Electrodiffusive model for astrocytic and neuronal ion concentration dynamics

Electrical neural signalling typically takes place at the time-scale of milliseconds, and is typically modeled using the cable equation. This is a good approximation for processes when ionic concentrations vary little during the time course of a simulation. During periods of intense neural signalling, however, the local extracellular K+ concentration may increase by several millimolars. Clearance of excess K+ likely depends partly on diffusion in the extracellular space, partly on local uptake by- and intracellular transport within astrocytes. This process takes place at the time scale of seconds, and can not be modeled accurately without accounting for the spatiotemporal variations in ion concentrations. The work presented here consists of two main parts: First, we developed a general electrodiffusive formalism for modeling ion concentration dynamics in a one-dimensional geometry, including both an intra- and extracellular domain. The formalism was based on the Nernst-Planck equations. It ensures (i) consistency between the membrane potential and ion concentrations, (ii) global particle/charge conservation, and (iii) accounts for diffusion and concentration dependent variations in resistivities. Second, we applied the formalism to model how astrocytes exchange ions with the ECS, and identified the key astrocytic mechanisms involved in K+ removal from high concentration regions. We found that a local increase in extracellular K\textsuperscript{+} evoked a local depolarization of the astrocyte membrane, which at the same time (i) increased the local astrocytic uptake of K\textsuperscript{+}, (ii) suppressed extracellular transport of K+, (iii) increased transport of K+ within astrocytes, and (iv) facilitated astrocytic relase of K+ in extracellular low concentration regions. In summary, these mechanisms seem optimal for shielding the extracellular space from excess K+.Comment: 19 pages, 5 figures, 1 table (Equations 37 & 38 and the two first equations in Figure 2 were corrected May 30th 2013

Global heart warming: kama muta evoked by climate change messages is associated with intentions to mitigate climate change

Concern about climate change is often rooted in sympathy, compassion, and care for nature, living beings, and future generations. Feeling sympathy for others temporarily forms a bond between them and us: we focus on what we have in common and feel a sense of common destiny. Thus, we temporarily experience communal sharing relationships. A sudden intensification in communal sharing evokes an emotion termed kama muta, which may be felt through tearing up, a warm feeling in the chest, or goosebumps. We conducted four pre-registered studies (n = 1,049) to test the relationship between kama muta and pro-environmental attitudes, intentions, and behavior. In each study, participants first reported their attitudes about climate change. Then, they received climate change-related messages. In Study 1, they saw one of the two moving video clips about environmental concerns. In Study 2, participants listened to a more or less moving version of a story about a typhoon in the Philippines. In Study 3, they listened to a different, also moving version of this story or an unrelated talk. In Study 4, they watched either a factual or a moving video about climate change. Participants then indicated their emotional responses. Finally, they indicated their intentions for climate mitigation actions. In addition, we measured time spent reading about climate-related information (Studies 1, 2, and 4) and donating money (Study 4). Across all studies, we found that feelings of kama muta correlated positively with pro-environmental intentions (r = 0.48 [0.34, 0.62]) and behavior (r = 0.10 [0.0004, 0.20]). However, we did not obtain evidence for an experimental effect of the type of message (moving or neutral) on pro-environmental intentions (d = 0.04 [−0.09, 0.18]), though this relationship was significantly mediated by felt kama muta across Studies 2–4. The relationship was not moderated by prior climate attitudes, which had a main effect on intentions. We also found an indirect effect of condition through kama muta on donation behavior. In sum, our results contribute to the question of whether kama muta evoked by climate-change messages can be a motivating force in efforts at climate-change mitigation

Discovery, characterization and engineering of bacterial thermostable cellulose- degrading enzymes

Lignocellulose is the most abundant biomass on Earth, and thus our largest organic carbon reservoir. Enzymatic depolymerization of recalcitrant polysaccharides, notably cellulose, is a major cost driver in accessing the renewable energy stored within lignocellulosic biomass. Natural biodiversities may be explored to discover microbial enzymes that have evolved to conquer this task in various environments. We are studying novel enzymes from various biodiversities for the conversion of lignocellulosic materials, using (meta)genome mining and functional screening of fosmid libraries. Targeted biodiversities include deep-sea hot vents of the Arctic mid-ocean ridge (AMOR), the microbiome of the wood-eating Arctic shipworm, thermophilic enrichment cultures from biogas reactors, the Svalbard reindeer gut microbiome, and publicly available metagenomic data from various hot environments. Bioprospecting of the different biodiversities has so far resulted in the discovery of approximately 20 novel enzymes active on lignocellulosic substrates. The significant differences in the origin of the enzymes is reflected in their properties, both beneficial and challenging, and provide us with interesting engineering targets for improved performance in industrial settings. We will present case studies, including work on a novel thermostable cellulase named mgCel6A, with good activity on sulfite-pulped Norway spruce. This enzyme consists of a glycoside hydrolase family 6 catalytic domain (GH6) connected to a family 2 carbohydrate binding module (CBM2) and both the activity profile and predicted structural similarities to known cellulases suggest that mgCel6A is an endo-acting cellulase. Comparison of the full-length enzyme with the catalytic domain showed that the CBM strongly increases substrate binding, while not affecting thermal stability. However, importantly, in reactions with higher substrate concentrations the full-length enzyme was outperformed by the catalytic domain alone, underpinning previous suggestions that CBMs may be less useful in high-consistency bioprocessing. This enzyme is currently being targeted for rational engineering in an effort to decrease the pH optimum and improve the pH stability. Other case studies include GH48 cellulases and lytic polysaccharide monooxygenases (LPMOs). One important aspect of this work concerns the possible assembly of novel enzyme cocktails for lignocellulose processing that can compete with exiting commercial cocktails, which are primarily composed of fungal enzymes. Thus, comparative studies of our most promising bacterial enzymes with their well-known fungal counterparts are also being conducted

