267 research outputs found

    The role of environmental factors in the etiology of schizophrenia

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    Introduction: Schizophrenia is a psychotic disease characterized by multifaceted psychopathology. To date, research has shown that it is an inherited disease and significant progress has been made in identifying genetic risk factors. Methods: This paper summarizes the current and most recent findings on the role of environmental factors, and demonstrates the continued need for more in-depth research to better understand how this type of disorder occurs. Results: Recent studies show that 15-40% of the risk that comes from environmental sources is not fully understood. Environmental factors that have been repeatedly studied and have been proven to influence the development of the disease include: obstetric complications, infections, childbirth in the winter or spring month, living in the city, severe childhood events or marijuana use. Discussion: Schizophrenia is a devastating mental illness that remains poorly understood. A full picture of how genetic and environmental risk factors affect the risk of developing schizophrenia requires an understanding of the interactions between them. It should be taken into account that for this disorder, the interactions between genetic and environmental risk factors are also not well understood and deserve further research in the future. In the case of schizophrenia, the interactions between environmental and genetic risk factors are not well understood and still require further research. Elucidating the mechanisms underlying the disease is extremely important, as it may have an impact on taking measures to prevent the development of the disorder. In addition, their discovery will help improve treatment. In conclusion, it is important to emphasize the need for further research to better understand the impact of environmental factors on the development of susceptibility to a mental disorder such as schizophrenia

    Deciphering the role of BMP4 signalling and gene regulation in the specification of human liver progenitor cells

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    Early hepatic specification and organogenesis can be modelled in vitro using human induced pluripotent stem cells (hiPSCs). These models apply differentiation protocols to direct hiPSCs through all the key developmental stages to accurately reflect in vivo development. Bone morphogenetic protein (BMP) and fibroblast growth factor (FGF) signalling are crucial for the specification of hepatic progenitors during early liver development. While the signalling cascades of these two morphogens are well characterized, the mechanisms by which they promote hepatic cell fate choice and hepatic gene expression in anterior foregut endoderm (FE) cells is not very well understood. In this project, we characterize hiPSCs-based model of early liver development and apply it to understand the role of BMP signalling in hepatic specification. We confirm that BMP4 signalling is also necessary for liver progenitor cells (LPCs) specification from FE during hiPSCs differentiation. Using RNA sequencing (RNA seq.) we examine transcriptome changes induced by BMP4 during the transition from FE to LPC stage. Overrepresentation analysis (ORA) and gene set enrichment analysis (GSEA) analysis revealed early activation of hepatocyte-specific functions such as lipid and protein homeostasis, haem metabolism or coagulation, while at the same time, cell adhesion and locomotion related genes are downregulated indicating preparation for cell migration out of the forming liver bud. We also notice upregulation of all four FGF receptors upon BMP signalling indicating at possible cross talk between the two pathways. The RNA seq. also detected a number of BMP4 upregulated transcription factors (TFs), several of these TFs are known for their roles in multiple developmental processes. Among them TBX3, previously reported to have a role in hepatic specification in mice, and two other TBX family members: TBX2 and TBX20. As a preliminary screen, we used a published, optimized protocol for creating inducible knockdown hiPSC lines to assess the importance of TBX and other TFs for the process of LPC specification. Double knockdown of TBX3 and TBX20 TFs significantly disrupted the hepatic induction process as shown by decreased expression of early hepatic genes such as TTR, AFP, AAT and ALB. Further studies are necessary to confirm and further characterize the role of TBX TFs for hepatic specification. Our study demonstrates that application of hiPSCs derived models for the study of development can aid the understanding of molecular mechanisms driving early liver specification and improve our understanding of human embryology and organogenesis. This knowledge can also be used to created more efficient differentiation platforms that can yield more mature, functional and clinically relevant populations of hiPSC-derived hepatocytes

