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We analyze institutional solutions to international cooperation when actors have heterogeneous preferences over the desirability of the action and split into supporters and opponents, all of whom can spend resources toward their preferred outcome. We study how actors can communicate their preferences through voting when they are not bound either by their own vote or the outcome of the collective vote. We identify two organizational types with endogenous coercive enforcement and find that neither is unambiguously preferable. Like the solutions to the traditional Prisoners' Dilemma these forms require long shadows of the future to sustain. We then show that cooperation can be sustained through a noncoercive organization where actors delegate execution to an agent. Even though this institution is costlier, it does not require any expertise by the agent and is independent of the shadow of the future, and thus is implementable when the others are not. Copyright © The IO Foundation 2013 Â.

Lizards in the genus Anolis comprise hundreds of species that display a wide range of phenotypic variation closely related to their environment. One example is the Guadeloupean anole (Anolis marmoratus ssp.) that display extreme phenotypic variation, primarily in adult male color and pattern, with twelve described subspecies on the archipelago. Here we examine the relationship between phenotypic and genetic divergence among five subspecies on the two main islands and test the role of geographic isolation and the environment in reducing gene flow. We also examined two offshore island populations to assess the impact of complete geographic isolation on gene flow. We analyzed color phenotypes by measuring spectral reflectance and genomic diversity using SNPs. Genetic divergence was correlated with dorsolateral head and body color phenotypes, and slope and geographic distance were nearly equivalent at explaining this divergence. There was minimal genome-wide divergence at neutral loci among phenotypically disparate subspecies on the two main islands and their differentiation is consistent with a model of divergence with gene flow. Our spatial visualization of gene flow showed an impact of environmental features consistent with a hypothesis of ecologically driven divergence. Nonetheless, subspecies on the two main islands remain interconnected by substantial gene flow and their phenotypic variation is likely maintained at selection-gene flow equilibrium by divergent selection at loci associated with their color phenotypes. Greater isolation, such as inhabiting a remote island, may be required for reducing gene flow. Our findings highlight the role of the environment, adaptation, and geographic isolation on gene flow., (© 2024. The Author(s).)

Introduction: Early child development occurs within an interactive environment, initially dominated by parents or caregivers, and is heavily influenced by the dynamics of this social context. The current study probed the neurobiology of "family personality", or family functioning, in the context of parent-child dyadic interaction using a two-person neuroimaging modality., Methods: One hundred and five parent-child dyads (child mean age 5 years 4 months) were recruited. Functional near-infrared spectroscopy (fNIRS) hyperscanning was employed to measure neural synchrony while dyads completed a mildly stressful interactive task. Family functioning was measured through the Family Adaptability and Cohesion Scale IV (FACES-IV)., Results: Synchrony during stress was significantly greater than synchrony during both baseline and recovery conditions for all dyads. A significant interaction between neural synchrony in each task condition and familial balanced flexibility was found, such that higher levels of balanced flexibility were associated with greater changes in frontal cortex neural synchrony as dyads progressed through the three task conditions., Discussion: Parent-child dyads from families who display heightened levels of balanced flexibility are also more flexible in their engagement of neural synchrony when shifting between social conditions. This is one of the first studies to utilize a two-person imaging modality to explore the links between family functioning and interbrain synchrony between parents and their children., (© 2024 Wiley Periodicals LLC.)

Background: Self-regulation in early childhood develops within a social context. Variations in such development can be attributed to inter-individual behavioral differences, which can be captured both as facets of temperament and across a normal:abnormal dimensional spectrum. With increasing emphasis on irritability as a robust early-life transdiagnostic indicator of broad psychopathological risk, linkage to neural mechanisms is imperative. Currently, there is inconsistency in the identification of neural circuits that underlie irritability in children, especially in social contexts. This study aimed to address this gap by utilizing a functional magnetic resonance imaging (fMRI) paradigm to investigate pediatric anger/frustration using social stimuli., Methods: Seventy-three children (M = 6 years, SD = 0.565) were recruited from a larger longitudinal study on irritability development. Caregivers completed questionnaires assessing irritable temperament and clinical symptoms of irritability. Children participated in a frustration task during fMRI scanning that was designed to induce frustration through loss of a desired prize to an animated character. Data were analyzed using both general linear modeling (GLM) and independent components analysis (ICA) and examined from the temperament and clinical perspectives., Results: ICA results uncovered an overarching network structure above and beyond what was revealed by traditional GLM analyses. Results showed that greater temperamental irritability was associated with significantly diminished spatial extent of activation and low-frequency power in a network comprised of the posterior superior temporal sulcus (pSTS) and the precuneus (p < .05, FDR-corrected). However, greater severity along the spectrum of clinical expression of irritability was associated with significantly increased extent and intensity of spatial activation as well as low- and high-frequency neural signal power in the right caudate (p < .05, FDR-corrected)., Conclusions: Our findings point to specific neural circuitry underlying pediatric irritability in the context of frustration using social stimuli. Results suggest that a deliberate focus on the construction of network-based neurodevelopmental profiles and social interaction along the normal:abnormal irritability spectrum is warranted to further identify comprehensive transdiagnostic substrates of the irritability., (© 2023 Association for Child and Adolescent Mental Health.)

Understanding how natural selection acts on the genome and contributes to the process of speciation is a primary aim of the study of evolution. Here we used natural variation in two subspecies of the Guadeloupean anole ( Anolis marmoratus ssp.), from the island of Guadeloupe in the Lesser Antilles, to explore the genomic basis of adaptation and speciation in Anolis lizards. These subspecies inhabit distinct ecological environments and display marked differences in adult male color and pattern. We sequenced the complete genomes of 20 anoles, 10 from each subspecies, at 1.4× coverage. We used genome-wide scans of population differentiation, allele frequency spectrum, and linkage disequilibrium to characterize the genomic architecture within and between the subspecies. While most of the genome was undifferentiated, we observed five large divergent regions. Within these regions we identified blocks, 5 kb pairs in length, enriched for fixed single nucleotide polymorphisms. These blocks encompass 97 genes, two of which are candidate pigmentation genes. One is melanophilin ( mlph ), which helps transport melanosomes within melanocytes. The other is a cluster of differentiation 36 ( cd36 ), which regulates carotenoid pigment sequestration. We used high-pressure liquid chromatography to confirm that carotenoid pigments are significantly more abundant in the conspicuous orange-pigmented skin of male A .  m .  marmoratus suggesting that cd36 may be regulating pigment deposition in this tissue. We identified for the first time a carotenoid gene that is a potential target of divergent sexual selection and may be contributing to the early stages of speciation in Anolis lizards., (© 2023 The Authors. Ecology and Evolution published by John Wiley & Sons Ltd.)

