Cell-cell communication enhances the capacity of cell ensembles to sense shallow gradients during morphogenesis

Collective cell responses to exogenous cues depend on cell-cell interactions. In principle, these can result in enhanced sensitivity to weak and noisy stimuli. However, this has not yet been shown experimentally, and, little is known about how multicellular signal processing modulates single cell sensitivity to extracellular signaling inputs, including those guiding complex changes in the tissue form and function. Here we explored if cell-cell communication can enhance the ability of cell ensembles to sense and respond to weak gradients of chemotactic cues. Using a combination of experiments with mammary epithelial cells and mathematical modeling, we find that multicellular sensing enables detection of and response to shallow Epidermal Growth Factor (EGF) gradients that are undetectable by single cells. However, the advantage of this type of gradient sensing is limited by the noisiness of the signaling relay, necessary to integrate spatially distributed ligand concentration information. We calculate the fundamental sensory limits imposed by this communication noise and combine them with the experimental data to estimate the effective size of multicellular sensory groups involved in gradient sensing. Functional experiments strongly implicated intercellular communication through gap junctions and calcium release from intracellular stores as mediators of collective gradient sensing. The resulting integrative analysis provides a framework for understanding the advantages and limitations of sensory information processing by relays of chemically coupled cells.Comment: paper + supporting information, total 35 pages, 15 figure

Limits on Enhanced Radio Wave Scattering by Supernova Remnants

We report multifrequency observations with the NRAO Very Long Baseline Array (VLBA) of the compact radio sources J0128+6306 and J0547+2721, which are viewed through the supernova remnants G127.1+0.5 and S147, respectively. Observations were made at frequencies of 1.427, 1.667, 2.271, and 4.987 GHz. The lines of sight to these sources pass through the shock wave and upstream and downstream turbulent layers of their respective supernova remnants, and thus might detect cosmic-ray generated turbulence produced during the Fermi acceleration process. For both sources, we detect interstellar scattering, characterized by a component of the angular size which scales as the square of the observing wavelength. The magnitude of the scattering is characterized by an effective scattering angular size theta_S0 at a frequency of 1 GHz of 13.2 +/- 2.6 milliarcseconds (mas) for J0128+6306 and 6.7 +/- 2.2 mas for J0547+2721. These angular sizes are consistent with the ``incidental'' scattering for any line of sight out of the galaxy at similar galactic latitudes and longitudes. There is therefore no evidence for enhanced turbulence at these supernova remnants. We establish upper limits to the supernova remnant-associated scattering measures of 8.1-14.8 m^-20/3-pc for J0128+6306 and 3.0 m^-20/3-pc for J0547+2721.Comment: To be published in ApJ, 25 pages, 4 figures, 2 table

The Chandra Multi-Wavelength Project: Optical Spectroscopy and the Broadband Spectral Energy Distributions of X-ray Selected AGN

From optical spectroscopy of X-ray sources observed as part of ChaMP, we present redshifts and classifications for a total of 1569 Chandra sources from our targeted spectroscopic follow up using the FLWO, SAAO, WIYN, CTIO, KPNO, Magellan, MMT and Gemini telescopes, and from archival SDSS spectroscopy. We classify the optical counterparts as 50% BLAGN, 16% NELG, 14% ALG, and 20% stars. We detect QSOs out to z~5.5 and galaxies out to z~3. We have compiled extensive photometry from X-ray to radio bands. Together with our spectroscopic information, this enables us to derive detailed SEDs for our extragalactic sources. We fit a variety of templates to determine bolometric luminosities, and to constrain AGN and starburst components where both are present. While ~58% of X-ray Seyferts require a starburst event to fit observed photometry only 26% of the X-ray QSO population appear to have some kind of star formation contribution. This is significantly lower than for the Seyferts, especially if we take into account torus contamination at z>1 where the majority of our X-ray QSOs lie. In addition, we observe a rapid drop of the percentage of starburst contribution as X-ray luminosity increases. This is consistent with the quenching of star formation by powerful QSOs, as predicted by the merger model, or with a time lag between the peak of star formation and QSO activity. We have tested the hypothesis that there should be a strong connection between X-ray obscuration and star-formation but we do not find any association between X-ray column density and star formation rate both in the general population or the star-forming X-ray Seyferts. Our large compilation also allows us to report here the identification of 81 XBONG, 78 z>3 X-ray sources and 8 Type-2 QSO candidates. Also we have identified the highest redshift (z=5.4135) X-ray selected QSO with optical spectroscopy.Comment: 17 pages, 16 figures, accepted for publication in ApJS. Full data table and README file can be found online at http://hea-www.harvard.edu/~pgreen/Papers.htm