Astrocytic Ion Dynamics: Implications for Potassium Buffering and Liquid Flow

We review modeling of astrocyte ion dynamics with a specific focus on the implications of so-called spatial potassium buffering, where excess potassium in the extracellular space (ECS) is transported away to prevent pathological neural spiking. The recently introduced Kirchoff-Nernst-Planck (KNP) scheme for modeling ion dynamics in astrocytes (and brain tissue in general) is outlined and used to study such spatial buffering. We next describe how the ion dynamics of astrocytes may regulate microscopic liquid flow by osmotic effects and how such microscopic flow can be linked to whole-brain macroscopic flow. We thus include the key elements in a putative multiscale theory with astrocytes linking neural activity on a microscopic scale to macroscopic fluid flow.Comment: 27 pages, 7 figure

Nationwide Survival Benefit after Implementation of First-Line Immunotherapy for Patients with Advanced NSCLC—Real World Efficacy

SIMPLE SUMMARY: The expected change in overall survival (OS) in patients with advanced non-small cell lung cancer (NSCLC) after the clinical implementation of immune checkpoint inhibitor therapy (ICI) has not been substantially investigated in large real-world cohorts outside randomized controlled trials (RCTs). In this nationwide study, we compared OS before and after the implementation of ICI and found that 3-year OS tripled from 6% to 18%. Patients receiving ICI had a lower OS than demonstrated in RCTs, except for patients with performance status (PS) 0. More than a fifth of the patients progressed early within the first six ICI cycles. Adverse prognostic factors were PS ≥ 1 and metastases to the bone and liver. ABSTRACT: Background The selection of patients with non-small cell lung cancer (NSCLC) for immune checkpoint inhibitor (ICI) treatment remains challenging. This real-world study aimed to compare the overall survival (OS) before and after the implementation of ICIs, to identify OS prognostic factors, and to assess treatment data in first-line (1L) ICI-treated patients without epidermal growth factor receptor mutation or anaplastic lymphoma kinase translocation. Methods Data from the Danish NSCLC population initiated with 1L palliative antineoplastic treatment from 1 January 2013 to 1 October 2018, were extracted from the Danish Lung Cancer Registry (DLCR). Long-term survival and median OS pre- and post-approval of 1L ICI were compared. From electronic health records, additional clinical and treatment data were obtained for ICI-treated patients from 1 March 2017 to 1 October 2018. Results The OS was significantly improved in the DLCR post-approval cohort (n = 2055) compared to the pre-approval cohort (n = 1658). The 3-year OS rates were 18% (95% CI 15.6–20.0) and 6% (95% CI 5.1–7.4), respectively. On multivariable Cox regression, bone (HR = 1.63) and liver metastases (HR = 1.47), performance status (PS) 1 (HR = 1.86), and PS ≥ 2 (HR = 2.19) were significantly associated with poor OS in ICI-treated patients. Conclusion OS significantly improved in patients with advanced NSCLC after ICI implementation in Denmark. In ICI-treated patients, PS ≥ 1, and bone and liver metastases were associated with a worse prognosis

Astrocytic Mechanisms Explaining Neural-Activity-Induced Shrinkage of Extraneuronal Space

Neuronal stimulation causes ∼30% shrinkage of the extracellular space (ECS) between neurons and surrounding astrocytes in grey and white matter under experimental conditions. Despite its possible implications for a proper understanding of basic aspects of potassium clearance and astrocyte function, the phenomenon remains unexplained. Here we present a dynamic model that accounts for current experimental data related to the shrinkage phenomenon in wild-type as well as in gene knockout individuals. We find that neuronal release of potassium and uptake of sodium during stimulation, astrocyte uptake of potassium, sodium, and chloride in passive channels, action of the Na/K/ATPase pump, and osmotically driven transport of water through the astrocyte membrane together seem sufficient for generating ECS shrinkage as such. However, when taking into account ECS and astrocyte ion concentrations observed in connection with neuronal stimulation, the actions of the Na+/K+/Cl− (NKCC1) and the Na+/HCO3− (NBC) cotransporters appear to be critical determinants for achieving observed quantitative levels of ECS shrinkage. Considering the current state of knowledge, the model framework appears sufficiently detailed and constrained to guide future key experiments and pave the way for more comprehensive astroglia–neuron interaction models for normal as well as pathophysiological situations

Climate change effects on people’s livelihood

Generally climate is defined as the long-term average weather conditions of a particular place, region, or the world. Key climate variables include surface conditions such as temperature, precipitation, and wind. The Intergovernmental Panel on Climate Change (IPCC) broadly defined climate change as any change in the state of climate which persists for extended periods, usually for decades or longer (Allwood et al. 2014). Climate change may occur due to nature’s both internal and external processes. External process involves anthropogenic emission of greenhouse gases to the atmosphere, and volcanic eruptions. The United Nations Framework Convention on Climate Change (UNFCCC) made a distinction between climate change attributable to human contribution to atmospheric composition and natural climate variability. In its Article 1, the UNFCCC defines climate change as “a change of climate which is attributed directly or indirectly to human activity that alters the composition of the global atmosphere and which is in addition to natural climate variability observed over comparable time periods” (United Nations 1992, p. 7)