When Less Is More: Non-monotonic Spike Sequence Processing in Neurons

Fundamental response properties of neurons centrally underly the computational capabilities of both individual nerve cells and neural networks. Most studies on neuronal input-output relations have focused on continuous-time inputs such as constant or noisy sinusoidal currents. Yet, most neurons communicate via exchanging action potentials (spikes) at discrete times. Here, we systematically analyze the stationary spiking response to regular spiking inputs and reveal that it is generically non-monotonic. Our theoretical analysis shows that the underlying mechanism relies solely on a combination of the discrete nature of the communication by spikes, the capability of locking output to input spikes and limited resources required for spike processing. Numerical simulations of mathematically idealized and biophysically detailed models, as well as neurophysiological experiments confirm and illustrate our theoretical predictions.     

When Less is More: Red Algae as Models for Studying Gene Loss and Genome Evolution in Eukaryotes

Genome evolution is usually viewed through the lens of growth in size and complexity over time, exemplified by plants and animals. In contrast, genome reduction is associated with a narrowing of ecological potential, such as in parasites and endosymbionts. But, can nuclear genome reduction also occur in, and potentially underpin a major radiation of free-living eukaryotes? An intriguing example of this phenomenon is provided by the red algae (Rhodophyta) that have lost many conserved pathways such as for flagellar motility, macroautophagy regulation, and phytochrome based light sensing. This anciently diverged, species-rich, and ecologically important algal lineage has undergone at least two rounds of large-scale genome reduction during its >1 billion-year evolutionary history. Here, using recent analyses of genome data, we review knowledge about the evolutionary trajectory of red algal nuclear and organelle gene inventories and plastid encoded autocatalytic introns. We compare and contrast Rhodophyta genome evolution to Viridiplantae (green algae and plants), both of which are members of the Archaeplastida, and highlight their divergent paths. We also discuss evidence for the speculative hypothesis that reduction in red algal plastid genome size through endosymbiotic gene transfer is counteracted by ongoing selection for compact nuclear genomes in red algae. Finally, we describe how the spliceosomal intron splicing apparatus provides an example of “evolution in action” in Rhodophyta and how the overall constraints on genome size in this lineage has left significant imprints on this key step in RNA maturation. Our review reveals the red algae to be an exciting, yet under-studied model that offers numerous novel insights as well as many unanswered questions that remain to be explored using modern genomic, genetic, and biochemical methods. The fact that a speciose lineage of free-living eukaryotes has spread throughout many aquatic habitats after having lost about 25% of its primordial gene inventory challenges us to elucidate the mechanisms underlying this remarkable feat.     

When Less Is More: Evolutionary Origins of the Affect Heuristic

The human mind is built for approximations. When considering the value of a large aggregate of different items, for example, we typically do not summate the many individual values. Instead, we appear to form an immediate impression of the likeability of the option based on the average quality of the full collection, which is easier to evaluate and remember. While useful in many situations, this affect heuristic can lead to apparently irrational decision-making. For example, studies have shown that people are willing to pay more for a small set of high-quality goods than for the same set of high-quality goods with lower-quality items added [e.g. 1]. We explored whether this kind of choice behavior could be seen in other primates. In two experiments, one in the laboratory and one in the field, using two different sets of food items, we found that rhesus monkeys preferred a highly-valued food item alone to the identical item paired with a food of positive but lower value. This finding provides experimental evidence that, under certain conditions, macaque monkeys follow an affect heuristic that can cause them to prefer less food. Conservation of this affect heuristic could account for similar ‘irrational’ biases in humans, and may reflect a more general complexity reduction strategy in which averages, prototypes, or stereotypes represent a set or group.     

When Less Is More: Reduced Usefulness Training for the Learning of Anticipation Skill in Tennis

Participants in this study practiced with feedback to anticipate the left-right direction of forehand tennis shots played by stick-figure players. A technique based on principal component analysis was used to remove dynamical differences that are associated with shots to different directions. Different body regions of the stick-figure players were neutralized with this procedure in the pretests and posttests, and in the practice phases. Experiment 1 showed that training is effective if during practice information is consistently present in the whole body of the player, but not if the information is neutralized in the whole body in half of the practice trials. Experiment 2 showed that training is effective if the variance associated with the direction of the shots is consistently present in one body region but neutralized in others, and that transfer occurs from practice with information in one body region to performance in conditions with information preserved only in other regions. Experiment 3 showed that occlusion has a much larger detrimental effect on learning than the applied neutralization technique, and that transfer between body regions occurs also with occlusion. Discussed are theoretical implications for understanding how biological motion is perceived and possible applications in a type of training referred to as reduced usefulness training.     

