Loss of survivin in intestinal epithelial progenitor cells leads to mitotic catastrophe and breakdown of gut immune homeostasis

A tightly regulated balance of proliferation and cell death of intestinal epithelial cells (IECs) is essential for maintenance of gut homeostasis. Survivin is highly expressed during embryogenesis and in several cancer types, but little is known about its role in adult gut tissue. Here, we show that Survivin is specifically expressed in transit-amplifying cells and Lgr5(+) stem cells. Genetic loss of Survivin in IECs resulted in destruction of intestinal integrity, mucosal inflammation, and death of the animals. Survivin deletion was associated with decreased epithelial proliferation due to defective chromosomal segregation. Moreover, Survivin-deficient animals showed induced phosphorylation of p53 and H2AX and increased levels of cell-intrinsic apoptosis in IECs. Consequently, induced deletion of Survivin in Lgr5(+) stem cells led to cell death. In summary, Survivin is a key regulator of gut tissue integrity by regulating epithelial homeostasis in the stem cell niche

Timing and nature of AMOC recovery across Termination 2 and magnitude of deglacial CO2 change

Large amplitude variations in atmospheric CO 2 were associated with glacial terminations of the Late Pleistocene. Here we provide multiple lines of evidence suggesting that the B 20 p.p.m.v. overshoot in CO 2 at the end of Termination 2 (T2) B 129 ka was associated with an abrupt ( r 400 year) deepening of Atlantic Meridional Overturning Circulation (AMOC). In contrast to Termination 1 (T1), which was interrupted by the Bølling-Allerød (B-A), AMOC recovery did not occur until the very end of T2, and was characterized by pronounced formation of deep waters in the NW Atlantic. Considering the variable influences of ocean circulation change on atmospheric CO 2 , we suggest that the net change in CO 2 across the last 2 terminations was approximately equal if the transient effects of deglacial oscillations in ocean circulation are taken into account

Associations between sole ulcer, white line disease and digital dermatitis and the milk yield of 1824 dairy cows on 30 dairy cow farms in England and Wales from February 2003–November 2004

The milk yields of 1824 cows were used to investigate the effect of lesion-specific causes of lameness, based on farmer treatment and diagnosis of lame cows, on milk yield. A three level hierarchical model of repeated test day yields within cows within herds was used to investigate the impact of lesion-specific causes of lameness (sole ulcer, white line disease, digital dermatitis and other causes) on milk yield before and after treatment compared with unaffected cows. Cattle which developed sole ulcer (SU) and white line disease (WLD) were higher yielding cattle before they were diagnosed. Their milk production fell to below that of the mean of unaffected cows before diagnosis and remained low after diagnosis. In cattle which developed digital dermatitis (DD) there was no significant difference in milk yield before treatment and a slightly raised milk yield immediately after treatment. The estimated milk loss attributable to SU and WLD was approximately 570kg and 370kg respectively. These results highlight that specific types of lameness vary by herds and within herds they are associated with higher yielding cattle. Consequently lesion-specific lameness reduction programmes targeting the cow and farm specific causes of lameness might be more effective than generic recommendations. They also highlight the importance of milk loss when estimating the economic impact of SU and WLD on the farms profitability

On the use of Ajisai and Jason-1 satellites for tests of General Relativity

Here we analyze in detail some aspects of the proposed use of Ajisai and Jason-1, together with the LAGEOS satellites, to measure the general relativistic Lense-Thirring effect in the gravitational field of the Earth. A linear combination of the nodes of such satellites is the proposed observable. The systematic error due to the mismodelling in the uncancelled even zonal harmonics would be \sim 1% according to the latest present-day CHAMP/GRACE-based Earth gravity models. In regard to the non-gravitational perturbations especially affecting Jason-1, only relatively high-frequency harmonic perturbations should occur: neither semisecular nor secular bias of non-gravitational origin should affect the proposed combination: their maximum impact is evaluated to \sim 4% over 2 years. Our estimation of the root-sum-square total error is about 4-5% over at least 3 years of data analysis required to average out the uncancelled tidal perturbations.Comment: Latex, 24 pages, 5 tables, 1 figure. Two references added, minor modifications. To appear in New Astronom

Absence of association between behavior problems in childhood and hypertension in midlife