    Model Teoretis Dinamika Psikologis Self-Regulated Learing

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    Terdapat beberapa simpulan urgen, yang dapat ditarik benang merah, dari seluruh pembahasan buku ini sebagai berikut. Pertama, model teoretis dinamika atribut psikologis self-regulated learning, atribut psikologis sikap orangtua terhadap anak dan atribut psikologis sikap guru terhadap peserta didik, melalui atribut psikologis self-regulated learning dengan prestasi belajar peserta didik dan model teoretis dinamika psikologis self-regulated learning yang dibangun terbukti layak (fit). Hal ini membuktikan secara ilmial bahwa model teoretik dinamika psikologis self-regulated learning mendapatkan dukungan empiris, dukungan empiris dimaksud sebagai berikut; (a) dinamika psikologis sikap orangtua terhadap anak, dinamika psikologis sikap guru terhadap peserta didik, dan dinamika psikologis self-regulated learning, berpengaruh terhadap prestasi belajar peserta didik, (b) dinamika psikologis sikap orangtua terhadap anak dan dinamika psikologis sikap guru terhadap peserta didik, berpengaruh terhadap self-regulated learning, dan (c) dinamika psikologis sikap orangtua terhadap anak dan dinamika psikologis sikap guru terhadap peserta didik, berpengaruh tidak langsung dengan prestasi belajar peserta didik melalui self-regulated learning. Kedua, dinamika psikologis prestasi belajar pada model kajian ini, dapat dijelaskan (a) dinamika psikologis sikap guru terhadap peserta didik merupakan jalur pengaruh langsung paling kuat dibanding jalur pengaruh langsung dinamika psikologis sikap orangtua terhadap anak dan jalur pengaruh langsung dinamika psikologis self-regulated learning dengan prestasi belajar, (b) dinamika psikologis sikap orangtua terhadap anak merupakan jalur pengaruh langsung paling kuat dibanding jalur pengaruh langsung dinamika psikologis sikap guru terhadap peserta didik dengan self-regulated learning,(c) dinamika psikologis sikap orangtua terhadap anak merupakan jalur pengaruh tidak langsung paling kuat dibanding jalur pengaruh tidak langsung dinamika psikologis sikap guru terhadap peserta didik dengan prestasi belajar peserta didik melalui self-regulated learning. Ketiga, model teoretis dinamika psikologis pada buku mendapat dukungan teori kognitif sosial sebagai grand theory untuk model interaksi satu arah yang dielaborasi dari model triadic reciprocality. Dinamika psikologis buku ini memperkuat prestasi belajar sebagai atribut psikologis endogenus yang dapat dipengaruhi oleh pertama, fakta eksternal dinamika psikologis sikap orangtua terhadap anak dan dinamika psikologis sikap guru terhadap peserta didik, dan kedua oleh faktor internal, yakni dinamika psikologis self-regulated learning/regulasi diri dalam belajar atau belajar dengan regulasi diri (keterampilan belajar). Keempat, selain kesimpulan umum di atas, dapat juga ditarik beberapa kesimpulan khusus sebagai berikut. (a) terdapat dinamika psikologis langsung atribut psikologis sikap orangtua terhadap anak dengan prestasi belajar peserta didik, (b) terdapat dinamika psikologis langsung atribut psikologis sikap guru terhadap peserta didik dengan prestasi belajar, (c) terdapat dinamika psikologis langsung atribut psikologis sikap orangtua terhadap anak dengan self-regulated learning peserta didik, (d) terdapat dinamika psikologis langsung atribut psikologis sikap guru terhadap peserta didik dengan self-regulated learning peserta didik, (e) terdapat dinamika psikologis langsung atribut psikologis self-regulated learning terhadap prestasi belajar peserta didik, (f) terdapat dinamika psikologis tidak langsung atribut psikologis sikap orangtua terhadap anak dengan prestasi belajar peserta didik melalui atribut psikologis self-regulated learning, dan (g) terdapat dinamika psikologis secara tidak langsung atribut psikologis sikap guru terhadap peserta didik dengan prestasi belajar peserta didik melalui atribut psikologis self-regulated learning. Kelima, konsep self-regulated learning sebagai atribut psikologis definisikan sebagai usaha sadar peserta didik dalam mengatur dan mengarahkan diri dalam menetapkan tujuan belajar (goal setting of learning), kontrol diri dalam belajar (action control of learning), mencari bantuan belajar (help-seeking of learning), motivasi belajar (learning motivation), strategi belajar (learning strategies), dan evaluasi diri dalam belajar (learning self-evaluation). Keenam, aspek-aspek self-regulated learning terdiri dari berikut. (1) menetapkan tujuan belajar, (2) kontrol diri dalam belajar, (3) mencari bantuan belajar, (4) motivasi belajar, (5) strategi belajar, dan (6) evaluasi diri dalam belajar. Ketujuh, self-regulated learning dalam psikologi Islam, nilai-nilai atribut psikologis self-regulated learning telah ada sepanjang peradapan manusia. Kisah para Nabi dan Rasul membuktikannya, seperti kisah belajar kehidupan Nabi Musa AS dan Nabi Ibrahim AS merupakan pembelajar yang memiliki karakter atribut psikologis self-regulated learning yang kuat. Kedua nabi dan Rasul ini memiliki kemampuan mengatur dan mengarahkan diri yang sangat baik dalam belajar, baik Ketika belajar mandiri maupun belajar bersama guru sebagai peserta didik. Nabi Musa AS dan Nabi Ibrahim AS juga memiliki perencanaan belajar yang sempurna, kedua nabi ini mampu menetapkan tujuan belajar benar, memiliki kontrol diri dalam belajar, mampu dengan baik mencari bantuan belajar, memiliki motivasi belajar kuat, memiliki strategi belajar dan evaluasi diri dalam belajar matang

