Enzyme replacement therapy in mice lacking arylsulfatase B targets bone-remodeling cells, but not chondrocytes

Mucopolysaccharidosis type VI (MPS-VI), caused by mutational inactivation of the glycosaminoglycan-degrading enzyme arylsulfatase B (Arsb), is a lysosomal storage disorder primarily affecting the skeleton. We have previously reported that Arsb-deficient mice display high trabecular bone mass and impaired skeletal growth. In the present study, we treated them by weekly injection of recombinant human ARSB (rhARSB) to analyze the impact of enzyme replacement therapy (ERT) on skeletal growth and bone remodeling. We found that all bone-remodeling abnormalities of Arsb-deficient mice were prevented by ERT, whereas chondrocyte defects were not. Likewise, histologic analysis of the surgically removed femoral head from an ERT-treated MPS-VI patient revealed that only chondrocytes were pathologically affected. Remarkably, a side-by-side comparison with other cell types demonstrated that chondrocytes have substantially reduced capacity to endocytose rhARSB, together with low expression of the mannose receptor. We finally took advantage of Arsb-deficient mice to establish quantification of chondroitin sulfation for treatment monitoring. Our data demonstrate that bone-remodeling cell types are accessible to systemically delivered rhARSB, whereas the uptake into chondrocytes is inefficient

Polarization and Strong Infra-Red Activity in Compressed Solid Hydrogen

Under a pressure of ~150 GPa solid molecular hydrogen undergoes a phase transition accompanied by a dramatic rise in infra-red absorption in the vibron frequency range. We use the Berry's phase approach to calculate the electric polarization in several candidate structures finding large, anisotropic dynamic charges and strongly IR-active vibron modes. The polarization is shown to be greatly affected by the overlap between the molecules in the crystal, so that the commonly used Clausius-Mossotti description in terms of polarizable, non-overlapping molecular charge densities is inadequate already at low pressures and even more so for the compressed solid.Comment: To appear in Phys. Rev. Let

Piezo1 Inactivation in Chondrocytes Impairs Trabecular Bone Formation

The skeleton is a dynamic tissue continuously adapting to mechanical stimuli. Although matrix‐embedded osteocytes are considered as the key mechanoresponsive bone cells, all other skeletal cell types are principally exposed to macroenvironmental and microenvironmental mechanical influences that could potentially affect their activities. It was recently reported that Piezo1, one of the two mechanically activated ion channels of the Piezo family, functions as a mechanosensor in osteoblasts and osteocytes. Here we show that Piezo1 additionally plays a critical role in the process of endochondral bone formation. More specifically, by targeted deletion of Piezo1 or Piezo2 in either osteoblast (Runx2Cre) or osteoclast lineage cells (Lyz2Cre), we observed severe osteoporosis with numerous spontaneous fractures specifically in Piezo1Runx2Cre mice. This phenotype developed at an early postnatal stage and primarily affected the formation of the secondary spongiosa. The presumptive Piezo1Runx2Cre osteoblasts in this region displayed an unusual flattened appearance and were positive for type X collagen. Moreover, transcriptome analyses of primary osteoblasts identified an unexpected induction of chondrocyte‐related genes in Piezo1Runx2Cre cultures. Because Runx2 is not only expressed in osteoblast progenitor cells, but also in prehypertrophic chondrocytes, these data suggested that Piezo1 functions in growth plate chondrocytes to ensure trabecular bone formation in the process of endochondral ossification. To confirm this hypothesis, we generated mice with Piezo1 deletion in chondrocytes (Col2a1Cre). These mice essentially recapitulated the phenotype of Piezo1Runx2Cre animals, because they displayed early‐onset osteoporosis with multiple fractures, as well as impaired formation of the secondary spongiosa with abnormal osteoblast morphology. Our data identify a previously unrecognized key function of Piezo1 in endochondral ossification, which, together with its role in bone remodeling, suggests that Piezo1 represents an attractive target for the treatment of skeletal disorders. © 2020 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)

