Effect of host sex and sex hormones on muscle-derived stem cell-mediated bone formation and defect healing

Muscle-derived stem cells (MDSCs) are known to exhibit sexual dimorphism, by donor sex, of osteogenic, chondrogenic, and myogenic differentiation potential in vitro. Moreover, host sex differences in the myogenic capacity of MDSCs in vivo are also observed. This study investigated the role of host sex and host sex hormones in MDSC-mediated bone formation and healing. Using unaltered male, castrated male, unaltered female, and ovariectomized female mice, both MDSC-mediated ectopic bone formation and cranial defect healing were examined. Male hosts, whether unaltered or castrated, form significantly larger volumes of MDSC-mediated ectopic bone than female hosts (either unaltered or ovariectomized), and no differences in ectopic bone volume were found between hosts of the same sex. In a cranial defect healing model, similar results were found-unaltered and castrated male hosts display larger volumes of bone formed when compared with unaltered and ovariectomized female hosts. However, in this healing model, some volume differences were found between hosts of the same sex. In both models, these differences were attributed to varying rates of endochondral bone formation in male and female hosts. © Copyright 2012, Mary Ann Liebert, Inc

Changes in the Standing Lumbar Spine at Above Bodyweight Loading

Introduction and Objectives: Understanding the mechanical response of the spine and intervertebral disc to various loading situations is vital to predicting its behaviour, to verify computer models of the spine and to gaining insight in to how loading and spinal posture may cause or exacerbate injury. Studies of the lumbar spine and intervertebral disc under compression have typically been carried out in vitro; those which have used in vivo methods have mostly been conducted in the supine position at loading equal to or below static bodyweight. This study measures the lumbar spine response to above bodyweight loading in the standing position at loads equivalent to walking. Methods: Sagittal plane magnetic resonance imaging scans of the spine were taken of nine asymptomatic male subjects (22-32 years of age, 167-195 cm, 66.3-93.2 kg) in the supine and standing positions with a third scan taken in the standing position with additional loading. Additional load was applied by having subjects hold two 6 kg kettlebells, one in each hand, enough to increase loading on the IVD to levels experienced during walking. Disc heights were measured as the average of anterior and posterior distance between adjacent vertebrae in the midsagittal plane. Change in lordosis was measured in two ways; the relative angle between the lumbar spine and pelvis was measured as the posterior angle between L5 and S1 vertebrae whilst change in the upper lumbar spine was measured by the angle between the superior facet of L3 with the vertical plane. Results: Increased axial loading resulted in reduced disc height and lumbar lordosis. Initial disc heights in the supine position for L3/L4, L4/L5 and L5/S1 were found to be 10.7(1.6), 12.0(2.8) and 11.4(1.9) mm respectively (Fig. 1a). These heights were reduced to 10.4(1.9), 11.4(2.1) and 10.8(1.6) mm in the standing position and 10.3(1.4), 11.4(2.0) and 10.4(1.8) mm with additional loading but these changes were not statistically significant (P>0.05). Lumbar angle in supine, standing and with additional loading was found to be 140(9), 145(11) and 145(12) degrees respectively (Fig. 1b) with L3 angled 0.7 (3.5), 4.4 (4.4) and 4.8 (4.2) degrees posteriorly from the horizontal in the three loading positions (Fig. 1c). In all cases disc height change was greater posteriorly as loading increased lumbar lordosis

From concept to crystals via prediction: multi‐component organic cage pots by social self‐sorting

We describe the a priori computational prediction and realization of multi‐component cage pots, starting with molecular predictions based on candidate precursors through to crystal structure prediction and synthesis using robotic screening. The molecules were formed by the social self‐sorting of a tri‐topic aldehyde with both a tri‐topic amine and di‐topic amine, without using orthogonal reactivity or precursors of the same topicity. Crystal structure prediction suggested a rich polymorphic landscape, where there was an overall preference for chiral recognition to form heterochiral rather than homochiral packings, with heterochiral pairs being more likely to pack window‐to‐window to form two‐component capsules. These crystal packing preferences were then observed in experimental crystal structures

Household Transmission of Rotavirus in a Community with Rotavirus Vaccination in Quininde, Ecuador

Background: We studied the transmission of rotavirus infection in households in peri-urban Ecuador in the vaccination era. Methods: Stool samples were collected from household contacts of child rotavirus cases, diarrhea controls and healthy controls following presentation of the index child to health facilities. Rotavirus infection status of contacts was determined by RT-qPCR. We examined factors associated with transmissibility (index-case characteristics) and susceptibility (householdcontact characteristics). Results: Amongst cases, diarrhea controls and healthy control household contacts, infection attack rates (iAR) were 55%, 8% and 2%, (n = 137, 130, 137) respectively. iARs were higher from index cases with vomiting, and amongst siblings. Disease ARs were higher when the index child was ,18 months and had vomiting, with household contact ,10 years and those sharing a room with the index case being more susceptible. We found no evidence of asymptomatic infections leading to disease transmission. Conclusion: Transmission rates of rotavirus are high in households with an infected child, while background infections are rare. We have identified factors associated with transmission (vomiting/young age of index case) and susceptibility (young age/sharing a room/being a sibling of the index case). Vaccination may lead to indirect benefits by averting episodes or reducing symptoms in vaccinees