When More Transmission Equals Less Disease: Reconciling the Disconnect between Disease Hotspots and Parasite Transmission

The assumed straightforward connection between transmission intensity and disease occurrence impacts surveillance and control efforts along with statistical methodology, including parameter inference and niche modeling. Many infectious disease systems have the potential for this connection to be more complicated–although demonstrating this in any given disease system has remained elusive. Hemorrhagic disease (HD) is one of the most important diseases of white-tailed deer and is caused by viruses in the Orbivirus genus. Like many infectious diseases, the probability or severity of disease increases with age (after loss of maternal antibodies) and the probability of disease is lower upon re-infection compared to first infection (based on cross-immunity between virus strains). These broad criteria generate a prediction that disease occurrence is maximized at intermediate levels of transmission intensity. Using published US field data, we first fit a statistical model to predict disease occurrence as a function of seroprevalence (a proxy for transmission intensity), demonstrating that states with intermediate seroprevalence have the highest level of case reporting. We subsequently introduce an independently parameterized mechanistic model supporting the theory that high case reporting should come from areas with intermediate levels of transmission. This is the first rigorous demonstration of this phenomenon and illustrates that variation in transmission rate (e.g. along an ecologically-controlled transmission gradient) can create cryptic refuges for infectious diseases.     

Glucose-6-phosphate Dehydrogenase Deficiency and Malaria: Cytochemical Detection of Heterozygous G6PD Deficiency in Women

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a X-chromosomally transmitted disorder of the erythrocyte that affects 400 million people worldwide. Diagnosis of heterozygously-deficient women is complicated: as a result of lyonization, these women have a normal and a G6PD-deficient population of erythrocytes. The cytochemical assay is the only reliable assay to discriminate between heterozygously-deficient women and non-deficient women or homozygously-deficient women. G6PD deficiency is mainly found in areas where malaria is or has been endemic. In these areas, malaria is treated with drugs that can cause (severe) hemolysis in G6PD-deficient individuals. A cheap and reliable test is necessary for diagnosing the deficiency to prevent hemolytic disorders when treating malaria. In this review, it is concluded that the use of two different tests for diagnosing men and women is the ideal approach to detect G6PD deficiency. The fluorescent spot test is inexpensive and easy to perform but only reliable for discriminating hemizygous G6PD-deficient men from non-deficient men. For women, the cytochemical assay is recommended. However, this assay is more expensive and difficult to perform and should be simplified into a kit for use in developing countries. (J Histochem Cytochem 57:1003–1011, 2009)     

IDO1 Deficiency Does Not Affect Disease in Mouse Models of Systemic Juvenile Idiopathic Arthritis and Secondary Hemophagocytic Lymphohistiocytosis

Objectives

Indoleamine 2,3-dioxygenase-1 (IDO1) is an immune-modulatory enzyme that catalyzes the degradation of tryptophan (Trp) to kynurenine (Kyn) and is strongly induced by interferon (IFN)-γ. We previously reported highly increased levels of IFN-γ and corresponding IDO activity in patients with hemophagocytic lymphohistiocytosis (HLH), a hyper-inflammatory syndrome. On the other hand, IFN-γ and IDO were low in patients with systemic juvenile idiopathic arthritis (sJIA), an autoinflammatory syndrome. As HLH can occur as a complication of sJIA, the opposing levels of both IFN-γ and IDO are remarkable. In animal models for sJIA and HLH, the role of IFN-γ differs from being protective to pathogenic. In this study, we aimed to unravel the role of IDO1 in the pathogenesis of sJIA and HLH.

Methods

Wild-type and IDO1-knockout (IDO1-KO) mice were used in 3 models of sJIA or HLH: complete Freund’s adjuvant (CFA)-injected mice developed an sJIA-like syndrome and secondary HLH (sHLH) was evoked by either repeated injection of unmethylated CpG oligonucleotide or by primary infection with mouse cytomegalovirus (MCMV). An anti-CD3-induced cytokine release syndrome was used as a non-sJIA/HLH control model.

Results

No differences were found in clinical, laboratory and hematological features of sJIA/HLH between wild-type and IDO1-KO mice. As IDO modulates the immune response via induction of regulatory T cells and inhibition of T cell proliferation, we investigated both features in a T cell-triggered cytokine release syndrome. Again, no differences were observed in serum cytokine levels, percentages of regulatory T cells, nor of proliferating or apoptotic thymocytes and lymph node cells.

