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The Hippo pathway plays a central role in tissue development and homeostasis. However, the function of Hippo in pancreatic endocrine development remains obscure. Here, we generated novel conditional genetically engineered mouse models to examine the roles of Hippo pathway-mediated YAP1/TAZ inhibition in the development stages of endocrine specification and differentiation. While YAP1 protein was localized to the nuclei in bipotent progenitor cells, Neurogenin 3 expressing endocrine progenitors completely lost YAP1 expression. Using genetically engineered mouse models, we found that inactivation of YAP1 requires both an intact Hippo pathway and Neurogenin 3 protein. Gene deletion of Lats1 and 2 kinases (Lats1&2) in endocrine progenitor cells of developing mouse pancreas using Neurog3Cre blocked endocrine progenitor cell differentiation and specification, resulting in reduced islets size and a disorganized pancreas at birth. Loss of Lats1&2 in Neurogenin 3 expressing cells activated YAP1/TAZ transcriptional activity and recruited macrophages to the developing pancreas. These defects were rescued by deletion of Yap1/Wwtr1 genes, suggesting that tight regulation of YAP1/TAZ by Hippo signaling is crucial for pancreatic endocrine specification. In contrast, deletion of Lats1&2 using β-cell-specific Ins1CreER resulted in a phenotypically normal pancreas, indicating that Lats1&2 are indispensable for differentiation of endocrine progenitors but not for that of β-cells. Our results demonstrate that loss of YAP1/TAZ expression in the pancreatic endocrine compartment is not a passive consequence of endocrine specification. Rather, Hippo pathway-mediated inhibition of YAP1/TAZ in endocrine progenitors is a prerequisite for endocrine specification and differentiation.

AbstractAlewives Alosa pseudoharengus are native to the Atlantic Coast but have been introduced to inland waters as forage for sportfish populations. Alewife introductions have benefitted sportfish growth and body condition but have also negatively influenced larval fish survival through predation or competition for zooplankton. In 1986, alewives were stocked into Lake McConaughy, Nebraska, and became abundant and self-sustaining shortly thereafter. It has since been hypothesized that the alewife introduction altered zooplankton size and species composition and potentially negatively influenced Walleye recruitment. However, no studies on alewife distribution or food habits have been conducted on Lake McConaughy to date to investigate the potential influences of alewife on the fish and zooplankton communities. We collected alewives in the nearshore areas of Lake McConaughy during May–July 2022 and 2023 using short-term (about 1 h) small mesh horizontal gill net sets. We spatially assessed alewives by sampling the north and side south sides in addition to four classified quadrants of the reservoir. Total lengths (mm) were recorded, and stomachs were collected from up to 20 alewife per net. Prey were identified and food habits were summarized as percent composition by number. Zooplankton consumption was also paired with vertical Wisconsin zooplankton net tows taken at each site to assess prey selectivity. There was no evidence of piscivory suggesting that alewife predation is not influencing fish recruitment in Lake McConaughy. Alewives almost exclusively consumed zooplankton throughout the study period, suggesting the potential for interspecific competition with young-of-year fish. Our research provides a greater understanding of how introducing a non-native prey species to benefit sport fishes may have unintended negative consequences.

Abstract Acute and chronic kidney disease continues to confer significant morbidity and mortality in the clinical setting. Despite high prevalence of these conditions, few validated biomarkers exist to predict kidney dysfunction. In this study, we utilized a novel kidney multiplex panel to measure 21 proteins in plasma and urine to characterize the spectrum of biomarker profiles in kidney disease. Blood and urine samples were obtained from age-/sex-matched healthy control subjects (HC), critically-ill COVID-19 patients with acute kidney injury (AKI), and patients with chronic or end-stage kidney disease (CKD/ESKD). Biomarkers were measured with a kidney multiplex panel, and results analyzed with conventional statistics and machine learning. Correlations were examined between biomarkers and patient clinical and laboratory variables. Median AKI subject age was 65.5 (IQR 58.5–73.0) and median CKD/ESKD age was 65.0 (IQR 50.0–71.5). Of the CKD/ESKD patients, 76.1% were on hemodialysis, 14.3% of patients had kidney transplant, and 9.5% had CKD without kidney replacement therapy. In plasma, 19 proteins were significantly different in titer between the HC versus AKI versus CKD/ESKD groups, while NAG and RBP4 were unchanged. TIMP-1 (PPV 1.0, NPV 1.0), best distinguished AKI from HC, and TFF3 (PPV 0.99, NPV 0.89) best distinguished CKD/ESKD from HC. In urine, 18 proteins were significantly different between groups except Calbindin, Osteopontin and TIMP-1. Osteoactivin (PPV 0.95, NPV 0.95) best distinguished AKI from HC, and β2-microglobulin (PPV 0.96, NPV 0.78) best distinguished CKD/ESKD from HC. A variety of correlations were noted between patient variables and either plasma or urine biomarkers. Using a novel kidney multiplex biomarker panel, together with conventional statistics and machine learning, we identified unique biomarker profiles in the plasma and urine of patients with AKI and CKD/ESKD. We demonstrated correlations between biomarker profiles and patient clinical variables. Our exploratory study provides biomarker data for future hypothesis driven research on kidney disease.

