BMP3 Suppresses Osteoblast Differentiation of Bone Marrow Stromal Cells Via Interaction With Acvr2b.

Enhancing bone morphogenetic protein (BMP) signaling increases bone formation in a variety of settings that target bone repair. However, the role of BMP in the maintenance of adult bone mass is not well understood. Targeted disruption of BMP3 in mice results in increased trabecular bone formation, whereas transgenic overexpression of BMP3 in skeletal cells leads to spontaneous fracture, consistent with BMP3 having a negative role in bone mass regulation. Here we investigate the importance of BMP3 as a mediator of BMP signaling in the adult skeleton. We find that osteoblasts (OBL) and osteocytes are the source of BMP3 in adult bone. Using in vitro cultures of primary bone marrow stromal cells, we show that overexpression of BMP3 suppresses OBL differentiation, whereas loss of BMP3 increases colony-forming unit fibroblasts and colony-forming unit OBL. The ability of BMP3 to affect OBL differentiation is due to its interaction with activin receptor type 2b (Acvr2b) because knockdown of endogenous Acvr2b in bone marrow stromal cells reduces the suppressive effect of BMP3 on OBL differentiation. These findings best fit a model in which BMP3, produced by mature bone cells, acts to reduce BMP signaling through Acvr2b in skeletal progenitor cells, limiting their differentiation to mature OBL. Our data further support the idea that endogenous BMPs have a physiological role in regulating adult bone mass

Cooperation between STAT3 and c-Jun Suppresses Fas Transcription

Decreased Fas expression during tumor progression often results in a loss of Fas-ligand (FasL)-mediated apoptosis. Human and mouse melanoma exhibit an inverse correlation between the degree of Fas cell surface expression, tumorigenicity, and metastatic capacity. The expression of dominant negative Stat3 or c-Jun in melanoma cells efficiently increased Fas expression and sensitized cells to FasL-induced apoptosis. Stat3+/− as well as c-Jun−/− cells exhibited increased Fas cell surface expression and higher sensitivity to FasL-mediated apoptosis. Suppression of Fas expression by Stat3 and c-Jun is uncoupled from Stat3-mediated transcriptional activation. Our findings indicate that Stat3 oncogenic activities could also be mediated through its cooperation with c-Jun, resulting in downregulation of Fas surface expression, which is implicated in the tumor's ability to resist therapy and metastasize

Aging is associated with a prefrontal lateral-medial shift during picture-induced negative affect

The capacity to adaptively respond to negative emotion is in part dependent upon lateral areas of the prefrontal cortex (PFC). Lateral PFC areas are particularly susceptible to age-related atrophy, which affects executive function (EF). We used structural and functional magnetic resonance imaging (MRI) to test the hypothesis that older age is associated with greater medial PFC engagement during processing of negative information, and that this engagement is dependent upon the integrity of grey matter structure in lateral PFC as well as EF. Participants (n = 64, 38–79 years) viewed negative and neutral scenes while in the scanner, and completed cognitive tests as part of a larger study. Grey matter probability (GMP) was computed to index grey matter integrity. FMRI data demonstrated less activity in the left ventrolateral PFC (VLPFC) and greater ventromedial PFC (VMPFC) activity with increasing age during negative-picture viewing. Age did not correlate with amygdala responding. GMP in VLPFC and EF were negatively associated with VMPFC activity. We conclude that this change from lateral to medial PFC engagement in response to picture-induced negative affect reflects decreased reliance on executive function-related processes, possibly associated with reduced grey matter in lateral PFC, with advancing age to maintain emotional functioning

Differential Temporal and Spatial Progerin Expression during Closure of the Ductus Arteriosus in Neonates

Closure of the ductus arteriosus (DA) at birth is essential for the transition from fetal to postnatal life. Before birth the DA bypasses the uninflated lungs by shunting blood from the pulmonary trunk into the systemic circulation. The molecular mechanism underlying DA closure and degeneration has not been fully elucidated, but is associated with apoptosis and cytolytic necrosis in the inner media and intima. We detected features of histology during DA degeneration that are comparable to Hutchinson Gilford Progeria syndrome and ageing. Immunohistochemistry on human fetal and neonatal DA, and aorta showed that lamin A/C was expressed in all layers of the vessel wall. As a novel finding we report that progerin, a splicing variant of lamin A/C was expressed almost selectively in the normal closing neonatal DA, from which we hypothesized that progerin is involved in DA closure. Progerin was detected in 16.2%±7.2 cells of the DA. Progerin-expressing cells were predominantly located in intima and inner media where cytolytic necrosis accompanied by apoptosis will develop. Concomitantly we found loss of α-smooth muscle actin as well as reduced lamin A/C expression compared to the fetal and non-closing DA. In cells of the adjacent aorta, that remains patent, progerin expression was only sporadically detected in 2.5%±1.5 of the cells. Data were substantiated by the detection of mRNA of progerin in the neonatal DA but not in the aorta, by PCR and sequencing analysis. The fetal DA and the non-closing persistent DA did not present with progerin expressing cells. Our analysis revealed that the spatiotemporal expression of lamin A/C and progerin in the neonatal DA was mutually exclusive. We suggest that activation of LMNA alternative splicing is involved in vascular remodeling in the circulatory system during normal neonatal DA closure

