Aberrant encoding of event saliency in the orbitofrontal cortex following loss of the psychiatric-associated circular RNA, circHomer1.

CircHomer1 is an activity-dependent circular RNA (circRNA) isoform produced from back-splicing of the Homer1 transcript. Homer1 isoforms are well-known regulators of homeostatic synaptic plasticity through post-synaptic density scaffold regulation. Homer1 polymorphisms have been associated with psychiatric diseases including schizophrenia (SCZ) and bipolar disorder (BD).

Influence of Polymer Fibre Reinforcement on Concrete Anchor Breakout Failure Capacity.

With the increasing use of fibre-reinforced concrete, e.g., in industrial floor and tunnel construction, the associated fastening technology in this material has increasingly become the focus of scientific attention in recent years.

The noncoding circular RNA regulates developmental experience-dependent plasticity in mouse visual cortex.

Circular RNAs (circRNAs) are noncoding RNAs abundant in brain tissue, and many are derived from activity-dependent, linear mRNAs encoding for synaptic proteins, suggesting that circRNAs may directly or indirectly play a role in regulating synaptic development, plasticity, and function. However, it is unclear if the circular forms of these RNAs are similarly regulated by activity and what role these circRNAs play in developmental plasticity. Here, we employed transcriptome-wide analysis comparing differential expression of both mRNAs and circRNAs in juvenile mouse primary visual cortex (V1) following monocular deprivation (MD), a model of developmental plasticity.

Regulation of neuronal circHomer1 biogenesis by PKA/CREB/ERK-mediated pathways and effects of glutamate and dopamine receptor blockade.

There are currently only very few efficacious drug treatments for SCZ and BD, none of which can significantly ameliorate cognitive symptoms. Thus, further research is needed in elucidating molecular pathways linked to cognitive function and antipsychotic treatment. Circular RNAs (circRNAs) are stable brain-enriched non-coding RNAs, derived from the covalent back-splicing of precursor mRNA molecules.

Bipolar disorder-iPSC derived neural progenitor cells exhibit dysregulation of store-operated Ca entry and accelerated differentiation.

While most of the efforts to uncover mechanisms contributing to bipolar disorder (BD) focused on phenotypes at the mature neuron stage, little research has considered events that may occur during earlier timepoints of neurodevelopment. Further, although aberrant calcium (Ca) signaling has been implicated in the etiology of this condition, the possible contribution of store-operated Ca entry (SOCE) is not well understood. Here, we report Ca and developmental dysregulations related to SOCE in BD patient induced pluripotent stem cell (iPSC)-derived neural progenitor cells (BD-NPCs) and cortical-like glutamatergic neurons.

Prenatal alcohol exposure dysregulates spinal and circulating immune cell circular RNA expression in adult female rats with chronic sciatic neuropathy.

Alcohol consumption during pregnancy is associated with Fetal Alcohol Spectrum Disorders (FASD) that results in a continuum of central nervous system (CNS) deficits. Emerging evidence from both preclinical and clinical studies indicate that the biological vulnerability to chronic CNS disease in FASD populations is driven by aberrant neuroimmune actions. Our prior studies suggest that, following minor nerve injury, prenatal alcohol exposure (PAE) is a risk factor for developing adult-onset chronic pathological touch sensitivity or allodynia.

Noncoding Regulatory RNAs: Isolation and Analysis of Neuronal Circular RNAs and MicroRNAs.

In addition to expressing a large number of protein-coding transcripts, including alternatively spliced isoforms of the same mRNAs, neurons express a large number of noncoding RNAs. These include microRNAs (miRNAs), circular RNAs (circRNAs), and other regulatory RNAs. The isolation and quantitative analyses of diverse types of RNAs in neurons are critical to understand not only the posttranscriptional mechanisms regulating mRNA levels and their translation but also the potential of several RNAs expressed in the same neurons to regulate these processes by generating networks of competing endogenous RNAs (ceRNAs).

Prenatal alcohol exposure results in brain region- and sex-specific changes in expression in adult mouse brain.

Circular RNAs (circRNAs) are a novel category of covalently-closed non-coding RNAs mainly derived from the back-splicing of exons or introns of protein-coding genes. In addition to their inherent high overall stability, circRNAs, have been shown to have strong functional effects on gene expression a multitude of transcriptional and post-transcriptional mechanisms. Furthermore, circRNAs, appear to be particularly enriched in the brain and able to influence both prenatal development and postnatal brain function.

Multilateral Assessment of Anchorage Bond Characteristics in Steel Fibre Reinforced Concrete.

Anchorage to concrete is a recurring application in construction. For such applications, bonded anchors, formed by means of a polymer adhesive injection into a borehole, are a widely used product due to their flexibility in regards to the construction logistics and positioning of the attached element as well as high load capacities. At the same time, fibre-reinforced concrete is the material of choice for many engineering applications where anchors have to be installed.

Tensile Performance of Headed Anchors in Steel Fiber Reinforced and Conventional Concrete in Uncracked and Cracked State.