A critical realist evaluation of advance care planning in care homes

Aims: To evaluate care planning in advance of end-of-life care in care homes. Design: A qualitative study. Methods: Qualitative data were collected from January 2018–July 2019 (using focus groups and semi-structured interviews) from three care homes in the South West of England. The data were analysed using thematic analysis followed by Critical Realist Evaluation. Results: Participants comprised of registered nurses (N = 4), care assistants (N = 8), bereaved relatives (N = 7), and domiciliary staff (N = 3). Although the importance of advance care planning was well recognized, the emotional labour of frequently engaging in discussions about death and dying was highlighted as a problem by some care home staff. It was evident that in some cases care home staff's unmet emotional needs led them to rushing and avoiding discussions about death and dying with residents and relatives. A sparsity of mechanisms to support care home staff's emotional needs was noted across all three care homes. Furthermore, a lack of training and knowledge appeared to inhibit care home staff's ability to engage in meaningful care planning conversations with specific groups of residents such as those living with dementia. The lack of training was principally evident amongst non-registered care home staff and those with non-formal caring roles such as housekeeping. Conclusion: There is a need for more focused education to support registered and non-registered care home staff to effectively engage in sensitive discussions about death and dying with residents. Furthermore, greater emotional support is necessary to help build workforce resilience and sustain change. Impact: Knowledge generated from this study can be used to inform the design and development of future advance care planning interventions capable of supporting the delivery of high-quality end-of-life care in care homes

A critical realist evaluation of advance care planning in care homes

Aims: To evaluate care planning in advance of end-of-life care in care homes. Design: A qualitative study. Methods: Qualitative data were collected from January 2018–July 2019 (using focus groups and semi-structured interviews) from three care homes in the South West of England. The data were analysed using thematic analysis followed by Critical Realist Evaluation. Results: Participants comprised of registered nurses (N = 4), care assistants (N = 8), bereaved relatives (N = 7), and domiciliary staff (N = 3). Although the importance of advance care planning was well recognized, the emotional labour of frequently engaging in discussions about death and dying was highlighted as a problem by some care home staff. It was evident that in some cases care home staff's unmet emotional needs led them to rushing and avoiding discussions about death and dying with residents and relatives. A sparsity of mechanisms to support care home staff's emotional needs was noted across all three care homes. Furthermore, a lack of training and knowledge appeared to inhibit care home staff's ability to engage in meaningful care planning conversations with specific groups of residents such as those living with dementia. The lack of training was principally evident amongst non-registered care home staff and those with non-formal caring roles such as housekeeping. Conclusion: There is a need for more focused education to support registered and non-registered care home staff to effectively engage in sensitive discussions about death and dying with residents. Furthermore, greater emotional support is necessary to help build workforce resilience and sustain change. Impact: Knowledge generated from this study can be used to inform the design and development of future advance care planning interventions capable of supporting the delivery of high-quality end-of-life care in care homes

Delayed Cutaneous Wound Healing and Aberrant Expression of Hair Follicle Stem Cell Markers in Mice Selectively Lacking Ctip2 in Epidermis

