Causal Discovery Under a Confounder Blanket

Inferring causal relationships from observational data is rarely straightforward, but the problem is especially difficult in high dimensions. For these applications, causal discovery algorithms typically require parametric restrictions or extreme sparsity constraints. We relax these assumptions and focus on an important but more specialized problem, namely recovering the causal order among a subgraph of variables known to descend from some (possibly large) set of confounding covariates, i.e. a confounder blanket. This is useful in many settings, for example when studying a dynamic biomolecular subsystem with genetic data providing background information. Under a structural assumption called the confounder blanket principle, which we argue is essential for tractable causal discovery in high dimensions, our method accommodates graphs of low or high sparsity while maintaining polynomial time complexity. We present a structure learning algorithm that is provably sound and complete with respect to a so-called lazy oracle. We design inference procedures with finite sample error control for linear and nonlinear systems, and demonstrate our approach on a range of simulated and real-world datasets. An accompanying R package, cbl, is available from CRAN

Operationalizing Complex Causes: A Pragmatic View of Mediation

We examine the problem of causal response estimation for complex objects (e.g., text, images, genomics). In this setting, classical \emph{atomic} interventions are often not available (e.g., changes to characters, pixels, DNA base-pairs). Instead, we only have access to indirect or \emph{crude} interventions (e.g., enrolling in a writing program, modifying a scene, applying a gene therapy). In this work, we formalize this problem and provide an initial solution. Given a collection of candidate mediators, we propose (a) a two-step method for predicting the causal responses of crude interventions; and (b) a testing procedure to identify mediators of crude interventions. We demonstrate, on a range of simulated and real-world-inspired examples, that our approach allows us to efficiently estimate the effect of crude interventions with limited data from new treatment regimes

Oncogenic Gain of Function in Glioblastoma Is Linked to Mutant p53 Amyloid Oligomers.

Tumor-associated p53 mutations endow cells with malignant phenotypes, including chemoresistance. Amyloid-like oligomers of mutant p53 transform this tumor suppressor into an oncogene. However, the composition and distribution of mutant p53 oligomers are unknown and the mechanism involved in the conversion is sparse. Here, we report accumulation of a p53 mutant within amyloid-like p53 oligomers in glioblastoma-derived cells presenting a chemoresistant gain-of-function phenotype. Statistical analysis from fluorescence fluctuation spectroscopy, pressure-induced measurements, and thioflavin T kinetics demonstrates the distribution of oligomers larger than the active tetrameric form of p53 in the nuclei of living cells and the destabilization of native-drifted p53 species that become amyloid. Collectively, these results provide insights into the role of amyloid-like mutant p53 oligomers in the chemoresistance phenotype of malignant and invasive brain tumors and shed light on therapeutic options to avert cancer

SPECT System Design Optimisation for a Simultaneous SPECT/MRI Clinical Scanner

The aim of this project was to optimize the design of a Single Photon Emission Computed Tomography (SPECT) insert based on high-resolution detectors and a high-sensitivity collimator, for a Magnetic Resonance Imaging (MRI) scanner, in order to perform simultaneous human brain SPECT/MRI and improve radionuclide-based therapies for glioma patients. The radionuclides of interest are 99mTc, 111In and 123I. Specific emphasis was given to the collimator and overall system design, data simulation and performance assessment, which would feed directly into the European-funded INSERT project. The SPECT insert was to consist of a stationary system with SiPM-based photodetectors, insensitive to magnetic fields. Regarding the design, a number of system and collimator geometries were evaluated considering the restricted space in the MRI bore and the limited angular sampling. High sensitivity was prioritised over high spatial resolution, because of the clinical application. Gamma shielding design was also addressed. Analytical calculations of system sensitivity and resolution, in addition to Monte Carlo simulations, were performed to compare various slit-slat and pinhole collimator designs. A new collimator design was proposed: multi-mini-slit slit-slat (MSS) collimator. The MSS has multiple mini-slits, some of which are shared between adjacent detectors, and they are embedded in the slat component, allowing for longer slats in comparison to a standard slit-slat collimator. The MSS design demonstrated to have the best overall performance, and the final system design consisted of a partial ring with 20 detectors. A framework for geometrical calibration of the system was developed and assessed, utilising a single prototype detector equipped with a prototype collimator. This framework takes advantage of the specific collimator design to estimate geometrical parameters from independent measurements of calibration phantoms. Experimental evaluation with tomographic acquisition of phantoms demonstrated the applicability of the new collimation concept, confirming the superiority of the MSS design over equivalent pinhole collimation