Genetically Diverse Coronaviruses in Wild Bird Populations of Northern England

Infectious bronchitis virus (IBV) causes a costly respiratory viral disease of chickens. The role of wild birds in the epidemiology of IBV is poorly understood. We detected diverse coronaviruses by PCR in wildfowl and wading birds in England. Sequence analysis showed some viruses to be related to IBV

Role of community engagement in maternal health in rural Pakistan: Findings from the CLIP randomized trial

Background: Community-based strategies to promote maternal health can help raise awareness of pregnancy danger signs and preparations for emergencies. The objective of this study was to assess change in birth preparedness and complication readiness (BPCR) and pregnant women\u27s knowledge about pre-eclampsia as part of community engagement (CE) activities in rural Pakistan during the Community Level Interventions for Pre-eclampsia (CLIP) Trial.Methods: The CLIP Trial was a cluster randomized controlled trial that aimed to reduce maternal and perinatal morbidity and mortality using CE strategies alongside mobile health-supported care by community health care providers. CE activities engaged pregnant women at their homes and male stakeholders through village meetings in Hyderabad and Matiari in Sindh, Pakistan. These sessions covered pregnancy complications, particularly pre-eclampsia/eclampsia, BPCR and details of the CLIP intervention package. BPCR was assessed using questions related to transport arrangement, permission for care, emergency funds, and choice of facility birth attendant for delivery during quarterly household surveys. Outcomes were assessed via multilevel logistic regression with adjustment for relevant confounders with effects summarized as odds ratios and 95% confidence intervals.Results: There were 15 137 home-based CE sessions with pregnant women and families (n = 46 614) and 695 village meetings with male stakeholders (n = 7784) over two years. The composite outcomes for BPCR and pre-eclampsia knowledge did not differ significantly between trial arms. However, CE activities were associated with improved pre-eclampsia knowledge in some areas. Specifically, pregnant women in the intervention clusters were twice as likely to know that seizures could be a complication of pregnancy (odds ratio (OR) = 2.17, 95% confidence interval (CI) = 1.11, 4.23) and 2.5 times more likely to know that high blood pressure is potentially life-threatening during pregnancy (OR = 2.52, 95% CI = 1.31, 4.83) vs control clusters.Conclusions: The findings suggested that a CE strategy for male and female community stakeholders increased some measures of knowledge regarding complications of pre-eclampsia in low-resource settings. However, the effect of this intervention on long-term health outcomes needs further study.Trial registration: Clinical Trials.gov - INCT01911494

Calcium for pre-eclampsia prevention: A systematic review and network meta-analysis to guide personalised antenatal care

