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BackgroundAntitumor antibody, or targeted immunotherapy, has revolutionized cancer treatment and markedly improved patient outcomes. A prime example is the monoclonal antibody (mAb) trastuzumab, which targets human epidermal growth factor receptor 2 (HER2). However, like many targeted immunotherapies, only a subset of patients benefit from trastuzumab long-term. In addition to tumor-intrinsic factors, we hypothesize that host genetics may influence subsequent immune activation.MethodsTo model the human population, we produced F1 crosses of genetically heterogeneous Diversity Outbred (DO) mice with BALB/c mice (DOCF1). Distinct DOCF1 mice were orthotopically implanted with the BALB/c-syngeneic TUBO mammary tumor line, which expresses the HER2 ortholog rat neu. Treatment with anti-neu mAb clone 7.16.4 began once tumors reached ∼200 mm3. Genetic linkage and quantitative trait locus (QTL) effects analyses in R/qtl2 identified loci associated with tumor growth rates. Locus validation was performed with BALB/c F1 crosses with recombinant-inbred Collaborative Cross (CC) strains selected for therapy-associated driver genetics (CCxCF1). The respective roles of natural killer (NK) cells and macrophages were investigated by selective depletion in vivo. Ex vivo macrophage antibody-dependent phagocytosis (ADCP) assays were evaluated by confocal microscopy using 7.16.4-opsonized E2Crimson-expressing TUBO tumor cells.ResultsWe observed a divergent response to anti-tumor antibody therapy in DOCF1 mice. Genetic linkage analysis detected a locus on chromosome 10 that correlates to a robust response to therapy, which was validated in CCxCF1 models. Single-cell RNA sequencing of tumors from responder and non-responder models identified key differences in tumor immune infiltrate composition, particularly within macrophage (Mφ) subsets. This is further supported byex vivoanalysis showing Mφ ADCP capacity correlates toin vivotreatment outcomes in both DOCF1 and CCxCF1 models.ConclusionsHost genetics play a key regulatory role in targeted immunotherapy outcomes, and putative causal genes are identified in murine chromosome 10 which may govern Mφ function during ADCP.

The variability of severity in hypoxia-ischemia (HI)-induced brain injury among research subjects is a major challenge in developmental brain injury research. Our laboratory developed a novel injury scoring tool based on our gross pathological observations during hippocampal extraction. The hippocampi received scores of 0–6 with 0 being no injury and 6 being severe injury post-HI. The hippocampi exposed to sham surgery were grouped as having no injury. We have validated the injury scoring tool with T2-weighted MRI analysis of percent hippocampal/hemispheric tissue loss and cell survival/death markers after exposing the neonatal mice to Vannucci’s rodent model of neonatal HI. In addition, we have isolated hippocampal nuclei and quantified the percent good quality nuclei to provide an example of utilization of our novel injury scoring tool. Our novel injury scores correlated significantly with percent hippocampal and hemispheric tissue loss, cell survival/death markers, and percent good quality nuclei. Caspase-3 and Poly (ADP-ribose) polymerase-1 (PARP1) have been implicated in different cell death pathways in response to neonatal HI. Another gene, sirtuin1 (SIRT1), has been demonstrated to have neuroprotective and anti-apoptotic properties. To assess the correlation between the severity of injury and genes involved in cell survival/death, we analyzed caspase-3, PARP1, and SIRT1 mRNA expressions in hippocampi 3 days post-HI and sham surgery, using quantitative reverse transcription polymerase chain reaction. The ipsilateral (IL) hippocampal caspase-3 and SIRT1 mRNA expressions post-HI were significantly higher than sham IL hippocampi and positively correlated with the novel injury scores in both males and females. We detected a statistically significant sex difference in IL hippocampal caspase-3 mRNA expression with comparable injury scores between males and females with higher expression in females.

