Revisiting protein aggregation as pathogenic in sporadic Parkinson and Alzheimer diseases.

The gold standard for a definitive diagnosis of Parkinson disease (PD) is the pathologic finding of aggregated α-synuclein into Lewy bodies and for Alzheimer disease (AD) aggregated amyloid into plaques and hyperphosphorylated tau into tangles. Implicit in this clinicopathologic-based nosology is the assumption that pathologic protein aggregation at autopsy reflects pathogenesis at disease onset. While these aggregates may in exceptional cases be on a causal pathway in humans (e.g., aggregated α-synuclein in SNCA gene multiplication or aggregated β-amyloid in APP mutations), their near universality at postmortem in sporadic PD and AD suggests they may alternatively represent common outcomes from upstream mechanisms or compensatory responses to cellular stress in order to delay cell death. These 3 conceptual frameworks of protein aggregation (pathogenic, epiphenomenon, protective) are difficult to resolve because of the inability to probe brain tissue in real time. Whereas animal models, in which neither PD nor AD occur in natural states, consistently support a pathogenic role of protein aggregation, indirect evidence from human studies does not. We hypothesize that (1) current biomarkers of protein aggregates may be relevant to common pathology but not to subgroup pathogenesis and (2) disease-modifying treatments targeting oligomers or fibrils might be futile or deleterious because these proteins are epiphenomena or protective in the human brain under molecular stress. Future precision medicine efforts for molecular targeting of neurodegenerative diseases may require analyses not anchored on current clinicopathologic criteria but instead on biological signals generated from large deeply phenotyped aging populations or from smaller but well-defined genetic-molecular cohorts

Digital multiplex ligation assay for highly multiplexed screening of beta-lactamase-encoding genes in bacterial isolates

Increasing incidence of antibiotic resistance in clinical and environmental settings calls for increased scalability in their surveillance. Current screening technologies are limited by the number of samples and genes that can easily be screened. We demonstrate here digital multiplex ligation assay (dMLA) as a low-cost targeted genomic detection workflow capable of highly-parallel screening of bacterial isolates for multiple target gene regions simultaneously. Here, dMLA is used for simultaneous detection of 1187 beta-lactamase-encoding genes, including extended spectrum beta-lactamase (ESBL) genes, in 74 bacterial isolates. We demonstrate dMLA as a light-weight and cost-efficient workflow which provides a highly scalable tool for antimicrobial resistance surveillance and is also adaptable to genetic screening applications beyond antibiotic resistance.Tamminen et al. develop a digital multiplex ligation assay (dMLA) that enables the detection of bacterial isolates using probe hybridization and ligation-based assays with next-generation sequencing. Their method can be applied in high-throughput and affordable screening for antibiotic resistance

Outcome measurement in functional neurological disorder: a systematic review and recommendations.

OBJECTIVES: We aimed to identify existing outcome measures for functional neurological disorder (FND), to inform the development of recommendations and to guide future research on FND outcomes. METHODS: A systematic review was conducted to identify existing FND-specific outcome measures and the most common measurement domains and measures in previous treatment studies. Searches of Embase, MEDLINE and PsycINFO were conducted between January 1965 and June 2019. The findings were discussed during two international meetings of the FND-Core Outcome Measures group. RESULTS: Five FND-specific measures were identified-three clinician-rated and two patient-rated-but their measurement properties have not been rigorously evaluated. No single measure was identified for use across the range of FND symptoms in adults. Across randomised controlled trials (k=40) and observational treatment studies (k=40), outcome measures most often assessed core FND symptom change. Other domains measured commonly were additional physical and psychological symptoms, life impact (ie, quality of life, disability and general functioning) and health economics/cost-utility (eg, healthcare resource use and quality-adjusted life years). CONCLUSIONS: There are few well-validated FND-specific outcome measures. Thus, at present, we recommend that existing outcome measures, known to be reliable, valid and responsive in FND or closely related populations, are used to capture key outcome domains. Increased consistency in outcome measurement will facilitate comparison of treatment effects across FND symptom types and treatment modalities. Future work needs to more rigorously validate outcome measures used in this population

