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According to the World Health Organization, approximately 15 million children are born prematurely each year. Many of these infants end up spending days to weeks in a neonatal intensive care unit (NICU). Infants who are born prematurely are often exposed to noise and light levels that affect auditory and visual development. Children often have long term impairments to cognition, visuospatial processing, hearing, and language. We have developed a rodent model of NICU exposure to light and sound using the Mongolian gerbil (Meriones unguiculatus), which has a low frequency human-like audiogram and is altricial. To simulate preterm infancy the eyes and ears were opened prematurely, and animals were exposed to the NICU-like sensory environment throughout the gerbil's cortical critical period of auditory development. After the animals mature into adults, auditory perceptual testing was carried out followed by auditory brainstem response recordings and then histology to assess white matter morphology of various brain regions. Compared to normal hearing control animals, NICU sensory exposed animals had significant impairments to learning at later stages of training, increased auditory thresholds reflecting hearing loss, and smaller cerebellar white matter volumes. These have all been reported in longitudinal studies of preterm infants. These preliminary results suggest that this animal model could provide researchers with an ethical way to explore the effects of the sensory environment in the neonatal intensive care unit on the preterm infant's brain development.

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Utilizing a comprehensive database spanning 110 exchanges in five geographic regions, we examine trends in trade activity and contract innovation of exchange-traded futures and options over the period 2002–2021. We find that global volume has experienced a ten-fold increase driven by significant increases at Asian and North American exchanges, and primarily in the equity, interest rate and currency asset classes. New contract innovation has been greatest in North America and in the energy and equity asset classes. Further, volume and open interest attributable to new contract innovation have now surpassed those of legacy contracts. Turnover showed a significant increase driven largely by trade activity in Asian markets. Finally, new contract failure rates have been highest at North American exchanges as well as in the interest rate and energy asset classes.

BackgroundThird window syndrome is a vestibular-cochlear disorder in humans in which a third mobile window of the otic capsule creates changes to the flow of sound pressure energy through the perilymph/endolymph. The nature and location of this third mobile window can occur at many different sites (or multiple sites); however, the most common third mobile window is superior semicircular canal dehiscence (SSCD). There are two essential objective diagnostic characteristics needed to validate a model of SSCD: the creation of a pseudoconductive hearing loss and cVEMP increased amplitude and decreased threshold.MethodsAdult Mongolian gerbils (n = 36) received surgical fenestration of the superior semicircular canal of the left inner ear. ABR and c+VEMP testing were carried out prior to surgery and over acute (small 1 mm SSCD, 1–10 days) or prolonged (large 2 mm SSCD, 28 days) recovery. Because recovery of function occurred quickly, condenser brightfield stereomicroscopic examination of the dehiscence site was carried out for the small SSCD animals post-hoc and compared to both ABRs and c+VEMPs. Micro-CT analysis was also completed with representative samples of control, day 3 and 10 post-SSCD animals.ResultsThe SSCD created a significant worsening of hearing thresholds of the left ear; especially in the lower frequency domain (1–4 kHz). Left (EXP)/right (CTL) ear comparisons via ABR show significant worsening thresholds at the same frequency representations, which is a proxy for the human pseudoconductive hearing loss seen in SSCD. For the c+VEMP measurements, increased amplitude of the sound-induced response (N1 2.5 ms and P1 3.2 ms) was observed in animals that received larger fenestrations. As the bone regrew, the c+VEMP and ABR responses returned toward preoperative values. For small SSCD animals, micro-CT data show that progressive osteoneogenesis results in resurfacing of the SSCD without bony obliteration.ConclusionThe large (2 mm) SSCD used in our gerbil model results in similar electrophysiologic findings observed in patients with SSCD. The changes observed also reverse and return to baseline as the SSCD heals by bone resurfacing (with the lumen intact). Hence, this model does not require a second surgical procedure to plug the SSCD.

Hepatocellular cancer (HCC) is the 3rd leading cause of cancer-associated deaths worldwide. Treatment with immune checkpoint antibodies has shown promise in advanced HCC, but the response is only 15-20% with monotherapy and 25-40% with combination therapy. We discovered a potential target for the treatment of HCC; the cholecystokinin-B receptor (CCK-BR). This receptor is over-expressed in murine and human HCC and not in normal liver tissue. Mice bearing syngeneic RIL-175 HCC tumors were treated with PBS (Control), proglumide (a CCK-receptor antagonist), an anti-PD1 antibody, or the combination of proglumide and the anti-PD1 antibody. In vitro, RNA was extracted from untreated or proglumide-treated murine Dt81Hepa1-6 HCC cells and analyzed for expression of fibrosis-associated genes. RNA was also extracted from human HepG2 HCC cells or HepG2 cells treated with proglumide and subjected to RNA sequencing. Results showed that proglumide decreased fibrosis in the tumor microenvironment and increased the number of intratumoral CD8+ T-cells in RIL-175 tumors. When proglumide was given in combination with the anti-PD1 antibody, there was a further significant increase in intratumoral CD8+ T-cells, improved survival, and alterations in genes regulating tumoral fibrosis and epithelial to mesenchymal transition. RNAseq results from human HepG2 HCC cells treated with proglumide showed significant changes in differentially expressed genes involved in tumorigenesis, fibrosis, and the tumor microenvironment. The use of the CCK receptor antagonist proglumide may improve efficacy of immune checkpoint antibodies and survival in those with advanced HCC.

