The effect of urbanization and temperature on thermal tolerance, foraging performance, and competition in cavity-dwelling ants.

Human disturbance including rapid urbanization and increased temperatures can have profound effects on the ecology of local populations. Eusocial insects, such as ants, have adapted to stressors of increasing temperature and urbanization; however, these evolutionary responses are not consistent among populations across geographic space. Here we asked how urbanization and incubation temperature influence critical thermal maximum (CTmax) and various ecologically relevant behaviors in three ant species in urban and rural locations in Worcester, MA, USA. We did this by incubating colonies of three species of cavity dwelling ant (Aphaenogaster picea, Tapinoma sessile, and Temnothorax longispinosus) from 2 habitat types (Rural and Urban), for 60-days at multiple temperatures. We found that incubation temperature, urbanization, and species of ant all significantly affected overall colony critical thermal maximum. We also found that recruitment time, colonization time, and defense response were significantly affected by incubation temperature and varied between species of ant, while recruitment and colonization time were additionally affected by urbanization. These variable changes in performance and competitive traits across species suggest that responses to urbanization and shifting temperatures are not universal across species. Changes in behavioral responses caused by urbanization may disrupt biodiversity, creating unusual competitive environments as a consequence of natural adaptations and cause both direct and indirect mechanisms for which human disturbance can lead to local species extinction.

Urban heat island conditions experienced by the Western black widow spider (Latrodectus hesperus): Extreme heat slows development but results in behavioral accommodations.

While shifts in organismal biology stemming from climate change are receiving increased attention, we know relatively little about how organisms respond to other forms of anthropogenic disturbance. The urban heat island (UHI) effect describes the capture of heat by built structures (e.g. asphalt), resulting in elevated urban temperatures. The UHI is a well-studied phenomenon, but only a handful of studies have investigated trait-based shifts resulting from the UHI, and even fewer have attempted to quantify the magnitude of the UHI experienced at the microclimate scale. Here, using a common urban exploiter, the Western black widow spider (Latrodectus hesperus), we show that the UHI experienced by spiders in July in their urban Phoenix, AZ refuges is 6°C hotter (33°C) than conditions in the refuges of spiders from Sonoran Desert habitat outside of Phoenix's development (27°C). We then use this field microclimate UHI estimate to compare the development speed, mass gain and mortality of replicate siblings from 36 urban lineages reared at 'urban' and 'desert' temperatures. We show that extreme heat is slowing the growth of spiderlings and increasing mortality. In contrast, we show that development of male spiders to their penultimate moult is accelerated by 2 weeks. Lastly, in terms of behavioral shifts, UHI temperatures caused late-stage juvenile male spiders to heighten their foraging voracity and late-stage juvenile female spiders to curtail their web-building behavior. Trait-based approaches like the one presented herein help us better understand the mechanisms that lead to the explosive population growth of urban (sometimes invasive) species, possibly at the expense of urban biodiversity. Studies of organismal responses to the present day UHI can be used as informative surrogates that help us grasp the impact that projected climate change will have on biodiversity.

The West coast regional safety pharmacology society meeting update: Filling translational gaps in safety assessment.

The Safety Pharmacology Society (SPS) held a West Coast Regional Meeting in Foster City, CA on November 14, 2018 at the Gilead Sciences Inc. site. The meeting was attended by scientists from the pharmaceutical and biotechnology industry, contract research organizations (CROs) and academia. A variety of scientific topics were presented by speakers, covering a broad variety of topics in the fields of safety risk assessment; from pro-arrhythmia and contractility risk evaluation, to models of heart failure and seizure in-a-dish; and discovery sciences; from stem cells and precision medicine, to models of inherited cardiomyopathy and precision cut tissue slices. The present review summarizes the highlights of the presentations and provides an overview of the high level of innovation currently underlying many frontiers in safety pharmacology.

Interrogation of transcriptomic changes associated with drug-induced hepatic sinusoidal dilatation in colorectal cancer.

Drug-related sinusoidal dilatation (SD) is a common form of hepatotoxicity associated with oxaliplatin-based chemotherapy used prior to resection of colorectal liver metastases (CRLM). Recently, hepatic SD has also been associated with anti-delta like 4 (DLL4) cancer therapies targeting the NOTCH pathway. To investigate the hypothesis that NOTCH signaling plays an important role in drug-induced SD, gene expression changes were examined in livers from anti-DLL4 and oxaliplatin-induced SD in non-human primate (NHP) and patients, respectively. Putative mechanistic biomarkers of bevacizumab (bev)-mediated protection against oxaliplatin-induced SD were also investigated. RNA was extracted from whole liver sections or centrilobular regions by laser-capture microdissection (LCM) obtained from NHP administered anti-DLL4 fragment antigen-binding (F(ab')2 or patients with CRLM receiving oxaliplatin-based chemotherapy with or without bev. mRNA expression was quantified using high-throughput real-time quantitative PCR. Significance analysis was used to identify genes with differential expression patterns (false discovery rate (FDR) < 0.05). Eleven (CCL2, CCND1, EFNB2, ERG, ICAM1, IL16, LFNG, NOTCH1, NOTCH4, PRDX1, and TGFB1) and six (CDH5, EFNB2, HES1, IL16, MIK67, HES1 and VWF) candidate genes were differentially expressed in the liver of anti-DLL4- and oxaliplatin-induced SD, respectively. Addition of bev to oxaliplatin-based chemotherapy resulted in differential changes in hepatic CDH5, HEY1, IL16, JAG1, MMP9, NOTCH4 and TIMP1 expression. This work implicates NOTCH and IL16 pathways in the pathogenesis of drug-induced SD and further explains the hepato-protective effect of bev in oxaliplatin-induced SD observed in CRLM patients.