Identification of coherent flood regions across Europe by using the longest streamflow records

This study compiles a new dataset, consisting of the longest available flow series from across Europe, and uses it to study the spatial and temporal clustering of flood events across the continent. Hydrological series at 102 gauging stations were collected from 25 European countries. Five geographically distinct large-scale homogeneous regions are identified: (i) an Atlantic region, (ii) a Continental region, (iii) a Scandinavian region, (iv) an Alpine region, and (v) a Mediterranean region. The months with a higher likelihood of flooding were identified in each region. The analysis of the clustering of annual counts of floods revealed an over-dispersion in the Atlantic and Continental regions, forming flood-rich and flood-poor periods, as well as an under-dispersion in the Scandinavian region that points to a regular pattern of flood occurrences at the inter-annual scale. The detection of trends in flood series is attempted by basing it on the identified regions, interpreting the results at a regional scale and for various time periods: 1900-1999; 1920-1999; 1939-1998 and 1956-1995. The results indicate that a decreasing trend in the magnitude of floods was observed mainly in the Continental region in the period 1920-1999 with 22% of the catchments revealing such a trend, as well as a decreasing trend in the timing of floods in the Alpine region in the period 1900-1999 with 75% of the catchments revealing this trend. A mixed pattern of changes in the frequency of floods over a threshold and few significant changes in the timing of floods were detected

Very Cold Gas and Dark Matter

We have recently proposed a new candidate for baryonic dark matter: very cold molecular gas, in near-isothermal equilibrium with the cosmic background radiation at 2.73 K. The cold gas, of quasi-primordial abundances, is condensed in a fractal structure, resembling the hierarchical structure of the detected interstellar medium. We present some perspectives of detecting this very cold gas, either directly or indirectly. The H$_2$ molecule has an "ultrafine" structure, due to the interaction between the rotation-induced magnetic moment and the nuclear spins. But the lines fall in the km domain, and are very weak. The best opportunity might be the UV absorption of H$_2$ in front of quasars. The unexpected cold dust component, revealed by the COBE/FIRAS submillimetric results, could also be due to this very cold H$_2$ gas, through collision-induced radiation, or solid H$_2$ grains or snowflakes. The $\gamma$-ray distribution, much more radially extended than the supernovae at the origin of cosmic rays acceleration, also points towards and extended gas distribution.Comment: 16 pages, Latex pages, crckapb macro, 3 postscript figures, uuencoded compressed tar file. To be published in the proceeedings of the "Dust-Morphology" conference, Johannesburg, 22-26 January, 1996, D. Block (ed.), (Kluwer Dordrecht

The phase diagram of Yang-Mills theory with a compact extra dimension

We present a non-perturbative study of the phase diagram of SU(2) Yang-Mills theory in a five-dimensional spacetime with a compact extra dimension. The non-renormalizable theory is regularized on an anisotropic lattice and investigated through numerical simulations in a regime characterized by a hierarchy between the scale of low-energy physics, the inverse compactification radius, and the cutoff scale. We map out the structure of the phase diagram and the pattern of lines corresponding to fixed values of the ratio between the mass of the fifth component of the gauge field and the non-perturbative mass gap of the four-dimensional modes. We discuss different limits of the model, and comment on the implications of our findings.Comment: 17 pages, 9 figure

The Maine Tidal Power Initiative: Transdisciplinary sustainability science research for the responsible development of tidal power

