Modeling Human Brain Circuitry Using Pluripotent Stem Cell Platforms

Neural circuits are the underlying functional units of the human brain that govern complex behavior and higher-order cognitive processes. Disruptions in neural circuit development have been implicated in the pathogenesis of multiple neurodevelopmental disorders such as autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), and schizophrenia. Until recently, major efforts utilizing neurological disease modeling platforms based on human induced pluripotent stem cells (hiPSCs), investigated disease phenotypes primarily at the single cell level. However, recent advances in brain organoid systems, microfluidic devices, and advanced optical and electrical interfaces, now allow more complex hiPSC-based systems to model neuronal connectivity and investigate the specific brain circuitry implicated in neurodevelopmental disorders. Here we review emerging research advances in studying brain circuitry using in vitro and in vivo disease modeling platforms including microfluidic devices, enhanced functional recording interfaces, and brain organoid systems. Research efforts in these areas have already yielded critical insights into pathophysiological mechanisms and will continue to stimulate innovation in this promising area of translational research

Supplementation with cyanidin and delphinidin mitigates high fat diet-induced endotoxemia and associated liver inflammation in mice

Consumption of high fat diets (HFD) and the associated metabolic endotoxemia can initiate liver inflammation and lipid deposition that with time can progress to non-alcoholic fatty liver disease (NAFLD). We previously observed that 14 weeks supplementation with the anthocyanidins cyanidin and delphinidin mitigated HFD-induced metabolic endotoxemia and liver insulin resistance, steatosis, inflammation and oxidative stress. This work investigated if a 4-week supplementation of mice with a cyanidin- and delphinidin-rich extract (CDRE) could mitigate or reverse HFD (60% calories from lard fat)-induced liver steatosis and inflammation. After a first 4-weeks period on the HFD, mice showed increased endotoxemia and activation of liver proinflammatory signaling cascades. Supplementation with CDRE between weeks 4 and 8 did not mitigate liver steatosis or the altered lipid and glucose plasma levels. However, CDRE supplementation reverted HFD-induced metabolic endotoxemia, in parallel with the mitigation of the overexpression of hepatic TLR2 and TLR4, and of the activation of: (i) NF-κB, (ii) AP-1 and upstream mitogen-activated kinases p38 and ERK1/2, and (iii) HIF-1. Thus, even a short-term consumption of cyanidin and delphinidin could help mitigate the adverse consequences, i.e. metabolic endotoxemia and associated liver inflammation, triggered by the regular consumption of diets rich in fat.Fil: Cremonini, Eleonora. University of California at Davis; Estados UnidosFil: Iglesias, Dario Ezequiel. University of California at Davis; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad Medicina. Instituto de Bioquímica y Medicina Molecular; ArgentinaFil: Matsukuma, Karen E.. University of California at Davis; Estados UnidosFil: Hester, Shelly N.. No especifíca;Fil: Wood, Steven M.. No especifíca;Fil: Bartlett, Mark. No especifíca;Fil: Fraga, César Guillermo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad Medicina. Instituto de Bioquímica y Medicina Molecular; ArgentinaFil: Oteiza, Patricia I.. University of California at Davis; Estados Unido

Влияние ледового сжатия на составляющие скорости движения жидкости под ледяным покровом в бегущей периодической изгибно-гравитационной волне конечной амплитуды

Методом многих масштабов с точностью до величин третьего порядка малости получены асимптотические разложения, определяющие составляющие скорости движения жидкости под плавающим ледяным покровом при распространении периодической поверхностной изгибногравитационной волны конечной амплитуды в условиях ледового сжатия. Рассмотрена зависимость распределений составляющих скорости вдоль профиля волны от величины сжимающего усилия и характеристик начальной гармоники. Показано, что с увеличением сжимающего усилия происходит уменьшение амплитудных значений составляющих скорости и отставание фазы колебаний.Методом багатьох масштабів з точністю до величин третього порядку малості отримані асимптотичні розкладання, які визначають складові швидкості руху рідини під плаваючим льодяним покривом при розповсюдженні періодичної поверхневої згинально-гравітаційної хвилі кінцевої амплітуди в умовах льодяного стиснення. Розглянуто залежність розподілів складових швидкості вздовж профілю хвилі від величини стискаючого зусилля та характеристик початкової гармоніки. Показано, що із збільшенням стискаючого зусилля відбувається зменшення амплітудних значень складових швидкості та відставання фази коливань.Using the method of multiple scales, the asymptotic expansions are obtained up to the values of the third order. The expansions condition the components of fluid movement velocity under floating ice cover at propagation of periodic surface flexural-gravity wave of finite amplitude in the condition of ice compression. Dependence of distribution of velocity components along the wave profile upon the compressive force value and the initial harmonic characteristics is considered. It is shown that rise of compressive force is accompanied by decrease of amplitude values of velocity components and lag of oscillations’ phase

