Physiological and pathological functions of neuroserpin: Regulation of cellular responses through multiple mechanisms.

It is 27 years since neuroserpin was first discovered in the nervous system and identified as a member of the serpin superfamily. Since that time potential roles for this serine protease inhibitor have been identified in neuronal and non-neuronal systems. Many are linked to inhibition of neuroserpin's principal enzyme target, tissue plasminogen activator (tPA), although some have been suggested to involve alternate non-inhibitory mechanisms. This review focuses mainly on the inhibitory roles of neuroserpin and discusses the evidence supporting tPA as the physiological target. While the major sites of neuroserpin expression are neural, endocrine and immune tissues, most progress on characterizing functional roles for neuroserpin have been in the brain. Roles in emotional behaviour, synaptic plasticity and neuroprotection in stroke and excitotoxicity models are discussed. Current knowledge on three neurological diseases associated with neuroserpin mutation or activity, Familial Encephalopathy with Neuroserpin Inclusion Bodies (FENIB), Alzheimer's disease and brain metastasis is presented. Finally, we consider mechanistic studies that have revealed a distinct inhibitory mechanism for neuroserpin and its possible implications for neuroserpin function.

Feasibility and Acceptability of an Online WhatsApp Support Group on Breastfeeding: Protocol for a Randomized Controlled Trial.

BACKGROUND: Mobile health, the use of mobile technology in delivering health care, has been found to be effective in changing health behaviors, including improving breastfeeding practices in postpartum women. With the widespread use of smartphones and instant messaging apps in Hong Kong, instant messaging groups could be a useful channel for delivering breastfeeding peer support. OBJECTIVE: The aim of this paper is to study the feasibility and acceptability of an online instant messaging peer support group by trained peer counselors on improving breastfeeding outcome in primiparous women in Hong Kong. METHODS: A two-arm, assessor-blind, randomized controlled feasibility study will be conducted on 40 primiparous women with the intention to breastfeed. Participants are recruited from the antenatal obstetrics and gynecology clinic of a public hospital in Hong Kong and randomly assigned at a 1:1 ratio to either intervention or control group. The intervention group receives peer support in an online instant messaging group with trained peer counselors on top of standard care, whereas the control group receives standard care. Breastfeeding outcome will be assessed for 6 months post partum or until weaned. The breastfeeding status, the proportion and duration of exclusive and any breastfeeding in each group, and the self-efficacy and attitude of participants will be assessed. The feasibility and acceptability of the study would also be assessed in preparation for a full randomized controlled trial. RESULTS: This study (protocol version 1 dated January 5, 2021) has been reviewed and approved by the institutional review board of the University of Hong Kong, Hospital Authority Hong Kong West Cluster (reference UW 21-039), on January 26, 2021. Data collection is ongoing and expected to be completed in December 2021. The findings will be updated on clinical trial registry and disseminated in peer-reviewed journals. CONCLUSIONS: This study aims to assess the feasibility and effectiveness of an online instant messaging peer support group in improving the breastfeeding outcome of primiparous women in Hong Kong. Its findings could inform the feasibility of a full-scale trial with this intervention design. TRIAL REGISTRATION: ClinicalTrials.gov NCT04826796; https://clinicaltrials.gov/ct2/show/NCT04826796. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/32338.

Eye-tracking study on facial emotion recognition tasks in individuals with high-functioning autism spectrum disorders.

The eye-tracking experiment was carried out to assess fixation duration and scan paths that individuals with and without high-functioning autism spectrum disorders employed when identifying simple and complex emotions. Participants viewed human photos of facial expressions and decided on the identification of emotion, the negative-positive emotion orientation, and the degree of emotion intensity. Results showed that there was an atypical emotional processing in the high-functioning autism spectrum disorder group to identify facial emotions when eye-tracking data were compared between groups. We suggest that the high-functioning autism spectrum disorder group prefers to use a rule-bound categorical approach as well as featured processing strategy in the facial emotion recognition tasks. Therefore, the high-functioning autism spectrum disorder group more readily distinguishes overt emotions such as happiness and sadness. However, they perform more inconsistently in covert emotions such as disgust and angry, which demand more cognitive strategy employment during emotional perception. Their fixation time in eye-tracking data demonstrated a significant difference from that of their controls when judging complex emotions, showing reduced "in" gazes and increased "out" gazes. The data were in compliance with the findings in their emotion intensity ratings which showed individuals with autism spectrum disorder misjudge the intensity of complex emotions especially the emotion of fear.

Comparing Eye-tracking Data of Children with High-functioning ASD, Comorbid ADHD, and of a Control Watching Social Videos.

