Global change is altering species distributions and thus interactions among organisms. Organisms live in concert with thousands of other species, some beneficial, some pathogenic, some which have ...little to no effect in complex communities. Since natural communities are composed of organisms with very different life history traits and dispersal ability it is unlikely they will all respond to climatic change in a similar way. Disjuncts in plant-pollinator and plant-herbivore interactions under global change have been relatively well described, but plant-soil microorganism and soil microbe-microbe relationships have received less attention. Since soil microorganisms regulate nutrient transformations, provide plants with nutrients, allow co-existence among neighbors, and control plant populations, changes in soil microorganism-plant interactions could have significant ramifications for plant community composition and ecosystem function. In this paper we explore how climatic change affects soil microbes and soil microbe-plant interactions directly and indirectly, discuss what we see as emerging and exciting questions and areas for future research, and discuss what ramifications changes in these interactions may have on the composition and function of ecosystems.
Excavations at Abu Hureyra, Syria, during the 1970s exposed a long sequence of occupation spanning the transition from hunting-and-gathering to agriculture. Dung spherulites preserved within curated ...flotation samples from Epipalaeolithic (ca. 13,300–11,400 calBP) and Neolithic (ca. 10,600–7,800 calBP) occupations are examined here alongside archaeological, archaeobotanical, and zooarchaeological data to consider animal management, fuel selection, and various uses of dung. Spherulites were present throughout the entire sequence in varying concentrations. Using a new method to quantify spherulites, exclusion criteria were developed to eliminate samples possibly contaminated with modern dung, strengthening observations of ancient human behavior. Darkened spherulites within an Epipalaeolithic 1B firepit (12,800–12,300 calBP) indicate burning between 500–700°C, documenting early use of dung fuel by hunter-gatherers as a supplement to wood, coeval with a dramatic shift to rectilinear architecture, increasing proportions of wild sheep and aurochsen, reduced emphasis on small game, and elevated dung concentrations immediately outside the 1B dwelling. Combined, these observations suggest that small numbers of live animals (possibly wild sheep) were tended on-site by Epipalaeolithic hunter-gatherers to supplement gazelle hunting, raising the question of whether early experiments in animal management emerged contemporaneously with, or pre-date, cultivation. Dung was used to prepare plaster floors during the Neolithic and continued to be burned as a supplemental fuel, indicating that spherulites were deposited via multiple human- and animal-related pathways. This has important implications for interpretations of archaeobotanical assemblages across the region. Spherulite concentrations dropped abruptly during Neolithic 2B (9,300–8,000 calBP) and 2C (8,000–7,800 calBP), when sheep/goat herding surpassed gazelle hunting, possibly corresponding with movement of animals away from the site as herd sizes increased. As hunter-gatherers at Abu Hureyra began interacting with wild taxa in different ways, they set in motion a remarkable transformation in the ways people interacted with animals, plants, and their environment.
Tremelimumab (CP-675,206) is a fully human monoclonal antibody binding to cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) on T cells that stimulates the immune system by blocking the ...CTLA4-negative regulatory signal. Combination with standard chemotherapy may strengthen antitumor therapy. This is a phase Ib, multisite, open-label, nonrandomized dose escalation trial evaluating the safety, tolerability, and maximum tolerated dose (MTD) of tremelimumab combined with gemcitabine in patients with metastatic pancreatic cancer.
Gemcitabine (1000 mg/m2 on days 1, 8, and 15 of each 28-day cycles) was administrated with escalating doses of i.v. tremelimumab (6, 10, or 15 mg/kg) on day 1 of each 84-day cycle for a maximum of 4 cycles. The first 18 patients had an initial 4-week gemcitabine-only lead-in period. Dose-limiting toxicities (DLTs) related to tremelimumab were evaluated during the first 6 weeks after the first dose of tremelimumab.
From June 2008 to August 2011, 34 patients were enrolled and received at least one dose of tremelimumab. No DLTs related to tremelimumab were observed at any dose, even when the maximum dose established for tremelimumab (15 mg/kg) was used. Most frequent grade 3/4 toxicities were asthenia (11.8%) and nausea (8.8%). Only one patient had a serious drug-related event (diarrhea with dehydration). The median overall survival was 7.4 months (95% confidence interval 5.8–9.4 months). At the end of treatment, two patients achieved partial response. Both patients received tremelimumab 15-mg/kg group (n = 2/19, 10.5%).
Tremelimumab plus gemcitabine demonstrated a safety and tolerability profile, warranting further study in patients with metastatic pancreatic cancer.
NCT00556023.
