Changes in Activity and Kinetic Properties of the Proteasome in Different Rat Organs during Development and Maturation

The proteasome is considered the most important proteolytic system for removal of damaged proteins with aging. Using fluorogenic peptide substrates, the chymotrypsin-like, the trypsin-like, and the peptidylglutamyl peptidase activities of the proteasome were measured in the soluble fractions of liver, brain, and lens rat homogenates. Specific activity was significantly decreased in liver and brain homogenates with maturation of the animal, that is, from newborn (7 days old) to fertile rats (2–4 months old). Rat lens homogenate exhibited an increase in activity with maturation and also with aging. Chymotrypsin-like activity was stimulated by calcium and this proteolytic activity was significantly decreased with maturation of the rat brain. The Michaelis-Menten constant (Km) increased with age in rat liver and lens, indicating a loss of affinity for its substrates by the proteasome in the animal with maturation and aging. The present data suggest that the loss of function of the proteasome with maturation may be due to structural changes of the proteasome or a decreased content of regulatory components

Blood Biomarkers for Alzheimer's Disease: Much Promise, Cautious Progress

Biomarkers in Alzheimer's disease (AD) have the potential to allow early and more accurate diagnosis, predict disease progression, stratify individuals and track response to candidate therapies in drug trials. The first fluid biomarkers reflecting aspects of AD neuropathology were identified in cerebrospinal fluid (CSF) in the 1990s. Three CSF biomarkers (amyloid-β 1-42, total tau and phospho-tau) have consistently been shown to have diagnostic utility and are incorporated into the new diagnostic criteria for AD. These markers have also been shown in longitudinal studies to predict conversion of mild cognitive impairment to AD. However, a key issue with the use of CSF biomarkers as a screening test is the invasiveness of lumbar puncture. Over the last 20 years there has been an active quest for blood biomarkers, which could be easily acquired and tested repeatedly throughout the disease course. One approach to identifying such markers is to attempt to measure candidates that have already been identified in CSF. Until recently, this approach has been limited by assay sensitivity, but newer platforms now allow single molecule-level detection. Another approach is identification of candidates in large multiplex panels that allow for multiple analytes to be quantified in parallel. While both approaches show promise, to date no blood-based biomarker or combination of biomarkers has sufficient predictive value to have utility in clinical practice. In this review, an overview of promising blood protein candidates is provided, and the challenges of validating and converting these into practicable tests are discussed

Fluid biomarkers and risk of neurodegenerative disease in retired athletes with multiple concussions: Results from the International Concussion and Head Injury Research Foundation Brain health in Retired athletes Study of Ageing and Impact-Related Neurodegenerative Disease (ICHIRF-BRAIN study)

Objectives To investigate the association and utility of blood plasma markers of neurodegeneration in a population of retired athletes self-reporting multiple concussions throughout a sporting career. It is hypothesised that this type of athletic history would cause an increased prevalence of neurodegenerative disease, as detected by biomarkers for neurodegenerative disease processes. Methods One hundred and fifty-nine participants were recruited (90 males, 69 females, mean age 61.3±9.13 years), including 121 participants who had retired from playing professional or semiprofessional sports and self-reported ≥1 concussion during their careers (range 1-74; mean concussions=10.7). The control group included 38 age-matched and sex-matched controls, with no history of concussion. We measured neurofilament light (NfL) and tau (neurodegeneration markers), glial fibrillar acidic protein (GFAP) (astrocytic activation marker) and 40 and 42 amino acid-long amyloid beta (Aβ40 and Aβ42) (Alzheimer-associated amyloid pathology markers) concentrations using ultrasensitive single molecule array technology. Results We found retired athletes reporting one or more concussions throughout an athletic career showed no significant changes in NfL, tau, GFAP and Aβ40 and Aβ42 concentrations in comparison to a control group. No correlations were found between biomarkers and number of concussions (mean=10.7). A moderate correlation was found between NfL concentration and age. Conclusion No difference in blood concentrations of neurodegeneration markers NfL, tau, GFAP and Aβ40 and Aβ42 was found in retired athletes with a history of concussion compared with controls. An increased prevalence of neurodegenerative diseases is not detected by biomarkers in a population self-reporting multiple concussions. Trial registration number ISRCTN 1131209

