This paper presents the design and implementation of a radiation-hardened analog front-end (AFE) integrated circuit (IC) developed for interfacing with solid state ionizing radiation detectors, ...providing accurate amplitude and time-of-arrival measurements. The AFE is designed for use in the Beam Conditions Monitor Prime (BCM') of the ATLAS experiment at the Large Hadron Collider (LHC). The proposed AFE is comprised of four channels, allowing for re-configuration to operate as either a low-noise high-gain amplifier for beam luminosity measurements, or a high-linearity low-gain amplifier for beam abort functionality. Each of the AFE channels consists of a low noise trans-impedance amplifier (TIA) optimized for minimal jitter and amplitude noise, a second stage differential amplifier, followed by a fully differential Constant Fraction Discriminator (CFD) to provide an amplitude independent time pick-off with a wide dynamic range. The CFD utilizes a new all-pass filter delay topology and high-performance zero-crossing detector to minimize time-walk. The core of each AFE channel occupies an area of 0.06 mm 2 in a 65 nm CMOS technology and consumes 57 mW, including the drivers. The measured AFE chips achieve 1 ns pulse rise time, 130 electron baseline equivalent noise charge (ENC), and <25 ps RMS jitter at 1 fC input charge. To the authors' best knowledge, this work demonstrates the lowest published time-walk of ±6 ps across 30 dB signal dynamic range. Furthermore, irradiated AFEs are shown to tolerate up to 225 Mrad total ionizing dose with no significant degradation in measured performance characteristics.
NK cells are primarily responsible for detecting malignant or pathogen-infected cells, and their function is influenced both by stress-associated activating signals and opposing inhibitory signals ...from receptors that recognize self MHC. The receptors that produce this inhibitory signal shift from the NKG2A:HLA-E system to that of KIR:HLA as the NK cells mature. This maturation is associated with an increase in lytic activity, as well as an increase in HLA-C protein levels controlled by the NK-specific
HLA-C
promoter, NK-Pro. We propose that modulation of the translatability of
HLA-C
transcripts in NK cells constitutes an evolutionary mechanism to control
cis
inhibitory signaling by HLA-C, which fine tunes NK cell activity. Furthermore, the high degree of variability in KIR receptor affinity for HLA alleles, as well as the variable expression levels of both KIR and HLA, suggest an evolutionary requirement for the tuning of NK lytic activity. Various data have demonstrated that mature NK cells may gain or lose lytic activity when placed in different environments. This indicates that NK cell activity may be more a function of constant tuning by inhibitory signals, rather than a static, irreversible “license to kill” granted to mature NK cells. Inhibitory signaling controls the filling of the cytolytic granule reservoir, which becomes depleted if there are insufficient inhibitory signals, leading to a hyporesponsive NK cell. We propose a novel model for the tuning of human NK cell activity via
cis
interactions in the context of recent findings on the mechanism of NK education.
The field of oncolytic virotherapy has seen remarkable advancements in last two decades, leading to approval of the first oncolytic immuno-virotherapy, Talimogene Laherparepvec, for the treatment of ...melanoma. A plethora of preclinical and clinical studies have demonstrated excellent safety profiles of other oncolytic viruses. While oncolytic viruses show clinical promise in already immunogenic malignancies, response rates are inconsistent. Response rates are even less consistent in immunosuppressed tumor microenvironments like those found in liver, pancreas, and MSI-stable colon cancers. Therefore, the efficacy of oncolytic viruses needs to be improved for more oncolytic viruses to enter mainstream cancer therapy. One approach to increase the therapeutic efficacy of oncolytic viruses is to use them as primers for other immunotherapeutics. The amenability of oncolytic viruses to transgene-arming provides an immense opportunity for investigators to explore different ways of improving the outcome of oncolytic therapy. In this regard, genes encoding immunomodulatory proteins are the most commonly studied genes for arming oncolytic viruses. Other transgenes used to arm oncolytic viruses include those with the potential to favorably modulate tumor stroma, making it possible to image the virus distribution and increase its suitability for combination with other therapeutics. This review will detail the progress made in arming oncolytic viruses with a focus on immune-modulatory transgenes, and will discuss the challenges that need to be addressed for more armed oncolytic viruses to find widespread clinical use.
