Recent advancements in the field of immunotherapy have yielded encouraging results for the treatment of advanced cancers. Cyclic dinucleotides (CDNs) are a powerful new class of immunotherapy drugs ...known as STING (Stimulator of Interferon Genes) agonists, currently in clinical trials. However, previous studies of CDNs in murine cancer models have required multiple injections, and improve survival only in relatively nonaggressive tumor models. Therefore, we sought to improve the efficacy of CDN immunotherapy by developing a novel biomaterial we call “STINGel.” STINGel is an injectable peptide hydrogel that localizes and provides controlled release of CDN delivery, showing an 8-fold slower release rate compared to a standard collagen hydrogel. The carrier hydrogel is a positively charged, MultiDomain Peptide (MDP) which self-assembles to form a nanofibrous matrix and is easily delivered by syringe. The highly localized delivery of CDN from this nanostructured biomaterial affects the local histological response in a subcutaneous model, and dramatically improves overall survival in a challenging murine model of head and neck cancer compared to CDN alone or CDN delivered from a collagen hydrogel. This study demonstrates the feasibility of biomaterial-based immunotherapy platforms like STINGel as strategies for increasing the efficacy of CDN immunotherapies.
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Mitral and aortic valve insufficiencies have been commonly reported in horses. The objective of this study was to establish the use of acoustic cardiography (Audicor
) in horses with aortic (AI) or ...mitral valve insufficiency (MI). A total of 17 healthy horses, 18 horses with AI, and 28 horses with MI were prospectively included. None of the horses was in heart failure. Echocardiography and Audicor
analyses were conducted. Electromechanical activating time (EMAT), rate-corrected EMATc, left ventricular systolic time (LVST), rate-corrected LVSTc, and intensity and persistence of the third and fourth heart sound (S3, S4) were reported by Audicor
. Graphical analysis of the three-dimensional (3D) phonocardiogram served to visually detect murmurs. Audicor
snapshot variables were compared between groups using one-way ANOVA followed by Tukey's multiple-comparisons test. The association between Audicor
snapshot variables and the corresponding echocardiographic variables was investigated by linear regression and Bland-Altman analyses. Heart murmurs were not displayed on Audicor
phonocardiograms. No significant differences were found between Audicor
variables obtained in clinically healthy horses and horses with valvular insufficiency. The Audicor
device is unable to detect heart murmurs in horses. Audicor
variables representing cardiac function are not markedly altered, and their association with corresponding echocardiographic variables is poor in horses with valvular insufficiency that are not in heart failure.
I present the results of the search for an optical precursor to the naked-eye burst – GRB080319B, which reached 5.87m optical peak luminosity in the “Pi of the Sky” data. A burst of such a high ...brightness could have been preceded by an optical precursor luminous enough to be in detection range of our experiment. The “Pi of the Sky” cameras observed the coordinates of the GRB for about 20 min prior to the explosion, thus provided crucial data for the precursor search. No signal within 3σ limit was found. A limit of 12m (V-band equivalent) was set based on the data combined from two cameras, the most robust limit to my knowledge for this precursor.
This note describes a newly developed technique for evaluation of cutaneous microcirculation. The technique called Flow Mediated Skin Fluorescence (FMSF) is based on monitoring of NADH fluorescence ...intensity emitted from the skin tissue cells of a forearm. The changes in fluorescence intensity as a function of time in response to blocking and releasing of blood flow in a forearm are used as a measure of oxygen transport with blood to the tissue, which directly correlates with the skin microcirculation status. Preliminary results collected for healthy volunteers and patients experiencing serious cardiovascular problems indicated a usefulness of FMSF technique for evaluation of health related perturbations in cutaneous microcirculation.
Abstract
Mini-EUSO is a telescope observing the Earth in the ultraviolet band from the International Space Station. It is a part of the JEM-EUSO program, paving the way to future larger missions, ...such as K-EUSO and POEMMA, devoted primarily to the observation of ultrahigh-energy cosmic rays from space. Mini-EUSO is capable of observing extensive air showers generated by ultrahigh-energy cosmic rays with an energy above 10
21
eV and to detect artificial showers generated with lasers from the ground. Other main scientific objectives of the mission are the search for nuclearites and strange quark matter, the study of atmospheric phenomena such as transient luminous events, meteors, and meteoroids, the observation of sea bioluminescence and of artificial satellites and man-made space debris. Mini-EUSO will map the nighttime Earth in the UV range (290–430 nm), with a spatial resolution of about 6.3 km and a temporal resolution of 2.5
μ
s, through a nadir-facing UV-transparent window in the Russian Zvezda module. The instrument, launched on 2019 August 22, from the Baikonur Cosmodrome, is based on an optical system employing two Fresnel lenses and a focal surface composed of 36 multianode photomultiplier tubes, 64 channels each, for a total of 2304 channels with single-photon counting sensitivity and an overall field of view of 44°. Mini-EUSO also contains two ancillary cameras to complement measurements in the near-infrared and visible ranges. In this paper, we describe the detector and present the various phenomena observed in the first months of operations.
Abstract
The study of ultra high energy cosmic rays (UHECRs) offers unique possibilities to probe the energies currently inaccessible by man-made accelerators. Recent years have shed light on several ...characteristics of these particles, but—due to their extremely low flux—their origin, nature, and acceleration mechanisms are still unclear. Space-based observations have the potential for an increase in statistics, up to several orders of magnitude, and would be able to cover the whole sky, allowing for a direct comparison of spectra and direction of arrival. A detector with the exposure of a few times that of the Pierre Auger Observatory would be able to clarify the observed differences between the northern and southern skies, confirm the existence of TA hot spot, and measure multipolar anisotropies with high precision. A number of novel technologies—from optics to sensors, front-end and read-out electronics—have been developed over the years to achieve this goal. In this paper we describe the progress and results obtained so far and discuss the perspectives of UHECR physics observation from space.
