Adult stem cell maintenance and tissue regeneration around the clock: do impaired stem cell clocks drive age-associated tissue degeneration?

Human adult stem cell research is a highly prolific area in modern tissue engineering as these cells have significant potential to provide future cellular therapies for the world’s increasingly aged population. Cellular therapies require a smart biomaterial to deliver and localise the cell population; protecting and guiding the stem cells toward predetermined lineage-specific pathways. The cells, in turn, can provide protection to biomaterials and increase its longevity. The right combination of stem cells and biomaterials can significantly increase the therapeutic efficacy. Adult stem cells are utilised to target many changes that negatively impact tissue functions with age. Understanding the underlying mechanisms that lead to changes brought about by the ageing process is imperative as ageing leads to many detrimental effects on stem cell activation, maintenance and differentiation. The circadian clock is an evolutionarily conserved timing mechanism that coordinates physiology, metabolism and behavior with the 24 h solar day to provide temporal tissue homeostasis with the external environment. Circadian rhythms deteriorate with age at both the behavioural and molecular levels, leading to age-associated changes in downstream rhythmic tissue physiology in humans and rodent models. In this review, we highlight recent advances in our knowledge of the role of circadian clocks in adult stem cell maintenance, driven by both cell-autonomous and tissue-specific factors, and the mechanisms by which they co-opt various cellular signaling pathways to impose temporal control on stem cell function. Future research investigating pharmacological and lifestyle interventions by which circadian rhythms within adult stem niches can be manipulated will provide avenues for temporally guided cellular therapies and smart biomaterials to ameliorate age-related tissue deterioration and reduce the burden of chronic disease

Mechanical stretch and chronotherapeutic techniques for progenitor cell transplantation and biomaterials

In the body, mesenchymal progenitor cells are subjected to a substantial amount external force from different mechanical stresses, each potentially influences their behaviour and maintenance differentially. Tensile stress, or compression loading are just two of these forces, and here we examine the role of cyclical or dynamic mechanical loading on progenitor cell proliferation and differentiation, as well as on other cellular processes including cell morphology, apoptosis and matrix mineralisation. Moreover, we also examine how mechanical stretch can be used to optimise and ready biomaterials before their implantation, and examine the role of the circadian rhythm, the body’s innate time keeping system, on biomaterial delivery and acceptance. Finally, we also investigate the effect of mechanical stretch on the circadian rhythm of progenitor cells, as research suggests that mechanical stimulation may be sufficient in itself to synchronise the circadian rhythm of human adult progenitor cells alone, and has also been linked to progenitor cell function. If proven correct, this could offer a novel, non- intrusive method by which human adult progenitor cells may be activated or preconditioned, being readied for differentiation, so that they may be more successfully integrated within a host body, thereby improving tissue engineering techniques and the efficacy of cellular therapies

Comparing circadian dynamics in primary derived stem cells from different sources of human adult tissue

Optimising cell/tissue constructs so that they can be successfully accepted and integrated within a host body is essential in modern tissue engineering. To do this, adult stem cells are frequently utilised, but there are many aspects of their environment in vivo that are not completely understood. There is evidence to suggest that circadian rhythms and daily circadian temporal cues have substantial effects on stem cell activation, cell cycle, and differentiation. It was hypothesised that the circadian rhythm in human adult stem cells differs depending on the source of tissue and that different entraining signals exert differential effects depending on the anatomical source. Dexamethasone and rhythmic mechanical stretch were used to synchronise stem cells derived from the bone marrow, tooth dental pulp, and abdominal subcutaneous adipose tissue, and it was experimentally evidenced that these different stem cells differed in their circadian clock properties in response to different synchronisation mechanisms. The more primitive dental pulp-derived stem cells did not respond as well to the chemical synchronisation but showed temporal clock gene oscillations following rhythmic mechanical stretch, suggesting that incorporating temporal circadian information of different human adult stem cells will have profound implications in optimising tissue engineering approaches and stem cell therapies