Purpose: Pancreatic ductal adenocarcinoma (PDAC) is associated with a poor prognosis. Multianalyte signatures, including liquid biopsy and traditional clinical variables, have shown promise for improving prognostication in other solid tumors but have not yet been rigorously assessed for PDAC., Materials and Methods: We performed a prospective cohort study of patients with newly diagnosed locally advanced pancreatic cancer (LAPC) or metastatic PDAC (mPDAC) who were planned to undergo systemic therapy. We collected peripheral blood before systemic therapy and assessed circulating tumor cells (CTCs), cell-free DNA concentration (cfDNA), and circulating tumor KRAS (ctKRAS)-variant allele fraction (VAF). Association of variables with overall survival (OS) was assessed in univariate and multivariate survival analysis, and comparisons were made between models containing liquid biopsy variables combined with traditional clinical prognostic variables versus models containing traditional clinical prognostic variables alone., Results: One hundred four patients, 40 with LAPC and 64 with mPDAC, were enrolled. CTCs, cfDNA concentration, and ctKRAS VAF were all significantly higher in patients with mPDAC than patients with LAPC. ctKRAS VAF (cube root; 0.05 unit increments; hazard ratio, 1.11; 95% CI, 1.03 to 1.21; P = .01), and CTCs ≥ 1/mL (hazard ratio, 2.22; 95% CI, 1.34 to 3.69; P = .002) were significantly associated with worse OS in multivariate analysis while cfDNA concentration was not. A model selected by backward selection containing traditional clinical variables plus liquid biopsy variables had better discrimination of OS compared with a model containing traditional clinical variables alone (optimism-corrected Harrell's C-statistic 0.725 v 0.681)., Conclusion: A multianalyte prognostic signature containing CTCs, ctKRAS, and cfDNA concentration outperformed a model containing traditional clinical variables alone suggesting that CTCs, ctKRAS, and cfDNA provide prognostic information complementary to traditional clinical variables in advanced PDAC.

Background: Adjuvant systemic therapy is selectively considered for high-risk stage II colon cancer, but which patients benefit most from adjuvant systemic therapy is unclear., Methods: Patients who underwent resection of stage II colon cancer were identified from the National Cancer Database (2010-2016). Risk-factors for decreased overall survival on multivariable analysis were used to establish a predictive risk-score model for all-cause mortality. After propensity matching within each risk group, 5-year overall survival was estimated based on receipt of adjuvant systemic therapy., Results: Of the 15,241 patients evaluated, 2,857 (18.8%) received adjuvant systemic therapy. Risk factors for decreased overall survival included age >75 (hazard ratio 3.3, P < .001), male sex (hazard ratio 1.2, P < .001), White/Black race (hazard ratio 1.4, P = .020), preoperative carcinoembryonic antigen >3.5 ng/mL (hazard ratio 1.6, P < .001), T4a T-stage (hazard ratio 2.0, P < .001), T4b T-stage (hazard ratio 2.4, P < .001), lymphovascular invasion (hazard ratio 1.2, P = .003), perineural invasion (hazard ratio 1.3, P = .003), and non-R0 proximal/distal resection margins (hazard ratio 1.7, P < .001). An internally validated risk-score model using these factors was developed composed of low-risk (n = 8,489), moderate-risk (n = 4,623), and high-risk (n = 2,129) groups; within each group, 19.9%, 15.7%, and 20.8% of patients, respectively, received adjuvant systemic therapy. After propensity matching, adjuvant systemic therapy was not associated with improved 5-year overall survival for low-risk patients (89.8% vs 88.3%, P = .280), but was for moderate-risk (80.5% vs 70.8%, P < .001), and high-risk (65.2% vs 45.7%, P < .001) patients., Conclusion: A predictive risk-score model incorporating patient and tumor factors identifies a high-risk cohort of stage II colon cancer patients who may benefit from adjuvant systemic therapy, although the minority of these patients appear to be receiving treatment., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: Platinum-based therapy is the standard of care in patients who have HER2-negative, advanced esophagogastric cancer (AEGC). Retrospective data suggest that intratumoral ERCC1 levels may determine platinum sensitivity. A randomized, phase II study was performed in patients with AEGC to explore whether the efficacy of a platinum-based therapy with fluorouracil, leucovorin, and oxaliplatin (FOLFOX) versus a non-platinum-containing regimen of irinotecan and docetaxel (IT) differed according to ERCC1 levels., Patients and Methods: Overall, 202 untreated patients with HER2-negative AEGC and a Zubrod performance status of 0-1 were evaluated prospectively for mRNA expression of ERCC1 level and then randomly assigned to FOLFOX or IT, stratified by the intratumoral statuses of ERCC1 low (< 1.7) or high (≥ 1.7). Objectives were to assess progression-free survival (PFS) and overall survival (OS) in all patients treated with FOLFOX compared with IT, stratified by low and high ERCC1 levels, and to assess for interactive effects between ERCC1 expression and treatment arm., Results: Eighty-six percent of patients had ERCC1 values < 1.7. Thus, evaluation of the ERCC1 -high subgroup was limited. Grade ≥ 3 anemia, dehydration, diarrhea, and fatigue were greater in patients with IT. Occurrences of grade ≥ 3 neuropathy and decreased neutrophils were greater in patients with FOLFOX. In all patients, FOLFOX had a statistically superior median PFS compared with IT (5.7 v 2.9 months; hazard ratio, 0.68; P = .02). In patients with ERCC1 levels < 1.7 receiving FOLFOX, PFS and response rate were statistically superior to IT, with no significant difference in OS., Conclusion: The evaluation of ERCC1 in patients with upper GI tumors was thwarted by an overwhelming predominance of low ERCC1 mRNA expression. Nonetheless, distribution of treatment effects on PFS did not vary with expression. For all patients and for those with low ERCC1 expression, FOLFOX was superior in efficacy to IT.

