Immune-Mobilizing Monoclonal T Cell Receptors Mediate Specific and Rapid Elimination of Hepatitis B-Infected Cells

Background and Aims: Therapies for chronic hepatitis B virus (HBV) infection are urgently needed because of viral integration, persistence of viral antigen expression, inadequate HBV‐specific immune responses, and treatment regimens that require lifelong adherence to suppress the virus. Immune mobilizing monoclonal T Cell receptors against virus (ImmTAV) molecules represent a therapeutic strategy combining an affinity‐enhanced T Cell receptor with an anti‐CD3 T Cell‐activating moiety. This bispecific fusion protein redirects T cells to specifically lyse infected cells expressing the target virus‐derived peptides presented by human leukocyte antigen (HLA). Approach and Results: ImmTAV molecules specific for HLA‐A*02:01‐restricted epitopes from HBV envelope, polymerase, and core antigens were engineered. The ability of ImmTAV‐Env to activate and redirect polyclonal T cells toward cells containing integrated HBV and cells infected with HBV was assessed using cytokine secretion assays and imaging‐based killing assays. Elimination of infected cells was further quantified using a modified fluorescent hybridization of viral RNA assay. Here, we demonstrate that picomolar concentrations of ImmTAV‐Env can redirect T cells from healthy and HBV‐infected donors toward hepatocellular carcinoma (HCC) cells containing integrated HBV DNA resulting in cytokine release, which could be suppressed by the addition of a corticosteroid in vitro. Importantly, ImmTAV‐Env redirection of T cells induced cytolysis of antigen‐positive HCC cells and cells infected with HBV in vitro, causing a reduction of hepatitis B e antigen and specific loss of cells expressing viral RNA. Conclusions: The ImmTAV platform has the potential to enable the elimination of infected cells by redirecting endogenous non‐HBV‐specific T cells, bypassing exhausted HBV‐specific T cells. This represents a promising therapeutic option in the treatment of chronic hepatitis B, with our lead candidate now entering trials

Lead-DBS v3.0: Mapping Deep Brain Stimulation Effects to Local Anatomy and Global Networks.

Following its introduction in 2014 and with support of a broad international community, the open-source toolbox Lead-DBS has evolved into a comprehensive neuroimaging platform dedicated to localizing, reconstructing, and visualizing electrodes implanted in the human brain, in the context of deep brain stimulation (DBS) and epilepsy monitoring. Expanding clinical indications for DBS, increasing availability of related research tools, and a growing community of clinician-scientist researchers, however, have led to an ongoing need to maintain, update, and standardize the codebase of Lead-DBS. Major development efforts of the platform in recent years have now yielded an end-to-end solution for DBS-based neuroimaging analysis allowing comprehensive image preprocessing, lead localization, stimulation volume modeling, and statistical analysis within a single tool. The aim of the present manuscript is to introduce fundamental additions to the Lead-DBS pipeline including a deformation warpfield editor and novel algorithms for electrode localization. Furthermore, we introduce a total of three comprehensive tools to map DBS effects to local, tract- and brain network-levels. These updates are demonstrated using a single patient example (for subject-level analysis), as well as a retrospective cohort of 51 Parkinson's disease patients who underwent DBS of the subthalamic nucleus (for group-level analysis). Their applicability is further demonstrated by comparing the various methodological choices and the amount of explained variance in clinical outcomes across analysis streams. Finally, based on an increasing need to standardize folder and file naming specifications across research groups in neuroscience, we introduce the brain imaging data structure (BIDS) derivative standard for Lead-DBS. Thus, this multi-institutional collaborative effort represents an important stage in the evolution of a comprehensive, open-source pipeline for DBS imaging and connectomics

Change in function, pain, and quality of life following structured nonoperative treatment in patients with degenerative cervical myelopathy: a systematic review

Study Design: Systematic review. Objectives: The objective of this study was to conduct a systematic review to determine (1) change in function, pain, and quality of life following structured nonoperative treatment for degenerative cervical myelopathy (DCM); (2) variability of change in function, pain, and quality of life following different types of structured nonoperative treatment; (3) differences in outcomes observed between certain subgroups (eg, baseline severity score, duration of symptoms); and (4) negative outcomes and harms resulting from structured nonoperative treatment. Methods: A systematic search was conducted in Embase, PubMed, and the Cochrane Collaboration for articles published between January 1, 1950, and February 9, 2015. Studies were included if they evaluated outcomes following structured nonoperative treatment, including therapeutic exercise, manual therapy, cervical bracing, and/or traction. The quality of each study was evaluated using the Newcastle-Ottawa Scale, and strength of the overall body of evidence was rated using guidelines outlined by the Grading of Recommendation Assessment, Development and Evaluation Working Group. Results: Of the 570 retrieved citations, 8 met inclusion criteria and were summarized in this review. Based on our results, there is very low evidence to suggest that structured nonoperative treatment for DCM results in either a positive or negative change in function as evaluated by the Japanese Orthopaedic Association score. Conclusion: There is a lack of evidence to determine the role of nonoperative treatment in patients with DCM. However, in the majority of studies, patients did not achieve clinically significant gains in function following structured nonoperative treatment. Furthermore, 23% to 54% of patients managed nonoperatively subsequently underwent surgical treatment

