Highlights • Parvalbumin (PV) cell alterations contribute to cognitive deficits in schizophrenia. • PV cells have multiple gene expression disturbances that impair their function. • These ...disturbances may arise from either cell-autonomous factors or altered inputs.
Certain clinical features of schizophrenia, such as working memory disturbances, appear to emerge from altered gamma oscillatory activity in the prefrontal cortex (PFC). Given the essential role of ...GABA neurotransmission in both working memory and gamma oscillations, understanding the cellular substrate for their disturbances in schizophrenia requires evidence from in vivo neuroimaging studies, which provide a means to link markers of GABA neurotransmission to gamma oscillations and working memory, and from postmortem studies, which provide insight into GABA neurotransmission at molecular and cellular levels of resolution. Here, we review findings from both types of studies which converge on the notions that 1) inhibitory GABA signaling in the PFC, especially between parvalbumin positive GABAergic basket cells and excitatory pyramidal cells, is required for gamma oscillatory activity and working memory function; and 2) disturbances in this signaling contribute to altered gamma oscillations and working memory in schizophrenia. Because the PFC is only one node in a distributed cortical network that mediates working memory, we also review evidence of GABA abnormalities in other cortical regions in schizophrenia.
Abstract Cognitive deficits are a core clinical feature of schizophrenia but respond poorly to available medications. Thus, understanding the neural basis of these deficits is crucial for the ...development of new therapeutic interventions. The types of cognitive processes affected in schizophrenia are thought to depend on the precisely timed transmission of information in cortical regions via synchronous oscillations at gamma band frequency. Here, we review 1) data from clinical studies suggesting that induction of frontal cortex gamma oscillations during tasks that engage cognitive or complex perceptual functions is attenuated in schizophrenia; 2) findings from basic neuroscience studies highlighting the features of parvalbumin-positive interneurons that are critical for gamma oscillation production; and 3) results from recent postmortem human brain studies providing additional molecular bases for parvalbumin-positive interneuron alterations in prefrontal cortical circuitry in schizophrenia.
Topography is a key driver of tropical forest structure and composition, as it constrains local nutrient and hydraulic conditions within which trees grow. Yet, we do not fully understand how changes ...in forest physiognomy driven by topography impact other emergent properties of forests, such as their aboveground carbon density (ACD). Working in Borneo – at a site where 70‐m‐tall forests in alluvial valleys rapidly transition to stunted heath forests on nutrient‐depleted dip slopes – we combined field data with airborne laser scanning and hyperspectral imaging to characterise how topography shapes the vertical structure, wood density, diversity and ACD of nearly 15 km2 of old‐growth forest. We found that subtle differences in elevation – which control soil chemistry and hydrology – profoundly influenced the structure, composition and diversity of the canopy. Capturing these processes was critical to explaining landscape‐scale heterogeneity in ACD, highlighting how emerging remote sensing technologies can provide new insights into long‐standing ecological questions.
Schizophrenia is a devastating disorder that is common, usually chronic, frequently associated with substantial co‐morbidity for addictive and medical disorders and, as a consequence, very costly in ...both personal and economic terms. At present, no proven means for preventing or modifying the course of the illness exist. This review discusses evidence supporting the ideas that: (i) impairments in certain cognitive processes are the core feature of schizophrenia; (ii) these cognitive impairments reflect abnormalities in specific cortical circuits; and (iii) these circuitry abnormalities arise during childhood–adolescence. The implications of these findings for the development and implementation of safe, preemptive, disease‐modifying interventions in individuals at high risk for a clinical diagnosis of schizophrenia are considered.
Schizophrenia is a common, usually chronic, and very costly illness with no proven means of prevention. Impairments in certain cognitive processes are the core feature of schizophrenia, reflect abnormalities in specific cortical circuits, and arise during childhood‐adolescence. The implications of these findings for the development of preemptive, disease‐modifying interventions in individuals at high risk for a clinical diagnosis of schizophrenia are discussed.
SARS-CoV-2 is a recently emerged respiratory pathogen that has significantly impacted global human health. We wanted to rapidly characterise the transcriptomic, proteomic and phosphoproteomic ...landscape of this novel coronavirus to provide a fundamental description of the virus's genomic and proteomic potential.
We used direct RNA sequencing to determine the transcriptome of SARS-CoV-2 grown in Vero E6 cells which is widely used to propagate the novel coronavirus. The viral transcriptome was analysed using a recently developed ORF-centric pipeline. Allied to this, we used tandem mass spectrometry to investigate the proteome and phosphoproteome of the same virally infected cells.
Our integrated analysis revealed that the viral transcripts (i.e. subgenomic mRNAs) generally fitted the expected transcription model for coronaviruses. Importantly, a 24 nt in-frame deletion was detected in over half of the subgenomic mRNAs encoding the spike (S) glycoprotein and was predicted to remove a proposed furin cleavage site from the S glycoprotein. Tandem mass spectrometry identified over 500 viral peptides and 44 phosphopeptides in virus-infected cells, covering almost all proteins predicted to be encoded by the SARS-CoV-2 genome, including peptides unique to the deleted variant of the S glycoprotein.
