Efficacy of immune checkpoint inhibitors for the treatment of advanced melanoma in patients with concomitant chronic lymphocytic leukemia.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have revolutionized the management of advanced melanoma (AM). However, data on ICI effectiveness have largely been restricted to clinical trials, thereby excluding patients with co-existing malignancies. Chronic lymphocytic leukemia (CLL) is the most prevalent adult leukemia and is associated with increased risk of melanoma. CLL alters systemic immunity and can induce T-cell exhaustion, which may limit the efficacy of ICIs in patients with CLL. We, therefore, sought to examine the efficacy of ICI in patients with these co-occurring diagnoses. PATIENTS AND METHODS: In this international multicenter study, a retrospective review of clinical databases identified patients with concomitant diagnoses of CLL and AM treated with ICI (US-MD Anderson Cancer Center, N = 24; US-Mayo Clinic, N = 15; AUS, N = 19). Objective response rates (ORRs), assessed by RECIST v1.1, and survival outcomes [overall survival (OS) and progression-free survival (PFS)] among patients with CLL and AM were assessed. Clinical factors associated with improved ORR and survival were explored. Additionally, ORR and survival outcomes were compared between the Australian CLL/AM cohort and a control cohort of 148 Australian patients with AM alone. RESULTS: Between 1997 and 2020, 58 patients with concomitant CLL and AM were treated with ICI. ORRs were comparable between AUS-CLL/AM and AM control cohorts (53% versus 48%, P = 0.81). PFS and OS from ICI initiation were also comparable between cohorts. Among CLL/AM patients, a majority were untreated for their CLL (64%) at the time of ICI. Patients with prior history of chemoimmunotherapy treatment for CLL (19%) had significantly reduced ORRs, PFS, and OS. CONCLUSIONS: Our case series of patients with concomitant CLL and melanoma demonstrate frequent, durable clinical responses to ICI. However, those with prior chemoimmunotherapy treatment for CLL had significantly worse outcomes. We found that CLL disease course is largely unchanged by treatment with ICI.

Mortality and histopathology in sheepshead minnow (Cyprinodon variegatus) larvae exposed to pectenotoxin-2 and Dinophysis acuminata.

Toxic species of the dinoflagellate genus Dinophysis can produce diarrheic toxins including okadaic acid (OA) and dinophysistoxins (DTXs), and the non-diarrheic pectenotoxins (PTXs). Okadaic acid and DTXs cause diarrheic shellfish poisoning (DSP) in human consumers, and also cause cytotoxic, immunotoxic and genotoxic effects in a variety of mollusks and fishes at different life stages in vitro. The possible effects of co-produced PTXs or live cells of Dinophysis to aquatic organisms, however, are less understood. Effects on an early life stage of sheepshead minnow (Cyprinodon variegatus), a common finfish in eastern USA estuaries, were evaluated using a 96-h toxicity bioassay. Three-week old larvae were exposed to PTX2 concentrations from 50 to 4000 nM, live Dinophysis acuminata culture (strain DAVA01), live cells resuspended in clean medium or culture filtrate. This D. acuminata strain produced mainly intracellular PTX2 (≈ 21 pg cell-1), with much lower levels of OA and dinophysistoxin-1. No mortality or gill damages were observed in larvae exposed to D. acuminata (from 5 to 5500 cells mL-1), resuspended cells and culture filtrate. However, exposure to purified PTX2 at intermediate to high concentrations (from 250 to 4000 nM) resulted in 8 to 100% mortality after 96 h (24-h LC50 of 1231 nM). Histopathology and transmission electron microscopy of fish exposed to intermediate to high PTX2 concentrations revealed important gill damage, including intercellular edema, necrosis and sloughing of gill respiratory epithelia, and damage to the osmoregulatory epithelium, including hypertrophy, proliferation, redistribution and necrosis of chloride cells. Tissue damage in gills is likely caused by the interaction of PTX2 with the actin cytoskeleton of the affected gill epithelia. Overall, the severe gill pathology observed following the PTX2 exposure suggested death was due to loss of respiratory and osmoregulatory functions in C. variegatus larvae.

Targeting improved resilience in Merino sheep - Correlations between immune competence and health and fitness traits.