THE COMMUNITY LEVERAGED UNIFIED ENSEMBLE (CLUE) IN THE 2016 NOAA/HAZARDOUS WEATHER TESTBED SPRING FORECASTING EXPERIMENT

One primary goal of annual Spring Forecasting Experiments (SFEs), which are coorganized by NOAA’s National Severe Storms Laboratory and Storm Prediction Center and conducted in the National Oceanic and Atmospheric Administration’s (NOAA) Hazardous Weather Testbed, is documenting performance characteristics of experimental, convection-allowing modeling systems (CAMs). Since 2007, the number of CAMs (including CAM ensembles) examined in the SFEs has increased dramatically, peaking at six different CAM ensembles in 2015. Meanwhile, major advances have been made in creating, importing, processing, verifying, and developing tools for analyzing and visualizing these large and complex datasets. However, progress toward identifying optimal CAM ensemble configurations has been inhibited because the different CAM systems have been independently designed, making it difficult to attribute differences in performance characteristics. Thus, for the 2016 SFE, a much more coordinated effort among many collaborators was made by agreeing on a set of model specifications (e.g., model version, grid spacing, domain size, and physics) so that the simulations contributed by each collaborator could be combined to form one large, carefully designed ensemble known as the Community Leveraged Unified Ensemble (CLUE). The 2016 CLUE was composed of 65 members contributed by five research institutions and represents an unprecedented effort to enable an evidence-driven decision process to help guide NOAA’s operational modeling efforts. Eight unique experiments were designed within the CLUE framework to examine issues directly relevant to the design of NOAA’s future operational CAM-based ensembles. This article will highlight the CLUE design and present results from one of the experiments examining the impact of single versus multicore CAM ensemble configurations

THE COMMUNITY LEVERAGED UNIFIED ENSEMBLE (CLUE) IN THE 2016 NOAA/HAZARDOUS WEATHER TESTBED SPRING FORECASTING EXPERIMENT

One primary goal of annual Spring Forecasting Experiments (SFEs), which are coorganized by NOAA’s National Severe Storms Laboratory and Storm Prediction Center and conducted in the National Oceanic and Atmospheric Administration’s (NOAA) Hazardous Weather Testbed, is documenting performance characteristics of experimental, convection-allowing modeling systems (CAMs). Since 2007, the number of CAMs (including CAM ensembles) examined in the SFEs has increased dramatically, peaking at six different CAM ensembles in 2015. Meanwhile, major advances have been made in creating, importing, processing, verifying, and developing tools for analyzing and visualizing these large and complex datasets. However, progress toward identifying optimal CAM ensemble configurations has been inhibited because the different CAM systems have been independently designed, making it difficult to attribute differences in performance characteristics. Thus, for the 2016 SFE, a much more coordinated effort among many collaborators was made by agreeing on a set of model specifications (e.g., model version, grid spacing, domain size, and physics) so that the simulations contributed by each collaborator could be combined to form one large, carefully designed ensemble known as the Community Leveraged Unified Ensemble (CLUE). The 2016 CLUE was composed of 65 members contributed by five research institutions and represents an unprecedented effort to enable an evidence-driven decision process to help guide NOAA’s operational modeling efforts. Eight unique experiments were designed within the CLUE framework to examine issues directly relevant to the design of NOAA’s future operational CAM-based ensembles. This article will highlight the CLUE design and present results from one of the experiments examining the impact of single versus multicore CAM ensemble configurations

The peatland map of Europe

Based on the ‘European Mires Book’ of the International Mire Conservation Group (IMCG), this article provides a composite map of national datasets as the first comprehensive peatland map for the whole of Europe. We also present estimates of the extent of peatlands and mires in each European country individually and for the entire continent. A minimum peat thickness criterion has not been strictly applied, to allow for (often historically determined) country-specific definitions. Our ‘peatland’ concept includes all ‘mires’, which are peatlands where peat is being formed. The map was constructed by merging national datasets in GIS while maintaining the mapping scales of the original input data. This ‘bottom-up’ approach indicates that the overall area of peatland in Europe is 593,727 km². Mires were found to cover more than 320,000 km² (around 54 % of the total peatland area). If shallow-peat lands (< 30 cm peat) in European Russia are also taken into account, the total peatland area in Europe is more than 1,000,000 km2, which is almost 10 % of the total surface area. Composite inventories of national peatland information, as presented here for Europe, may serve to identify gaps and priority areas for field survey, and help to cross-check and calibrate remote sensing based mapping approaches

