Recent findings in psychiatric genetics have crystallized concerns that diagnostic categories used in the clinic map poorly onto the underlying biology. If we are to harness developments in genetics ...and neuroscience to understand disease mechanisms and develop new treatments, we need new approaches to patient stratification that recognize the complexity and continuous nature of psychiatric traits and that are not constrained by current categorical approaches. Recognizing this, the National Institute for Mental Health (NIMH) has developed a novel framework to encourage more research of this kind. The implications of these recent findings and funding policy developments for neuroscience research are considerable.
Owen reviews recent genetic findings suggesting that psychiatric diagnoses map poorly onto the underlying biology. He argues that new approaches to patient stratification are needed if we are to harness developments in genetics and neuroscience to understand disease mechanisms and develop new treatments.
The properties of catenated nitrogen molecules, molecules containing internal chains of bonded nitrogen atoms, is of fundamental scientific interest in chemical structure and bonding, as nitrogen is ...uniquely situated in the periodic table to form kinetically stable compounds often with chemically stable N–N bonds but which are thermodynamically unstable in that the formation of stable multiply bonded N2 is usually thermodynamically preferable. This unique placement in the periodic table makes catenated nitrogen compounds of interest for development of high-energy-density materials, including explosives for defense and construction purposes, as well as propellants for missile propulsion and for space exploration. This review, designed for a chemical audience, describes foundational subjects, methods, and metrics relevant to the energetic materials community and provides an overview of important classes of catenated nitrogen compounds ranging from theoretical investigation of hypothetical molecules to the practical application of real-world energetic materials. The review is intended to provide detailed chemical insight into the synthesis and decomposition of such materials as well as foundational knowledge of energetic science new to most chemists.
We sought to obtain novel insights into schizophrenia pathogenesis by exploiting the association between the disorder and chromosomal copy number (CNV) burden. We combined data from 5,745 cases and ...10,675 controls with other published datasets containing genome-wide CNV data. In this much-enlarged sample of 11,355 cases and 16,416 controls, we show for the first time that case CNVs are enriched for genes involved in GABAergic neurotransmission. Consistent with non-genetic reports of GABAergic deficits in schizophrenia, our findings now show disrupted GABAergic signaling is of direct causal relevance, rather than a secondary effect or due to confounding. Additionally, we independently replicate and greatly extend previous findings of CNV enrichment among genes involved in glutamatergic signaling. Given the strong functional links between the major inhibitory GABAergic and excitatory glutamatergic systems, our findings converge on a broad, coherent set of pathogenic processes, providing firm foundations for studies aimed at dissecting disease mechanisms.
•First genetic evidence for disruption of GABAergic signaling in schizophrenia•No evidence for CNV disruption of biological processes beyond the CNS•Support for involvement of NMDAR and ARC complexes in schizophrenia•Additional, independent evidence for disruption of glutamatergic signaling
Pocklington et al. show for the first time that CNVs from individuals with schizophrenia are enriched for genes involved in GABAergic neurotransmission. Previous findings of CNV enrichment among genes involved in glutamatergic signaling are independently replicated and greatly extended.
The idea that disturbances occurring early in brain development contribute to the pathogenesis of schizophrenia, often referred to as the neurodevelopmental hypothesis, has become widely accepted. ...Despite this, the disorder is viewed as being distinct nosologically, and by implication pathophysiologically and clinically, from syndromes such as autism spectrum disorders, attention‐deficit/hyperactivity disorder (ADHD) and intellectual disability, which typically present in childhood and are grouped together as “neurodevelopmental disorders”. An alternative view is that neurodevelopmental disorders, including schizophrenia, rather than being etiologically discrete entities, are better conceptualized as lying on an etiological and neurodevelopmental continuum, with the major clinical syndromes reflecting the severity, timing and predominant pattern of abnormal brain development and resulting functional abnormalities. It has also been suggested that, within the neurodevelopmental continuum, severe mental illnesses occupy a gradient of decreasing neurodevelopmental impairment as follows: intellectual disability, autism spectrum disorders, ADHD, schizophrenia and bipolar disorder. Recent genomic studies have identified large numbers of specific risk DNA changes and offer a direct and robust test of the predictions of the neurodevelopmental continuum model and gradient hypothesis. These findings are reviewed in detail. They not only support the view that schizophrenia is a disorder whose origins lie in disturbances of brain development, but also that it shares genetic risk and pathogenic mechanisms with the early onset neurodevelopmental disorders (intellectual disability, autism spectrum disorders and ADHD). They also support the idea that these disorders lie on a gradient of severity, implying that they differ to some extent quantitatively as well as qualitatively. These findings have important implications for nosology, clinical practice and research.
The pharmaceutical industry remains under huge pressure to address the high attrition rates in drug development. Attempts to reduce the number of efficacy- and safety-related failures by analysing ...possible links to the physicochemical properties of small-molecule drug candidates have been inconclusive because of the limited size of data sets from individual companies. Here, we describe the compilation and analysis of combined data on the attrition of drug candidates from AstraZeneca, Eli Lilly and Company, GlaxoSmithKline and Pfizer. The analysis reaffirms that control of physicochemical properties during compound optimization is beneficial in identifying compounds of candidate drug quality and indicates for the first time a link between the physicochemical properties of compounds and clinical failure due to safety issues. The results also suggest that further control of physicochemical properties is unlikely to have a significant effect on attrition rates and that additional work is required to address safety-related failures. Further cross-company collaborations will be crucial to future progress in this area.
Advances in Biomaterials for Drug Delivery Fenton, Owen S.; Olafson, Katy N.; Pillai, Padmini S. ...