Schistosome parasites cause a chronic inflammatory disease in humans, and recent studies have emphasized the importance of control programs for understanding the aquatic phases of schistosomiasis transmission. The host-seeking behavior of larval schistosomes (miracidia) for their snail intermediate hosts plays a critical role in parasite transmission. Using field-derived strains of Kenyan snails and parasites, we tested two main hypotheses: (1) Parasites prefer the most compatible host, and (2) parasites avoid hosts that are already infected. We tested preference to three

During developmental critical periods (CPs), early-life stress (ELS) induces cognitive deficits and alters neural circuitry in regions underlying learning, memory, and attention. Mechanisms underlying critical period plasticity are shared by sensory cortices and these higher neural regions, suggesting that sensory processing may also be vulnerable to ELS. In particular, the perception and auditory cortical (ACx) encoding of temporally-varying sounds both mature gradually, even into adolescence, providing an extended postnatal window of susceptibility. To examine the effects of ELS on temporal processing, we developed a model of ELS in the Mongolian gerbil, a well-established model for auditory processing. In both male and female animals, ELS induction impaired the behavioral detection of short gaps in sound, which are critical for speech perception. This was accompanied by reduced neural responses to gaps in auditory cortex, the auditory periphery, and auditory brainstem. ELS thus degrades the fidelity of sensory representations available to higher regions, and could contribute to well-known ELS-induced problems with cognition.SIGNIFICANCE STATEMENTIn children and animal models, early-life stress (ELS) leads to deficits in cognition, including problems with learning, memory, and attention. Such problems could arise in part from a low-fidelity representation of sensory information available to higher-level neural regions. Here, we demonstrate that ELS degrades sensory responses to rapid variations in sound at multiple levels of the auditory pathway, and concurrently impairs perception of these rapidly-varying sounds. As these sound variations are intrinsic to speech, ELS may thus pose a challenge to communication and cognition through impaired sensory encoding.

High saturated fat diets have been shown to raise blood levels of cholecystokinin (CCK) and induce nonalcoholic steatohepatitis (NASH). CCK receptors are expressed on stellate cells and are responsible for hepatic fibrosis when activated. The purpose of this study was to test the safety and dose of a CCK receptor antagonist, proglumide, in human participants with NASH. An open-label single ascending dose study was conducted in 18 participants with clinical NASH based upon steatosis by liver ultrasound, elevated hepatic transaminases, and a component of the metabolic syndrome. Three separate cohorts (N = 6 each) were treated with oral proglumide for 12 weeks in a sequential ascending fashion with 800 (Cohort 1), 1,200 (Cohort 2), and 1,600 (Cohort 3) mg/day, respectively. Blood hematology, chemistries, proglumide levels, a biomarker panel for fibrosis, and symptom surveys were determined at baseline and every 4 weeks. Abdominal ultrasounds and transient elastography utilizing FibroScan were obtained at baseline and at Week 12. Proglumide was well tolerated at all doses without any serious adverse events. There was no change in body weight from baseline to Week 12. For Cohorts 1, 2, and 3, the median percent change in alanine aminotransferase was 8.42, -5.05, and -22.23 and median percent change in fibrosis score by FibroScan was 8.13, -5.44, and -28.87 (kPa), respectively. Hepatic steatosis as measured by controlled attenuation parameter score significantly decreased with proglumide, (P 0.05). Blood microRNA biomarkers and serum 4-hydroxyproline were consistent with decreased fibrosis at Week 12 compared with baseline. These findings suggest proglumide exhibits anti-inflammatory and anti-fibrotic properties and this compound is well tolerated in participants with NASH.

Tropical forests are pivotal to global climate and biogeochemical cycles, yet the geographic distribution of nutrient limitation to plants and microbes across the biome is unresolved. One long-standing generalization is that tropical montane forests are nitrogen (N)-limited whereas lowland forests tend to be N-rich. However, empirical tests of this hypothesis have yielded equivocal results. Here we evaluate the topographic signature of the ecosystem-level tropical N cycle by examining climatic and geophysical controls of surface soil N content and stable isotopes (δ15N) from elevational gradients distributed across tropical mountains globally. We document steep increases in soil N concentration and declining δ15N with increasing elevation, consistent with decreased microbial N processing and lower gaseous N losses. Temperature explained much of the change in N, with an apparent temperature sensitivity (Q10) of ~1.9. Although montane forests make up 11% of forested tropical land area, we estimate they account for >17% of the global tropical forest soil N pool. Our findings support the existence of widespread microbial N limitation across tropical montane forest ecosystems and high sensitivity to climate warming.

