The effect of TG2-inhibitory monoclonal antibody zampilimab on tissue fibrosis in human in vitro and primate in vivo models of chronic kidney disease.

Fibrotic remodeling is the primary driver of functional loss in chronic kidney disease, with no specific anti-fibrotic agent available for clinical use. Transglutaminase 2 (TG2), a wound response enzyme that irreversibly crosslinks extracellular matrix proteins causing dysregulation of extracellular matrix turnover, is a well-characterized anti-fibrotic target in the kidney. We describe the humanization and characterization of two anti-TG2 monoclonal antibodies (zampilimab [hDC1/UCB7858] and BB7) that inhibit crosslinking by TG2 in human in vitro and rabbit/cynomolgus monkey in vivo models of chronic kidney disease. Determination of zampilimab half-maximal inhibitory concentration (IC50) against recombinant human TG2 was undertaken using the KxD assay and determination of dissociation constant (Kd) by surface plasmon resonance. Efficacy in vitro was established using a primary human renal epithelial cell model of tubulointerstitial fibrosis, to assess mature deposited extracellular matrix proteins. Proof of concept in vivo used a cynomolgus monkey unilateral ureteral obstruction model of chronic kidney disease. Zampilimab inhibited TG2 crosslinking transamidation activity with an IC50 of 0.25 nM and Kd of <50 pM. In cell culture, zampilimab inhibited extracellular TG2 activity (IC50 119 nM) and dramatically reduced transforming growth factor-ß1-driven accumulation of multiple extracellular matrix proteins including collagens I, III, IV, V, and fibronectin. Intravenous administration of BB7 in rabbits resulted in a 68% reduction in fibrotic index at Day 25 post-unilateral ureteral obstruction. Weekly intravenous administration of zampilimab in cynomolgus monkeys with unilateral ureteral obstruction reduced fibrosis at 4 weeks by >50%, with no safety signals. Our data support the clinical investigation of zampilimab for the treatment of kidney fibrosis.

Temporal dynamics of fecal microbiota community succession in broiler chickens, calves, and piglets under aerobic exposure.

Researchers have extensively studied the effect of oxygen on the growth and survival of bacteria. However, the impact of oxygen on bacterial community structure, particularly its ability to select for taxa within the context of a complex microbial community, is still unclear. In a 21-day microcosm experiment, we investigated the effect of aerobic exposure on the fecal community structure and succession pattern in broiler, calf, and piglet feces (n = 10 for each feces type). Bacterial diversity decreased and community structure changed rapidly in the broiler microbiome (P < 0.001), while the fecal community of calves and piglets, which have higher initial diversity, was stable after initial exposure but decreased in diversity after 3 days (P < 0.001). The response to aerobic exposure was host animal specific, but in all three animals, the change in community structure was driven by a decrease in anaerobic species, primarily belonging to Firmicutes and Bacteroidetes (except in broilers where Bacteroidetes increased), along with an increase in aerobic species belonging to Proteobacteria and Actinobacteria. Using random forest regression, we identified microbial features that predict aerobic exposure. In all three animals, host-beneficial Prevotella-related ASVs decreased after exposure, while ASVs belonging to Acinetobacter, Corynbacterium, and Tissierella were increased. The decrease of Prevotella was rapid in broilers but delayed in calves and piglets. Knowing when these pathobionts increase in abundance after aerobic exposure could inform farm sanitation practices and could be important in designing animal experiments that modulate the microbiome.IMPORTANCEThe fecal microbial community is contained within a dynamic ecosystem of interacting microbes that varies in biotic and abiotic components across different animal species. Although oxygen affects bacterial growth, its specific impact on the structure of complex communities, such as those found in feces, and how these effects vary between different animal species are poorly understood. In this study, we demonstrate that the effect of aerobic exposure on the fecal microbiota was host-animal-specific, primarily driven by a decrease in Firmicutes and Bacteroidetes, but accompanied by an increase in Actinobacteria, Proteobacteria, and other pathobionts. Interestingly, we observed that more complex communities from pig and cattle exhibited initial resilience, while a less diverse community from broilers displayed a rapid response to aerobic exposure. Our findings offer insights that can inform farm sanitation practices, as well as experimental design, sample collection, and processing protocols for microbiome studies across various animal species.