Immune checkpoint inhibitors (ICI) have improved outcomes for a variety of malignancies; however, many patients fail to benefit. While tumor-intrinsic mechanisms are likely involved in therapy resistance, it is unclear to what extent host genetic background influences response. To investigate this, we utilized the Diversity Outbred (DO) and Collaborative Cross (CC) mouse models. DO mice are an outbred stock generated by crossbreeding 8 inbred founder strains, and CC mice are recombinant inbred mice generated from the same 8 founders. We generated 207 DOB6F1 mice representing 48 DO dams and demonstrated that these mice reliably accept the C57BL/6-syngeneic B16F0 tumor and that host genetic background influences response to ICI. Genetic linkage analysis from 142 mice identified multiple regions including one within chromosome 13 that associated with therapeutic response. We utilized 6 CC strains bearing the positive (NZO) or negative (C57BL/6) driver genotype in this locus. We found that 2/3 of predicted responder CCB6F1 crosses show reproducible ICI response. The chromosome 13 locus contains the murine prolactin family, which is a known immunomodulating cytokine associated with various autoimmune disorders. To directly test whether prolactin influences ICI response rates, we implanted inbred C57BL/6 mice with subcutaneous slow-release prolactin pellets to induce mild hyperprolactinemia. Prolactin augmented ICI response against B16F0, with increased CD8 infiltration and 5/8 mice exhibiting slowed tumor growth relative to controls. This study highlights the role of host genetics in ICI response and supports the use of F1 crosses in the DO and CC mouse populations as powerful cancer immunotherapy models.One Sentence SummaryUsing germline genetic analysis in Diversity Outbred and Collaborative Cross models, we identify prolactin as a host-intrinsic regulator of response to combined immune checkpoint inhibitors.

The immune cytokine interleukin-12 (IL-12) is involved in cancer initiation and progression, autoimmunity, as well as graft versus host disease. The ability to monitor IL-12 via imaging may provide insight into various immune processes, including levels of antitumor immunity, inflammation, and infection due to its functions in immune signaling. Here, we report the development and preclinical evaluation of an antibody-based IL-12-specific positron emission tomography (PET) tracer. To mimic localized infection and stimulate IL-12 production, BALB/c mice were administered lipopolysaccharide (LPS) intramuscularly. [89Zr]Zr-DFO-αIL12 tracer was given one hour post LPS administration and PET images were taken after 5, 24, 48, and 72 hours. We observed significantly higher uptake in LPS-treated mice as compared to controls. Biodistribution of the tracer was evaluated in a separate cohort of mice, where tracer uptake was elevated in muscle, spleen, lymph nodes, and intestines after LPS administration. To evaluate the utility of [89Zr]Zr-DFO-αIL12 as an indicator of antigen presenting cell activation after cancer immunotherapy, we compared PET imaging with and without intratumoral delivery of oncolytic adenovirus expressing granulocyte-macrophage colony-stimulating factor (Adv/GM-CSF), which we have shown promotes anti-tumor immunity. BALB/c mice were inoculated orthotopically with the mouse mammary carcinoma line TUBO. Once TUBO tumors reached a volume of ~50 mm3, mice were treated with either three intratumoral injections of 108 PFU Adv/GM-CSF or vehicle control, given every other day. Upon the last dose, [89Zr]Zr-DFO-αIL12 was injected intravenously and 72 hours later all mice were imaged via PET. Tumor-specific uptake of [89Zr]Zr-DFO-αIL12 was higher in Adv/GM-CSF treated mice versus controls. Tissues were harvested after imaging, and elevated levels of macrophages and CD8+ Tc cells were detected in Adv/GM-CSF treated tumors by immunohistochemistry. We validated that IL-12 expression was induced after Adv/GM-CSF by qRT-PCR. Importantly, expression of genes activated by IL-12 (IFNγ, TNFα, and IL-18) were unaffected after IL-12 imaging relative to mice receiving an IgG control tracer, suggesting the tracer antibody does not significantly disrupt signaling. Our results indicate that targeting soluble cytokines such as IL-12 by PET imaging with antibody tracers may serve as a noninvasive method to evaluate the function of the immune milieu in situ.

