Clearing the Brain’s Cobwebs: The Role of Autophagy in Neuroprotection

Protein aggregates or inclusion bodies are common hallmarks of age-related neurodegenerative disorders. Why these aggregates form remains unclear. Equally debated is whether they are toxic, protective, or simple by-products. Increasing evidence, however, supports the notion that in general aggregates confer toxicity and disturb neuronal function by hampering axonal transport, synaptic integrity, transcriptional regulation, and mitochondrial function. Thus, neuroscientists in search of effective treatments to slow neural loss during neurodegeneration have long been interested in finding new ways to clear inclusion bodies. Intriguingly, two studies using conditional neuron-specific gene ablations of autophagy regulators in mice revealed that autophagy loss elicits inclusion body formation and a neurodegenerative cascade.Such studies indicate autophagy may be a built-in defense mechanism to clear the nervous system of inclusion bodies.This new finding has implications for our understanding of aging and neurodegeneration and the development of new therapies. First, we discuss the pathways underlying autophagy and its controversial role in cell death and survival regulation.We then discuss the physiological role of autophagy in the aging process of the nervous system. In the final portion of this review, we discuss the therapeutic promise of inducing autophagy and the potential side effects of such treatments

Molecular antimicrobial resistance surveillance for neisseria gonorrhoeae, Northern Territory, Australia

Neisseria gonorrhoeae antimicrobial resistance (AMR) is a globally recognized health threat; new strategies are needed to enhance AMR surveillance. The Northern Territory of Australia is unique in that 2 different first-line therapies, based primarily on geographic location, are used for gonorrhea treatment. We tested 1,629 N. gonorrhoeae nucleic acid amplification test–positive clinical samples, collected from regions where ceftriaxone plus azithromycin or amoxicillin plus azithromycin are recommended first-line treatments, by using 8 N. gonorrhoeae AMR PCR assays. We compared results with those from routine culture-based surveillance data. PCR data confirmed an absence of ceftriaxone resistance and a low level of azithromycin resistance (0.2%), and that penicillin resistance was \u3c5% in amoxicillin plus azithromycin regions. Rates of ciprofloxacin resistance and penicillinase-producing N. gonorrhoeae were lower when molecular methods were used. Molecular methods to detect N. gonorrhoeae AMR can increase the evidence base for treatment guidelines, particularly in settings where culture-based surveillance is limited

Gaseous chemistry for a Titan's atmospheric plasma experimental simulation

We present the first study of gaseous composition monitoring for the PAMPRE experiment, which simulates Titan's atmospheric chemistry by radio-frequency N 2-CH 4 plasma. Methane consumption is quantified for various N 2-CH 4 gas mixtures. Moreover in situ mass spectrometry (MS) and ex-situ gas chromatography coupled with mass spectrometry (GC-MS) analyses reveal a large dominance of nitrile species in the gas phase chemistry

Preservation of Mitochondrial Structure and Function after Bid- or Bax-Mediated Cytochrome c Release

Proapoptotic members of the Bcl-2 protein family, including Bid and Bax, can activate apoptosis by directly interacting with mitochondria to cause cytochrome c translocation from the intermembrane space into the cytoplasm, thereby triggering Apaf-1–mediated caspase activation. Under some circumstances, when caspase activation is blocked, cells can recover from cytochrome c translocation; this suggests that apoptotic mitochondria may not always suffer catastrophic damage arising from the process of cytochrome c release. We now show that recombinant Bid and Bax cause complete cytochrome c loss from isolated mitochondria in vitro, but preserve the ultrastructure and protein import function of mitochondria, which depend on inner membrane polarization. We also demonstrate that, if caspases are inhibited, mitochondrial protein import function is retained in UV-irradiated or staurosporine-treated cells, despite the complete translocation of cytochrome c. Thus, Bid and Bax act only on the outer membrane, and lesions in the inner membrane occurring during apoptosis are shown to be secondary caspase-dependent events

Onset of a pandemic: characterizing the initial phase of the swine flu (H1N1) epidemic in Israel

