Gut γδ T cells as guardians, disruptors and instigators of cancer

Colorectal cancer is the third most common cancer worldwide with nearly 2 million cases per year. Immune cells and inflammation are a critical component of colorectal cancer progression, and they are used as reliable prognostic indicators of patient outcome. With the growing appreciation for immunology in colorectal cancer, interest is growing on the role γδ T cells have to play, as they represent one of the most prominent immune cell populations in gut tissue. This group of cells consists of both resident populations—γδ intraepithelial lymphocytes (γδ IELs)—and transient populations that each has unique functions. The homeostatic role of these γδ T cell subsets is to maintain barrier integrity and prevent microorganisms from breaching the mucosal layer, which is accomplished through crosstalk with enterocytes and other immune cells. Recent years have seen a surge in discoveries regarding the regulation of γδ IELs in the intestine and the colon with particular new insights into the butyrophilin family. In this review, we discuss the development, specialities, and functions of γδ T cell subsets during cancer progression. We discuss how these cells may be used to predict patient outcome, as well as how to exploit their behavior for cancer immunotherapy

First Evidence for Adoption in California Sea Lions

Demographic parameters such as birth and death rates determine the persistence of populations. Understanding the mechanisms that influence these rates is essential to developing effective management strategies. Alloparental behavior, or the care of non-filial young, has been documented in many species and has been shown to influence offspring survival. However, the role of alloparental behavior in maintaining population viability has not been previously studied. Here, we provide the first evidence for adoption in California sea lions and show that adoption potentially works to maintain a high survival rate of young and may ultimately contribute to population persistence. Alloparental behavior should have a positive effect on the population growth rate when the sum of the effects on fitness for the alloparent and beneficiary is positive

Expression and functional analysis of Nr2e3, a photoreceptor-specific nuclear receptor, suggest common mechanisms in retinal development between avians and mammals

The photoreceptor-specific nuclear receptor (PNR; Nr2e3) is a transcription factor important for retinal development. We report here the identification and expression analysis of the avian Nr2e3. Nr2e3 mRNA is expressed in the photoreceptor layer of the neural retina during early stages of chick embryogenesis. Its temporal expression is distinct from that of a related nuclear receptor, Tlx. Chick Nr2e3 recognizes and binds to the same target DNA sequence as its vertebrate orthologs. Functional assays revealed that chick Nr2e3 acts as a transcriptional repressor. Our results suggest that Nr2e3 plays a common role in retinal development in vertebrates

First-pass perfusion CMR two days after infarction predicts severity of functional impairment six weeks later in the rat heart

<p>Abstract</p> <p>Background</p> <p>In humans, dynamic contrast CMR of the first pass of a bolus infusion of Gadolinium-based contrast agent has become a standard technique to identify under-perfused regions of the heart and can accurately demonstrate the severity of myocardial infarction. Despite the clinical importance of this method, it has rarely been applied in small animal models of cardiac disease. In order to identify perfusion delays in the infarcted rat heart, here we present a method in which a T₁weighted MR image has been acquired during each cardiac cycle.</p> <p>Methods and results</p> <p>In isolated perfused rat hearts, contrast agent infusion gave uniform signal enhancement throughout the myocardium. Occlusion of the left anterior descending coronary artery significantly reduced the rate of signal enhancement in anterior regions of the heart, demonstrating that the first-pass method was sensitive to perfusion deficits. <it>In vivo </it>measurements of myocardial morphology, function, perfusion and viability were made at 2 and 8 days after infarction. Morphology and function were further assessed using cine-MRI at 42 days. The perfusion delay was larger in rat hearts that went on to develop greater functional impairment, demonstrating that first-pass CMR can be used as an early indicator of infarct severity. First-pass CMR at 2 and 8 days following infarction better predicted outcome than cardiac ejection fraction, end diastolic volume or end systolic volume.</p> <p>Conclusion</p> <p>First-pass CMR provides a predictive measure of the severity of myocardial impairment caused by infarction in a rodent model of heart failure.</p

Inertial picobalance reveals fast mass fluctuations in mammalian cells

The regulation of size, volume and mass in living cells is physiologically important, and dysregulation of these parameters gives rise to many diseases. Cell mass is largely determined by the amount of water, proteins, lipids, carbohydrates and nucleic acids present in a cell, and is tightly linked to metabolism, proliferation and gene expression. Technologies have emerged in recent years that make it possible to track the masses of single suspended cells and adherent cells. However, it has not been possible to track individual adherent cells in physiological conditions at the mass and time resolutions required to observe fast cellular dynamics. Here we introduce a cell balance (a 'picobalance'), based on an optically excited microresonator, that measures the total mass of single or multiple adherent cells in culture conditions over days with millisecond time resolution and picogram mass sensitivity. Using our technique, we observe that the mass of living mammalian cells fluctuates intrinsically by around one to four per cent over timescales of seconds throughout the cell cycle. Perturbation experiments link these mass fluctuations to the basic cellular processes of ATP synthesis and water transport. Furthermore, we show that growth and cell cycle progression are arrested in cells infected with vaccinia virus, but mass fluctuations continue until cell death. Our measurements suggest that all living cells show fast and subtle mass fluctuations throughout the cell cycle. As our cell balance is easy to handle and compatible with fluorescence microscopy, we anticipate that our approach will contribute to the understanding of cell mass regulation in various cell states and across timescales, which is important in areas including physiology, cancer research, stem-cell differentiation and drug discovery

