Establishing a Regional AIS Application Specific Message Register

The goal of the Regional AIS Application Specific Message Register is to provide awareness of what applications exist, facilitate harmonization, and promote proper binary messaging for regional applications. To be hosted on the IALA website, establishing the Register will be a 3-step process: 1) Compile all existing AIS binaries into a Jcollection.K 2) Convert the JcollectionK into a Register. 3) Develop IALA guidance on best practices for creating and using AIS Binary Messages. Recommendations are provided in regard to: - Benefit of a web-based HTML user interface for input/output. - Use of XML to organize/format register applications in a consistent manner. - Having the collection/registration become a JloopK process. - Conforming to ISO standards to organize and manage the Register. - Benefit of a joint IMO-IALA register for both international and regional applications

CSF protein biomarkers predicting longitudinal reduction of CSF β-amyloid42 in cognitively healthy elders.

β-amyloid (Aβ) plaque accumulation is a hallmark of Alzheimer's disease (AD). It is believed to start many years prior to symptoms and is reflected by reduced cerebrospinal fluid (CSF) levels of the peptide Aβ1-42 (Aβ42). Here we tested the hypothesis that baseline levels of CSF proteins involved in microglia activity, synaptic function and Aβ metabolism predict the development of Aβ plaques, assessed by longitudinal CSF Aβ42 decrease in cognitively healthy people. Forty-six healthy people with three to four serial CSF samples were included (mean follow-up 3 years, range 2-4 years). There was an overall reduction in Aβ42 from a mean concentration of 211-195 pg ml(-1) after 4 years. Linear mixed-effects models using longitudinal Aβ42 as the response variable, and baseline proteins as explanatory variables (n=69 proteins potentially relevant for Aβ metabolism, microglia or synaptic/neuronal function), identified 10 proteins with significant effects on longitudinal Aβ42. The most significant proteins were angiotensin-converting enzyme (ACE, P=0.009), Chromogranin A (CgA, P=0.009) and Axl receptor tyrosine kinase (AXL, P=0.009). Receiver-operating characteristic analysis identified 11 proteins with significant effects on longitudinal Aβ42 (largely overlapping with the proteins identified by linear mixed-effects models). Several proteins (including ACE, CgA and AXL) were associated with Aβ42 reduction only in subjects with normal baseline Aβ42, and not in subjects with reduced baseline Aβ42. We conclude that baseline CSF proteins related to Aβ metabolism, microglia activity or synapses predict longitudinal Aβ42 reduction in cognitively healthy elders. The finding that some proteins only predict Aβ42 reduction in subjects with normal baseline Aβ42 suggest that they predict future development of the brain Aβ pathology at the earliest stages of AD, prior to widespread development of Aβ plaques

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

STUDIES OF EFFECTS OF GSM-900 MICROWAVE EXPOSURE ON DNA ”MICRONUCLEUS” FORMATION IN MICE

Possible genotoxic effects of microwave exposure from GSM-900 mobile telephones have investigated with in vivo micronucleus assay of mouse erythrocytes from CBA mice and GFAP knockout mice. No significant change in the frequency of erythrocytes with micronuclei neither in the young (polychromatic PCE) or mature (normichromatic NCE) erythrocytes. There is, however, a tendency but not significant to increased MPCE in female mice after 35 days of exposure. There is a marked tendency to lower PCE-fraction in the exposed groups. When male and female is studied separately there is no significant difference. However, if the values are normalised to eliminate the sex-difference there is a significant lower fraction in the exposed mice. Another observation is lower weight of the exposed male. If normalised data for both sexes are pooled there is an almost significant difference (95% level) in weight. We found a less pronounced difference in the CBE mice than in the GFAP experiment. Thus genotype might play a role in microwave exposure. Differences in exposure time and number of controls in GFAP and CBA experiment might influence the results. We observe a moderate decrease of formation of new erythrocytes in the exposed animals. This might fit the tendency of lower weight in the exposed animals and might indicate a general decreased cell-proliferation in the exposed animals

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

Label-free quantitative comparison of cerebrospinal fluid glycoproteins and endogenous peptides in subjects with Alzheimer's disease, mild cognitive impairment, and healthy individuals

PURPOSE: The goal of this study is to investigate putative molecular dynamic changes in cerebrospinal fluids (CSFs) collected from individuals with mild cognitive impairment (MCI) and Alzheimer's disease (AD) as compared to healthy controls. EXPERIMENTAL DESIGN: The CSF samples from 12 subjects comprised of four cognitively normal individuals and eight patients with MCI and AD, respectively. Two aliquots of each CSF samples (total 1 mL) of each participant are used for this study. Endogenous peptide separations are performed using 10 000 molecular weight cut-off filters followed by LC-MS/MS identification and quantitation while lectin-enrichment chromatography is used to enrich glycoproteins in CSF followed by trypsin digestion and subsequent LC-MS/MS for shotgun identification and label-free quantitation. RESULTS: Using an optimized submicrogram peptide separation with molecular weight cut-off filtration and an in house-constructed database, 645 peptides are identified. Glycoproteins are enriched by lectin affinity chromatography, resulting in 795 identified proteins. The discovery and alterations of proSAAS-derived peptides and transthyretin are described and their roles in AD are discussed. CONCLUSIONS AND CLINICAL RELEVANCE: Comprehensive identification of endogenous CSF peptidome is achieved. Fifteen proteins are found to be differentially expressed among the three groups. The dynamic changes of transthyretin are reported for the first time

Quantification of mutant huntingtin protein in cerebrospinal fluid from Huntington's disease patients.

