Mechanism of eIF6 release from the nascent 60S ribosomal subunit.

SBDS protein (deficient in the inherited leukemia-predisposition disorder Shwachman-Diamond syndrome) and the GTPase EFL1 (an EF-G homolog) activate nascent 60S ribosomal subunits for translation by catalyzing eviction of the antiassociation factor eIF6 from nascent 60S ribosomal subunits. However, the mechanism is completely unknown. Here, we present cryo-EM structures of human SBDS and SBDS-EFL1 bound to Dictyostelium discoideum 60S ribosomal subunits with and without endogenous eIF6. SBDS assesses the integrity of the peptidyl (P) site, bridging uL16 (mutated in T-cell acute lymphoblastic leukemia) with uL11 at the P-stalk base and the sarcin-ricin loop. Upon EFL1 binding, SBDS is repositioned around helix 69, thus facilitating a conformational switch in EFL1 that displaces eIF6 by competing for an overlapping binding site on the 60S ribosomal subunit. Our data reveal the conserved mechanism of eIF6 release, which is corrupted in both inherited and sporadic leukemias.Supported by a Federation of European Biochemical Societies Long term Fellowship (to FW), Specialist Programme from Bloodwise [12048] (AJW), the Medical Research Council [MC_U105161083] (AJW) and [U105115237] (RRK), Wellcome Trust strategic award to the Cambridge Institute for Medal Research [100140], Tesni Parry Trust (AJW), Ted’s Gang (AJW) and the Cambridge NIHR Biomedical Research Centre.This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/nsmb.311

Prevalence of childhood and early adolescence mental disorders among children attending primary health care centers in Mosul, Iraq: a cross-sectional study

<p>Abstract</p> <p>Background</p> <p>Children and adolescents are more vulnerable to the affects of war and violence than adults. At the time of initiation of this study, nothing was known about the prevalence of childhood and early adolescence mental disorders. The aim of the present study is to measure the point prevalence of mental disorders among children of 1–15 years age in the city of Mosul, Iraq.</p> <p>Methods</p> <p>A cross-sectional study design was adopted. Four primary health care centers were chosen consecutively as a study setting. The subjects of the present study were mothers who came to the primary health care center for vaccination of their children. The chosen mothers were included by systematic sampling randomization. All children (aged 1–15) that each mother had were considered in the interview and examination.</p> <p>Results</p> <p>Out of 3079 children assessed, 1152 have childhood mental disorders, giving a point prevalence of 37.4%, with a male to female ratio of to 1.22:1. The top 10 disorders among the examined children are post-traumatic stress disorder (10.5%), enuresis (6%), separation anxiety disorder (4.3%), specific phobia (3.3%) stuttering and refusal to attend school (3.2% each), learning and conduct disorders (2.5% each), stereotypic movement (2.3%) and feeding disorder in infancy or early childhood (2.0%). Overall, the highest prevalence of mental disorders was among children 10–15 years old (49.2%) while the lowest was among 1–5 year olds (29.1%). Boys are more affected than girls (40.2% and 33.2%, respectively).</p> <p>Conclusion</p> <p>Childhood mental disorders are a common condition highly prevalent amongst the children and early adolescents in Mosul. Data from the present study mirrors the size of the problem in local community. Several points deserve attention, the most important of which include giving care at the community level, educating the public on mental health, involving communities and families, monitoring community mental health indicators, and providing treatment at primary health care level.</p

Effects of short-term unloading and active recovery on human motor unit properties, neuromuscular junction transmission and transcriptomic profile

