Nitric oxide (NO) has important functions in biology and atmospheric chemistry as a toxin, signaling molecule, ozone depleting agent and the precursor of the greenhouse gas nitrous oxide (N
O). ...Although NO is a potent oxidant, and was available on Earth earlier than oxygen, it is unclear whether NO can be used by microorganisms for growth. Anaerobic ammonium-oxidizing (anammox) bacteria couple nitrite reduction to ammonium oxidation with NO and hydrazine as intermediates, and produce N
and nitrate. Here, we show that the anammox bacterium Kuenenia stuttgartiensis is able to grow in the absence of nitrite by coupling ammonium oxidation to NO reduction, and produce only N
. Under these growth conditions, the transcription of proteins necessary for NO generation is downregulated. Our work has potential implications in the control of N
O and NO emissions from natural and manmade ecosystems, where anammox bacteria contribute significantly to N
release to the atmosphere. We hypothesize that microbial NO-dependent ammonium oxidation may have existed on early Earth.
Only three biological pathways are known to produce oxygen: photosynthesis, chlorate respiration and the detoxification of reactive oxygen species. Here we present evidence for a fourth pathway, ...possibly of considerable geochemical and evolutionary importance. The pathway was discovered after metagenomic sequencing of an enrichment culture that couples anaerobic oxidation of methane with the reduction of nitrite to dinitrogen. The complete genome of the dominant bacterium, named 'Candidatus Methylomirabilis oxyfera', was assembled. This apparently anaerobic, denitrifying bacterium encoded, transcribed and expressed the well-established aerobic pathway for methane oxidation, whereas it lacked known genes for dinitrogen production. Subsequent isotopic labelling indicated that 'M. oxyfera' bypassed the denitrification intermediate nitrous oxide by the conversion of two nitric oxide molecules to dinitrogen and oxygen, which was used to oxidize methane. These results extend our understanding of hydrocarbon degradation under anoxic conditions and explain the biochemical mechanism of a poorly understood freshwater methane sink. Because nitrogen oxides were already present on early Earth, our finding opens up the possibility that oxygen was available to microbial metabolism before the evolution of oxygenic photosynthesis.
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This review presents recent data supporting the methotrexate (MTX) mechanisms of action, which are likely to account for its anti-proliferative and immunosuppressive effects in rheumatoid arthritis ...(RA). The effects of MTX in vivo may be mediated by reducing cell proliferation, increasing the rate of apoptosis of T cells, increasing endogenous adenosine release, altering the expression of cellular adhesion molecules, influencing production of cytokines, humoral responses and bone formation. Several reports indicate that the effects of MTX are influenced by genetic variants, specific dynamic processes and micro-environmental elements such as nucleotide deprivation or glutathione levels. The challenge for the future will be linking biological and genetic markers relevant to the response to MTX in RA.
Mitochondrial complex I is the largest integral membrane enzyme of the respiratory chain and consists of 44 different subunits encoded in the mitochondrial and nuclear genome. Its biosynthesis is a ...highly complicated and multifaceted process involving at least 14 additional assembly factors. How these subunits assemble into a functional complex I and where the assembly factors come into play is largely unknown. Here, we applied a dynamic complexome profiling approach to elucidate the assembly of human mitochondrial complex I and its further incorporation into respiratory chain supercomplexes. We delineate the stepwise incorporation of all but one subunit into a series of distinct assembly intermediates and their association with known and putative assembly factors, which had not been implicated in this process before. The resulting detailed and comprehensive model of complex I assembly is fully consistent with recent structural data and the remarkable modular architecture of this multiprotein complex.
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•Dynamic complexome profiling defines a stepwise assembly of subunits into complex I•Complex I assembly mirrors its modular architecture and evolutionary origin•Complex I assembly is completed before supercomplex formation starts•Composition of complex I subassemblies reveals three putative assembly proteins
Guerrero-Castillo et al. use a dynamic complexome profiling approach delineating the stepwise incorporation of all but one subunit into complex I and the involvement of all known and three putative assembly factors. After completion of its assembly, complex I is incorporated into the supercomplexes together with complexes III and IV.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Accurate classification of focal liver lesions is an important part of liver disease diagnostics. In clinical practice, the lesion type is often determined from the abdominal MR examination, which ...includes T2-weighted and dynamic contrast enhanced (DCE) MR images. To date, only T2-weighted images are exploited for automatic classification of focal liver lesions. In this study additional MR sequences and risk factors are used for automatic classification to improve the results and to make a step forward to a clinically useful aid for radiologists.