Advanced materials (Weinheim),
05/2018, Letnik:
30, Številka:
29
Journal Article
Recenzirano
Odprti dostop
Advances in biomaterials for drug delivery are enabling significant progress in biology and medicine. Multidisciplinary collaborations between physical scientists, engineers, biologists, and ...clinicians generate innovative strategies and materials to treat a range of diseases. Specifically, recent advances include major breakthroughs in materials for cancer immunotherapy, autoimmune diseases, and genome editing. Here, strategies for the design and implementation of biomaterials for drug delivery are reviewed. A brief history of the biomaterials field is first established, and then commentary on RNA delivery, responsive materials development, and immunomodulation are provided. Current challenges associated with these areas as well as opportunities to address long‐standing problems in biology and medicine are discussed throughout.
Biomaterials for drug delivery have enabled the treatment of a wide range of diseases. A historical background is presented alongside recent advances in therapeutic RNA delivery, the engineering of responsive polymers, and immunotherapy strategies against disease. Emerging applications and potential challenges within the biomaterials field are also discussed.
Recent genomic studies have revealed the highly polygenic nature of psychiatric disorders, including schizophrenia, bipolar disorder and major depressive disorder. Many of the individual genetic ...associations are shared across multiple disorders in a way that points to extensive biological pleiotropy and further challenges the biological validity of existing diagnostic approaches. Here we argue that the existence of risk alleles specific to a single diagnostic category is unlikely. We also highlight some of the important clinical repercussions of pleiotropy.
Background The UK Biobank is a unique resource for biomedical research, with extensive phenotypic and genetic data on half a million adultsfrom the general population. We aimed to examine the effect ...of neurodevelopmental copy number variants (CNVs) on the cognitive performance of participants. Methods We used Affymetrix Power Tools and PennCNV-Affy software to analyse Affymetrix microarraysof the first 152,728genotypedindividuals. We annotated a list of 93 CNVs and compared their frequencies with control datasets. Weanalysed the performance on seven cognitive tests of carriers of 12 CNVs associated with schizophrenia (N = 1,087) and of carriers of another 41neurodevelopmental CNVs (N = 484). Results The frequencies of the 93 CNVs in the Biobank subjects were remarkably similar to those among 26,628 controls from other datasets. Carriersof schizophrenia-associated CNVs and of the group of 41 other neurodevelopmental CNVs had impaired performance on the cognitive tests, with nine of 14 comparisons remaining statistically significant aftercorrection for multiple testing.They also had lower educational and occupational attainment (p-values between 10-7 and 10-18 ).Thedeficits in cognitive performance were modest (z score reductions between 0.01 and 0.51), compared to individuals with schizophrenia in the Biobank (z score reductions between 0.35 and 0.90). Conclusions This is the largest study on the cognitive phenotypes of CNVs to date. Adult carriers of neurodevelopmentalCNVs from the general population have significant cognitivedeficits. The UK Biobank will allow unprecedented opportunities for analysis of furtherphenotypic consequences of CNVs.
Abstract The dopamine hypothesis is the longest standing pathoetiologic theory of schizophrenia. Because it was initially based on indirect evidence and findings in patients with established ...schizophrenia, it was unclear what role dopamine played in the onset of the disorder. However, recent studies in people at risk of schizophrenia have found elevated striatal dopamine synthesis capacity and increased dopamine release to stress. Furthermore, striatal dopamine changes have been linked to altered cortical function during cognitive tasks, in line with preclinical evidence that a circuit involving cortical projections to the striatum and midbrain may underlie the striatal dopamine changes. Other studies have shown that a number of environmental risk factors for schizophrenia, such as social isolation and childhood trauma, also affect presynaptic dopaminergic function. Advances in preclinical work and genetics have begun to unravel the molecular architecture linking dopamine, psychosis, and psychosocial stress. Included among the many genes associated with risk of schizophrenia are the gene encoding the dopamine D2 receptor and those involved in the upstream regulation of dopaminergic synthesis, through glutamatergic and gamma-aminobutyric acidergic pathways. A number of these pathways are also linked to the stress response. We review these new lines of evidence and present a model of how genes and environmental factors may sensitize the dopamine system so that it is vulnerable to acute stress, leading to progressive dysregulation and the onset of psychosis. Finally, we consider the implications for rational drug development, in particular regionally selective dopaminergic modulation, and the potential of genetic factors to stratify patients.
Silicone Surface Fundamentals Owen, Michael J.
Macromolecular rapid communications.,
March 2021, Letnik:
42, Številka:
5
Journal Article
Recenzirano
Many of the applications of the most familiar silicone polymer, polydimethylsiloxane (PDMS), are a consequence of its hydrophobic nature. The key quantities underlying this behavior are the water ...contact angle with water droplets, the surface tension of the polymer, and its interfacial tension with water. These quantities are reviewed for PDMS and the fluorsilicone polymethyltrifluoropropylsiloxane (PMTFPS) as well as some other less common, more highly fluorinated, fluorosilicones. As aliphatic fluorocarbons are usually introduced into polymers to lower surface tension, it is unexpected that the surface tension of PMTFPS is higher than PDMS. However, this observation is consistent with Zisman's early extensive studies. It is also somewhat surprising that there are no definitive values accepted for the water contact angle with PDMS and the interfacial tension at the PDMS/water interface. Some reasons for this are explored and relevant limitations considered. The variety of ways in which a PDMS surface can be presented must have a major effect on the range of water contact angles reported.
Polydimethylsiloxane (PDMS) is widely used for its fundamental surface properties such as liquid surface tension, water contact angle, and PDMS/water interfacial tension. The first of these is well defined but there is no general agreement on the values of the other two. Significant historic and recent data regarding these properties are reviewed.
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