Electrophysiological alterations of the neuromuscular junction (NMJ) and motor unit potential (MUP) with unloading are poorly studied. We aimed to investigate these aspects and the underlying molecular mechanisms with short-term unloading and active recovery (AR). Eleven healthy males underwent a 10-day unilateral lower limb suspension (ULLS) period, followed by 21-day AR based on resistance exercise. Quadriceps femoris (QF) cross-sectional area (CSA) and isometric maximum voluntary contraction (MVC) were evaluated. Intramuscular electromyographic recordings were obtained during 10% and 25% MVC isometric contractions from the vastus lateralis (VL). Biomarkers of NMJ molecular instability (serum c-terminal agrin fragment, CAF), axonal damage (neurofilament light chain) and denervation status were assessed from blood samples and VL biopsies. NMJ and ion channel transcriptomic profiles were investigated by RNA-sequencing. QF CSA and MVC decreased with ULLS. Increased CAF and altered NMJ transcriptome with unloading suggested the emergence of NMJ molecular instability, which was not associated with impaired NMJ transmission stability. Instead, increased MUP complexity and decreased motor unit firing rates were found after ULLS. Downregulation of ion channel gene expression was found together with increased neurofilament light chain concentration and partial denervation. The AR period restored most of these neuromuscular alterations. In conclusion, the human NMJ is destabilized at the molecular level but shows functional resilience to a 10-day unloading period at least at relatively low contraction intensities. However, MUP properties are altered by ULLS, possibly due to alterations in ion channel dynamics and initial axonal damage and denervation. These changes are fully reversed by 21 days of AR. (Figure presented.). Key points: We used integrative electrophysiological and molecular approaches to comprehensively investigate changes in neuromuscular integrity and function after a 10-day unilateral lower limb suspension (ULLS), followed by 21 days of active recovery in young healthy men, with a particular focus on neuromuscular junction (NMJ) and motor unit potential (MUP) properties alterations. After 10-day ULLS, we found significant NMJ molecular alterations in the absence of NMJ transmission stability impairment. These findings suggest that the human NMJ is functionally resilient against insults and stresses induced by short-term disuse at least at relatively low contraction intensities, at which low-threshold, slow-type motor units are recruited. Intramuscular electromyography analysis revealed that unloading caused increased MUP complexity and decreased motor unit firing rates, and these alterations could be related to the observed changes in skeletal muscle ion channel pool and initial and partial signs of fibre denervation and axonal damage. The active recovery period restored these neuromuscular changes

Binarity at LOw Metallicity (BLOeM) Multiplicity properties of Oe and Be stars

\ua9 The Authors 2025. Context. Rapidly rotating classical OBe stars have been proposed as the products of binary interactions, and the fraction of Be stars with compact companions implies that at least some are. However, to constrain the interaction physics spinning up the OBe stars, a large sample of homogeneously analyzed OBe stars with well-determined binary characteristics and orbital parameters are required. Aims. We investigated the multiplicity properties of a sample of 18 Oe, 62 Be, and two Of?p stars observed within the BLOeM survey in the Small Magellanic Cloud. We analyzed the first nine epochs of spectroscopic observations obtained over approximately three months in 2023. Methods. Radial velocities (RVs) of all stars were measured using cross-correlation based on different sets of absorption and emission lines. Applying commonly used binarity criteria, we classified objects as binaries, binary candidates, and apparently single (RV stable) objects. We further inspected the spectra for double-lined spectroscopic binaries and cross-matched with catalogs of X-ray sources and photometric binaries. Results. We classify 14 OBe stars as binaries, and an additional 11 as binary candidates. The two Of?p stars are apparently single. We find two more objects that are most likely currently interacting binaries. Without those, the observed binary fraction for the remaining OBe sample of 78 stars is fOBeobs = 0.18 \ub1 0.04 (fOBeobs+cand = 0.32\ub10.05 including candidates). This binary fraction is less than half of that measured for OB stars in BLOeM. Combined with the lower fraction of SB2s, this suggests that OBe stars do indeed have fundamentally different present-day binary properties than OB stars. We find no evidence for OBe binaries with massive compact companions, in contrast to expectations from binary population synthesis. Conclusions. Our results support the binary scenario as an important formation channel for OBe stars, as post-interaction binaries may have been disrupted or the stripped companions of OBe stars are harder to detect. Further observations are required to characterize the detected binaries, their orbital parameters, and the nature of their companions

Evolutionary Pathways of the Pandemic Influenza A (H1N1) 2009 in the UK

The emergence of the influenza (H1N1) 2009 virus provided a unique opportunity to study the evolution of a pandemic virus following its introduction into the human population. Virological and clinical surveillance in the UK were comprehensive during the first and second waves of the pandemic in 2009, with extensive laboratory confirmation of infection allowing a detailed sampling of representative circulating viruses. We sequenced the complete coding region of the haemagglutinin (HA) segment of 685 H1N1 pandemic viruses selected without bias during two waves of pandemic in the UK (April-December 2009). Phylogenetic analysis showed that although temporal accumulation of amino acid changes was observed in the HA sequences, the overall diversity was less than that typically seen for seasonal influenza A H1N1 or H3N2. There was co-circulation of multiple variants as characterised by signature amino acid changes in the HA. A specific substitution (S203T) became predominant both in UK and global isolates. No antigenic drift occurred during 2009 as viruses with greater than four-fold reduction in their haemagglutination inhibition (HI) titre (“low reactors”) were detected in a low proportion (3%) and occurred sporadically. Although some limited antigenic divergence in viruses with four-fold reduction in HI titre might be related to the presence of 203T, additional studies are needed to test this hypothesis

