Glucose-dependent insulinotropic polypeptide (GIP) directly affects collagen fibril diameter and collagen cross-linking in osteoblast cultures.

Glucose-dependent insulinotropic polypeptide (GIP) is absolutely crucial in order to obtain optimal bone strength and collagen quality. However, as the GIPR is expressed in several tissues other than bone, it is difficult to ascertain whether the observed modifications of collagen maturity, reported in animal studies, were due to direct effects on osteoblasts or indirect through regulation of signals originating from other tissues. The aims of the present study were to investigate whether GIP can directly affect collagen biosynthesis and processing in osteoblast cultures and to decipher which molecular pathways were necessary for such effects. MC3T3-E1 cells were cultured in the presence of GIP ranged between 10 and 100pM. Collagen fibril diameter was investigated by electron microscopy whilst collagen maturity was determined by Fourier transform infra-red microspectroscopy (FTIRM). GIP treatment resulted in dose-dependent increases in lysyl oxidase activity and collagen maturity. Furthermore, GIP treatment shifted the collagen fiber diameter towards lower value but did not significantly affect collagen heterogeneity. GIP acted directly on osteoblasts by activating the adenylyl cyclase-cAMP pathway. This study provides evidences that GIP acts directly on osteoblasts and is capable of improving collagen maturity and fibril diameter

Les effets extra-osseux de la vitamine D : faits, questions et controverses

La vitamine D a été longtemps considérée comme une hormone utile pour réguler le métabolisme phosphocalcique et la minéralisation osseuse. Depuis dix ans, la progression des connaissances fondamentales et cliniques sur son influence pluritissulaire est vertigineuse. Les auteurs passent en revue les effets biologique et clinique de la vitamine D en particulier sur le système immunitaire, les maladies auto-immunes, les infections, le cancer, le syndrome métabolique, le risque de chute, les fonctions cognitives et le fonctionnement musculaire

Comparison between the Parks Medical Doppler and the Mano Médical Vet BP Doppler for recording indirect systemic blood pressure in conscious dogs

Background: The acquisition of systemic blood pressure (SBP) provides valuable information regarding cardiovascular function and tissue perfusion in human and veterinary species.Aim: To evaluate the agreement between Parks Medical Doppler (PMD) and Mano Médical Vet BP (MMVBP) Doppler for assessing SBP in conscious dogs.Methods: 40 client-owned dogs were prospectively enrolled; SBP measurements were acquired by a single operator using the PMD and then the MMVBP. The mean of five consecutive measurements for each device was classified according to target organ damage (TOD) risk scores (1: <140 mmHg; 2: 140–160 mmHg; 3: 160–180 mmHg; 4: ≥ 180 mmHg).Results: Total mean SBP for the devices was not statistically different (p = 0.77). However, the Bland–Altman analysis revealed wide limits of agreement (LoA), with MMVBP slightly underestimating SBP compared to PMD (bias = −0.6 mmHg, 95% LoA: −26.3 to 25.09). Both devices correlated well (r = 0.8269; p < 0.0001) and had identically acceptable intra-observer repeatability (coefficients of variation = 4.09% for MMVBP and 3.86% for PMD). Four dogs (10%) had a TOD score of 3 by one device but scored <3 with the other.Conclusion: A good agreement and correlation was observed between the PMD and the MMVBP, suggesting that both devices can be used interchangeably for assessment of SBP in conscious dogs. The wide LoA observed between both devices was most likely associated with intraindividual variability in SBP over time

Extraskeletal effects of vitamin D: Facts, uncertainties, and controversies

Vitamin D was long viewed as a hormone acting chiefly to regulate calcium-phosphate metabolism and bone mineralization. Over the last decade, however, basic science and clinical researchers have produced a bewildering amount of information on the extraskeletal effects of vitamin D. This article is a review of the clinical and biological actions of vitamin D including effects on the immune system, auto-immune diseases, infections, cancer, metabolic syndrome, fall risk, cognitive function, and muscle function

Motherhood, Moral Authority and the Charismatic Matriarch in the Aftermath of Lethal Violence

Images of maternal suffering are an evocative and powerful means of communication in a world where the private grief of victims has increasingly become subject to commodification and public consumption. This article looks at the influence of bereaved mothers as symbols of respect, peace and dignity in the aftermath of violence, and as a result their persuasive presence in family activism. Drawing upon two case studies, this article explores the importance of victims’ stories in public life and, in particular, the presence of the charismatic matriarch in creating communities of solidarity, raising awareness of harms that have previously gone unheard and prompting policy change. It considers the ‘canonical’ story of the mother in public life and concludes by arguing that more attention should be paid to victims’ stories and their influence on policy-making, politics and eventually in becoming public grievances