Value of thrombus CT Characteristics in Patients with Acute Ischemic Stroke

BACKGROUND AND PURPOSE: Thrombus CT characteristics might be useful for patient selection for intra-arterial treatment. Our objective was to study the association of thrombus CT characteristics with outcome and treatment effect in patients with acute ischemic stroke. MATERIALS AND METHODS: We included 199 patients for whom thin-section NCCT and CTA within 30 minutes from each other were available in the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute ischemic stroke in the Netherlands (MR CLEAN) study. We assessed the following thrombus characteristics: location, distance from ICA terminus to thrombus, length, volume, absolute and relative density

Sequence-based prediction for vaccine strain selection and identification of antigenic variability in foot-and-mouth disease virus

Identifying when past exposure to an infectious disease will protect against newly emerging strains is central to understanding the spread and the severity of epidemics, but the prediction of viral cross-protection remains an important unsolved problem. For foot-and-mouth disease virus (FMDV) research in particular, improved methods for predicting this cross-protection are critical for predicting the severity of outbreaks within endemic settings where multiple serotypes and subtypes commonly co-circulate, as well as for deciding whether appropriate vaccine(s) exist and how much they could mitigate the effects of any outbreak. To identify antigenic relationships and their predictors, we used linear mixed effects models to account for variation in pairwise cross-neutralization titres using only viral sequences and structural data. We identified those substitutions in surface-exposed structural proteins that are correlates of loss of cross-reactivity. These allowed prediction of both the best vaccine match for any single virus and the breadth of coverage of new vaccine candidates from their capsid sequences as effectively as or better than serology. Sub-sequences chosen by the model-building process all contained sites that are known epitopes on other serotypes. Furthermore, for the SAT1 serotype, for which epitopes have never previously been identified, we provide strong evidence - by controlling for phylogenetic structure - for the presence of three epitopes across a panel of viruses and quantify the relative significance of some individual residues in determining cross-neutralization. Identifying and quantifying the importance of sites that predict viral strain cross-reactivity not just for single viruses but across entire serotypes can help in the design of vaccines with better targeting and broader coverage. These techniques can be generalized to any infectious agents where cross-reactivity assays have been carried out. As the parameterization uses pre-existing datasets, this approach quickly and cheaply increases both our understanding of antigenic relationships and our power to control disease

Post-zygotic rescue of meiotic errors causes brain mosaicism and focal epilepsy

Somatic mosaicism is a known cause of neurological disorders, including developmental brain malformations and epilepsy. Brain mosaicism is traditionally attributed to post-zygotic genetic alterations arising in fetal development. Here we describe post-zygotic rescue of meiotic errors as an alternate origin of brain mosaicism in patients with focal epilepsy who have mosaic chromosome 1q copy number gains. Genomic analysis showed evidence of an extra parentally derived chromosome 1q allele in the resected brain tissue from five of six patients. This copy number gain is observed only in patient brain tissue, but not in blood or buccal cells, and is strongly enriched in astrocytes. Astrocytes carrying chromosome 1q gains exhibit distinct gene expression signatures and hyaline inclusions, supporting a novel genetic association for astrocytic inclusions in epilepsy. Further, these data demonstrate an alternate mechanism of brain chromosomal mosaicism, with parentally derived copy number gain isolated to brain, reflecting rescue in other tissues during development

Post-Zygotic Rescue of Meiotic Errors Causes Brain Mosaicism and Focal Epilepsy

Somatic mosaicism is a known cause of neurological disorders, including developmental brain malformations and epilepsy. Brain mosaicism is traditionally attributed to post-zygotic genetic alterations arising in fetal development. Here we describe post-zygotic rescue of meiotic errors as an alternate origin of brain mosaicism in patients with focal epilepsy who have mosaic chromosome 1q copy number gains. Genomic analysis showed evidence of an extra parentally derived chromosome 1q allele in the resected brain tissue from five of six patients. This copy number gain is observed only in patient brain tissue, but not in blood or buccal cells, and is strongly enriched in astrocytes. Astrocytes carrying chromosome 1q gains exhibit distinct gene expression signatures and hyaline inclusions, supporting a novel genetic association for astrocytic inclusions in epilepsy. Further, these data demonstrate an alternate mechanism of brain chromosomal mosaicism, with parentally derived copy number gain isolated to brain, reflecting rescue in other tissues during development