Cooperative action in eukaryotic gene regulation: physical properties of a viral example

The Epstein-Barr virus (EBV) infects more than 90% of the human population, and is the cause of several both serious and mild diseases. It is a tumorivirus, and has been widely studied as a model system for gene (de)regulation in human. A central feature of the EBV life cycle is its ability to persist in human B cells in states denoted latency I, II and III. In latency III the host cell is driven to cell proliferation and hence expansion of the viral population, but does not enter the lytic pathway, and no new virions are produced, while the latency I state is almost completely dormant. In this paper we study a physico-chemical model of the switch between latency I and latency III in EBV. We show that the unusually large number of binding sites of two competing transcription factors, one viral and one from the host, serves to make the switch sharper (higher Hill coefficient), either by cooperative binding between molecules of the same species when they bind, or by competition between the two species if there is sufficient steric hindrance.Comment: 7 pages, 6 figures, 1 tabl

Neurochemical biomarkers to study CNS effects of COVID-19: a narrative review and synthesis

Neurological symptoms are frequently reported in patients suffering from COVID-19. Common CNS-related symptoms include anosmia, caused by viral interaction with either neurons or supporting cells in nasal olfactory tissues. Diffuse encephalopathy is the most common sign of CNS dysfunction, which likely results from the CNS consequences of the systemic inflammatory syndrome associated with severe COVID-19. Additionally, microvascular injuries and thromboembolic events likely contribute to the neurologic impact of acute COVID-19. These observations are supported by evidence of CNS immune activation in cerebrospinal fluid (CSF) and in autopsy tissue, along with detection of microvascular injuries in both pathological and neuroimaging studies. The frequent occurrence of thromboembolic events in patients with COVID-19 has generated different hypotheses, among which viral interaction with perivascular cells is particularly attractive, yet unproven. A distinguishing feature of CSF findings in SARS-CoV-2 infection is that clinical signs characteristic of neurotropic viral infections (CSF pleocytosis and blood brain barrier injury) are mild or absent. Moreover, virus detection in CSF is rare, and often of uncertain significance. In this review, we provide an overview of the neurological impact that occur in the acute phase of COVID-19, and the role of CSF biomarkers in the clinical management and research to better treat and understand the disease. In addition to aiding as diagnostic and prognostic tools during acute infection, the use of comprehensive and well characterized CSF and blood biomarkers will be vital in understanding the potential impact on the CNS in the rapidly increasing number of individuals recovering from COVID-19

EU Peatlands: Current Carbon Stocks and Trace Gas Fluxes

Peatlands in Europe has formed a significant sink for atmospheric CO2 since the last glacial maximum. Currently they are estimated to hold ca. 42 Gt carbon in the form of peat and are therefore a considerable component in the European carbon budget. Due to the generally wet soil conditions in peatlands they are also significant emitters of the strong greenhouse gas (GHG) methane (CH4) and in some cases also of nitrous oxide (N2O). The EU funded CarboEurope-GHG Concerted Action attempts to develop a reliable and complete greenhouse gas budget for Europe and this report aims to provide a review and synthesis of the available information about GHG exchanges in European peatlands and their underlying processes. A best estimate for all the European countries shows that some are currently sinks for atmospheric CO2 while others are sources. In contrast, for CH4 and N2O, only the sources are relevant. Whilst some countries are CO2 sinks, all countries are net GHG emitters from peatlands. The results presented, however, carry large uncertainties, which cannot be adequately quantified yet. One outstanding uncertainty is the distribution of land use types, particular in Russia, the largest European peat nation. The synthesis of GHG exchange, nevertheless, indicates some interesting features. Russia hosts an estimated 41% of European peatlands and contributes most to all GHG exchanges (CO2: 25%, CH4: 52%, N2O: 26%, Total: 37%). Germany is the second-largest emitter (12% of European total) although it contains only 3.2% of European peatlands. The reason is the use of most of the peatland area for intensive cropland and grassland. The largest CO2 emitters are countries with large agricultural peatland areas (Russia, Germany, Belarus, Poland), the largest N2O emitters are those with large agricultural fen areas (Russia, Germany, Finland). In contrast, the largest CH4 emitters are concentrated in regions with large areas of intact mires, namely Russia and Scandinavia. High average emission densities above 3.5 t C-equiv. ha-1 are found in the Southeast Mediterranean, Germany and the Netherlands where agricultural use of peatlands is intense. Low average emission densities below 0.3 t C-equiv. ha-1 occur where mires and peatland forests dominate, e.g. Finland and the UK. This report concludes by pointing at key gaps in our knowledge about peatland carbon stocks and GHG exchanges which include insufficient basic information on areal distribution of peatlands, measurements of peat depth and also a lack of flux datasets providing full annual budgets of GHG exchanges

