Effect of bite force and diet composition on craniofacial diversification of Southern South American human populations

Ecological factors can be important to shape the patterns of morphological variation among human populations. Particularly, diet plays a fundamental role in craniofacial variation due to both the effect of the nutritional status—mostly dependent on the type and amount of nutrients consumed—on skeletal growth and the localized effects of masticatory forces. We examine these two dimensions of diet and evaluate their influence on morphological diversification of human populations from southern South America during the late Holocene. Cranial morphology was measured as 3D coordinates defining the face, base and vault. Size, form, and shape variables were obtained for 474 adult individuals coming from 12 samples. Diet composition was inferred from carious lesions and δ¹³C data, whereas bite forces were estimated using traits of main jaw muscles. The spatial structure of the morphological and ecological variables was measured using correlograms. The influence of diet composition and bite force on morphometric variation was estimated by a spatial regression model. Cranial variation and diet composition display a geographical structure, while no geographical pattern was observed in bite forces. Cranial variation in size and form is significantly associated with diet composition, suggesting a strong effect of systemic factors on cranial growth. Conversely, bite forces do not contribute significantly to the pattern of morphological variation among the samples analyzed. Overall, these results show that an association between diet composition and hardness cannot be assumed, and highlight the complex relationship between morphological diversification and diet in human populations. Am J Phys Anthropol 155:114–127, 2014. © 2014 Wiley Periodicals, Inc.     

Syntaxin13 Expression Is Regulated by Mammalian Target of Rapamycin (mTOR) in Injured Neurons to Promote Axon Regeneration

Injured peripheral neurons successfully activate intrinsic signaling pathways to enable axon regeneration. We have previously shown that dorsal root ganglia (DRG) neurons activate the mammalian target of rapamycin (mTOR) pathway following injury and that this activity enhances their axon growth capacity. mTOR plays a critical role in protein synthesis, but the mTOR-dependent proteins enhancing the regenerative capacity of DRG neurons remain unknown. To identify proteins whose expression is regulated by injury in an mTOR-dependent manner, we analyzed the protein composition of DRGs from mice in which we genetically activated mTOR and from mice with or without a prior nerve injury. Quantitative label-free mass spectrometry analyses revealed that the injury effects were correlated with mTOR activation. We identified a member of the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) family of proteins, syntaxin13, whose expression was increased by injury in an mTOR-dependent manner. Increased syntaxin13 levels in injured nerves resulted from local protein synthesis and not axonal transport. Finally, knockdown of syntaxin13 in cultured DRG neurons prevented axon growth and regeneration. Together, these data suggest that syntaxin13 translation is regulated by mTOR in injured neurons to promote axon regeneration.     

Dramatic Potentiation of the Antiviral Activity of HIV Antibodies by Cholesterol Conjugation

The broadly neutralizing antibodies HIV 2F5 and 4E10, which bind to overlapping epitopes in the membrane-proximal external region of the fusion protein gp41, have been proposed to use a two-step mechanism for neutralization; first, they bind and preconcentrate at the viral membrane through their long, hydrophobic CDRH3 loops, and second, they form a high affinity complex with the protein epitope. Accordingly, mutagenesis of the CDRH3 can abolish their neutralizing activity, with no change in the affinity for the peptide epitope. We show here that we can mimic this mechanism by conjugating a cholesterol group outside of the paratope of an antibody. Cholesterol-conjugated antibodies bind to lipid raft domains on the membrane, and because of this enrichment, they show increased antiviral potency. In particular, we find that cholesterol conjugation (i) rescues the antiviral activity of CDRH3-mutated 2F5, (ii) increases the antiviral activity of WT 2F5, (iii) potentiates the non-membrane-binding HIV antibody D5 10–100-fold (depending on the virus strain), and (iv) increases synergy between 2F5 and D5. Conjugation can be made at several positions, including variable and constant domains. Cholesterol conjugation therefore appears to be a general strategy to boost the potency of antiviral antibodies, and, because membrane affinity is engineered outside of the antibody paratope, it can complement affinity maturation strategies.     