Background It is known that behavior in childhood is associated with certain physical and mental health problems in midlife. However, there is limited evidence on the role of childhood behavior problems in the development of hypertension in adulthood. The present study aimed to examine whether behavior problems in childhood influenced the risk of hypertension in midlife in the United Kingdom 1958 birth cohort. Methods The 1958 British birth cohort comprised 17,638 individuals born in the first week of March 1958 in the United Kingdom. Behavior problems were assessed at 7, 11, and 16 years of age by parents and teachers. At age 45, blood pressure was measured and hypertension was recorded if blood pressure was ≥140/90 mm Hg or if the participants were informed by their health professionals that they had high blood pressure. Behavioral information was reported according to the Rutter Children's Behaviour Questionnaire (RCBQ) and the Bristol Social Adjustment Guide (BSAG). Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to examine behavior problems in childhood in relation to hypertension at 45 years of age according to logistic regression analysis, with adjustment for sex, social class in childhood and adulthood, childhood cognition, birth weight, gestational age at birth, body mass index (BMI), smoking, alcohol consumption, and physical activity. Results Behavior problems reported by parents at 7, 11, and 16 years were not associated with hypertension in midlife (OR, 0.93; 95% CI, 0.81, 1.07; OR, 0.95; 95% CI, 0.81, 1.11; OR, 0.98; 95% CI, 0.85, 1.12, respectively). Similarly, teacher-reported behavior problems at 7, 11, and 16 years were not associated with hypertension in midlife (OR, 0.92; 95% CI, 0.72, 1.18; OR, 0.92; 95% CI, 0.84, 1.02; OR, 1.03; 95% CI, 0.92, 1.15, respectively). Further separate analyses showed similar results for males and females. Conclusion There is no association between behavior problems in childhood and hypertension in midlife

Carbon isotope signatures from land snail shells: Implications for palaeovegetation reconstruction in the eastern Mediterranean

In this studywecompare carbon isotope values inmodern Helix melanostoma shell carbonate (d13Cshell) from the Gebel al-Akhdar region of Libya with carbon isotope values in H. melanostomabody tissue (d13Cbody), local vegetation (d13Cplant) and soil (d13Csoil). All vegetation in the study area followed the C3 photosynthetic pathway. However, the d13Cplant values of different species formed two distinct isotopic groups. This can be best explained by different water use efficiencies with arid adapted species having significantly more positive d13Cplant values than less water efficient species. The ranges and means of d13Cbody and d13Cplant were statistically indistinguishable from one another suggesting that d13Cbody was primarily a function of local vegetation composition. H. melanostoma d13Cshell reflected the d13Cplant of local vegetation with a positive offset between body/diet and shell of 14.5± 1.4‰. Therefore, in the Gebel al-Akhdar where only C3 plants are present, highermeand13C shell values likely reflect greater abundances ofwater-efficientC3 plants in the snails diet and therefore in the landscape, whilst lower mean d13Cshell values likely reflect the consumption of less water-efficient C3 plants. The distribution of these plants is in turn affected by environmental factors such as rainfall. These findings can be applied to archaeological and geological shell deposits to reconstruct late Pleistocene to Holocene vegetation change in the southeast Mediterranean

Foundation of a computable solid modelling

Solid modelling and computational geometry are based on classical topology and geometry in which the basic predicates and operations, such as membership, subset inclusion, union and intersection, are not continuous and therefore not computable. But a sound computational framework for solids and geometry can only be built in a framework with computable predicates and operations. In practice, correctness of algorithms in computational geometry is usually proved using the unrealistic Real RAM machine model of computation, which allows comparison of real numbers, with the undesirable result that correct algorithms, when implemented, turn into unreliable programs. Here, we use a domaintheoretic approach to recursive analysis to develop the basis of an eective and realistic framework for solid modelling. This framework is equipped with a well-dened and realistic notion of computability which reects the observable properties of real solids. The basic predicates and operations o..

Mimivirus in Pneumonia Patients

Mimivirus, the largest virus known to date, is an amebal pathogen like Legionella spp. When mimivirus was used as an antigen in a migration inhibition factor assay, seroconversion was found in patients with both community- and hospital-acquired pneumonia. Mimivirus DNA was found in respiratory samples of patients with hospital-acquired pneumonia

Canonical Wnt signals combined with suppressed TGFβ/BMP pathways promote renewal of the native human colonic epithelium

Background: A defining characteristic of the human intestinal epithelium is that it is the most rapidly renewing tissue in the body. However, the processes underlying tissue renewal and the mechanisms that govern their coordination have proved difficult to study in the human gut. Objective: To investigate the regulation of stem cell-driven tissue renewal by canonical Wnt and TGFβ/bone morphogenetic protein (BMP) pathways in the native human colonic epithelium. Design: Intact human colonic crypts were isolated from mucosal tissue samples and placed into 3D culture conditions optimised for steady-state tissue renewal. High affinity mRNA in situ hybridisation and immunohistochemistry were complemented by functional genomic and bioimaging techniques. The effects of signalling pathway modulators on the status of intestinal stem cell biology, crypt cell proliferation, migration, differentiation and shedding were determined. Results: Native human colonic crypts exhibited distinct activation profiles for canonical Wnt, TGFβ and BMP pathways. A population of intestinal LGR5/OLFM4-positive stem/progenitor cells were interspersed between goblet-like cells within the crypt-base. Exogenous and crypt cell-autonomous canonical Wnt signals supported homeostatic intestinal stem/progenitor cell proliferation and were antagonised by TGFβ or BMP pathway activation. Reduced Wnt stimulation impeded crypt cell proliferation, but crypt cell migration and shedding from the crypt surface were unaffected and resulted in diminished crypts. Conclusions: Steady-state tissue renewal in the native human colonic epithelium is dependent on canonical Wnt signals combined with suppressed TGFβ/BMP pathways. Stem/progenitor cell proliferation is uncoupled from crypt cell migration and shedding, and is required to constantly replenish the crypt cell population