Hohlraum fields with monoenergetic proton radiography at OMEGA.

A more complete understanding of laser-driven hohlraum plasmas is critical for the continued development and improvement of ICF experiments. In these hohlraums, self-generated electric and magnetic fields can play an important role in modifying plasma properties such as heat transport; however, the strength and distribution of electromagnetic fields in such hohlraums remain largely uncertain. To explore this question, we conducted experiments at the OMEGA laser facility, using monoenergetic proton radiography to probe laser-driven vacuum hohlraums. We then utilized reconstructive methods to recover information about proton deflections. To interpret these reconstructions, a new technique for detangling the contributions of electric and magnetic fields to proton deflections was developed. This work was supported in part by the U.S. Department of Energy, the National Laser Users' Facility, and the Laboratory for Laser Energetics.

Persistence of vaccine origin Salmonella Typhimurium through the poultry production continuum, and development of a rapid typing scheme for their differentiation from wild type field isolates.

Salmonella enterica serovar Typhimurium is one of the top Salmonella serovars annually linked to poultry production and corresponding human illnesses. Because of this, vaccination of commercial poultry against Salmonella Typhimurium has been a focal point in recent years. There are several commercially available Salmonella Typhimurium vaccines available for use in poultry production. Among these are modified live vaccines, including Poulvac ST (Zoetis), Megan Egg (AviPro), and Megan Vac 1 (AviPro). In this study, analyses of 27 field isolates of Salmonella Typhimurium from poultry sources indicated evidence for the persistence of some vaccine-origin strains through the commercial production cycle. Further analyses of 26,812 database isolates indicated vaccine-origin isolates are persisting frequently through processing, are present on retail meat products, and are even occasionally found in human patients. A novel polymerase chain reaction (PCR) was created and validated which enables simultaneous identification of Salmonella enterica sp., the Salmonella Typhimurium serovar, and differentiation of wild type Salmonella Typhimurium from live attenuated vaccines involving mutations in the cya/crp or aroA genes. The PCR was developed considering whole genome differences between the vaccines and wild type field isolates and was validated using different field isolates and recovered vaccine strains. This method enables poultry producers to rapidly determine if recovered field isolates have a vaccine origin.

Development of Opioid Use Disorder After Breast Reconstruction: Effects of Nicotine Exposure.

INTRODUCTION: After undergoing breast reconstructive surgery, patients are typically prescribed opioids. Smoking tobacco increases rate of opioid metabolism and is associated with development of opioid use disorder (OUD). The aim of this study was to determine whether patients who smoke have an increased risk of OUD after breast reconstructive surgery. Given that OUD is a known risk factor for injection drug use and intravenous drug use increases risk of acquiring blood-borne diseases including human immunodeficiency virus (HIV) and hepatitis, the secondary aim was to determine if these patients are also at increased risk of acquiring these communicable diseases associated with OUD. METHODS: A retrospective analysis was conducted using TriNetX, a multi-institutional deidentified database. Individuals included underwent a breast reconstructive surgery and received postoperative opioid treatment. The exposed group included patients who smoke. The control group did not smoke. Risk of developing OUD, hepatitis B virus (HBV), hepatitis C virus (HCV), and HIV from 12 to 36 months after surgery was compared between groups. Patients with preexisting OUD or associated diseases were excluded. Cohorts were matched to control for confounding factors including age, sex, race, mental health history, and concomitant substance use. RESULTS: There were 8648 patients included in the analysis. After matching, 4324 patients comprised the exposure group, and 4324 patients remained in the control group. Preoperative smoking was significantly associated with increased risk of OUD at 12, 24, and 36 months after breast reconstruction (36 months: odds ratio [OR], 2.722; confidence interval [CI], 2.268-6.375). Smoking was also associated with increased risk of HIV and HCV at all time points after surgery (36 months HIV: OR, 2.614; CI, 1.977-3.458; 36 months HCV: OR, 3.718; CI, 2.268-6.375) and increased risk of HBV beginning at 24 months after surgery (36 months HBV: OR, 2.722; CI, 1.502-4.935). CONCLUSIONS: Individuals who smoke have an increased risk of developing OUD, HIV, HCV, and HBV after breast reconstructive surgery. This risk persists for at least 3 years after surgery. Additional research and clinical interventions focusing on early identification of OUD, prevention efforts, and harm reduction strategies for patients who smoke or have nicotine dependence undergoing breast reconstruction are warranted.

