Bruton's Tyrosine Kinase Inhibition Attenuates the Cardiac Dysfunction Caused by Cecal Ligation and Puncture in Mice

Sepsis is one of the most prevalent diseases in the world. The development of cardiac dysfunction in sepsis results in an increase of mortality. It is known that Bruton's tyrosine kinase (BTK) plays a role in toll-like receptor signaling and NLRP3 inflammasome activation, two key components in the pathophysiology of sepsis and sepsis-associated cardiac dysfunction. In this study we investigated whether pharmacological inhibition of BTK (ibrutinib 30 mg/kg and acalabrutinib 3 mg/kg) attenuates sepsis associated cardiac dysfunction in mice. 10-week old male C57BL/6 mice underwent CLP or sham surgery. One hour after surgery mice received either vehicle (5% DMSO + 30% cyclodextrin i.v.), ibrutinib (30 mg/kg i.v.), or acalabrutinib (3 mg/kg i.v.). Mice also received antibiotics and an analgesic at 6 and 18 h. After 24 h, cardiac function was assessed by echocardiography in vivo. Cardiac tissue underwent western blot analysis to determine the activation of BTK, NLRP3 inflammasome and NF-\u3baB pathway. Serum analysis of 33 cytokines was conducted by a multiplex assay. When compared to sham-operated animals, mice subjected to CLP demonstrated a significant reduction in ejection fraction (EF), fractional shortening (FS), and fractional area change (FAC). The cardiac tissue from CLP mice showed significant increases of BTK, NF-\u3baB, and NLRP3 inflammasome activation. CLP animals resulted in a significant increase of serum cytokines and chemokines (TNF-\u3b1, IL-6, IFN-\u3b3, KC, eotaxin-1, eotaxin-2, IL-10, IL-4, CXCL10, and CXCL11). Delayed administration of ibrutinib and acalabrutinib attenuated the decline of EF, FS, and FAC caused by CLP and also reduced the activation of BTK, NF-\u3baB, and NLRP3 inflammasome. Both ibrutinib and acalabrutinib significantly suppressed the release of cytokines and chemokines. Our study revealed that delayed intravenous administration of ibrutinib or acalabrutinib attenuated the cardiac dysfunction associated with sepsis by inhibiting BTK, reducing NF-\u3baB activation and the activation of the inflammasome. Cytokines associated with sepsis were significantly reduced by both BTK inhibitors. Acalabrutinib is found to be more potent than ibrutinib and could potentially prove to be a novel therapeutic in sepsis. Thus, the FDA-approved BTK inhibitors ibrutinib and acalabrutinib may be repurposed for the use in sepsis

Circulation and intrusions northeast of Taiwan : chasing and predicting uncertainty in the cold dome

Author Posting. © The Oceanography Society, 2011. This article is posted here by permission of The Oceanography Society for personal use, not for redistribution. The definitive version was published in Oceanography 24 no. 4 (2011): 110–121, doi:10.5670/oceanog.2011.99.An important element of present oceanographic research is the assessment and quantification of uncertainty. These studies are challenging in the coastal ocean due to the wide variety of physical processes occurring on a broad range of spatial and temporal scales. In order to assess new methods for quantifying and predicting uncertainty, a joint Taiwan-US field program was undertaken in August/September 2009 to compare model forecasts of uncertainties in ocean circulation and acoustic propagation, with high-resolution in situ observations. The geographical setting was the continental shelf and slope northeast of Taiwan, where a feature called the "cold dome" frequently forms. Even though it is hypothesized that Kuroshio subsurface intrusions are the water sources for the cold dome, the dome's dynamics are highly uncertain, involving multiple scales and many interacting ocean features. During the experiment, a combination of near-surface and profiling drifters, broad-scale and high-resolution hydrography, mooring arrays, remote sensing, and regional ocean model forecasts of fields and uncertainties were used to assess mean fields and uncertainties in the region. River runoff from Typhoon Morakot, which hit Taiwan August 7–8, 2009, strongly affected shelf stratification. In addition to the river runoff, a cold cyclonic eddy advected into the region north of the Kuroshio, resulting in a cold dome formation event. Uncertainty forecasts were successfully employed to guide the hydrographic sampling plans. Measurements and forecasts also shed light on the evolution of cold dome waters, including the frequency of eddy shedding to the north-northeast, and interactions with the Kuroshio and tides. For the first time in such a complex region, comparisons between uncertainty forecasts and the model skill at measurement locations validated uncertainty forecasts. To complement the real-time model simulations, historical simulations with another model show that large Kuroshio intrusions were associated with low sea surface height anomalies east of Taiwan, suggesting that there may be some degree of predictability for Kuroshio intrusions.We thank the National Science Council of Taiwan as well as the Office of Naval Research for generous support of this effort