Nonalcoholic steatohepatitis (NASH) is associated with obesity, metabolic syndrome, and dysbiosis of the gut microbiome. Cholecystokinin (CCK) is released by saturated fats and plays an important role in bile acid secretion. CCK receptors are expressed on cholangiocytes, and CCK-B receptor expression increases in the livers of mice with NASH. The farnesoid X receptor (FXR) is involved in bile acid transport and is a target for novel therapeutics for NASH. The aim of this study was to examine the role of proglumide, a CCK receptor inhibitor, in a murine model of NASH and its interaction at FXR. Mice were fed a choline deficient ethionine (CDE) diet to induce NASH. Some CDE-fed mice received proglumide-treated drinking water. Blood was collected and liver tissues were examined histologically. Proglumide’s interaction at FXR was evaluated by computer modeling, a luciferase reporter assay, and tissue FXR expression. Stool microbiome was analyzed by RNA-Sequencing. CDE-fed mice developed NASH and the effect was prevented by proglumide. Computer modeling demonstrated specific binding of proglumide to FXR. Proglumide binding in the reporter assay was consistent with a partial agonist at the FXR with a mean binding affinity of 215 nM. FXR expression was significantly decreased in livers of CDE-fed mice compared to control livers, and proglumide restored FXR expression to normal levels. Proglumide therapy altered the microbiome signature by increasing beneficial and decreasing harmful bacteria. These data highlight the potential novel mechanisms by which proglumide therapy may improve NASH through interaction with the FXR and consequent alteration of the gut microbiome.

Introduction: The goal of clinical and translational science (CTS) is to fill gaps in medical knowledge toward improving human health. However, one of our most pressing challenges does not reside within the biological map we navigate to find sustainable cures but rather the moral compass to recognize and overcome racial and ethnic injustices that continue to influence our society and hinder diverse research rigor. The Georgetown-Howard Universities Center for Clinical and Translational Science includes an inter-institutional TL1-funded training program for predoctoral/postdoctoral trainees in Translational Biomedical Science (TBS). Methods: In the fall of 2020, the TBS program responded to the national social justice crisis by incorporating a curriculum focused on structural racism in biomedical research. Educational platforms, including movie reviews, Journal Clubs, and other workshops, were threaded throughout the curriculum by ensuring safe spaces to discuss racial and ethnic injustices and providing trainees with practical steps to recognize, approach, and respond to these harmful biases in the CTS. Workshops also focused on why individuals underrepresented in science are vital for addressing and closing gaps in CTS. Results: Paring analysis using REDCap software de-identified participants after invitations were sent and collected in the system to maintain anonymity for pre- and post-analysis. The Likert scale evaluated respondents’ understanding of diverse scientific circumstances. The pre/Fall and post/Spring surveys suggested this curriculum was successful at raising institutional awareness of racial and ethnic biases. Evaluating the effectiveness of our program with other training Clinical and Translational Science Awards (CTSA) consortiums will strengthen both the academic and professional TBS programs.

Bioenergy carbon capture and storage (BECCS) systems can serve as decarbonization pathways for climate mitigation. Perennial grasses are a promising second-generation lignocellulosic bioenergy feedstock for BECCS expansion, but optimizing their sustainability, productivity, and climate mitigation potential requires an evaluation of how nitrogen (N) fertilizer strategies interact with greenhouse gas (GHG) and soil organic carbon (SOC) dynamics. Furthermore, crop and fertilizer choice can affect the soil microbiome which is critical to soil organic matter turnover, nutrient cycling, and sustaining crop productivity but these feedbacks are poorly understood due to the paucity of data from certain agroecosystems. Here, we examine the climate mitigation potential and soil microbiome response to establishing two functionally different perennial grasses, switchgrass (Panicum virgatum, C4) and tall wheatgrass (Thinopyrum ponticum, C3), in a cool semi-arid agroecosystem under two fertilizer applications, a novel cyanobacterial biofertilizer (CBF) and urea. We find that in contrast to the C4 grass, the C3 grass achieved 98% greater productivity and had a higher N use efficiency when fertilized. For both crops, the CBF produced the same biomass enhancement as urea. Non-CO2 GHG fluxes across all treatments were low and we observed a 3-year net loss of SOC under the C4 crop and a net gain under the C3 crop at a 0–30 cm soil depth regardless of fertilization. Finally, we detected crop-specific changes in the soil microbiome, including an increased relative abundance of arbuscular mycorrhizal fungi under the C3, and potentially pathogenic fungi in the C4 grass. Taken together, these findings highlight the potential of CBF-fertilized C3 crops as a second-generation bioenergy feedstock in semi-arid regions as a part of a climate mitigation strategy.

The emergence of therapeutics targeted at hearing loss holds great promise in the development of novel treatments for this heterogenous condition. Whilst such therapeutics are largely designed to be efficacious in and of themselves, the possibility of combination with devices, namely cochlear implants, could result in much more effective treatment options. Here, we review the otoprotective molecules currently in clinical development, as well as generic steroids, discussing mechanisms of action and mode of delivery to the perilymph of the cochlea. Presenting both preclinical and clinical data, we explore the challenges these molecules face in reaching the inner ear. Furthermore, we consider the role of the cochlear implant as a drug delivery platform along with the ability of these drugs to preserve residual hearing and improve outcomes in implant recipients.