    A tablet-based quantitative assessment of manual dexterity for detection of early psychosis

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    BackgroundWe performed a pilot study on whether tablet-based measures of manual dexterity can provide behavioral markers for detection of first-episode psychosis (FEP), and whether cortical excitability/inhibition was altered in FEP.MethodsBehavioral and neurophysiological testing was undertaken in persons diagnosed with FEP (N = 20), schizophrenia (SCZ, N = 20), autism spectrum disorder (ASD, N = 20), and in healthy control subjects (N = 20). Five tablet tasks assessed different motor and cognitive functions: Finger Recognition for effector (finger) selection and mental rotation, Rhythm Tapping for temporal control, Sequence Tapping for control/memorization of motor sequences, Multi Finger Tapping for finger individuation, and Line Tracking for visuomotor control. Discrimination of FEP (from other groups) based on tablet-based measures was compared to discrimination through clinical neurological soft signs (NSS). Cortical excitability/inhibition, and cerebellar brain inhibition were assessed with transcranial magnetic stimulation.ResultsCompared to controls, FEP patients showed slower reaction times and higher errors in Finger Recognition, and more variability in Rhythm Tapping. Variability in Rhythm Tapping showed highest specificity for the identification of FEP patients compared to all other groups (FEP vs. ASD/SCZ/Controls; 75% sensitivity, 90% specificity, AUC = 0.83) compared to clinical NSS (95% sensitivity, 22% specificity, AUC = 0.49). Random Forest analysis confirmed FEP discrimination vs. other groups based on dexterity variables (100% sensitivity, 85% specificity, balanced accuracy = 92%). The FEP group had reduced short-latency intra-cortical inhibition (but similar excitability) compared to controls, SCZ, and ASD. Cerebellar inhibition showed a non-significant tendency to be weaker in FEP.ConclusionFEP patients show a distinctive pattern of dexterity impairments and weaker cortical inhibition. Easy-to-use tablet-based measures of manual dexterity capture neurological deficits in FEP and are promising markers for detection of FEP in clinical practice