Mammalian Comparative Sequence Analysis of the Agrp Locus

Agouti-related protein encodes a neuropeptide that stimulates food intake. Agrp expression in the brain is restricted to neurons in the arcuate nucleus of the hypothalamus and is elevated by states of negative energy balance. The molecular mechanisms underlying Agrp regulation, however, remain poorly defined. Using a combination of transgenic and comparative sequence analysis, we have previously identified a 760 bp conserved region upstream of Agrp which contains STAT binding elements that participate in Agrp transcriptional regulation. In this study, we attempt to improve the specificity for detecting conserved elements in this region by comparing genomic sequences from 10 mammalian species. Our analysis reveals a symmetrical organization of conserved sequences upstream of Agrp, which cluster into two inverted repeat elements. Conserved sequences within these elements suggest a role for homeodomain proteins in the regulation of Agrp and provide additional targets for functional evaluation

Optimization of supply diversity for the self-assembly of simple objects in two and three dimensions

The field of algorithmic self-assembly is concerned with the design and analysis of self-assembly systems from a computational perspective, that is, from the perspective of mathematical problems whose study may give insight into the natural processes through which elementary objects self-assemble into more complex ones. One of the main problems of algorithmic self-assembly is the minimum tile set problem (MTSP), which asks for a collection of types of elementary objects (called tiles) to be found for the self-assembly of an object having a pre-established shape. Such a collection is to be as concise as possible, thus minimizing supply diversity, while satisfying a set of stringent constraints having to do with the termination and other properties of the self-assembly process from its tile types. We present a study of what we think is the first practical approach to MTSP. Our study starts with the introduction of an evolutionary heuristic to tackle MTSP and includes results from extensive experimentation with the heuristic on the self-assembly of simple objects in two and three dimensions. The heuristic we introduce combines classic elements from the field of evolutionary computation with a problem-specific variant of Pareto dominance into a multi-objective approach to MTSP.Comment: Minor typos correcte

Modular and predictable assembly of porous organic molecular crystals

Nanoporous molecular frameworks are important in applications such as separation, storage and catalysis. Empirical rules exist for their assembly but it is still challenging to place and segregate functionality in three-dimensional porous solids in a predictable way. Indeed, recent studies of mixed crystalline frameworks suggest a preference for the statistical distribution of functionalities throughout the pores rather than, for example, the functional group localization found in the reactive sites of enzymes. This is a potential limitation for 'one-pot' chemical syntheses of porous frameworks from simple starting materials. An alternative strategy is to prepare porous solids from synthetically preorganized molecular pores. In principle, functional organic pore modules could be covalently prefabricated and then assembled to produce materials with specific properties. However, this vision of mix-and-match assembly is far from being realized, not least because of the challenge in reliably predicting three-dimensional structures for molecular crystals, which lack the strong directional bonding found in networks. Here we show that highly porous crystalline solids can be produced by mixing different organic cage modules that self-assemble by means of chiral recognition. The structures of the resulting materials can be predicted computationally, allowing in silico materials design strategies. The constituent pore modules are synthesized in high yields on gram scales in a one-step reaction. Assembly of the porous co-crystals is as simple as combining the modules in solution and removing the solvent. In some cases, the chiral recognition between modules can be exploited to produce porous organic nanoparticles. We show that the method is valid for four different cage modules and can in principle be generalized in a computationally predictable manner based on a lock-and-key assembly between modules

Visceral hyperalgesia induced by forebrain-specific suppression of native Kv7/KCNQ/M-current in mice

<p>Abstract</p> <p>Background</p> <p>Dysfunction of brain-gut interaction is thought to underlie visceral hypersensitivity which causes unexplained abdominal pain syndromes. However, the mechanism by which alteration of brain function in the brain-gut axis influences the perception of visceral pain remains largely elusive. In this study we investigated whether altered brain activity can generate visceral hyperalgesia.</p> <p>Results</p> <p>Using a forebrain specific αCaMKII promoter, we established a line of transgenic (Tg) mice expressing a dominant-negative pore mutant of the Kv7.2/KCNQ2 channel which suppresses native KCNQ/M-current and enhances forebrain neuronal excitability. Brain slice recording of hippocampal pyramidal neurons from these Tg mice confirmed the presence of hyperexcitable properties with increased firing. Behavioral evaluation of Tg mice exhibited increased sensitivity to visceral pain induced by intraperitoneal (i.p.) injection of either acetic acid or magnesium sulfate, and intracolon capsaicin stimulation, but not cutaneous sensation for thermal or inflammatory pain. Immunohistological staining showed increased c-Fos expression in the somatosensory SII cortex and insular cortex of Tg mice that were injected intraperitoneally with acetic acid. To mimic the effect of cortical hyperexcitability on visceral hyperalgesia, we injected KCNQ/M channel blocker XE991 into the lateral ventricle of wild type (WT) mice. Intracerebroventricular injection of XE991 resulted in increased writhes of WT mice induced by acetic acid, and this effect was reversed by co-injection of the channel opener retigabine.</p> <p>Conclusions</p> <p>Our findings provide evidence that forebrain hyperexcitability confers visceral hyperalgesia, and suppression of central hyperexcitability by activation of KCNQ/M-channel function may provide a therapeutic potential for treatment of abdominal pain syndromes.</p