Clinical MRI data sets of 95 patients with in total 125 benign lesions (40 adenomas, 29 cysts and 56 hemangiomas) and 88 malignant lesions (30 hepatocellular carcinomas (HCC) and 58 metastases) were included in this study. Contrast curve, gray level histogram, and gray level co-occurrence matrix texture features were extracted from the DCE-MR and T2-weighted images. In addition, risk factors including the presence of steatosis, cirrhosis, and a known primary tumor were used as features. Fifty features with the highest ANOVA F-score were selected and fed to an extremely randomized trees classifier. The classifier evaluation was performed using the leave-one-out principle and receiver operating characteristic (ROC) curve analysis.
The overall accuracy for the classification of the five major focal liver lesion types is 0.77. The sensitivity/specificity is 0.80/0.78, 0.93/0.93, 0.84/0.82, 0.73/0.56, and 0.62/0.77 for adenoma, cyst, hemangioma, HCC, and metastasis, respectively.
The proposed classification system using features derived from clinical DCE-MR and T2-weighted images, with additional risk factors is able to differentiate five common types of lesions and is a step forward to a clinically useful aid for focal liver lesion diagnosis.
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Abstract
BACKGROUND
Neurotrophins of the nerve growth factor family are soluble polypeptides that are best known for their role in nerve growth, survival and differentiation in the central nervous ...system. A growing body of literature shows that neurotrophins and their receptors are also expressed throughout the reproductive tract.
OBJECTIVE AND RATIONALE
Neurotrophins are key regulatory proteins in reproductive physiology during development and throughout adult life. Of the neurotrophins, the literature describing the expression and function of brain-derived neurotrophic factor (BDNF) and its high-affinity receptor, neurotrophin receptor kinase-2 (NTRK2), has been expanding rapidly. We therefore conducted a systematic inductive qualitative review of the literature to better define the role of the BDNF in the reproductive tract. We postulate that BDNF and NTRK2 are central regulatory proteins throughout the reproductive system.
SEARCH METHODS
An electronic search of Medline (PubMed) and Web of Science for articles relating to BDNF and the reproductive system was carried out between January 2018 and February 2019.
OUTCOMES
In the ovary, BDNF expression and levels have been linked with follicle organisation during ovarian development, follicle recruitment and growth and oocyte maturation. In the endometrium, BDNF is involved in cell proliferation and neurogenesis. In contrast, literature describing the role of BDNF in other reproductive tissues is sparse and BDNF-NTRK2 signalling in the male reproductive tract has been largely overlooked. Whilst estradiol appears to be the primary regulator of BDNF expression, we also identified reports describing binding sites for glucocorticoid and myocyte enhancer factor-2, a calcium-response element through activation of an N-methyl-D-aspartate (NMDA) receptor, and aryl hydrocarbon receptor nuclear transporter protein-4 (ARNT) response elements in promoter regions of the BDNF gene. Expression is also regulated by multiple microRNAs and post-translational processing of precursor proteins and intracellular shuttling. BDNF-NTRK2 signalling is modulated through tissue specific receptor expression of either the full-length or truncated NTRK2 receptor; however, the functional importance remains to be elucidated. Dysregulation of BDNF expression and circulating concentrations have been implicated in several reproductive disorders including premature ovarian failure, endometriosis, pre-eclampsia, intra-uterine growth restriction (IUGR) and several reproductive cancers.
WIDER IMPLICATIONS
We conclude that BDNF and its receptors are key regulatory proteins central to gonadal development, ovarian regulation and uterine physiology, as well as embryo and placenta development. Furthermore, dysregulation of BDNF-NTRK2 in reproductive diseases suggests their potential role as candidate clinical markers of disease and potential therapeutic targets.
Current antibody-drug conjugates (ADCs) target internalising receptors on cancer cells leading to intracellular drug release. Typically, only a subset of patients with solid tumours has sufficient ...expression of such a receptor, while there are suitable non-internalising receptors and stroma targets. Here, we demonstrate potent therapy in murine tumour models using a non-internalising ADC that releases its drugs upon a click reaction with a chemical activator, which is administered in a second step. This was enabled by the development of a diabody-based ADC with a high tumour uptake and very low retention in healthy tissues, allowing systemic administration of the activator 2 days later, leading to efficient and selective activation throughout the tumour. In contrast, the analogous ADC comprising the protease-cleavable linker used in the FDA approved ADC Adcetris is not effective in these tumour models. This first-in-class ADC holds promise for a broader applicability of ADCs across patient populations.