Steel fiber reinforced concrete (SFRC) is currently the material of choice for a broad range of structural components. Through the use of SFRC, the entire, or a large portion of, conventional rebar reinforcement can be replaced, in order to improve the load-bearing behavior but also the serviceability and durability characteristics of engineering structures. The use of fiber reinforcement therefore plays a vital role in acute current and future construction industry objectives, these being a simultaneous increase in the service life of structures and the reduction of their environmental impact, in addition to resilience to extreme loads and environmental actions.

A bidirectional competitive interaction between circHomer1 and Homer1b within the orbitofrontal cortex regulates reversal learning.

Although circular RNAs (circRNAs) are enriched in the brain, their relevance for brain function and psychiatric disorders is poorly understood. Here, we show that circHomer1 is inversely associated with relative HOMER1B mRNA isoform levels in both the orbitofrontal cortex (OFC) and stem-cell-derived neuronal cultures of subjects with psychiatric disorders. We further demonstrate that in vivo circHomer1 knockdown (KD) within the OFC can inhibit the synaptic expression of Homer1b mRNA.

Circular RNA circCCNT2 is upregulated in the anterior cingulate cortex of individuals with bipolar disorder.

Gene expression dysregulation in the brain has been associated with bipolar disorder, but little is known about the role of non-coding RNAs. Circular RNAs are a novel class of long noncoding RNAs that have recently been shown to be important in brain development and function. However, their potential role in psychiatric disorders, including bipolar disorder, has not been well investigated.

Proteopathic tau primes and activates interleukin-1β via myeloid-cell-specific MyD88- and NLRP3-ASC-inflammasome pathway.

Pathological hyperphosphorylation and aggregation of tau (pTau) and neuroinflammation, driven by interleukin-1β (IL-1β), are the major hallmarks of tauopathies. Here, we show that pTau primes and activates IL-1β. First, RNA-sequence analysis suggests paired-helical filaments (PHFs) from human tauopathy brain primes nuclear factor κB (NF-κB), chemokine, and IL-1β signaling clusters in human primary microglia.

Transcriptomic changes due to early, chronic intermittent alcohol exposure during forebrain development implicate WNT signaling, cell-type specification, and cortical regionalization as primary determinants of fetal alcohol syndrome.

Background: Fetal alcohol syndrome (FAS) due to gestational alcohol exposure represents one of the most common causes of nonheritable lifelong disability worldwide. In vitro and in vivo models have successfully recapitulated multiple facets of the disorder, including morphological and behavioral deficits, but far less is understood regarding the molecular and genetic mechanisms underlying FAS.

Methods: In this study, we utilized an in vitro human pluripotent stem cell-based (hPSC) model of corticogenesis to probe the effects of early, chronic intermittent alcohol exposure on the transcriptome of first trimester-equivalent cortical neurons.

Astrocyte glutamate uptake coordinates experience-dependent, eye-specific refinement in developing visual cortex.

The uptake of glutamate by astrocytes actively shapes synaptic transmission, however its role in the development and plasticity of neuronal circuits remains poorly understood. The astrocytic glutamate transporter, GLT1 is the predominant source of glutamate clearance in the adult mouse cortex. Here, we examined the structural and functional development of the visual cortex in GLT1 heterozygous (HET) mice using two-photon microscopy, immunohistochemistry and slice electrophysiology.

Prenatal Alcohol Exposure Results in Sex-Specific Alterations in Circular RNA Expression in the Developing Mouse Brain.

Fetal alcohol spectrum disorders (FASD) are heterogeneous disorders associated with alcohol exposure to the developing fetus that are characterized by a range of adverse neurodevelopmental deficits. Despite the numerous genomics and genetic studies on FASD models, the comprehensive molecular understanding of the mechanisms that underlie FASD-related neurodevelopmental deficits remains elusive. Circular RNAs (circRNAs) are a subtype of long non-coding RNAs that are derived from back-splicing and covalent joining of exons and/or introns of protein-coding genes.

Using Bayesian hierarchical modelling to capture cyanobacteria dynamics in Northern European lakes.

Cyanobacteria blooms in lakes and reservoirs currently threaten water security and affect the ecosystem services provided by these freshwater ecosystems, such as drinking water and recreational use. Climate change is expected to further exacerbate the situation in the future because of higher temperatures, extended droughts and nutrient enrichment, due to urbanisation and intensified agriculture. Nutrients are considered critical for the deterioration of water quality in lakes and reservoirs and responsible for the widespread increase in cyanobacterial blooms.

Systems thinking on the resource nexus: Modeling and visualisation tools to identify critical interlinkages for resilient and sustainable societies and institutions.

Achieving the UN Sustainable Development Goals depends on using resources efficiently, avoiding fragmentation in decision-making, recognising the trade-offs and synergies across sectors and adopting an integrated Nexus thinking among policymakers. Nexus Informatics develops the science of recognising and quantifying nexus interlinkages. Nexus-coherent solutions enhance the effect of policymaking in achieving adequate governance, leading to successful strategic vision and efficient resource management.