Purpose: We evaluated the addition of bevacizumab, a humanized monoclonal antibody that targets vascular endothelial growth factor, to platinum-based chemotherapy in recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN)., Patients and Methods: Patients with chemotherapy-naïve (or with prior platinum as part of multimodal therapy completed ≥ 4 months earlier) recurrent or metastatic SCCHN were randomly assigned to receive a platinum-based chemotherapy doublet with or without bevacizumab 15 mg/kg given intravenously every 3 weeks until disease progression. Chemotherapy could be discontinued after six cycles if a maximum response was achieved., Results: The study randomly assigned 403 patients. Median overall survival (OS) was 12.6 months with bevacizumab plus chemotherapy (BC) and 11.0 months with chemotherapy alone (hazard ratio, 0.87; 95% CI, 0.70 to 1.09; P = .22). At 2, 3, and 4 years, the OS rates were 25.2% v 18.1%, 16.4% v 10.0%, and 11.8% v 6.4% for BC versus chemotherapy, respectively. In an analysis of 365 eligible patients who started treatment, the hazard ratio was 0.82 (95% CI, 0.65 to 1.04; P = .10), with a median OS of 14.2 months on BC v 11.1 months on chemotherapy. Median progression-free survival with BC was 6.0 months v 4.3 months with chemotherapy ( P = .0014). Overall response rates were 35.5% with BC and 24.5% with chemotherapy ( P = .016). There was increased toxicity, including a higher rate of treatment-related grade 3 to 5 bleeding events (6.7% v 0.5%; P < .001) and treatment-related deaths (9.3% v 3.5%; P = .022) with BC versus chemotherapy., Conclusion: The addition of bevacizumab to chemotherapy did not improve OS but improved the response rate and progression-free survival with increased toxicities. These results encourage biomarker-driven studies of angiogenesis inhibitors with better toxicity profiles in select patients with SCCHN.

Background: Chemotherapy-induced oral thermal hyperalgesia (OTH) is a common and debilitating side effect of platinum-based anticancer agents. This study evaluated the efficacy of oral cryotherapy in preventing OTH during oxaliplatin chemotherapy infusion., Methods: Patients with gastrointestinal cancer treated with biweekly oxaliplatin (85 mg/m2 over 120 minutes) at Abramson Cancer Center at the University of Pennsylvania were randomized to receive oral cryotherapy (ice chips) during oxaliplatin infusion or standard-of-care treatment. All patients completed baseline questionnaires regarding oral and peripheral symptoms and on-treatment questionnaires on day 1 of each subsequent chemotherapy cycle. Those in the treatment arm were asked to document how long they kept the ice chips in their mouths (0, <30, 30, 60, 90, or 120 minutes) and to report their discomfort associated with oral cryotherapy. Evaluable patients were those who had completed at least 2 cycles of oxaliplatin therapy., Results: Of 62 randomized patients with a variety of gastrointestinal malignancies, 50 (25 per treatment arm) were evaluable for efficacy. The rate of patients with oral symptoms after the first treatment cycle was significantly lower in the intervention arm (n=8; 32%) than in the control arm (n=18; 72%), meeting the primary study objective (P=.01). The magnitude of difference in symptom scores before versus after the first treatment cycle was significantly less in the intervention versus control arm (P=.001). No difference in oral symptoms over time was seen between the intervention and control groups (P=.20), although a high attrition rate was noted. Duration of ice chip exposure was associated with improved oral symptoms over time (P=.02)., Conclusions: Oral cryotherapy is a tolerable and cost-effective method of diminishing OTH in patients receiving oxaliplatin chemotherapy, and seems to be most effective in the early stages of treatment.