In vitro assembly of Ebola virus nucleocapsid-like complex expressed in E. coli

Ebola virus (EBOV) harbors an RNA genome encapsidated by nucleoprotein (NP) along with other viral proteins to form a nucleocapsid complex. Previous Cryo-eletron tomography and biochemical studies have shown the helical structure of EBOV nucleocapsid at nanometer resolution and the first 450 amino-acid of NP (NPΔ451–739) alone is capable of forming a helical nucleocapsid-like complex (NLC). However, the structural basis for NP-NP interaction and the dynamic procedure of the nucleocapsid assembly is yet poorly understood. In this work, we, by using an E. coli expression system, captured a series of images of NPΔ451–739 conformers at different stages of NLC assembly by negative-stain electron microscopy, which allowed us to picture the dynamic procedure of EBOV nucleocapsid assembly. Along with further biochemical studies, we showed the assembly of NLC is salt-sensitive, and also established an indispensible role of RNA in this process. We propose the diverse modes of NLC elongation might be the key determinants shaping the plasticity of EBOV virions. Our findings provide a new model for characterizing the self-oligomerization of viral nucleoproteins and studying the dynamic assembly process of viral nucleocapsid in vitro

Organizational factors and depression management in community-based primary care settings

Abstract Background Evidence-based quality improvement models for depression have not been fully implemented in routine primary care settings. To date, few studies have examined the organizational factors associated with depression management in real-world primary care practice. To successfully implement quality improvement models for depression, there must be a better understanding of the relevant organizational structure and processes of the primary care setting. The objective of this study is to describe these organizational features of routine primary care practice, and the organization of depression care, using survey questions derived from an evidence-based framework. Methods We used this framework to implement a survey of 27 practices comprised of 49 unique offices within a large primary care practice network in western Pennsylvania. Survey questions addressed practice structure (e.g., human resources, leadership, information technology (IT) infrastructure, and external incentives) and process features (e.g., staff performance, degree of integrated depression care, and IT performance). Results The results of our survey demonstrated substantial variation across the practice network of organizational factors pertinent to implementation of evidence-based depression management. Notably, quality improvement capability and IT infrastructure were widespread, but specific application to depression care differed between practices, as did coordination and communication tasks surrounding depression treatment. Conclusions The primary care practices in the network that we surveyed are at differing stages in their organization and implementation of evidence-based depression management. Practical surveys such as this may serve to better direct implementation of these quality improvement strategies for depression by improving understanding of the organizational barriers and facilitators that exist within both practices and practice networks. In addition, survey information can inform efforts of individual primary care practices in customizing intervention strategies to improve depression management.http://deepblue.lib.umich.edu/bitstream/2027.42/78269/1/1748-5908-4-84.xmlhttp://deepblue.lib.umich.edu/bitstream/2027.42/78269/2/1748-5908-4-84-S1.PDFhttp://deepblue.lib.umich.edu/bitstream/2027.42/78269/3/1748-5908-4-84.pdfPeer Reviewe

Protein-retention expansion microscopy of cells and tissues labeled using standard fluorescent proteins and antibodies

Expansion microscopy (ExM) enables imaging of preserved specimens with nanoscale precision on diffraction-limited instead of specialized super-resolution microscopes. ExM works by physically separating fluorescent probes after anchoring them to a swellable gel. The first ExM method did not result in the retention of native proteins in the gel and relied on custom-made reagents that are not widely available. Here we describe protein retention ExM (proExM), a variant of ExM in which proteins are anchored to the swellable gel, allowing the use of conventional fluorescently labeled antibodies and streptavidin, and fluorescent proteins. We validated and demonstrated the utility of proExM for multicolor super-resolution (~70 nm) imaging of cells and mammalian tissues on conventional microscopes.United States. National Institutes of Health (1R01GM104948)United States. National Institutes of Health (1DP1NS087724)United States. National Institutes of Health ( NIH 1R01EY023173)United States. National Institutes of Health (1U01MH106011

The comparative osmoregulatory ability of two water beetle genera whose species span the fresh-hypersaline gradient in inland waters (Coleoptera: Dytiscidae, Hydrophilidae).