Resilience can be defined as the ability of an animal to remain productive in the face of diverse environmental challenges. Several factors contribute to an animal's resilience including its ability to resist disease, cope with climatic extremes and respond to stressors. Immune competence, a proxy trait for general disease resistance, is expected to contribute to an animal's resilience. This research aimed to develop a practical method to assess immune competence in Merino sheep which would not restrict the future sale of tested animals, and to estimate genetic parameters associated with the novel trait. We also aimed to explore associations between immune competence and other industry-relevant disease resistance and fitness-related traits and to assess the ability of immune competence phenotypes to predict health outcomes. Here, the ability of Merino wethers (n = 1 339) to mount both an antibody-mediated and cell-mediated immune response was used to define their immune competence phenotype. For that purpose, antigens in a commercial vaccine were administered at the commencement of weaning and their responses were assessed. Univariate sire models were used to estimate variance components and heritabilities for immune competence and its component traits. Bivariate sire models were used to estimate genetic correlations between immune competence and a range of disease resistance and fitness-related traits. The heritability of immune competence and its component traits, antibody-mediated immune response and cell-mediated immune response were estimated at 0.49 ±â€¯0.14, 0.52 ±â€¯0.14 and 0.36 ±â€¯0.11, respectively. Immune competence was favourably genetically correlated with breech flystrike incidence (-0.44 ±â€¯0.39), worm egg count (-0.19 ±â€¯0.23), dag score (-0.26 ±â€¯0.31) and fitness compromise (-0.35 ±â€¯0.24) but not fleece rot (0.17 ±â€¯0.23). Results suggest that selection for immune competence has the potential to improve the resilience of Merino sheep; however, due to the large standard errors associated with correlation estimates reported here, further studies will be required in larger populations to validate associations between immune competence and disease resistance and fitness traits in Australian Merino sheep.

Robust bulk micro-nano hierarchical copper structures possessing exceptional bactericidal efficacy.

Conventional copper (Cu) metal surfaces are well recognized for their bactericidal properties. However, their slow bacteria-killing potency has historically excluded them as a rapid bactericidal material. We report the development of a robust bulk superhydrophilic micro-nano hierarchical Cu structure that possesses exceptional bactericidal efficacy. It resulted in a 4.41 log10 reduction (>99.99%) of the deadly Staphylococcus aureus (S. aureus) bacteria within 2 min vs. a 1.49 log10 reduction (96.75%) after 240 min on common Cu surfaces. The adhered cells exhibited extensive blebbing, loss of structural integrity and leakage of vital intracellular material, demonstrating the rapid efficacy of the micro-nano Cu structure in destructing bacteria membrane integrity. The mechanism was attributed to the synergistic degradation of the cell envelope through enhanced release and therefore uptake of the cytotoxic Cu ions and the adhesion-driven mechanical strain due to its rapid ultimate superhydrophilicity (contact angle drops to 0° in 0.18 s). The scalable fabrication of this micro-nano Cu structure was enabled by integrating bespoke precursor alloy design with microstructure preconditioning for dealloying and demonstrated on 2000 mm2 Cu surfaces. This development paves the way to the practical exploitation of Cu as a low-cost antibiotic-free fast bactericidal material.

Altered Processing of Complex Visual Stimuli in Patients with Postconcussive Visual Motion Sensitivity.

BACKGROUND AND PURPOSE: Vestibular symptoms are common after concussion. Vestibular Ocular Motor Screening identifies vestibular impairment, including postconcussive visual motion sensitivity, though the underlying functional brain alterations are not defined. We hypothesized that alterations in multisensory processing are responsible for postconcussive visual motion sensitivity, are detectable on fMRI, and correlate with symptom severity. MATERIALS AND METHODS: Twelve patients with subacute postconcussive visual motion sensitivity and 10 healthy control subjects underwent vestibular testing and a novel fMRI visual-vestibular paradigm including 30-second "neutral" or "provocative" videos. The presence of symptoms/intensity was rated immediately after each video. fMRI group-level analysis was performed for a "provocative-neutral" condition. Z-statistic images were nonparametrically thresholded using clusters determined by Z > 2.3 and a corrected cluster significance threshold of P = .05. Symptoms assessed on Vestibular Ocular Motor Screening were correlated with fMRI mean parameter estimates using Pearson correlation coefficients. RESULTS: Subjects with postconcussive visual motion sensitivity had significantly more Vestibular Ocular Motor Screening abnormalities and increased symptoms while viewing provocative videos. While robust mean activation in the primary and secondary visual areas, the parietal lobe, parietoinsular vestibular cortex, and cingulate gyrus was seen in both groups, selective increased activation was seen in subjects with postconcussive visual motion sensitivity in the primary vestibular/adjacent cortex and inferior frontal gyrus, which are putative multisensory visual-vestibular processing centers. Moderate-to-strong correlations were found between Vestibular Ocular Motor Screening scores and fMRI activation in the left frontal eye field, left middle temporal visual area, and right posterior hippocampus. CONCLUSIONS: Increased fMRI brain activation in visual-vestibular multisensory processing regions is selectively seen in patients with postconcussive visual motion sensitivity and is correlated with Vestibular Ocular Motor Screening symptom severity, suggesting that increased visual input weighting into the vestibular network may underlie postconcussive visual motion sensitivity.