Cerebrospinal Fluid Concentration of Neurogranin in Hip Fracture Patients with Delirium

BACKGROUND: Delirium is associated with an increased risk of incident dementia and accelerated progression of existing cognitive symptoms. Reciprocally, dementia increases the risk of delirium. Cerebrospinal fluid (CSF) concentration of the dendritic protein neurogranin has been shown to increase in early Alzheimer's disease (AD), likely reflecting synaptic dysfunction and/or degeneration. OBJECTIVE: To elucidate the involvement of synaptic dysfunction in delirium pathophysiology, we tested the association between CSF neurogranin concentration and delirium in hip fracture patients with different AD-biomarker profiles, while comparing them to cognitively unimpaired older adults (CUA) and AD patients. METHODS: The cohort included hip fracture patients with (n = 70) and without delirium (n = 58), CUA undergoing elective surgery (n = 127), and AD patients (n = 46). CSF was collected preoperatively and diagnostically in surgery and AD patients respectively. CSF neurogranin concentrations were analyzed in all samples with an in-house ELISA. Delirium was assessed pre-and postoperatively in hip fracture patients by trained investigators using the Confusion Assessment Method. Hip fracture patients were further stratified based on pre-fracture dementia status, delirium subtype, and AD fluid biomarkers. RESULTS: No association was found between delirium and CSF neurogranin concentration (main analysis: delirium versus no delirium, p = 0.68). Hip fracture patients had lower CSF neurogranin concentration than AD patients (p = 0.001) and CUA (p = 0.035) in age-adjusted sensitivity analyses. CONCLUSION: The findings suggest that delirium is not associated with increased CSF neurogranin concentration in hip fracture patients, possibly due to advanced neurodegenerative disease and age and/or because synaptic degeneration is not an important pathophysiological process in delirium

The localization of amyloid precursor protein to ependymal cilia in vertebrates and its role in ciliogenesis and brain development in zebrafish

Amyloid precursor protein (APP) is expressed in many tissues in human, mice and in zebrafish. In zebrafish, there are two orthologues, Appa and Appb. Interestingly, some cellular processes associated with APP overlap with cilia-mediated functions. Whereas the localization of APP to primary cilia of in vitro-cultured cells has been reported, we addressed the presence of APP in motile and in non-motile sensory cilia and its potential implication for ciliogenesis using zebrafish, mouse, and human samples. We report that Appa and Appb are expressed by ciliated cells and become localized at the membrane of cilia in the olfactory epithelium, otic vesicle and in the brain ventricles of zebrafish embryos. App in ependymal cilia persisted in adult zebrafish and was also detected in mouse and human brain. Finally, we found morphologically abnormal ependymal cilia and smaller brain ventricles in appa-/-appb-/- mutant zebrafish. Our findings demonstrate an evolutionary conserved localisation of APP to cilia and suggest a role of App in ciliogenesis and cilia-related functions