The Computational Complexity of Knot and Link Problems

We consider the problem of deciding whether a polygonal knot in 3-dimensional Euclidean space is unknotted, capable of being continuously deformed without self-intersection so that it lies in a plane. We show that this problem, {\sc unknotting problem} is in {\bf NP}. We also consider the problem, {\sc unknotting problem} of determining whether two or more such polygons can be split, or continuously deformed without self-intersection so that they occupy both sides of a plane without intersecting it. We show that it also is in NP. Finally, we show that the problem of determining the genus of a polygonal knot (a generalization of the problem of determining whether it is unknotted) is in {\bf PSPACE}. We also give exponential worst-case running time bounds for deterministic algorithms to solve each of these problems. These algorithms are based on the use of normal surfaces and decision procedures due to W. Haken, with recent extensions by W. Jaco and J. L. Tollefson.Comment: 32 pages, 1 figur

Few figs for frugivores: Riparian fig trees in Zimbabwe may not be a dry season keystone resource

Most plants flower and fruit at times of year when probabilities of pollination and seedling establishment are high. Fig trees (Ficus spp.) are often considered as keystone resources for vertebrate frugivores, in part because of year‐round fig production. This unusual fruiting phenology results in the maintenance of fig wasp populations, but in seasonal environments this means fruiting occurs during periods when the chances of seedling establishment are low. Under these circumstances, selection is expected to favour any individuals that reduce or eliminate fruiting at these times. Here, we describe a large‐scale survey of the extent of dry season fruiting by three riparian Ficus species in Gonarezhou National Park, Zimbabwe. Few trees of two monoecious species, F. sycomorus and F. abutilifolia, had figs, and most crops of F. sycomorus were far smaller than the trees were capable of producing. Large stands of the dioecious F. capreifolia were present, but fig densities were low and no mature female (seed containing) figs were recorded. Even though fig trees may have been the only species bearing fruit, the consequences of the low investment in reproduction by the three Ficus species were clear—there were too few figs for a landscape‐scale keystone role

The role of biophysical cohesion on subaqueous bed form size

Biologically active, fine-grained sediment forms abundant sedimentary deposits on Earth's surface, and mixed mud-sand dominates many coasts, deltas, and estuaries. Our predictions of sediment transport and bed roughness in these environments presently rely on empirically based bed form predictors that are based exclusively on biologically inactive cohesionless silt, sand, and gravel. This approach underpins many paleoenvironmental reconstructions of sedimentary successions, which rely on analysis of cross-stratification and bounding surfaces produced by migrating bed forms. Here we present controlled laboratory experiments that identify and quantify the influence of physical and biological cohesion on equilibrium bed form morphology. The results show the profound influence of biological cohesion on bed form size and identify how cohesive bonding mechanisms in different sediment mixtures govern the relationships. The findings highlight that existing bed form predictors require reformulation for combined biophysical cohesive effects in order to improve morphodynamic model predictions and to enhance the interpretations of these environments in the geological record

Triad3a induces the degradation of early necrosome to limit RipK1-dependent cytokine production and necroptosis.

Understanding the molecular signaling in programmed cell death is vital to a practical understanding of inflammation and immune cell function. Here we identify a previously unrecognized mechanism that functions to downregulate the necrosome, a central signaling complex involved in inflammation and necroptosis. We show that RipK1 associates with RipK3 in an early necrosome, independent of RipK3 phosphorylation and MLKL-induced necroptotic death. We find that formation of the early necrosome activates K48-ubiquitin-dependent proteasomal degradation of RipK1, Caspase-8, and other necrosomal proteins. Our results reveal that the E3-ubiquitin ligase Triad3a promotes this negative feedback loop independently of typical RipK1 ubiquitin editing enzymes, cIAPs, A20, or CYLD. Finally, we show that Triad3a-dependent necrosomal degradation limits necroptosis and production of inflammatory cytokines. These results reveal a new mechanism of shutting off necrosome signaling and may pave the way to new strategies for therapeutic manipulation of inflammatory responses

Mouse Acetylcholinesterase Enhances Neurite Outgrowth of Rat R28 Cells Through Interaction With Laminin-1

The enzyme acetylcholinesterase (AChE) terminates synaptic transmission at cholinergic synapses by hydrolyzing the neurotransmitter acetylcholine, but can also exert ‘non-classical’, morpho-regulatory effects on developing neurons such as stimulation of neurite outgrowth. Here, we investigated the role of AChE binding to laminin-1 on the regulation of neurite outgrowth by using cell culture, immunocytochemistry, and molecular biological approaches. To explore the role of AChE, we examined fiber growth of cells overexpressing different forms of AChE, and/or during their growth on laminin-1. A significant increase of neuritic growth as compared with controls was observed for neurons over-expressing AChE. Accordingly, addition of globular AChE to the medium increased total length of neurites. Co-transfection with PRIMA, a membrane anchor of AChE, led to an increase in fiber length similar to AChE overexpressing cells. Transfection with an AChE mutant that leads to the retention of AChE within cells had no stimulatory effect on neurite length. Noticeably, the longest neurites were produced by neurons overexpressing AChE and growing on laminin-1, suggesting that the AChE/laminin interaction is involved in regulating neurite outgrowth. Our findings demonstrate that binding of AChE to laminin-1 alters AChE activity and leads to increased neurite growth in culture. A possible mechanism of the AChE effect on neurite outgrowth is proposed due to the interaction of AChE with laminin-1