    Pharmacogenomics

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    This Special Issue focuses on the current state of pharmacogenomics (PGx) and the extensive translational process, including the identification of functionally important PGx variation; the characterization of PGx haplotypes and metabolizer statuses, their clinical interpretation, clinical decision support, and the incorporation of PGx into clinical care

    Nematode chromosomes

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    The nematode Caenorhabditis elegans has shed light on many aspects of eukaryotic biology, including genetics, development, cell biology, and genomics. A major factor in the success of C. elegans as a model organism has been the availability, since the late 1990s, of an essentially gap-free and well-annotated nuclear genome sequence, divided among 6 chromosomes. In this review, we discuss the structure, function, and biology of C. elegans chromosomes and then provide a general perspective on chromosome biology in other diverse nematode species. We highlight malleable chromosome features including centromeres, telomeres, and repetitive elements, as well as the remarkable process of programmed DNA elimination (historically described as chromatin diminution) that induces loss of portions of the genome in somatic cells of a handful of nematode species. An exciting future prospect is that nematode species may enable experimental approaches to study chromosome features and to test models of chromosome evolution. In the long term, fundamental insights regarding how speciation is integrated with chromosome biology may be revealed

    MEASURING NONCOVALENT INTERACTIONS INVOLVED IN THE RECOGNITION OF HISTONE POST-TRANSLATIONAL MODIFICATIONS AND ENGINEERING READER PROTEIN SCAFFOLDS INTO IMPROVED TOOLS FOR EPIGENETICS RESEARCH

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    Precise and temporal regulation of DNA-templated processes is maintained by the hierarchical systems of epigenetics. As a core structural unit of the epigenome, chromatin architecture is in part governed by the histone code – the covalent modifications to histone proteins that direct biological functions through the physiochemical properties of the posttranslational modifications (PTMs) themselves. As required features for maintaining the homeostasis of the phenotypic genome, dysregulation of these marks is equally devastating to eukaryotic biology, and aberrant levels of PTMs are associated with the development of disease. Consequentially, detailed investigations are needed for understanding the chemical basis by which PTMs influence dynamic epigenetic states. These insights contextualize the implications of the histone code among the other levels of epigenetic regulatory elements and inform the design of therapeutics that specifically target the macromolecular complexes that associate with these marks. The work herein describes our contributions to both mechanistically characterizing the discrete noncovalent interactions necessary for selective recognition of the important histone PTM trimethyllysine (Kme3), and engineering the protein scaffolds that natively bind these marks, called reader proteins, into beneficial detection reagents for epigenetics research. Towards our first aim, two classes of reader proteins for Kme3 were extensively studied to measure the contributions of individual residues within their conserved site for recognition called an aromatic cage. Using biophysical and chemical biology techniques, we evaluated differences in the noncovalent driving forces implicated in binding Kme3. In pursuit of this goal, we discovered several readers that do not selectively recognize this mark on the premise of its positive charge and characterizing the change in mechanism between binding Kme3 and a neutral analog is impactful for the development of chemical probes and inhibitors. Secondly, we capitalized on the inherent selectivity of reader proteins and through a rational design approach engineered a native Kme3 reader protein into a modular reagent that provides enhanced detection of Kme3 in standard chromatin assays. Together, our work furthers our understanding of the balance of noncovalent interactions that contribute to the dynamic regulation of epigenetic states by Kme3 and has provided additional tools for detecting these marks in chromatin research.Doctor of Philosoph

    La dynamique biogéochimique des espÚces Redox dans les sédiments modernes du Golfe de Gascogne