Growth of pancreatic cancer is stimulated by gastrin in both a paracrine and an autocrine fashion. Traditional therapies have not significantly improved survival, and recently pancreatic cancer has been deemed a “cold” tumor due to its poor response to immunotherapy. Strategies to improve survival of pancreatic cancer are desperately needed. In the current investigation, we studied the effects of an anti-gastrin cancer vaccine, polyclonal antibody stimulator (PAS; formerly called G17DT and Gastrimmune), used alone or in combination with a programmed cell death receptor (PD)-1 immune checkpoint antibody on pancreatic cancer growth, metastases, and the tumor microenvironment (TME). Immune-competent female C57BL/6 mice bearing syngeneic orthotopic murine pancreatic cancer treated with PAS had significantly smaller tumors and fewer metastases. Examination of the TME demonstrated decreased fibrosis with fewer M2 and more M1 tumor-associated macrophages. Expression of the E-cadherin gene was significantly increased and expression of the TGFβR2 gene was decreased compared with controls. Mice treated with PAS or the combination of PAS and PD-1 antibody exhibited significantly less tumor expression of phospho-paxillin, the focal adhesion protein β-catenin, and matrix metalloproteinase-7. This study suggests that inhibition of the cancer-promoting effects of gastrin in pancreatic cancer can decrease metastases by altering the TME and decreasing pathways that activate the epithelial mesenchymal transition. The PAS vaccine appears to change the TME, making it more susceptible to therapy with an immune checkpoint antibody. This novel combination of two immunotherapies may improve survival of pancreatic cancer by decreasing both tumor growth and metastasis formation.NEW & NOTEWORTHY Survival from advanced pancreatic cancer is poor, in part due to dense fibrosis of the tumor microenvironment, increased number of M2-polarized macrophages that promote angiogenesis and invasion, and lack of “target-specific” therapy. Herein, we report that a tumor vaccine that selectively targets gastrin decreases pancreatic cancer growth and metastases. Furthermore, the gastrin vaccine polyclonal antibody stimulator alters the tumor microenvironment rendering it more responsive to immunotherapy with a programmed cell death receptor-1 immune checkpoint antibody.

Urgency and deliberateness are often at odds when executing conservation projects, especially as the scale and complexity of objectives increases. The pace of environmental degradation supports immediate and measurable action. However, best practices for adaptive governance and building resilient social-ecological systems call for more deliberate efforts and participatory processes, which can be slow. We explore conflicts between urgency and deliberateness and the potential for their reconciliation through a case study of the challenges of conserving native rangelands in North America's Northern Great Plains, an ecoregion targeted for global conservation initiatives. This region is undergoing a significant social-ecological transition, which underscores a need to rethink conservation strategies in light of the social-ecological system dynamics and potential future trajectories. Based on a structured narrative literature review process and iterative engagement with key regional stakeholders, we identify three interrelated factors critical to the system's future outcomes that illustrate system complexity as well as trade-offs between urgent and deliberate action and unilateral and multilateral approaches to conservation: (1) influences of land management on biodiversity, (2) economic restructuring and shifting land use priorities, and (3) changing climate and disturbance regimes. We identify key gaps in the literature for each factor and across the factors - an effort that informs our call for research and practice agendas that address uncertainty and complexity at regional scales through more inclusive and future-oriented approaches.

Extension agents are finding themselves engaged in problem-solving roles as public needs adjust to a climate where issues facing the agricultural and natural resource industry are more often contentious than benign. As connectors between the Land-grant university system and the public, Extension agents need to know how to effectively communicate about contentious issues with clientele. This study used an online survey design to determine Extension agents’ attitudes toward contentious issues, challenges that they face, and effective means of communication. The findings revealed Extension agents’ attitudes toward communicating about contentious issues were more positive than negative. Additionally, they found the availability of misinformation and the complexity of contentious issues to be most challenging when communicating with clientele. One-on-one in-person, workshops, phone calls, and group meetings were identified as the most effective methods of communicating about contentious issues. Additional training and familiarization with current contentious issues were recommended. Future research should examine the contentious issues Extension agents are discussing, methods being used to facilitate conversations, the effect of contentious issues on job satisfaction, and the factors hindering Extension agents as they address contentious issues.