Preclinical pharmacokinetic characterization of an adipose tissue-targeting monoclonal antibody in obese and non-obese animals.

Target receptor levels can influence pharmacokinetics (PK) or pharmacodynamics (PD) of monoclonal antibodies (mAbs), and can affect drug development of this class of molecules. We generated an effector-less humanized bispecific antibody that selectively activates fibroblast growth factor receptor (FGFR)1 and ßKlotho receptor, a FGF21 receptor complex highly expressed in both white and brown adipocytes. The molecule shows cross-species binding with comparable equilibrium binding affinity (Kd) for human, cynomolgus monkey, and mouse FGFR1/ßKlotho. To understand the PK/PD relationship in non-obese and obese animals, we evaluated the adipose tissue distribution of the antibody, serum exposures, and an associated PD marker (high-molecular-weight adiponectin), in both non-obese and obese mice and monkeys. Antibody uptake into fat tissue was found to be higher on a per gram basis in non-obese animals compared to obese animals. Since obesity has been reported to be associated with reduced expression of FGFR1 and ßKlotho receptor in white adipose tissues in mice, our results suggest that the distribution in adipose tissues was influenced by target expression levels. Even so, the overall dose-normalized serum exposures were comparable between non-obese and obese mice and monkeys, suggesting that adipose tissue uptake plays a limited role in overall systemic PK determination. It remains to be determined if and how obesity and receptor expression in humans influence the PK and PD profile of this novel therapeutic candidate.

A Blinded, Case-Control Trial Assessing the Value of Steady State Free Precession Magnetic Resonance Imaging in the Diagnosis of Trigeminal Neuralgia.

OBJECTIVE: High-resolution magnetic resonance imaging (MRI) may be a useful and readily available adjunct in identifying trigeminal neuralgia secondary to vascular contact (TNVC). This study evaluated the reliability and predictive ability of 1.5-tesla steady state free precession (SSFP) MRI sequences for the diagnosis of symptomatic vascular contact and response to operative intervention in patients with TNVC. METHODS: We performed a blinded, case-matched control trial evaluating SSFP MRI sequences in consecutive patients with unilateral TNVC with operatively proven vascular contact of the trigeminal nerve compared with healthy control subjects matched on age, sex, and laterality of the pathologic neurovascular complex. Interrater reliability was compared between 2 blinded, expert reviewers. Predictive ability of MRI was assessed in regard to accuracy, discrimination, and clinical utility. RESULTS: Inclusion criteria were met by 44 patients (22 consecutive patients with TNVC and 22 matched control subjects). Interrater reliability ranged from fair to excellent for vessel contact (κ = 0.40), location (κ = 0.81), type (κ = 0.72), and multiplicity (κ = 0.31). Vascular contact on MRI sequences did not differ significantly between cases and controls (75% vs. 82%, P = 0.30). MRI demonstrates accurate (Brier 0.15) and good discriminatory ability for clinical response after microvascular decompression (area under the receiver operating characteristic curve 0.81, 95% confidence interval = 0.6-1.0). Decision-curve analysis demonstrated that MRI could result in a net reduction of 5 cases likely to be unsuccessful per 100 patients treated. CONCLUSIONS: These results suggest the utility of SSFP MRI lies not in the diagnosis of TNVC, but rather in stratifying the likelihood of response to microvascular decompression in patients with characteristic symptoms.

Sustained Brown Fat Stimulation and Insulin Sensitization by a Humanized Bispecific Antibody Agonist for Fibroblast Growth Factor Receptor 1/ßKlotho Complex.

