An integrated model for the nucleo-cytoplasmic transport of cytoplasmic poly(A)-binding proteins

Cytoplasmic poly(A)-binding proteins (PABPs) regulate mRNA stability and translation. Although predominantly localized in the cytoplasm, PABP proteins also cycle through the nucleus. Recent work has established that their steady-state localization can be altered by cellular stresses such as ultraviolet (UV) radiation, and infection by several viruses, resulting in nuclear accumulation of PABPs. Here, we present further evidence that their interaction with and release from mRNA and translation complexes are important in determining their sub-cellular distribution and propose an integrated model for regulated nucleo-cytoplasmic transport of PABPs

Globally important plant functional traits for coping with climate change

The last decade has seen a proliferation of studies that use plant functional traits to assess how plants respond to climate change. However, it remains unclear whether there is a global set of traits that can predict plants’ ability to cope or even thrive when exposed to varying manifestations of climate change. We conducted a systematic global review which identified 148 studies to assess whether there is a set of common traits across biomes that best predict positive plant responses to multiple climate changes and associated environmental changes. Eight key traits appear to best predict positive plant responses to multiple climate/environmental changes across biomes: lower or higher specific leaf area (SLA), lower or higher plant height, greater water-use efficiency (WUE), greater resprouting ability, lower relative growth rate, greater clonality/bud banks/below-ground storage, higher wood density, and greater rooting depth. Trait attributes associated with positive responses appear relatively consistent within biomes and climate/environmental changes, except for SLA and plant height, where both lower and higher trait attributes are associated with a positive response depending on the biome and climate/environmental change considered. Overall, our findings illustrate important and general trait-climate responses within and between biomes that help us understand which plant phenotypes may cope with or thrive under current and future climate change.publishedVersio

Endoscopic vacuum therapy for in- and outpatient treatment of colorectal defects

Background. Evidence for endoscopic vacuum therapy (EVT) for colorectal defects is still based on small patient series from various institutions, employing different treatment algorithms and methods. As EVT was invented at our institution 20 years ago, the aim was to report the efficacy and safety of EVT for colorectal defects as well as to analyze factors associated with efficacy, therapy duration, and outpatient treatment. Methods. Cohort study with analysis of prospectively collected data of patients receiving EVT for colorectal defects at a tertiary referral center in Germany (n=281). Results. The majority of patients had malignant disease (83%) and an American Society of Anesthesiologists classification of III/IV (81%). Most frequent indications for EVT were anastomotic leakage after sigmoid or rectal resection (67%) followed by rectal stump leakage (20%). EVT was successful in 256 out of 281 patients (91%). EVT following multi-visceral resection (P = 0.037) and recent surgical revision after primary surgery (P = 0.009) were risk factors for EVT failure. EVT-associated adverse events occurred in 27 patients (10%). Median treatment duration was 25 days. Previous chemo-radiation (P = 0.006) was associated with a significant longer duration of EVT. Outpatient treatment was conducted in 49% of patients with a median hospital stay reduction of 15 days and 98% treatment success. Younger patient age (P = 0.044) was associated with the possibility of outpatient treatment. Restoration of intestinal continuity was achieved in 60% of patients where technically possible with a 12-month rate of 52%. Conclusions. In patients with colorectal defects, EVT appears to be a safe and effective, minimally invasive option for in- and outpatient treatment

Spatial arrangement of several flagellins within bacterial flagella improves motility in different environments

Bacterial flagella are helical proteinaceous fibers, composed of the protein flagellin, that confer motility to many bacterial species. The genomes of about half of all flagellated species include more than one flagellin gene, for reasons mostly unknown. Here we show that two flagellins (FlaA and FlaB) are spatially arranged in the polar flagellum of Shewanella putrefaciens, with FlaA being more abundant close to the motor and FlaB in the remainder of the flagellar filament. Observations of swimming trajectories and numerical simulations demonstrate that this segmentation improves motility in a range of environmental conditions, compared to mutants with single-flagellin filaments. In particular, it facilitates screw-like motility, which enhances cellular spreading through obstructed environments. Similar mechanisms may apply to other bacterial species and may explain the maintenance of multiple flagellins to form the flagellar filament

Memory/effector (CD45RBlo) CD4 T cells are controlled directly by IL-10 and cause IL-22–dependent intestinal pathology

Interleukin-10 acts directly on CD45RBlo but not CD45RBhi cells to control colitis upon transfer into Rag1-deficient recipients

