The growth plate’s response to load is partially mediated by mechano-sensing via the chondrocytic primary cilium

Mechanical load plays a significant role in bone and growth-plate development. Chondrocytes sense and respond to mechanical stimulation; however, the mechanisms by which those signals exert their effects are not fully understood. The primary cilium has been identified as a mechano-sensor in several cell types, including renal epithelial cells and endothelium, and accumulating evidence connects it to mechano-transduction in chondrocytes. In the growth plate, the primary cilium is involved in several regulatory pathways, such as the non-canonical Wnt and Indian Hedgehog. Moreover, it mediates cell shape, orientation, growth, and differentiation in the growth plate. In this work, we show that mechanical load enhances ciliogenesis in the growth plate. This leads to alterations in the expression and localization of key members of the Ihh-PTHrP loop resulting in decreased proliferation and an abnormal switch from proliferation to differentiation, together with abnormal chondrocyte morphology and organization. Moreover, we use the chondrogenic cell line ATDC5, a model for growth-plate chondrocytes, to understand the mechanisms mediating the participation of the primary cilium, and in particular KIF3A, in the cell’s response to mechanical stimulation. We show that this key component of the cilium mediates gene expression in response to mechanical stimulation.     

Nanoparticle-based drug delivery: case studies for cancer and cardiovascular applications

Nanoparticles (NPs) comprised of nanoengineered complexes are providing new opportunities for enabling targeted delivery of a range of therapeutics and combinations. A range of functionalities can be included within a nanoparticle complex, including surface chemistry that allows attachment of cell-specific ligands for targeted delivery, surface coatings to increase circulation times for enhanced bioavailability, specific materials on the surface or in the nanoparticle core that enable storage of a therapeutic cargo until the target site is reached, and materials sensitive to local or remote actuation cues that allow controlled delivery of therapeutics to the target cells. However, despite the potential benefits of NPs as smart drug delivery and diagnostic systems, much research is still required to evaluate potential toxicity issues related to the chemical properties of NP materials, as well as their size and shape. The need to validate each NP for safety and efficacy with each therapeutic compound or combination of therapeutics is an enormous challenge, which forces industry to focus mainly on those nanoparticle materials where data on safety and efficacy already exists, i.e., predominantly polymer NPs. However, the enhanced functionality affordable by inclusion of metallic materials as part of nanoengineered particles provides a wealth of new opportunity for innovation and new, more effective, and safer therapeutics for applications such as cancer and cardiovascular diseases, which require selective targeting of the therapeutic to maximize effectiveness while avoiding adverse effects on non-target tissues.     

Prostacyclin-like activity of endothelium and subendothelium — important for atherosclerosis?

Summary Morphological control of Moncada's bioassay for prostacyclin (PG I₂) activity measurement shows that the activity depends not only on endothelium, but in important amounts on subendothelial tissue too. Therefore, it can be concluded that platelet thrombus formation after endothelial cell injury does not depend only on the PG I₂-producing ability of the tissue.     

Differential modulation of endotoxin responsiveness by human caspase-12 polymorphisms

Caspases mediate essential key proteolytic events in inflammatory cascades and the apoptotic cell death pathway. Human caspases functionally segregate into two distinct subfamilies: those involved in cytokine maturation (caspase-1, -4 and -5) and those involved in cellular apoptosis (caspase-2, -3, -6, -7, -8, -9 and -10). Although caspase-12 is phylogenetically related to the cytokine maturation caspases, in mice it has been proposed as a mediator of apoptosis induced by endoplasmic reticulum stress including amyloid-beta cytotoxicity, suggesting that it might contribute to the pathogenesis of Alzheimer's disease. Here we show that a single nucleotide polymorphism in caspase-12 in humans results in the synthesis of either a truncated protein (Csp12-S) or a full-length caspase proenzyme (Csp12-L). The read-through single nucleotide polymorphism encoding Csp12-L is confined to populations of African descent and confers hypo-responsiveness to lipopolysaccharide-stimulated cytokine production in ex vivo whole blood, but has no significant effect on apoptotic sensitivity. In a preliminary study, we find that the frequency of the Csp12-L allele is increased in African American individuals with severe sepsis. Thus, Csp12-L attenuates the inflammatory and innate immune response to endotoxins and in doing so may constitute a risk factor for developing sepsis.     

Countering medical nihilism by reconnecting facts and values

A pessimistic strain of thought is fomenting in the health studies literature regarding the status of medicine. Ioannidis’s (2005) now famous finding that “most published research findings are false” and Stegenga’s (2018) book-length argument for medical nihilism are examples of this. In this paper, we argue that these positions are incorrect insofar as they rest on an untenable account of the nature of facts. Proper attention to fallibilism and the social organization of knowledge, as well as Bayesian probabilities in medical reasoning, prompt us to ask why the cynics expect the results of quantitative studies to be incontrovertibly true in the first place. While we agree with Ioannidis and others’ identified flaws in the medical research enterprise, and encourage rectification, we conclude that medical nihilism is not the natural outcome of the current state of research.     

Wall development and tetrazolium chloride reduction in heterocysts of blue-green algae,Anabaena ambigua

Zusammenfassung 2,3,5-Triphenyl-Tetrazolium-Chlorid (TTC) wird in den Heterocysten der BlaualgeAnabaena ambigua nur bei einer gut ausgebildeten Zellwand in grösseren Mengen reduziert. In allen übrigen Zellen, auch in den Proheterocysten, ist höchstens eine schwache TTC-Reduktion zu beobachten.

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Our thanks are due to the UGC, CSIR for the financial assistance and to the Head of the Department of Botany, for facilities.