Quantification of disease-associated proteins in the cerebrospinal fluid (CSF) has been critical for the study and treatment of several neurodegenerative disorders; however, mutant huntingtin protein (mHTT), the cause of Huntington's disease (HD), is at very low levels in CSF and, to our knowledge, has never been measured previously

Neurofilament light chain and total tau in the differential diagnosis and prognostic evaluation of acute and chronic inflammatory polyneuropathies

BACKGROUND AND PURPOSE: To investigate the diagnostic and prognostic value of axonal injury biomarkers in patients with inflammatory polyneuropathies. METHODS: Neurofilament light (NfL) chain and total tau (T-tau) were measured in the CSF and plasma in 41 patients with Guillain-Barré syndrome (GBS), 32 patients with chronic inflammatory demyelinating polyneuropathy (CIDP), 10 with paraproteinemia-related demyelinating polyneuropathy (PDN) and 8 with multifocal motor neuropathy (MMN), in comparison with 39 disease-free controls and 59 other controls. Outcome was measured with the GBS-disability score (GBS-ds) or Inflammatory Neuropathy Cause and Treatment (INCAT) disability score. RESULTS: NfL levels in CSF and plasma were higher in GBS, CIDP and PDN vs. disease-free controls. Patients with MMN had higher NfL levels in plasma vs. disease-free controls, but lower levels in CSF and plasma vs. patients with ALS. T-tau levels in plasma were higher in GBS, CIDP, PDN, and MMN vs. all control groups. NfL levels in CSF and plasma in patients with GBS correlated with GBS-ds, as higher levels were associated with inability to run after 6 and 12 months. NfL levels in CSF and plasma in CIDP did not correlate significantly with outcome. CONCLUSIONS: Acute and chronic inflammatory neuropathies are associated with increase in levels of NfL in CSF and plasma, but NfL is validated as a prognostic biomarker only in GBS. NfL could be used in differentiating patients with MMN from ALS. T-tau in plasma is a novel biomarker that could be used in a diagnostic assessment of patients with acute and chronic inflammatory polyneuropathies

Serum Neurofilament Light and Multiple Sclerosis Progression Independent of Acute Inflammation

Introduction Efforts to explore the utility of neurofilament light (NfL) as a biomarker associated with disability progression in multiple sclerosis (MS) have accelerated in recent years in the absence of pharmacodynamic or treatment response markers for clinical trials or patient care.1 The International Progressive MS Alliance stated in 2020 that serum NfL (sNfL) measurements may serve as a useful biomarker associated with progressive MS, although further work is needed to define the relative contributions of inflammatory activity and neurodegeneration to longitudinal changes in disability and sNfL.2 Using data from a large clinical trial of patients with secondary progressive MS (a phase 3, randomized, double-blind, placebo-controlled trial exploring the effect of natalizumab on disease progression in participants with Secondary Progressive Multiple Sclerosis [ASCEND in SPMS]; NCT01416181), we investigated whether sNfL could be used as a dynamic biomarker associated with progressive MS disease course. That is, we investigated whether longitudinal changes in sNfL concentration were associated with disability progression measures in the absence of relapses and magnetic resonance imaging (MRI) evidence of inflammatory activit

TREM2 is down-regulated by HSV1 in microglia and involved in antiviral defense in the brain

Immunological control of viral infections in the brain exerts immediate protection and also long-term maintenance of brain integrity. Microglia are important for antiviral defense in the brain. Here, we report that herpes simplex virus type 1 (HSV1) infection of human induced pluripotent stem cell (hiPSC)-derived microglia down-regulates expression of genes in the TREM2 pathway. TREM2 was found to be important for virus-induced IFNB induction through the DNA-sensing cGAS-STING pathway in microglia and for phagocytosis of HSV1-infected neurons. Consequently, TREM2 depletion increased susceptibility to HSV1 infection in human microglia-neuron cocultures and in the mouse brain. TREM2 augmented STING signaling and activation of downstream targets TBK1 and IRF3. Thus, TREM2 is important for the antiviral immune response in microglia. Since TREM2 loss-of-function mutations and HSV1 serological status are both linked to Alzheimer's disease, this work poses the question whether genetic or virus-induced alterations of TREM2 activity predispose to post-infection neurological pathologies