Background: Calcium supplementation reduces the risk of pre-eclampsia, but questions remain about the dosage to prescribe and who would benefit most. Objectives: To evaluate the effectiveness of high (≥1 g/day) and low (<1 g/day) calcium dosing for pre-eclampsia prevention, according to baseline dietary calcium, pre-eclampsia risk and co-interventions, and intervention timing. Search strategy: CENTRAL, PubMed, Global Index Medicus and CINAHL, from inception to 2 February 2021, clinical trial registries, reference lists and expert input (CRD42018111239). Selection criteria: Randomised controlled trials of calcium supplementation for pre-eclampsia prevention, for women before or during pregnancy. Network meta-analysis (NMA) also included trials of different calcium doses. Data collection and analysis: Two independent reviewers extracted published data. The meta-analysis employed random-effects models and the NMA, a Bayesian random-effects model, to obtain direct and indirect effect estimates. Main results: The meta-analysis included 30 trials (N = 20 445 women), and the NMA to evaluate calcium dosage included 25 trials (N = 15 038). Calcium supplementation prevented pre-eclampsia similarly with a high dose (RR 0.49, 95% CI 0.36–0.66) or a low dose (RR 0.49, 95% CI 0.36–0.65). By NMA, high-dose (vs low-dose) calcium did not differ in effect (RR 0.79, 95% CI 0.43–1.40). Calcium was similarly effective regardless of baseline pre-eclampsia risk, vitamin D co-administration or timing of calcium initiation, but calcium was ineffective among women with adequate average baseline calcium intake. Conclusions: Low- and high-dose calcium supplementation are effective for pre-eclampsia prevention in women with low calcium intake. This has implications for population-level implementation where dietary calcium is low, and targeted implementation where average intake is adequate. Tweetable abstract: A network meta-analysis of 25 trials found that low-dose calcium supplementation (<1 g/day) is as effective as high-dose calcium supplementation (≥1 g/day) in halving the risk of pre-eclampsia when baseline calcium intake is low.Fil: Woo Kinshella, Mai-Lei. University of British Columbia; CanadáFil: Sarr, Catherine. Kings College London (kcl);Fil: Sandhu, Akshdeep. University of British Columbia; CanadáFil: Bone, Jeffrey N.. University of British Columbia; CanadáFil: Vidler, Marianne. University of British Columbia; CanadáFil: Moore, Sophie E.. Kings College London (kcl);Fil: Elango, Rajavel. University of British Columbia; CanadáFil: Cormick, Gabriela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones en Epidemiología y Salud Pública. Instituto de Efectividad Clínica y Sanitaria. Centro de Investigaciones en Epidemiología y Salud Pública; ArgentinaFil: Belizan, Jose. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones en Epidemiología y Salud Pública. Instituto de Efectividad Clínica y Sanitaria. Centro de Investigaciones en Epidemiología y Salud Pública; ArgentinaFil: Hofmeyr, G. Justus. University of the Witwatersrand; Sudáfrica. University of Walter Sisulu; Sudáfrica. University of Fort Hare; Sudáfrica. University of Botswana; BotsuanaFil: Magee, Laura A.. University of British Columbia; Canadá. Kings College London (kcl);Fil: von Dadelszen, Peter. University of British Columbia; Canadá. Kings College London (kcl)

Supermassive Black Holes in Galactic Nuclei: Past, Present and Future Research

This review discusses the current status of supermassive black hole research, as seen from a purely observational standpoint. Since the early '90s, rapid technological advances, most notably the launch of the Hubble Space Telescope, the commissioning of the VLBA and improvements in near-infrared speckle imaging techniques, have not only given us incontrovertible proof of the existence of supermassive black holes, but have unveiled fundamental connections between the mass of the central singularity and the global properties of the host galaxy. It is thanks to these observations that we are now, for the first time, in a position to understand the origin, evolution and cosmic relevance of these fascinating objects.Comment: Invited Review, 114 pages. Because of space requirements, this version contains low resolution figures. The full resolution version can be downloaded from http://www.physics.rutgers.edu/~lff/publications.htm

Vitamin D supplementation and breast cancer prevention : a systematic review and meta-analysis of randomized clinical trials

In recent years, the scientific evidence linking vitamin D status or supplementation to breast cancer has grown notably. To investigate the role of vitamin D supplementation on breast cancer incidence, we conducted a systematic review and meta-analysis of randomized controlled trials comparing vitamin D with placebo or no treatment. We used OVID to search MEDLINE (R), EMBASE and CENTRAL until April 2012. We screened the reference lists of included studies and used the “Related Article” feature in PubMed to identify additional articles. No language restrictions were applied. Two reviewers independently extracted data on methodological quality, participants, intervention, comparison and outcomes. Risk Ratios and 95% Confident Intervals for breast cancer were pooled using a random-effects model. Heterogeneity was assessed using the I2 test. In sensitivity analysis, we assessed the impact of vitamin D dosage and mode of administration on treatment effects. Only two randomized controlled trials fulfilled the pre-set inclusion criteria. The pooled analysis included 5372 postmenopausal women. Overall, Risk Ratios and 95% Confident Intervals were 1.11 and 0.74–1.68. We found no evidence of heterogeneity. Neither vitamin D dosage nor mode of administration significantly affected breast cancer risk. However, treatment efficacy was somewhat greater when vitamin D was administered at the highest dosage and in combination with calcium (Risk Ratio 0.58, 95% Confident Interval 0.23–1.47 and Risk Ratio 0.93, 95% Confident Interval 0.54–1.60, respectively). In conclusions, vitamin D use seems not to be associated with a reduced risk of breast cancer development in postmenopausal women. However, the available evidence is still limited and inadequate to draw firm conclusions. Study protocol code: FARM8L2B5L

