The geometry of spontaneous spiking in neuronal networks

The mathematical theory of pattern formation in electrically coupled networks of excitable neurons forced by small noise is presented in this work. Using the Freidlin-Wentzell large deviation theory for randomly perturbed dynamical systems and the elements of the algebraic graph theory, we identify and analyze the main regimes in the network dynamics in terms of the key control parameters: excitability, coupling strength, and network topology. The analysis reveals the geometry of spontaneous dynamics in electrically coupled network. Specifically, we show that the location of the minima of a certain continuous function on the surface of the unit n-cube encodes the most likely activity patterns generated by the network. By studying how the minima of this function evolve under the variation of the coupling strength, we describe the principal transformations in the network dynamics. The minimization problem is also used for the quantitative description of the main dynamical regimes and transitions between them. In particular, for the weak and strong coupling regimes, we present asymptotic formulas for the network activity rate as a function of the coupling strength and the degree of the network. The variational analysis is complemented by the stability analysis of the synchronous state in the strong coupling regime. The stability estimates reveal the contribution of the network connectivity and the properties of the cycle subspace associated with the graph of the network to its synchronization properties. This work is motivated by the experimental and modeling studies of the ensemble of neurons in the Locus Coeruleus, a nucleus in the brainstem involved in the regulation of cognitive performance and behavior

Molecular structure and developmental expression of zebrafish atp2a genes

[[abstract]]We isolated two atp2a genes, atp2a1 and atp2a2a, from embryonic zebrafish. Amino acid sequences deduced from zebrafish atp2a genes are aligned with orthologue proteins from other species, the results showed that they share high percentage of identities (82%–94%) and acidic pIs (5.03–5.33). Whole mount in situ hybridization experiments showed that atp2a1 and atp2a2a are maternal inherited genes which can be detected at 1-cell stage embryos and express in the entire animal pole from 6 hours post-fertilization (hpf) to 12 hpf. At the later stages (48–96 hpf), expression of atp2a1 was restricted in head and trunk muscles as well as in some neurons. In contrast to the strongly expression of atp2a1 in head muscle, expression of atp2a2a was detected in head muscle in a fainter manner. In addition, transcripts of atp2a2a were observed in the developing heart during early cardiogenesis. The present studies not only help us to comparatively analyze atp2a genes across species, but also provide useful information about expressions during early embryogenesis that will help in further investigations of functional studies of Atp2a in the future.[[incitationindex]]SCI[[booktype]]紙

Soluble forms of tau are toxic in Alzheimer's disease

Accumulation of neurofibrillary tangles (NFT), intracellular inclusions of fibrillar forms of tau, is a hallmark of Alzheimer Disease. NFT have been considered causative of neuronal death, however, recent evidence challenges this idea. Other species of tau, such as soluble misfolded, hyperphosphorylated, and mislocalized forms, are now being implicated as toxic. Here we review the data supporting soluble tau as toxic to neurons and synapses in the brain and the implications of these data for development of therapeutic strategies for Alzheimer’s disease and other tauopathies

Viral coinfections in hospitalized coronavirus disease 2019 patients recruited to the international severe acute respiratory and emerging infections consortium WHO clinical characterisation protocol UK study

Background We conducted this study to assess the prevalence of viral coinfection in a well characterized cohort of hospitalized coronavirus disease 2019 (COVID-19) patients and to investigate the impact of coinfection on disease severity. Methods Multiplex real-time polymerase chain reaction testing for endemic respiratory viruses was performed on upper respiratory tract samples from 1002 patients with COVID-19, aged <1 year to 102 years old, recruited to the International Severe Acute Respiratory and Emerging Infections Consortium WHO Clinical Characterisation Protocol UK study. Comprehensive demographic, clinical, and outcome data were collected prospectively up to 28 days post discharge. Results A coinfecting virus was detected in 20 (2.0%) participants. Multivariable analysis revealed no significant risk factors for coinfection, although this may be due to rarity of coinfection. Likewise, ordinal logistic regression analysis did not demonstrate a significant association between coinfection and increased disease severity. Conclusions Viral coinfection was rare among hospitalized COVID-19 patients in the United Kingdom during the first 18 months of the pandemic. With unbiased prospective sampling, we found no evidence of an association between viral coinfection and disease severity. Public health interventions disrupted normal seasonal transmission of respiratory viruses; relaxation of these measures mean it will be important to monitor the prevalence and impact of respiratory viral coinfections going forward

Delayed mucosal anti-viral responses despite robust peripheral inflammation in fatal COVID-19

Background While inflammatory and immune responses to SARS-CoV-2 infection in peripheral blood are extensively described, responses at the upper respiratory mucosal site of initial infection are relatively poorly defined. We sought to identify mucosal cytokine/chemokine signatures that distinguished COVID-19 severity categories, and relate these to disease progression and peripheral inflammation. Methods We measured 35 cytokines and chemokines in nasal samples from 274 patients hospitalised with COVID-19. Analysis considered the timing of sampling during disease, as either the early (0-5 days post-symptom onset) or late (6-20 days post-symptom onset). Results Patients that survived severe COVID-19 showed IFN-dominated mucosal immune responses (IFN-γ, CXCL10 and CXCL13) early in infection. These early mucosal responses were absent in patients that would progress to fatal disease despite equivalent SARS-CoV-2 viral load. Mucosal inflammation in later disease was dominated by IL-2, IL-10, IFN-γ, and IL-12p70, which scaled with severity but did not differentiate patients who would survive or succumb to disease. Cytokines and chemokines in the mucosa showed distinctions from responses evident in the peripheral blood, particularly during fatal disease. Conclusions Defective early mucosal anti-viral responses anticipate fatal COVID-19 but are not associated with viral load. Early mucosal immune responses may define the trajectory of severe COVID-19

Post-acute COVID-19 neuropsychiatric symptoms are not associated with ongoing nervous system injury

A proportion of patients infected with severe acute respiratory syndrome coronavirus 2 experience a range of neuropsychiatric symptoms months after infection, including cognitive deficits, depression and anxiety. The mechanisms underpinning such symptoms remain elusive. Recent research has demonstrated that nervous system injury can occur during COVID-19. Whether ongoing neural injury in the months after COVID-19 accounts for the ongoing or emergent neuropsychiatric symptoms is unclear. Within a large prospective cohort study of adult survivors who were hospitalized for severe acute respiratory syndrome coronavirus 2 infection, we analysed plasma markers of nervous system injury and astrocytic activation, measured 6 months post-infection: neurofilament light, glial fibrillary acidic protein and total tau protein. We assessed whether these markers were associated with the severity of the acute COVID-19 illness and with post-acute neuropsychiatric symptoms (as measured by the Patient Health Questionnaire for depression, the General Anxiety Disorder assessment for anxiety, the Montreal Cognitive Assessment for objective cognitive deficit and the cognitive items of the Patient Symptom Questionnaire for subjective cognitive deficit) at 6 months and 1 year post-hospital discharge from COVID-19. No robust associations were found between markers of nervous system injury and severity of acute COVID-19 (except for an association of small effect size between duration of admission and neurofilament light) nor with post-acute neuropsychiatric symptoms. These results suggest that ongoing neuropsychiatric symptoms are not due to ongoing neural injury