Prenatal alcohol exposure (PAE) interferes with neurodevelopment. The brain is particularly susceptible to the adverse consequences of prenatal alcohol exposure, and numerous studies have documented ...changes to brain anatomy and function, as well as consequences for cognition, behavior, and mental health. Studies in typically developing individuals have shown that the brain undergoes dynamic developmental processes over an individual's lifespan. Furthermore, magnetic resonance imaging (MRI) studies in other neurodevelopmental and psychiatric disorders have shown that their developmental trajectories differ from the typical pattern. Therefore, to understand long-term clinical outcomes of fetal alcohol spectrum disorders (FASD), it is necessary to investigate changes in neurodevelopmental trajectories in this population. Here we review studies that have used MRI to evaluate changes in brain structure and function over time
cross-sectional or longitudinal methods in individuals with PAE. Research demonstrates that individuals with PAE have atypical cortical and white matter microstructural developmental trajectories through childhood and adolescence. More research is needed to understand how factors such as sex and postnatal experiences may further mediate these trajectories. Furthermore, nothing is known about the trajectories beyond young adulthood.
The mechanical properties of cells influence their cellular and subcellular functions, including cell adhesion, migration, polarization, and differentiation, as well as organelle organization and ...trafficking inside the cytoplasm. Yet reported values of cell stiffness and viscosity vary substantially, which suggests differences in how the results of different methods are obtained or analyzed by different groups. To address this issue and illustrate the complementarity of certain approaches, here we present, analyze, and critically compare measurements obtained by means of some of the most widely used methods for cell mechanics: atomic force microscopy, magnetic twisting cytometry, particle-tracking microrheology, parallel-plate rheometry, cell monolayer rheology, and optical stretching. These measurements highlight how elastic and viscous moduli of MCF-7 breast cancer cells can vary 1,000-fold and 100-fold, respectively. We discuss the sources of these variations, including the level of applied mechanical stress, the rate of deformation, the geometry of the probe, the location probed in the cell, and the extracellular microenvironment.
The free-energy landscape of the Sherrington-Kirkpatrick (SK) Ising spin glass is simple in the framework of the Thouless-Anderson-Palmer (TAP) equations as each solution (which are minima of the ...free energy) has associated with it a nearby index-one saddle point. The free-energy barrier to escape the minimum is just the difference between the saddle point free energy and that at its associated minimum. This difference is calculated for the states with free energies f>f_{c}. It is very small for these states, decreasing as 1/N^{2}, where N is the number of spins in the system. These states are not marginally stable. We argue that such small barriers are why numerical studies never find these states when N is large. Instead, the states that are found are those that have marginal stability. For them the barriers are at least of O(1). f_{c} is the free energy per spin below which the states develop broken replica-symmetry-like overlaps with each other. In the regime f<f_{c} we can only offer some possibilities based around scaling arguments. One of these suggest that the barriers might become as large as N^{1/3}. That might be consistent with recent numerical studies on the Viana-Bray model, which were at variance with the expectations of Cugliandolo and Kurchan for the SK model.
Microbes are now well regarded for their important role in mammalian health. The microbiology of skin--a unique interface between the host and environment--is a major research focus in human health ...and skin disorders, but is less explored in other mammals. Here, we report on a cross-population study of the skin-associated bacterial community of humpback whales (Megaptera novaeangliae), and examine the potential for a core bacterial community and its variability with host (endogenous) or geographic/environmental (exogenous) specific factors. Skin biopsies or freshly sloughed skin from 56 individuals were sampled from populations in the North Atlantic, North Pacific and South Pacific oceans and bacteria were characterized using 454 pyrosequencing of SSU rRNA genes. Phylogenetic and statistical analyses revealed the ubiquity and abundance of bacteria belonging to the Flavobacteria genus Tenacibaculum and the Gammaproteobacteria genus Psychrobacter across the whale populations. Scanning electron microscopy of skin indicated that microbial cells colonize the skin surface. Despite the ubiquity of Tenacibaculum and Psychrobater spp., the relative composition of the skin-bacterial community differed significantly by geographic area as well as metabolic state of the animals (feeding versus starving during migration and breeding), suggesting that both exogenous and endogenous factors may play a role in influencing the skin-bacteria. Further, characteristics of the skin bacterial community from these free-swimming individuals were assembled and compared to two entangled and three dead individuals, revealing a decrease in the central or core bacterial community members (Tenacibaculum and Psychrobater spp.), as well as the emergence of potential pathogens in the latter cases. This is the first discovery of a cross-population, shared skin bacterial community. This research suggests that the skin bacteria may be connected to humpback health and immunity and could possibly serve as a useful index for health and skin disorder monitoring of threatened and endangered marine mammals.
