Hematopoietic stem cells (HSCs) rely on instructive cues from the bone marrow (BM) niche to maintain their quiescence and adapt blood production to the organism’s needs. Alterations in the BM niche ...are commonly observed in blood malignancies and directly contribute to the aberrant function of disease-initiating leukemic stem cells (LSCs). Here, we review recent insights into the cellular and molecular determinants of the normal HSC niche and describe how genetic changes in stromal cells and leukemia-induced BM niche remodeling contribute to blood malignancies. Moreover, we discuss how these findings can be applied to non-cell-autonomous therapies targeting the LSC niche.
Passegué and colleagues review recent insights into the cellular and molecular determinants of the normal hematopoietic stem cell niche and describe how genetic changes in stromal cells and leukemia-induced niche remodeling contribute to blood malignancies. They also discuss strategies for developing non-cell-autonomous therapies targeting the leukemia stem cell niche.
Summary
Background
Application of modern rapid DNA sequencing technology has transformed our understanding of the gut microbiota. Diet, in particular plant‐based fibre, appears critical in ...influencing the composition and metabolic activity of the microbiome, determining levels of short‐chain fatty acids (SCFAs) important for intestinal health.
Aim
To assess current epidemiological, experimental and clinical evidence of how long‐term and short‐term alterations in dietary fibre intake impact on the microbiome and metabolome.
Methods
A Medline search including items ‘intestinal microbiota’, ‘nutrition’, ‘diet’, ‘dietary fibre’, ‘SCFAs’ and ‘prebiotic effect’ was performed.
Results
Studies found evidence of fibre‐influenced differences in the microbiome and metabolome as a consequence of habitual diet, and of long‐term or short‐term intervention (in both animals and humans).
Conclusions
Agrarian diets high in fruit/legume fibre are associated with greater microbial diversity and a predominance of Prevotella over Bacteroides. ‘Western’‐style diets, high in fat/sugar, low in fibre, decrease beneficial Firmicutes that metabolise dietary plant‐derived polysaccharides to SCFAs and increase mucosa‐associated Proteobacteria (including enteric pathogens). Short‐term diets can also have major effects, particularly those exclusively animal‐based, and those high‐protein, low‐fermentable carbohydrate/fibre ‘weight‐loss’ diets, increasing the abundance of Bacteroides and lowering Firmicutes, with long‐term adherence to such diets likely increasing risk of colonic disease. Interventions to prevent intestinal inflammation may be achieved with fermentable prebiotic fibres that enhance beneficial Bifidobacteria or with soluble fibres that block bacterial–epithelial adherence (contrabiotics). These mechanisms may explain many of the differences in microbiota associated with long‐term ingestion of a diet rich in fruit and vegetable fibre.
Activation of mechanosensitive ion channels by physical force underlies many physiological processes including the sensation of touch, hearing and pain. TRAAK (also known as KCNK4) ion channels are ...neuronally expressed members of the two-pore domain K(+) (K2P) channel family and are mechanosensitive. They are involved in controlling mechanical and temperature nociception in mice. Mechanosensitivity of TRAAK is mediated directly through the lipid bilayer--it is a membrane-tension-gated channel. However, the molecular mechanism of TRAAK channel gating and mechanosensitivity is unknown. Here we present crystal structures of TRAAK in conductive and non-conductive conformations defined by the presence of permeant ions along the conduction pathway. In the non-conductive state, a lipid acyl chain accesses the channel cavity through a 5 Å-wide lateral opening in the membrane inner leaflet and physically blocks ion passage. In the conductive state, rotation of a transmembrane helix (TM4) about a central hinge seals the intramembrane opening, preventing lipid block of the cavity and permitting ion entry. Additional rotation of a membrane interacting TM2-TM3 segment, unique to mechanosensitive K2Ps, against TM4 may further stabilize the conductive conformation. Comparison of the structures reveals a biophysical explanation for TRAAK mechanosensitivity--an expansion in cross-sectional area up to 2.7 nm(2) in the conductive state is expected to create a membrane-tension-dependent energy difference between conformations that promotes force activation. Our results show how tension of the lipid bilayer can be harnessed to control gating and mechanosensitivity of a eukaryotic ion channel.
Posttraumatic stress disorder (PTSD) is associated with impairments in relationship functioning. Beyond the abundance of research that has demonstrated this basic link, more recent research has begun ...to explore possible mediators and moderators of this association. The present paper reviews and synthesizes existing literature in the context of an overarching organizational framework of potential ways in which PTSD impacts relationship functioning. The framework organizes findings in terms of specific elements of PTSD and comorbid conditions, mediators (factors that are posited to explain or account for the association), and moderators (factors that are posited to alter the strength of the association). Specific symptoms of PTSD, comorbid symptoms, and many of the potential mediators explored have extensive overlap, raising questions of possible tautology and redundancy in findings. Some findings suggest that non-specific symptoms, such as depression or anger, account for more variance in relationship impairments than trauma-specific symptoms, such as re-experiencing. Moderators, which are characterized as individual, relational, or environmental in nature, have been the subject of far less research in comparison to other factors. Recommendations for future research and clinical implications of the findings reviewed are also presented.