Assessing the Risk of Antimicrobial Resistant Enterococcal Infections in Humans Due to Bacitracin Usage in Poultry.

Bacitracin is an antimicrobial used in the feed or water of poultry in the U.S. for the prevention, treatment, and control of clostridial diseases such as necrotic enteritis. Concern has been raised that bacitracin can select for antimicrobial-resistant bacteria that can be transmitted to humans and subsequently cause disease that is more difficult to treat because of the resistance. The objective of the present study was to perform a quantitative risk assessment (QRA) to estimate the potential risk in the U.S. of human infection with antimicrobial-resistant Enterococcus faecalis and E. faecium derived from chicken and turkey products as a result of bacitracin usage in U.S. poultry. The modeling approach estimated the annual number of healthcare-associated enterococcal infections in the U.S. that would be resistant to antimicrobial therapy and that would be derived from poultry sources because of bacitracin use in poultry. Parameter estimates were developed to be "maximum risk" to overestimate the risk to humans. While approximately 60% of E. faecalis and E. faecium derived from poultry were predicted to possess bacitracin resistance based on the presence of the bcrABDR gene locus, very few human-derived isolates possessed this trait. Furthermore, no vancomycin or linezolid-resistant strains of E. faecalis or E. faecium were detected in poultry sources between the years 2002 and 2019. The model estimated the number of antimicrobial-resistant E. faecalis and E. faecium cases per year that might resist therapy due to bacitracin use in poultry as 0.86 and 0.14, respectively, which translates to an annual risk estimate for E. faecalis of less than 1 in 350 million and for E. faecium of less than 1 in 2 billion for members of the U.S. population. Even with the use of risk-maximizing assumptions, the results indicate that there is a high probability that the use of bacitracin according to label instructions in U.S. poultry presents a negligible risk to human health.

Efficacy of a novel multi-enzyme feed additive on growth performance, nutrient digestibility, and gut microbiome of weanling pigs fed corn-wheat or wheat-barley-based diet.

One-hundred-and-ninety-two weanling pigs (6.7 kg body weight) were used to evaluate the impact of a carbohydrases-protease enzyme complex (CPEC) on growth performance, nutrient digestibility, and gut microbiome. Pigs were assigned to one of the four dietary treatments for 42 d according to a 2 × 2 factorial arrangement of diet type (low fiber [LF] or high fiber [HF]) and CPEC supplementation (0 or 170 mg/kg diet). The LF diet was prepared as corn-wheat-based diet while the HF diet was wheat-barley-based and contained wheat middlings and canola meal. Each dietary treatment consisted of 12 replicate pens (six replicates per gender) and four pigs per replicate pen. Over the 42-d period, there was no interaction between diet type and CPEC supplementation on growth performance indices of pigs. Dietary addition of CPEC improved (P < 0.05) the body weight of pigs at days 28 and 42 and the gain-to-feed ratio of pigs from days 0 to 14. During the entire experimental period, dietary CPEC supplementation improved (P < 0.05) the average daily gain and gain-to-feed ratio of pigs. There were interactions between diet type and CPEC supplementation on apparent total tract digestibility (ATTD) of dry matter (DM; P < 0.01), gross energy (GE; P < 0.01), and neutral detergent fiber (NDF; P < 0.05) at d 42. Dietary CPEC addition improved (P < 0.05) ATTD of DM, GE, and NDF in the HF diets. At day 43, dietary CPEC addition resulted in improved (P < 0.05) apparent ileal digestibility (AID) of NDF and interactions (P < 0.05) between diet type and CPEC supplementation on AID of DM and crude fiber. Alpha diversity indices including phylogenetic diversity and observed amplicon sequence variants of fecal microbiome increased (P < 0.05) by the addition of CPEC to the HF diets on day 42. An interaction (P < 0.05) between diet type and CPEC addition on Bray-Curtis dissimilarity index and Unweighted UniFrac distances was observed on day 42. In conclusion, CPEC improved weanling pig performance and feed efficiency, especially in wheat-barley diets, while dietary fiber composition had a more significant impact on fecal microbial communities than CPEC administration. The results of this study underscores carbohydrase's potential to boost pig performance without major microbiome changes.