Purpose: Many authors suggest that extremity soft tissue sarcomas (ESTS) do not change significantly in size during preoperative radiation therapy (RT). This cone beam computed tomography study investigates the justification to deliver the entire course with 1 initial RT plan by observing anatomic changes during RT., Methods and Materials: Between 2015 and 2017, 99 patients with ESTS were treated with either curative (n = 80) or palliative intent (n = 19) with a regimen of at least 6 fractions. The clinical target volume to planning target volume margin was 1 cm. Action levels were assigned by radiation technicians. An extremity contour change of >1 cm and/or tumor size change >0.5 cm required a physician's action before the next fraction., Results: A total of 982 cone beam computed tomography logfiles were studied. In 41 of 99 patients, the dose coverage of the initial treatment plan was fully satisfactory throughout the RT course. However, action levels were observed in 58 patients (59%). In 41 of these 58 patients, a contour increase of 5 to 23 mm was noted (29 tumor size increase only, 3 extremity contour increase, and 9 both). In 21 of 58 patients, a decrease of 5 to 33 mm was observed (20 tumor size decrease only and 1 tumor size decrease and extremity contour decrease). In 4 cases, contours initially increased and subsequently decreased. In 33 of 41 patients with increasing contours, the dose distribution adequately covered gross tumor volume because of the 1 cm planning target volume margin applied. For the remaining 8 patients (8%), the plan needed to be adapted., Conclusions: ESTS volumes may change substantially during RT in 59% of all patients, leading to plan adaptations resulting from increased volumes in 8%. Daily critical observation of these patients is mandatory to avoid geographic misses because of increases in size and overdosing of normal tissues when masses shrink., (Copyright © 2018 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Pseudophilautus comprises an endemic diversification predominantly associated with the wet tropical regions of Sri Lanka that provides an opportunity to examine the effects of geography and historical climate change on diversification. Using a time-calibrated multi-gene phylogeny, we analyze the tempo of diversification in the context of past climate and geography to identify historical drivers of current patterns of diversity and distribution. Molecular dating suggests that the diversification was seeded by migration across a land-bridge connection from India during a period of climatic cooling and drying, the Oi-1 glacial maximum around the Eocene-Oligocene boundary. Lineage-through-time plots suggest a gradual and constant rate of diversification, beginning in the Oligocene and extending through the late Miocene and early Pliocene with a slight burst in the Pleistocene. There is no indication of an early-burst phase of diversification characteristic of many adaptive radiations, nor were there bursts of diversification associated with favorable climate shifts such as the intensification of monsoons. However, a late Miocene (8.8 MYA) back-migration to India occurred following the establishment of the monsoon. The back migration did not trigger a diversification in India similar to that manifest in Sri Lanka, likely due to occupation of available habitat, and consequent lack of ecological opportunity, by the earlier radiation of a sister lineage of frogs (Raorchestes) with similar ecology. Phylogenetic area reconstructions show a pattern of sister species distributed across adjacent mountain ranges or from different parts of large montane regions, highlighting the importance of isolation and allopatric speciation. Hence, local species communities are composed of species from disparate clades that, in most cases, have been assembled through migration rather than in situ speciation. Lowland lineages are derived from montane lineages. Thus, the hills of Sri Lanka acted as species pumps as well as refuges throughout the 31 million years of evolution, highlighting the importance of tropical montane regions for both the generation and maintenance of biodiversity., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Importance: Immunotherapy for recurrent and/or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN) is promising. The toll-like receptor 8 (TLR8) agonist motolimod may stimulate innate and adaptive immunity., Objective: To determine whether motolimod improves outcomes for R/M SCCHN when combined with standard therapy., Design, Setting, and Participants: The Active8 study was a multicenter, randomized, double-blind, placebo-controlled clinical trial enrolling adult patients (age ≥18 years) with histologically confirmed R/M SCCHN of the oral cavity, oropharynx, hypopharynx, or larynx between October 2013 and August 2015. Follow-up ended September 2016. Analysis for the present report was conducted between June 2016 and December 2017., Interventions: Combination treatment with platinum (carboplatin or cisplatin), fluorouracil, cetuximab (the EXTREME regimen), and either placebo or motolimod, each administered intravenously every 3 weeks. Patients received a maximum of 6 chemotherapy cycles, after which patients received weekly cetuximab with either placebo or motolimod every 4 weeks., Main Outcomes and Measures: Progression-free survival (PFS) as determined by independent central review using immune-related RECIST (Response Evaluation Criteria in Solid Tumors). Key secondary end points included overall survival (OS) and safety., Results: Of 195 patients enrolled, 85% were men (n = 166); 82% were white (n = 159); median age was 58 years (range 23-81 years). Median PFS was 6.1 vs 5.9 months (hazard ratio [HR], 0.99; 1-sided 90% CI, 0.00-1.22; P = .47), and median OS was 13.5 vs 11.3 months (HR, 0.95; 1-sided 90% CI, 0.00-1.22; P = .40) for motolimod vs placebo. Increased incidence of injection site reactions, pyrexia, chills, anemia, and acneiform rash were noted with motolimod. Of 83 cases oropharyngeal cancer, 52 (63%) were human papillomavirus (HPV) positive. In a prespecified subgroup analysis of HPV-positive participants, motolimod vs placebo resulted in significantly longer PFS (7.8 vs 5.9 months; HR, 0.58; 1-sided 90% CI, 0.00-0.90; P = .046) and OS (15.2 vs 12.6 months; HR, 0.41; 1-sided 90% CI, 0.00-0.77; P = .03). In an exploratory analysis, patients with injection site reactions had longer PFS and OS (median PFS, 7.1 vs 5.9 months; HR, 0.69; 1-sided 90% CI, 0.00-0.93; P = .06; and median OS, 18.7 vs 12.6; HR, 0.56; 1-sided 90% CI, 0.00-0.81; P = .02)., Conclusions and Relevance: Adding motolimod to the EXTREME regimen was well tolerated but did not improve PFS or OS in the intent-to-treat population. Significant benefit was observed in HPV-positive patients and those with injection site reactions, suggesting that TLR8 stimulation may benefit subset- and biomarker-selected patients., Trial Registration: ClinicalTrials.gov identifier: NCT01836029.

Lung cancer remains the leading cause of cancer death throughout the world. Despite new chemotherapeutic, immunomodulating and molecularly targeted agents, patients with locally advanced or metastatic disease still have a poor prognosis. This trial looked to combine antiangiogenic therapy with a first-line cytotoxic chemotherapy doublet, hoping to extend median progression-free survival (PFS) while minimizing toxicity in patients with advanced nonsquamous non-small-cell lung cancer (NSCLC). In this single institution, single-arm study, 51 patients (age >18 yo) were followed from 2007 to 2012. Patients with stage IV nonsquamous NSCLC and patients with recurrent unresectable disease (nonradiation candidates) were eligible. Treatment consisted of carboplatin AUC 5 IV 30-60 minutes, pemetrexed 500/mg 2 IV 10 minutes, bevacizumab 15 mg/kg IV (90 minutes 1st dose, 60 minutes 2nd dose, 30 minutes subsequent doses). Treatment was administered every 21 days and planned for 6 cycles, in the absence of disease progression or unacceptable toxicities. Growth factor support was not permitted prophylactically but allowed for toxicities, as were dose reductions. Maintenance treatment for those with stable disease or better consisted of Bevacizumab 15 mg/kg every 3 weeks for up to 1 year. Between November 2007 and March 2012, 51 patients were followed in the phase II trial of carboplatin, pemetrexed, and bevacizumab. Patients were enrolled over a 24-month period. After the end of treatment visits, subjects were followed at least every 3 months for survival data. The median follow-up period was 49 weeks (6 weeks to 178), and the median number of treatment cycles was 6 (range, 1-6). Among the 50 patients assessable for response, median overall survival was 49 weeks (95% CI, 0-62.7) with median PFS of 28 weeks (95% CI, 0-132.4). A complete or partial response was seen in 28 (59.5%) patients. Grade 3-4 treatment-related adverse events occurred in 9 (17.6%) of 51 patients; the most common were thrombocytopenia (4 [7.8%]) and neutropenia (3 [5.9%]). Three (5.8%) of 51 patients were discontinued because of treatment-related adverse events (grade 3 diarrhea, thrombocytopenia, dehydration, fatigue, and grade 4 respiratory distress), and 1 patient (1.9%) was found to be ineligible due to anticoagulation use. A novel 3-drug combination for advanced nonsquamous NSCLC shows promising efficacy with modest toxicity., (© 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Three experiments evaluated the effects of corn oil removal using centrifugation in ethanol plants, on animal performance and digestion characteristics by finishing cattle fed by-products. In Exp. 1, 225 crossbred steers (300 ± 9.1 kg) were utilized in a randomized block design with a 2 × 2 + 1 factorial arrangement of treatments. Factors consisted of oil concentration [de-oiled (DO) or full fat (FF)] and by-product type [condensed distillers solubles (CDS) or modified distillers grains plus solubles (MDGS)] compared to a corn-based control. Fat concentration was 6.0% for DO CDS, 21.1% for FF CDS, 9.2% for DO MDGS, and 11.8% for FF MDGS. No oil concentration by by-product type interactions (P ≥ 0.17) were observed. There were no differences in DMI, ADG, or G:F between DO and FF CDS (P ≥ 0.29) or DO and FF MDGS (P ≥ 0.58). No differences (P ≥ 0.25) due to oil concentration were observed for carcass characteristics. Experiment 2 was a 5 × 5 Latin Square digestion trial with treatments similar to Exp. 1. Fat concentration was 8.7% or 15.4% for DO or FF CDS and 9.2% or 12.3% for DO or FF MDGS. Intake and total tract digestibility of fat were greater (P ≤ 0.02) for FF CDS compared with DO CDS. Digestible energy (megacalorie per kilogram), adjusted for intake, was greater (P = 0.02) for steers fed FF CDS compared to DO CDS. Average ruminal pH for cattle fed FF MDGS was greater than DO MDGS (P = 0.06). In Exp. 3, 336 yearling, crossbred steers (352 ± 19 kg) were utilized in a randomized block design with a 2 × 3 + 1 factorial arrangement of treatments. Factors included oil concentration (DO or FF) and inclusion [35%, 50%, and 65% wet distillers grains plus solubles (WDGS)] along with a corn-based control. The fat concentrations of DO and FF WDGS were 7.9% and 12.4%, respectively. A linear interaction (P < 0.01) was observed for DMI, which produced different slopes for DO and FF WDGS. No linear or quadratic interactions were observed for BW, ADG, or G:F (P ≥ 0.31). For the main effect of oil concentration, there were no statistical differences (P > 0.19) for final BW, ADG, or G:F. No statistical differences were observed for all carcass traits (P ≥ 0.34). Corn oil removal via centrifugation had minimal impact on finishing performance suggesting that cattle fed DO by-products will have similar performance to cattle fed FF by-products in dry-rolled and high-moisture corn diets.