•Presents organizational framework of links between PTSD and relationship functioning.•Specific elements of psychopathology, mediators, and moderators are discussed.•Moderators are categorized as individual, relational, or environmental.•Clinical implications of findings are discussed.•Recommendations for future research are made.
Li@C60 as a multi-state molecular switch Chandler, Henry J.; Stefanou, Minas; Campbell, Eleanor E. B. ...
Nature communications,
05/2019, Volume:
10, Issue:
1
Journal Article
Peer reviewed
Open access
Abstract
The field of molecular electronics aims at advancing the miniaturization of electronic devices, by exploiting single molecules to perform the function of individual components. A molecular ...switch is defined as a molecule that displays stability in two or more states (e.g. “on” and “off” involving conductance, conformation etc.) and upon application of a controlled external perturbation, electric or otherwise, undergoes a reversible change such that the molecule is altered. Previous work has shown multi-state molecular switches with up to four and six distinct states. Using low temperature scanning tunnelling microscopy and spectroscopy, we report on a multi-state single molecule switch using the endohedral fullerene Li@C
60
that displays 14 molecular states which can be statistically accessed. We suggest a switching mechanism that relies on resonant tunnelling via the superatom molecular orbitals (SAMOs) of the fullerene cage as a means of Li activation, thereby bypassing the typical vibronic excitation of the carbon cage that is known to cause molecular decomposition.
CLC proteins transport chloride (Cl
) ions across cellular membranes to regulate muscle excitability, electrolyte movement across epithelia, and acidification of intracellular organelles. Some CLC ...proteins are channels that conduct Cl
ions passively, whereas others are secondary active transporters that exchange two Cl
ions for one H
. The structural basis underlying these distinctive transport mechanisms is puzzling because CLC channels and transporters are expected to share the same architecture on the basis of sequence homology. Here we determined the structure of a bovine CLC channel (CLC-K) using cryo-electron microscopy. A conserved loop in the Cl
transport pathway shows a structure markedly different from that of CLC transporters. Consequently, the cytosolic constriction for Cl
passage is widened in CLC-K such that the kinetic barrier previously postulated for Cl
/H
transporter function would be reduced. Thus, reduction of a kinetic barrier in CLC channels enables fast flow of Cl
down its electrochemical gradient.
SARS-CoV-2 infection can cause severe respiratory COVID-19. However, many individuals present with isolated upper respiratory symptoms, suggesting potential to constrain viral pathology to the ...nasopharynx. Which cells SARS-CoV-2 primarily targets and how infection influences the respiratory epithelium remains incompletely understood. We performed scRNA-seq on nasopharyngeal swabs from 58 healthy and COVID-19 participants. During COVID-19, we observe expansion of secretory, loss of ciliated, and epithelial cell repopulation via deuterosomal cell expansion. In mild and moderate COVID-19, epithelial cells express anti-viral/interferon-responsive genes, while cells in severe COVID-19 have muted anti-viral responses despite equivalent viral loads. SARS-CoV-2 RNA+ host-target cells are highly heterogenous, including developing ciliated, interferon-responsive ciliated, AZGP1high goblet, and KRT13+ “hillock”-like cells, and we identify genes associated with susceptibility, resistance, or infection response. Our study defines protective and detrimental responses to SARS-CoV-2, the direct viral targets of infection, and suggests that failed nasal epithelial anti-viral immunity may underlie and precede severe COVID-19.
Display omitted
•scRNA-seq on nasopharyngeal swabs of 58 COVID-19 and healthy participants•SARS-CoV-2 induces ciliated cell loss with secretory and deuterosomal expansion•Early, muted anti-viral responses in nasal epithelia in severe COVID-19•Host-virus co-detection maps cell tropism and intrinsic responses to SARS-CoV-2
A study of nasopharyngeal swabs from healthy and COVID-19-infected individuals shows how infection leads to compositional changes in the respiratory epithelium, with early dampened antiviral responses in the nasal epithelia likely underlying and preceding severe disease.
Morphological analyses of Utopia Planitia, Mars, have led to the hypothesis that the region contains a substantial amount of near‐surface ice. This paper tests this hypothesis using ...ground‐penetrating radar techniques. We have identified an expansive radar reflective region spanning approximately 375,000 km2 in SHAllow RADar (SHARAD) data over western Utopia Planitia. The SHARAD reflective regions coincides with high densities of scalloped depressions and polygonal terrain. The reflectors are associated with layered mesas ∼80–170 m thick. We find a value of 2.8 ± 0.8 for the dielectric constant of the material overlying the reflectors. This work finds that the dielectric constant is consistent with a mixture of ice, air, and dust, containing a water ice volume up to 14,300 km3 in this unit.
Key Points
Layered mesas up to 170 m high in western Utopia Planitia, Mars, exhibit periglacial morphologies
SHARAD data were used to map a regional subsurface reflector associated with the layered mesas
The dielectric constant is consistent with a 50‐85% water ice composition, with an ice volume of up to 14,300 km3
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