Emotional design and human-robot interaction

Recent years have shown an increase in the importance of emotions applied to the Design field - Emotional Design. In this sense, the emotional design aims to elicit (e.g., pleasure) or prevent (e.g., displeasure) determined emotions, during human product interaction. That is, the emotional design regulates the emotional interaction between the individual and the product (e.g., robot). Robot design has been a growing area whereby robots are interacting directly with humans in which emotions are essential in the interaction. Therefore, this paper aims, through a non-systematic literature review, to explore the application of emotional design, particularly on Human-Robot Interaction. Robot design features (e.g., appearance, expressing emotions and spatial distance) that affect emotional design are introduced. The chapter ends with a discussion and a conclusion.info:eu-repo/semantics/acceptedVersio

Phylogeography and Molecular Evolution of Potato virus Y

Potato virus Y (PVY) is an important plant pathogen, whose host range includes economically important crops such as potato, tobacco, tomato, and pepper. PVY presents three main strains (PVYO, PVYN and PVYC) and several recombinant forms. PVY has a worldwide distribution, yet the mechanisms that promote and maintain its population structure and genetic diversity are still unclear. In this study, we used a pool of 77 complete PVY genomes from isolates collected worldwide. After removing the effect of recombination in our data set, we used Bayesian techniques to study the influence of geography and host species in both PVY population structure and dynamics. We have also performed selection and covariation analyses to identify evolutionarily relevant amino acid residues. Our results show that both geographic and host-driven adaptations explain PVY diversification. Furthermore, purifying selection is the main force driving PVY evolution, although some indications of positive selection accounted for the diversification of the different strains. Interestingly, the analysis of P3N-PIPO, a recently described gene in potyviruses, seems to show a variable length among the isolates analyzed, and this variability is explained, in part, by host-driven adaptation

Binarity at LOw Metallicity (BLOeM): A spectroscopic VLT monitoring survey of massive stars in the SMC

\ua9 The Authors 2024.Surveys in the Milky Way and Large Magellanic Cloud have revealed that the majority of massive stars will interact with companions during their lives. However, knowledge of the binary properties of massive stars at low metallicity, and therefore in conditions approaching those of the Early Universe, remain sparse. We present the Binarity at LOw Metallicity (BLOeM) campaign, an ESO large programme designed to obtain 25 epochs of spectroscopy for 929 massive stars in the Small Magellanic Cloud, allowing us to probe multiplicity in the lowest-metallicity conditions to date (Z = 0.2 Z⊙). BLOeM will provide (i) the binary fraction, (ii) the orbital configurations of systems with periods of P ≲ 3 yr, (iii) dormant black-hole binary candidates (OB+BH), and (iv) a legacy database of physical parameters of massive stars at low metallicity. Main sequence (OB-type) and evolved (OBAF-type) massive stars are observed with the LR02 setup of the GIRAFFE instrument of the Very Large Telescope (3960- 4570 \uc5 resolving power R = 6200; typical signal-to-noise ratio(S/N) ≈70- 100). This paper utilises the first nine epochs obtained over a three-month time period. We describe the survey and data reduction, perform a spectral classification of the stacked spectra, and construct a Hertzsprung-Russell diagram of the sample via spectral-type and photometric calibrations. Our detailed classification reveals that the sample covers spectral types from O4 to F5, spanning the effective temperature and luminosity ranges 6.5 ≲ Teff/kK ≲ 45 and 3.7 &lt; log L/L⊙ &lt; 6.1 and initial masses of 8 ≲ Mini ≲ 80 M⊙. The sample comprises 159 O-type stars, 331 early B-type (B0- 3) dwarfs and giants (luminosity classes V- III), 303 early B-type supergiants (II- I), and 136 late-type BAF supergiants. At least 82 stars are OBe stars: 20 O-type and 62 B-type (13% and 11% of the respective samples). In addition, the sample includes 4 high-mass X-ray binaries, 3 stars resembling luminous blue variables, 2 bloated stripped-star candidates, 2 candidate magnetic stars, and 74 eclipsing binaries