Pharmacological Polarization of Tumor-Associated Macrophages Toward a CXCL9 Antitumor Phenotype.

Tumor-associated macrophages (TAM) are a diverse population of myeloid cells that are often abundant and immunosuppressive in human cancers. CXCL9 <sup>Hi</sup> TAM has recently been described to have an antitumor phenotype and is linked to immune checkpoint response. Despite the emerging understanding of the unique antitumor TAM phenotype, there is a lack of TAM-specific therapeutics to exploit this new biological understanding. Here, the discovery and characterization of multiple small-molecule enhancers of chemokine ligand 9 (CXCL9) and their targeted delivery in a TAM-avid systemic nanoformulation is reported. With this strategy, it is efficient encapsulation and release of multiple drug loads that can efficiently induce CXCL9 expression in macrophages, both in vitro and in vivo in a mouse tumor model. These observations provide a window into the molecular features that define TAM-specific states, an insight a novel therapeutic anticancer approach is used to discover

Co-bedding as a Comfort measure For Twins undergoing painful procedures (CComForT Trial)

<p>Abstract</p> <p>Background</p> <p>Co-bedding, a developmental care strategy, is the practice of caring for diaper clad twins in one incubator (versus separating and caring for each infant in separate incubators), thus creating the opportunity for skin-to-skin contact and touch between the twins. In studies of mothers and their infants, maternal skin-to-skin contact has been shown to decrease procedural pain response according to both behavioral and physiological indicators in very preterm neonates. It is uncertain if this comfort is derived solely from maternal presence or from stabilization of regulatory processes from direct skin contact. The intent of this study is to compare the comfort effect of co-bedding (between twin infants who are co-bedding and those who are not) on infant pain response and physiologic stability during a tissue breaking procedure (heelstick).</p> <p>Methods/Design</p> <p>Medically stable preterm twin infants admitted to the Neonatal Intensive Care Unit will be randomly assigned to a co-bedding group or a standard care group. Pain response will be measured by physiological and videotaped facial reaction using the Premature Infant Pain Profile scale (PIPP). Recovery from the tissue breaking procedure will be determined by the length of time for heart rate and oxygen saturation to return to baseline. Sixty four sets of twins (n = 128) will be recruited into the study. Analysis and inference will be based on the intention-to-treat principle.</p> <p>Discussion</p> <p>If twin contact while co-bedding is determined to have a comforting effect for painful procedures, then changes in current neonatal care practices to include co-bedding may be an inexpensive, non invasive method to help maintain physiologic stability and decrease the long term psychological impact of procedural pain in this high risk population. Knowledge obtained from this study will also add to existing theoretical models with respect to the exact mechanism of comfort through touch.</p> <p>Trial registration</p> <p>NCT00917631</p

The Stromal Processing Peptidase of Chloroplasts is Essential in Arabidopsis, with Knockout Mutations Causing Embryo Arrest after the 16-Cell Stage

Stromal processing peptidase (SPP) is a metalloendopeptidase located in the stroma of chloroplasts, and it is responsible for the cleavage of transit peptides from preproteins upon their import into the organelle. Two independent mutant Arabidopsis lines with T-DNA insertions in the SPP gene were analysed (spp-1 and spp-2). For both lines, no homozygous mutant plants could be detected, and the segregating progeny of spp heterozygotes contained heterozygous and wild-type plants in a ratio of 2∶1. The siliques of heterozygous spp-1 and spp-2 plants contained many aborted seeds, at a frequency of ∼25%, suggesting embryo lethality. By contrast, transmission of the spp mutations through the male and female gametes was found to be normal, and so gametophytic effects could be ruled out. To further elucidate the timing of the developmental arrest, mutant and wild-type seeds were cleared and analysed by Nomarski microscopy. A significant proportion (∼25%) of the seeds in mutant siliques exhibited delayed embryogenesis compared to those in wild type. Moreover, the mutant embryos never progressed normally beyond the 16-cell stage, with cell divisions not completing properly thereafter. Heterozygous spp mutant plants were phenotypically indistinguishable from the wild type, indicating that the spp knockout mutations are completely recessive and suggesting that one copy of the SPP gene is able to produce sufficient SPP protein for normal development under standard growth conditions

Nearly inviscid Faraday waves

Many powerful techniques from Hamiltonian mechanics are available for the study of ideal hydrodynamics. This article explores some of the consequences of including small viscosity in a study of surface gravity-capillary waves excited by the vertical vibration of a container. It is shown that in this system, as in others, the addition of small viscosity provides a singular perturbation of the ideal fluid system, and that as a result its effects are nontrivial. The relevance of existing studies of ideal fluid problems is discussed from this point of view