This multicenter study evaluated the performance of the Cepheid Xpert Carba-R assay, a qualitative PCR test designed for the rapid detection of
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carbapenem resistance genes from bacterial ...isolates grown on blood agar or MacConkey agar. The results were compared to those obtained from bidirectional DNA sequence analysis of nucleic acid extracted from pure colonies. Isolates of
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that tested as either intermediate or resistant to a carbapenem antibiotic were analyzed. A total of 467 isolates were evaluated, including prospectively collected clinical isolates, frozen isolates, and a group of contrived broth specimens sent by a central reference laboratory. The assay was run on the GeneXpert platform and took 48 min, with less than 1 min of hands-on time. Compared to the results of the reference methods, the overall sensitivity of the assay was 100% (95% confidence interval CI, 99.0 to 100%) for isolates grown on both blood and MacConkey agars. Overall specificity was 98.1% (95% CI, 93.1 to 99.8%) and 97.1% (95% CI, 91.7 to 99.4%) for blood and MacConkey agars, respectively. This platform, previously demonstrated to be effective for the detection of carbapenemase genes in rectal swabs, is also adequate for the detection of these genes in bacterial colonies isolated from blood and MacConkey agars.
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Cell-laden hydrogels whose crosslinking density can be dynamically and reversibly tuned are highly sought-after for studying pathophysiological cellular fate processes, including ...embryogenesis, fibrosis, and tumorigenesis. Special efforts have focused on controlling network crosslinking in poly(ethylene glycol) (PEG) based hydrogels to evaluate the impact of matrix mechanics on cell proliferation, morphogenesis, and differentiation. In this study, we sought to design dynamic PEG-peptide hydrogels that permit cyclic/reversible stiffening and softening. This was achieved by utilizing reversible enzymatic reactions that afford specificity, biorthogonality, and predictable reaction kinetics. To that end, we prepared PEG-peptide conjugates to enable sortase A (SrtA) induced tunable hydrogel crosslinking independent of macromer contents. Uniquely, these hydrogels can be completely degraded by the same enzymatic reactions and the degradation rate can be tuned from hours to days. We further synthesized SrtA-sensitive peptide linker (i.e., KCLPRTGCK) for crosslinking with 8-arm PEG-norbornene (PEG8NB) via thiol-norbornene photocrosslinking. These hydrogels afford diverse softening paradigms through control of network structures during crosslinking or by adjusting enzymatic parameters during on-demand softening. Importantly, user-controlled hydrogel softening promoted spreading of human mesenchymal stem cells (hMSCs) in 3D. Finally, we designed a bis-cysteine-bearing linear peptide flanked with SrtA substrates at the peptide’s N- and C-termini (i.e., NH2-GGGCKGGGKCLPRTG-CONH2) to enable cyclic/reversible hydrogel stiffening/softening. We show that matrix stiffening and softening play a crucial role in growth and chemoresistance in pancreatic cancer cells. These results represent the first dynamic hydrogel platform that affords cyclic gel stiffening/softening based on reversible enzymatic reactions. More importantly, the chemical motifs that affords such reversible crosslinking were built-in on the linear peptide crosslinker without any post-synthesis modification.
Cell-laden ‘dynamic’ hydrogels are typically designed to enable externally stimulated stiffening or softening of the hydrogel network. However, no enzymatic reaction has been used to reversibly control matrix crosslinking. The application of SrtA-mediated transpeptidation in crosslinking and post-gelation modification of biomimetic hydrogels is innovative because of the specificity of the reaction and reversible tunability of crosslinking kinetics. While SrtA has been previously used to crosslink and fully degrade hydrogels, matrix softening and reversible stiffening of cell-laden hydrogels has not been reported. By designing simple peptide substrates, this unique enzymatic reaction can be employed to form a primary network, to gradually soften hydrogels, or to reversibly stiffen hydrogels. As a result, this dynamic hydrogel platform can be used to answer important matrix-related biological questions that are otherwise difficult to address.
Neuroinflammation is a recognized complication of immunotherapeutic approaches such as immune checkpoint inhibitor treatment, chimeric antigen receptor therapy, and graft versus host disease (GVHD) ...occurring after allogeneic hematopoietic stem cell transplantation. While T cells and inflammatory cytokines play a role in this process, the precise interplay between the adaptive and innate arms of the immune system that propagates inflammation in the central nervous system remains incompletely understood. Using a murine model of GVHD, we demonstrate that type 2 cannabinoid receptor (CB2R) signaling plays a critical role in the pathophysiology of neuroinflammation. In these studies, we identify that CB2R expression on microglial cells induces an activated inflammatory phenotype that potentiates the accumulation of donor-derived proinflammatory T cells, regulates chemokine gene regulatory networks, and promotes neuronal cell death. Pharmacological targeting of this receptor with a brain penetrant CB2R inverse agonist/antagonist selectively reduces neuroinflammation without deleteriously affecting systemic GVHD severity. Thus, these findings delineate a therapeutically targetable neuroinflammatory pathway and have implications for the attenuation of neurotoxicity after GVHD and potentially other T cell-based immunotherapeutic approaches.
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