tRNAs links cellular stress to neuro-developmental disorders.

Mutations in the cytosine-5 RNA methyltransferase NSun2 cause microcephaly and other neurological abnormalities in mice and human. How post-transcriptional methylation contributes to the human disease is currently unknown. By comparing gene expression data with global cytosine-5 RNA methylomes in patient fibroblasts and NSun2-deficient mice, we find that loss of cytosine-5 RNA methylation increases the angiogenin-mediated endonucleolytic cleavage of transfer RNAs (tRNA) leading to an accumulation of 5' tRNA-derived small RNA fragments. Accumulation of 5' tRNA fragments in the absence of NSun2 reduces protein translation rates and activates stress pathways leading to reduced cell size and increased apoptosis of cortical, hippocampal and striatal neurons. Mechanistically, we demonstrate that angiogenin binds with higher affinity to tRNAs lacking site-specific NSun2-mediated methylation and that the presence of 5' tRNA fragments is sufficient and required to trigger cellular stress responses. Furthermore, the enhanced sensitivity of NSun2-deficient brains to oxidative stress can be rescued through inhibition of angiogenin during embryogenesis. In conclusion, failure in NSun2-mediated tRNA methylation contributes to human diseases via stress-induced RNA cleavage

Dominant ACO2 mutations are a frequent cause of isolated optic atrophy.

Biallelic mutations in ACO2, encoding the mitochondrial aconitase 2, have been identified in individuals with neurodegenerative syndromes, including infantile cerebellar retinal degeneration and recessive optic neuropathies (locus OPA9). By screening European cohorts of individuals with genetically unsolved inherited optic neuropathies, we identified 61 cases harbouring variants in ACO2, among whom 50 carried dominant mutations, emphasizing for the first time the important contribution of ACO2 monoallelic pathogenic variants to dominant optic atrophy. Analysis of the ophthalmological and clinical data revealed that recessive cases are affected more severely than dominant cases, while not significantly earlier. In addition, 27% of the recessive cases and 11% of the dominant cases manifested with extraocular features in addition to optic atrophy. In silico analyses of ACO2 variants predicted their deleterious impacts on ACO2 biophysical properties. Skin derived fibroblasts from patients harbouring dominant and recessive ACO2 mutations revealed a reduction of ACO2 abundance and enzymatic activity, and the impairment of the mitochondrial respiration using citrate and pyruvate as substrates, while the addition of other Krebs cycle intermediates restored a normal respiration, suggesting a possible short-cut adaptation of the tricarboxylic citric acid cycle. Analysis of the mitochondrial genome abundance disclosed a significant reduction of the mitochondrial DNA amount in all ACO2 fibroblasts. Overall, our data position ACO2 as the third most frequently mutated gene in autosomal inherited optic neuropathies, after OPA1 and WFS1, and emphasize the crucial involvement of the first steps of the Krebs cycle in the maintenance and survival of retinal ganglion cells

RNA targeting with CRISPR–Cas13

RNA has important and diverse roles in biology, but molecular tools to manipulate and measure it are limited. For example, RNA interference1-3 can efficiently knockdown RNAs, but it is prone to off-target effects4, and visualizing RNAs typically relies on the introduction of exogenous tags5. Here we demonstrate that the class 2 type VI6,7 RNA-guided RNA-targeting CRISPR-Cas effector Cas13a8(previously known as C2c2) can be engineered for mammalian cell RNA knockdown and binding. After initial screening of 15 orthologues, we identified Cas13a from Leptotrichia wadei (LwaCas13a) as the most effective in an interference assay in Escherichia coli. LwaCas13a can be heterologously expressed in mammalian and plant cells for targeted knockdown of either reporter or endogenous transcripts with comparable levels of knockdown as RNA interference and improved specificity. Catalytically inactive LwaCas13a maintains targeted RNA binding activity, which we leveraged for programmable tracking of transcripts in live cells. Our results establish CRISPR-Cas13a as a flexible platform for studying RNA in mammalian cells and therapeutic development.National Institute of Mental Health (U.S.) (Grant 5DP1-MH100706)National Institute of Mental Health (U.S.) (Grant 1R01-MH110049