Hepatocellular carcinoma (HCC) is the fastest growing cancer worldwide in part due to the obesity epidemic and fatty liver disease, particularly nonalcoholic steatohepatitis (NASH). Chronic inflammation with the release of cytokines and chemokines with activation of hepatic stellate cells results in changes of the liver extracellular matrix (ECM) that predisposes to the development of HCC. Blood levels of the gastrointestinal peptide cholecystokinin (CCK) are increased in humans and mice consuming a high-fat diet. We found that the CCK-B receptor (CCK-BR) expression increased in the livers of mice with NASH. Treatment of mice with a CCK-BR antagonist, proglumide, prevented NASH, lowered hepatic inflammatory cytokines and chemokines, reduced oxidative stress, decreased F4/80+ hepatic macrophages, and prevented HCC. CCK-AR and CCK-BR expression was increased in both murine and human HCC cell lines compared with that of normal liver, and CCK stimulated the growth of wild-type and CCK-A receptor knockout HCC cells in vitro, but not CCK-BR knockout cells suggesting that the CCK-BR mediates proliferation. Proglumide therapy significantly reduced growth by 70% and 73% in mice bearing Dt81Hepa1–6 or in RIL-75 HCC tumors, respectively. IHC of a human liver tissue array with a selective CCK-BR antibody revealed staining of human HCC and no staining in normal liver. Prevention Relevance: This investigation demonstrates the role of the gastrointestinal peptide cholecystokinin (CCK) in hepatocellular carcinoma (HCC) and how CCK-BR blockade reverses the premalignant state of the hepatic extracellular matrix hence, rendering it less susceptible to the development of HCC. Thereby, CCK-BR blockade is a novel approach for the prevention/treatment of HCC.

The demand for local food has risen dramatically over the last decade, and many states have created brands to promote products grown within that state. However, the effect of state brands on consumer perceptions remains unknown. Extension agents serve as change agents and a bridge between science and the public to purvey information for adoption decisions. This study sought to determine if differences existed between consumers’ perceptions of food labeled local and food labeled Fresh from Florida to inform Extension programming. Florida residents (N = 530) were surveyed utilizing a between-subjects experimental design. Respondents were asked questions about their attitudes, trust and transparency, and information preferences toward food labeled Fresh from Florida or local food, depending on the experimental treatment they received. Results of this study indicated that consumers shared similar perceptions of local and Fresh from Florida food, except for the belief that Fresh from Florida comes from larger farms, Fresh from Florida labeling is more trustworthy, and there is a greater desire to see a definition of Fresh from Florida food. When Extension agents develop programming on economic viability, information on local food and state brands should be included to help producers market their products and increase revenues.

The resoneut detector setup is described, which was developed for resonance spectroscopy using (d,n) reactions with radioactive beams in inverse kinematics and at energies around the Coulomb barrier. The goal of experiments with this setup is to determine the spectrum and proton-transfer strengths of the low-lying resonances, which have an impact on astrophysical reaction rates. The setup is optimized for l = 0 proton transfers in inverse kinematics, for which most neutrons are emitted at backward angles with energies in the 80–300 keV range. The detector system is comprised of 9 p-terphenyl scintillators as neutron detectors, two annular silicon-strip detectors for light charged particles, one position-resolving gas ionization chamber for heavy ion detection, and a barrel of NaI-detectors for the detection of γ -rays. The detector commissioning and performance characteristics are described with an emphasis on the neutron-detector components.

Simple Summary Our research team has identified the cholecystokinin-B receptor (or CCK-BR) as a novel target for treatment of pancreatic cancer. CCK-BRs are over-expressed in pancreatic cancer and activation stimulates growth in cell culture and in animal models. CCK-BRs are also expressed on pancreatic stellate cells—or the fibroblasts that are responsible for the dense fibrosis in the tumor microenvironment that impedes the penetration of chemotherapy. We show strong evidence that treatment with a CCK receptor antagonist, proglumide, decreases fibrosis in the pancreatic tumor microenvironment and increases the influx of T-cells rendering chemotherapy-resistant cancer, sensitive to gemcitabine. Mice treated with the combination therapy had fewer metastases and greater survival. Tumors from these mice had higher gemcitabine levels and novel differentially expressed genes by RNA-Seq. Proglumide is an older drug that was developed many years ago for peptic ulcer disease but is no longer in use. Repurposing this older drug may improve survival from this recalcitrant malignancy. Abstract Pancreatic cancer is resistant to chemotherapy in part due to the dense desmoplastic fibrosis surrounding the tumor, the immunosuppressive cells in the tumor microenvironment (TME), and the early rate of metastases. In this study, we examined the effects of a CCK receptor antagonist, proglumide, alone and in combination with gemcitabine in murine models of pancreatic cancer. Tumor growth rate, metastases, and survival were assessed in mice bearing syngeneic murine or human pancreatic tumors treated with PBS (control), gemcitabine, proglumide, or the combination of gemcitabine and proglumide. Excised tumors were evaluated histologically for fibrosis, immune cells, molecular markers, and uptake of chemotherapy by mass spectroscopy. Peripheral blood was analyzed with a microRNAs biomarker panel associated with fibrosis and oncogenesis. Differentially expressed genes between tumors of mice treated with gemcitabine monotherapy and combination therapy were compared by RNAseq. When given in combination the two compounds exhibited inhibitory effects by decreasing tumor growth rate by 70%, metastases, and prolonging survival. Proglumide monotherapy altered the TME by decreasing fibrosis, increasing intratumoral CD8+ T-cells, and decreasing arginase-positive cells, thus rendering the tumor sensitive to chemotherapy. Proglumide altered the expression of genes involved in fibrosis, epithelial–mesenchymal transition, and invasion. CCK-receptor antagonism with proglumide renders pancreatic cancer susceptible to chemotherapy.

