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Leucine-rich repeat-containing G-protein coupled receptor (LGR5 or GPR49) potentiates canonical Wnt/β-catenin signalling and is a marker of normal stem cells in several tissues, including the intestine. Consistent with stem cell potential, single isolated LGR5+ cells from the gut generate self-organising crypt/villus structures in vitro termed organoids or ‘mini-guts’, which accurately model the parent tissue. The well characterised deregulation of Wnt/β-catenin signalling that occurs during the adenoma-carcinoma sequence in colorectal cancer (CRC) renders LGR5 an interesting therapeutic target. Furthermore, recent studies demonstrating that CRC tumours contain LGR5+ subsets and retain a degree of normal tissue architecture has heightened translational interest. Such reports fuel hope that specific subpopulations or molecules within a tumour may be therapeutically targeted to prevent relapse and induce long-term remissions. Despite these observations, many studies within this field have produced conflicting and confusing results with no clear consensus on the therapeutic value of LGR5. This review will recap the various oncogenic and tumour suppressive roles that have been described for the LGR5 molecule in CRC. It will further highlight recent studies indicating the plasticity or redundancy of LGR5+ cells in intestinal cancer progression and assess the overall merit of therapeutically targeting LGR5 in CRC.

Operational psychology plays a unique role in supporting issues of nationa security, national defense, and public safety. In this book, authors Mark A. Staal and Sally C. Harvey, both operational psychologists and retired military colonels, lead a team of experts explaining the field, its many roles, and how it is expanding--back cover.

Colorectal cancer (CRC) is a significant global health burden with a rising incidence worldwide. Distinct bacterial populations are associated with CRC development and progression, and it is thought that the relationship between CRC and associated gut bacteria changes during the progression from normal epithelium to benign adenoma and eventually malignant carcinoma and metastasis. This study compared the interaction of CRC-associated species Enterotoxigenic Bacteroides fragilis , Enterococcus faecalis and Fusobacterium nucleatum and one probiotic species, Escherichia coli Nissle 1917 with a colorectal adenoma (S/RG/C2) and a colorectal adenocarcinoma (HCT116) derived cell line. Gentamicin protection assays showed that all species displayed higher attachment to benign tumour monolayers when compared to malignant monolayers. However, invasion of 3/4 species was higher in the HCT116 cells than in the adenoma cells. All species were found to persist within tumour cell monolayers for a minimum of 48 h under standard aerobic cell culture conditions, with persistence significantly higher in HCT116 cells. Downstream assays were performed to analyse the behaviour of S/RG/C2 and HCT116 cells post-infection and revealed that all species increased the tumour cell yield of both cell lines. The migratory and invasive potential of HCT116 cells was increased after infection with F. nucleatum ; however, no species significantly altered these characteristics in S/RG/C2 cells. These results add to the growing evidence for the involvement of microorganisms in CRC progression and suggest that these interactions may be dependent on tumour cell-specific characteristics.

The coupling at the interface between tectonic plates is a key geophysical parameter to capture the frictional locking across plate boundaries and provides a means to estimate where tectonic strain is accumulating through time. Here, we use both interferometric radar (InSAR) and Global Navigation Satellite System (GNSS) data to investigate the plate coupling of the Hikurangi subduction zone beneath the North Island of New Zealand, where multiple slow slip cycles are superimposed on the long‐term loading. We estimate the plate coupling across the subduction zone over three multi‐year observational periods targeting different stages of the slow slip cycle. Our results highlight the importance of the observational time period when interpreting coupling maps, emphasizing the temporal variability of plate coupling. Leveraging multiple geodetic data sets, we demonstrate how InSAR provides powerful constraints on the spatial resolution of both plate coupling and slow fault slip, even in a region where a dense GNSS network exists. Plain Language Summary Plate coupling as a concept describes to what degree the boundaries between tectonic plates are locked and building up stress. Such accumulated stress (over hundreds to thousands of years) will eventually be released in earthquakes, and therefore provides important information about the potential for future earthquakes. Our study uses satellite data to investigate how coupling between tectonic plates along the Hikurangi subduction zone (New Zealand's largest and most dangerous plate boundary fault) changes with time. We analyzed Interferometric Synthetic Aperture Radar and Global Navigation Satellite System data to map the areas where the plates are stuck together (coupled) and where they move past each other (uncoupled). We show that plate coupling varies significantly in space over 2, 4, and 10‐year time scales, highlighting the importance of carefully considering the observational time period when interpreting coupling maps. Key Points Integration of high‐resolution displacement maps from radar imagery captures plate coupling at fine scales Estimates of plate coupling depend strongly on the time period over which surface velocities are measured Temporal variations in plate coupling highlight when and where slow slip dominates the slip budget