There is a pressing need to enhance livestock production efficiency to meet the growing global demand for meat. Carbohydrases and proteases are enzymes typically added to swine diets to improve nutrient utilization, leading to better growth rates and feed efficiency. This ultimately contributes to sustainable and economically viable pig farming. However, more research is required to better understand how carbohydrases and proteases interact with different diet types to optimize dietary formulations, and how this may influence gut microbiome composition. In this study, 192 weaner pigs (~7 kg) were assigned to a low-fiber diet or a high-fiber diet. Each diet type was with or without a carbohydrases and protease multi-enzyme supplementation. The results showed that adding a multi-enzyme combination to the pigs' diet significantly improved the pig's performance, regardless of diet type. Improvement in nutrient digestibility was more pronounced in pigs fed the high-fiber diet and that dietary fiber had a greater influence on the composition of fecal microbes. In essence, the study demonstrates that the multi-enzyme can boost pig growth and feed efficiency in diets with varying fiber complexity without causing significant changes in their gut microbiome.

Method to derive the infrared complex refractive indices n(λ) and k(λ) for organic solids from KBr pellet absorption measurements.

Obtaining the complex refractive index vectors n(ν~) and k(ν~) allows calculation of the (infrared) reflectance spectrum that is obtained from a solid in any of its many morphological forms. We report an adaptation to the KBr pellet technique using two gravimetric dilutions to derive quantitative n(ν~)/k(ν~) for dozens of powders with greater repeatability. The optical constants of bisphenol A and sucrose are compared to those derived by other methods, particularly for powdered materials. The variability of the k values for bisphenol A was examined by 10 individual measurements, showing an average coefficient of variation for k peak heights of 5.6%. Though no established standards exist, the pellet-derived k peak values of bisphenol A differ by 11% and 31% from their single-angle- and ellipsometry-derived values, respectively. These values provide an initial estimate of the precision and accuracy of complex refractive indices that can be derived using this method. Limitations and advantages of the method are discussed, the salient advantage being a more rapid method to derive n/k for those species that do not readily form crystals or specular pellets.

Combination of autochthonous Lactobacillus strains and trans-Cinnamaldehyde in water reduces Salmonella Heidelberg in turkey poults.

Reducing the colonization of Salmonella in turkeys is critical to mitigating the risk of its contamination at later stages of production. Given the increased susceptibility of newly hatched poults to Salmonella colonization, it is crucial to implement interventions that target potential transmission routes, including drinking water. As no individual intervention explored to date is known to eliminate Salmonella, the United States Department of Agriculture-Food Safety Inspection Service (USDA-FSIS) recommends employing multiple hurdles to achieve a more meaningful reduction and minimize the potential emergence of resistance. Probiotics and plant-derived antimicrobials (PDAs) have demonstrated efficacy as interventions against Salmonella in poultry. Therefore, this study aimed to investigate the use of turkey-derived Lactobacillus probiotics (LB; a mixture of Lactobacillus salivarius UMNPBX2 and L. ingluviei UMNPBX19 isolated from turkey ileum) and a PDA, trans-cinnamaldehyde (TC), alone and in combination (CO), against S. Heidelberg in turkey drinking water and poults. The presence of 5% nutrient broth or cecal contents as contaminants in water resulted in S. Heidelberg growth. TC eliminated S. Heidelberg, regardless of the contaminants present. In contrast, the cecal contents led to increased survival of Lactobacillus in the CO group. Unlike TC, LB was most effective against S. Heidelberg when the nutrient broth was present, suggesting the role of secondary metabolites in its mechanism of action. In the experiments with poults, individual TC and LB supplementation reduced cecal S. Heidelberg in challenged poults by 1.2- and 1.7-log10 colony-forming units (CFU)/g cecal contents, respectively. Their combination yielded an additive effect, reducing S. Heidelberg by 2.7 log10 CFU/g of cecal contents compared to the control (p ≤ 0.05). However, the impact of TC and LB on the translocation of S. Heidelberg to the liver was more significant than CO. TC and LB are effective preharvest interventions against S. Heidelberg in poultry production. Nonetheless, further investigations are needed to determine the optimum application method and its efficacy in adult turkeys.