In childhood, partial hearing loss can produce prolonged deficits in speech perception and temporal processing. However, early therapeutic interventions targeting temporal processing may improve later speech-related outcomes. Gap detection is a measure of auditory temporal resolution that relies on the auditory cortex (ACx), and early auditory deprivation alters intrinsic and synaptic properties in the ACx. Thus, early deprivation should induce deficits in gap detection, which should be reflected in ACx gap sensitivity. We tested whether earplugging-induced, early transient auditory deprivation in male and female Mongolian gerbils caused correlated deficits in behavioral and cortical gap detection, and whether these could be rescued by a novel therapeutic approach: brief exposure to gaps in background noise. Two weeks after earplug removal, animals that had been earplugged from hearing onset throughout auditory critical periods displayed impaired behavioral gap detection thresholds (GDTs), but this deficit was fully reversed by three 1 h sessions of exposure to gaps in noise. In parallel, after earplugging, cortical GDTs increased because fewer cells were sensitive to short gaps, and gap exposure normalized this pattern. Furthermore, in deprived animals, both first-spike latency and first-spike latency jitter increased, while spontaneous and evoked firing rates decreased, suggesting that deprivation causes a wider range of perceptual problems than measured here. These cortical changes all returned to control levels after gap exposure. Thus, brief stimulus exposure, perhaps in a salient context such as the unfamiliar placement into a testing apparatus, rescued impaired gap detection and may have potential as a remediation tool for general auditory processing deficits.SIGNIFICANCE STATEMENT Hearing loss in early childhood leads to impairments in auditory perception and language processing that can last well beyond the restoration of hearing sensitivity. Perceptual deficits can be improved by training, or by acoustic enrichment in animal models, but both approaches involve extended time and effort. Here, we used a novel remediation technique, brief periods of auditory stimulus exposure, to fully remediate cortical and perceptual deficits in gap detection induced by early transient hearing loss. This technique also improved multiple cortical response properties. Rescue by this efficient exposure regime may have potential as a therapeutic tool to remediate general auditory processing deficits in children with perceptual challenges arising from early hearing loss.

A semiselective, diagnostic agar medium (T-5) and low temperature incubation technique were developed for recovering Pseudomonas viridiflava from the environment or plant material. Medium T-5 contains the following per liter: NaCl, 5.0 g; NH4H2PO4, 1.0 g; K2HPO4, 1.0 g; MgSO4·H2O, 0.2 g; D-tartaric acid, 3.0 g; phenol red, 0.01 g; agar, 20.0 g; bacitracin, 10 mg; vancomycin, 6 mg; cycloheximide, 75 mg; novobiocin, 45 mg; penicillin G, 5 mg. The pH is adjusted to 7.4. Antibiotics are added aseptically after autoclaving. P. viridiflava recovery from artificially infested, field-soil (Tifton loamy-sand), with a cropping history of no onion production, was high, with a corresponding reduction of 99.99% of nontarget bacteria. However, soils from fields with a long history of onion production, near Vidalia, Georgia, contained significantly larger populations of background microflora that grew on medium T-5. Incubation at 5°C reduced contaminating microflora 1,000- to 10,000-fold with no reduction in recovery of the target organism. However, this low temperature incubation required an increased incubation period of 3 weeks and reduced the level of fluorescence of P. viridiflava.

Background and Aims Nonalcoholic steatohepatitis (NASH) is a common inflammatory liver condition that may lead to cirrhosis and hepatocellular carcinoma (HCC). Risk factors for NASH include a saturated fat diet, altered lipid metabolism, and genetic and epigenetic factors, including microRNAs. Serum levels of cholecystokinin (CCK) are elevated in mice and humans that consume a high-saturated fat diet. CCK receptors (CCK-Rs) have been reported on fibroblasts which when activated can induce fibrosis; however, their role in hepatic fibrosis remains unknown. We hypothesized that elevated levels of CCK acting on the CCK-Rs play a role in the development of NASH and in NASH-associated HCC. Methods We performed a NASH Prevention study and Reversal study in mice fed a saturated fat 75% choline-deficient–ethionine-supplemented (CDE) diet for 12 or 18 weeks. In each study, half of the mice received untreated drinking water, while the other half received water supplemented with the CCK-R antagonist proglumide. CCK-R expression was evaluated in mouse liver and murine HCC cells. Results CCK receptor antagonist treatment not only prevented NASH but also reversed hepatic inflammation, fibrosis, and steatosis and normalized hepatic transaminases after NASH was established. Thirty-five percent of the mice on the CDE diet developed HCC compared with none in the proglumide-treated group. We found that CCK-BR expression was markedly upregulated in mouse CDE liver and HCC cells compared with normal hepatic parenchymal cells, and this expression was epigenetically regulated by microRNA-148a. Conclusion These results support the novel role of CCK receptors in the pathogenesis of NASH and HCC.