Polyethylene Naphthalate (PEN) plastic scintillator has been identified as potential self-vetoing structural material in low-background physics experiments. Radio-pure scintillating components have been produced from PEN using injection compression molding technology. These low-background PEN components will be used as optically active holders to mount the Germanium detectors in the Legend-200 neutrinoless double beta decay experiment. In this paper, we present the measurement of the optical properties of these PEN components. The scintillation light emission spectrum, time constant, attenuation and bulk absorption length as well as light output and light yield are reported. In addition, the surface of these PEN components has been characterized and an estimation of the surface roughness is presented. The light output of the final Legend-200 detector holders has been measured and is reported. These measurements were used to estimate the self-vetoing efficiency of these holders.

There is an urgent need to reform the regulation of transgenic and genome-edited food animals. Now is the time to simplify regulatory safety guidelines based on science before it is too late to have these animals in place to meet societal needs in coming decades.

Blastocyst complementation combined with gene editing is an emerging approach in the field of regenerative medicine that could potentially solve the worldwide problem of organ shortages for transplantation. In theory, blastocyst complementation can generate fully functional human organs or tissues, grown within genetically engineered livestock animals. Targeted deletion of a specific gene(s) using gene editing to cause deficiencies in organ development can open a niche for human stem cells to occupy, thus generating human tissues. Within this review, we will focus on the pancreas, liver, heart, kidney, lung, and skeletal muscle, as well as cells of the immune and nervous systems. Within each of these organ systems, we identify and discuss (i) the common causes of organ failure; (ii) the current state of regenerative therapies; and (iii) the candidate genes to knockout and enable specific exogenous organ development via the use of blastocyst complementation. We also highlight some of the current barriers limiting the success of blastocyst complementation.

Genome editing therapies hold great promise for the cure of monogenic and other diseases; however, the application of nonviral gene delivery methods is limited by both a lack of fundamental knowledge of interactions of the gene-carrier in complex animals and biocompatibility. Herein, we characterize nonviral gene delivery vehicle formulations that are based on diblock polycations containing a hydrophilic and neutral glucose block chain extended with cationic secondary amines of three lengths, poly(methacrylamido glucopyranose- block-2-methylaminoethyl methacrylate) [P(MAG- b-MAEMt)-1, -2, -3]. These polymers were formulated with plasmid DNA to prepare polyelectrolyte complexes (polyplexes). In addition, two controls, P(EG- b-MAEMt) and P(MAEMt), were synthesized, formulated into polyplexes and the ex vivo hemocompatibility, or blood compatibility, and in vivo biodistribution of the formulations were compared to the glycopolymers. While both polymer structure and N/P (amine to phosphate) ratio were important factors affecting hemocompatibility, N/P ratio played a stronger role in determining polyplex biodistribution. P(EG- b-MAEMt) and P(MAEMt) lysed red blood cells at both high and low N/P formulations while P(MAG- b-MAEMt) did not significantly lyse cells at either formulation at short and medium polymer lengths. Conversely, P(MAG- b-MAEMt) did not affect coagulation at N/P = 5, but significantly delayed coagulation at N/P = 15. P(EG- b-MAEMt) and P(MAEMt) did not affect coagulation at either formulation. After polymer and pDNA cargo distribution was observed in vivo, P(EG- b-MAEMt) N/P = 5 and P(MAG- b-MAEMt) N/P = 5 both dissociated and deposited polymer in the liver, while pDNA cargo from P(MAG- b-MAEMt) N/P = 15 was found in the liver, lungs, and spleen. The contrast between P(MAG- b-MAEMt) at N/P = 5 and 15 demonstrates that polyplex stability in the blood can be improved with N/P ratio and potentially aid polyplex biodistribution through simply varying the formulation ratios.

Genetically modified food animals (GMFAs) are needed to address early the cumulative effects of livestock production on the environment, and to accommodate future food demands. In 2020 China and the USA, the world's two largest economies, embarked on regulatory reforms to boost the commercialization of such animals. However, gaining social acceptance of GMFAs for commercialization remains a global challenge. We propose a framework that focuses on social license for commercialization of GMFAs by defining four classes of improvement using precision genetics: (1) animals equivalent to natural variation to obtain the improved effect of cross-breeding (ENV); (2) animals with an inactivated gene that could occur via natural mutation (ENC−); (3) animals harboring a natural genetic sequence isolated from another species (ENC+); and (4) animals with synthetic sequences encoding novel genes (BNE). Our approach can guide regulators and the public to support orderly commercialization of GMFAs.