RELEASE-HF study:a protocol for an observational, registry-based study on the effectiveness of telemedicine in heart failure in the Netherlands

Introduction:Meta-analyses show postive effects of telemedicine in heart failure (HF) management on hospitalisation, mortality and costs. However, these effects are heterogeneous due to variation in the included HF population, the telemedicine components and the quality of the comparator usual care. Still, telemedicine is gaining acceptance in HF management. The current nationwide study aims to identify (1) in which subgroup(s) of patients with HF telemedicine is (cost-)effective and (2) which components of telemedicine are most (cost-) effective. Methods and analysis:The RELEASE-HF ('REsponsible roLl-out of E-heAlth through Systematic Evaluation -Heart Failure') study is a multicentre, observational, registry-based cohort study that plans to enrol 6480 patients with HF using data from the HF registry facilitated by the Netherlands Heart Registration. Collected data include patient characteristics, treatment information and clinical outcomes, and are measured at HF diagnosis and at 6 and 12 months afterwards. The components of telemedicine are described at the hospital level based on closed-ended interviews with clinicians and at the patient level based on additional data extracted from electronic health records and telemedicine-generated data. The costs of telemedicine are calculated using registration data and interviews with clinicians and finance department staff. To overcome missing data, additional national databases will be linked to the HF registry if feasible. Heterogeneity of the effects of offering telemedicine compared with not offering on days alive without unplanned hospitalisations in 1 year is assessed across predefined patient characteristics using exploratory stratified analyses. The effects of telemedicine components are assessed by fitting separate models for component contrasts. Ethics and dissemination:The study has been approved by the Medical Ethics Committee 2021 of the University Medical Center Utrecht (the Netherlands). Results will be published in peer-reviewed journals and presented at (inter)national conferences. Effective telemedicine scenarios will be proposed among hospitals throughout the country and abroad, if applicable and feasible.</p

RELEASE-HF study:a protocol for an observational, registry-based study on the effectiveness of telemedicine in heart failure in the Netherlands

Introduction:Meta-analyses show postive effects of telemedicine in heart failure (HF) management on hospitalisation, mortality and costs. However, these effects are heterogeneous due to variation in the included HF population, the telemedicine components and the quality of the comparator usual care. Still, telemedicine is gaining acceptance in HF management. The current nationwide study aims to identify (1) in which subgroup(s) of patients with HF telemedicine is (cost-)effective and (2) which components of telemedicine are most (cost-) effective. Methods and analysis:The RELEASE-HF ('REsponsible roLl-out of E-heAlth through Systematic Evaluation -Heart Failure') study is a multicentre, observational, registry-based cohort study that plans to enrol 6480 patients with HF using data from the HF registry facilitated by the Netherlands Heart Registration. Collected data include patient characteristics, treatment information and clinical outcomes, and are measured at HF diagnosis and at 6 and 12 months afterwards. The components of telemedicine are described at the hospital level based on closed-ended interviews with clinicians and at the patient level based on additional data extracted from electronic health records and telemedicine-generated data. The costs of telemedicine are calculated using registration data and interviews with clinicians and finance department staff. To overcome missing data, additional national databases will be linked to the HF registry if feasible. Heterogeneity of the effects of offering telemedicine compared with not offering on days alive without unplanned hospitalisations in 1 year is assessed across predefined patient characteristics using exploratory stratified analyses. The effects of telemedicine components are assessed by fitting separate models for component contrasts. Ethics and dissemination:The study has been approved by the Medical Ethics Committee 2021 of the University Medical Center Utrecht (the Netherlands). Results will be published in peer-reviewed journals and presented at (inter)national conferences. Effective telemedicine scenarios will be proposed among hospitals throughout the country and abroad, if applicable and feasible.</p

Postoperative serum proteomic profiles may predict recurrence-free survival in high-risk primary breast cancer

Item does not contain fulltextPURPOSE: Better breast cancer prognostication may improve selection of patients for adjuvant therapy. We conducted a retrospective longitudinal study in which we investigated sera of high-risk primary breast cancer patients, to search for proteins predictive of recurrence-free survival. METHODS: Sera of 82 breast cancer patients obtained after surgery, but prior to the administration of adjuvant therapy, were fractionated using anion-exchange chromatography, to facilitate the detection of the low-abundant serum peptides. Selected fractions were subsequently analysed by surface-enhanced laser desorption/ionisation time-of-flight mass spectrometry (SELDI-TOF MS), and the resulting protein profiles were searched for prognostic markers by appropriate bioinformatics tools. RESULTS: Four peak clusters (i.e. m/z 3073, m/z 3274, m/z 4405 and m/z 7973) were found to bear significant prognostic value (P </= 0.01). The m/z 3274 candidate marker was structurally identified as inter-alpha-trypsin inhibitor heavy chain 4 fragment(658-688) in serum. Except for the m/z 7973 peak cluster, these peaks remained independently associated with recurrence-free survival upon multivariate Cox regression analysis, including clinical parameters of known prognostic value in this study population. CONCLUSION: Investigation of the postoperative serum proteome by, e.g., anion-exchange fractionation followed by SELDI-TOF MS analysis is promising for the detection of novel prognostic factors. However, regarding the rather limited study population, validation of these results by analysis of independent study populations is warranted to assess the true clinical applicability of discovered prognostic markers. In addition, structural identification of the other markers will aid in elucidation of their role in breast cancer prognosis, as well as enable development of absolute quantitative assays