The relationship between share prices and macroeconomic variables is well documented for the United States and other major economies. However, what is the relationship between share prices and economic activity in emerging economies? The goal of this study is to investigate the time-series relationship between stock market index prices and the macroeconomic variables of exchange rate and oil price for Brazil, Russia, India, and China (BRIC) using the Box-Jenkins ARIMA model. Although no significant relationship was found between respective exchange rate and oil price on the stock market index prices of either BRIC country, this may be due to the influence other domestic and international macroeconomic factors on stock market returns, warranting further research. Also, there was no significant relationship found between present and past stock market returns, suggesting the markets of Brazil, Russia, India, and China exhibit the weak-form of market efficiency.

Background: The fastest-growing cause of cancer-related death is hepatocellular carcinoma (HCC), which is in part attributable to the obesity epidemic and nonalcoholic steatohepatitis (NASH). The gastrointestinal (GI) peptides, gastrin and cholecystokinin (CCK), regulate digestive functions and growth of the GI tract through the G-protein coupled receptors CCK- receptors (CCK-Rs). Both peptides activate the CCK-B receptor (CCK-BR) whereas only CCK peptide activates the CCK-A receptor (CCK-AR). CCK-Rs and gastrin are low or absent in normal mouse hepatocytes. We have previously shown that CCK blood levels increase and CCK-Rs become overexpressed in the livers of mice eating a high saturated fat diet that induced NASH and HCC. Hypothesis: CCK and gastrin mediate the growth of HCC through the CCK-R and that interruption of this signaling pathway could decrease growth of HCC. Methods: RNA was extracted from murine Hepa1-6, RIL-175, and human HepG2 cells and was evaluated by qRT-PCR for expression of CCK-AR, CCK-BR, and gastrin. CCK-R protein expression was analyzed by flow cytometry. In order to determine which CCK-R mediated the growth effects, growth was studied in vitro using selective receptor antagonists or CRISPR Cas9 technology to knock-out each receptor. HCC cells were treated in vitro with CCK peptide (1-10nM), the CCK-AR antagonist (L364,718), or the CCK-BR antagonist (L365,260). Proliferation of selective CCK-R KO cells was compared to that of wild-type cells. To determine the effect of a CCK-R antagonist on tumor growth in vivo, two cohorts of mice bearing subcutaneous Hepa1-6 or RIL-175 HCC tumors were treated with an oral bioavailable CCK-R antagonist, proglumide (1 mg/ml) or untreated water (controls) for 3-4 weeks. The mice bearing Hepa1-6 tumors were placed on a high-fat diet to raise blood CCK levels. Mice bearing RIL-175 tumors were fed standard chow to determine if proglumide could block autocrine growth by gastrin. Results: The mRNA expression of CCK-AR, CCK-BR and gastrin were increased 80-90-fold in all HCC cell lines compared to that of normal liver. CCK-BRs were detected on >85% of the cells by flow cytometry. CCK peptide (1nM) stimulated HCC growth in vitro in both wild-type cells and in CCK-AR KO cells but not in CCK-BR KO cells. CCK-BR antagonist blocked CCK-stimulated growth in vitro but the CCK-AR antagonist did not, suggesting that the CCK-BR was responsible for mediating proliferation. In vivo tumor growth was significantly reduced with proglumide treatment by 70% (p Conclusion: CCK-Rs are overexpressed in HCC and proliferation appears to be mediated through the CCK-BR. Downregulation with CRISPR Cas9 or blockade of the CCK-BR with an antagonist decreases growth in vitro and proglumide therapy decreases tumor growth in vivo. Strategies that block signaling at the CCK-BR may provide a novel therapeutic option for HCC treatment. Citation Format: Martha D. Gay, Anita Safronenka, Hong Cao, Robin Tucker, Narayan Shivapurkar, Jill P. Smith. Cholecystokinin-B receptor mediates growth of hepatocellular carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5193.

Summary Emergency cricothyrotomy is a common feature in all difficult airway algorithms. It is the final step following a ‘can't intubate, can't oxygenate’ scenario. It is rarely performed and has a significant failure rate. There is variation in the reported size of the cricothyroid membrane, especially across population groups. Procedural failure may result from attempting to pass a device with too large an external diameter through the cricothyroid membrane. We aimed to determine the maximum height of the cricothyroid membrane in a UK trauma population. Electronic callipers were used to measure the maximum height of the cricothyroid membrane on 482 reformatted trauma computed tomography scans, 377 (78.2%) of which were in male patients. The mean (SD) height of the cricothyroid membrane, as independently measured by two radiologists, was 7.89 (2.21) mm and 7.88 (2.22) mm in male patients, and 6.00 (1.76) mm and 5.92 (1.71) mm in female patients. The presence of concurrent tracheal intubation or cervical spine immobilisation was found not to have a significant effect on cricothyroid membrane height. The cricothyroid membrane height in the study population was much smaller than that previously reported. Practitioners encountering patients who may require an emergency surgical airway should be aware of these data. Rescue airway equipment with variety of external diameters should be immediately available.