Bearing My Heart: The Role of Extracellular Matrix on Cardiac Development, Homeostasis, and Injury Response

The extracellular matrix (ECM) is an essential component of the heart that imparts fundamental cellular processes during organ development and homeostasis. Most cardiovascular diseases involve severe remodeling of the ECM, culminating in the formation of fibrotic tissue that is deleterious to organ function. Treatment schemes effective at managing fibrosis and promoting physiological ECM repair are not yet in reach. Of note, the composition of the cardiac ECM changes significantly in a short period after birth, concurrent with the loss of the regenerative capacity of the heart. This highlights the importance of understanding ECM composition and function headed for the development of more efficient therapies. In this review, we explore the impact of ECM alterations, throughout heart ontogeny and disease, on cardiac cells and debate available approaches to deeper insights on cell–ECM interactions, toward the design of new regenerative therapies.This work was funded by the European Regional Development Fund (ERDF) through COMPETE 2020, Portugal 2020, and by the FCT (Fundação para a Ciência e Tecnologia) (POCI-01-0145-FEDER-030985) and by the FCT/Ministério da Ciência, Tecnologia e Inovação in the framework of individual funding (CEECINST/00091/2018) to DN

Human-animal relationships and interactions during the Covid-19 lockdown phase in the UK: Investigating links with mental health and loneliness

BACKGROUND: The Covid-19 pandemic raises questions about the role that relationships and interactions between humans and animals play in the context of widespread social distancing and isolation measures. We aimed to investigate links between mental health and loneliness, companion animal ownership, the human-animal bond, and human-animal interactions; and to explore animal owners' perceptions related to the role of their animals during lockdown. METHODS: A cross-sectional online survey of UK residents over 18 years of age was conducted between April and June 2020. The questionnaire included validated and bespoke items measuring demographics; exposures and outcomes related to mental health, wellbeing and loneliness; the human-animal bond and human-animal interactions. RESULTS: Of 5,926 participants, 5,323 (89.8%) had at least one companion animal. Most perceived their animals to be a source of considerable support, but concerns were reported related to various practical aspects of providing care during lockdown. Strength of the human-animal bond did not differ significantly between species. Poorer mental health pre-lockdown was associated with a stronger reported human-animal bond (b = -.014, 95% CI [-.023 - -.005], p = .002). Animal ownership compared with non-ownership was associated with smaller decreases in mental health (b = .267, 95% CI [.079 - .455], p = .005) and smaller increases in loneliness (b = -.302, 95% CI [-.461 - -.144], p = .001) since lockdown. CONCLUSION: The human-animal bond is a construct that may be linked to mental health vulnerability in animal owners. Strength of the human-animal bond in terms of emotional closeness or intimacy dimensions appears to be independent of animal species. Animal ownership seemed to mitigate some of the detrimental psychological effects of Covid-19 lockdown. Further targeted investigation of the role of human-animal relationships and interactions for human health, including testing of the social buffering hypothesis and the development of instruments suited for use across animal species, is required

Robust gap repair in the contractile ring ensures timely completion of cytokinesis.

