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

The Hi-GAL catalogue of dusty filamentary structures in the Galactic plane

The recent data collected by Herschel have confirmed that interstellar structures with a filamentary shape are ubiquitously present in the Milky Way. Filaments are thought to be formed by several physical mechanisms acting from large Galactic scales down to subparsec fractions of molecular clouds, and they might represent a possible link between star formation and the large-scale structure of the Galaxy. In order to study this potential link, a statistically significant sample of filaments spread throughout the Galaxy is required. In this work, we present the first catalogue of 32 059 candidate filaments automatically identified in the Herschel Infrared Galactic plane Survey (Hi-GAL) of the entire Galactic plane. For these objects, we determined morphological (length la and geometrical shape) and physical (average column density NH2 and average temperature T) properties. We identified filaments with a wide range of properties: 2 ≤ la ≤ 100 arcmin, 1020≤NH2≤1023 cm−2 and 10 ≤ T ≤ 35 K. We discuss their association with the Hi-GAL compact sources, finding that the most tenuous (and stable) structures do not host any major condensation. We also assign a distance to ∼18 400 filaments, for which we determine mass, physical size, stability conditions and Galactic distribution. When compared with the spiral arms structure, we find no significant difference between the physical properties of on-arm and inter-arm filaments. We compare our sample with previous studies, finding that our Hi-GAL filament catalogue represents a significant extension in terms of Galactic coverage and sensitivity. This catalogue represents a unique and important tool for future studies devoted to understanding the filament life-cycle

A polymorphic microsatellite from the Squalius alburnoides complex (Osteichthyes, Cyprinidae) cloned by serendipity can be useful in genetic analysis of polyploids

A new microsatellite locus (SAS1) for Squalius alburnoides was obtained through cloning by serendipity. The possible usefulness of this new species-specific microsatellite in genetic studies of this hybrid-species complex, was explored. The polymorphism exhibited by SAS1 microsatellite is an important addition to the set of microsatellites previously used in genetic studies in S. alburnoides complex, that mostly relied in markers described for other species. Moreover, the SAS1 microsatellite could be used to identify the parental genomes of the complex, complementing other methods recently described for the same purpose.

Three People Can Synchronize as Coupled Oscillators during Sports Activities

We experimentally investigated the synchronized patterns of three people during sports activities and found that the activity corresponded to spatiotemporal patterns in rings of coupled biological oscillators derived from symmetric Hopf bifurcation theory, which is based on group theory. This theory can provide catalogs of possible generic spatiotemporal patterns irrespective of their internal models. Instead, they are simply based on the geometrical symmetries of the systems. We predicted the synchronization patterns of rings of three coupled oscillators as trajectories on the phase plane. The interactions among three people during a 3 vs. 1 ball possession task were plotted on the phase plane. We then demonstrated that two patterns conformed to two of the three patterns predicted by the theory. One of these patterns was a rotation pattern (R) in which phase differences between adjacent oscillators were almost 2π/3. The other was a partial anti-phase pattern (PA) in which the two oscillators were anti-phase and the third oscillator frequency was dead. These results suggested that symmetric Hopf bifurcation theory could be used to understand synchronization phenomena among three people who communicate via perceptual information, not just physically connected systems such as slime molds, chemical reactions, and animal gaits. In addition, the skill level in human synchronization may play the role of the bifurcation parameter

A novel TLR3 inhibitor encoded by African swine fever virus (ASFV)

African swine fever virus (ASFV) encodes proteins that manipulate important host antiviral mechanisms. Bioinformatic analysis of the ASFV genome revealed ORF I329L, a gene without any previous functional characterization as a possible inhibitor of TLR signaling. We demonstrate that ORF I329L encodes a highly glycosylated protein expressed in the cell membrane and on its surface. I329L also inhibited dsRNA-stimulated activation of NFκB and IRF3, two key players in innate immunity. Consistent with this, expression of I329L protein also inhibited the activation of interferon-β and CCL5. Finally, overexpression of TRIF reversed I329L-mediated inhibition of both NFκB and IRF3 activation. Our results suggest that TRIF, a key MyD88-independent adaptor molecule, is a possible target of this viral host modulation gene. The demonstration of an ASFV host evasion molecule inhibiting TLR responses is consistent with the ability of this virus to infect vertebrate and invertebrate hosts, both of which deploy innate immunity controlled by conserved TLR systems