Immune checkpoint inhibitors (ICI) for cancer therapy have improved outcomes for a variety of malignancies, however many patients fail to benefit. To date, most pre-clinical studies investigating the tumor microenvironment (TME) have utilized different spontaneous or implanted tumor lines to separately investigate immunologically cold or hot TMEs. These models are often in different mouse strains, leading to confounding variables and a disconnect as to whether the tumor or the host is contributing to the observed immunological phenotype. To account for host diversity and reduce variation on the part of the tumor, we have developed immunotherapy models using genetically heterogeneous Diversity Outbred (DO) and recombinant inbred Collaborative Cross (CC) mice. We crossed DO mice with C57BL/6 (B6) to generate DOB6F1 mice that reliably accept B6-syngeneic B16F0 tumors after subcutaneous inoculation. DOB6F1 mice (n=142) treated with combined anti-PD1/anti-CTLA-4 ICI on days 3, 6, and 10 after inoculation exhibited a wide variation in tumor latency, up to a maximum of 65 days, with 19 mice never developing tumor. Quantitative Trait Locus analysis revealed multiple loci influencing response to ICI. We utilized this data to challenge 12 CCB6F1 strains selected based on predicted response where ICI outcomes range from non-responsive to near complete response. In addition, we show evidence that the DOB6F1 model recreates acquired resistance to ICI, with 9 mice having an extremely delayed tumor latency (>40 days). Melanin-free regions were observed in 3/9 of these tumors, suggesting tumor editing. Acquired resistance was also noted 3/10 ICI-treated CC051B6F1 mice. Whole transcriptomic analysis compared tumors from non-responder versus delayed latency DOB6F1 mice. Despite implantation within genetically heterogeneous mice, transcriptomic profiles from late-onset tumors cluster together. Gene Set Enrichment Analysis identified immune processes, with antigen processing and presentation as the most significantly dysregulated gene set. Many of the upregulated genes in late-onset tumors are driven by IFNγ, suggesting IFNγ signaling may contribute to immune escape. We tested this directly by culturing B16 cells with IFNγ prior to inoculation. Short exposure of B16 to IFNγ results in aggressive growth regardless of treatment, but long exposure increases tumor immunogenicity and responsiveness to ICI in inbred B6 mice. Experiments in ICI-responsive CT26-bearing BALB/c mice indicate IFNγ signaling contributes to ICI response, as demonstrated by increased tumor burden after a single 250 µg dose of neutralizing anti-IFNγ antibody concurrent with ICI treatment. Collectively, our DO and CC F1 models allow for reduced tumor variation with a focus on the host and associated TME, and we show differential roles of IFNγ in response to ICI based on the timing of IFNγ exposure. Citation Format: Justin B. Hackett, James Glassbrook, Nasrin Movahhedin, Madeline Bross, Alicia Kevelin, Maria Múniz, Heather Gibson. Genetically heterogeneous mouse models identify IFNg signaling as a shared signature of acquired resistance to immune checkpoint inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB065.

PEN is an industrial polyester plastic which has become interesting for the physics community as a new type of plastic scintillator. PEN scintillates in the blue regime, which is ideal for most photosensor devices. In addition, PEN has excellent mechanical properties and very good radiopurity has been achieved. Thus, it is an ideal candidate for active structural components in low-background experiments. One possible application are holders for germanium detectors operating in cryogenic liquids (LAr, LN2). Such structures can help to reject surface and external backgrounds, boosting the sensitivity of experiments. In this contribution, the R\&D on PEN is outlined and an evaluation of the first production of PEN structures for the LEGEND-200 experiment is reported., Conference ICHEP2020