Abstract Aims Long-COVID occurs after SARS-CoV-2 infection and results in diverse, prolonged symptoms. The present study aimed to unveil potential mechanisms, and to inform prognosis and treatment. Methods Plasma proteome from Long-COVID outpatients was analyzed in comparison to matched acutely ill COVID-19 (mild and severe) inpatients and healthy control subjects. The expression of 3072 protein biomarkers was determined with proximity extension assays and then deconvoluted with multiple bioinformatics tools into both cell types and signaling mechanisms, as well as organ specificity. Results Compared to age- and sex-matched acutely ill COVID-19 inpatients and healthy control subjects, Long-COVID outpatients showed natural killer cell redistribution with a dominant resting phenotype, as opposed to active, and neutrophils that formed extracellular traps. This potential resetting of cell phenotypes was reflected in prospective vascular events mediated by both angiopoietin-1 (ANGPT1) and vascular-endothelial growth factor-A (VEGFA). Several markers (ANGPT1, VEGFA, CCR7, CD56, citrullinated histone 3, elastase) were validated by serological methods in additional patient cohorts. Signaling of transforming growth factor-β1 with probable connections to elevated EP/p300 suggested vascular inflammation and tumor necrosis factor-α driven pathways. In addition, a vascular proliferative state associated with hypoxia inducible factor 1 pathway suggested progression from acute COVID-19 to Long-COVID. The vasculo-proliferative process predicted in Long-COVID might contribute to changes in the organ-specific proteome reflective of neurologic and cardiometabolic dysfunction. Conclusions Taken together, our findings point to a vasculo-proliferative process in Long-COVID that is likely initiated either prior hypoxia (localized or systemic) and/or stimulatory factors (i.e., cytokines, chemokines, growth factors, angiotensin, etc). Analyses of the plasma proteome, used as a surrogate for cellular signaling, unveiled potential organ-specific prognostic biomarkers and therapeutic targets.

This study examined roadway flooding event data provided by the Nebraska Department of Transportation via the Condition Acquisition Reporting System (CARS) 511 archive (2016–2021). With these data, a novel analysis was completed to further the understanding of where, when, and why (meteorologically) roadway flooding occurs on Nebraska state and federal highways. In the study period, 298 roadway floods occurred, with an annual median of 16 per year. There was a greater risk for roadway floods to transpire more frequently in eastern Nebraska, which was attributed to the spatial climatology of heavy rainfall and the higher density of roadways and rivers. Consequently, this increases the exposure and vulnerability of the highway system across the eastern portion of the state. Further, precursor soil moisture and river conditions proved to be critical initiators of roadway floods, as precipitation totals prior to each flood only averaged at 40 mm, while precursor Palmer Hydrological Drought Index values for 75% of events were above 4.0 and river levels were 200 cm above its daily medians. Overall, the complexities of these roadway flooding events are challenging for proactively forecasting as opposed to reacting to the situation. With the top roadway flooding locations identified along with the weather-related causes, further investigation of roadway flooding hotspots across the state needs to take place for mitigation and resiliency in a changing climate. The methods of this research can be used across other states and by other agencies to analyze and increase the resilience of their respective roadway networks.

Abstract Background Survivors of acute COVID-19 often suffer prolonged, diffuse symptoms post-infection, referred to as “Long-COVID”. A lack of Long-COVID biomarkers and pathophysiological mechanisms limits effective diagnosis, treatment and disease surveillance. We performed targeted proteomics and machine learning analyses to identify novel blood biomarkers of Long-COVID. Methods A case–control study comparing the expression of 2925 unique blood proteins in Long-COVID outpatients versus COVID-19 inpatients and healthy control subjects. Targeted proteomics was accomplished with proximity extension assays, and machine learning was used to identify the most important proteins for identifying Long-COVID patients. Organ system and cell type expression patterns were identified with Natural Language Processing (NLP) of the UniProt Knowledgebase. Results Machine learning analysis identified 119 relevant proteins for differentiating Long-COVID outpatients (Bonferonni corrected P