Children with autism spectrum disorders (ASD) are known to have sensory-perceptual processing deficits that weaken their abilities to attend and perceive social stimuli in daily living contexts. Since daily social episodes consist of subtle dynamic changes in social information, any failure to attend to or process subtle human nonverbal cues, such as facial expression, postures, and gestures, might lead to inappropriate social interaction. Traditional behavioral rating scales or assessment tools based on static social scenes have limitations in capturing the moment-to-moment changes in social scenarios. An eye-tracking assessment, which can be administered in a video-based mode, is therefore preferred, to augment clinical observation. In this study, using the single-case comparison design, the eye-tracking data of three participants, a child with autism spectrum disorder (ASD), another with comorbid attention deficit-hyperactive disorder (ADHD), and a neurotypical control, are captured while they view a video of social scenarios. The eye-tracking experiment has helped answer the research question: How does social attention differ between the three participants? By predefining areas of interest (AOIs), their visual attention on relevant or irrelevant social stimuli, how fast each participant attends to the first social stimuli appearing in the videos, for how long each participant continues to attend to those stimuli within the AOIs, and the gaze shifts between multiple social stimuli appearing concurrently in the same social scene are captured, compared, and analyzed in a video-based eye-tracking experiment.

Physiological and pathological roles of tissue plasminogen activator and its inhibitor neuroserpin in the nervous system.

Although its roles in the vascular space are most well-known, tissue plasminogen activator (tPA) is widely expressed in the developing and adult nervous system, where its activity is believed to be regulated by neuroserpin, a predominantly brain-specific member of the serpin family of protease inhibitors. In the normal physiological state, tPA has been shown to play roles in the development and plasticity of the nervous system. Ischemic damage, however, may lead to excess tPA activity in the brain and this is believed to contribute to neurodegeneration. In this article, we briefly review the physiological and pathological roles of tPA in the nervous system, which includes neuronal migration, axonal growth, synaptic plasticity, neuroprotection and neurodegeneration, as well as a contribution to neurological disease. We summarize tPA's multiple mechanisms of action and also highlight the contributions of the inhibitor neuroserpin to these processes.

Duplicate zebrafish runx2 orthologues are expressed in developing skeletal elements.

The differentiation of cells in the vertebrate skeleton is controlled by a precise genetic program. One crucial regulatory gene in the pathway encodes the transcription factor Runx2, which in mouse is required for differentiation of all osteoblasts and the proper development of a subset of hypertrophic chondrocytes. To explore the differentiation of skeletogenic cells in the model organism zebrafish (Danio rerio), we have identified two orthologues of the mammalian gene, runx2a and runx2b. Both genes share sequence homology and gene structure with the mammalian genes, and map to regions of the zebrafish genome displaying conserved synteny with the region where the human gene is localized. While both genes are expressed in developing skeletal elements, they show evidence of partial divergence in expression pattern, possibly explaining why both orthologues have been retained through teleost evolution.

AAV-mediated overexpression of neuroserpin in the hippocampus decreases PSD-95 expression but does not affect hippocampal-dependent learning and memory.

Neuroserpin is a serine protease inhibitor, or serpin, that is expressed in the nervous system and inhibits the protease tissue plasminogen activator (tPA). Neuroserpin has been suggested to play a role in learning and memory but direct evidence for such a role is lacking. Here we have used an adeno-associated virus (AAV) vector expression system to investigate the effect of neuroserpin on hippocampal-dependent learning and memory in the young adult rat. A FLAG-tagged neuroserpin construct was initially characterized by in vitro transcription/translation and transfection into HEK293 cells and shown to interact with tPA and be targeted to the secretory pathway. Targeted injection of a chimeric AAV1/2 vector expressing FLAG-neuroserpin resulted in localized overexpression in the dorsal hippocampus. Neuroserpin overexpression led to the appearance of an unstable neuroserpin:tPA complex in zymographic assays consistent with interaction with endogenous tPA in vivo. Rats overexpressing neuroserpin also showed a significant decrease in the levels of postsynaptic density protein 95, a major postsynaptic scaffolding protein. Three weeks after injection, a range of behavioural tests was performed to measure spatial and associative learning and memory, as well as innate and acquired fear. These tests provided no evidence of a role for neuroserpin in hippocampal-dependent learning and memory. In summary this study does not support a role for neuroserpin in hippocampal-dependent learning and memory in young adult rats but does suggest an involvement of neuroserpin in hippocampal synaptic plasticity.

Synaptic plasticity-associated proteases and protease inhibitors in the brain linked to the processing of extracellular matrix and cell adhesion molecules.

Research on the molecular and cellular basis of learning and memory has focused on the mechanisms that underlie the induction and expression of synaptic plasticity. There is increasing evidence that structural changes at the synapse are associated with synaptic plasticity and that extracellular matrix (ECM) components and cell adhesion molecules are associated with these changes. The functions of both groups of molecules can be regulated by proteolysis. In this article we review the roles of selected proteases and protease inhibitors in perisynaptic proteolysis of the ECM and synaptic adhesion proteins and the impact of proteolysis on synaptic modification and cognitive function.