Maternal nutritional risk factors for pre-eclampsia incidence: findings from a narrative scoping review

BACKGROUND: Pre-eclampsia is a leading cause of maternal mortality and morbidity that involves pregnancy-related stressors on the maternal cardiovascular and metabolic systems. As nutrition is important to support optimal development of the placenta and for the developing fetus, maternal diets may play a role in preventing pre-eclampsia. The purpose of this scoping review is to map the maternal nutritional deficiencies and imbalances associated with pre-eclampsia incidence and discuss evidence consistency and linkages with current understandings of the etiology of pre-eclampsia. METHODS: A narrative scoping review was conducted to provide a descriptive account of available research, summarize research findings and identify gaps in the evidence base. Relevant observational studies and reviews of observational studies were identified in an iterative two-stage process first involving electronic database searches then more sensitive searches as familiarity with the literature increased. Results were considered in terms of their consistency of evidence, effect sizes and biological plausibility. RESULTS: The review found evidence for associations between nutritional inadequacies and a greater risk of pre-eclampsia. These associations were most likely mediated through oxidative stress, inflammation, maternal endothelial dysfunction and blood pressure in the pathophysiology of pre-eclampsia. Maternal nutritional risk factors for pre-eclampsia incidence with the strongest consistency, effect and biological plausibility include vitamin C and its potential relationship with iron status, vitamin D (both on its own and combined with calcium and magnesium), and healthy dietary patterns featuring high consumption of fruits, vegetables, whole grains, fish, seafood and monounsaturated vegetable oils. Foods high in added sugar, such as sugary drinks, were associated with increased risk of pre-eclampsia incidence. CONCLUSION: A growing body of literature highlights the involvement of maternal dietary factors in the development of pre-eclampsia. Our review findings support the need for further investigation into potential interactions between dietary factors and consideration of nutritional homeostasis and healthy dietary patterns. Further research is recommended to explore gestational age, potential non-linear relationships, dietary diversity and social, cultural contexts of food and meals

Pain and the risk for falls in community-dwelling older adults: systematic review and meta-analysis

Objective: To conduct a systematic review and meta-analysis to establish the association between pain and falls in community dwelling older adults. Data Sources: Electronic databases from inception until 1st March 2013 including Cochrane Library, CINAHL, EBSCO, EMBASE, PubMed and PsycINFO. Study Selection: Two reviewers independently conducted the searches and completed methodological assessment of all included studies. Studies were included that (a) focussed on older adults over 60 years old, (b) recorded falls over 6 or more months, (c) identified a group with and without pain. Studies were excluded that (d) included participants with dementia, a neurological condition (e.g. stroke), (e) participants whose pain was caused by a previous fall, (f) individuals with surgery/ fractures in the past 6 months. Data extraction: One author extracted all data and this was independently validated by another author. Data synthesis: 1,334 articles were screened and 21 studies met the eligibility criteria. 50.5% of older adults with pain reported one or more fall over 12 months compared to 25.7% of controls (p<0.001). A global meta-analysis with 14 studies (n=17,926) demonstrated that pain was associated with an increased odds of falling (OR: 1.56, 95% Confidence Interval (CI): 1.36 to 1.79, I2=53%). A subgroup meta-analysis incorporating studies that monitored falls prospectively established that the odds of falling was significantly higher in those with pain (n=4,674; OR: 1.71, CI: 1.48 to 1.98, I2=0%). Foot pain was strongly associated with falls (n=691; OR: 2.38, CI: 1.62 to 3.48, I2=8%) as was chronic pain (n= 5,367; OR 1.80, CI: 1.56 to 2.09, I2=0%). Conclusion: Community dwelling older adults with pain were more likely to have fallen in the past 12 months and fall again in the future. Foot and chronic pain were particularly strong risk factors for falls and clinicians should routinely enquire about these when completing falls risk assessments