Longitudinal positron emission tomography and postmortem analysis reveals widespread neuroinflammation in SARS-CoV-2 infected rhesus macaques

BACKGROUND: Coronavirus disease 2019 (COVID-19) patients initially develop respiratory symptoms, but they may also suffer from neurological symptoms. People with long-lasting effects after acute infections with severe respiratory syndrome coronavirus 2 (SARS-CoV-2), i.e., post-COVID syndrome or long COVID, may experience a variety of neurological manifestations. Although we do not fully understand how SARS-CoV-2 affects the brain, neuroinflammation likely plays a role. METHODS: To investigate neuroinflammatory processes longitudinally after SARS-CoV-2 infection, four experimentally SARS-CoV-2 infected rhesus macaques were monitored for 7 weeks with 18-kDa translocator protein (TSPO) positron emission tomography (PET) using [18F]DPA714, together with computed tomography (CT). The baseline scan was compared to weekly PET-CTs obtained post-infection (pi). Brain tissue was collected following euthanasia (50 days pi) to correlate the PET signal with TSPO expression, and glial and endothelial cell markers. Expression of these markers was compared to brain tissue from uninfected animals of comparable age, allowing the examination of the contribution of these cells to the neuroinflammatory response following SARS-CoV-2 infection. RESULTS: TSPO PET revealed an increased tracer uptake throughout the brain of all infected animals already from the first scan obtained post-infection (day 2), which increased to approximately twofold until day 30 pi. Postmortem immunohistochemical analysis of the hippocampus and pons showed TSPO expression in cells expressing ionized calcium-binding adaptor molecule 1 (IBA1), glial fibrillary acidic protein (GFAP), and collagen IV. In the hippocampus of SARS-CoV-2 infected animals the TSPO+ area and number of TSPO+ cells were significantly increased compared to control animals. This increase was not cell type specific, since both the number of IBA1+TSPO+ and GFAP+TSPO+ cells was increased, as well as the TSPO+ area within collagen IV+ blood vessels. CONCLUSIONS: This study manifests [18F]DPA714 as a powerful radiotracer to visualize SARS-CoV-2 induced neuroinflammation. The increased uptake of [18F]DPA714 over time implies an active neuroinflammatory response following SARS-CoV-2 infection. This inflammatory signal coincides with an increased number of TSPO expressing cells, including glial and endothelial cells, suggesting neuroinflammation and vascular dysregulation. These results demonstrate the long-term neuroinflammatory response following a mild SARS-CoV-2 infection, which potentially precedes long-lasting neurological symptoms

Changes in the urinary extracellular vesicle proteome are associated with nephronophthisis-related ciliopathies

Nephronophthisis is one of the leading genetic causes of end-stage renal disease in childhood. Early diagnostics and prognostics for nephronophthisis are currently limited. We aimed to identify non-invasive protein biomarkers for nephronophthisis in urinary extracellular vesicles. Extracellular vesicles were isolated from urine of 12 patients with a nephronophthisis-related ciliopathy and 12 age- and gender-matched controls, followed by in-depth label-free LC-MS/MS proteomics analysis of gel fractionated extracellular vesicle proteins. Supervised cluster analysis of proteomic profiles separated patients from controls. We identified 156 differentially expressed proteins with fold change ≥4 in patients compared to controls (P <.05). Importantly, expression levels of discriminating proteins were correlated with chronic kidney disease stage, suggesting possible applications for urinary extracellular vesicle biomarkers in prognostics for nephronophthisis. Enrichment analysis of gene ontology terms revealed GO terms including signaling, actin cytoskeleton and endocytosis among the downregulated proteins in patients, whereas terms related to response to wounding and extracellular matrix organization were enriched among upregulated proteins. Our findings represent the first step towards a non-invasive diagnostic test for nephronophthisis. Further research is needed to determine specificity of the candidate biomarkers. In conclusion, proteomic profiles of urinary extracellular vesicles differentiate nephronophthisis-related ciliopathy patients from healthy controls. Significance: Nephronophthisis is an important cause of end-stage renal disease in children and is associated with an average diagnostic delay of 3.5 years. This is the first study investigating candidate biomarkers for nephronophthisis using global proteomics analysis of urinary extracellular vesicles in patients with nephronophthisis compared to control individuals. We show that measuring protein markers in urinary extracellular vesicles is a promising approach for non-invasive early diagnostics of nephronophthisis