The role of the universally conserved A2450–C2063 base pair in the ribosomal peptidyl transferase center

Despite the fact that all 23S rRNA nucleotides that build the ribosomal peptidyl transferase ribozyme are universally conserved, standard and atomic mutagenesis studies revealed the nucleobase identities being non-critical for catalysis. This indicates that these active site residues are highly conserved for functions distinct from catalysis. To gain insight into potential contributions, we have manipulated the nucleobases via an atomic mutagenesis approach and have utilized these chemically engineered ribosomes for in vitro translation reactions. We show that most of the active site nucleobases could be removed without significant effects on polypeptide production. Our data however highlight the functional importance of the universally conserved non-Watson-Crick base pair at position A2450–C2063. Modifications that disrupt this base pair markedly impair translation activities, while having little effects on peptide bond formation, tRNA drop-off and ribosome-dependent EF-G GTPase activity. Thus it seems that disruption of the A2450–C2063 pair inhibits a reaction following transpeptidation and EF-G action during the elongation cycle. Cumulatively our data are compatible with the hypothesis that the integrity of this A-C wobble base pair is essential for effective tRNA translocation through the peptidyl transferase center during protein synthesis

Critical role of the disintegrin metalloprotease ADAM17 for intestinal inflammation and regeneration in mice

The protease a disintegrin and metalloprotease (ADAM) 17 cleaves tumor necrosis factor (TNF), L-selectin, and epidermal growth factor receptor (EGF-R) ligands from the plasma membrane. ADAM17 is expressed in most tissues and is up-regulated during inflammation and cancer. ADAM17-deficient mice are not viable. Conditional ADAM17 knockout models demonstrated proinflammatory activities of ADAM17 in septic shock via shedding of TNF. We used a novel gene targeting strategy to generate mice with dramatically reduced ADAM17 levels in all tissues. The resulting mice called ADAM17ex/ex were viable, showed compromised shedding of ADAM17 substrates from the cell surface, and developed eye, heart, and skin defects as a consequence of impaired EGF-R signaling caused by failure of shedding of EGF-R ligands. Unexpectedly, although the intestine of unchallenged homozygous ADAM17ex/ex mice was normal, ADAM17ex/ex mice showed substantially increased susceptibility to inflammation in dextran sulfate sodium colitis. This was a result of impaired shedding of EGF-R ligands resulting in failure to phosphorylate STAT3 via the EGF-R and, consequently, in defective regeneration of epithelial cells and breakdown of the intestinal barrier. Besides regulating the systemic availability of the proinflammatory cytokine TNF, our results demonstrate that ADAM17 is needed for vital regenerative activities during the immune response. Thus, our mouse model will help investigate ADAM17 as a potential drug target

Early mobilisation in critically ill COVID-19 patients: a subanalysis of the ESICM-initiated UNITE-COVID observational study

Background Early mobilisation (EM) is an intervention that may improve the outcome of critically ill patients. There is limited data on EM in COVID-19 patients and its use during the first pandemic wave. Methods This is a pre-planned subanalysis of the ESICM UNITE-COVID, an international multicenter observational study involving critically ill COVID-19 patients in the ICU between February 15th and May 15th, 2020. We analysed variables associated with the initiation of EM (within 72 h of ICU admission) and explored the impact of EM on mortality, ICU and hospital length of stay, as well as discharge location. Statistical analyses were done using (generalised) linear mixed-effect models and ANOVAs. Results Mobilisation data from 4190 patients from 280 ICUs in 45 countries were analysed. 1114 (26.6%) of these patients received mobilisation within 72 h after ICU admission; 3076 (73.4%) did not. In our analysis of factors associated with EM, mechanical ventilation at admission (OR 0.29; 95% CI 0.25, 0.35; p = 0.001), higher age (OR 0.99; 95% CI 0.98, 1.00; p ≤ 0.001), pre-existing asthma (OR 0.84; 95% CI 0.73, 0.98; p = 0.028), and pre-existing kidney disease (OR 0.84; 95% CI 0.71, 0.99; p = 0.036) were negatively associated with the initiation of EM. EM was associated with a higher chance of being discharged home (OR 1.31; 95% CI 1.08, 1.58; p = 0.007) but was not associated with length of stay in ICU (adj. difference 0.91 days; 95% CI − 0.47, 1.37, p = 0.34) and hospital (adj. difference 1.4 days; 95% CI − 0.62, 2.35, p = 0.24) or mortality (OR 0.88; 95% CI 0.7, 1.09, p = 0.24) when adjusted for covariates. Conclusions Our findings demonstrate that a quarter of COVID-19 patients received EM. There was no association found between EM in COVID-19 patients' ICU and hospital length of stay or mortality. However, EM in COVID-19 patients was associated with increased odds of being discharged home rather than to a care facility. Trial registration ClinicalTrials.gov: NCT04836065 (retrospectively registered April 8th 2021)

Individual Learner Differences and Different Learning Styles

Research findings have not yet been able to give a complete answer to questions such as: „Should a learner possess a natural aptitude or linguistic intelligence to learn a second language successfully?“, „To what extent do motivation and learners’ personality traits impact the process of second language learning?“ and „Are children better learners than adults?“. Considering these questions we will try to give a brief overview of the components that make up the notion of individual differences and, above all, their impact on learners’ success. At the very beginning, the terms age, intelligence, aptitude and motivation will be analyzed and their impact on learners’ progress will be explained. In addition, this paper will define the notion of learning styles and will provide some guidelines for teachers how to teach heterogeneous classes effectively. This paper will try to give a clear picture of the significant role of individual learner differences in second language acquisition and will try to determine which factors have the greatest impact on learners’ success