Reactor neutrino experiments have seen major improvements in precision in recent years. With the experimental uncertainties becoming lower than those from theory, carefully considering all sources of ν ¯ e is important when making theoretical predictions. One source of ν ¯ e that is often neglected arises from the irradiation of the nonfuel materials in reactors. The ν ¯ e rates and energies from these sources vary widely based on the reactor type, configuration, and sampling stage during the reactor cycle and have to be carefully considered for each experiment independently. In this article, we present a formalism for selecting the possible ν ¯ e sources arising from the neutron captures on reactor and target materials. We apply this formalism to the High Flux Isotope Reactor (HFIR) at Oak Ridge National Laboratory, the ν ¯ e source for the the Precision Reactor Oscillation and Spectrum Measurement (PROSPECT) experiment. Overall, we observe that the nonfuel ν ¯ e contributions from HFIR to PROSPECT amount to 1% above the inverse beta decay threshold with a maximum contribution of 9% in the 1.8-2.0 MeV range. Nonfuel contributions can be particularly high for research reactors like HFIR because of the choice of structural and reflector material in addition to the intentional irradiation of target material for isotope production. We show that typical commercial pressurized water reactors fueled with low-enriched uranium will have significantly smaller nonfuel ν ¯ e contribution.

Polyethylene naphthalate (PEN) is an industrial plastic which is interesting to the physics community as a wavelength-shifting scintillator. Recently, PEN structures with excellent radiopurity have been successfully produced using injection compression molding technology. This opens the possibility for the usage of optically active structural components with wavelength shifting capabilities in low-background experiments. Thus, PEN holders will be used to mount the germanium detectors in the LEGEND-200 experiment. In this contribution the ongoing R&D on PEN is outlined with a focus on the evaluation of its optical properties. In addition, the ongoing efforts for further application of PEN in the LEGEND-1000 experiment are presented.

The Sleeping Beauty transposon system has been extensively tested for integration of reporter and therapeutic genes in vitro and in vivo in mice. Dogs were used as a large animal model for human therapy and minimally invasive infusion of DNA solutions. DNA solutions were delivered into the entire liver or the left side of the liver using balloon catheters for temporary occlusion of venous outflow. A peak intravascular pressure between 80 and 140 mmHg supported sufficient DNA delivery in dog liver for detection of secretable reporter proteins. Secretable reporters allowed monitoring of the time course of gene products detectable in the circulation postinfusion. Canine secreted alkaline phosphatase reporter protein levels were measured in plasma, with expression detectable for up to 6 weeks, while expression of canine erythropoietin was detectable for 7-10 days. All animals exhibited a transient increase in blood transaminases that normalized within 10 days; otherwise the treated animals were clinically normal. These results demonstrate the utility of a secreted reporter protein for real-time monitoring of gene expression in the liver in a large animal model but highlight the need for improved delivery in target tissues to support integration and long-term expression of Sleeping Beauty transposons.

The PICO Collaboration wishes to thank SNOLAB and its staff for support through underground space, logistical and technical services. SNOLAB operations are supported by the Canada Foundation for Innovation and the Province of Ontario Ministry of Research and Innovation, with underground access provided by Vale at the Creighton mine site. We wish to acknowledge the support of the Natural Sciences and Engineering Research Council of Canada (NSERC) and the Canada Foundation for Innovation (CFI) for funding. We acknowledge the support from National Science Foundation (NSF) (Grants No. 0919526, No. 1506337, No. 1242637, No. 1205987, and No. 1806722). We acknowledge that this work is supported by the U.S. Department of Energy (DOE) Office of Science, Office of High Energy Physics (under Award No. DE-SC-0012161), by DGAPA-UNAM (PAPIIT No. IA100118) and Consejo Nacional de Ciencia y Tecnologia (CONACyT, M?exico, Grants No. 252167 and No. A1-S-8960), by the Department of Atomic Energy (DAE), Government of India, under the Centre for AstroParticle Physics II project (CAPP-II) at the Saha Institute of Nuclear Physics (SINP), European Regional Development Fund?Project ?Engineering Applications of Microworld Physics? (Project No. CZ.02.1.01/0.0/0.0/ 16_019/0000766), and the Spanish Ministerio de Ciencia, Innovacion y Universidades (Red Consolider MultiDark, Grant No. FPA2017-90566-REDC). This work is partially supported by the Kavli Institute for Cosmological Physics at the University of Chicago through NSF Grant No. 1125897, and an endowment from the Kavli Foundation and its founder Fred Kavli. We also wish to acknowledge the support from Fermi National Accelerator Laboratory under Contract No. DE-AC02-07CH11359, and Pacific Northwest National Laboratory, which is operated by Battelle for the U.S. Department of Energy under Contract No. DE-AC05- 76RL01830. We also thank Compute Canada [75] and the Center for Advanced Computing, ACENET, Calcul Qu?ebec, Compute Ontario, and WestGrid for computational support.