Reliable measurement of total testosterone is essential for the diagnosis, treatment and prevention of a number of hormone-related diseases affecting adults and children. A mass spectrometric method for testosterone determination in human serum was carefully developed and thoroughly validated. Total testosterone from 100 μL serum is released from proteins with acidic buffer and isolated by two serial liquid–liquid extraction steps. The first extraction step isolates the lipid fractions from an acidic buffer solution using ethyl acetate and hexane. The organic phase is dried down and reconstituted in a basic buffer solution. The second extraction step removes the phospholipids and other components by hexane extraction. Liquid chromatography–isotopic dilution tandem mass spectrometry is used to quantify the total testosterone. The sample preparation is automatically conducted in a liquid-handling system with 96-deepwell plates. The method limit of detection is 9.71 pmol/L (0.280 ng/dL) and the method average percent bias is not significantly different from reference methods. The performance of this method has proven to be consistent with the method precision over a 2-year period ranging from 3.7 to 4.8% for quality control pools at the concentrations 0.527, 7.90 and 30.7 nmol/L (15.2, 228, and 886 ng/dL), respectively. This method provides consistently high accuracy and excellent precision for testosterone determination in human serum across all clinical relevant concentrations.

Background: The fastest growing cause of cancer related death is hepatocellular carcinoma (HCC), in part due to the rising prevalence of nonalcoholic steatohepatitis (NASH). HCC cases are expected to increase during 2015-2030. Cholecystokinin (CCK), blood levels are increased in those consuming high fat diets and CCK receptors have been identified in normal liver, fibroblasts, and immune cells. Hypothesis: We hypothesize that CCK receptor blockade could decrease NASH and prevent HCC in a mouse model.Methods: We examined whether CCK receptor blockade with proglumide could decrease NASH in the choline deficient ethionine supplemented (CDE)-diet mouse model. Two cohorts of Female C57BL/6 mice (N=65) mice were examined: (1) a preventive study in which mice were treated for 12 and 18 weeks to determine if proglumide could prevent NASH and HCC and (2) a ‘reversal study’ in which histologic and biochemical NASH was induced on a 75% CDE high fat diet for 12 weeks followed by treatment with proglumide for 6 weeks (until week 18) while remaining on the CDE diet to determine if CCK-receptor blockade could reverse NASH once established. Control mice received the same high fat diet with choline and half received proglumide therapy. Results: Alanine aminotransferase, aspartate aminotransferases, and bilirubin were increased in mice on the CDE/Regular (untreated water) diet and these values returned to near normal with proglumide therapy in the prevention study and also reversed after NASH was established. Histologic scoring showed significant decreased inflammation, fibrosis and steatosis in mice on the high fat CDE diet when treated with proglumide. 35% of the mice (N=23) at week 18 developed HCC or dysplastic nodules on the CDE diet while none of the mice in the CDE/proglumide prevention (N=15) or reversal therapy groups (N=15) had HCC. Mice on the lard-control diet had fatty livers at week 18 but no evidence of NASH histologically or biochemically and no HCC. Fibrosis was decreased in mice treated with proglumide as evidence by Masson’s trichrome stain and Western blot for FAP. Gene expression of the liver’s collagen-4, TGFβR11, PDGH-Rβ, and collagen-1α1 as determined by qRT-PCR decreased with proglumide treatment. Control diet fed mice had normal serum tests and fibrosis biomarkers. Conclusion: This data supports our novel hypothesis that CCK receptors play a role in NASH-associated HCC. CCK receptor blockade decreased histologic and biochemical evidence of NASH and prevented HCC. Since proglumide has already been tested in human subjects for peptic ulcer disease decades ago and is known to be orally bioavailable, results of our study could easily be translated into a clinical trial in human subjects to improve NASH to prevent HCC. Supported by AGA Research Foundation, Ruesch Foundation, and a grant from NIH, TL1TR001431 Citation Format: Martha D. Gay, Victor Ciofoaia, Sandeep Nadella, Hong Cao, Matthew Huber, Robin D. Tucker, Narayan Shivapurkar, Bhaskar Kallakury, Alexander H. Kroemer, Jill P. Smith. Cholecystokinin receptor antagonist proglumide reverses nonalcoholic steatohepatitis and prevents hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2728.

Current control is the most basic control loop for a current controlled inverter-fed machine. Current controllers fall into two categories depending on the reference frames they operate in — rotating reference frame controllers, and stationary frame controllers. This paper introduces a novel current control technique for inverter controlled machines known as Local Vector Control (LVC). This control technique can be used for the current control loops as well as outer control loops, and can operate without alteration in a stationary or rotating reference frame. Due to its high gain properties it potentially offers excellent transient performance, minimises the effects of disturbances, and operates with varying system parameters. This paper is a preliminary investigation of this algorithm applied to power electronic applications.

This paper presents the Local Vector Control (LVC) algorithm that is applicable to power electronic systems. This controller does not differentiate between linear or non-linear systems and can operate, without change, in stationary or rotating reference frames. The performance of this current controller with particular emphasis on current clamp minimisation will be the paper's focus. A comparison between the LVC, PI and predictive dead-beat current controllers (PCC) is presented.