Structural Analysis of Glucuronoxylan-specific Xyn30D and Its Attached CBM35 Domain Gives Insights into the Role of Modularity in Specificity

Glucuronoxylanase Xyn30D is a modular enzyme containing a family 30 glycoside hydrolase catalytic domain and an attached carbohydrate binding module of the CBM35 family. We present here the three-dimensional structure of the full-length Xyn30D at 2.4 Å resolution. The catalytic domain folds into an (α/β)₈ barrel with an associated β-structure, whereas the attached CBM35 displays a jellyroll β-sandwich including two calcium ions. Although both domains fold in an independent manner, the linker region makes polar interactions with the catalytic domain, allowing a moderate flexibility. The ancillary Xyn30D-CBM35 domain has been expressed and crystallized, and its binding abilities have been investigated by soaking experiments. Only glucuronic acid-containing ligands produced complexes, and their structures have been solved. A calcium-dependent glucuronic acid binding site shows distinctive structural features as compared with other uronic acid-specific CBM35s, because the presence of two aromatic residues delineates a wider pocket. The nonconserved Glu¹²⁹ makes a bidentate link to calcium and defines region E, previously identified as specificity hot spot. The molecular surface of Xyn30D-CBM35 shows a unique stretch of negative charge distribution extending from its binding pocket that might indicate some oriented interaction with its target substrate. The binding ability of Xyn30D-CBM35 to different xylans was analyzed by affinity gel electrophoresis. Some binding was observed with rye glucuronoarabinoxylan in presence of calcium chelating EDTA, which would indicate that Xyn30D-CBM35 might establish interaction to other components of xylan, such as arabinose decorations of glucuronoarabinoxylan. A role in depolymerization of highly substituted chemically complex xylans is proposed.     

Impact of Replacing Smear Microscopy with Xpert MTB/RIF for Diagnosing Tuberculosis in Brazil: A Stepped-Wedge Cluster-Randomized Trial

BackgroundAbundant evidence on Xpert MTB/RIF accuracy for diagnosing tuberculosis (TB) and rifampicin resistance has been produced, yet there are few data on the population benefit of its programmatic use. We assessed whether the implementation of Xpert MTB/RIF in routine conditions would (1) increase the notification rate of laboratory-confirmed pulmonary TB to the national notification system and (2) reduce the time to TB treatment initiation (primary endpoints).ConclusionsReplacing smear microscopy with Xpert MTB/RIF in Brazil increased confirmation of pulmonary TB. An additional benefit was the accurate detection of rifampicin resistance. However, no increase on overall notification rates was observed, possibly because of high rates of empirical TB treatment.

Trial registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01363765","term_id":"NCT01363765"}}NCT01363765Please see later in the article for the Editors'' Summary     

Aβ1-42 monomers or oligomers have different effects on autophagy and apoptosis

The role of autophagy and its relationship with apoptosis in Alzheimer disease (AD) pathogenesis is poorly understood. Disruption of autophagy leads to buildup of incompletely digested substrates, amyloid-β (Aβ) peptide accumulation in vacuoles and cell death. Aβ, in turn, has been found to affect autophagy. Thus, Aβ might be part of a loop in which it is both the substrate of altered autophagy and its cause. Given the relevance of different soluble forms of Aβ1-42 in AD, we have investigated whether monomers and oligomers of the peptide have a differential role in causing altered autophagy and cell death. Using differentiated SK-N-BE neuroblastoma cells, we found that monomers hamper the formation of the autophagic BCL2-BECN1/Beclin 1 complex and activate the MAPK8/JNK1-MAPK9/JNK2 pathway phosphorylating BCL2. Monomers also inhibit apoptosis and allow autophagy with intracellular accumulation of autophagosomes and elevation of levels of BECN1 and LC3-II, resulting in an inhibition of substrate degradation due to an inhibitory action on lysosomal activity. Oligomers, in turn, favor the formation of the BCL2-BECN1 complex favoring apoptosis. In addition, they cause a less profound increase in BECN1 and LC3-II levels than monomers without affecting the autophagic flux. Thus, data presented in this work show a link for autophagy and apoptosis with monomers and oligomers, respectively. These studies are likely to help the design of novel disease modifying therapies.     

