Harnessing radiotherapy-induced NK-cell activity by combining DNA damage-response inhibition and immune checkpoint blockade.

BackgroundDespite therapeutic gains from immune checkpoint inhibitors (ICI) in many tumor types, new strategies are needed to extend treatment benefits, especially in patients failing to mount effective antitumor T-cell responses. Radiation and drug therapies can profoundly affect the tumor immune microenvironment. Here, we aimed to identify immunotherapies to increase the antitumor response conferred by combined ataxia telangiectasia and Rad3-related kinase inhibition and radiotherapy.MethodsUsing the human papillomavirus (HPV)-negative murine oral squamous cell carcinoma model, MOC2, we assessed the nature of the antitumor response following ataxia telangiectasia and Rad3-related inhibitor (ATRi)/radiotherapy (RT) by performing RNA sequencing and detailed flow cytometry analyses in tumors. The benefit of immunotherapies based on T cell immunoreceptor with Ig and ITIM domains (TIGIT) and Programmed cell death protein 1 (PD-1) immune checkpoint blockade following ATRi/RT treatment was assessed in the MOC2 model and confirmed in another HPV-negative murine oral squamous cell carcinoma model called SCC7. Finally, immune profiling was performed by flow cytometry on blood samples in patients with head and neck squamous cell carcinoma enrolled in the PATRIOT clinical trial of combined ATRi/RT.ResultsATRi enhances radiotherapy-induced inflammation in the tumor microenvironment, with natural killer (NK) cells playing a central role in maximizing treatment efficacy. We demonstrated that antitumor activity of NK cells can be further boosted with ICI targeting TIGIT and PD-1. Analyses of clinical samples from patients receiving ATRi (ceralasertib) confirm the translational potential of our preclinical studies.ConclusionThis work delineates a previously unrecognized role for NK cells in the antitumor immune response to radiotherapy that can be augmented by small-molecule DNA damage-response inhibitors and immune checkpoint blockade

Modeling the distribution of a wide-ranging invasive species using the sampling efforts of expert and citizen scientists

1- Results for the models calibrated with <i>Weigted Pts</i> pseudo-absences for the paper 'Modelling the distribution of a wide-ranging invasive species using the sampling efforts of expert and citizen scientists'.<div>2- Final figure of the probability of distribution of rabbits in black and white.</div><div>3- Final figure of the probability of distribution of rabbits in ASC format.<br></div

Genetic differentiation of European grayling (Thymallus thymallus) populations in Serbia, based on mitochondrial and nuclear DNA analyses

<p>Abstract</p> <p>Background</p> <p>The structure and diversity of grayling (<it>Thymallus thymallus</it>) populations have been well studied in most of its native habitat; however the southernmost populations of the Balkan Peninsula remain largely unexplored. The purpose of this study was to assess the genetic diversity of Serbian grayling populations, detect the impact of stocking and provide guidelines for conservation and management.</p> <p>Methods</p> <p>Eighty grayling individuals were collected from four rivers (Ibar, Lim, Drina and Rzav). The mitochondrial DNA control region (CR; 595 bp of the 3'end and 74 bp of flanking tRNA) and the ATP6 gene (630 bp fragment) were sequenced for 20 individuals (five from each locality). In addition, all individuals were genotyped with 12 microsatellite loci. The diversity and structure of the populations as well as the recent and ancient population declines were studied using specialized software.</p> <p>Results</p> <p>We detected three new haplotypes in the mtDNA CR and four haplotypes in the ATP6 gene of which three had not been described before. Previously, one CR haplotype and two ATP6 gene haplotypes had been identified as allochthonous, originating from Slovenia. Reconstruction of phylogenetic relations placed the remaining two CR haplotypes from the River Danube drainage of Serbia into a new clade, which is related to the previously described sister Slovenian clade. These two clades form a new Balkan clade. Microsatellite marker analysis showed that all four populations are genetically distinct from each other without any sign of intra-population structure, although stocking of the most diverse population (Drina River) was confirmed by mtDNA analysis. Recent and historical population declines of Serbian grayling do not differ from those of other European populations.</p> <p>Conclusions</p> <p>Our study shows that (1) the Ibar, Lim and Drina Rivers grayling populations are genetically distinct from populations outside of Serbia and thus should be managed as native populations in spite of some introgression in the Drina River population and (2) the Rzav River population is not appropriate for further stocking activities since it originates from stocked Slovenian grayling. However, the Rzav River population does not represent an immediate danger to other populations because it is physically isolated from these.</p

Aerobic training protects cardiac function during advancing age: a meta-analysis of four decades of controlled studies