Cytokinesis in animal cells requires the constriction of an actomyosin contractile ring, whose architecture and mechanism remain poorly understood. We use laser microsurgery to explore the biophysical properties of constricting rings in Caenorhabditis elegans embryos. Laser cutting causes rings to snap open. However, instead of disintegrating, ring topology recovers and constriction proceeds. In response to severing, a finite gap forms and is repaired by recruitment of new material in an actin polymerization-dependent manner. An open ring is able to constrict, and rings repair from successive cuts. After gap repair, an increase in constriction velocity allows cytokinesis to complete at the same time as controls. Our analysis demonstrates that tension in the ring increases while net cortical tension at the site of ingression decreases throughout constriction and suggests that cytokinesis is accomplished by contractile modules that assemble and contract autonomously, enabling local repair of the actomyosin network. Consequently, cytokinesis is a highly robust process impervious to discontinuities in contractile ring structure.This project has received funding from the European Research Council (grants 640553, 260892, and 338410), Fundo Europeu de Desenvolvimento Regional (FED ER) funds through the Operational Competitiveness Program (COM PETE), national funds through Fundação para a Ciência e a Tecnologia (FCT) under the project FCO MP-01-0124-FED ER-028255 (PTDC/BEX-BCM/0654/2012), Fundação Luso-Americana para o Desenvolvimento Life Science 2020, and the Louis-Jeantet Young Investigator Award to H. Maiato. A.X. Carvalho, R. Gassmann, and I.A. Telley have FCT Investigator positions funded by FCT and cofunded by the European Social Fund through Programa Operacional Temático Potencial Type 4.2 promotion of scientific employment. A.M. Silva holds an FCT fellowship (SFRH/BPD/95707/2013). D.S. Osório was cofunded by the Programa Operacional Regional do Norte under the Quadro de Downloaded from jcb.rupress.org on February 27, 2018 Laser microsurgery in the contractile ring • Silva et al. 799 Referência Estratégico Nacional through FED ER and by FCT grant NOR TE-07-0124-FED ER-000003 (Cell Homeostasis Tissue Organization and Organism Biology)

Establishing a link between endothelial cell metabolism and vascular behaviour in a type 1 diabetes mouse model

Background/Aims: Vascular complications contribute significantly to the extensive morbidity and mortality rates observed in people with diabetes. Despite well known that the diabetic kidney and heart exhibit imbalanced angiogenesis, the mechanisms implicated in this angiogenic paradox remain unknown. In this study, we examined the angiogenic and metabolic gene expression profile (GEP) of endothelial cells (ECs) isolated from a mouse model with type1 diabetes mellitus (T1DM). Methods: ECs were isolated from kidneys and hearts of healthy and streptozocin (STZ)-treated mice. RNA was then extracted for molecular studies. GEP of 84 angiogenic and 84 AMP-activated Protein Kinase (AMPK)-dependent genes were examined by microarrays. Real time PCR confirmed the changes observed in significantly altered genes. Microvessel density (MVD) was analysed by immunohistochemistry, fibrosis was assessed by the Sirius red histological staining and connective tissue growth factor (CTGF) was quantified by ELISA. Results: The relative percentage of ECs and MVD were increased in the kidneys of T1DM animals whereas the opposite trend was observed in the hearts of diabetic mice. Accordingly, the majority of AMPK-associated genes were upregulated in kidneys and downregulated in hearts of these animals. Angiogenic GEP revealed significant differences in Tgfß, Notch signaling and Timp2 in both diabetic organs. These findings were in agreement with the angiogenesis histological assays. Fibrosis was augmented in both organs in diabetic as compared to healthy animals. Conclusion: Altogether, our findings indicate, for the first time, that T1DM heart and kidney ECs present opposite metabolic cues, which are accompanied by distinct angiogenic patterns. These findings enable the development of innovative organ-specific therapeutic strategies targeting diabetic-associated vascular disorders.This work was supported by CAPES (Sciences without Borders - Full Doctorate Fellowship – Process 10010-13-0); FEDER funds by COMPETE: [POCI-01-0145-FEDER-007440, POCI-01-0145-FEDER-016385]; NORTE2020 [NORTE-01-0145FEDER-000012]; HealthyAging2020 [CENTRO-01-0145-FEDER-000012-N2323]; FCT - Fundação para a Ciência e a Tecnologia [UID/BIM/04293/2013, EXPL/BIM-MED/0492/2012, SFRH/BPD/88745/2012, SFRH/BD/111799/2015]; Claude Pepper Older Americans Independence Center; grant: P30 AG028718, NIGMS Award P20GM109096; European Structural and Investment Funds (ESIF). AUTHOR CONTRIBUTION: CS and RS participated in the design and conception of the study; CS performed the whole laboratory and statistical analyses and drafted the manuscript; VSP, PPO, DSN carried out the FACS assay design and data acquisition, as well as the interpretation of FACS data; SA advised and performed microarray and RT-PCR assays; IR headed the parafin embedded tissue and histologial staining; SG, EC were responsible for the animal studies and immunohistochemistry analyses; RC advised the methodological laboratorial analysis and animal studies; RS and EC critically revised the manuscript for important intellectual content. All authors were involved in drafting and revising the article. All authors read and approved the final version of the manuscript

