Objectively measured physical activity and fat mass in a large cohort of children

Background Previous studies have been unable to characterise the association between physical activity and obesity, possibly because most relied on inaccurate measures of physical activity and obesity. Methods and Findings We carried out a cross sectional analysis on 5,500 12-year-old children enrolled in the Avon Longitudinal Study of Parents and Children. Total physical activity and minutes of moderate and vigorous physical activity (MVPA) were measured using the Actigraph accelerometer. Fat mass and obesity (defined as the top decile of fat mass) were measured using the Lunar Prodigy dual x-ray emission absorptiometry scanner. We found strong negative associations between MVPA and fat mass that were unaltered after adjustment for total physical activity. We found a strong negative dose-response association between MVPA and obesity. The odds ratio for obesity in adjusted models between top and the bottom quintiles of minutes of MVPA was 0.03 (95% confidence interval [CI] 0.01-0.13, p-value for trend < 0.0001) in boys and 0.36 (95% CI 0.17-0.74, p-value for trend = 0.006) in girls. Conclusions We demonstrated a strong graded inverse association between physical activity and obesity that was stronger in boys. Our data suggest that higher intensity physical activity may be more important than total activity

Operon gene order is optimized for ordered protein complex assembly

SummaryThe assembly of heteromeric protein complexes is an inherently stochastic process in which multiple genes are expressed separately into proteins, which must then somehow find each other within the cell. Here, we considered one of the ways by which prokaryotic organisms have attempted to maximize the efficiency of protein complex assembly: the organization of subunit-encoding genes into operons. Using structure-based assembly predictions, we show that operon gene order has been optimized to match the order in which protein subunits assemble. Exceptions to this are almost entirely highly expressed proteins for which assembly is less stochastic and for which precisely ordered translation offers less benefit. Overall, these results show that ordered protein complex assembly pathways are of significant biological importance and represent a major evolutionary constraint on operon gene organization

Edaphic controls of soil organic carbon in tropical agricultural landscapes

Predicting soil organic carbon (SOC) is problematic in tropical soils because mechanisms of SOC (de)stabilization are not resolved. We aimed to identify such storage mechanisms in a tropical soil landscape constrained by 100 years of similar soil inputs and agricultural disturbance under the production of sugarcane, a C-4 grass and bioenergy feedstock. We measured soil physicochemical parameters, SOC concentration, and SOC dynamics by soil horizon to one meter to identify soil parameters that can predict SOC outcomes. Applying correlative analyses, linear mixed model (LMM) regression, model selection by AICc, and hierarchical clustering we found that slow moving SOC was related to many soil parameters, while the fastest moving SOC was only related to soil surface charge. Our models explained 78-79%, 51-57%, 7-8% of variance in SOC concentration, slow pool decay, and fast pool decay, respectively. Top SOC predictors were roots, the ratio of organo-complexed iron (Fe) to aluminum (Al), water stable aggregates (WSagg), and cation exchange capacity (CEC). Using hierarchical clustering we also assessed SOC predictors across gradients of depth and rainfall with strong reductions in Roots, SOC, and slow pool decay associated with increasing depth, while increased rainfall was associated with increased Clay and WSagg and reduced CEC in surface soils. Increased negative surface charge, water stable aggregation, organo-Fe complexation, and root inputs were key SOC protection mechanisms despite high soil disturbance. Further development of these relationships is expected to improve understanding of SOC storage mechanisms and outcomes in similar tropical agricultural soils globally

Regulation, evolution and consequences of cotranslational protein complex assembly.