A better knowledge of the physiological basis of salinity tolerance is essential to understanding the ecology and evolutionary history of organisms that have colonized inland saline waters. Coleoptera are amongst the most diverse macroinvertebrates in inland waters, including saline habitats; however, the osmoregulatory strategies they employ to deal with osmotic stress remain unexplored. Survival and haemolymph osmotic concentration at different salinities were examined in adults of eight aquatic beetle species which inhabit different parts of the fresh-hypersaline gradient. Studied species belong to two unrelated genera which have invaded saline waters independently from freshwater ancestors; Nebrioporus (Dytiscidae) and Enochrus (Hydrophilidae). Their osmoregulatory strategy (osmoconformity or osmoregulation) was identified and osmotic capacity (the osmotic gradient between the animal's haemolymph and the external medium) was compared between species pairs co-habiting similar salinities in nature. We show that osmoregulatory capacity, rather than osmoconformity, has evolved independently in these different lineages. All species hyperegulated their haemolymph osmotic concentration in diluted waters; those living in fresh or low-salinity waters were unable to hyporegulate and survive in hyperosmotic media (> 340 mosmol kg(-1)). In contrast, the species which inhabit the hypo-hypersaline habitats were effective hyporegulators, maintaining their haemolymph osmolality within narrow limits (ca. 300 mosmol kg(-1)) across a wide range of external concentrations. The hypersaline species N. ceresyi and E. jesusarribasi tolerated conductivities up to 140 and 180 mS cm(-1), respectively, and maintained osmotic gradients over 3500 mosmol kg(-1), comparable to those of the most effective insect osmoregulators known to date. Syntopic species of both genera showed similar osmotic capacities and in general, osmotic responses correlated well with upper salinity levels occupied by individual species in nature. Therefore, osmoregulatory capacity may mediate habitat segregation amongst congeners across the salinity gradient

Correlated insulator behaviour at half-filling in magic-angle graphene superlattices

Van der Waals (vdW) heterostructures are an emergent class of metamaterials comprised of vertically stacked two-dimensional (2D) building blocks, which provide us with a vast tool set to engineer their properties on top of the already rich tunability of 2D materials. 1 One of the knobs, the twist angle between different layers, plays a crucial role in the ultimate electronic properties of a vdW heterostructure and does not have a direct analog in other systems such as MBE-grown semiconductor heterostructures. For small twist angles, the moiré pattern produced by the lattice misorientation creates a long-range modulation. So far, the study of the effect of twist angles in vdW heterostructures has been mostly concentrated in graphene/hex a gonal boron nitride (h-BN) twisted structures, which exhibit relatively weak interlayer interaction due to the presence of a large bandgap in h-BN. 2-5 Here we show that when two graphene sheets are twisted by an angle close to the theoretically predicted ‘magic angle’, the resulting flat band structure near charge neutrality gives rise to a strongly-correlated electronic system . 6 These flat bands exhibit half-filling insulating phases at zero magnetic field, which we show to be a Mott-like insulator arising from electrons localized in the moiré superlattice. These unique properties of magic-angle twisted bilayer graphene (TwBLG) open up a new playground for exotic many-body quantum phases in a 2D platform made of pure carbon and without mag netic field. The easy accessibility of the flat bands, the electrical tunability, and the bandwidth tunability though twist angle may pave the way towards more exotic correlated systems, such as unconventional superconductors or quantum spin liquids

Study of hadronic event-shape variables in multijet final states in pp collisions at √s=7 TeV

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Constraints on parton distribution functions and extraction of the strong coupling constant from the inclusive jet cross section in pp collisions at √s=7 TeV

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