'Stat' workflow modifications to expedite care after needlestick injuries.

BACKGROUND: Post-exposure prophylaxis (PEP) for human immunodeficiency virus (HIV) is recommended to start within hours of needlestick injuries (NSIs) among healthcare workers (HCWs). Delays associated with awaiting the results of testing from the source patient (whose blood was involved in the NSI) can lead to psychological consequences for the exposed HCW as well as symptomatic toxicities from empiric PEP. AIMS: After developing a 'stat' (immediate) workflow that prioritized phlebotomy and resulting of source patient bloodwork for immediate handling and processing, we retrospectively investigated whether our new workflow had (i) decreased HIV order-result interval times for source patient HIV bloodwork and (ii) decreased the frequency of HIV PEP prescriptions being dispensed to exposed HCWs. METHODS: We retrospectively analysed NSI records to identify source patient HIV order-result intervals and PEP dispensing frequencies across a 6-year period (encompassing a 54-month pre-intervention period and 16-month post-intervention period). RESULTS: We identified 251 NSIs, which occurred at similar frequencies before versus after our intervention (means 3.54 NSIs and 3.75 NSIs per month, respectively). Median HIV order-result intervals decreased significantly (P < 0.05) from 195 to 156 min after our intervention, while the proportion of HCWs who received one or more doses of PEP decreased significantly (P < 0.001) from 50% (96/191) to 23% (14/60). CONCLUSION: Using a 'stat' workflow to prioritize source patient testing after NSIs, we achieved a modest decrease in order-result intervals and a dramatic decrease in HIV PEP dispensing rates. This simple intervention may improve HCWs' physical and psychological health during a traumatic time.

Sweet Corn Sentinel Monitoring for Lepidopteran Field-Evolved Resistance to Bt Toxins.

As part of an insect resistance management plan to preserve Bt transgenic technology, annual monitoring of target pests is mandated to detect susceptibility changes to Bt toxins. Currently Helicoverpa zea (Boddie) monitoring involves investigating unexpected injury in Bt crop fields and collecting larvae from non-Bt host plants for laboratory diet bioassays to determine mortality responses to diagnostic concentrations of Bt toxins. To date, this monitoring approach has not detected any significant change from the known range of baseline susceptibility to Bt toxins, yet practical field-evolved resistance in H. zea populations and numerous occurrences of unexpected injury occur in Bt crops. In this study, we implemented a network of 73 sentinel sweet corn trials, spanning 16 U.S. states and 4 Canadian provinces, for monitoring changes in H. zea susceptibility to Cry and Vip3A toxins by measuring differences in ear damage and larval infestations between isogenic pairs of non-Bt and Bt hybrids over three years. This approach can monitor susceptibility changes and regional differences in other ear-feeding lepidopteran pests. Temporal changes in the field efficacy of each toxin were evidenced by comparing our current results with earlier published studies, including baseline data for each Bt trait when first commercialized. Changes in amount of ear damage showed significant increases in H. zea resistance to Cry toxins and possibly lower susceptibility to Vip3a. Our findings demonstrate that the sentinel plot approach as an in-field screen can effectively monitor phenotypic resistance and document field-evolved resistance in target pest populations, improving resistance monitoring for Bt crops.

The α2,3-selective potentiators of GABAA receptors, KRM-II-81 and MP-III-80, produce anxiolytic-like effects and block chemotherapy-induced hyperalgesia in mice without tolerance development.