Background: Complete tumour response (pCR) to neo-adjuvant chemo-radiotherapy for rectal cancer is associated with a reduction in local recurrence and improved disease-free and overall survival, but is achieved in only 20–30% of patients. Drug repurposing for anti-cancer treatments is gaining momentum, but the potential of such drugs as adjuncts, to increase tumour response to chemo-radiotherapy in rectal cancer, is only just beginning to be recognised. Methods: A systematic literature search was conducted and all studies investigating the use of drugs to enhance response to neo-adjuvant radiation in rectal cancer were included. 2137 studies were identified and following review 12 studies were extracted for full text review, 9 studies were included in the final analysis. Results: The use of statins or aspirin during neo-adjuvant therapy was associated with a significantly higher rate of tumour downstaging. Statins were identified as a significant predictor of pCR and aspirin users had a greater 5-year progression-free survival and overall survival. Metformin use was associated with a significantly higher overall and disease-free survival, in a subset of diabetic patients. Conclusions: Aspirin, metformin and statins are associated with increased downstaging of rectal tumours and thus may have a role as adjuncts to neoadjuvant treatment, highlighting a clear need for prospective randomised controlled trials to determine their true impact on tumour response and overall survival.

The invention of optical tweezers almost forty years ago has triggered applications spanning multiple disciplines and has also found its way into commercial products. A major breakthrough came with the invention of holographic optical tweezers (HOTs), allowing simultaneous manipulation of many particles, traditionally done with arrays of scalar beams. Here we demonstrate a vector HOT with arrays of digitally controlled Higher-Order Poincaré Sphere (HOPS) beams. We employ a simple set-up using a spatial light modulator and show that each beam in the array can be manipulated independently and set to an arbitrary HOPS state, including replicating traditional scalar beam HOTs. We demonstrate trapping and tweezing with customized arrays of HOPS beams comprising scalar orbital angular momentum and cylindrical vector beams, including radially and azimuthally polarized beams simultaneously in the same trap. Our approach is general enough to be easily extended to arbitrary vector beams, could be implemented with fast refresh rates and will be of interest to the structured light and optical manipulation communities alike.

Adult neural stem cells (NSCs) must tightly regulate quiescence and proliferation. Single-cell analysis has suggested a continuum of cell states as NSCs exit quiescence. Here we capture and characterize in vitro primed quiescent NSCs and identify LRIG1 as an important regulator. We show that BMP-4 signaling induces a dormant non-cycling quiescent state (d-qNSCs), whereas combined BMP-4/FGF-2 signaling induces a distinct primed quiescent state poised for cell cycle re-entry. Primed quiescent NSCs (p-qNSCs) are defined by high levels of LRIG1 and CD9, as well as an interferon response signature, and can efficiently engraft into the adult subventricular zone (SVZ) niche. Genetic disruption of Lrig1 in vivo within the SVZ NSCs leads an enhanced proliferation. Mechanistically, LRIG1 primes quiescent NSCs for cell cycle re-entry and EGFR responsiveness by enabling EGFR protein levels to increase but limiting signaling activation. LRIG1 is therefore an important functional regulator of NSC exit from quiescence. How neural stem cells can transition between states of proliferation and quiescence is unclear. Here, the authors identify Lrig1 as a specific marker for the primed quiescent state and demonstrate that Lrig1 maintains cells in a quiescent state via modulation of the EGFR pathway.

In this published article, members of ‘The Tourette Association of America Neuroimaging Consortium’ were not cited in PubMed. These consortium members are listed in the associated correction.

Bax inhibitor 1 (BI-1) was originally discovered as an inhibitor of Bax-induced apoptosis; this review highlights the fundamental importance of BI-1 in a wider context, including in tissue homeostasis and as a regulator of cellular stress. BI-1 has been shown to interact with a broad range of partners to inhibit many facets of apoptosis, such as reactive oxygen species production, cytosolic acidification and calcium levels as well as endoplasmic reticulum stress signalling pathways. BI-1's anti-apoptotic action initially enables the cell to adapt to stress, although if the stress is prolonged or severe the actions of BI-1 may promote apoptosis. This almost universal anti-apoptotic capacity has been shown to be manipulated during infection with enteropathogenic and enterohaemorrhagic Escherichia coli inhibiting host cell death through direct interaction between their effector NleH and BI-1. In addition, BI-1 activity is important in a large number of cancers, promoting metastasis by modulating actin dynamics, a process dependent upon the BI-1 C-terminus and BI-1:actin interaction. Manipulation of BI-1 therefore has the potential for significant therapeutic benefit in a wide range of human diseases.