Preliminary Limits on the WIMP-Nucleon Cross Section from the Cryogenic Dark Matter Search (CDMS)

We are conducting an experiment to search for WIMPs, or weakly-interacting massive particles, in the galactic halo using terrestrial detectors. This generic class of hypothetical particles, whose properties are similar to those predicted by extensions of the standard model of particle physics, could comprise the cold component of non-baryonic dark matter. We describe our experiment, which is based on cooled germanium and silicon detectors in a shielded low-background cryostat. The detectors achieve a high degree of background rejection through the simultaneous measurement of the energy in phonons and ionization. Using exposures on the order of one kilogram-day from initial runs of our experiment, we have achieved (preliminary) upper limits on the WIMP-nucleon cross section that are comparable to much longer runs of other experiments.Comment: 5 LaTex pages, 5 eps figs, epsf.sty, espcrc2dsa2.sty. Proceedings of TAUP97, Gran Sasso, Italy, 7-11 Sep 1997, Nucl. Phys. Suppl., A. Bottino, A. di Credico and P. Monacelli (eds.). See also http://cfpa.berkeley.ed

Intraprostatic Botulinum Toxin Type A injection in patients with benign prostatic enlargement: duration of the effect of a single treatment

<p>Abstract</p> <p>Background</p> <p>Botulinum Toxin Type-A (BoNT/A) intraprostatic injection can induce prostatic involution and improve LUTS and urinary flow in patients with Benign Prostatic Enlargement (BPE). However, the duration of these effects is unknown. The objective of this work was to determine the duration of prostate volume reduction after one single intraprostatic injection of 200U of Botulinum Toxin Type-A.</p> <p>Methods</p> <p>This is an extension of a 6 month study in which 21 frail elderly patients with refractory urinary retention and unfit for surgery were submitted to intraprostatic injection of BoNT/A-200U, by ultrasound guided transrectal approach. In spite of frail conditions, eleven patients could be followed during 18 months. Prostate volume, total serum PSA, maximal flow rate (Qmax), residual volume (PVR) and IPSS-QoL scores were determined at 1, 3, 6, 12 and 18 months post-treatment.</p> <p>Results</p> <p>Mean prostate volume at baseline, 82 ± 16 ml progressively decreased from month one coming to 49 ± 9,5 ml (p = 0,003) at month six. From this moment on, prostate volume slowly recovered, becoming identical to baseline at 18 months (73 ± 16 ml, p = 0.03). Albeit non significant, serum PSA showed a 25% decrease from baseline to month 6. The 11 patients resumed spontaneous voiding at month one. Mean Qmax was 11,3 ± 1,7 ml/sec and remained unchanged during the follow-up period. PVR ranged from 55 ± 17 to 82 ± 20 ml and IPSS score from10 to 12 points.</p> <p>Conclusion</p> <p>Intraprostatic BoNT/A injection is safe and can reduce prostate volume for a period of 18 months. During this time a marked symptomatic improvement can be maintained.</p