Left/right asymmetry in the early avian embryo

Left/right asymmetry was investigated during the development of the early avian embryo with particular reference to the normal asymmetry of the heart, which loops to the embryo's right-hand side. The structure of the pre-looped and post-looped heart was studied using light and electron microscopy. In the pre-looped heart, the right and left myocardial wall were of equal thickness. In the looping heart the right wall had thinned in comparison to the left. The direction of rotation in right and left looped hearts was examined using fluorescent carbocyanine dyes and viewed with a confocal microscope. The direction of rotation was found to be the same as the direction of looping. The situs of multiple embryos was studied by dividing the unincubated quail blastoderm in ovo. Singles, twins and triplet embryos were formed. Twins and triplets showed great variation in their orientation to each other. The majority of embryos had normal situs of the heart and body but 14% showed left-hand looping of the heart. No universal mechanism controlling situs was found at this stage. Areas of precardiac mesoderm were exchanged in the stage 4-6 embryo, in order to form double-right and double-left sided embryos. At stage 6, double-left sided embryos and controls formed right-sided loops, whereas the situs of hearts in double-right sided embryos approximated randomness. Left-handed heart loops were formed by cutting the right splanchnopleure at stage 8-9. following the work of Lepori. Teratological agents were applied both in ovo and in vitro. Retinoic acid was applied systemically and locally to form a right/left gradient using formate beads. Retinoic acid gave a dose-dependent and stage-related spectrum of heart malformations, including altering the situs. No significant difference was found in heart shape resulting from a right or left gradient. Methoxamine, βFGF, heparininase and ultraviolet light caused malformations of the heart but no significant alteration in the situs of the heart

A Note on the Integral Formulation of Einstein's Equations Induced on a Braneworld

We revisit the integral formulation (or Green's function approach) of Einstein's equations in the context of braneworlds. The integral formulation has been proposed independently by several authors in the past, based on the assumption that it is possible to give a reinterpretation of the local metric field in curved spacetimes as an integral expression involving sources and boundary conditions. This allows one to separate source-generated and source-free contributions to the metric field. As a consequence, an exact meaning to Mach's Principle can be achieved in the sense that only source-generated (matter fields) contributions to the metric are allowed for; universes which do not obey this condition would be non-Machian. In this paper, we revisit this idea concentrating on a Randall-Sundrum-type model with a non-trivial cosmology on the brane. We argue that the role of the surface term (the source-free contribution) in the braneworld scenario may be quite subtler than in the 4D formulation. This may pose, for instance, an interesting issue to the cosmological constant problem.Comment: 10 pages, no figures, accepted for publication in the General Relativity and Gravitation Journa

Improving dementia diagnosis and management in primary care: a cohort study of the impact of a training and support program on physician competency, practice patterns, and community linkages

Abstract Background Primary care physicians routinely provide dementia care, but may lack the clinical skills and awareness of available resources to provide optimal care. We conducted a community-based pilot dementia training intervention designed to both improve clinical competency and increase utilization of local dementia care services. Methods Physicians (N = 29) and affiliated staff (N = 24) participated in a one-day training program on dementia screening, diagnosis and management that included direct engagement with local support service providers. Questionnaires about their dementia care competency and referral patterns were completed before and 6 months after the training intervention. Results Physicians reported significantly higher overall confidence in their dementia care competency 6 months post-training compared to pre-training. The largest reported improvements were in their ability to educate patients and caregivers about dementia and making appropriate referrals to community care services. Participants also reported markedly increased use of cognitive screening tools in providing care. Community service providers recorded approximately 160 physician-initiated referrals over a 2 year-period post-training, compared to few beforehand. Conclusions Combining a targeted physician practice-based educational intervention with community service engagement improves dementia care competency in clinicians and promotes linkages between clinical and community dementia care providers

Phase transition observations and discrimination of small cloud particles by light polarization in expansion chamber experiments

Cloud microphysical processes involving the ice phase in tropospheric clouds are among the major uncertainties in cloud formation, weather, and general circulation models. The detection of aerosol particles, liquid droplets, and ice crystals, especially in the small cloud particle-size range below 50 μm, remains challenging in mixed phase, often unstable environments. The Cloud Aerosol Spectrometer with Polarization (CASPOL) is an airborne instrument that has the ability to detect such small cloud particles and measure the variability in polarization state of their backscattered light. Here we operate the versatile Cosmics Leaving OUtdoor Droplets (CLOUD) chamber facility at the European Organization for Nuclear Research (CERN) to produce controlled mixed phase and other clouds by adiabatic expansions in an ultraclean environment, and use the CASPOL to discriminate between different aerosols, water, and ice particles. In this paper, optical property measurements of mixed-phase clouds and viscous secondary organic aerosol (SOA) are presented. We report observations of significant liquid–viscous SOA particle polarization transitions under dry conditions using CASPOL. Cluster analysis techniques were subsequently used to classify different types of particles according to their polarization ratios during phase transition. A classification map is presented for water droplets, organic aerosol (e.g., SOA and oxalic acid), crystalline substances such as ammonium sulfate, and volcanic ash. Finally, we discuss the benefits and limitations of this classification approach for atmospherically relevant concentrations and mixtures with respect to the CLOUD 8–9 campaigns and its potential contribution to tropical troposphere layer analysis

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment

Fgf9 and Wnt4 Act as Antagonistic Signals to Regulate Mammalian Sex Determination

The genes encoding members of the wingless-related MMTV integration site (WNT) and fibroblast growth factor (FGF) families coordinate growth, morphogenesis, and differentiation in many fields of cells during development. In the mouse, Fgf9 and Wnt4 are expressed in gonads of both sexes prior to sex determination. Loss of Fgf9 leads to XY sex reversal, whereas loss of Wnt4 results in partial testis development in XX gonads. However, the relationship between these signals and the male sex-determining gene, Sry, was unknown. We show through gain- and loss-of-function experiments that fibroblast growth factor 9 (FGF9) and WNT4 act as opposing signals to regulate sex determination. In the mouse XY gonad, Sry normally initiates a feed-forward loop between Sox9 and Fgf9, which up-regulates Fgf9 and represses Wnt4 to establish the testis pathway. Surprisingly, loss of Wnt4 in XX gonads is sufficient to up-regulate Fgf9 and Sox9 in the absence of Sry. These data suggest that the fate of the gonad is controlled by antagonism between Fgf9 and Wnt4. The role of the male sex-determining switch— Sry in the case of mammals—is to tip the balance between these underlying patterning signals. In principle, sex determination in other vertebrates may operate through any switch that introduces an imbalance between these two signaling pathways