Real-time database searching allows for simpler and automated proteomics workflows as it eliminates technical bottlenecks in high-throughput experiments. Most importantly, it enables ...results-dependent acquisition (RDA), where search results can be used to guide data acquisition during acquisition. This is especially beneficial for glycoproteomics since the wide range of physicochemical properties of glycopeptides lead to a wide range of optimal acquisition parameters. We established here the GlycoPaSER prototype by extending the Parallel Search Engine in Real-time (PaSER) functionality for real-time glycopeptide identification from fragmentation spectra. Glycopeptide fragmentation spectra were decomposed into peptide and glycan moiety spectra using common N-glycan fragments. Each moiety was subsequently identified by a specialized algorithm running in real-time. GlycoPaSER can keep up with the rate of data acquisition for real-time analysis with similar performance to other glycoproteomics software and produces results that are in line with the literature reference data. The GlycoPaSER prototype presented here provides the first proof-of-concept for real-time glycopeptide identification that unlocks the future development of RDA technology to transcend data acquisition.
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Skrywers skryf oor wat hulle sien, hoor, lees en ervaar. Mense lees dit en lewer kommentaar daarop. Die uiteenlopende response op dieselfde teks weerspieël hoe die lees van 'n teks kan verskil. Die ...diskoers wat gevolg het op 'n rubriek deur Hennie van Coller in Mei 2022 dien as voorbeeld en opper vrae oor hoe geskryf en gelees word, maar ook hoe geskryf en gelees behoort te word. Die soeke na antwoorde begin deur bepaalde vertrekpunte te openbaar in 'n oorsig van die diskoers, gevolg deur 'n besinning oor die fundamentele vertrekpunte. 'n Ontleding van geselekteerde lesinge van die Van Coller-rubriek, asook response op dergelike lesinge, volg aan die hand van 'n model van interafhanklike leesmodaliteite ten einde 'n oorwoë antwoord op bogenoemde vrae te kan gee. Dit blyk uit die lees van die geselekteerde lesings van die rubriek dat sommige mank gaan aan respek vir die letter van die rubriek se teks. Die eintlike bedoeling van die Van Coller-teks is meesal genegeer ter wille van die lees van 'n alternatiewe teks (dit wat ook uit die teks afgelei kon word). Gevolglik slaag weinig lesings daarin om daarvan sin te maak binne die konteks wat die outeur beskryf. Argumente in die aanvanklike response, sowel as latere reaksies in die verloop van die diskoers, is meesal in 'n uitsluitende trant met eenduidige logikas gevoer. Die idioom en konteks waarin die diskoers ontvou het, was dus oorwegend vyandig, aggressief en etosvreemd. Hierdie diskoers maak mens opnuut bewus van die noodsaaklikheid van 'n oop en omvattende gesprek oor sake van belang vir ons land, ons taal Afrikaans, en die toekoms van kinder- en jeugliteratuur. Só 'n gesprek is slegs moontlik binne 'n milieu van etosverwesenliking waarin almal tuis kan wees.
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Impact assessment (IA) follow-up is necessary to determine the environmental effects of a project or plan to inform ongoing management. No previous research confirms if visitor surveys may be used to ...this extent for developments within a protected. This paper explores if and how visitor surveys may be used as a tool for supporting EIA follow-up within protected areas. Relevant EIA documentation was appraised to determine EIA performance expectations for management of the Nombolo Mdhluli Conference Centre development in the Kruger National Park. Forty-four expectations were identified, translated into questions, and included in a survey scale. Eighty-nine conference delegates completed the survey whereafter an Importance Performance Analysis (IPA) method was used to map the responses in four IPA map quadrants: 1. Possible overkill, 2. Low priority, 3. Q3 Keep up the good work, and 4. Concentrate here. The IPA map displays 29 items of statistical significance in the four IPA map quadrants with 12 items in the 'Concentrate here' quadrant. The IPA results mapped the need for management to concentrate on responsible building, waste, water, energy, compliance, awareness, cumulative impact management. The paper shows that visitor surveys may be used as a simple but effective tool for supporting EIA follow-up monitoring.
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BFBNIB, GIS, IJS, KISLJ, NUK, PNG, UL, UM, UPUK
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