<p>Abstract</p> <p>Background</p> <p>The swine influenza H1N1 first identified in Mexico, spread rapidly across the globe and is considered the fastest moving pandemic in history. The early phase of an outbreak, in which data is relatively scarce, presents scientific challenges on key issues such as: scale, severity and immunity which are fundamental for establishing sound and rapid policy schemes. Our analysis of an Israeli dataset aims at understanding the spatio-temporal dynamics of H1N1 in its initial phase.</p> <p>Methods</p> <p>We constructed and analyzed a unique dataset from Israel on all confirmed cases (between April 26 to July 7, 2009), representing most swine flu cases in this period. We estimated and characterized fundamental epidemiological features of the pandemic in Israel (e.g. effective reproductive number, age-class distribution, at-risk social groups, infections between sexes, and spatial dynamics). Contact data collected during this stage was used to estimate the generation time distribution of the pandemic.</p> <p>Results</p> <p>We found a low effective reproductive number (<it>R</it>_{<it>e </it>}= 1.06), an age-class distribution of infected individuals (skewed towards ages 18-25), at-risk social groups (soldiers and ultra Orthodox Jews), and significant differences in infections between sexes (skewed towards males). In terms of spatial dynamics, the pandemic spread from the central coastal plain of Israel to other regions, with higher infection rates in more densely populated sub-districts with higher income households.</p> <p>Conclusions</p> <p>Analysis of high quality data holds much promise in reducing uncertainty regarding fundamental aspects of the initial phase of an outbreak (e.g. the effective reproductive number R_e, age-class distribution, at-risk social groups). The formulation for determining the effective reproductive number <it>R</it>_{<it>e </it>}used here has many advantages for studying the initial phase of the outbreak since it neither assumes exponential growth of infectives and is independent of the reporting rate. The finding of a low <it>R</it>_{<it>e </it>}(close to unity threshold), combined with identification of social groups with high transmission rates would have enabled the containment of swine flu during the summer in Israel. Our unique use of contact data provided new insights into the differential dynamics of influenza in different ages and sexes, and should be promoted in future epidemiological studies. Thus our work highlights the importance of conducting a comprehensive study of the initial stage of a pandemic in real time.</p

The Flying Fish Persistent Ocean Surveillance Platform

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/77030/1/AIAA-2009-1902-584.pd

The Pro-Apoptotic Proteins, Bid and Bax, Cause a Limited Permeabilization of the Mitochondrial Outer Membrane That Is Enhanced by Cytosol

During apoptosis, an important pathway leading to caspase activation involves the release of cytochrome c from the intermembrane space of mitochondria. Using a cell-free system based on Xenopus egg extracts, we examined changes in the outer mitochondrial membrane accompanying cytochrome c efflux. The pro-apoptotic proteins, Bid and Bax, as well as factors present in Xenopus egg cytosol, each induced cytochrome c release when incubated with isolated mitochondria. These factors caused a permeabilization of the outer membrane that allowed the corelease of multiple intermembrane space proteins: cytochrome c, adenylate kinase and sulfite oxidase. The efflux process is thus nonspecific. None of the cytochrome c-releasing factors caused detectable mitochondrial swelling, arguing that matrix swelling is not required for outer membrane permeability in this system. Bid and Bax caused complete release of cytochrome c but only a limited permeabilization of the outer membrane, as measured by the accessibility of inner membrane-associated respiratory complexes III and IV to exogenously added cytochrome c. However, outer membrane permeability was strikingly increased by a macromolecular cytosolic factor, termed PEF (permeability enhancing factor). We hypothesize that PEF activity could help determine whether cells can recover from mitochondrial cytochrome c release

Macrophages support pathological erythropoiesis in Polycythemia Vera and Beta-Thalassemia

Regulation of erythropoiesis is achieved by integration of distinct signals. Among these, macrophages are emerging as erythropoietin-complementary regulators of erythroid development, particularly under stress conditions. We investigated the contribution of macrophages for physiological and pathological conditions of enhanced erythropoiesis. We utilized mouse models of induced anemia, Polycythemia vera and β-thalassemia in which macrophages were chemically depleted. Our data indicate that macrophages contribute decisively for recovery from induced anemia as well as the pathological progression of Polycythemia vera and β-thalassemia by modulating erythroid proliferation and differentiation. We validated these observations in primary human cultures, showing a critical direct impact of macrophages on proliferation and enucleation of erythroblasts from healthy individuals and Polycythemia vera or β-thalassemic patients. In summary, we identify a new mechanism that we named “Stress Erythropoiesis Macrophage-supporting Activity” (SEMA) that contributes to the pathophysiology of these disorders and will have critical scientific and therapeutic implications in the near future

The phylodynamics of SARS-CoV-2 during 2020 in Finland

Finland has had a low incidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infections as compared to most European countries. Here we report the origins and turnover of SARS-CoV-2 lineages circulating in Finland in 2020. SARS-CoV-2 introduced to Finland in January 2020 and spread rapidly across southern Finland during spring. We observed rapid turnover among Finnish lineages during this period. Clade 20C became the most prevalent among sequenced cases and was replaced by other strains in fall 2020. Bayesian phylogeographic reconstructions suggested 42 independent introductions into Finland during spring 2020, mainly from Italy, Austria, and Spain, which might have been the source for a third of cases. The investigations of the original introductions of SARS-CoV-2 to Finland during the early stages of the pandemic and of the subsequent lineage dynamics could be utilized to assess the role of transboundary movements and effects of early intervention and public health measures.Peer reviewe