Oncolytic viral therapy, which makes use of replication-competent lytic viruses, has emerged as a promising modality to treat malignancies. It has shown meaningful outcomes in both solid tumor and ...hematologic malignancies. Advancements during the last decade, mainly genetic engineering of oncolytic viruses have resulted in improved specificity and efficacy of oncolytic viruses in cancer therapeutics. Oncolytic viral therapy for treating cancer with herpes simplex virus-1 has been of particular interest owing to its range of benefits like: (a) large genome and power to infiltrate in the tumor, (b) easy access to manipulation with the flexibility to insert multiple transgenes, (c) infecting majority of the malignant cell types with quick replication in the infected cells and (d) as Anti-HSV agent to terminate HSV replication. This review provides an exhaustive list of oncolytic herpes simplex virus-1 along with their genetic alterations. It also encompasses the major developments in oncolytic herpes simplex-1 viral therapy and outlines the limitations and drawbacks of oncolytic herpes simplex viral therapy.
We consider a simple, guns-versus-butter model in which agents choose between “war” and “peace” to study the implications of inequality in resource ownership for equilibrium outcomes. Provided war is ...destructive, peace can emerge as the stable equilibrium, but only if the distribution of resource ownership is sufficiently even. We establish that, when this condition fails, the richer agent can destroy a portion of its resource endowment to even out the ex post distribution and thereby support peace. We also examine the importance of ex ante resource transfers and show that they are Pareto superior to burning resources.
•We study a single-period guns-vs-butter model of conflict between two agents.•The agents can choose either war or peace identified with the status quo.•Peace is more likely to emerge when resources are more evenly distributed.•Resource burning can promote peace, but is dominated by resource transfers.
Cell surface display of proteins/peptides has been established based on mechanisms of localizing proteins to the cell surface. In contrast to conventional intracellular and extracellular (secretion) ...expression systems, this method, generally called an arming technology, is particularly effective when using yeasts as a host, because the control of protein folding that is often required for the preparation of proteins can be natural. This technology can be employed for basic and applied research purposes. In this review, I describe various strategies for the construction of engineered yeasts and provide an outline of the diverse applications of this technology to industrial processes such as the production of biofuels and chemicals, as well as bioremediation and health-related processes. Furthermore, this technology is suitable for novel protein engineering and directed evolution through high-throughput screening, because proteins/peptides displayed on the cell surface can be directly analyzed using intact cells without concentration and purification. Functional proteins/peptides with improved or novel functions can be created using this beneficial, powerful, and promising technique.
Research summary
In the wake of repeated school shootings, today's youth have acquired the label of the “mass shooting generation.” Another fitting label would be the “armed school generation.” Most ...states now permit school security officers to carry firearms, and at least 466 school districts in 19 states allow teachers or staff members to be armed. In this context, understanding public opinion about guns in schools is essential. Using a 2018 national survey of 1,100 American adults, we examined public support for arming our nation's schools. Although consensus exists for school resource officers carrying weapons, respondents are divided about arming teachers and nonteaching staff. Those who believe in gun defensive effectiveness, lean right politically, are racially resentful, older, and have children are more likely to endorse arming nonlaw enforcement school personnel. National Rifle Association membership and altruistic fear are associated with support for arming teachers, while a belief in the moral wrongness of harming others predicts opposition to teachers having a gun in one hand and an apple in the other.
Policy implications
The controversy around arming teachers will likely be ongoing. With decisions made locally, public opinion will continue to play an influential role in this debate. Our study provides important new evidence about the extent and correlates of public opinion on guns in schools. The next step is to examine how public attitudes change in response to information about the policy issues associated with arming schools. Future polls should examine the impact being armed has on the teaching profession and localized variations in support for arming the school.
In the effort to prevent school shootings in the United States, policies that aim to arm teachers with guns have received considerable attention. Recent research on public support for these policies ...finds that African Americans are substantially less likely to support them, indicating that support for arming teachers is a racial issue. Given the racialized nature of support for punitive crime policies in the United States, it is possible that racial sentiment shapes support for arming teachers as well. This study aims to determine the association between two types of racial sentiment—explicit negative feelings toward racial/ethnic minority groups and racial resentment—and support for arming teachers using a nationally representative data set. While explicit negative feelings toward African Americans and Hispanics are not associated with support for arming teachers, those with racial resentments are significantly more likely to support arming teachers. Racial resentment also weakens the effect of other variables found to be associated with support for arming teachers, including conservative ideology and economic pessimism. Implications for policy and research are discussed.
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