Post-zygotic Rescue of Meiotic Errors Causes Brain Mosaicism and Focal Epilepsy

Somatic mosaicism is a known cause of neurological disorders, including developmental brain malformations and epilepsy. Brain mosaicism is traditionally attributed to post-zygotic genetic alterations arising in fetal development. Here we describe post-zygotic rescue of meiotic errors as an alternate origin of brain mosaicism in patients with focal epilepsy who have mosaic chromosome 1q copy number gains. Genomic analysis showed evidence of an extra parentally derived chromosome 1q allele in the resected brain tissue from five of six patients. This copy number gain is observed only in patient brain tissue, but not in blood or buccal cells, and is strongly enriched in astrocytes. Astrocytes carrying chromosome 1q gains exhibit distinct gene expression signatures and hyaline inclusions, supporting a novel genetic association for astrocytic inclusions in epilepsy. Further, these data demonstrate an alternate mechanism of brain chromosomal mosaicism, with parentally derived copy number gain isolated to brain, reflecting rescue in other tissues during development

Commentary on "Fish Oil-Containing Lipid Emulsions in Adult Parenteral Nutrition: A Review of the Evidence" (https://doi.org/10.1177/0148607117721907).

This is the peer reviewed version of the following article: Adolph, M. , Calder, P. C., Deutz, N. E., Carmona, T. G., Klek, S. , Lev, S. , Mayer, K. , Michael‐Titus, A. T., Pradelli, L. , Puder, M. , Singer, P. and Vlaardingerbroek, H. (2019), Commentary on “Fish Oil–Containing Lipid Emulsions in Adult Parenteral Nutrition: A Review of the Evidence”. Journal of Parenteral and Enteral Nutrition, 43: 454-455. doi:10.1002/jpen.1047, which has been published in final form at https://doi.org/10.1002/jpen.1047. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived VersionsAbbasoglu et al published a narrative review concerning the use of fish oil–containing lipid emulsions in adult parenteral nutrition (PN).1 We wholeheartedly agree with the authors when they state that “high‐quality and adequately powered RCTs are necessary” and “well‐conducted meta‐analyses can be key to demonstrating positive or negative effects.” However, we disagree with other aspects of their review, particularly assertions of a lack of evidence in favor of using fish oil–containing lipid emulsions rather than more traditional lipid formulations

Resectability and Ablatability Criteria for the Treatment of Liver Only Colorectal Metastases:Multidisciplinary Consensus Document from the COLLISION Trial Group

The guidelines for metastatic colorectal cancer crudely state that the best local treatment should be selected from a 'toolbox' of techniques according to patient- and treatment-related factors. We created an interdisciplinary, consensus-based algorithm with specific resectability and ablatability criteria for the treatment of colorectal liver metastases (CRLM). To pursue consensus, members of the multidisciplinary COLLISION and COLDFIRE trial expert panel employed the RAND appropriateness method (RAM). Statements regarding patient, disease, tumor and treatment characteristics were categorized as appropriate, equipoise or inappropriate. Patients with ECOG≤2, ASA≤3 and Charlson comorbidity index ≤8 should be considered fit for curative-intent local therapy. When easily resectable and/or ablatable (stage IVa), (neo)adjuvant systemic therapy is not indicated. When requiring major hepatectomy (stage IVb), neo-adjuvant systemic therapy is appropriate for early metachronous disease and to reduce procedural risk. To downstage patients (stage IVc), downsizing induction systemic therapy and/or future remnant augmentation is advised. Disease can only be deemed permanently unsuitable for local therapy if downstaging failed (stage IVd). Liver resection remains the gold standard. Thermal ablation is reserved for unresectable CRLM, deep-seated resectable CRLM and can be considered when patients are in poor health. Irreversible electroporation and stereotactic body radiotherapy can be considered for unresectable perihilar and perivascular CRLM 0-5cm. This consensus document provides per-patient and per-tumor resectability and ablatability criteria for the treatment of CRLM. These criteria are intended to aid tumor board discussions, improve consistency when designing prospective trials and advance intersociety communications. Areas where consensus is lacking warrant future comparative studies.</p