Development of 3D detectors at FBK-irst

We report on the development of 3D detectors at Fondazione Bruno Kessler - irst in the framework of the CERN RD-50 Collaboration. Technological and design aspects dealing with the 3D Single Type Column detectors are reviewed, and selected results from the electrical and functional characterization of prototypes are reported and discussed. A new detector concept, namely 3D Double-side Double Type Column detectors, allowing for significant performance enhancement while maintaining a reasonable process complexity, is final ly addressed

Entry of Herpes Simplex Virus Type 1 (HSV-1) into the Distal Axons of Trigeminal Neurons Favors the Onset of Nonproductive, Silent Infection

Following productive, lytic infection in epithelia, herpes simplex virus type 1 (HSV-1) establishes a lifelong latent infection in sensory neurons that is interrupted by episodes of reactivation. In order to better understand what triggers this lytic/latent decision in neurons, we set up an organotypic model based on chicken embryonic trigeminal ganglia explants (TGEs) in a double chamber system. Adding HSV-1 to the ganglion compartment (GC) resulted in a productive infection in the explants. By contrast, selective application of the virus to distal axons led to a largely nonproductive infection that was characterized by the poor expression of lytic genes and the presence of high levels of the 2.0-kb major latency-associated transcript (LAT) RNA. Treatment of the explants with the immediate-early (IE) gene transcriptional inducer hexamethylene bisacetamide, and simultaneous co-infection of the GC with HSV-1, herpes simplex virus type 2 (HSV-2) or pseudorabies virus (PrV) helper virus significantly enhanced the ability of HSV-1 to productively infect sensory neurons upon axonal entry. Helper-virus-induced transactivation of HSV-1 IE gene expression in axonally-infected TGEs in the absence of de novo protein synthesis was dependent on the presence of functional tegument protein VP16 in HSV-1 helper virus particles. After the establishment of a LAT-positive silent infection in TGEs, HSV-1 was refractory to transactivation by superinfection of the GC with HSV-1 but not with HSV-2 and PrV helper virus. In conclusion, the site of entry appears to be a critical determinant in the lytic/latent decision in sensory neurons. HSV-1 entry into distal axons results in an insufficient transactivation of IE gene expression and favors the establishment of a nonproductive, silent infection in trigeminal neurons

Effectiveness and safety of opicapone in Parkinson’s disease patients with motor fluctuations: the OPTIPARK open-label study

Background The efficacy and safety of opicapone, a once-daily catechol-O-methyltransferase inhibitor, have been established in two large randomized, placebo-controlled, multinational pivotal trials. Still, clinical evidence from routine practice is needed to complement the data from the pivotal trials. Methods OPTIPARK (NCT02847442) was a prospective, open-label, single-arm trial conducted in Germany and the UK under clinical practice conditions. Patients with Parkinson’s disease and motor fluctuations were treated with opicapone 50 mg for 3 (Germany) or 6 (UK) months in addition to their current levodopa and other antiparkinsonian treatments. The primary endpoint was the Clinician’s Global Impression of Change (CGI-C) after 3 months. Secondary assessments included Patient Global Impressions of Change (PGI-C), the Unified Parkinson’s Disease Rating Scale (UPDRS), Parkinson’s Disease Questionnaire (PDQ-8), and the Non-Motor Symptoms Scale (NMSS). Safety assessments included evaluation of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs). Results Of the 506 patients enrolled, 495 (97.8%) took at least one dose of opicapone. Of these, 393 (79.4%) patients completed 3 months of treatment. Overall, 71.3 and 76.9% of patients experienced any improvement on CGI-C and PGI-C after 3 months, respectively (full analysis set). At 6 months, for UK subgroup only (n = 95), 85.3% of patients were judged by investigators as improved since commencing treatment. UPDRS scores at 3 months showed statistically significant improvements in activities of daily living during OFF (mean ± SD change from baseline: − 3.0 ± 4.6, p < 0.0001) and motor scores during ON (− 4.6 ± 8.1, p < 0.0001). The mean ± SD improvements of − 3.4 ± 12.8 points for PDQ-8 and -6.8 ± 19.7 points for NMSS were statistically significant versus baseline (both p < 0.0001). Most of TEAEs (94.8% of events) were of mild or moderate intensity. TEAEs considered to be at least possibly related to opicapone were reported for 45.1% of patients, with dyskinesia (11.5%) and dry mouth (6.5%) being the most frequently reported. Serious TEAEs considered at least possibly related to opicapone were reported for 1.4% of patients. Conclusions Opicapone 50 mg was effective and generally well-tolerated in PD patients with motor fluctuations treated in clinical practice. Trial registration Registered in July 2016 at clinicaltrials.gov (NCT02847442)

Abstracts from the 8th International Conference on cGMP Generators, Effectors and Therapeutic Implications

This work was supported by a restricted research grant of Bayer AG