Dissipating excess calories as heat through therapeutic stimulation of brown adipose tissues (BAT) has been proposed as a potential treatment for obesity-linked disorders. Here, we describe the generation of a humanized effector-less bispecific antibody that activates fibroblast growth factor receptor (FGFR) 1/ßKlotho complex, a common receptor for FGF21 and FGF19. Using this molecule, we show that antibody-mediated activation of FGFR1/ßKlotho complex in mice induces sustained energy expenditure in BAT, browning of white adipose tissue, weight loss, and improvements in obesity-associated metabolic derangements including insulin resistance, hyperglycemia, dyslipidemia and hepatosteatosis. In mice and cynomolgus monkeys, FGFR1/ßKlotho activation increased serum high-molecular-weight adiponectin, which appears to contribute over time by enhancing the amplitude of the metabolic benefits. At the same time, insulin sensitization by FGFR1/ßKlotho activation occurs even before the onset of weight loss in a manner that is independent of adiponectin. Together, selective activation of FGFR1/ßKlotho complex with a long acting therapeutic antibody represents an attractive approach for the treatment of type 2 diabetes and other obesity-linked disorders through enhanced energy expenditure, insulin sensitization and induction of high-molecular-weight adiponectin.

Thin-slice T2 MRI imaging predicts vascular pathology in hemifacial spasm: a case-control study.

Hemifacial spasm (HFS) is a condition that may severely reduce patients' quality of life. We sought to determine the sensitivity and specificity of thin-slice T2 magnetic resonance imaging (MRI) for detecting vascular compression in HFS patients. Prospective information was collected on 28 patients with HFS who presented to our center between March 2011 and March 2012 with thin-slice T2 MR imaging. The sensitivity and specificity for differentiating patients from controls were calculated. Sensitivities were 78.6% and 92.9% for the blinded radiologists and 75% for the partially blinded neurosurgeon. Specificities were 42.9% and 28.6% for the blinded radiologists and 75% for the partially blinded neurosurgeon. Magnetic resonance imaging of the facial nerve can guide clinicians in selecting patients who are good surgical candidates. Thin-slice T2 MRI should be viewed as supportive rather than diagnostic.

Combined administration of RG7652, a recombinant human monoclonal antibody against PCSK9, and atorvastatin does not result in reduction of immune function.

RG7652 is a human IgG1 monoclonal antibody designed to inhibit proprotein convertase subtilisin/kexin type 9 (PCSK9) binding to hepatic low density lipoprotein receptor (LDL-r), thereby blocking PCSK9-mediated degradation of LDL-r. This therapeutic candidate is under development for the prevention of cardiovascular mortality and morbidity in dyslipidemic patients. The primary objective of this study was to evaluate the potential immunotoxicological effects of RG7652 when given to cynomolgus monkeys either alone or in combination with a daily oral dose of atorvastatin. Administration of RG7652 via subcutaneous injection every other week for 12 weeks (a total of seven doses), daily oral doses of atorvastatin (total of 85 doses), and combinations of each up to 15 and 20 mg/kg/dose, respectively, were well tolerated and there was no evidence of alteration in immune function. Administration of pharmacologically relevant doses of RG7652 in combination with atorvastatin to healthy monkeys does not result in clinically meaningful immunosuppression as measured by T-cell dependent antibody responses, natural killer cell activity, immunophenotype, or delayed type hypersensitivity. The only pharmacologically mediated changes observed during the dosing period were the anticipated changes in circulating cholesterol.

Categorization and characterization of lesions of the orbital apex.

INTRODUCTION: The apex of the orbit is formed by the union of the lesser and greater wings of the sphenoid bone and acts as an osseous tunnel for numerous neurovascular structures entering the orbit from the cranial vault. Lesions of the orbital apex are clinically important as they can have an adverse effect on vision. A broad range of lesions can occur here, and our purpose is to organize the pathologic processes which occur in the orbital apex into logical imaging differentials, establish an organized approach to image analysis, and present examples of representative lesions. METHODS: We review the anatomy of the orbital apex and categorize and describe the pathologic entities that are encountered most frequently in this anatomically compact region and identify imaging patterns that can help to narrow the differential diagnosis. RESULTS: Categories of orbital apex lesions include neoplasms, inflammatory processes, infections, lesions causing extrinsic compression, and vascular lesions. This categorization provides an organized framework to facilitate a reasonable differential diagnosis. Computed tomography and magnetic resonance imaging are the modalities of choice to evaluate and characterize orbital apex lesions, and imaging examples utilizing these modalities will be presented. CONCLUSION: The orbital apex is a clinically important anatomical region and hosts diverse pathologic processes. An awareness of common imaging patterns can help to generate a focused differential diagnosis. A systematic categorical approach can be of help to radiologists attempting to accurately characterize lesions in this area.

Gaussian-beam-induced photorefractive birefringence and its application to radio-frequency signal excision.

For Gaussian-beam-induced optical limiting based on photoconductive field shielding of electro-optic (EO) birefringence, power-limiting notch widths may be accurately determined by considering the power-limiting threshold for the photorefractive crystal where excess charge accumulates. With sufficient optical intensity the space-charge field completely screens the externally applied electric field, and only a small diffusion field remains. The upper limit of light intensity attenuation is the extinction ratio for the combination of polarizers and EO crystal.