Local Resting Ca2+ Controls the Scale of Astroglial Ca2+ Signals

Astroglia regulate neurovascular coupling while engaging in signal exchange with neurons. The underlying cellular machinery is thought to rely on astrocytic Ca2+ signals, but what controls their amplitude and waveform is poorly understood. Here, we employ time-resolved two-photon excitation fluorescence imaging in acute hippocampal slices and in cortex in vivo to find that resting [Ca2+] predicts the scale (amplitude) and the maximum (peak) of astroglial Ca2+ elevations. We bidirectionally manipulate resting [Ca2+] by uncaging intracellular Ca2+ or Ca2+ buffers and use ratiometric imaging of a genetically encoded Ca2+ indicator to establish that alterations in resting [Ca2+] change co-directionally the peak level and anti-directionally the amplitude of local Ca2+ transients. This relationship holds for spontaneous and for induced (for instance by locomotion) Ca2+ signals. Our findings uncover a basic generic rule of Ca2+ signal formation in astrocytes, thus also associating the resting Ca2+ level with the physiological “excitability” state of astroglia

Coupling models of cattle and farms with models of badgers for predicting the dynamics of bovine tuberculosis (TB)

Bovine TB is a major problem for the agricultural industry in several countries. TB can be contracted and spread by species other than cattle and this can cause a problem for disease control. In the UK and Ireland, badgers are a recognised reservoir of infection and there has been substantial discussion about potential control strategies. We present a coupling of individual based models of bovine TB in badgers and cattle, which aims to capture the key details of the natural history of the disease and of both species at approximately county scale. The model is spatially explicit it follows a very large number of cattle and badgers on a different grid size for each species and includes also winter housing. We show that the model can replicate the reported dynamics of both cattle and badger populations as well as the increasing prevalence of the disease in cattle. Parameter space used as input in simulations was swept out using Latin hypercube sampling and sensitivity analysis to model outputs was conducted using mixed effect models. By exploring a large and computationally intensive parameter space we show that of the available control strategies it is the frequency of TB testing and whether or not winter housing is practised that have the most significant effects on the number of infected cattle, with the effect of winter housing becoming stronger as farm size increases. Whether badgers were culled or not explained about 5%, while the accuracy of the test employed to detect infected cattle explained less than 3% of the variance in the number of infected cattle

Superficial simplicity of the 2010 El Mayor–Cucapah earthquake of Baja California in Mexico

The geometry of faults is usually thought to be more complicated at the surface than at depth and to control the initiation, propagation and arrest of seismic ruptures. The fault system that runs from southern California into Mexico is a simple strike-slip boundary: the west side of California and Mexico moves northwards with respect to the east. However, the M_w 7.2 2010 El Mayor–Cucapah earthquake on this fault system produced a pattern of seismic waves that indicates a far more complex source than slip on a planar strike-slip fault. Here we use geodetic, remote-sensing and seismological data to reconstruct the fault geometry and history of slip during this earthquake. We find that the earthquake produced a straight 120-km-long fault trace that cut through the Cucapah mountain range and across the Colorado River delta. However, at depth, the fault is made up of two different segments connected by a small extensional fault. Both segments strike N130° E, but dip in opposite directions. The earthquake was initiated on the connecting extensional fault and 15 s later ruptured the two main segments with dominantly strike-slip motion. We show that complexities in the fault geometry at depth explain well the complex pattern of radiated seismic waves. We conclude that the location and detailed characteristics of the earthquake could not have been anticipated on the basis of observations of surface geology alone

Improving response rates using a monetary incentive for patient completion of questionnaires: an observational study

Background: Poor response rates to postal questionnaires can introduce bias and reduce the statistical power of a study. To improve response rates in our trial in primary care we tested the effect of introducing an unconditional direct payment of 5 pound for the completion of postal questionnaires. Methods: We recruited patients in general practice with knee problems from sites across the United Kingdom. An evidence-based strategy was used to follow-up patients at twelve months with postal questionnaires. This included an unconditional direct payment of 5 pound to patients for the completion and return of questionnaires. The first 105 patients did not receive the 5 pound incentive, but the subsequent 442 patients did. We used logistic regression to analyse the effect of introducing a monetary incentive to increase the response to postal questionnaires. Results: The response rate following reminders for the historical controls was 78.1% ( 82 of 105) compared with 88.0% ( 389 of 442) for those patients who received the 5 pound payment (diff = 9.9%, 95% CI 2.3% to 19.1%). Direct payments significantly increased the odds of response ( adjusted odds ratio = 2.2, 95% CI 1.2 to 4.0, P = 0.009) with only 12 of 442 patients declining the payment. The incentive did not save costs to the trial - the extra cost per additional respondent was almost 50 pound. Conclusion: The direct payment of 5 pound significantly increased the completion of postal questionnaires at negligible increase in cost for an adequately powered study

Women’s experiences of receiving care for pelvic organ prolapse: a qualitative study