Opiate analgesics are one of the treatment options for severe chronic pain, including late-stage cancer, chronic back pain and other disorders. The recent resurgence in opioid overdose has highlighted the serious need for alternative medicines for pain management. While a role for potentiators of α2/3-containing GABAA receptors in the modulation of pain has been known for several years, advancements in this area required data from selective compounds. KRM-II-81(5-(8-ethynyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,5-a][1,4]diazepin-3- yl)oxazole) and analogs selectively potentiate GABAA receptors containing α2/3 subunits and have recently been shown to attenuate pain behaviors in several acute and chronic pain models in rodents. The present study was designed to ascertain whether KRM-II-81 and the structural analog MP-III-80 (3-ethyl-5-(8-ethynyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,5-a][1,4]diazepin-3-yl)-1,2,4-oxadiazole) would block chemotherapeutic agent paclitaxel-induced pain in male, C57BL/6 mice. Both compounds significantly inhibited pain behaviors evoked by cold and tactile stimulation in paclitaxel-treated mice as did the neuropathic pain drug gabapentin. Subchronic dosing for 22 days with KRM-II-81 and MP-III-80 demonstrated enduring analgesic efficacy without tolerance development, while the effects of gabapentin showed evidence of tolerance development. KRM-II-81 and MP-III-80 also decreased marble-burying behavior in this mouse strain as did the anxiolytic drug chlordiazepoxide. In contrast to KRM-II-81 and MP-III-80, chlordiazepoxide had motor-impairing effects at anxiolytic-like doses. The data add to the literature documenting that these selective potentiators of α2/3-containing GABAA receptors are effective in a host of animal models used to detect novel analgesic drugs. The anxiolytic-like efficacy of these compounds fits well with the comorbidity of anxiety in patients with chronic pain and cancer.

R-(-)-ketamine modifies behavioral effects of morphine predicting efficacy as a novel therapy for opioid use disorder1.

Substance abuse disorder continues to have devastating consequences for individuals and society and current therapies are not sufficient to provide the magnitude of medical impact required. Although some evidence suggests the use of ketamine in treating various substance use related- symptoms, its adverse event profile including dissociation, dysphoria, and abuse liability limit its potential as a therapy. Here, we outline experiments to test our hypothesis that (R)-ketamine can both alleviate withdrawal symptoms and produce effects that help sustain abstinence. In morphine-dependent rats, (R)-ketamine alleviated naloxone-precipitated withdrawal signs. (R)-ketamine also blocked morphine-induced place preference in mice without inducing place preference on its own. We also evaluated whether (R)-ketamine would induce anhedonia, a counter-indicated effect for a drug abuse treatment agent. S-(+)- but not R-(-)-ketamine produced anhedonia-like responses in rats that electrically self-stimulated the medial forebrain bundle (ICSS). However, time-course studies of ICSS are needed to fully appreciate these differences. These data begin to support the claim that (R)-ketamine will dampen withdrawal symptoms and drug liking, factors known to contribute to the cycle of drug addiction. In addition, these data suggest that (R)-ketamine would not produce negative mood or anhedonia that could interfere with treatment. It is suggested that continued investigation of (R)-ketamine as a novel therapeutic for substance abuse disorder be given consideration by the preclinical and clinical research communities. This suggestion is further encouraged by a recent report on the efficacy of (R)-ketamine in treatment-resistant depressed patients at a dose with little measurable dissociative side-effects.

The α2,3-selective potentiator of GABAA receptors, KRM-II-81, reduces nociceptive-associated behaviors induced by formalin and spinal nerve ligation in rats.