Recent trends in the use of electrical neuromodulation in Parkinson's disease

Purpose of Review: This review aims to survey recent trends in electrical forms of neuromodulation, with a specific application to Parkinson’s disease (PD). Emerging trends are identified, highlighting synergies in state-of-the-art neuromodulation strategies, with directions for future improvements in stimulation efficacy suggested. Recent Findings: Deep brain stimulation remains the most common and effective form of electrical stimulation for the treatment of PD. Evidence suggests that transcranial direct current stimulation (tDCS) most likely impacts the motor symptoms of the disease, with the most prominent results relating to rehabilitation. However, utility is limited due to its weak effects and high variability, with medication state a key confound for efficacy level. Recent innovations in transcranial alternating current stimulation (tACS) offer new areas for investigation. Summary: Our understanding of the mechanistic foundations of electrical current stimulation is advancing and as it does so, trends emerge which steer future clinical trials towards greater efficacy

Changes of water conditions, plant cover and soils on bagno ławki in the Biebrza River lower basin

Celem pracy jest określenie warunków siedliskowych panujących w basenie dolnym doliny Biebrzy metodą transektów dolinowych, na podstawie szczegółowego rozpoznania stosunków wodnych, glebowych i fitosocjologicznych. W pracy zawarto charakterystykę siedliskową zabagnionej doliny rzeki, na przykładzie dolnego odcinka Biebrzy. Szczególną uwagę poświęcono warunkom hydrologicznym, które w decydującej mierze wpływają na siedlisko i zachodzące w nim procesy. Na podstawie rozpoznania stratygrafii złoża torfowego na przeważającej części przekroju dolinowego odtworzono prawdopodobny, historyczny przebieg procesu zabagnienia doliny. Na podstawie wierzchniej warstwy torfowiska można ocenić obecnie zachodzące procesy glebowe. Informacje o występujących zbiorowiskach roślinnych były podstawą do wyznaczenia pięciu stref ekologicznych różniących się rodzajem roślinności, sposobem zasilania hydrologicznego, dynamiką procesów sukcesji roślinnej. Na podstawie ponad pięćdziesięcioletnich obserwacji stanów wody w rzece ustalono dla każdej ze stref: długość trwania zalewu, częstość trwania zalewu o określonej intensywności, liczbę wystąpień zalewu w poszczególnych latach oraz czas trwania zalewu podczas okresu wegetacyjnego. Wyznaczono w ten sposób zasięg oddziaływania wód rzecznych na przyległe tereny zalewowe. W wyniku analizy danych hydrologicznych nie stwierdzono zmniejszenia się wielkości, częstości lub czasu trwania zalewów rzecznych. Przeciwnie, od lat 70. XX w. obserwuje się pewne wydłużenie trwania zalewów. Może mieć to związek ze zmniejszeniem retencji basenów środkowego i górnego na skutek przeprowadzonych prac melioracyjnych. W celu wytłumaczenia zmian w części zbiorowisk roślinnych i korzeniowej warstwie gleby, wskazujących na okresowe przesychanie siedlisk, należy przeprowadzić badania dynamiki zmian retencji śniegowej i zmian w zasilaniu Bagna Ławki wodą z tych zasobów.The paper presents results of the study along the transect through Bagno Ławki, part of the floodplain of the Biebrza River in its lower basin. The study involved organic soil analysis, sampling of plant communities and hydrological studies on flood phenomena. The main focus of the work was on identification of water conditions using surface hydrology analysis of fifty years data set, on peat soil characteristics describing in a qualitative way the historical water conditions and on vegetation in the late sixties and now which enabled description of ecological changes in the site. Stratigraphic data showed the way the valley had been inundated and colonised by wetland plant communities. The surface soil cover, which reflects current status of soil-water conditions, showed by a slight moorsh layer the decrease of water saturation in the soil profile. Changes of plant communities during the last thirty years proved the increase of water dynamics in some areas which allowed for the expansion of communities tolerant to water changes. In the meantime, however, significant changes of agricultural practices took place there i.e. part of the area was abandoned by farmers and only seldom mowed or (close to the river) grazed by cattle. So, the vegetation response is not only due to the hydrology. Analysis of hydrological data for the closest gauge station in Burzyn allowed to compare zonal location of plant communities with flood extension. Contrary to the general expectation, water heights, frequency and duration of waterlogged periods did not prove a decrease in flood magnitude. Flooding phenomena seem to occur longer since the seventies than before. Changes in the duration of snow cover might be responsible for the general decrease of water saturation. These phenomena will be analysed in details during further studies