Murine noroviruses (MNVs) are highly prevalent in laboratory mice, can cause persistent infections, and have been shown to infect macrophages, dendritic cells, and B cells. To address the potential ...impact of MNV infection on research outcomes, numerous studies have been conducted with various mouse models of human disease and have generated mixed results, ranging from no impact to significant disease. Many of these studies included histologic evaluations after MNV infection, and these results have similarly been variable in terms of whether MNV induces lesions, despite the fact that localization of MNV by viral culture and molecular techniques have demonstrated systemic distribution regardless of mouse immune status. The aim of this review is to summarize the histologic findings that have been reported with MNV infection in several mouse models. The studies demonstrate that experimental infection of MNV in wild-type mice results in minimal to no histologic changes. In contrast, immunodeficient mice consistently have detectable MNV-induced lesions that are typically inflammatory and, in the most severe cases, accompanied by necrosis. In these, the liver is commonly affected, with more variable lesions reported in the lung, gastrointestinal tract, mesenteric lymph nodes, brain, and spleen. In specific disease models including atherosclerosis, MNV infection had a variable impact that was dependent on the mouse model, viral strain, timing of infection, or other experimental variables. It is important to recognize the reported MNV lesions to help discern the possible influence of MNV infection on data generated in mouse models.
The paper analyses the possibility of post weld heat treatment (PWHT) quality assessment with the help of magnetoacoustic emission (MAE) signal measurements. Two welded superheater tubes, made of ...high chromium VM12 steel, were analysed—as welded and heat treated one. The analysed sample in the as welded state exhibited significantly higher hardness, accompanied by a big difference in the MAE signal intensity (of order of about 50%). In order to explain that, the influence of tempering on the MAE signal intensity is demonstrated for the very similar X20CrMoV12.1 steel. It is shown that the observed increase of the MAE intensity as a function of annealing time is directly correlated with the change in hardness. The as described dependence allows to propose a method based on the MAE signal measurements as a new tool for the PWHT assessment.
Societies characterized by fission–fusion dynamics consist of subgroups that frequently change in size and composition. Although this flexible lifestyle permits individuals to reduce conflicts of ...interest, it simultaneously imposes a unique set of challenges on group members that are regularly subject to prolonged separation. Theory predicts animals should evolve ritualized and risky displays to quickly update relationships at reunions. Here we investigated the function of nonconciliatory greetings among adult female spotted hyaenas, Crocuta crocuta, belonging to a single, large female-dominated social group in Kenya. We tested three hypotheses forwarded to explain the occurrence of these multimodal signals: formal submission, tension reduction and social bonding hypotheses. In contrast to predictions of the formal submission hypothesis, rank distance and relative rank were excluded from our best model predicting greetings among adult females. Moreover, directional consistency of greetings was low (0.65) compared to that of submissive behaviours during dyadic agonistic interactions (0.97). Instead, our data revealed that adult females greeted coalition partners and close associates, including kin, most often per opportunity, and they did so in neutral contexts more frequently than in situations characterized by social tension. Although these findings are in direct contrast to the predictions of the tension reduction and formal submission hypotheses, they strongly support the social bonding hypothesis. Importantly, the immediate act of greeting promoted cooperation among allies during intragroup and intergroup coalition formation. Thus, these risky, multimodal signals permit hyaenas to effectively communicate cooperative affiliations within a continuously shifting social milieu.
Immunotherapeutic treatments in head and neck cancer clinical trials include cancer vaccines targeting foreign viral antigens or mutational neoantigens derived from cancer-expressed proteins. ...Anti-tumor immune responses place cancer cells under selective pressure to lose or downregulate target antigens; therefore, vaccination against virus- or host- "driver" oncogenes are proposed as a strategy to overcome immune escape. Herein, we demonstrate the impact of immunogenic viral antigens on anti-tumor response and immune editing in MOC2-E6E7, a syngeneic murine oral cancer cell line expressing HPV-16 E6 and E7 oncoproteins. Using orthotopic syngeneic models, we observed in vivo tumor growth kinetics of MOC2-E6E7 is delayed in immunocompetent mice compared to parental MOC2 tumors. In contrast, tumor growth remained similar in Rag1
-/-
mice lacking adaptive immunity. MOC2-E6E7 tumors demonstrated an "inflamed" or immune-activated tumor microenvironment and greater infiltration of CD8
+
T cells compared to MOC2. By real-time PCR, we detected downregulation of E6 and E7 genes in MOC2-E6E7 tumors only in immunocompetent mice, suggesting the loss of ectopic viral antigen expression due to immune editing. We then assessed the efficacy of a biomaterials-based mesoporous silica rod (MSR) cancer vaccine targeting HPV-16 E7 in our model. Vaccination induced robust infiltration of antigen-specific CD8
+
T cells, which led to tumor growth delay and modestly prolonged survival in MOC2-E6E7 tumors. Increased efficacy was seen in a separate head and neck cancer tumor model, mEER, which obligately expresses E7 antigen. Collectively, our data highlight the need for both immunogenicity and 'driver' status of target antigens to be considered in cancer vaccine design.
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