IntroductionIt is important to relate different greenhouse gas (GHG) emissions to a carbon dioxide (CO2) equivalence (CO2-e) basis. This is typically done by multiplying the emissions of a GHG by its global warming potential (GWP), usually on a 100-year basis (GWP100). For methane (CH4), the predominant GHG from livestock production, the GWP100 value is 28. The GWP100 method has been shown to not adequately relate CH4 emissions to actual climate warming due to CH4′s short atmospheric lifespan (~12 years). As such, a newer method has been developed, termed GWP*. This method relates current emission rates to previous emission rates, typically on a 20-year time horizon. To date, the implications of using GWP* rather than GWP100 have not been discussed for manure emissions and have not been discussed for enteric and manure emissions relative to different livestock species or geographical regions of the United States.MethodsUsing emission estimate data from the U.S. Environmental Protection Agency (EPA), we assessed how national manure and enteric CH4 emissions changed from 1990 to 2020.ResultsThe average rate of change was analyzed by regression. Enteric CH4 emissions remained relatively constant with a non-significant slope (P = 0.51), whereas manure CH4 emissions have been increasing (P < 0.01; R2 = 0.96) by 0.03-MMT/year. Furthermore, investigation demonstrated that the increase in manure CH4 emissions was largely driven by the dairy (25.9-kt increase in manure CH4 per year; P < 0.01; R2 = 0.98) and swine (5.4-kt increase in manure CH4 per year; P < 0.01; R2 = 0.50) industries. Due to the increasing emission estimates, manure CH4 [90.8-MMT CO2-warming equivalence (CO2-we) on average] was a larger contributor to climate warming than enteric CH4 (89.2-MMT CO2-we on average) from 2010 through 2020, when calculated with the GWP* methodology. This stands in contrast to the GWP100 methodology, which suggests that enteric CH4 emissions (191-MMT CO2-e) from 2010 to 2020 were on average 206% greater contributors to warming than manure CH4 emissions (62.3-MMT CO2-e).DiscussionThese results suggest that manure CH4 emissions may be contributing more to climate warming than enteric CH4, and more effort may be required to mitigate this source of emissions.

Traditional distillers dried grains, co-products from the ethanol industry, can be utilized as sustainable ingredients for pet food. However, negative consumer perception prevents their widespread use. Corn fermented protein (CFP) is produced using post-fermentation separation technology, resulting in a high protein ingredient, which may increase consumer appeal compared to traditional distillers dried grains. The study objective was to compare the effect of CFP with that of traditional distillers dried grains on stool quality, nutrient digestibility, and palatability when fed to dogs. The control diet (CON) contained 15% soybean meal and the experimental diets contained 3.5% brewer’s dried yeast (BDY), 2.5% brewer’s dried yeast plus 17.5% distillers dried grains with solubles (BDY+DDGS), or 17.5% corn fermented protein (CFP). Experimental diets were fed to adult dogs (n = 12) in a 4 × 4 replicated Latin square design. Dogs were adapted to the diets for 9 days; this was followed by 5 days of total fecal collection. Titanium dioxide (0.4%) was added to all diets as an external marker to estimate digestibility. Data were analyzed using a mixed model in SAS, with treatment as a fixed effect and dog and period as random effects. Fecal output was greatest (p 0.05) in total short-chain or branched-chain fatty acid concentrations in the fresh fecal samples of dogs fed these dietary treatments. However, the percentage of propionate was higher (p

There has been increased interest among pet owners to feed vegetarian diets to their pets. However, the primary protein sources used in pet food today are animal based, warranting a need to evaluate novel plant-based ingredients to meet the protein demand. Corn fermented protein (CFP), a coproduct from ethanol production, may provide a plant-based alternative protein source for pet food. Therefore, the objectives of this study were to determine the effects of increasing levels of CFP on extrusion processing, stool quality, apparent total tract digestibility, and palatability in dog diets. Four extruded diets were fed to 12 adult beagle dogs in a replicated 4 × 4 Latin square design. The control diet contained 15% soybean meal (0C) and CFP was exchanged at either 5%, 10%, or 15% of soybean meal (5C, 10C, and 15C, respectively). Dogs were fed each dietary treatment for 9 days of adaption followed by 5 days of total fecal collection. Feces were scored on a 1–5 scale, with 1 representing liquid diarrhea and 5 representing hard pellet-like. Titanium dioxide (0.4%) was added to all diets as an external marker to estimate digestibility. Data were analyzed using orthogonal contrasts in SAS (version 9.4; SAS Institute, Inc., Cary, NC, USA). Dry bulk density of kibble decreased (P 0.05) to 0C. There was a decrease (P