Gender injustice in compensating injury to autonomy in English and Singaporean negligence law

The extent to which English law remedies injury to autonomy (ITA) as a stand-alone actionable damage in negligence is disputed. In this article I argue that the remedy available is not only partial and inconsistent (Keren-Paz in Med Law Rev, 2018) but also gendered and discriminatory against women. I first situate the argument within the broader feminist critique of tort law as failing to appropriately remedy gendered harms, and of law more broadly as undervaluing women’s interest in reproductive autonomy. I then show by reference to English remedies law’s first principles how imposed motherhood cases—Rees v Darlington and its predecessor McFarlane v Tayside Health Board—result in gender injustice when compared with other autonomy cases such as Chester v Afshar and Yearworth v North Bristol NHS Trust: A minor gender-neutral ITA is better remedied than the significant gendered harm of imposing motherhood on the claimant; men’s reproductive autonomy is protected to a greater extent than women’s; women’s reproductive autonomy is protected by an exceptional, derisory award. Worst of all, courts refuse to recognise imposed motherhood as detriment; and the deemed, mansplained, nonpecuniary joys of motherhood are used to offset pecuniary upkeep costs, forcing the claimant into a position she sought to avoid and thus further undermining her autonomy. The recent Singaporean case ACB v Thomson Medical Pte Ltd, awarding compensation for undermining the claimant’s genetic affinity in an IVF wrong-sperm-mix-up demonstrates some improvement in comparison to English law, and some shared gender injustices in the context of reproductive autonomy. ACB’s analysis is oblivious to the nature of reproductive autonomy harm as gendered; and prioritises the father’s interest in having genetic affinity with the baby over a woman’s interest in not having motherhood imposed upon her

Molecular analysis of a putative transposable retroelement from the Zea genus with internal clusters of tandem repeats

8 pages, 5 figures.-- 8867799 [PubMed].The molecular characterization of a recently discovered family of long repetitive sequences, termed ZLRS, is described. These elements belong to the class of moderate dispersed repetitive DNA and are specific to the Zea genus. An 8089-bp sequence from a Zea diploperennis ZLRS element have been elucidated. Sequence analysis reveals the presence of a long terminal repeat-like region, two clusters of different tandem repeats and several ORFs. On these grounds, ZLRS could be considered a new member of the superfamily of transposable retroelements. Tandems are present in the majority of ZLRS elements, they show an important stem-loop secondary structure predicted by the computer and their sequence conservation suggests a functional role.This work has been supported by grants from DGPC (PB90-0129 and PB93-0043) to J.A.M.I. A.M. was the recipient of a postdoctoral reincorporation fellowship (CIRIT). C.M.Y. was the recipient of an FPI fellowship (CIRIT). R.R. was the recipient of a PFPI fellowship (MEC).Peer reviewe

Chromosome localization and characterization of a family of long interspersed repetitive DNA elements from the genus Zea

This paper describes the characterization and chromosomal distribution of new long repetitive sequences present in all species of the genus Zea. These sequences constitute a family of moderately repetitive elements ranging approximately from 1350 to 1700 copies per haploid genome in modern maize (Zea mays ssp. mays) and teosinte (Zea diploperennis), respectively. The elements are long, probably larger than 9 kb, and they show a highly conserved internal organization among Zea subspecies and species. The elements are present in all maize chromosomes in an interspersed pattern of distribution, are absent from centromeric and pericentric heterochromatin, and with some clustering in the distal regions of chromosome arms.This work has been supported by a grant from DGPC (BIO 91/0129) to J.A.M.I. R.A. was the recipient of a postdoctoral reincorporation fellowship (MEC). R.R. was the recipient of a PFPI fellowship (MEC). A.M. was the recipient of a postdoctoral reincorporation fellowship (CIRIT). C.M.V. is the recipient of a FPI fellowship (CIRIT).Peer reviewe

Expression of a maize cell wall hydroxyproline-rich glycoprotein gene in early leaf and root vascular differentiation.

The spatial pattern of expression for a maize gene encoding a hydroxyproline-rich glycoprotein (HRGP) was determined by in situ hybridization. During normal development of roots and leaves, the expression of the gene was transient and particularly high in regions initiating vascular elements and associated sclerenchyma. Its expression was also associated with the differentiation of vascular elements in a variety of other tissues. The gene encoded an HRGP that had been extracted from the cell walls of maize suspension culture cells and several other embryonic and post-embryonic tissues. The gene was present in one or two copies in different varieties of maize and in the related monocots teosinte and sorghum. A single gene was cloned from maize using a previously characterized HRGP cDNA clone [Stiefel et al. (1988). Plant Mol. Biol. 11, 483-493]. In addition to the coding sequences for the HRGP and an N-terminal signal sequence, the gene contained a single intron in the nontranslated 3' end