Most proteins assemble into complexes, which are involved in almost all cellular processes. Thus it is crucial for cell viability that mechanisms for correct assembly exist. The timing of assembly plays a key role in determining the fate of the protein: if the protein is allowed to diffuse into the crowded cellular milieu, it runs the risk of forming non-specific interactions, potentially leading to aggregation or other deleterious outcomes. It is therefore expected that strong regulatory mechanisms should exist to ensure efficient assembly. In this review we discuss the cotranslational assembly of protein complexes and discuss how it occurs, ways in which it is regulated, potential disadvantages of cotranslational interactions between proteins and the implications for the inheritance of dominant-negative genetic disorders

Shank3 mutant mice display autistic-like behaviours and striatal dysfunction

Autism spectrum disorders (ASDs) comprise a range of disorders that share a core of neurobehavioural deficits characterized by widespread abnormalities in social interactions, deficits in communication as well as restricted interests and repetitive behaviours. The neurological basis and circuitry mechanisms underlying these abnormal behaviours are poorly understood. SHANK3 is a postsynaptic protein, whose disruption at the genetic level is thought to be responsible for the development of 22q13 deletion syndrome (Phelan–McDermid syndrome) and other non-syndromic ASDs. Here we show that mice with Shank3 gene deletions exhibit self-injurious repetitive grooming and deficits in social interaction. Cellular, electrophysiological and biochemical analyses uncovered defects at striatal synapses and cortico-striatal circuits in Shank3 mutant mice. Our findings demonstrate a critical role for SHANK3 in the normal development of neuronal connectivity and establish causality between a disruption in the Shank3 gene and the genesis of autistic-like behaviours in mice.National Institute of Mental Health (U.S.) (NIMH/NIH (R01MH081201))Hartwell Foundation (Hartwell Individual Biomedical Research Award)Simons Foundation (Autism Research Initiative (SFARI) grant Award)Brain and Behavior Research Foundation (NARSAD Young Investigator Award)National Institutes of Health (U.S.) (Ruth L. Kirschstein National Research Service Award (F32MH084460))National Institutes of Health (U.S.) (NIH grant (R03MH085224))Fundação para a Ciência e a Tecnologia (SFRH/BD/15231/2004)Fundação para a Ciência e a Tecnologia (SFRH/BD/15855/2005)Instituto Gulbenkian de Ciência (“Programa Gulbenkian de Doutoramento em Biomedicina” (PGDB, Oeiras, Portugal))University of Coimbra. Center for Neuroscience and Cell Biology (“Programa Doutoral em Biologia Experimental e Biomedicina” (CNC, Coimbra, Portugal)

New Multisite Bioelectrical Impedance Device Compared to Hydrostatic Weighing and Skinfold Body Fat Methods

International Journal of Exercise Science 13(4): 1718-1728, 2020. The purpose of this study was to compare the Skulpt Chisel™ to seven-site skinfold (SKF) and hydrostatic weighing (HW) body fat percentage (%BF) estimates. Twenty-six participants (aged 24 ± 4 years; BMI 23.1 ± 3.5 kg∙m-2) were assessed. Significant differences in %BF estimates were found for all methodological pairings; p \u3c 0.05. The SKF method underestimated %BF compared to HW (-2.52 ± 3.42 %BF). The Skulpt Chisel™ overestimated %BF compared to both HW (3.38 ± 6.10 %BF) and SKF (5.90 ± 5.26 %BF). Limits of agreement comparing HW to Skulpt Chisel™ indicated a difference between 95% confidence interval bounds (Upper bound: 5.84 %BF, Lower bound 0.92 %BF) and for HW to SKF (Upper bound: -1.14 %BF, Lower bound: -3.91 %BF). Regression analysis showed no significant bias for any methodological pairing; (p \u3e 0.05). In conclusion, the Skulpt Chisel™ method should be used with caution when evaluating %BF of adults with similar demographics reported in this study

Protein aggregation mediates stoichiometry of protein complexes in aneuploid cells

Aneuploidy, a condition characterized by chromosome gains and losses, causes reduced fitness and numerous cellular stresses, including increased protein aggregation. Here, we identify protein complex stoichiometry imbalances as a major cause of protein aggregation in aneuploid cells. Subunits of protein complexes encoded on excess chromosomes aggregate in aneuploid cells, which is suppressed when expression of other subunits is coordinately altered. We further show that excess subunits are either degraded or aggregate and that protein aggregation is nearly as effective as protein degradation at lowering levels of excess proteins. Our study explains why proteotoxic stress is a universal feature of the aneuploid state and reveals protein aggregation as a form of dosage compensation to cope with disproportionate expression of protein complex subunits