The Precision Reactor Oscillation and Spectrum (PROSPECT) Experiment is a reactor neutrino experiment designed to search for sterile neutrinos with a mass on the order of 1 eV/c$^2$ and to measure the spectrum of electron antineutrinos from a highly-enriched $^{235}$U nuclear reactor. The PROSPECT detector consists of an 11 by 14 array of optical segments in $^{6}$Li-loaded liquid scintillator at the High Flux Isotope Reactor in Oak Ridge National Laboratory. Antineutrino events are identified via inverse beta decay and read out by photomultiplier tubes located at the ends of each segment. The detector response is characterized using a radioactive source calibration system. This paper describes the design, operation, and performance of the PROSPECT source calibration system.

Although theSleeping Beauty(SB) transposon is the most validated DNA transposon used as a gene delivery vehicle in vertebrates, many details of the excision and integration steps in the transposition process are unclear. We have probed in detail the products of the excision step and apparent selective integration of a subset of those products during transposition. The standard model of SB transposase-mediated transposition includes symmetrical cleavages at both ends of the transposon for excision and re-integration in another DNA sequence. In our analysis of excised transposon fragments (ETFs), we found evidence for the requirement of certain flanking sequences for efficient cleavage and a significant rate of asymmetrical cleavage during the excision process that generates multiple ETFs. Our results suggest that the cleavage step by SB transposase is not as precise as indicated in most models. Repair of the donor ends can produce eight footprint sequences (TACTGTA, TACAGTA, TACATA, TACGTA, TATGTA, TACTA, TAGTA and TATA). Our data also suggest that mismatch repair (MMR) is not an essential requirement for footprint formation. Among the twenty liberated ETFs, only eight appear to effectively re-integrate into TA sites distributed across the genome, supporting earlier findings of unequal rates of excision and reintegration during SB transposition. These findings may be important in considerations of efficiency of SB transposon remobilization, selection of TA integration sites and detection of SB excision and integration loci, all of which may be important in human gene therapy.

Summary Background & aims Cancer patients frequently experience weight loss, with negative consequences for functionality and prognosis. The extent to which muscle atrophy contributes to weight loss, however, is not clear, as few studies have directly measured muscle fiber morphology in cancer patients. Methods Whole body and regional tissue composition were measured, along with the cross-sectional area (CSA) and fiber type of mechanically-isolated, single muscle fibers, in 19 cancer patients (8 with a history of weight loss, 11 weight-stable) and 15 non-diseased controls. Results Whole body fat mass was reduced in cancer patients with a history of weight loss, but no differences in whole body or leg fat-free mass were apparent. In contrast, reductions (∼20%) in single muscle fiber CSA were found in both slow-twitch, myosin heavy chain (MHC) I and fast-twitch, MHC IIA fibers in both weight-stable patients and those with a history of weight loss. Fiber type distribution showed a shift towards a fast-twitch phenotype compared to controls, which may preserve muscle function in cancer patients despite atrophy, as positive relationships were found between the fractions of hybrid MHC IIAX and I/IIA fibers and 6-min walk performance. Conclusions Our results suggest that, although not apparent from whole body or regional measurements, cancer is associated with reduced skeletal muscle fiber size independent of weight loss history and a shift towards fast-twitch fibers, phenotypes that resemble adaptations to muscle disuse.