Environmental variables, habitat discontinuity and life history shaping the genetic structure of Pomatoschistus marmoratus

Coastal lagoons are semi-isolated ecosystems exposed to wide fluctuations of environmental conditions and showing habitat fragmentation. These features may play an important role in separating species into different populations, even at small spatial scales. In this study, we evaluate the concordance between mitochondrial (previous published data) and nuclear data analyzing the genetic variability of Pomatoschistus marmoratus in five localities, inside and outside the Mar Menor coastal lagoon (SE Spain) using eight microsatellites. High genetic diversity and similar levels of allele richness were observed across all loci and localities, although significant genic and genotypic differentiation was found between populations inside and outside the lagoon. In contrast to the FST values obtained from previous mitochondrial DNA analyses (control region), the microsatellite data exhibited significant differentiation among samples inside the Mar Menor and between lagoonal and marine samples. This pattern was corroborated using Cavalli-Sforza genetic distances. The habitat fragmentation inside the coastal lagoon and among lagoon and marine localities could be acting as a barrier to gene flow and contributing to the observed genetic structure. Our results from generalized additive models point a significant link between extreme lagoonal environmental conditions (mainly maximum salinity) and P. marmoratus genetic composition. Thereby, these environmental features could be also acting on genetic structure of coastal lagoon populations of P. marmoratus favoring their genetic divergence. The mating strategy of P. marmoratus could be also influencing our results obtained from mitochondrial and nuclear DNA. Therefore, a special consideration must be done in the selection of the DNA markers depending on the reproductive strategy of the species

Loss of Gnas Imprinting Differentially Affects REM/NREM Sleep and Cognition in Mice

It has been suggested that imprinted genes are important in the regulation of sleep. However, the fundamental question of whether genomic imprinting has a role in sleep has remained elusive up to now. In this work we show that REM and NREM sleep states are differentially modulated by the maternally expressed imprinted gene Gnas. In particular, in mice with loss of imprinting of Gnas, NREM and complex cognitive processes are enhanced while REM and REM–linked behaviors are inhibited. This is the first demonstration that a specific overexpression of an imprinted gene affects sleep states and related complex behavioral traits. Furthermore, in parallel to the Gnas overexpression, we have observed an overexpression of Ucp1 in interscapular brown adipose tissue (BAT) and a significant increase in thermoregulation that may account for the REM/NREM sleep phenotypes. We conclude that there must be significant evolutionary advantages in the monoallelic expression of Gnas for REM sleep and for the consolidation of REM–dependent memories. Conversely, biallelic expression of Gnas reinforces slow wave activity in NREM sleep, and this results in a reduction of uncertainty in temporal decision-making processes

Posture Does Not Matter! Paw Usage and Grasping Paw Preference in a Small-Bodied Rooting Quadrupedal Mammal

BACKGROUND: Recent results in birds, marsupials, rodents and nonhuman primates suggest that phylogeny and ecological factors such as body size, diet and postural habit of a species influence limb usage and the direction and strength of limb laterality. To examine to which extent these findings can be generalised to small-bodied rooting quadrupedal mammals, we studied trees shrews (Tupaia belangeri). METHODOLOGY/PRINCIPAL FINDINGS: We established a behavioural test battery for examining paw usage comparable to small-bodied primates and tested 36 Tupaia belangeri. We studied paw usage in a natural foraging situation (simple food grasping task) and measured the influence of varying postural demands (triped, biped, cling, sit) on paw preferences by applying a forced-food grasping task similar to other small-bodied primates. Our findings suggest that rooting tree shrews prefer mouth over paw usage to catch food in a natural foraging situation. Moreover, we demonstrated that despite differences in postural demand, tree shrews show a strong and consistent individual paw preference for grasping across different tasks, but no paw preference at a population level. CONCLUSIONS/SIGNIFICANCE: Tree shrews showed less paw usage than small-bodied quadrupedal and arboreal primates, but the same paw preference. Our results confirm that individual paw preferences remain constant irrespective of postural demand in some small-bodied quadrupedal non primate and primate mammals which do not require fine motoric control for manipulating food items. Our findings suggest that the lack of paw/hand preference for grasping food at a population level is a universal pattern among those species and that the influence of postural demand on manual lateralisation in quadrupeds may have evolved in large-bodied species specialised in fine manipulations of food items