Objectives: The objective of this study was to investigate the safety, tolerability and preliminary efficacy of radiotherapy plus cetuximab in high risk CSCC patients., Materials and Methods: Patients with high-risk CSCC diagnosed between 2006 and 2013 were analyzed. Patients were divided into two groups: radiotherapy alone versus radiotherapy plus cetuximab. Among 68 patients meeting study criteria, we identified 29 treated with cetuximab plus RT and 39 with RT alone. Primary analysis examined disease-free and overall survival, freedom from local and distant recurrence in the propensity score matched cohort. Propensity score analysis was performed with weighted factors including: Charlson Comorbidity Index score, age. KPS, primary location, T and N stage, recurrent status, margin status, LVSI, PNI and grade. Toxicity was assessed using the CTCAE v4.0., Results: Median follow-up for living patients was 30 months. Patients in the cetuximab group were more likely to have advanced N stage, positive margins and recurrent disease. After propensity score matching the groups were well balanced. Six patients experienced ≥ grade 3 acute toxicity in the cetuximab group. The 1-year, 2-year and 5-year progression free survival (PFS) for patients in the cetuximab group were 86%, 72% and 66%, respectively. The 1-year, 2-year and 5-year overall survival (OS) for patients in the cetuximab group was 98%, 80% and 80%, respectively., Conclusions: Although limited by small numbers, the combination of cetuximab and radiotherapy in CSCC appears well tolerated there were more long-term survivors and less distant metastasis in the cetuximab group. These promising finding warrant further studies., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Purpose: We evaluated a Trop-2-targeting antibody conjugated with SN-38 in metastatic small cell lung cancer (mSCLC) patients. Experimental Design: Sacituzumab govitecan was studied in patients with pretreated (median, 2; range, 1-7) mSCLC who received either 8 or 10 mg/kg i.v. on days 1 and 8 of 21-day cycles. The primary endpoints were safety and objective response rate (ORR); duration of response, progression-free survival (PFS), and overall survival (OS) were secondary endpoints. Results: Sixty percent of patients showed tumor shrinkage from baseline CTs. On an intention-to-treat basis ( N = 50), the ORR was 14% (17% for the 10-mg/kg group); the median response duration, 5.7 months; the clinical benefit rate (CBR ≥4 months), 34%; median PFS, 3.7 months; and median OS, 7.5 months. There was a suggested improvement in PR, CBR, and PFS with sacituzumab govitecan in second-line patients who were sensitive to first-line therapy, but no difference between first-line chemosensitive versus chemoresistant patients in the overall population. There was a statistically significant higher OS in those patients who received prior topotecan versus no topotecan therapy in a small subgroup. Grade ≥3 adverse events included neutropenia (34%), fatigue (13%), diarrhea (9%), and anemia (6%). Trop-2 tumor staining was not required for patient selection. No antibodies to the drug conjugate or its components were detected on serial blood collections. Conclusions: Sacituzumab govitecan appears to have a safe and effective therapeutic profile in heavily pretreated mSCLC patients, including those who are chemosensitive or chemoresistant to first-line chemotherapy. Additional studies as a monotherapy or combination therapy are warranted. Clin Cancer Res; 23(19); 5711-9. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Four experiments evaluated the use of a complete starter feed (RAMP; Cargill Corn Milling, Blair, NE) for grain adaptation. In Exp. 1, 229 yearling steers (397 ± 28.4 kg BW) were used to compare a traditional adaptation program (CON) with adapting cattle with RAMP in either a 1- (RAMP-1RS) or 2- (RAMP-2RS) ration system. From d 23 to slaughter, cattle were fed a common finishing diet. In Exp. 2, 390 yearling steers (341 ± 14 kg BW) were used to compare accelerated grain adaptation programs with RAMP with 2 control treatments where RAMP was blended with a finishing diet containing either 25 (CON25) or 47.5% (CON47) Sweet Bran (Cargill Corn Milling) in 4 steps fed over 24 d to adapt cattle. Rapid adaptation treatments involved feeding RAMP for 10 d followed by a blend of RAMP and a 47% Sweet Bran finishing diet to transition cattle with 3 blends fed for 1 d each (3-1d), 2 blends fed for 2 d each (2-2d), or 1 blend fed for 4 d (1-4d). From d 29 to slaughter, all cattle were fed a common finishing diet. In Exp. 3, 300 steer calves (292 ± 21 kg BW) were used to compare the CON47 and 1-4d adaptation programs with directly transitioning cattle from RAMP, which involved feeding RAMP for 10 d and then switching directly to F1 on d 11 (1-STEP). From d 29 until slaughter, F2 was fed to all cattle. In Exp. 4, 7 ruminally fistulated steers (482 ± 49 kg BW) were used in a 35-d trial to compare the CON47 and 1-STEP adaptation programs. Ruminal pH and intake data from the first 6 d of F1and first 6 d of F2 were used to compare adaptation systems. Adaptation with RAMP-1RS and RAMP-2RS increased ( < 0.01) G:F compared with cattle adapted using CON in Exp. 1. Feeding RAMP-1RS increased ADG ( = 0.03) compared with CON. Intakes were similar ( = 0.39) among treatments. Daily gain, DMI, G:F, and carcass traits were similar ( > 0.11) among treatments in Exp. 2. Daily gain, DMI, and G:F were not different ( > 0.20) among treatments on d 39 or over the entire feeding period in Exp. 3. When F1 or F2 was being fed, DMI was similar ( ≥ 0.40) for CON47 and 1-STEP in Exp. 4. When F1 or F2 was being fed, 1-STEP cattle had lower average ruminal pH ( ≤ 0.03) and greater time below a pH of 5.3 ( ≤ 0.03). Using RAMP for grain adaptation improved performance compared with traditional adaptation. Rapid adaptation with RAMP decreased pH, but no performance differences were observed between long and rapid RAMP adaptation programs. Therefore, cattle started on RAMP do not require extensive adaptation before feeding a finishing diet with Sweet Bran.