Conclusions

Our data demonstrate that IDO1 deficiency does not affect inflammation in sJIA, sHLH and a T cell-triggered cytokine release model. We hypothesize that other tryptophan-catabolizing enzymes like IDO2 and tryptophan 2,3-dioxygenase (TDO) might compensate for the lack of IDO1.     

Telomerase Activity in the Various Regions of Mouse Brain: Non-Radioactive Telomerase Repeat Amplification Protocol (TRAP) Assay

Telomerase, a ribonucleoprotein, is responsible for maintaining the telomere length and therefore promoting genomic integrity, proliferation, and lifespan. In addition, telomerase protects the mitochondria from oxidative stress and confers resistance to apoptosis, suggesting its possible importance for the surviving of non-mitotic, highly active cells such as neurons. We previously demonstrated the ability of novel telomerase activators to increase telomerase activity and expression in the various mouse brain regions and to protect motor neurons cells from oxidative stress. These results strengthen the notion that telomerase is involved in the protection of neurons from various lesions. To underline the role of telomerase in the brain, we here compare the activity of telomerase in male and female mouse brain and its dependence on age. TRAP assay is a standard method for detecting telomerase activity in various tissues or cell lines. Here we demonstrate the analysis of telomerase activity in three regions of the mouse brain by non-denaturing protein extraction using CHAPS lysis buffer followed by modification of the standard TRAP assay.In this 2-step assay, endogenous telomerase elongates a specific telomerase substrate (TS primer) by adding TTAGGG 6 bp repeats (telomerase reaction). The telomerase reaction products are amplified by PCR reaction creating a DNA ladder of 6 bp increments. The analysis of the DNA ladder is made by 4.5% high resolution agarose gel electrophoresis followed by staining with highly sensitive nucleic acid stain.Compared to the traditional TRAP assay that utilize ³²P labeled radioactive dCTP''s for DNA detection and polyacrylamide gel electrophoresis for resolving the DNA ladder, this protocol offers a non-toxic time saving TRAP assay for evaluating telomerase activity in the mouse brain, demonstrating the ability to detect differences in telomerase activity in the various female and male mouse brain region.     

More or Less Integrated Ocean Management: Multiple Integrated Approaches and Two Norms

Abstract

Through a normative lens, this article investigates integrated ocean management and the multiple concepts that it involves. Although international law provides legal authority to coastal states to manage their ocean area entitlements, no single legally binding norm specific to integrated ocean management exists. Nevertheless, by combining different internationally recognized sources, this article identifies and discusses two normative concepts applicable in coastal state integrated ocean management. These are (1) the framing of integrated ocean management as a management process and (2) the incorporation of environmental, economic, and social concerns into an ocean management policy.     

Less is More: Dopant‐Free Hole Transporting Materials for High‐Efficiency Perovskite Solar Cells

Perovskite solar cells have delivered power conversion efficiency beyond 22% in less than seven years, implying the potential for the paradigm shift of low‐cost photovoltaics with high efficiency and low embedded energy. Besides the “perovskite fever,” the development of new hole transport materials (HTM), especially dopant‐free HTMs, is another research hotspot. This is because the currently used HTMs, such as spiro‐OMeTAD derivatives, require additional chemical doping process to ensure sufficient conductivity and proper ionic potential level for efficient hole transport and collection. However, the commonly used dopants are volatile and hygroscopic which not only increase the complexity and cost of device fabrication but also deteriorate the device stability. So far, there have been several reviews on new HTMs, but review or analysis on dopant‐free HTMs is scarce. In this review, all reported dopant‐free HTMs are categorized into four primary different types and lessons will be learned during the separate discussions. The stability test behavior of all the intrinsic HTMs will be evaluated directly. In the end, the correlations between the properties of the intrinsic HTMs and parameters of the devices will be plotted to shed light on the future direction of development of this field.     

Diagnosis and Treatment of Essential Fatty Acid Deficiency in Man

Essential fatty acid deficiency was found on four occasions in three adult patients with malabsorption after intestinal resection. Diagnosis was primarily based on the gas chromatographic finding of the abnormal fatty acid 5, 8, 11- (ω9) eicosatrienoic acid in plasma lecithin. None of the patients had received parenteral nutrition with a fat-free source of calories but all had been on a reduced intake of dietary fat at some stage. Treatment with intravenous Intralipid rapidly reversed the abnormal plasma fatty acid pattern and also cleared the rash in the patient wih he most severe deficiency.