Anticancer properties of distinct antimalarial drug classes

We have tested five distinct classes of established and experimental antimalarial drugs for their anticancer potential, using a panel of 91 human cancer lines. Three classes of drugs: artemisinins, synthetic peroxides and DHFR (dihydrofolate reductase) inhibitors effected potent inhibition of proliferation with IC 50 s in the nM- low µM range, whereas a DHODH (dihydroorotate dehydrogenase) and a putative kinase inhibitor displayed no activity. Furthermore, significant synergies were identified with erlotinib, imatinib, cisplatin, dasatinib and vincristine. Cluster analysis of the antimalarials based on their differential inhibition of the various cancer lines clearly segregated the synthetic peroxides OZ277 and OZ439 from the artemisinin cluster that included artesunate, dihydroartemisinin and artemisone, and from the DHFR inhibitors pyrimethamine and P218 (a parasite DHFR inhibitor), emphasizing their shared mode of action. In order to further understand the basis of the selectivity of these compounds against different cancers, microarray-based gene expression data for 85 of the used cell lines were generated. For each compound, distinct sets of genes were identified whose expression significantly correlated with compound sensitivity. Several of the antimalarials tested in this study have well-established and excellent safety profiles with a plasma exposure, when conservatively used in malaria, that is well above the IC 50 s that we identified in this study. Given their unique mode of action and potential for unique synergies with established anticancer drugs, our results provide a strong basis to further explore the potential application of these compounds in cancer in pre-clinical or and clinical settings

Embedding Flipped SU(5) into SO(10)

We embed the flipped SU(5) models into the SO(10) models. After the SO(10) gauge symmetry is broken down to the flipped SU(5) \times U(1)_X gauge symmetry, we can split the five/one-plets and ten-plets in the spinor \mathbf{16} and \mathbf{\bar{16}} Higgs fields via the stable sliding singlet mechanism. As in the flipped SU(5) models, these ten-plet Higgs fields can break the flipped SU(5) gauge symmetry down to the Standard Model gauge symmetry. The doublet-triplet splitting problem can be solved naturally by the missing partner mechanism, and the Higgsino-exchange mediated proton decay can be suppressed elegantly. Moreover, we show that there exists one pair of the light Higgs doublets for the electroweak gauge symmetry breaking. Because there exist two pairs of additional vector-like particles with similar intermediate-scale masses, the SU(5) and U(1)_X gauge couplings can be unified at the GUT scale which is reasonably (about one or two orders) higher than the SU(2)_L \times SU(3)_C unification scale. Furthermore, we briefly discuss the simplest SO(10) model with flipped SU(5) embedding, and point out that it can not work without fine-tuning.Comment: RevTex4, 28 pages, 3 figures, typos correcte

A WDR35-dependent coat protein complex transports ciliary membrane cargo vesicles to cilia

Intraflagellar transport (IFT) is a highly conserved mechanism for motor-driven transport of cargo within cilia, but how this cargo is selectively transported to cilia is unclear. WDR35/IFT121 is a component of the IFT-A complex best known for its role in ciliary retrograde transport. In the absence of WDR35, small mutant cilia form but fail to enrich in diverse classes of ciliary membrane proteins. In Wdr35 mouse mutants, the non-core IFT-A components are degraded and core components accumulate at the ciliary base. We reveal deep sequence homology of WDR35 and other IFT-A subunits to α and ß′ COPI coatomer subunits and demonstrate an accumulation of ‘coat-less’ vesicles that fail to fuse with Wdr35 mutant cilia. We determine that recombinant non-core IFT-As can bind directly to lipids and provide the first in situ evidence of a novel coat function for WDR35, likely with other IFT-A proteins, in delivering ciliary membrane cargo necessary for cilia elongation