Aims: Recent studies have demonstrated RAMP, a complete starter feed, to have beneficial effects for animal performance. However, how RAMP may elicit such responses is unknown. To understand if RAMP adaptation results in changes in the rumen bacterial community that can potentially affect animal performance, we investigated the dynamics of rumen bacterial community composition in corn-adapted and RAMP-adapted cattle., Methods and Results: During gradual acclimation of the rumen bacterial communities, we compared the bacterial community dynamics in corn and RAMP-adapted using 16S rRNA gene amplicon sequencing. Significant shifts in bacterial populations across diets were identified. The shift in corn-adapted animals occurred between adaptation step3 and step4, whereas in RAMP-adapted cattle, the shift occurred between step2 and step3. As the adaptation program progressed, the abundance of OTUs associated with family Prevotellaceae and S24-7 changed in corn-adapted animals. In RAMP-adapted animals, OTUs belonging to family Ruminococcaceae and Lachnospiraceae changed in abundance., Conclusions: Rumen bacteria can be acclimated faster to high concentrate diets, such as RAMP, than traditional adaptation programs and the speed of bacterial community acclimation depends on substrate composition., Significance and Impact of the Study: These findings may have implications for beef producers to reduce feedlot costs, as less time adapting animals would result in lower feed costs. However, animal feeding behavior patterns and other factors must be considered., (© 2016 The Authors published by John Wiley & Sons Ltd on behalf of Society for Applied Microbiology.)

Two studies were conducted to optimize use of alkaline-treated corn stover and wheat straw and distillers grains as partial corn replacements. In Exp. 1, a finishing experiment used 30 pens (12 steers/pen) of calf-fed steers (initial BW = 374 ± 23.9 kg) with a 2 × 2 + 1 factorial arrangement of treatments with 6 replications per treatment. Factors were grind size, where corn stover was processed through a 2.54- or 7.62-cm screen, and chemical treatment (corn stover either fed in native, non-treated form [NT; 93.4% DM] or alkaline treated [AT; 5% CaO hydrated to 50% DM]). No interactions (P ≥ 0.38) were noted between grind size and chemical treatment. Feeding AT compared with NT improved (P ≤ 0.02) final BW, ADG, and G:F. Reducing grind size improved (P ≤ 0.01) ADG and G:F, and no interaction with chemical treatment was observed. Steers fed AT had similar DMI, ADG, G:F, and carcass characteristics compared with a 5% roughage control that contained 15 percentage units (DM basis) more corn. In Exp. 2, 60 individually fed steers (initial BW = 402 ± 61.4 kg) were randomly assigned to 10 diets. Six treatments evaluated 10, 25, or 40% dry-rolled corn (DRC), which was replaced with either a 2:1 or 3:1 ratio (DM basis) of modified distillers grains plus solubles (MDGS) and treated corn stover analyzed as a 2 × 3 factorial. An additional 3 treatments were added where a 3:1 ratio of MDGS:straw were compared with a 3:1 ratio of MDGS:stover. As DRC increased, G:F (P = 0.06) quadratically increased for 3:1 MDGS:stover diets. Increasing DRC increased (P = 0.07) G:F in treated stover diets, regardless of ratio. Increasing DRC increased (P = 0.10) ADG for 3:1 ratios for both straw and stover. Reducing grind size, feeding a maximum of 20% treated crop residue, and maintaining at least 25% corn in the diet are strategies for optimizing cattle performance when replacing dry-rolled and high-moisture corn with treated crop residues and distillers grains.

Purpose: To update the outcomes of an institutional clinical management approach using ipsilateral neck radiotherapy in the treatment of node-positive squamous cell carcinoma of the tonsil with a well-lateralized primary lesion., Methods and Materials: Between August 2003 and April 2014, 61 consecutive patients with ipsilateral node-positive squamous cell carcinoma of the tonsil without involvement of the base of the tongue or midline soft palate were treated at a community hospital-based cancer center with radiotherapy to the primary site and ipsilateral neck. Overall survival, disease-free survival and freedom from contralateral failure were calculated., Results: Median follow up was 37.2months (range 4-121months). Freedom from contralateral nodal failure at 5years was 98% with one contralateral nodal failure noted. The patient underwent a salvage neck dissection and was treated with post-operative radiotherapy with no evidence of disease to date. 5-year overall survival (OS) was 92.4% and 5year disease-free survival (DFS) was 86.7%., Conclusions: This represents the single largest series reported from a community hospital-based cancer center in which lateralized tonsil cancers with N+ disease were treated with ipsilateral neck radiotherapy. In this carefully selected cohort of patients with well-lateralized tonsil cancers, the risk of contralateral nodal failure appears to be <5%, suggesting that prophylactic radiation of the contralateral neck may not be necessary. Future planned studies will focus on prospectively selecting subgroups of patients eligible for treatment de-intensification as survivorship issues in excellent prognosis HPV positive patients are increasingly becoming relevant., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Our understanding of the neuronal mechanisms behind epilepsy dynamics has recently advanced due to the application of novel technologies, monitoring hundreds of neurons with single cell resolution. These developments have provided new theories on the relationship between physiological and pathological states, as well as common motifs for the propagation of paroxysmal activity. Although traditional electroencephalogram (EEG) recordings continue to describe normal network oscillations and abnormal epileptic events within and outside of the seizure focus, analysis of epilepsy dynamics at the microscale has found variability in the composition of macroscopically repetitive epileptiform events. These novel results point to heterogeneity in the underlying dynamics of the disorder, highlighting both the need and potential for more specific and targeted therapies., (Published by Elsevier Ltd.)