Neoadjuvant chemotherapy for high-grade serous ovarian cancer: radiologic-pathologic correlation of response assessment and predictors of progression.

PURPOSE: Neoadjuvant chemotherapy is often administered for high-grade serous ovarian carcinoma (HGSC) prior to cytoreductive surgery. We evaluated treatment response by CT (simplified peritoneal carcinomatosis index [S-PCI]), pathology (chemotherapy response score [CRS]), laboratory markers (serum CA-125), and surgical outcomes, to identify predictors of disease-free survival. METHODS: For this retrospective, HIPAA-compliant, IRB-approved study, we identified 396 women with HGSC receiving neoadjuvant chemotherapy between 2010 and 2019. Two hundred and ninety-nine patients were excluded (surgery not performed; imaging/pathology unavailable). Pre- and post-treatment abdominopelvic CTs were assigned CT S-PCI scores 0-24 (higher score indicating more tumor). Specimens were assigned CRS of 1-3 (minimal to complete response). Clinical data were obtained via chart review. Univariate, multivariate, and survival analyses were performed. RESULTS: Ninety-seven women were studied, with mean age of 65 years ± 10. Interreader agreement was good to excellent for CT S-PCI scores (ICC 0.64-0.77). Despite a significant decrease in CT S-PCI scores after treatment (p < 0.001), mean decrease in CT S-PCI did not differ significantly among CRS categories (p = 0.20) or between patients who were optimally versus suboptimally debulked (p = 0.29). In a survival analysis, lower CRS (more viable tumor) was associated with shorter time to progression (p < 0.001). A joint Cox proportional-hazard models showed that only residual pathologic disease (CRS 1/2) (HR 4.19; p < 0.001) and change in CA-125 (HR 1.79; p = 0.01) predicted progression. CONCLUSION: HGSC response to neoadjuvant therapy by CT S-PCI did not predict pathologic CRS score, optimal debulking, or progression, revealing discordance between imaging, pathologic, biochemical, and surgical assessments of tumor response.

The Impact of Early-Life Cecal Microbiota Transplantation on Social Stress and Injurious Behaviors in Egg-Laying Chickens.

Injurious behaviors (i.e., aggressive pecking, feather pecking, and cannibalism) in laying hens are a critical issue facing the egg industry due to increased social stress and related health and welfare issues as well as economic losses. In humans, stress-induced dysbiosis increases gut permeability, releasing various neuroactive factors, causing neuroinflammation and related neuropsychiatric disorders via the microbiota-gut-brain axis, and consequently increasing the frequency and intensity of aggression and violent behaviors. Restoration of the imbalanced gut microbial composition has become a novel treatment strategy for mental illnesses, such as depression, anxiety, bipolar disorder, schizophrenia, impulsivity, and compulsivity. A similar function of modulating gut microbial composition following stress challenge may be present in egg-laying chickens. The avian cecum, as a multi-purpose organ, has the greatest bacterial biodiversity (bacterial diversity, richness, and species composition) along the gastrointestinal tract, with vitally important functions in maintaining physiological and behavioral homeostasis, especially during the periods of stress. To identify the effects of the gut microbiome on injurious behaviors in egg-laying chickens, we have designed and tested the effects of transferring cecal contents from two divergently selected inbred chicken lines on social stress and stress-related injurious behaviors in recipient chicks of a commercial layer strain. This article reports the outcomes from a multi-year study on the modification of gut microbiota composition to reduce injurious behaviors in egg-laying chickens. An important discovery of this corpus of experiments is that injurious behaviors in chickens can be reduced or inhibited through modifying the gut microbiota composition and brain serotonergic activities via the gut-brain axis, without donor-recipient genetic effects.