Improving food security in Nigeria through livestock innovation

The challenge of ensuring food security, which concerns not only the availability of food products but also their nutritional quality, is particularly important for modern Nigeria. The diet of the population lacks sufficient animal protein, which entails many health problems. Nigeria’s livestock sector, despite its considerable size, is not able to satisfy the demand of the rapidly growing population for animal protein. The steady development of animal husbandry in Nigeria is hindered by the escalating conflict between farmers and pastoralists, which causes loss of life, destruction of crops and livestock. The Nigerian authorities have made repeated attempts to find a solution to resolve the conflict, one of them being the decision to establish livestock ranches that would limit the grazing area and thereby eliminate the main cause of the tensions – constant migrations of livestock, but to no avail. Modern laws do not take into account many of the nuances that make attempts to organize livestock farming in fenced areas unfeasible. However, keeping farm animals on ranches is an innovative way to develop livestock in Nigeria. The author believes that Nigerian laws regulating the livestock sector require significant modification, where special attention should be paid to innovative components

Soldiers as farmers: army agriculture and food security in contemporary Nigeria

FAO estimates that most of Nigeria’s population is underserved; besides hunger, people experience effects of poor nutrition – diabetes, obesity, anaemia, etc. Formerly Nigeria was an agricultural country, but now its local production does not satisfy its own food demand. Farming is inefficient due to many factors, including conflicts between farmers and pastoralists, rooted in the very method of livestock breeding: pastoralists roam Nigeria all year round, while raising animals on ranches is barely practiced; as the population grows rapidly, agricultural plots begin to occupy traditional migration routes, and passing cattle destroy crops. Farmers take revenge by killing or stealing cattle. Consequently, Nigerians suffer from loss of livestock and crops and forced displacement. The government and the army established the Nigerian Army Farms and Ranches Limited (NAFARL), which enabled small-scale agricultural enterprises to organize on army lands. Thereby the army demonstrates advantages of non-nomadic livestock breeding and creates jobs. It is too early to draw conclusions on the effectiveness of NAFARL, as less than two years have passed since its inception. However, it may be argued that the army is capable of not only resolving conflicts, but also supporting the development of agriculture and achieving food security

INDIVIDUAL LEARNER DIFFERENCES AND DIFFERENT LEARNING STYLES

Research findings have not yet been able to give a complete answer to questions such as: „Should a learner possess a natural aptitude or linguistic intelligence to learn a second language successfully?“, „To what extent do motivation and learners’ personality traits impact the process of second language learning?“ and „Are children better learners than adults?“. Considering these questions we will try to give a brief overview of the components that make up the notion of individual differences and, above all, their impact on learners’ success. At the very beginning, the terms age, intelligence, aptitude and motivation will be analyzed and their impact on learners’ progress will be explained. In addition, this paper will define the notion of learning styles and will provide some guidelines for teachers how to teach heterogeneous classes effectively. This paper will try to give a clear picture of the significant role of individual learner differences in second language acquisition and will try to determine which factors have the greatest impact on learners’ success

ESR Investigations of the Submicron LiFe_1−xMn_xPO₄ Systems

Magnetic properties of the submicron carbon-coated LiFe1−xMnxPO4 (x = 0, 0.01, 0.1) systems were investigated using the electron spin resonance (ESR) method. The observed ESR signal consisted of two broad resonance lines with a Lorentzian line shape for all samples. The temperature dependence character of the integral intensity of these lines changed significantly with increasing manganese concentration, indicating a change in the nature of the magnetic interactions between the manganese and iron ions. We suggest that the noticeable capacity loss observed in the LiFe1−xMnxPO4 systems with increasing Mn content can be explained by the random distribution of Mn ions and changes to the type of magnetic ordering in these systems, despite the attractiveness of the electrochemical Mn2+/Mn3+ pair compared with Fe+2/Fe+3

Influence of Lipid Composition of Cationic Liposomes 2X3-DOPE on mRNA Delivery into Eukaryotic Cells

The design of cationic liposomes for efficient mRNA delivery can significantly improve mRNA-based therapies. Lipoplexes based on polycationic lipid 1,26-bis(cholest-5-en-3β-yloxycarbonylamino)-7,11,16,20-tetraazahexacosane tetrahydrochloride (2X3) and helper lipid 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) were formulated in different molar ratios (1:1, 1:2, 1:3) to efficiently deliver model mRNAs to BHK-21 and A549. The objective of this study was to examine the effect of 2X3-DOPE composition as well as lipid-to-mRNA ratio (amino-to-phosphate group ratio, N/P) on mRNA transfection. We found that lipoplex-mediated transfection efficiency depends on both liposome composition and the N/P ratio. Lipoplexes with an N/P ratio of 10/1 showed nanometric hydrodynamic size, positive ζ potential, maximum loading, and transfection efficiency. Liposomes 2X3-DOPE (1:3) provided the superior delivery of both mRNA coding firefly luciferase and mRNA-eGFP into BHK-21 cells and A549 cells, compared with commercial Lipofectamine MessengerMax