Opening the Courthouse Doors: Allowing a Cause of Action to Arise Directly from a Violation of the Ohio Constitution

This note will explain why Ohio\u27s Constitution should be looked to as the source of meaningful remedy when its provisions are violated. I will demonstrate that a cause of action grounded upon a violation of the Ohio Constitution is not only meaningful, but necessary to the notion of constitutional rights. Section two will briefly discuss the necessity of allowing a cause of action to arise from a violation of the Ohio Constitution. In particular, I will discuss the independence of the Ohio Constitution; the federal courts\u27 increasing hostility toward the vindication of federal constitutional rights; and the benefit of allowing the aggrieved a choice, with respect to the vindication of his constitutional rights, between remedies offered under federal law and those afforded under Ohio law

Opening the Courthouse Doors: Allowing a Cause of Action to Arise Directly from a Violation of the Ohio Constitution

This note will explain why Ohio\u27s Constitution should be looked to as the source of meaningful remedy when its provisions are violated. I will demonstrate that a cause of action grounded upon a violation of the Ohio Constitution is not only meaningful, but necessary to the notion of constitutional rights. Section two will briefly discuss the necessity of allowing a cause of action to arise from a violation of the Ohio Constitution. In particular, I will discuss the independence of the Ohio Constitution; the federal courts\u27 increasing hostility toward the vindication of federal constitutional rights; and the benefit of allowing the aggrieved a choice, with respect to the vindication of his constitutional rights, between remedies offered under federal law and those afforded under Ohio law

High fat diet causes depletion of intestinal eosinophils associated with intestinal permeability.

The development of intestinal permeability and the penetration of microbial products are key factors associated with the onset of metabolic disease. However, the mechanisms underlying this remain unclear. Here we show that, unlike liver or adipose tissue, high fat diet (HFD)/obesity in mice does not cause monocyte/macrophage infiltration into the intestine or pro-inflammatory changes in gene expression. Rather HFD causes depletion of intestinal eosinophils associated with the onset of intestinal permeability. Intestinal eosinophil numbers were restored by returning HFD fed mice to normal chow and were unchanged in leptin-deficient (Ob/Ob) mice, indicating that eosinophil depletion is caused specifically by a high fat diet and not obesity per se. Analysis of different aspects of intestinal permeability in HFD fed and Ob/Ob mice shows an association between eosinophil depletion and ileal paracelullar permeability, as well as leakage of albumin into the feces, but not overall permeability to FITC dextran. These findings provide the first evidence that a high fat diet causes intestinal eosinophil depletion, rather than inflammation, which may contribute to defective barrier integrity and the onset of metabolic disease

Glacial Isostatic Adjustment of the Laurentian Great Lakes Basin: Using the Empirical Record of Strandline Deformation for Reconstruction of Early Holocene Paleo-Lakes and Discovery of a Hydrologically Closed Phase

In the Great Lakes region, the vertical motion of crustal rebound since the last glaciation has decelerated with time, and is described by exponential decay constrained by observed warping of strandlines of former lakes. A composite isostatic response surface relative to an area southwest of Lake Michigan beyond the limit of the last glacial maximum was prepared for the complete Great Lakes watershed at 10.6 ka BP (12.6 cal ka BP). Uplift of sites computed using values from the response surface facilitated the transformation of a digital elevation model of the present Great Lakes basins to represent the paleogeography of the watershed at selected times. Similarly, the original elevations of radiocarbon-dated geomorphic and stratigraphic indicators of former lake levels were reconstructed and plotted against age to define lake level history. A comparison with the independently computed basin outlet paleo-elevations reveals a phase of severely reduced water levels and hydrologically-closed lakes below overflow outlets between 7.9 and 7.0 ka BP (8.7 and 7.8 cal ka BP) in the Huron-Michigan basin. Severe evaporative draw-down is postulated to result from the early Holocene dry climate when inflows of meltwater from the upstream Agassiz basin began to bypass the upper Great Lakes basin.Dans la région des Grands Lacs, le soulèvement isostatique lié à la dernière glaciation a ralenti selon une courbe de décroissance exponentielle établie à partir du gauchissement observé dans les anciennes lignes de rivage lacustres. Une surface de référence composite de la réponse isostatique datant de 10,6 ka BP (12,6 cal ka BP) a été préparée pour l’ensemble du bassin-versant des Grands Lacs, par rapport à une région au sud-ouest du lac Michigan située au-delà de la limite du dernier maximum glaciaire. Le calcul du soulèvement des sites en fonction des altitudes de la surface de référence a facilité la conversion d’un modèle altimétrique de terrain du bassin actuel des Grands Lacs en des cartes paléo-géographiques pour différents âges choisis. De plus, afin de définir l’évolution des niveaux lacustres, les altitudes initiales des indicateurs géomorphologiques et stratigraphiques des paléo-niveaux lacustres, datés au 14C, ont été reconstituées puis reportées en fonction de l’âge. La comparaison de cette courbe à celles des paléo-altitudes des exutoires lacustres, calculée indépendamment, révèle, entre 7,9 et 7 ka BP (8,7 et 7,8 cal ka BP), une phase d’abaissement majeur des niveaux lacustres au-dessous de ceux des exutoires et la fermeture hydrologique des lacs dans le bassin des lacs Huron-Michigan. La forte évaporation nécessaire à l’abaissement du niveau d’eau est attribuée à un climat sec peu après le début de l’Holocène, dans un contexte de détournement progressif hors des Grands Lacs des eaux de fonte du lac Agassiz