Lingering Effects of COVID-19 Stressors on Mental Health and Alcohol Use in Middle Aged to Older Adults.

Background: Older adults have faced not only health threats but grave mental health challenges since the emergence of the Coronavirus disease 2019 (COVID-19) pandemic. Using factor analysis, this study is the first to identify the underlying dimensions of COVID-19-related stressors, then examine the relationship between these factors and mental health and alcohol use/misuse longitudinally in a middle aged to older adult sample in the United States. Methods: As part of a long-term follow-up study, 921 survey participants completed measures of COVID-related stressors, psychological distress, and alcohol use/misuse in a 2020 survey. An exploratory factor analysis was conducted to examine the dimensionality of COVID-related stress. Regression models were utilized to examine relationships between the extracted factors and depression, anxiety, and alcohol-related outcomes measured approximately one year later, in 2021. Results: Four dimensions of COVID-19 stressors were extracted, including 1) jobs, finances and loss of routine; 2) practical difficulties; 3) social worries and challenges; and 4) supply shortages. Practical difficulties were associated with higher depression at follow-up, while jobs, finances and loss of routine were associated with past 12 month frequency of intoxication at follow-up. Conclusions: Challenges from the pandemic may have longer-term implications for mental health in older adults past the acute phase of the pandemic. It is important to allocate sufficient attention and resources to the prevention of late life depression and mental health as policymakers and health professionals continue to deal with the pandemic and future variants of the virus.

Analysis of Poly(ethylene terephthalate) degradation kinetics of evolved IsPETase variants using a surface crowding model.

Poly(ethylene terephthalate) (PET) is a major plastic polymer utilized in the single-use and textile industries. The discovery of PET-degrading enzymes (PETases) has led to an increased interest in the biological recycling of PET in addition to mechanical recycling. IsPETase from Ideonella sakaiensis is a candidate catalyst, but little is understood about its structure-function relationships with regards to PET degradation. To understand the effects of mutations on IsPETase productivity, we develop a directed evolution assay to identify mutations beneficial to PET film degradation at 30 °C. IsPETase also displays enzyme concentration-dependent inhibition effects, and surface crowding has been proposed as a causal phenomenon. Based on total internal reflectance fluorescence microscopy and adsorption experiments, IsPETase is likely experiencing crowded conditions on PET films. Molecular dynamics simulations of IsPETase variants reveal a decrease in active site flexibility in free enzymes and reduced probability of productive active site formation in substrate-bound enzymes under crowding. Hence, we develop a surface crowding model to analyze the biochemical effects of three hit mutations (T116P, S238N, S290P) that enhanced ambient temperature activity and/or thermostability. We find that T116P decreases susceptibility to crowding, resulting in higher PET degradation product accumulation despite no change in intrinsic catalytic rate. In conclusion, we show that a macromolecular crowding-based biochemical model can be used to analyze the effects of mutations on properties of PETases and that crowding behavior is a major property to be targeted for enzyme engineering for improved PET degradation.

Transient intermediate in the formation of an amorphous metal-organic framework.

Amorphous metal-organic frameworks are rarely formed via direct synthesis. Our limited understanding of their atomic assembly in solution prevents full exploitation of their unique structural complexity. Here, we use in situ synchrotron X-ray absorption spectroscopy with sub-second time resolution to probe the formation of the amorphous Fe-BTC framework. Using a combination of spectral fingerprinting, linear combination analysis, and principal component analysis coupled with kinetic analyses, we reveal a multi-stage formation mechanism that, crucially, proceeds via the generation of a transient intermediate species.