সর্ব সাধারনের জন্য সাস্থ্য প্রযুক্তিঃ বিশ্বাসযোগ্য,সাশ্রয়ী,অভিযোজনযোগ্য

বিনিয়োগ বৃদ্ধি সত্ত্বেও এখন পর্যন্ত প্রতি ১০ জনের মধ্যে ৬ জনের স্বাস্থ্যের যত্ন নেই, অথবা নিজেরাও যত্ন নেয় না. অ্যালকোহল ভিত্তিক হ্যান্ড স্যানিটাইজার এবং উইকিমেড দেখায় কিভাবে পুনর্ব্যবহারযোগ্য উপকরন এবং সফটওয়্যার উৎপাদন একটি সম্প্রদায়ের লক্ষ লক্ষ মানুষের জীবন বাঁচাতে, বৈজ্ঞানিক সত্যতা বৃদ্ধি এবং ৯০ শতাংশ খরচ কমাতে পারে।সবার মধ্যে সমন্বয় সাধনই হলো ২০৩০ এজেন্ডাকে বাস্তবায়িত করার একমাত্র পন্থাঃ সবার জন্য সাস্থ্য. আমরা উন্নয়নশীল,দায়িত্ববান এবং ঐক্যবদ্ধ সমাজ গড়তে উদ্ভাবনীয় মডেলের বাইরেও ৯ টি বিকল্প প্রদান করে থাকি। আমরা বার্ধক্য,জননীতি,গুনমান ব্যবস্থাপনা এবং ক্রিপ্টোকারেন্সি বিষয়েও পরামর্শ দিয়ে থাকি

Технологии здравоохранения для всех: надежные, доступные, адаптивные

Несмотря на рост инвестиций в сферу здравоохранения, 6 из 10 человек все еще не имеют возможности получать медицинское лечение или же не соблюдают его. Антисептики на спиртовой основе и WikiMed являются примерами того, как сообщества, совместно разрабатывающие технические и программные средства открытого доступа, могут сохранить миллионы жизней, гарантировать научную честность и снизить расходы на 90%. Здравоохранение, ориентированное на сотрудничество, - это единственный способ реализовать Повестку дня 2030: «Доступное здравоохранение для каждого». Мы представляем 9 альтернативных вариантов к уже имеющимся моделям для построения ответственного и солидарного общества. Кроме того мы рассматриваем вопросы старения населения, социальной политики, системы контроля качества и криптовалюты

आमजन-स्वामित्व के रूप में स्वास्थ्य प्रौद्योगिकी: विश्वसनीय, अनुकूल एवं किफ़ायती

निवेशों में वृद्धि होने के बावजूद, अभी तक 10 में से 6 व्यक्ति के पास स्वास्थ्य सेवाओं की पहुँच नहीं है, न ही वे देखभाल के प्रति कर्तव्य का पालन करते हैं। एल्कोहॉल आधारित हाथ सफाई और विकीमेड ने यह दिखाया है कि किस प्रकार से ‘मुक्त पुनरुत्पादनीय उपकरण’ और सॉफ्टवेयर के निर्माण से लाखों लोगों की जान बचायी जा सकती है, वैज्ञानिक प्रमाणिकता में वृद्धि की जा सकती है और लागत को 90% तक कम किया जा सकता है। एजेंडा 2030- ‘सभी के लिए स्वास्थ्य’ को समय से क्रियान्वयन के लिए सहयोगात्मक देखरेख एकमात्र विकल्प है। जिम्मेदार एवं सशक्त समाज के निर्माण हेतु हम नवाचार मॉडल के अतिरिक्त नौ प्रमुख विकल्पों को प्रस्तुत करते हैं: हम बुजुर्गों, सार्वजनिक नीतियों, गुणवत्तापूर्ण प्रणाली एवं क्रिप्टोकरेंसी पर भी चर्चा करते हैं