Precision genetics and breeding have the potential to meet the agricultural needs and goals of the world in the 21st century. These needs include increasing the efficiency of production of animals and improving their products with minimal impact on the environment. The USA is the major innovator in genomic science and the acknowledged leader in formulating policies to regulate genetic applications in medicine and agriculture. However, governments worldwide have been exceedingly reluctant to support the introduction of genetically modified (GM) animals into agriculture. Regulatory policies have stagnated due to legal guidelines that could not anticipate the needs and solutions that are evident today. This must change if we are to maintain planetary integrity. I propose a new, market-based regulatory model for GM livestock that has both a strong scientific foundation and has worked for 10000 years. The model is similar to that for information technology in which specific algorithms drive computer and cell phone applications. Genome engineers write genetic algorithms that drive the traits in biological organisms. Accordingly, GM products should be viewed in terms of their use and public benefit rather than by limitations to the genetic programing coming from a few highly vocal groups. Genetic algorithms (Genapps) of the 21st century will include not only introduction of synthetic genes, but also complete natural and synthetic biochemical pathways to produce agricultural products that are maximally efficient, healthy to humans and animals, and sustainable in an era of changing climates while avoiding environmental degradation.

Antiemetics are commonly prescribed during the treatment of canine parvoviral enteritis. This blinded, randomized prospective study compared the quality of clinical recovery and duration of hospitalization in canine parvoviral dogs receiving either maropitant (1 mg/kg [0.45 mg/lb] IV q 24 hr, n = 11) or ondansetron (0.5 mg/kg [0.23 mg/lb] IV q 8 hr, n = 11). All dogs were treated with IV fluids, cefoxitin, and enteral nutrition. Frequency of vomiting and pain scoring were recorded twice daily. Rescue analgesics and antiemetics were administered as dictated by specific pain and vomiting criteria. Clinical severity scoring, body weight, and caloric intake were monitored daily. When comparing dogs receiving maropitant versus ondansetron, respectively, there were no differences in duration of hospitalization (3.36 ± 0.56 versus 2.73 ± 0.38 days, P = .36), requirement of rescue antiemetic (3/11 versus 5/11 dogs, P = .66), duration of vomiting (5 versus 4 days, P = .65), or days to voluntary food intake (2 versus 1.5 days, P = 1.0). Results of this study suggest that maropitant and ondansetron are equally effective in controlling clinical signs associated with parvoviral enteritis.

This paper describes the design and performance of a 50 liter, two-segment $^{6}$Li-loaded liquid scintillator detector that was designed and operated as prototype for the PROSPECT (Precision Reactor Oscillation and Spectrum) Experiment. The two-segment detector was constructed according to the design specifications of the experiment. It features low-mass optical separators, an integrated source and optical calibration system, and materials that are compatible with the $^{6}$Li-doped scintillator developed by PROSPECT. We demonstrate a high light collection of 850$\pm$20 PE/MeV, an energy resolution of $\sigma$ = 4.0$\pm$0.2% at 1 MeV, and efficient pulse-shape discrimination of low $dE/dx$ (electronic recoil) and high $dE/dx$ (nuclear recoil) energy depositions. An effective scintillation attenuation length of 85$\pm$3 cm is measured in each segment. The 0.1% by mass concentration of $^{6}$Li in the scintillator results in a measured neutron capture time of $\tau$ = 42.8$\pm$0.2 $\mu s$. The long-term stability of the scintillator is also discussed. The detector response meets the criteria necessary for achieving the PROSPECT physics goals and demonstrates features that may find application in fast neutron detection., Comment: 16 pages, 13 figures; minor edits to design detail and references

The Precision Reactor Oscillation and Spectrum Experiment, PROSPECT, is designed to make both a precise measurement of the antineutrino spectrum from a highly-enriched uranium reactor and to probe eV-scale sterile neutrinos by searching for neutrino oscillations over meter-long baselines. PROSPECT utilizes a segmented $^6$Li-doped liquid scintillator detector for both efficient detection of reactor antineutrinos through the inverse beta decay reaction and excellent background discrimination. PROSPECT is a movable 4-ton antineutrino detector covering distances of 7m to 13m from the High Flux Isotope Reactor core. It will probe the best-fit point of the $\bar\nu_e$ disappearance experiments at 4$\sigma$ in 1 year and the favored regions of the sterile neutrino parameter space at more than 3$\sigma$ in 3 years. PROSPECT will test the origin of spectral deviations observed in recent $\theta_{13}$ experiments, search for sterile neutrinos, and address the hypothesis of sterile neutrinos as an explanation of the reactor anomaly. This paper describes the design, construction, and commissioning of PROSPECT and reports first data characterizing the performance of the PROSPECT antineutrino detector., Comment: 30 pages, 33 figures; updated with journal revision and reference