Realized thermal niche approach eliminates temperature bias in bioenergetic model estimates.

Bioenergetics models estimate ectotherm growth, production, and prey consumption - all key for effective ecosystem management during changing global temperatures. Based on species-specific allometric and thermodynamic relationships, these models typically use the species' lab-derived optimum temperatures (physiological optimum) as opposed to empirical field data (realized thermal niche) that reflect actual thermal experience. Yet, dynamic behavioral thermoregulation mediated by biotic and abiotic interactions may provide substantial divergence between physiological optimum and realized thermal niche temperatures to significantly bias model outcomes. Here, using the Wisconsin bioenergetics model and in-situ year-round temperature data, we tested the two approaches and compared the maximum attainable lifetime weight and lifetime prey consumption estimates for two salmonid species with differing life histories. We demonstrate that using the realized thermal niche is the better approach because it eliminates significant biases in estimates produced by the physiological optimum. Specifically, using the physiological optimum, slower-growing Salvelinus namaycush maximum attainable lifetime weight was underestimated, and consumption overestimated, while fast-growing Oncorhynchus tshawytscha maximum attainable weight was overestimated. While the physiological optimum approach is useful for theoretical studies, our results demonstrate the critical importance that models used by management utilize up-to-date system- and species-specific field data representing actual in-situ behaviors (i.e., realized thermal niche).

Optimal Spectral Resolution for Infrared Studies of Solids and Liquids.

Due to a legacy originating in the limited capability of early computers, the spectroscopic resolution used in Fourier transform infrared spectroscopy and other systems has largely been implemented using only powers of two for more than 50 years. In this study, we investigate debunking the spectroscopic lore of, e.g., using only 2, 4, 8, or 16 cm-1 resolution and determine the optimal resolution in terms of both (i) a desired signal-to-noise ratio and (ii) efficient use of acquisition time. The study is facilitated by the availability of solids and liquids reference spectral data recorded at 2.0 cm-1 resolution and is based on an examination in the 4000-400 cm-1 range of 61 liquids and 70 solids spectra, with a total analysis of 4237 peaks, each of which was also examined for being singlet/multiplet in nature. Of the 1765 liquid bands examined, only 27 had widths <5 cm-1. Of the 2472 solid bands examined, only 39 peaks have widths <5 cm-1. For both the liquid and solid bands, a skewed distribution of peak widths was observed: For liquids, the mean peak width was 24.7 cm-1 but the median peak width was 13.7 cm-1, and, similarly, for solids, the mean peak width was 22.2 cm-1 but the median peak width was 11.2 cm-1. While recognizing other studies may differ in scope and limiting the analysis to only room temperature data, we have found that a resolution to resolve 95% of all bands is 5.7 cm-1 for liquids and 5.3 cm-1 for solids; such a resolution would capture the native linewidth (not accounting for instrumental broadening) for 95% of all the solids and liquid bands, respectively. After decades of measuring liquids and solids at 4, 8, or 16 cm-1 resolution, we suggest that, when accounting only for intrinsic linewidths, an optimized resolution of 6.0 cm-1 will capture 91% of all condensed-phase bands, i.e., broadening of only 9% of the narrowest of bands, but yielding a large gain in signal-to-noise with minimal loss of specificity.

Ataxia-Telangiectasia Mutated Loss-of-Function Displays Variant and Tissue-Specific Differences across Tumor Types.