Clinical evidence indicates that positive allosteric modulators (PAMs) of GABAA receptors have analgesic benefit in addition to efficacy in anxiety disorders. However, the utility of GABAA receptor PAMs as analgesics is compromised by the central nervous system side effects of non-selective potentiators. A selective potentiator of GABAA receptors associated with α2/3 subunits, KRM-II-81(5-(8-ethynyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,5-a][1,4]diazepin-3-yl)oxazole), has demonstrated anxiolytic, anticonvulsant, and antinociceptive effects in rodents with reduced motoric side effects. The present study evaluated the potential of KRM-II-81 as a novel analgesic. Oral administration of KRM-II-81 attenuated formalin-induced flinching; in contrast, diazepam was not active. KRM-II-81 attenuated nociceptive-associated behaviors engendered by chronic spinal nerve ligation (L5/L6). Diazepam decreased locomotion of rats at the dose tested in the formalin assay (10 mg/kg) whereas KRM-II-81 produced small decreases that were not dose-dependent (10-100 mg/kg). Plasma and brain levels of KRM-II-81 were used to demonstrate selectivity for α2/3- over α1-associated GABAA receptors and to define the degree of engagement of these receptors. Plasma and brain concentrations of KRM-II-81 were positively-associated with analgesic efficacy. GABA currents from isolated rat dorsal-root ganglion cultures were potentiated by KRM-II-81 with an ED50 of 32 nM. Measures of respiratory depression were reduced by alprazolam whereas KRM-II-81 was either inactive or produced effects with lower potency and efficacy. These findings add to the growing body of data supporting the idea that α2/3-selective GABAA receptor PAMs will have efficacy and tolerability as pain medications including those for neuropathic pain. Given their predicted anxiolytic effects, α2/3-selective GABAA receptor PAMs offer an additional inroad into the management of pain.

Leptospirosis: An important infectious disease in North American horses.

North American horses are commonly exposed to Leptospira organisms. Leptospira Bratislava is the most common infecting serovar but this serovar has not been confirmed to cause clinical disease in North American horses. Leptospira Pomona type kennewicki is responsible for most of the clinical diseases (leptospirosis) in North American horses. Leptospirosis is most commonly associated with diseases of the placenta and fetus, the kidneys and the eyes in horses. In-utero infections in pregnant mares may result in abortion, neonatal illness or birth of an antibody positive healthy foal. Acute renal failure in younger horses and recurrent uveitis in adult horses are other well documented clinical syndromes of leptospirosis. Abortions, neonatal disease and acute renal failure are caused by a subacute infection, while horses with Leptospira associated recurrent uveitis develop ocular disease months or years after the initial Leptospira infection. Diagnosis of Leptospirosis is made by a combination of antigen or antibody testing methods. Mares that abort following Leptospira infection have no additional clinical signs at the time of abortion but may shed the offending Leptospira spp. in the urine for several weeks. Antibiotic treatments are sometimes used in hopes of decreasing Leptospira shedding in infected horses or prophylactically in exposed pregnant mares but documentation of efficacy is lacking. Horses with Leptospira - associated acute renal failure can be successfully treated with antibiotics and supportive care. Recurrent uveitis is commonly associated with leptospirosis in North American horses and although horses may have chronic intraocular infection triggering an immune disease, systemic antimicrobial therapy has not been effective in eliminating the organism from the eye. An equine approved Leptospira Pomona type kennewicki vaccine is now available in North America.

Establishment of Striacosta albicosta (Lepidoptera: Noctuidae) as a Primary Pest of Corn in the Great Lakes Region.

Western bean cutworm, Striacosta albicosta Smith (Lepidoptera: Noctuidae), is a pest of corn, Zea maize L., and dry edible beans, Phaseolus sp. L., native to the western United States. Following the range expansion into the U.S. Corn Belt, pheromone trap monitoring began in the Great Lakes region in 2006. The first S. albicosta was captured in Michigan in 2006 and in Ontario, Canada in 2008. Pheromone traps were used to document spread and increasing captures of S. albicosta across Michigan and Ontario until 2012. Trapping confirmed the univoltine life cycle of S. albicosta in this region and identified peak flight, typically occurring in late July. Overwintering of S. albicosta in this region was confirmed by emergence from infested fields and overwintering experiments. Multiple soil textures were infested with prepupae, and recovery was assessed throughout the winter. Overwintering success was not affected by soil texture; however, prepupae were found at greater depths in coarse-textured soils. Soil temperatures at overwintering depths did not reach the supercooling point. Injury to corn by S. albicosta increased in incidence, severity and geographic range from 2010 to 2014 in field plots. Decreasing control of injury by Cry1F corn hybrids was observed over time. These findings show that S. albicosta has established as a perennial corn pest in the Great Lakes region due to observations of overwintering success and unmanaged injury. We recommend S. albicosta obtain primary pest status in this region within regulatory framework and a resistance management plan be required for traits targeting this pest.

Bioisosteres of ethyl 8-ethynyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo [1,5-a][1,4]diazepine-3-carboxylate (HZ-166) as novel alpha 2,3 selective potentiators of GABAA receptors: Improved bioavailability enhances anticonvulsant efficacy.