Zonal management of cereal–legume cover crop mixtures may help address weed and nitrogen management challenges common in organic reduced tillage systems. During a field study conducted over 3 years in Michigan, we evaluated the effects of cover crop management, tillage, and supplemental mulch on organically produced acorn squash (Cucurbita pepo). During the fall season before squash production, rye (Secale cereale L.) and vetch (Vicia villosa Roth) cover crop mixtures were sown in two distinct spatial arrangements: a “mixed planting,” in which seeds were sown in the same rows, and a “zonal planting,” in which vetch was planted only in the in-row zone and rye was planted only in the between-row zone of the subsequent squash crop. During the following spring season, cover crops were mowed, and four tillage and cover crop management combinations were established: full-width tillage with the mixed planting of rye–vetch (full-till mixed); strip-till with the same mixed planting (strip-till mixed); strip-till with the rye–vetch zonal planting (strip-till zonal); and strip-till with the zonal planting and additional rye mulch added between crop rows immediately after crop establishment (strip-till zonal plus rye). The strip-till mixed treatment resulted in yields equivalent to those of the full-till mixed treatment despite lower available nitrogen and greater early weed competition in some cases. Within strip-till treatments, zonal planting of rye–vetch provided no benefits relative to full-width planting (treatment 2 vs 3) and resulted in lower total cover crop biomass, a higher density of escaped weeds, and lower squash yields during 1 of 3 years. Supplemental rye mulch improved weed suppression and yields in strip-till zonal treatments and resulted in yields equivalent to those of the full-till mixed treatment in all years, but it provided no benefits relative to strip-till mixed. Our results demonstrate that strip-till organic squash production can produce yields equivalent to full-till production in Northern climates, but that zonal planting and supplemental mulch have limited benefits for addressing ongoing weed and nitrogen management challenges. Growers must weigh costs associated with these challenges against potential benefits for soil and pest regulating ecosystem services before adopting these agricultural conservation practices.

Abstract Background Long-COVID is characterized by prolonged, diffuse symptoms months after acute COVID-19. Accurate diagnosis and targeted therapies for Long-COVID are lacking. We investigated vascular transformation biomarkers in Long-COVID patients. Methods A case–control study utilizing Long-COVID patients, one to six months (median 98.5 days) post-infection, with multiplex immunoassay measurement of sixteen blood biomarkers of vascular transformation, including ANG-1, P-SEL, MMP-1, VE-Cad, Syn-1, Endoglin, PECAM-1, VEGF-A, ICAM-1, VLA-4, E-SEL, thrombomodulin, VEGF-R2, VEGF-R3, VCAM-1 and VEGF-D. Results Fourteen vasculature transformation blood biomarkers were significantly elevated in Long-COVID outpatients, versus acutely ill COVID-19 inpatients and healthy controls subjects (P

Background: Recent literature suggests wide variations exist in the international management of locally advanced pancreatic cancer. This study sought to evaluate how geography contributes to variations in management of locally advanced pancreatic cancer. Methods: An electronic survey investigating preferences for the evaluation and management of locally advanced pancreatic cancer was distributed to an international cohort of pancreatic surgeons. Surgeons were classified according to geographic location of practice, and survey responses were compared across locations. Results: A total of 153 eligible responses were received from 4 continents: North and South America (n = 94, 61.4%), Europe (n = 25, 16.3%), and Asia (n = 34, 22.2%). Preferences for the use and duration of neoadjuvant chemotherapy and radiotherapy varied widely. For example, participants in Asia commonly preferred 2 months of neoadjuvant chemotherapy (61.8%), whereas North and South American participants preferred 4 months (52.1%), and responses in Europe were mixed (P = .006). Participants in Asia were less likely to consider isolated liver or lung metastases contraindications to exploration and consequently had a greater propensity to consider exploration in a vignette of oligometastatic disease (56.7% vs North and South America: 25.6%, Europe: 43.5%; P = .007). Conclusion: In an international survey of pancreatic surgeons, attitudes regarding locally advanced pancreatic cancer and metastatic disease management varied widely across geographic locations. Better evidence is needed to define optimal management of locally advanced pancreatic cancer.

Recolonization by native species following removal of invasive plant species can often be uneven and lead to the rapid increase of one or a few native plant species. This can result in the formation of a significant resource pulse that may consequently affect populations of herbivorous species and their natural enemies. Here we present results from observations of parasitism rates during a localized outbreak of the Asimina webworm moth, Omphalocera munroei, a locally monophagous herbivore of the common paw-paw. Asimina triloba. This outbreak initiated from locations of increased understory growth of A. triloba, following the removal of Amur Honeysuckle (Lonicera maackii). Parasitism rates during the outbreak reached 50%, with higher parasitism rates observed in larvae collected at the end of the local outbreak relative to those the year following the peak of the outbreak. Parasitism rates remained high 3 y after the end of the local O. munroei outbreak, indicating >7 y of high parasitoid densities. O. munroei emerges late in the growing season, making it fairly inaccessible as a host or prey to many generalist predators/parasitoids, which emerge earlier the following year. This suggests the O. munroei outbreak potentially contributed to an increase in natural enemy pressure of other native species in the community., INTRODUCTION Invasive plant species can have extensive negative impacts on diversity, species interactions, community composition, ecosystem function, socioeconomic conditions, and human health (Vila et al, 2011; Rai and Singh, 2020). [...]