PURPOSE: Mutations in the ATM gene are common in multiple cancers, but clinical studies of therapies targeting ATM-aberrant cancers have yielded mixed results. Refinement of ATM loss of function (LOF) as a predictive biomarker of response is urgently needed. EXPERIMENTAL DESIGN: We present the first disclosure and preclinical development of a novel, selective ATR inhibitor, ART0380, and test its antitumor activity in multiple preclinical cancer models. To refine ATM LOF as a predictive biomarker, we performed a comprehensive pan-cancer analysis of ATM variants in patient tumors and then assessed the ATM variant-to-protein relationship. Finally, we assessed a novel ATM LOF biomarker approach in retrospective clinical data sets of patients treated with platinum-based chemotherapy or ATR inhibition. RESULTS: ART0380 had potent, selective antitumor activity in a range of preclinical cancer models with differing degrees of ATM LOF. Pan-cancer analysis identified 10,609 ATM variants in 8,587 patient tumors. Cancer lineage-specific differences were seen in the prevalence of deleterious (Tier 1) versus unknown/benign (Tier 2) variants, selective pressure for loss of heterozygosity, and concordance between a deleterious variant and ATM loss of protein (LOP). A novel ATM LOF biomarker approach that accounts for variant classification, relationship to ATM LOP, and tissue-specific penetrance significantly enriched for patients who benefited from platinum-based chemotherapy or ATR inhibition. CONCLUSIONS: These data help to better define ATM LOF across tumor types in order to optimize patient selection and improve molecularly targeted therapeutic approaches for patients with ATM LOF cancers.

Impact of maternal live yeast supplementation to sows on intestinal inflammatory cytokine expression and tight junction proteins in suckling and weanling piglets.

Recent studies have highlighted the importance of maternal nutrition during gestation and lactation in modulating the gastrointestinal development and health of offspring. Therefore, the objective of this study was to determine the effects of live yeast (LY) supplementation to sows during late gestation and throughout lactation on markers of gut health of piglets prior to weaning and immediately postweaning. On day 77 of gestation, forty sows were allotted based on parity and expected farrowing dates to two dietary treatments: without (CON) or with (LY) supplementation at 0.05% and 0.1% of diet during gestation and lactation, respectively. On postnatal days (PND) 0, 10, 18, and postweaning days (PWD) 7 and 14, one piglet from each of 10 sows per treatment were selected for intestinal tissue collection (n = 10). Real-time PCR and western blotting analyses were used to determine the mucosal expression of immune and antioxidant-regulatory genes and tight junction markers of gut health in the duodenum, jejunum, and ileum. Inflammatory and tight junction markers on PND 0 were not affected by maternal dietary treatment. On PND 18, maternal LY supplementation increased (P < 0.05) mRNA expression of interleukin (IL)-6 and tended (P = 0.08) to increase expression of IL-10 in the ileal muocsa. Maternal LY supplementation also increased (P < 0.05) expression of IL-1ß in the ileal mucosa on PWD 14. Likewise, expression of superoxide dismutase (SOD) 1 was increased (P < 0.05) by LY on PND 10, 18, and PWD 14, with a tendency (P = 0.09) for a greater mRNA abundance of catalase on PND 14 in the ileal mucosa. Compared to CON piglets, LY piglets had a higher (P < 0.05) protein abundance of E-cadherin in the jejunal mucosa on PND 0, PWD 7, and PWD 14. Levels of occludin and claudin-4 were also higher (P < 0.05) in the jejunum of LY piglets on PWD 14. No differences were found in jejunal histomorphological measurements between treatments. In conclusion, this study shows that maternal LY supplementation affects key markers of gut health and development in the offspring that may impact the future growth potential and health of newborn piglets.

Increasing evidence supports the benefits of improving sow nutrition during gestation and lactation to promote gastrointestinal development and overall health of piglets. The objective of this research was to investigate the effects of maternal live yeast (LY) supplementation to sows during late gestation and lactation periods on the intestinal health of suckling and weaned piglets. Sows were fed LY during gestation and lactation and piglets were killed for sampling at different time points to track the temporal effect of maternal LY supplementation on changes in markers of intestinal health and development on postnatal days 0, 10, and 18, and postweaning days 7 and 14. Results showed that maternal LY supplementation affected several markers of health and development in the offspring, especially the expression of tight junction proteins, inflammatory cytokines, and antioxidant enzymes. These results indicate that nutritional intervention during gestation and lactation could serve as an effective strategy for raising piglets with better health and growth performance.