HZ-166 has previously been characterized as an α2,3-selective GABAA receptor modulator with anticonvulsant, anxiolytic, and anti-nociceptive properties but reduced motor effects. We discovered a series of ester bioisosteres with reduced metabolic liabilities, leading to improved efficacy as anxiolytic-like compounds in rats. In the present study, we evaluated the anticonvulsant effects KRM-II-81 across several rodent models. In some models we also evaluated key structural analogs. KRM-II-81 suppressed hyper-excitation in a network of cultured cortical neurons without affecting the basal neuronal activity. KRM-II-81 was active against electroshock-induced convulsions in mice, pentylenetetrazole (PTZ)-induced convulsions in rats, elevations in PTZ-seizure thresholds, and amygdala-kindled seizures in rats with efficacies greater than that of diazepam. KRM-II-81 was also active in the 6 Hz seizure model in mice. Structural analogs of KRM-II-81 but not the ester, HZ-166, were active in all models in which they were evaluated. We further evaluated KRM-II-81 in human cortical epileptic tissue where it was found to significantly-attenuate picrotoxin- and AP-4-induced increases in firing rate across an electrode array. These molecules generally had a wider margin of separation in potencies to produce anticonvulsant effects vs. motor impairment on an inverted screen test than did diazepam. Ester bioisosters of HZ-166 are thus presented as novel agents for the potential treatment of epilepsy acting via selective positive allosteric amplification of GABAA signaling through α2/α3-containing GABA receptors. The in vivo data from the present study can serve as a guide to dosing parameters that predict engagement of central GABAA receptors.

Assessment of the relationship between a written measure of empathy and an independently rated interview of Motivational Interviewing.

Motivational Interviewing (MI) is an evidence-based practice shown to be effective when working with people in treatment for substance use disorders. However, MI is a complex treatment modality optimized by training with feedback. Feedback, assessment and monitoring of treatment fidelity require measurement, which is typically done using audiotaped sessions. The gold standard for such measurement of MI skill has been an audiotaped interview, scored by a rater with a detailed structured instrument such as the Motivational Interviewing Treatment Integrity 2.0 (MITI 2.0) Coding System (Moyers, et al., 2005). The Helpful Responses Questionnaire (HRQ) (Miller, Hedrick, & Orlofsky, 1991) is a pen-and-paper test of empathy (a foundational MI skill) that does not require an audiotaped session. A randomized trial of three different regimens for training counselors in MI (live supervision using Teleconferencing, Tape-based supervision and Workshop only) (Smith et al., 2012) offered the opportunity to evaluate the performance of the HRQ as a measure of MI ability, compared to the several MITI 2.0 global scores and subscales. Participants were counselors (N=97) working at community-based substance use treatment programs, whose MI proficiency was measured at four time points: baseline (before an initial 2-day MI workshop), post-workshop, 8weeks post-workshop (i.e., post-supervision), and 20weeks post-workshop with both MITI 2.0 and HRQ. HRQ total scores correlated significantly with the Reflection to Question Ratio from the MITI 2.0 at post-workshop (r=0.33), week 8 (r=0.34), and week 20 (r=0.38), and with the Spirit (r=0.32) and Empathy (r=0.32) global scores at week 20. Correlations of HRQ with other MITI 2.0 subscales and time points after workshop were small and not significant. As predicted, HRQ scores differed between training conditions (X2(2)=7.88, p=0.02), with counselors assigned to live supervision achieving better HRQ scores than those in Workshop only. In summary, HRQ is a modestly accurate measure, mainly of the Reflection to Question Ratio, considered a core marker of MI skill. It is sensitive to training effects and may help identify counselors needing more intensive supervision. Given its ease of administration and scoring, HRQ may be a useful marker of MI skill during training efforts.

Evidence for Field-Evolved Resistance of Striacosta albicosta (Lepidoptera: Noctuidae) to Cry1F Bacillus thuringiensis Protein and Transgenic Corn Hybrids in Ontario, Canada.