Detection of an apparently viable deletion in the furin cleavage site of the S glycoprotein, a leading vaccine target, shows that this and other regions of SARS-CoV-2 proteins may readily mutate. The furin site directs cleavage of the S glycoprotein into functional subunits during virus entry or exit and likely contributes strongly to the pathogenesis and zoonosis of this virus. Our data emphasises that the viral genome sequence should be carefully monitored during the growth of viral stocks for research, animal challenge models and, potentially, in clinical samples. Such variations may result in different levels of virulence, morbidity and mortality.
The PI3K Pathway in Human Disease Fruman, David A.; Chiu, Honyin; Hopkins, Benjamin D. ...
Cell,
08/2017, Letnik:
170, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Phosphoinositide 3-kinase (PI3K) activity is stimulated by diverse oncogenes and growth factor receptors, and elevated PI3K signaling is considered a hallmark of cancer. Many PI3K pathway-targeted ...therapies have been tested in oncology trials, resulting in regulatory approval of one isoform-selective inhibitor (idelalisib) for treatment of certain blood cancers and a variety of other agents at different stages of development. In parallel to PI3K research by cancer biologists, investigations in other fields have uncovered exciting and often unpredicted roles for PI3K catalytic and regulatory subunits in normal cell function and in disease. Many of these functions impinge upon oncology by influencing the efficacy and toxicity of PI3K-targeted therapies. Here we provide a perspective on the roles of class I PI3Ks in the regulation of cellular metabolism and in immune system functions, two topics closely intertwined with cancer biology. We also discuss recent progress developing PI3K-targeted therapies for treatment of cancer and other diseases.
As a central hub for cellular signaling, PI3K is an important regulator of cellular growth and function. This Review focuses on its basic signaling mechanisms as well as its role in metabolism and immune function in the context of cancer.
Progress Toward Cardiac Xenotransplantation Pierson, Richard N; Fishman, Jay A; Lewis, Gregory D ...
Circulation (New York, N.Y.),
2020-October-06, Letnik:
142, Številka:
14
Journal Article
Recenzirano
Odprti dostop
Consistent survival of life-supporting pig heart xenograft recipients beyond 90 days was recently reported using genetically modified pigs and a clinically applicable drug treatment regimen. If this ...remarkable achievement proves reproducible, published benchmarks for clinical translation of cardiac xenografts appear to be within reach. Key mechanistic insights are summarized here that informed recent pig design and therapeutic choices, which together appear likely to enable early clinical translation.
Kraepelin, in his early descriptions of schizophrenia (SZ), characterized the illness as having "an orchestra without a conductor." Kraepelin further speculated that this "conductor" was situated in ...the frontal lobes. Findings from multiple studies over the following decades have clearly implicated pathology of the dorsolateral prefrontal cortex (DLPFC) as playing a central role in the pathophysiology of SZ, particularly with regard to key cognitive features such as deficits in working memory and cognitive control. Following an overview of the cognitive mechanisms associated with DLPFC function and how they are altered in SZ, we review evidence from an array of neuroscientific approaches addressing how these cognitive impairments may reflect the underlying pathophysiology of the illness. Specifically, we present evidence suggesting that alterations of the DLPFC in SZ are evident across a range of spatial and temporal resolutions: from its cellular and molecular architecture, to its gross structural and functional integrity, and from millisecond to longer timescales. We then present an integrative model based upon how microscale changes in neuronal signaling in the DLPFC can influence synchronized patterns of neural activity to produce macrocircuit-level alterations in DLPFC activation that ultimately influence cognition and behavior. We conclude with a discussion of initial efforts aimed at targeting DLPFC function in SZ, the clinical implications of those efforts, and potential avenues for future development.
Inverse vulcanization is a copolymerization of elemental sulfur and alkenes that provides unique materials with high sulfur content (typically ≥50% sulfur by mass). These polymers contain a dynamic ...and reactive polysulfide network that creates many opportunities for processing, assembly, and repair that are not possible with traditional plastics, rubbers and thermosets. In this study, we demonstrate that two surfaces of these sulfur polymers can be chemically joined at room temperature through a phosphine or amine-catalyzed exchange of the S-S bonds in the polymer. When the nucleophile is pyridine or triethylamine, we show that S-S metathesis only occurs at room temperature for a sulfur rank > 2-an important discovery for the design of polymers made by inverse vulcanization. This mechanistic understanding of the S-S metathesis was further supported with small molecule crossover experiments in addition to computational studies. Applications of this chemistry in latent adhesives, additive manufacturing, polymer repair, and recycling are also presented.
Polymers made by inverse vulcanization can be assembled, repaired, and recycled at room temperature through nucleophile-catalyzed S-S metathesis.
PDF