A new stable GIP-Oxyntomodulin hybrid peptide improved bone strength both at the organ and tissue levels in genetically-inherited type 2 diabetes mellitus

Obesity and type 2 diabetes mellitus (T2DM) progress worldwide with detrimental effects on several physiological systems including bone tissue mainly by affecting bone quality. Several gut hormones analogues have been proven potent in ameliorating bone quality. In the present study, we used the leptin receptor-deficient db/db mice as a model of obesity and severe T2DM to assess the extent of bone quality alterations at the organ and tissue levels. We also examined the beneficial effects of gut hormone therapy in this model by using a new triple agonist ([d-Ala(2)]GIP-Oxm) active at the GIP, GLP-1 and glucagon receptors. As expected, db/db mice presented with dramatic alterations of bone strength at the organ level associated with deterioration of trabecular and cortical microarchitectures and an augmentation in osteoclast numbers. At the tissue level, these animals presented also with alterations of bone strength (reduced hardness, indentation modulus and dissipated energy) with modifications of tissue mineral distribution, collagen glycation and collagen maturity. The use of [d-Ala(2)]GIP-Oxm considerably improved bone strength at the organ level with modest effects on trabecular microarchitecture. At the tissue level, [d-Ala(2)]GIP-Oxm ameliorated bone strength reductions with positive effects on collagen glycation and collagen maturity. This study provides support for including gut hormone analogues as possible new therapeutic strategies for improving bone quality in bone complications associated to T2DM

Osteoblast mineralization requires β1 integrin/ICAP-1–dependent fibronectin deposition

ICAP-1 prevents recruitment of kindlin-2 to β1 integrin to control dynamics of fibrillar adhesion sites, fibronectin deposition, and osteoblast mineralization during bone formation

Gamma oscillations in V1 are correlated with GABA(A) receptor density: A multi-modal MEG and Flumazenil-PET study.

High-frequency oscillations in the gamma-band reflect rhythmic synchronization of spike timing in active neural networks. The modulation of gamma oscillations is a widely established mechanism in a variety of neurobiological processes, yet its neurochemical basis is not fully understood. Modeling, in-vitro and in-vivo animal studies suggest that gamma oscillation properties depend on GABAergic inhibition. In humans, search for evidence linking total GABA concentration to gamma oscillations has led to promising -but also to partly diverging- observations. Here, we provide the first evidence of a direct relationship between the density of GABA(A) receptors and gamma oscillatory gamma responses in human primary visual cortex (V1). By combining Flumazenil-PET (to measure resting-levels of GABA(A) receptor density) and MEG (to measure visually-induced gamma oscillations), we found that GABA(A) receptor densities correlated positively with the frequency and negatively with amplitude of visually-induced gamma oscillations in V1. Our findings demonstrate that gamma-band response profiles of primary visual cortex across healthy individuals are shaped by GABA(A)-receptor-mediated inhibitory neurotransmission. These results bridge the gap with in-vitro and animal studies and may have future clinical implications given that altered GABAergic function, including dysregulation of GABA(A) receptors, has been related to psychiatric disorders including schizophrenia and depression

Human papillomavirus 16 L2 inhibits the transcriptional activation function, but not the DNA replication function, of HPV-16 E2

In this study we analysed the outcome of the interaction between HPV-16 L2 and E2 on the transactivation and DNA replication functions of E2. When E2 was expressed on its own, it transactivated a number of E2-responsive promoters but co-expression of L2 led to the down-regulation of the transcription transactivation activity of the E2 protein. This repression is not mediated by an increased degradation of the E2 protein. In contrast, the expression of L2 had no effect on the ability of E2 to activate DNA replication in association with the viral replication factor E1. Deletion mutagenesis identified L2 domains responsible for binding to E2 (first 50 N-terminus amino acid residues) and down-regulating its transactivation function (residues 301–400). The results demonstrate that L2 selectively inhibits the transcriptional activation property of E2 and that there is a direct interaction between the two proteins, although this is not sufficient to mediate the transcriptional repression. The consequences of the L2–E2 interaction for the viral life cycle are discussed