Machine Learning in Melanoma Diagnosis. Limitations About to be Overcome

[spa] Antecedentes: La clasificación automática de imágenes es una rama prometedora del aprendi-zaje automático (de sus siglas en inglés Machine Learning [ML]), y es una herramienta útil enel diagnóstico de cáncer de piel. Sin embargo, poco se ha estudiado acerca de las limitacionesde su uso en la práctica clínica diaria.Objetivo: Determinar las limitaciones que existen en cuanto a la selección de imágenes usadaspara el análisis por ML de las neoplasias cutáneas, en particular del melanoma.Métodos: Se dise ̃nó un estudio de cohorte retrospectivo, donde se incluyeron de forma conse-cutiva 2.849 imágenes dermatoscópicas de alta calidad de tumores cutáneos para su valoraciónpor un sistema de ML, recogidas entre los a ̃nos 2010 y 2014. Cada imagen dermatoscópica fueclasificada según las características de elegibilidad para el análisis por ML.Resultados: De las 2.849 imágenes elegidas a partir de nuestra base de datos, 968 (34%) cum-plieron los criterios de inclusión. De los 528 melanomas, 335 (63,4%) fueron excluidos. Laausencia de piel normal circundante (40,5% de todos los melanomas de nuestra base de datos)y la ausencia de pigmentación (14,2%) fueron las causas más frecuentes de exclusión para elanálisis por ML.Discusión: Solo el 36,6% de nuestros melanomas se consideraron aceptables para el análisispor sistemas de ML de última generación. Concluimos que los futuros sistemas de ML deberánser entrenados a partir de bases de datos más grandes que incluyan imágenes representativasde la práctica clínica habitual. Afortunadamente, muchas de estas limitaciones están siendosuperadas gracias a los avances realizados recientemente por la comunidad científica, como seha demostrado en trabajos recientes. [eng] Background: Automated image classification is a promising branch of machine learning (ML)useful for skin cancer diagnosis, but little has been determined about its limitations for generalusability in current clinical practice.Objective: To determine limitations in the selection of skin cancer images for ML analysis,particularly in melanoma.Methods: Retrospective cohort study design, including 2,849 consecutive high-quality dermos-copy images of skin tumors from 2010 to 2014, for evaluation by a ML system. Each dermoscopyimage was assorted according to its eligibility for ML analysis.Results: Of the 2,849 images chosen from our database, 968 (34%) met the inclusion criteriafor analysis by the ML system. Only 64.7% of nevi and 36.6% of melanoma met the inclusioncriteria. Of the 528 melanomas, 335 (63.4%) were excluded. An absence of normal surroundingskin (40.5% of all melanomas from our database) and absence of pigmentation (14.2%) were themost common reasons for exclusion from ML analysis.Discussion: Only 36.6% of our melanomas were admissible for analysis by state-of-the-art MLsystems. We conclude that future ML systems should be trained on larger datasets which includerelevant non-ideal images from lesions evaluated in real clinical practice. Fortunately, many ofthese limitations are being overcome by the scientific community as recent works show

Involvement of Schizosaccharomyces pombe rrp1+ and rrp2+ in the Srs2- and Swi5/Sfr1-dependent pathway in response to DNA damage and replication inhibition