The development and thorough characterization of nonviral delivery agents for nucleic acid and genome editing therapies are of high interest to the field of nanomedicine. Indeed, this vehicle class offers the ability to tune chemical architecture/biological activity and readily package nucleic acids of various sizes and morphologies for a variety of applications. Herein, we present the synthesis and characterization of a class of trehalose-based block copolycations designed to stabilize polyplex formulations for lyophilization and in vivo administration. A 6-methacrylamido-6-deoxy trehalose (MAT) monomer was synthesized from trehalose and polymerized via reversible addition–fragmentation chain transfer (RAFT) polymerization to yield pMAT43. The pMAT43 macro-chain transfer agent was then chain-extended with aminoethylmethacrylamide (AEMA) to yield three different pMAT-b-AEMA cationic-block copolymers, pMAT-b-AEMA-1 (21 AEMA repeats), -2 (44 AEMA repeats), and -3 (57 AEMA repeats). These polymers along with a series of controls were used to form polyplexes with plasmids encoding firefly luciferase behind a strong ubiquitous promoter. The trehalose-coated polyplexes were characterized in detail and found to be resistant to colloidal aggregation in culture media containing salt and serum. The trehalose-polyplexes also retained colloidal stability and promoted high gene expression following lyophilization and reconstitution. Cytotoxicity, cellular uptake, and transfection ability were assessed in vitro using both human glioblastoma (U87) and human liver carcinoma (HepG2) cell lines wherein pMAT-b-AEMA-2 was found to have the optimal combination of high gene expression and low toxicity. pMAT-b-AEMA-2 polyplexes were evaluated in mice via slow tail vein infusion. The vehicle displayed minimal toxicity and discouraged nonspecific internalization in the liver, kidney, spleen, and lungs as determined by quantitative polymerase chain reaction (qPCR) and fluorescence imaging experiments. Hydrodynamic infusion of the polyplexes, however, led to very specific localization of the polyplexes to the mouse liver and promoted excellent gene expression in vivo.

In integrated assessment models (IAMs) economic activity leads to global warming, which causes future economic costs. However, typical IAMs do not explicitly represent the role of natural capital. In this paper, the DICE model by Nordhaus (2008) is expanded with a natural capital variable that is affected both by climate change and by depletive effects of economic activity. Due to a synergy between the two effects, the optimal policy of the expanded model features more and earlier abatement of CO2 emissions than DICE. Interestingly, the policy implications are different from what follows if one tries to capture the depletive effects on natural capital by simply reducing factor productivity growth in DICE. Acknowledging considerable uncertainty, simulations show that climate- and savings rate policies from the expanded model are more robust in the long term than policies that do not consider non-climatic depletion effects on natural capital.

Most lysosomal storage disorders affect the nervous system as well as other tissues and organs of the body. Previously, the complexities of these diseases, particularly in treating neurologic abnormalities, were too great to surmount. However, based on recent developments there are realistic expectations that effective therapies are coming soon. Gene therapy offers the possibility of affordable, comprehensive treatment associated with these diseases currently not provided by standards of care. With a focus on correction of neurologic disease by systemic gene therapy of mucopolysaccharidoses types I and IIIA, we review some of the major recent advances in viral and non-viral vectors, methods of their delivery and strategies leading to correction of both the nervous and somatic tissues as well as evaluation of functional correction of neurologic manifestations in animal models. We discuss two questions: what systemic gene therapy strategies work best for correction of both somatic and neurologic abnormalities in a lysosomal storage disorder and is there evidence that targeting peripheral tissues (e.g., in the liver) has a future for ameliorating neurologic disease in patients?