Behavioural responses of Anopheles gambiae sensu stricto M and S molecular form larvae to an aquatic predator in Burkina Faso

Background: Predation of aquatic immature stages has been identified as a major evolutionary force driving habitat segregation and niche partitioning in the malaria mosquito Anopheles gambiae sensu stricto in the humid savannahs of Burkina Faso, West Africa. Here, we explored behavioural responses to the presence of a predator in wild populations of the M and S molecular forms of An. gambiae that typically breed in permanent (e.g., rice field paddies) and temporary (e.g., road ruts) water collections. Methods: Larvae used in these experiments were obtained from eggs laid by wild female An. gambiae collected from two localities in south-western Burkina Faso during the 2008 rainy season. Single larvae were observed in an experimental arena, and behavioural traits were recorded and quantified a) in the absence of a predator and b) in the presence of a widespread mosquito predator, the backswimmer Anisops jaczewskii. Differences in the proportion of time allocated to each behaviour were assessed using Principal Component Analysis and Multivariate Analysis of Variance. Results: The behaviour of M and S form larvae was found to differ significantly; although both forms mainly foraged at the water surface, spending 60-90% of their time filtering water at the surface or along the wall of the container, M form larvae spent on average significantly more time browsing at the bottom of the container than S form larvae (4.5 vs. 1.3% of their overall time, respectively; P < 0.05). In the presence of a predator, larvae of both forms modified their behaviour, spending significantly more time resting along the container wall (P < 0.001). This change in behaviour was at least twice as great in the M form (from 38.6 to 66.6% of the time at the wall in the absence and presence of the predator, respectively) than in the S form (from 48.3 to 64.1%). Thrashing at the water surface exposed larvae to a significantly greater risk of predation by the notonectid (P < 0.01), whereas predation occurred significantly less often when larvae were at the container wall (P < 0.05) and might reflect predator vigilance. Conclusions: Behavioural differences between larvae of the M and S form of An. gambiae in response to an acute predation risk is likely to be a reflection of different trade-offs between foraging and predator vigilance that might be of adaptive value in contrasting aquatic ecosystems. Future studies should explore the relevance of these findings under the wide range of natural settings where both forms co-exist in Africa

Biodiversity on Broadway - Enigmatic Diversity of the Societies of Ants (Formicidae) on the Streets of New York City

Each year, a larger proportion of the Earth's surface is urbanized, and a larger proportion of the people on Earth lives in those urban areas. The everyday nature, however, that humans encounter in cities remains poorly understood. Here, we consider perhaps the most urban green habitat, street medians. We sampled ants from forty-four medians along three boulevards in New York City and examined how median properties affect the abundance and species richness of native and introduced ants found on them. Ant species richness varied among streets and increased with area but was independent of the other median attributes measured. Ant assemblages were highly nested, with three numerically dominant species present at all medians and additional species present at a subset of medians. The most common ant species were the introduced Pavement ant (Tetramorium caespitum) and the native Thief ant (Solenopsis molesta) and Cornfield ant (Lasius neoniger). The common introduced species on the medians responded differently to natural and disturbed elements of medians. Tetramorium caespitum was most abundant in small medians, with the greatest edge/area ratio, particularly if those medians had few trees, whereas Nylanderia flavipes was most abundant in the largest medians, particularly if they had more trees. Many of the species encountered in Manhattan were similar to those found in other large North American cities, such that a relatively small subset of ant species probably represent most of the encounters humans have with ants in North America