This is the publisher’s final pdf. The published article is copyrighted by PLoS and can be found at: http://www.plosone.org/home.action.Background: COUP-TF interacting protein 2 [(Ctip2), also known as Bcl11b] is an important regulator of skin homeostasis, and is overexpressed in head and neck cancer. Ctip2(ep-/-) mice, selectively ablated for Ctip2 in epidermal keratinocytes, exhibited impaired terminal differentiation and delayed epidermal permeability barrier (EPB) establishment during development, similar to what was observed in Ctip2 null (Ctip2(-/-)) mice. Considering that as an important role of Ctip2, and the fact that molecular networks which underlie cancer progression partially overlap with those responsible for tissue remodeling, we sought to determine the role of Ctip2 during cutaneous wound healing. \ud \ud Methodology/Principal Findings: Full thickness excisional wound healing experiments were performed on Ctip2(L2/L2) and Ctip2(ep-/-) animals per time point and used for harvesting samples for histology, immunohistochemistry (IHC) and immunoblotting. Results demonstrated inherent defects in proliferation and migration of Ctip2 lacking keratinocytes during re-epithelialization. Mutant mice exhibited reduced epidermal proliferation, delayed keratinocyte activation, altered cell-cell adhesion and impaired ECM development. Post wounding, Ctip2(ep-/-) mice wounds displayed lack of E-Cadherin suppression in the migratory tongue, insufficient expression of alpha smooth muscle actin (alpha SMA) in the dermis, and robust induction of K8. Importantly, dysregulated expression of several hair follicle (HF) stem cell markers such as K15, NFATc1, CD133, CD34 and Lrig1 was observed in mutant skin during wound repair. \ud \ud Conclusions/Significance: Results confirm a cell autonomous role of keratinocytic Ctip2 to modulate cell migration, proliferation and/or differentiation, and to maintain HF stem cells during cutaneous wounding. Furthermore, Ctip2 in a non-cell autonomous manner regulated granulation tissue formation and tissue contraction during wound closure

A general refutation of Okishio’s theorem and a proof of the falling rate of profit

This is the first published general refutation of the Okishio theorem. An earlier refutation based on a specific example was published by Kliman and McGlone in 1988. Okishio’s theorem, published in 1961, asserts that if real wages stay constant, the rate of profit necessarily rises in consequence of any cost-reducing technical change. It proves this within a simultaneous equation (general equlibrium) framework. This paper establishes that this proposition is false within a differential equation (temporal) approach. In such a framework the denominator of the rate of profit rises continuously, regardless of whether or not there is technical change, unless capitalist consumption exceeds profit, as occurs in a slump. Okishio himself asserts that his theorem is ‘contrary to Marx’s Gesetz des Tendentiellen Falls der Profitrate’ – contrary to Marx’s law of the tendency of the rate of profit to fall. This assertion is, within the literature, universally taken to be the substantive content of the ‘Okishio Theorem’. Thus, if Marx’s approach to value is in fact temporal, and not simultaneist, this assertion by Okishio is false, since it applies not to Marx’s own theory, but to the interpretation of that theory subsequently attributed to Marx by a specific school of thought represented principally by Bortkiewicz, Sweezy, Morishima, Seton, and Steedman. The subsequent accumulation of hermeneutic evidence strongly supports the thesis that Marx’s theory is temporalist and not simultaneist. Since the Okishio theorem makes the general assertion that the rate of profit must necessarily rise if there are cost-saving technical changes, and since Kliman and McGlone demonstrate a particular case in which cost-saving technical change leads to a fall in the profit rate, the Kliman-McGlone paper is the first published refutation of the Okishio theorem. The present paper is a generalisation of this refutation which establishes the precise conditions under which the profit rate rise or falls, and establishes the general result that the profit rate necessarily falls as a consequence of capitalist accumulation with a constant real wage, until and unless accumulation ceases in value terms. Consequently the mathematical findings set out in this paper, refute the Okishio Theorem

Basement membrane components are key players in specialized extracellular matrices

More than three decades ago, basement membranes (BMs) were described as membrane-like structures capable of isolating a cell from and connecting a cell to its environment. Since this time, it has been revealed that BMs are specialized extracellular matrices (sECMs) with unique components that support important functions including differentiation, proliferation, migration, and chemotaxis of cells during development. The composition of these sECM is as unique as the tissues to which they are localized, opening the possibility that such matrices can fulfill distinct functions. Changes in BM composition play significant roles in facilitating the development of various diseases. Furthermore, tissues have to provide sECM for their stem cells during development and for their adult life. Here, we briefly review the latest research on these unique sECM and their components with a special emphasis on embryonic and adult stem cells and their niches