Contrasted Patterns of Molecular Evolution in Dominant and Recessive Self-Incompatibility Haplotypes in Arabidopsis

Self-incompatibility has been considered by geneticists a model system for reproductive biology and balancing selection, but our understanding of the genetic basis and evolution of this molecular lock-and-key system has remained limited by the extreme level of sequence divergence among haplotypes, resulting in a lack of appropriate genomic sequences. In this study, we report and analyze the full sequence of eleven distinct haplotypes of the self-incompatibility locus (S-locus) in two closely related Arabidopsis species, obtained from individual BAC libraries. We use this extensive dataset to highlight sharply contrasted patterns of molecular evolution of each of the two genes controlling self-incompatibility themselves, as well as of the genomic region surrounding them. We find strong collinearity of the flanking regions among haplotypes on each side of the S-locus together with high levels of sequence similarity. In contrast, the S-locus region itself shows spectacularly deep gene genealogies, high variability in size and gene organization, as well as complete absence of sequence similarity in intergenic sequences and striking accumulation of transposable elements. Of particular interest, we demonstrate that dominant and recessive S-haplotypes experience sharply contrasted patterns of molecular evolution. Indeed, dominant haplotypes exhibit larger size and a much higher density of transposable elements, being matched only by that in the centromere. Overall, these properties highlight that the S-locus presents many striking similarities with other regions involved in the determination of mating-types, such as sex chromosomes in animals or in plants, or the mating-type locus in fungi and green algae

Psycholinguistic variables matter in odor naming

People from Western societies generally find it difficult to name odors. In trying to explain this, the olfactory literature has proposed several theories that focus heavily on properties of the odor itself but rarely discuss properties of the label used to describe it. However, recent studies show speakers of languages with dedicated smell lexicons can name odors with relative ease. Has the role of the lexicon been overlooked in the olfactory literature? Word production studies show properties of the label, such as word frequency and semantic context, influence naming; but this field of research focuses heavily on the visual domain. The current study combines methods from both fields to investigate word production for olfaction in two experiments. In the first experiment, participants named odors whose veridical labels were either high-frequency or low-frequency words in Dutch, and we found that odors with high-frequency labels were named correctly more often. In the second experiment, edibility was used for manipulating semantic context in search of a semantic interference effect, presenting the odors in blocks of edible and inedible odor source objects to half of the participants. While no evidence was found for a semantic interference effect, an effect of word frequency was again present. Our results demonstrate psycholinguistic variables-such as word frequency-are relevant for olfactory naming, and may, in part, explain why it is difficult to name odors in certain languages. Olfactory researchers cannot afford to ignore properties of an odor's label

Response of cell wall composition and RNA-seq transcriptome to methyl-jasmonate in Brachypodium distachyon callus

Main conclusion: Methyl-jasmonate induces large increases in p-coumarate linked to arabinoxylan in Brachypodium and in abundance of GT61 and BAHD family transcripts consistent with a role in synthesis of this linkage. Jasmonic acid (JA) signalling is required for many stress responses in plants, inducing large changes in the transcriptome, including up-regulation of transcripts associated with lignification. However, less is known about the response to JA of grass cell walls and the monocot-specific features of arabinoxylan (AX) synthesis and acylation by ferulic acid (FA) and para-coumaric acid (pCA). Here, we show that methyl-jasmonate (MeJA) induces moderate increases in FA monomer, > 50% increases in FA dimers, and five–sixfold increases in pCA ester-linked to cell walls in Brachypodium callus. Direct measurement of arabinose acylated by pCA (Araf-pCA) indicated that most or all the increase in cell-wall pCA was due to pCA ester-linked to AX. Analysis of the RNA-seq transcriptome of the callus response showed that these cell-wall changes were accompanied by up-regulation of members of the GT61 and BAHD gene families implicated in AX decoration and acylation; two BAHD paralogues were among the most up-regulated cell-wall genes (seven and fivefold) after 24 h exposure to MeJA. Similar responses to JA of orthologous BAHD and GT61 transcripts are present in the RiceXPro public expression data set for rice seedlings, showing that they are not specific to Brachypodium or to callus. The large response of AX-pCA to MeJA may, therefore, indicate an important role for this linkage in response of primary cell walls of grasses to JA signalling