The Maine Tidal Power Initiative (MTPI), an interdisciplinary team of engineers, marine scientists, oceanographers, and social scientists, is using a transdisciplinary sustainability science approach to collect biophysical and social data necessary for understanding interactions between human and natural systems in the context of tidal power development in Maine. MTPI offers a unique opportunity to better understand how group structure and process influence outcomes in transdisciplinary sustainability science research. Through extensive participant observation and semi-structured interviews we: (1) describe MTPI’s organizational structure; (2) examine MTPI’s research approach and engagement with stakeholders from different sectors of society (i.e., industry, government, and the local community); and (3) identify challenges and opportunities for involving different disciplinary expertise and diverse stakeholders in transformational sustainability science research. We found that MTPI’s holistic mission, non-hierarchical structure, and iterative stakeholder engagement process led to important benefits and significant challenges. Positive outcomes include knowledge development, a transferable research framework, shared resources, personal reward, and a greater understanding of the local environment and community. Challenges identified include balancing diverse interests and priorities, maintaining engagement, managing stakeholder relationships, and limited resources. Lessons learned from the process of integrative collaborative research in Maine can offer guidance on what should be considered when carrying out similar transdisciplinary sustainability science projects in other research contexts

Needs-oriented discharge planning and monitoring for high utilisers of psychiatric services (NODPAM): Design and methods

<p>Abstract</p> <p>Background</p> <p>Attempts to reduce high utilisation of psychiatric inpatient care by targeting the critical time of hospital discharge have been rare.</p> <p>Methods</p> <p>This paper presents design and methods of the study "Effectiveness and Cost-Effectiveness of Needs-Oriented Discharge Planning and Monitoring for High Utilisers of Psychiatric Services" (NODPAM), a multicentre RCT conducted in five psychiatric hospitals in Germany. Inclusion criteria are receipt of inpatient psychiatric care, adult age, diagnosis of schizophrenia or affective disorder, defined high utilisation of psychiatric care during two years prior to the current admission, and given informed consent. Consecutive recruitment started in April 2006. Since then, during a period of 18 months, comprehensive outcome data of 490 participants is being collected at baseline and during three follow-up measurement points.</p> <p>The manualised intervention applies principles of needs-led care and focuses on the inpatient-outpatient transition. A trained intervention worker provides two intervention sessions: (a) Discharge planning: Just before discharge with the patient and responsible clinician at the inpatient service; (b) Monitoring: Three months after discharge with the patient and outpatient clinician. A written treatment plan is signed by all participants after each session.</p> <p>Primary endpoints are whether participants in the intervention group will show fewer hospital days and readmissions to hospital. Secondary endpoints are better compliance with aftercare, better clinical outcome and quality of life, as well as cost-effectiveness and cost-utility.</p> <p>Discussion</p> <p>If a needs-oriented discharge planning and monitoring proves to be successful in this RCT, a tool will be at hand to improve patient outcome and reduce costs via harmonising fragmented mental health service provision.</p> <p>Trial Registration</p> <p>ISRCTN59603527</p

Motor Properties of Peripersonal Space in Humans

Background: A stimulus approaching the body requires fast processing and appropriate motor reactions. In monkeys, fronto-parietal networks are involved both in integrating multisensory information within a limited space surrounding the body (i.e. peripersonal space, PPS) and in action planning and execution, suggesting an overlap between sensory representations of space and motor representations of action. In the present study we investigate whether these overlapping representations also exist in the human brain. Methodology/Principal Findings: We recorded from hand muscles motor-evoked potentials (MEPs) induced by single-pulse of transcranial magnetic stimulation (TMS) after presenting an auditory stimulus either near the hand or in far space. MEPs recorded 50 ms after the near-sound onset were enhanced compared to MEPs evoked after far sounds. This near-far modulation faded at longer inter-stimulus intervals, and reversed completely for MEPs recorded 300 ms after the sound onset. At that time point, higher motor excitability was associated with far sounds. Such auditory modulation of hand motor representation was specific to a hand-centred, and not a body-centred reference frame. Conclusions/Significance: This pattern of corticospinal modulation highlights the relation between space and time in the PPS representation: an early facilitation for near stimuli may reflect immediate motor preparation, whereas, at later time intervals, motor preparation relates to distant stimuli potentially approaching the body