In contrast to younger athletes, there is comparatively less literature examining cardiac structure and function in older athletes. However, a progressive accumulation of studies during the past four decades offers a body of literature worthy of systematic scrutiny. We conducted a systematic review, meta-analysis and meta-regression of controlled echocardiography studies comparing left ventricular (LV) structure and function in aerobically trained older athletes (> 45 years) with age-matched untrained controls, in addition to investigating the influence of chronological age. statistic. , 95% CI 0.05-1.86, p = 0.04). Meta-regression for chronological age identified that athlete-control differences, in the main, are maintained during advancing age. Athletic older men have larger cardiac dimensions and enjoy more favourable cardiac function than healthy, non-athletic counterparts. Notably, the athlete groups maintain these effects during chronological ageing

ANK, a Host Cytoplasmic Receptor for the Tobacco mosaic virus Cell-to-Cell Movement Protein, Facilitates Intercellular Transport through Plasmodesmata

Plasmodesma (PD) is a channel structure that spans the cell wall and provides symplastic connection between adjacent cells. Various macromolecules are known to be transported through PD in a highly regulated manner, and plant viruses utilize their movement proteins (MPs) to gate the PD to spread cell-to-cell. The mechanism by which MP modifies PD to enable intercelluar traffic remains obscure, due to the lack of knowledge about the host factors that mediate the process. Here, we describe the functional interaction between Tobacco mosaic virus (TMV) MP and a plant factor, an ankyrin repeat containing protein (ANK), during the viral cell-to-cell movement. We utilized a reverse genetics approach to gain insight into the possible involvement of ANK in viral movement. To this end, ANK overexpressor and suppressor lines were generated, and the movement of MP was tested. MP movement was facilitated in the ANK-overexpressing plants, and reduced in the ANK-suppressing plants, demonstrating that ANK is a host factor that facilitates MP cell-to-cell movement. Also, the TMV local infection was largely delayed in the ANK-suppressing lines, while enhanced in the ANK-overexpressing lines, showing that ANK is crucially involved in the infection process. Importantly, MP interacted with ANK at PD. Finally, simultaneous expression of MP and ANK markedly decreased the PD levels of callose, β-1,3-glucan, which is known to act as a molecular sphincter for PD. Thus, the MP-ANK interaction results in the downregulation of callose and increased cell-to-cell movement of the viral protein. These findings suggest that ANK represents a host cellular receptor exploited by MP to aid viral movement by gating PD through relaxation of their callose sphincters

Seasonal Movement and Distribution of Fluvial Adult Bull Trout in Selected Watersheds in the Mid-Columbia River and Snake River Basins

From 1997 to 2004, we used radio telemetry to investigate movement and distribution patterns of 206 adult fluvial bull trout (mean, 449 mm FL) from watersheds representing a wide range of habitat conditions in northeastern Oregon and southwestern Washington, a region for which there was little previous information about this species. Migrations between spawning and wintering locations were longest for fish from the Imnaha River (median, 89 km) and three Grande Ronde River tributaries, the Wenaha (56 km) and Lostine (41 km) rivers and Lookingglass Creek (47 km). Shorter migrations were observed in the John Day (8 km), Walla Walla (20 km) and Umatilla river (22 km) systems, where relatively extensive human alterations of the riverscape have been reported. From November through May, fish displayed station-keeping behavior within a narrow range (basin medians, 0.5–6.2 km). Prespawning migrations began after snowmelt-driven peak discharge and coincided with declining flows. Most postspawning migrations began by late September. Migration rates of individuals ranged from 0.1 to 10.7 km/day. Adults migrated to spawning grounds in consecutive years and displayed strong fidelity to previous spawning areas and winter locations. In the Grande Ronde River basin, most fish displayed an unusual fluvial pattern: After exiting the spawning tributary and entering a main stem river, individuals moved upstream to wintering habitat, often a substantial distance (maximum, 49 km). Our work provides additional evidence of a strong migratory capacity in fluvial bull trout, but the short migrations we observed suggest adult fluvial migration may be restricted in basins with substantial anthropogenic habitat alteration. More research into bull trout ecology in large river habitats is needed to improve our understanding of how adults establish migration patterns, what factors influence adult spatial distribution in winter, and how managers can protect and enhance fluvial populations

Feeding habits of Mysis relicta — an overview

Mysis relicta has been recognized as an important component of many limnetic food webs. The first approach to studying the feeding habits of M. relicta was the analysis of stomach contents. Assumptions regarding stomach content analysis have been tested and seasonal feeding estimates of M. relicta have been reported recently. Laboratory grazing and/or predation experiments have recently been completed using M. relicta primarily from Lakes Michigan and Tahoe. Mysis relicta is concluded to be opportunistic, capable of utilizing a variety of food resources. It may play an important role in structuring limnetic food webs.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/42916/1/10750_2004_Article_BF00008103.pd