Background Pelvic organ prolapse is a common urogenital condition affecting 41–50% of women over the age of 40. To achieve early diagnosis and appropriate treatment, it is important that care is sensitive to and meets women’s needs, throughout their patient journey. This study explored women’s experiences of seeking diagnosis and treatment for prolapse and their needs and priorities for improving person-centred care. Methods Twenty-two women receiving prolapse care through urogynaecology services across three purposefully selected NHS UK sites took part in three focus groups and four telephone interviews. A topic guide facilitated discussions about women’s experiences of prolapse, diagnosis, treatment, follow-up, interactions with healthcare professionals, overall service delivery, and ideals for future services to meet their needs. Data were analysed thematically. Results Three themes emerged relating to women’s experiences of a) Evaluating what is normal b) Hobson’s choice of treatment decisions, and c) The trial and error of treatment and technique. Women often delayed seeking help for their symptoms due to lack of awareness, embarrassment and stigma. When presented to GPs, their symptoms were often dismissed and unaddressed until they became more severe. Women reported receiving little or no choice in treatment decisions. Choices were often influenced by health professionals’ preferences which were subtly reflected through the framing of the offer. Women’s embodied knowledge of their condition and treatment was largely unheeded, resulting in decisions that were inconsistent with women’s preferences and needs. Physiotherapy based interventions were reported as helping women regain control over their symptoms and life. A need for greater awareness of prolapse and physiotherapy interventions among women, GPs and consultants was identified alongside greater focus on prevention, early diagnosis and regular follow-up. Greater choice and involvement in treatment decision making was desired. Conclusions As prolapse treatment options expand to include more conservative choices, greater awareness and education is needed among women and professionals about these as a first line treatment and preventive measure, alongside a multi-professional team approach to treatment decision making. Women presenting with prolapse symptoms need to be listened to by the health care team, offered better information about treatment choices, and supported to make a decision that is right for them

Use of Site-Specifically Tethered Chemical Nucleases to Study Macromolecular Reactions

During a complex macromolecular reaction multiple changes in molecular conformation and interactions with ligands may occur. X-ray crystallography may provide only a limited set of snapshots of these changes. Solution methods can augment such structural information to provide a more complete picture of a macromolecular reaction. We analyzed the changes in protein conformation and protein:nucleic acid interactions which occur during transcription initiation by using a chemical nuclease tethered to cysteines introduced site-specifically into the RNA polymerase of bacteriophage T7 (T7 RNAP). Changes in cleavage patterns as the polymerase steps through transcription reveal a series of structural transitions which mediate transcription initiation. Cleavage by tethered chemical nucleases is seen to be a powerful method for revealing the conformational dynamics of macromolecular reactions, and has certain advantages over cross-linking or energy transfer approaches

A proposed potential role for increasing atmospheric CO2 as a promoter of weight gain and obesity

Human obesity has evolved into a global epidemic. Interestingly, a similar trend has been observed in many animal species, although diet composition, food availability and physical activity have essentially remained unchanged. This suggests a common factor—potentially an environmental factor affecting all species. Coinciding with the increase in obesity, atmospheric CO2 concentration has increased more than 40%. Furthermore, in modern societies, we spend more time indoors, where CO2 often reaches even higher concentrations. Increased CO2 concentration in inhaled air decreases the pH of blood, which in turn spills over to cerebrospinal fluids. Nerve cells in the hypothalamus that regulate appetite and wakefulness have been shown to be extremely sensitive to pH, doubling their activity if pH decreases by 0.1 units. We hypothesize that an increased acidic load from atmospheric CO2 may potentially lead to increased appetite and energy intake, and decreased energy expenditure, and thereby contribute to the current obesity epidemic

Symbolic Computation via Program Transformation

Symbolic computation is an important approach in automated program analysis. Most state-of-the-art tools perform symbolic computation as interpreters and directly maintain symbolic data. In this paper, we show that it is feasible, and in fact practical, to use a compiler-based strategy instead. Using compiler tooling, we propose and implement a transformation which takes a standard program and outputs a program that performs semantically equivalent, but partially symbolic, computation. The transformed program maintains symbolic values internally and operates directly on them hence the program can be processed by a tool without support for symbolic manipulation. The main motivation for the transformation is in symbolic verification, but there are many other possible use-cases, including test generation and concolic testing. Moreover using the transformation simplifies tools, since the symbolic computation is handled by the program directly. We have implemented the transformation at the level of LLVM bitcode. The paper includes an experimental evaluation, based on an explicit-state software model checker as a verification backend

Cytologic features of nipple aspirate fluid using an automated non-invasive collection device: a prospective observational study

BACKGROUND: Detection of cytologic atypia in nipple aspirate fluid (NAF) has been shown to be a predictor of risk for development of breast carcinoma. Manual collection of NAF for cytologic evaluation varies widely in terms of efficacy, ease of use, and patient acceptance. We investigated a new automated device for the non-invasive collection of NAF in the office setting. METHODS: A multi-center prospective observational clinical trial involving asymptomatic women designed to assess fluid production, adequacy, safety and patient acceptance of the HALO NAF Collection System (NeoMatrix, Irvine, CA). Cytologic evaluation of all NAF samples was performed using previously described classification categories. RESULTS: 500 healthy women were successfully enrolled. Thirty-eight percent (190/500) produced fluid and 187 were available for cytologic analysis. Cytologic classification of fluid producers showed 50% (93/187) Category 0 (insufficient cellular material), 38% (71/187) Category I (benign non-hyperplastic ductal epithelial cells), 10% (18/187) Category II (benign hyperplastic ductal epithelial cells), 3% (5/187) Category III (atypical ductal epithelial cells) and none were Category IV (unequivocal malignancy). Overall, 19% of the subjects produced NAF with adequate cellularity and 1% were found to have cytologic atypia. CONCLUSION: The HALO system is a simple, safe, rapid, automated method for standardized collection of NAF which is acceptable to patients. Cytologic assessment of HALO-collected NAF showed the ability to detect benign and pre-neoplastic ductal epithelial cells from asymptomatic volunteers