The Evolution of Compact Binary Star Systems

We review the formation and evolution of compact binary stars consisting of white dwarfs (WDs), neutron stars (NSs), and black holes (BHs). Binary NSs and BHs are thought to be the primary astrophysical sources of gravitational waves (GWs) within the frequency band of ground-based detectors, while compact binaries of WDs are important sources of GWs at lower frequencies to be covered by space interferometers (LISA). Major uncertainties in the current understanding of properties of NSs and BHs most relevant to the GW studies are discussed, including the treatment of the natal kicks which compact stellar remnants acquire during the core collapse of massive stars and the common envelope phase of binary evolution. We discuss the coalescence rates of binary NSs and BHs and prospects for their detections, the formation and evolution of binary WDs and their observational manifestations. Special attention is given to AM CVn-stars -- compact binaries in which the Roche lobe is filled by another WD or a low-mass partially degenerate helium-star, as these stars are thought to be the best LISA verification binary GW sources.Comment: 105 pages, 18 figure

Opportunities to Learn Mathematics Pedagogy and Connect Classroom Learning to Practice: A Study of Future Teachers in the United States and Singapore

In this study, we conducted secondary analyses using the TEDS-M database to explore future mathematics specialists teachers’ opportunities to learn (OTL) how to teach mathematics. We applied latent class analysis techniques to differentiate among groups of prospective mathematics specialists with potentially different OTL mathematics pedagogy within the United States and Singapore. Within the United States, three subgroups were identified: (a) Comprehensive OTL, (b) Limited OTL, and (c) OTL Mathematics Pedagogy. Within Singapore, four subgroups were identified: (a) Comprehensive OTL, (b) Limited Opportunities to Connect Classroom Learning with Practice, (c) OTL Mathematics Pedagogy, and (d) Basic OTL. Understanding the opportunities different prospective teachers had to learn from and their experiences with different components of instructional practice in university and practicum settings has implications for teacher preparation programs

Morbidity, outcomes and cost-benefit analysis of wildlife rehabilitation in Catalonia (Spain)

Background There are few studies of careful examination of wildlife casualties in Wildlife Rehabilitation Centers. These studies are essential for detecting menaces to wild species and providing objective criteria about cost-benefit of treatments in those centers. The release rate is considered the main outcome indicator, but other parameters such as length of stay at the center and a cost-benefit index expressed as number of released animals per euro and day, could be used as reliable estimators of the rehabilitation costs. Methodology A retrospective study based on 54772 admissions recorded from 1995-2013 in the database of the Wildlife Rehabilitation Center of Torreferrussa (Catalonia, NW Spain) assessed the morbidity, outcomes and cost-benefits of the rehabilitation practices. Results Three hundred and two species were included: 232 birds (n = 48633), 37 mammals (n = 3293), 20 reptiles (n = 2705) and 13 amphibians (n = 141). The most frequent causes of admission were: 39.8% confiscation of protected species (89.4% passerines), 31.8% orphaned young animals (35.3% swifts, 21.7% diurnal raptors and owls) and 17.4% trauma casualties (46.7% raptors and owls). The highest proportion of releases was found in the captivity confiscation category [87.4% passerines (median time of stay: 12 days)], followed by the orphaned category [78% owls (66 days), 76.5% diurnal birds of prey (43 days), 75.6% hedgehogs (49 days), 52.7% swifts (19 days) and 52% bats (55 days)]. For the trauma group, 46.8% of releases were hedgehogs (44 days) and 25.6% owls (103 days). As regards the cost-benefit index, the trauma casualties and infectious diseases had the worse values with 1.3 and 1.4 released animals/euro/day respectively, and were particularly low in raptors, waders, marine birds and chiroptera. On the contrary, captivity (4.6) and misplacement (4.1) had the best index, particulary in amphibian, reptiles and passerines. Conclusions/significance Cost-benefit studies including the release rate, the time of stay at the center and the costbenefit index should be implemented for improving management efficiency of the Wildlife Rehabilitation Centers

Training compliance control yields improvements in drawing as a function of beery scores

Many children have difficulty producing movements well enough to improve in sensori-motor learning. Previously, we developed a training method that supports active movement generation to allow improvement at a 3D tracing task requiring good compliance control. Here, we tested 7–8 year old children from several 2nd grade classrooms to determine whether 3D tracing performance could be predicted using the Beery VMI. We also examined whether 3D tracing training lead to improvements in drawing. Baseline testing included Beery, a drawing task on a tablet computer, and 3D tracing. We found that baseline performance in 3D tracing and drawing co-varied with the visual perception (VP) component of the Beery. Differences in 3D tracing between children scoring low versus high on the Beery VP replicated differences previously found between children with and without motor impairments, as did post-training performance that eliminated these differences. Drawing improved as a result of training in the 3D tracing task. The training method improved drawing and reduced differences predicted by Beery scores