TNFR1 is essential for CD40, but not for lipopolysaccharide-induced sickness behavior and clock gene dysregulation

Autoimmune and infectious diseases are associated with behavioral changes referred to as sickness behavior syndrome (SBS). In autoimmunity, the generation of anti-self T lymphocytes and autoantibodies critically involves binding of CD40 ligand on T-cells to its receptor CD40 on B-cells, dendritic cells and macrophages. Activation of CD40 leads to production of proinflammatory cytokines and, as shown here, induces SBS. Here we report that these behavioral changes depend on the expression of tumor necrosis factor alpha receptor 1 (TNFR1), but not on interleukin-1 receptor 1 or interleukin-6. Moreover, the intensity of SBS correlates with suppression of E-box controlled clock genes, including Dbp, and upregulation of Bmal1. However, the absence of TNFR1 does not interfere with the development of SBS and dysregulation of clock genes in mice treated with lipopolysaccharide. Thus, our results suggest that TNFR1 mediates SBS and dysregulation of clock genes in autoimmune diseases.

Transforming growth factor-beta inhibits the expression of clock genes

Disturbances of sleep-wake rhythms are an important problem in Alzheimer's disease (AD). Circadian rhythms are regulated by clock genes. Transforming growth factor-beta (TGF-β) is overexpressed in neurons in AD and is the only cytokine that is increased in cerebrospinal fluid (CSF). Our data show that TGF-β2 inhibits the expression of the clock genes Period (Per)1, Per2, and Rev-erbα, and of the clock-controlled genes D-site albumin promoter binding protein (Dbp) and thyrotroph embryonic factor (Tef). However, our results showed that TGF-β2 did not alter the expression of brain and muscle Arnt-like protein-1 (Bmal1). The concentrations of TGF-β2 in the CSF of 2 of 16 AD patients and of 1 of 7 patients with mild cognitive impairment were in the dose range required to suppress the expression of clock genes. TGF-β2-induced dysregulation of clock genes may alter neuronal pathways, which may be causally related to abnormal sleep-wake rhythms in AD patients.

Macroevolutionary patterns in the diversification of parrots: effects of climate change, geological events and key innovations

Aim Parrots are thought to have originated on Gondwana during the Cretaceous. The initial split within crown group parrots separated the New Zealand taxa from the remaining extant species and was considered to coincide with the separation of New Zealand from Gondwana 82-85 Ma, assuming that the diversification of parrots was mainly shaped by vicariance. However, the distribution patterns of several extant parrot groups cannot be explained without invoking transoceanic dispersal, challenging this assumption. Here, we present a temporal and spatial framework for the diversification of parrots using external avian fossils as calibration points in order to evaluate the relative importance of the influences of past climate change, plate tectonics and ecological opportunity. Location Australasian, African, Indo-Malayan and Neotropical regions. Methods Phylogenetic relationships were investigated using partial sequences of the nuclear genes c-mos, RAG-1 and Zenk of 75 parrot and 21 other avian taxa. Divergence dates and confidence intervals were estimated using a Bayesian relaxed molecular clock approach. Biogeographic patterns were evaluated taking temporal connectivity between areas into account. We tested whether diversification remained constant over time and if some parrot groups were more species-rich than expected given their age. Results Crown group diversification of parrots started only about 58 Ma, in the Palaeogene, significantly later than previously thought. The Australasian lories and possibly also the Neotropical Arini were found to be unexpectedly species-rich. Diversification rates probably increased around the Eocene/Oligocene boundary and in the middle Miocene, during two periods of major global climatic aberrations characterized by global cooling. Main conclusions The diversification of parrots was shaped by climatic and geological events as well as by key innovations. Initial vicariance events caused by continental break-up were followed by transoceanic dispersal and local radiations. Habitat shifts caused by climate change and mountain orogenesis may have acted as a catalyst to the diversification by providing new ecological opportunities and challenges as well as by causing isolation as a result of habitat fragmentation. The lories constitute the only highly nectarivorous parrot clade, and their diet shift, associated with morphological innovation, may have acted as an evolutionary key innovation, allowing them to explore underutilized niches and promoting their diversification.