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    Les mĂ©canismes biogĂ©ochimiques benthiques modifient la chimie et la minĂ©ralogie dans les premiers centimĂštres sous l’interface eau/sĂ©diment. Ces mĂ©canismes sont liĂ©s Ă  la dĂ©gradation de la matiĂšre organique exportĂ©e vers le plancher ocĂ©anique et dĂ©terminent les cycles benthiques des espĂšces rĂ©dox majeures et en trace, le devenir de la matiĂšre organique sĂ©dimentaire et des contaminants...Ce travail de thĂšse permet de prĂ©ciser la dynamique des espĂšces rĂ©dox dans les sĂ©diments marins modernes du Golfe de Gascogne (marge Aquitaine et canyon de Capbreton), mais aussi aide Ă  la calibration et Ă  l’interprĂ©tation de traceurs chimiques des conditions d’oxydorĂ©duction et de la productivitĂ© exportĂ©e. Les profils verticaux des composĂ©s rĂ©dox majeurs acquis aussi bien dans la fraction dissoute (O2, NO3-, NH4+, Mn2+, Fe2+, SO42-) que particulaire (oxy-hydroxydes de Mn, carbonates de Mn, oxydes de Fe rĂ©actif, soufre total, carbone organique et inorganique) ont permis d’identifier et de quantifier des sĂ©quences temporaires de rĂ©actions diagĂ©nĂ©tiques (nature et prĂ©dominance des rĂ©actions, flux, variations spatio-temporelles). Si le schĂ©ma classique de zonation rĂ©dox est bien respectĂ©, de nouvelles rĂ©actions peuvent aussi se mettre en place et crĂ©er des voix mĂ©taboliques alternatives. Ces mĂ©canismes mettent principalement en interaction les cycles benthiques des espĂšces azotĂ©es et des mĂ©taux (Mn et Fe) et peuvent contribuer Ă  une production anoxique d’espĂšces oxydĂ©es (exemple des nitrates). Les sĂ©diments dĂ©tritiques du canyon de Capbreton ont permis plus particuliĂšrement d’étudier l’évolution temporelle des rĂ©actions diagĂ©nĂ©tiques en milieu remaniĂ©. L’analyse de U, Mo, Cd, As et des terres rares rĂ©vĂšle que la distribution des mĂ©taux en trace est intimement liĂ©e Ă  la prĂ©sence de phases diagĂ©nĂ©tiques majeures, telles que les sulfures et les oxydes de Mn et Fe. Les cycles benthiques de ces mĂ©taux en traces sont donc dĂ©pendants des conditions rĂ©dox, mais l’interprĂ©tation de leurs signaux sĂ©dimentaires, en terme d’enregistrement des conditions environnementales passĂ©es, requiert une grande attention.Benthic biogeochemical processes change the chemistry and the mineralogy of the first centimetres below the water/sediment interface. These processes are linked to the mineralisation of organic matter, which fall on the sea floor. They control the benthic behaviour of redox species, OM or pollutants...The objectives of this study is to clarify the dynamic of the diagenetic redox species in the modern sediments of the Bay of Biscay (Aquitan margin and Capbreton canyon), and to calibrate geochemical proxies used to interpret redox properties of marine environment in the past. Vertical distribution of major redox compounds has been analysed in pore waters (O2, NO3+, NH4+, Mn2+, Fe2+, SO42-) and in solid fraction (Mn-oxihydroxides, -carbonate, amorphous Fe-oxides, total sulfur and both organic and inorganic carbon) in order to study and quantify depth sequences of diagenetic reactions (nature and prevailing processes, fluxes, seasonal variations). The classical sequence of redox zones has been observed, but several secondary diagenetic reactions occur, and create alternative metabolic pathways. These processes involve mainly benthic cycle of nitrogen species and metals (Fe and Mn) and could produce oxidised compounds in anoxic horizon (example of anoxic NO3- -production). The recent deposition of turbidites in the Capbreton canyon allowed to study the non steady-state diagenetic processes. The vertical distribution of trace metals (U, Mo, Cd, As, and REE) is related to the presence of major diagenetic phases, such as sulfides and reactive metal-oxides (Mn- and Fe-oxides). Although their diagenetic behaviour is controlled by redox conditions, their use as markers of past surficial redox conditions needs further investigations
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