Previously we identified Rrp1 and Rrp2 as two proteins required for the Sfr1/Swi5-dependent branch of homologous recombination (HR) in Schizosaccharomyces pombe. Here we use a yeast two-hybrid approach to demonstrate that Rrp1 and Rrp2 can interact with each other and with Swi5, an HR mediator protein. Rrp1 and Rrp2 form co-localizing methyl methanesulphonate–induced foci in nuclei, further suggesting they function as a complex. To place the Rrp1/2 proteins more accurately within HR sub-pathways, we carried out extensive epistasis analysis between mutants defining Rrp1/2, Rad51 (recombinase), Swi5 and Rad57 (HR-mediators) plus the anti-recombinogenic helicases Srs2 and Rqh1. We confirm that Rrp1 and Rrp2 act together with Srs2 and Swi5 and independently of Rad57 and show that Rqh1 also acts independently of Rrp1/2. Mutants devoid of Srs2 are characterized by elevated recombination frequency with a concomitant increase in the percentage of conversion-type recombinants. Strains devoid of Rrp1 or Rrp2 did not show a change in HR frequency, but the number of conversion-type recombinants was increased, suggesting a possible function for Rrp1/2 with Srs2 in counteracting Rad51 activity. Our data allow us to propose a model placing Rrp1 and Rrp2 functioning together with Swi5 and Srs2 in a synthesis-dependent strand annealing HR repair pathway

SUMO-2 and PIAS1 modulate insoluble mutant Huntingtin protein accumulation

A key feature in Huntington disease (HD) is the accumulation of mutant Huntingtin (HTT) protein, which may be regulated by posttranslational modifications. Here, we define the primary sites of SUMO modification in the amino-terminal domain of HTT, show modification downstream of this domain, and demonstrate that HTT is modified by the stress-inducible SUMO-2. A systematic study of E3 SUMO ligases demonstrates that PIAS1 is an E3 SUMO ligase for both HTT SUMO-1 and SUMO-2 modification and that reduction of dPIAS in a mutant HTT Drosophila model is protective. SUMO-2 modification regulates accumulation of insoluble HTT in HeLa cells in a manner that mimics proteasome inhibition and can be modulated by overexpression and acute knockdown of PIAS1. Finally, the accumulation of SUMO-2-modified proteins in the insoluble fraction of HD postmortem striata implicates SUMO-2 modification in the age-related pathogenic accumulation of mutant HTT and other cellular proteins that occurs during HD progression

Formyl Peptide Receptor as a Novel Therapeutic Target for Anxiety-Related Disorders

Formyl peptide receptors (FPR) belong to a family of sensors of the immune system that detect microbe-associated molecules and inform various cellular and sensorial mechanisms to the presence of pathogens in the host. Here we demonstrate that Fpr2/3-deficient mice show a distinct profile of behaviour characterised by reduced anxiety in the marble burying and light-dark box paradigms, increased exploratory behaviour in an open-field, together with superior performance on a novel object recognition test. Pharmacological blockade with a formyl peptide receptor antagonist, Boc2, in wild type mice reproduced most of the behavioural changes observed in the Fpr2/3(-/-) mice, including a significant improvement in novel object discrimination and reduced anxiety in a light/dark shuttle test. These effects were associated with reduced FPR signalling in the gut as shown by the significant reduction in the levels of p-p38. Collectively, these findings suggest that homeostatic FPR signalling exerts a modulatory effect on anxiety-like behaviours. These findings thus suggest that therapies targeting FPRs may be a novel approach to ameliorate behavioural abnormalities present in neuropsychiatric disorders at the cognitive-emotional interface

Dose response of the 16p11.2 distal copy number variant on intracranial volume and basal ganglia.

Carriers of large recurrent copy number variants (CNVs) have a higher risk of developing neurodevelopmental disorders. The 16p11.2 distal CNV predisposes carriers to e.g., autism spectrum disorder and schizophrenia. We compared subcortical brain volumes of 12 16p11.2 distal deletion and 12 duplication carriers to 6882 non-carriers from the large-scale brain Magnetic Resonance Imaging collaboration, ENIGMA-CNV. After stringent CNV calling procedures, and standardized FreeSurfer image analysis, we found negative dose-response associations with copy number on intracranial volume and on regional caudate, pallidum and putamen volumes (β = -0.71 to -1.37; P < 0.0005). In an independent sample, consistent results were obtained, with significant effects in the pallidum (β = -0.95, P = 0.0042). The two data sets combined showed significant negative dose-response for the accumbens, caudate, pallidum, putamen and ICV (P = 0.0032, 8.9 × 10-6, 1.7 × 10-9, 3.5 × 10-12 and 1.0 × 10-4, respectively). Full scale IQ was lower in both deletion and duplication carriers compared to non-carriers. This is the first brain MRI study of the impact of the 16p11.2 distal CNV, and we demonstrate a specific effect on subcortical brain structures, suggesting a neuropathological pattern underlying the neurodevelopmental syndromes