Muc5b Is the Major Polymeric Mucin in Mucus from Thoroughbred Horses With and Without Airway Mucus Accumulation

Mucus accumulation is a feature of inflammatory airway disease in the horse and has been associated with reduced performance in racehorses. In this study, we have analysed the two major airways gel-forming mucins Muc5b and Muc5ac in respect of their site of synthesis, their biochemical properties, and their amounts in mucus from healthy horses and from horses with signs of airway mucus accumulation. Polyclonal antisera directed against equine Muc5b and Muc5ac were raised and characterised. Immunohistochemical staining of normal equine trachea showed that Muc5ac and Muc5b are produced by cells in the submucosal glands, as well as surface epithelial goblet cells. Western blotting after agarose gel electrophoresis of airway mucus from healthy horses, and horses with mucus accumulation, was used to determine the amounts of these two mucins in tracheal wash samples. The results showed that in healthy horses Muc5b was the predominant mucin with small amounts of Muc5ac. The amounts of Muc5b and Muc5ac were both dramatically increased in samples collected from horses with high mucus scores as determined visually at the time of endoscopy and that this increase also correlated with increase number of bacteria present in the sample. The change in amount of Muc5b and Muc5ac indicates that Muc5b remains the most abundant mucin in mucus. In summary, we have developed mucin specific polyclonal antibodies, which have allowed us to show that there is a significant increase in Muc5b and Muc5ac in mucus accumulated in equine airways and these increases correlated with the numbers of bacteria

Patient-centric trials for therapeutic development in precision oncology

An enhanced understanding of the molecular pathology of disease gained from genomic studies is facilitating the development of treatments that target discrete molecular subclasses of tumours. Considerable associated challenges include how to advance and implement targeted drug-development strategies. Precision medicine centres on delivering the most appropriate therapy to a patient on the basis of clinical and molecular features of their disease. The development of therapeutic agents that target molecular mechanisms is driving innovation in clinical-trial strategies. Although progress has been made, modifications to existing core paradigms in oncology drug development will be required to realize fully the promise of precision medicine

Evolutionary conservation and in vitro reconstitution of microsporidian iron–sulfur cluster biosynthesis

This work was supported by Marie Curie Postdoctoral Fellowships to T.A.W., E. H. and S. L., a European Research Council Advanced Investigator Grant (ERC-2010-AdG-268701) to T.M.E., and a Wellcome Trust Programme Grant (number 045404) to T.M.E. and J.M.L. R.L. acknowledges generous financial support from Deutsche Forschungsgemeinschaft (SFB 593, SFB 987, GRK 1216, LI 415/5), LOEWE program of state Hessen, Max-Planck Gesellschaft, von Behring-Röntgen StiftungMicrosporidians are a diverse group of obligate intracellular parasites that have minimized their genome content and simplified their sub-cellular structures by reductive evolution. Functional studies are limited because we lack reliable genetic tools for their manipulation. Here, we demonstrate that the cristae-deficient mitochondrion (mitosome) of the microsporidian Trachipleistophora hominis is the functional site of iron-sulphur cluster (ISC) assembly, which we suggest is the essential task of this organelle. Cell fractionation, fluorescence imaging and fine-scale immunoelectron microscopy demonstrate that mitosomes contain a complete pathway for [2Fe-2S] cluster biosynthesis that we biochemically reconstituted using purified recombinant mitosomal ISC proteins. Reconstitution proceeded as rapidly and efficiently as observed for yeast or fungal mitochondrial ISC components. Core components of the T. hominis cytosolic iron-sulphur protein assembly (CIA) pathway were also identified including the essential Cfd1-Nbp35 scaffold complex that assembles a [4Fe-4S] cluster as shown by spectroscopic methods in vitro. Phylogenetic analyses reveal that both the ISC and CIA biosynthetic pathways are predominantly bacterial, but their cytosolic and nuclear target Fe/S proteins are mainly archaeal. This mixed evolutionary history of the Fe/S-related proteins and pathways, and their strong conservation among highly reduced parasites, provides additional compelling evidence for the ancient chimeric ancestry of eukaryotes.Publisher PDFPeer reviewe

Design agency:prototyping multi-agent systems in architecture

This paper presents research on the prototyping of multi-agent systems for architectural design. It proposes a design exploration methodology at the intersection of architecture, engineering, and computer science. The motivation of the work includes exploring bottom up generative methods coupled with optimizing performance criteria including for geometric complexity and objective functions for environmental, structural and fabrication parameters. The paper presents the development of a research framework and initial experiments to provide design solutions, which simultaneously satisfy complexly coupled and often contradicting objectives. The prototypical experiments and initial algorithms are described through a set of different design cases and agents within this framework; for the generation of façade panels for light control; for emergent design of shell structures; for actual construction of reciprocal frames; and for robotic fabrication. Initial results include multi-agent derived efficiencies for environmental and fabrication criteria and discussion of future steps for inclusion of human and structural factors