Age of cichlids: new dates for ancient lake fish radiations

Timing divergence events allow us to infer the conditions under which biodiversity has evolved and gain important insights into the mechanisms driving evolution. Cichlid fishes are a model system for studying speciation and adaptive radiation, yet, we have lacked reliable timescales for their evolution. Phylogenetic reconstructions are consistent with cichlid origins prior to Gondwanan landmass fragmentation 121-165 MYA, considerably earlier than the first known fossil cichlids (Eocene). We examined the timing of cichlid evolution using a relaxed molecular clock calibrated with geological estimates for the ages of 1) Gondwanan fragmentation and 2) cichlid fossils. Timescales of cichlid evolution derived from fossil-dated phylogenies of other bony fishes most closely matched those suggested by Gondwanan breakup calibrations, suggesting the Eocene origins and marine dispersal implied by the cichlid fossil record may be due to its incompleteness. Using Gondwanan calibrations, we found accumulation of genetic diversity within the radiating lineages of the African Lakes Malawi, Victoria and Barombi Mbo, and Palaeolake Makgadikgadi began around or after the time of lake basin formation. These calibrations also suggest Lake Tanganyika was colonized independently by the major radiating cichlid tribes that then began to accumulate genetic diversity thereafter. These results contrast with the widely accepted theory that diversification into major lineages took place within the Tanganyika basin. Together, this evidence suggests that ancient lake habitats have played a key role in generating and maintaining diversity within radiating lineages and also that lakes may have captured preexisting cichlid diversity from multiple sources from which adaptive radiations have evolved.

The Accumulation of Reproductive Incompatibilities in African Cichlid Fish

The rate at which different components of reproductive isolation accumulate with divergence time between species has only been studied in a limited, but growing, number of species. We measured premating isolation and hybrid inviability at four different ontogenetic stages from zygotes to adults in interspecific hybrids of 26 pairs of African cichlid species, spanning the entire East African haplochromine radiation. We then used multiple relaxed molecular clock calibrations to translate genetic distances into absolute ages to compare evolutionary rates of different components of reproductive isolation. We find that premating isolation accumulates fast initially but then changes little with increasing genetic distance between species. In contrast, postmating isolation between closely related species is negligible but then accumulates rapidly, resulting in complete hybrid inviability after 4.4/8.5/18.4 million years (my). Thus, the rate at which complete intrinsic incompatibilities arise in this system is orders of magnitude lower than rates of speciation within individual lake radiations. Together these results suggest divergent ecological adaptations may prevent populations from interbreeding and help maintain cichlid species diversity, which may be vulnerable to environmental degradation. By quantifying the capacity to produce viable hybrids between allopatric, distantly related lineages our results also provide an upper divergence time limit for the "hybrid swarm origin" model of adaptive radiation.

Gravity-based Local Clock Synchronization in Wireless Sensor Networks

Contention-based MAC protocols follow periodic listen/sleep cycles. These protocols face the problem of virtual clustering if different unsynchronized listen/sleep schedules occur in the network, which has been shown to happen in wireless sensor networks. To interconnect these virtual clusters, border nodes maintaining all respective listen/sleep schedules are required. However, this is a waste of energy, if locally a common schedule can be determined. We propose to achieve local synchronization with a mechanism that is similar to gravitation. Clusters represent the mass, whereas synchronization messages sent by each cluster represent the gravitation force of the according cluster. Due to the mutual attraction caused by the clusters, all clusters merge finally. The exchange of synchronization messages itself is not altered by LACAS. Accordingly, LACAS introduces no overhead. Only a not yet used property of synchronization mechanisms is exploited.

Visual exploration behaviour during clock reading in Alzheimer's disease

Eye movement behaviour during visual exploration of 24 patients with probable Alzheimer's disease and 24 age-matched controls was compared in a clock reading task. Controls were found to focus exploration on distinct areas at the end of each clock hand. The sum of these two areas of highest fixation density was defined as the informative region of interest (ROI). In Alzheimer's disease patients, visual exploration was less focused, with fewer fixations inside the ROI, and the time until the first fixation was inside the ROI was significantly delayed. Changes of fixation distribution correlated significantly with the ability to read the clock correctly, but did not correlate with dementia severity. In Alzheimer's disease patients, fixations were longer and saccade amplitudes were smaller. The altered visual exploration in Alzheimer's disease might be related to parietal dysfunction or to an imbalance between a degraded occipito-parietal and relatively preserved occipito-temporal visual network.