A psychiatric disease-related circular RNA controls synaptic gene expression and cognition.

Although circular RNAs (circRNAs) are enriched in the mammalian brain, very little is known about their potential involvement in brain function and psychiatric disease. Here, we show that circHomer1a, a neuronal-enriched circRNA abundantly expressed in the frontal cortex, derived from Homer protein homolog 1 (HOMER1), is significantly reduced in both the prefrontal cortex (PFC) and induced pluripotent stem cell-derived neuronal cultures from patients with schizophrenia (SCZ) and bipolar disorder (BD). Moreover, alterations in circHomer1a were positively associated with the age of onset of SCZ in both the dorsolateral prefrontal cortex (DLPFC) and orbitofrontal cortex (OFC).

The LFA-1 antagonist BIRT377 reverses neuropathic pain in prenatal alcohol-exposed female rats via actions on peripheral and central neuroimmune function in discrete pain-relevant tissue regions.

Previous reports show that moderate prenatal alcohol exposure (PAE) poses a risk factor for developing neuropathic pain following adult-onset peripheral nerve injury in male rats. Recently, evidence suggests that immune-related mechanisms underlying neuropathic pain in females are different compared to males despite the fact that both sexes develop neuropathy of similar magnitude and duration following chronic constriction injury (CCI) of the sciatic nerve. Data suggest that the actions of peripheral T cells play a greater role in mediating neuropathy in females.

Exosomal secretion of a psychosis-altered miRNA that regulates glutamate receptor expression is affected by antipsychotics.

The ability of small secretory microvesicles known as exosomes to influence neuronal and glial function via their microRNA (miRNA) cargo has positioned them as a novel and effective method of cell-to-cell communication. However, little is known about the role of exosome-secreted miRNAs in the regulation of glutamate receptor gene expression and their relevance for schizophrenia (SCZ) and bipolar disorder (BD). Using mature miRNA profiling and quantitative real-time PCR (qRT-PCR) in the orbitofrontal cortex (OFC) of SCZ (N = 29; 20 male and 9 female), BD (N = 26; 12 male and 14 female), and unaffected control (N = 25; 21 male and 4 female) subjects, we uncovered that miR-223, an exosome-secreted miRNA that targets glutamate receptors, was increased at the mature miRNA level in the OFC of SCZ and BD patients with positive history of psychosis at the time of death and was inversely associated with deficits in the expression of its targets glutamate ionotropic receptor NMDA-type subunit 2B (GRIN2B) and glutamate ionotropic receptor AMPA-type subunit 2 (GRIA2).

LFA-1 antagonist (BIRT377) similarly reverses peripheral neuropathic pain in male and female mice with underlying sex divergent peripheral immune proinflammatory phenotypes.

Aim: The majority of preclinical studies investigating aberrant glial-neuroimmune actions underlying neuropathic pain have focused on male rodent models. Recently, studies have shown peripheral immune cells play a more prominent role than glial cells in mediating pathological pain in females. Here, we compared the onset and duration of allodynia in males and females, and the anti-allodynic action of a potentially novel therapeutic drug (BIRT377) that not only antagonizes the action of lymphocyte function-associated antigen-1 (LFA-1) to reduce cell migration in the periphery, but may also directly alter the cellular inflammatory bias.

Targeting the β2-integrin LFA-1, reduces adverse neuroimmune actions in neuropathic susceptibility caused by prenatal alcohol exposure.

Recently, moderate prenatal alcohol exposure (PAE) was shown to be a risk factor for peripheral neuropathy following minor nerve injury. This effect coincides with elevated spinal cord astrocyte activation and ex vivo immune cell reactivity assessed by proinflammatory cytokine interleukin (IL) -1β protein expression. Additionally, the β2-integrin adhesion molecule, lymphocyte function-associated antigen-1 (LFA-1), a factor that influences the expression of the proinflammatory/anti-inflammatory cytokine network is upregulated.

Rett syndrome: insights into genetic, molecular and circuit mechanisms.

Rett syndrome (RTT) is a severe neurological disorder caused by mutations in the gene encoding methyl-CpG-binding protein 2 (MeCP2). Almost two decades of research into RTT have greatly advanced our understanding of the function and regulation of the multifunctional protein MeCP2. Here, we review recent advances in understanding how loss of MeCP2 impacts different stages of brain development, discuss recent findings demonstrating the molecular role of MeCP2 as a transcriptional repressor, assess primary and secondary effects of MeCP2 loss and examine how loss of MeCP2 can result in an imbalance of neuronal excitation and inhibition at the circuit level along with dysregulation of activity-dependent mechanisms.

Effects of spinal non-viral interleukin-10 gene therapy formulated with d-mannose in neuropathic interleukin-10 deficient mice: Behavioral characterization, mRNA and protein analysis in pain relevant tissues.

Studies show that spinal (intrathecal; i.t.) interleukin-10 (IL-10) gene therapy reverses neuropathic pain in animal models, and co-administration with the mannose receptor (MR; CD206) ligand d-mannose (DM) greatly improves therapeutic efficacy.