Characteristic invariants in Hennessy-Milner logic

In this paper, we prove that Hennessy–Milner Logic (HML), despite its structural limitations, is sufficiently expressive to specify an initial property φ0 and a characteristic invariant χI for an arbitrary finite-state process P such that φ0∧AG(χI) is a characteristic formula for P. This means that a process Q, even if infinite state, is bisimulation equivalent to P iff Q⊨φ0∧AG(χI). It follows, in particular, that it is sufficient to check an HML formula for each state of a finite-state process to verify that it is bisimulation equivalent to P. In addition, more complex systems such as context-free processes can be checked for bisimulation equivalence with P using corresponding model checking algorithms. Our characteristic invariant is based on so called class-distinguishing formulas that identify bisimulation equivalence classes in P and which are expressed in HML. We extend Kanellakis and Smolka’s partition refinement algorithm for bisimulation checking in order to generate concise class-distinguishing formulas for finite-state processes

Endozytose und Resekretion von Apolipoprotein AI durch humane Endothelzellen

Viele antiatherogene Eigenschaften der High-Density Lipoproteine (HDL) werden im extraluminalen vaskulären Interstitium vermittelt, jedoch ist unklar, wie HDL und sein Hauptapolipoprotein, ApoAI, das Gefäßendothel passieren. Favorisiert wird ein passiver parazellulärer Weg, jedoch ist ein spezifischer transzellulärer Transport denkbar. In Assoziations- und Dissoziationsstudien mit fluorescein- und goldmarkiertem ApoAI an Endothelzellen menschlicher Nabelvenen (HUVEC) fanden sich Hinweise für spezifischen transzellulären Transport. Markiertes ApoAI zeigt eine spezifische temperatur- und kationenabhängige Assoziation und Dissoziation mit HUVEC. Die ApoAI-Assoziation ist durch unmarkiertes ApoAI und acyliertes LDL kompetitiv hemmbar. Morphologisch konnte ApoAI in clathrin-coated pits und vesicles, clathrinfreien Vesikeln und Caveolae nachgewiesen werden. Resezerniertes ApoAI besitzt eine Lipidhülle, möglicherweise nach intrazellulärer Lipidierung mit Bildung cholesterinarmer HDL-Vorstufen

Mid-range outcomes in 64 consecutive cases of multilevel fusion for degenerative diseases of the lumbar spine

In the treatment of multilevel degenerative disorders of the lumbar spine, spondylodesis plays a controversial role. Most patients can be treated conservatively with success. Multilevel lumbar fusion with instrumentation is associated with severe complications like failed back surgery syndrome, implant failure, and adjacent segment disease (ASD). This retrospective study examines the records of 70 elderly patients with degenerative changes or instability of the lumbar spine treated between 2002 and 2007 with spondylodesis of more than two segments. Sixty-four patients were included; 5 patients had died and one patient was lost to follow-up. We evaluated complications, clinical/radiological outcomes, and success of fusion. Flexion-extension and standing X-rays in two planes, MRI, and/or CT scans were obtained pre-operatively. Patients were assessed clinically using the Oswestry disability index (ODI) and a Visual Analogue Scale (VAS). Surgery performed was dorsolateral fusion (46.9%) or dorsal fusion with anterior lumbar interbody fusion (ALIF; 53.1%). Additional decompression was carried out in 37.5% of patients. Mean follow-up was 29.4±5.4 months. Average patient age was 64.7±4.3 years. Clinical outcomes were not satisfactory for all patients. VAS scores improved from 8.6±1.3 to 5.6±3.0 pre- to post-operatively, without statistical significance. ODI was also not significantly improved (56.1±22.3 pre- and 45.1±26.4 post-operatively). Successful fusion, defined as adequate bone mass with trabeculation at the facets and transverse processes or in the intervertebral segments, did not correlate with good clinical outcomes. Thirty-five of 64 patients (54%) showed signs of pedicle screw loosening, especially of the screws at S1. However, only 7 of these 35 (20%) complained of corresponding back pain. Revision surgery was required in 24 of 64 patients (38%). Of these, indications were adjacent segment disease (16 cases), pedicle screw loosening (7 cases), and infection (one case). At follow-up of 29.4 months, patients with radiographic ASD had worse ODI scores than patients without (54.7 vs. 36.6; P<0.001). Multilevel fusion for degenerative disease still has a high rate of complications, up to 50%. The problem of adjacent segment disease after fusion surgery has not yet been solved. This study underscores the need for strict indication guidelines to perform lumbar spine fusion of more than two levels

Three necessary conditions for establishing effective sustainable development goals in the Anthropocene

The purpose of the United Nations-guided process to establish Sustainable Development Goals is to galvanize governments and civil society to rise to the interlinked environmental, societal, and economic challenges we face in the Anthropocene. We argue that the process of setting Sustainable Development Goals should take three key aspects into consideration. First, it should embrace an integrated social-ecological system perspective and acknowledge the key dynamics that such systems entail, including the role of ecosystems in sustaining human wellbeing, multiple cross-scale interactions, and uncertain thresholds. Second, the process needs to address trade-offs between the ambition of goals and the feasibility in reaching them, recognizing biophysical, social, and political constraints. Third, the goal-setting exercise and the management of goal implementation need to be guided by existing knowledge about the principles, dynamics, and constraints of social change processes at all scales, from the individual to the global. Combining these three aspects will increase the chances of establishing and achieving effective Sustainable Development Goals

How many human proteoforms are there?

Despite decades of accumulated knowledge about proteins and their post-translational modifications (PTMs), numerous questions remain regarding their molecular composition and biological function. One of the most fundamental queries is the extent to which the combinations of DNA-, RNA- and PTM-level variations explode the complexity of the human proteome. Here, we outline what we know from current databases and measurement strategies including mass spectrometry-based proteomics. In doing so, we examine prevailing notions about the number of modifications displayed on human proteins and how they combine to generate the protein diversity underlying health and disease. We frame central issues regarding determination of protein-level variation and PTMs, including some paradoxes present in the field today. We use this framework to assess existing data and to ask the question, "How many distinct primary structures of proteins (proteoforms) are created from the 20,300 human genes?" We also explore prospects for improving measurements to better regularize protein-level biology and efficiently associate PTMs to function and phenotype

Genomics and epidemiology of the P.1 SARS-CoV-2 lineage in Manaus, Brazil

Cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in Manaus, Brazil, resurged in late 2020 despite previously high levels of infection. Genome sequencing of viruses sampled in Manaus between November 2020 and January 2021 revealed the emergence and circulation of a novel SARS-CoV-2 variant of concern. Lineage P.1 acquired 17 mutations, including a trio in the spike protein (K417T, E484K, and N501Y) associated with increased binding to the human ACE2 (angiotensin-converting enzyme 2) receptor. Molecular clock analysis shows that P.1 emergence occurred around mid-November 2020 and was preceded by a period of faster molecular evolution. Using a two-category dynamical model that integrates genomic and mortality data, we estimate that P.1 may be 1.7- to 2.4-fold more transmissible and that previous (non-P.1) infection provides 54 to 79% of the protection against infection with P.1 that it provides against non-P.1 lineages. Enhanced global genomic surveillance of variants of concern, which may exhibit increased transmissibility and/or immune evasion, is critical to accelerate pandemic responsiveness