Western bean cutworm, Striacosta albicosta (Smith) (Lepidoptera: Noctuidae), is a pest of corn (Zea mays L.) that has recently expanded its range into Ontario, Canada. Control of S. albicosta damage to corn hybrids containing event TC1507-expressing Cry1F Bacillus thuringiensis protein alone or pyramided with event MON 89034 expressing Cry1A.105 and Cry2Ab2 Bt proteins was tested in 2011-2015 in Ontario in small- and large-scale field plots with natural infestation. In 2011, significantly lower incidence and severity of kernel damage was sustained by Cry1F × Cry1A.105 + Cry2Ab2 corn compared with a non-Bt near-isogenic hybrid. However, from 2012 to 2015, there was no difference in incidence or severity of damage comparing non-Bt hybrids with Cry1F hybrids alone or pyramided with Cry1A.105 and Cry2Ab2 planted as a pure stand or with an integrated refuge (95% Bt: 5% non-Bt seeds). In 2015, neonate larvae derived from Ontario field-collections were tested in concentration-response diet-overlay bioassays with lyophilized Cry1F protein at concentrations up to 75 µg cm-2. The concentrations at which mortality of 50% (LC50) of the collections occurred ranged from approximately 10 µg cm-2 (F0) to >28 µg cm-2 (F1) in a 7-d bioassay, indicating relative insensitivity to Cry1F. Results from field experiments, laboratory bioassays, and the history of exposure to Cry1F in corn show that S. albicosta in Ontario are not controlled by Cry1F-expressing corn hybrids and provide evidence for the conclusion that the evolution of resistance to Cry1F has occurred.

Piezomagnetism and magnetoelastic memory in uranium dioxide.

The thermal and magnetic properties of uranium dioxide, a prime nuclear fuel and thoroughly studied actinide material, remain a long standing puzzle, a result of strong coupling between magnetism and lattice vibrations. The magnetic state of this cubic material is characterized by a 3-k non-collinear antiferromagnetic structure and multidomain Jahn-Teller distortions, likely related to its anisotropic thermal properties. Here we show that single crystals of uranium dioxide subjected to strong magnetic fields along threefold axes in the magnetic state exhibit the abrupt appearance of positive linear magnetostriction, leading to a trigonal distortion. Upon reversal of the field the linear term also reverses sign, a hallmark of piezomagnetism. A switching phenomenon occurs at ±18 T, which persists during subsequent field reversals, demonstrating a robust magneto-elastic memory that makes uranium dioxide the hardest piezomagnet known. A model including a strong magnetic anisotropy, elastic, Zeeman, Heisenberg exchange, and magnetoelastic contributions to the total energy is proposed.The nuclear fuel uranium dioxide is of intrinsic interest due to its industrial applications but it also exhibits intriguing electronic and magnetic properties. Here, the authors demonstrate how its complex magnetic structure and interactions give rise to a strong piezomagnetic effect.

The effect of topical treatments for CRS on the sinonasal epithelial barrier.

BACKGROUND: Several topical treatments are used in the management of Chronic Rhinosinusitis (CRS), some of which the safety and efficacy has yet to be determined. The purpose of this study was to investigate the effect of commonly used topical treatments on the sinonasal epithelial barrier. METHODS: Normal saline (0.9% Sodium Chloride), hypertonic saline (3% Sodium Chloride), FESS Sinu-Cleanse Hypertonic, FLO Sinus Care and Budesonide 1 mg/ 2 ml were applied to the apical side of air-liquid interface (ALI) cultures of primary human nasal epithelial cells (HNECs) from CRS patients (n=3) and non-CRS controls (n=3) for 24 hours. Epithelial barrier structure and function was assessed using trans-epithelial electrical resistance (TEER), measuring the passage of Fluorescein Isothiocyanate labelled Dextrans (FITC-Dextrans) and assessing the expression of the tight junction protein Zona Occludens-1 (ZO-1) using immunofluorescence. Toxicity was assessed using a Lactate Dehydrogenase (LDH) assay. Data was analysed using ANOVA, followed by Tukey HSD post hoc test. RESULTS: Hypertonic solution and budesonide significantly increased TEER values in CRS derived HNECs. In contrast, FESS Sinu-Cleanse Hypertonic significantly reduced TEER 5 minutes after application of the solution followed by an increase in paracellular permeability of FITC-Dextrans (30 minutes) and increased LDH levels 6 hours after application of the solution. CONCLUSIONS: Our findings confirm that isotonic and hypertonic saline solutions do not compromise epithelial barrier function in vitro but underscore the importance of examining safety and efficacy of over-the-counter wash solutions.