High-energy protons constitute at least 85% of the fluence of energetic ions in interplanetary space. Although protons are only sparsely ionizing compared to higher atomic mass ions, they nevertheless significantly contribute to the delivered dose received by astronauts that can potentially affect central nervous system function at high fluence, especially during prolonged deep space missions such as to Mars. Here we report on the long-term effects of 1 Gy proton irradiation on electrophysiological properties of CA1 pyramidal neurons in the mouse hippocampus. The hippocampus is a key structure for the formation of long-term episodic memory, for spatial orientation and for information processing in a number of other cognitive tasks. CA1 pyramidal neurons form the last and critical relay point in the trisynaptic circuit of the hippocampal principal neurons through which information is processed before being transferred to other brain areas. Proper functioning of CA1 pyramidal neurons is crucial for hippocampus-dependent tasks. Using the patch-clamp technique to evaluate chronic effects of 1 Gy proton irradiation on CA1 pyramidal neurons, we found that the intrinsic membrane properties of CA1 pyramidal neurons were chronically altered at 3 months postirradiation, resulting in a hyperpolarization of the resting membrane potential (VRMP) and a decrease in input resistance (Rin). These small but significant alterations in intrinsic properties decreased the excitability of CA1 pyramidal neurons, and had a dramatic impact on network function in a computational model of the CA1 microcircuit. We also found that proton-radiation exposure upregulated the persistent Na(+) current (INaP) and increased the rate of miniature excitatory postsynaptic currents (mEPSCs). Both the INaP and the heightened rate of mEPSCs contribute to neuronal depolarization and excitation, and at least in part, could compensate for the reduced excitability resulting from the radiation effects on the VRMP and the Rin. These results show long-term alterations in the intrinsic properties of CA1 pyramidal cells after realistic, low-dose proton irradiation.

Dendritic morphology has been shown to have a dramatic impact on neuronal function. However, population features such as the inherent variability in dendritic morphology between cells belonging to the same neuronal type are often overlooked when studying computation in neural networks. While detailed models for morphology and electrophysiology exist for many types of single neurons, the role of detailed single cell morphology in the population has not been studied quantitatively or computationally. Here we use the structural context of the neural tissue in which dendritic trees exist to drive their generation in silico. We synthesize the entire population of dentate gyrus granule cells, the most numerous cell type in the hippocampus, by growing their dendritic trees within their characteristic dendritic fields bounded by the realistic structural context of (1) the granule cell layer that contains all somata and (2) the molecular layer that contains the dendritic forest. This process enables branching statistics to be linked to larger scale neuroanatomical features. We find large differences in dendritic total length and individual path length measures as a function of location in the dentate gyrus and of somatic depth in the granule cell layer. We also predict the number of unique granule cell dendrites invading a given volume in the molecular layer. This work enables the complete population-level study of morphological properties and provides a framework to develop complex and realistic neural network models.

Purpose: Optimal adjuvant chemotherapy for early-stage breast cancer balances efficacy and toxicity. We sought to determine whether single-agent paclitaxel (T) was inferior to doxorubicin and cyclophosphamide (AC), when each was administered for four or six cycles of therapy, and whether it offered less toxicity., Patients and Methods: Patients with operable breast cancer with 0 to 3 positive nodes were enrolled onto the study to address the noninferiority of single-agent T to AC, defined as the one-sided 95% upper-bound CI (UCB) of hazard ratio (HR) of T versus AC less than 1.30 for the primary end point of relapse-free survival (RFS). As a 2 × 2 factorial design, duration of therapy was also addressed and was previously reported., Results: With 3,871 patients enrolled onto the trial, a median follow-up period of 6.1 years, and 437 RFS events, we achieved an HR of 1.26 (one sided 95% UCB, 1.48; favoring AC does not allow a conclusion of noninferiority of T with AC; UCB > 1.3). With 266 patient deaths, the HR for overall survival (OS) was 1.27 favoring AC (UCB, 1.56). The estimated absolute advantage of AC at 5 years is 3% for RFS (91 v 88%) and 1% for OS (95 v 94%). All nine treatment-related deaths were patients receiving AC and are included in the analyses of both RFS and OS. Hematologic toxicity was more common in patients treated with AC, and neuropathy was more common in patients treated with T., Conclusion: This trial did not show noninferiority of T to AC, a conclusion that is unlikely to change with additional events and follow-up. T was less toxic than AC., (© 2014 by American Society of Clinical Oncology.)