Correction of defective CFTR/ENaC function and tightness of cystic fibrosis airway epithelium by amniotic mesenchymal stromal (stem) cells

Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, with most of the mortality given by the lung disease. Human amniotic mesenchymal stromal (stem) cells (hAMSCs) hold great promise for regenerative medicine in the field of lung disease; however, their potential as therapeutics for CF lung disease has not been fully explored. In the present study, hAMSCs were analysed in co‐cultures on Transwell filters with CF immortalized airway epithelial cells (CFBE41o‐ line) at different ratios to exploit their potency to resume basic defects associated with CF. The results show that F‐actin content was increased in co‐cultures as compared with CF cells and actin was reorganized to form stress fibres. Confocal microscopy studies revealed that co‐cultures had a tendency of increased expression of occludin and ZO‐1 at the intercellular borders, paralleled by a decrease in dextran permeability, suggestive of more organized tight junctions (TJs). Spectrofluorometric analysis of CFTR function demonstrated that hAMSC‐CFBE co‐cultures resumed chloride transport, in line with the appearance of the mature Band C of CFTR protein by Western blotting. Moreover, hAMSC‐CFBE co‐cultures, at a 1:5 ratio, showed a decrease in fluid absorption, as opposed to CFBE cell monolayers that displayed a great rate of fluid resorption from the apical side. Our data show that human amniotic MSCs can be used in co‐culture with CF respiratory epithelial cells to model their engraftment into the airways and have the potential to resume a tight epithelium with partial correction of the CF phenotype.     

From Cassyrane to Cashmeran – The Molecular Parameters of Odorants

This review, including some new experimental results, is the summary of a talk at the ‘flavors & fragrances 2013’ conference in Leipzig, organized jointly by the GDCh, the Liebig‐Vereinigung, and the EuCheMS. After times of searching for natural odor principles and serendipitous discoveries by chemical inspiration, directed odorant design today offers the highest hit rates for the discovery of new odorants, although serendipity still plays a role. Keeping intact the electronic shape required for a certain olfactophore‐binding geometry, one can add or subtract structural elements, rigidify molecular structures, or introduce more structural flexibility. To find out which structural features are critical, the ‘seco‐approach’, in which different fragments are removed by cutting strategic bonds, is the most analytical. Following this approach, such ingredients as Serenolide, Sylkolide, and Pomarose were designed. Transferring this design principle from the family of damascones to that of the theaspiranes led to the discovery of Cassyrane, though completely different structural features turned out to be relevant. Application of the seco‐concept to a 3,7a‐substituted 2,6,7,7a‐tetrahydro‐1H‐inden‐5‐yl musk lead structure derived from carotol resulted in the discovery of a new family of dienone musks with novel structure? odor correlations. However, cutting the C(2)? O bond of Cassyrane and oxidizing the resulting seco‐structure to the 1,2,5,1″‐tetradehydro derivative links the family of dienone musks with that of blackcurrant odorants, but the resulting target structures turned out to be potent orris odorants. (3E,5E)‐5‐(tert‐Butyl)octadeca‐3,5‐dien‐2‐one even possesses the lowest odor threshold in the whole ionone family (0.036 ng/l air), which could be rationalized by a superposition analysis on (?)‐cis‐γ‐irone. In the course of the synthesis of these high‐impact orris odorants, we discovered that, depending on the reaction conditions, the dehydration step of the intermediate 5‐hydroxyalk‐3‐yn‐2‐ones was accompanied by a carbenium‐ion rearrangement. Depending on the substitution pattern, these rearrangement products and their derivatives possessed interesting musky‐woody olfactory properties reminiscent of Cashmeran, demonstrating that the same structural elements can code for completely different odors, i.e., cassis, musk, orris, violet, and Cashmeran‐type, depending only on their spatial arrangement.