Isolation of the Male-Specific Transformer Exon as a Method for Immature Specimen Sex Identification in Chrysomya megacephala (Diptera: Calliphoridae).

Being able to efficiently differentiate between male and female individuals in the immature forms of insects allows for investigations into sexually dimorphic patterns of growth rates and gene expression. For species lacking sex-specific morphological characteristics during these periods, alternative methods must be devised. Commonly, isolation of sex determination genes reveals sex-specific band patterns and allows for markers that can be used in insect control. For blow flies, a family that includes flies of medical and forensic importance, sex has previously been identified in some members using the male-specific exon in the transformer gene. This gene is relatively conserved between members of the genera Cochliomyia and Lucilia (Diptera: Calliphoridae), and we isolated a portion of this gene in an additional forensically and medically important blow fly genus using the widespread Chrysomya megacephala (F.). We found a relatively high level of conservation between exons 1 and 2 of transformer and were able to amplify a region containing the male-specific exon in C. megacephala. A sex-specific molecular diagnostic test based on the presence of sexually dimorphic PCR product bands showed the expected genotype for adults and intrapuparial period specimens of known sex. The same result could be obtained from single third-instar larval specimens, opening up the possibility to not only determine if development rates are sex dependent, but also to investigate the development of sexually dimorphic traits of interest in C. megacephala.

Effect of European Chafer Larvae (Coleoptera: Scarabaeidae) on Winter Wheat and Role of Neonicotinoid Seed Treatments in Their Management.

A critical density of four third-instar larvae per 900 cm2 for European chafer, Rhizotrogus (Amphimallon) majalis (Razoumowsky), in winter wheat, Triticum aestivum L., was derived from small-plot greenhouse and field experiments conducted under favorable crop growing conditions at several Ontario and Michigan locations from 2001-2003. On average, plant weight was decreased by 14% and plant stand by 11% between zero and four larvae per 900 cm2. In a commercial field under moisture stress, a yield loss of 35% occurred at a density of two third-instars per 900 cm2. In short-term greenhouse experiments, density-dependent mortality was evident, whereas low larval recovery in field experiments indicates a high level of overwintering mortality, regardless of larval density. Winter wheat seed treatments of neonicotinoid insecticides, clothianidin, imidacloprid, and thiamethoxam provided protection from damage by larvae, but the level of protection was inconsistent between greenhouse and field small plots, and there was no apparent difference in protection amongst active ingredients or between application rates. There was little evidence of larval mortality owing to seed treatment, which supports the suggestion that neonicotinoid insecticides protect seedlings from loss by a nonlethal mechanism. Overall, we estimate that a low rate of neonicotinoid insecticide used at larval densities just less than the critical density will mitigate winter wheat losses by 85%.

Impact of the Bt Corn Proteins Cry34/35Ab1 and Cry3Bb1, Alone or Pyramided, on Western Corn Rootworm (Coleoptera: Chrysomelidae) Beetle Emergence in the Field.

Western corn rootworm, Diabrotica virgifera virgifera LeConte, is a major pest of corn, Zea mays L. The effect of the Bt proteins Cry34/35Ab1 and Cry3Bb1, alone or pyramided in corn hybrids on D. v. virgifera adult emergence was evaluated in field experiments for 3 yr. Experiments were infested artificially with 2,500 viable D. v. virgifera eggs per row meter of corn. The reduction in beetle emergence compared with non-Bt controls, from Cry34/35Ab1, Cry3Bb1, and the pyramided hybrids ranged from 64.3 to 97.4%, 91.1 to 95.2%, and 98.1 to 99.6%, respectively. The sex ratio of emerged beetles was usually female-biased from the Cry3Bb1 and pyramided treatments, but not from Cry34/35Ab1 treatment alone. Emergence from all Bt hybrids was delayed compared with the control, with the delay longest from the pyramided hybrid. In 2013, three egg infestation levels were tested, with density-dependent mortality observed at 1,250 viable eggs per row meter. The effect of Bt proteins on the emergence timing and sex ratio of D. v. virgifera may impact the suitability of resistance management plans, specifically the effectiveness of the refuge strategy. Susceptible males emerging from refuge might not be synchronized to mate with potentially resistant females emerging later from Bt corn hybrids.