We investigated the pattern of genetic and morphological variation and the timing of diversification in a Neotropical direct developing frog, Pristimantis w-nigrum (Craugastoridae) to gain insight into the historical biogeography of the northern Andes. Phylogenetic inference and analyses of genetic differentiation at mitochondrial and nuclear markers reveal eight mitochondrial clades that display concordant and highly structured nuclear genetic variation along both eastern and western slopes of the Ecuadorian Andes. These eight phylogroups are deeply divergent and show little evidence of change in effective size over substantial periods of time. Consistent with other phylogenetic studies of vertebrates in the Andes, the timing of genetic divergence among lineages coincides with sequential bouts of Andean orogenesis during the late Miocene and early Pliocene. Morphometric analyses recover little morphological variation among populations in spite of considerable genetic divergence. The deep genetic differentiation among populations of P. w-nigrum suggests that this species harbors unrecognized diversity and may represent a complex of cryptic species. These results illuminate the evolutionary processes that generate diversity in tropical montane biomes and underscore the fact that cryptic diversity may be an important component of Neotropical montane biodiversity., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Adaptive divergence in coloration is expected to produce reproductive isolation in species that use colourful signals in mate choice and species recognition. Indeed, many adaptive radiations are characterized by differentiation in colourful signals, suggesting that divergent selection acting on coloration may be an important component of speciation. Populations in the Anolis marmoratus species complex from the Caribbean island of Guadeloupe display striking divergence in the colour and pattern of adult males that occurs over small geographic distances, suggesting strong divergent selection. Here we test the hypothesis that divergence in coloration results in reduced gene flow among populations. We quantify variation in adult male coloration across a habitat gradient between mesic and xeric habitats, use a multilocus coalescent approach to infer historical demographic parameters of divergence, and examine gene flow and population structure using microsatellite variation. We find that colour variation evolved without geographic isolation and in the face of gene flow, consistent with strong divergent selection and that both ecological and sexual selection are implicated. However, we find no significant differentiation at microsatellite loci across populations, suggesting little reproductive isolation and high levels of contemporary gene exchange. Strong divergent selection on loci affecting coloration probably maintains clinal phenotypic variation despite high gene flow at neutral loci, supporting the notion of a porous genome in which adaptive portions of the genome remain fixed whereas neutral portions are homogenized by gene flow and recombination. We discuss the impact of these findings for studies of colour evolution and ecological speciation., (© 2013 Blackwell Publishing Ltd.)

Predicting where threatened species occur is useful for making informed conservation decisions. However, because they are usually rare, surveying threatened species is often expensive and time intensive. Here, we show how regions where common species exhibit high genetic and morphological divergence among populations can be used to predict the occurrence of species of conservation concern. Intraspecific variation of common species of birds, bats and frogs from Ecuador were found to be a significantly better predictor for the occurrence of threatened species than suites of environmental variables or the occurrence of amphibians and birds. Fully 93 per cent of the threatened species analysed had their range adequately represented by the geographical distribution of the morphological and genetic variation found in seven common species. Both higher numbers of threatened species and greater genetic and morphological variation of common species occurred along elevation gradients. Higher levels of intraspecific divergence may be the result of disruptive selection and/or introgression along gradients. We suggest that collecting data on genetic and morphological variation in common species can be a cost effective tool for conservation planning, and that future biodiversity inventories include surveying genetic and morphological data of common species whenever feasible.

Deficiencies in the mismatch repair (MMR) pathway are associated with several types of cancers, as well as resistance to commonly used chemotherapeutics. Rhodium metalloinsertors have been found to bind DNA mismatches with high affinity and specificity in vitro, and also exhibit cell-selective cytotoxicity, targeting MMR-deficient cells over MMR-proficient cells. Ten distinct metalloinsertors with varying lipophilicities have been synthesized and their mismatch binding affinities and biological activities determined. Although DNA photocleavage experiments demonstrate that their binding affinities are quite similar, their cell-selective antiproliferative and cytotoxic activities vary significantly. Inductively coupled plasma mass spectrometry (ICP-MS) experiments have uncovered a relationship between the subcellular distribution of these metalloinsertors and their biological activities. Specifically, we find that all of our metalloinsertors localize in the nucleus at sufficient concentrations for binding to DNA mismatches. However, the metalloinsertors with high rhodium localization in the mitochondria show toxicity that is not selective for MMR-deficient cells, whereas metalloinsertors with less mitochondrial rhodium show activity that is highly selective for MMR-deficient versus proficient cells. This work supports the notion that specific targeting of the metalloinsertors to nuclear DNA gives rise to their cell-selective cytotoxic and antiproliferative activities. The selectivity in cellular targeting depends upon binding to mismatches in genomic DNA.

Purpose: The ideal duration of adjuvant chemotherapy for patients with lower risk primary breast cancer is not known. Cancer and Leukemia Group B trial 40101 was conducted using a phase III factorial design to define whether six cycles of a chemotherapy regimen are superior to four cycles. We also sought to determine whether paclitaxel (T) is as efficacious as doxorubicin/cyclophosphamide (AC), but with reduced toxicity., Patients and Methods: Between 2002 and 2008, the study enrolled women with operable breast cancer and zero to three positive nodes. Patients were randomly assigned to either four or six cycles of either AC or T. Study stratifiers were estrogen receptor/progesterone receptor (ER/PgR), human epidermal growth factor receptor 2 (HER2), and menopausal status. After 2003, all treatment was administered in dose-dense fashion. The primary efficacy end point was relapse-free survival (RFS)., Results: A total of 3,171 patients were enrolled; 94% were node-negative and 6% had one to three positive nodes. At a median follow-up of 5.3 years, the 4-year RFS was 90.9% and 91.8% for six and four cycles, respectively. The adjusted hazard ratio (HR) of six to four cycles regarding RFS was 1.03 (95% CI, 0.84 to 1.28; P=.77). The 4-year OS was 95.3% and 96.3% for six and four cycles, respectively, with an HR of six to four cycles of 1.12 (95% CI, 0.84 to 1.49; P=.44). There was no interaction between treatment duration and chemotherapy regimen, ER/PgR, or HER2 status on RFS or OS., Conclusion: For women with resected primary breast cancer and zero to three positive nodes, we found no evidence that extending chemotherapy regimens of AC or single-agent T from four to six cycles improves clinical outcome.

Recent advances in parallel computing, including the creation of the parallel version of the NEURON simulation environment, have allowed for a previously unattainable level of complexity and detail in neural network models. Previously, we published a functional NEURON model of the rat dentate gyrus with over 50,000 biophysically realistic, multicompartmental neurons, but network simulations could only utilize a single processor. By converting the model to take advantage of parallel NEURON, we are now able to utilize greater computational resources and are able to simulate the full-scale dentate gyrus, containing over a million neurons. This has eliminated the previous necessity for scaling adjustments and allowed for a more direct comparison to experimental techniques and results. The translation to parallel computing has provided a superlinear speedup of computation time and dramatically increased the overall computer memory available to the model. The incorporation of additional computational resources has allowed for more detail and elements to be included in the model, bringing the model closer to a more complete and accurate representation of the biological dentate gyrus. As an example of a major step toward an increasingly accurate representation of the biological dentate gyrus, we discuss the incorporation of realistic granule cell dendrites into the model. Our previous model contained simplified, two-dimensional dendritic morphologies that were identical for neurons of the same class. Using the software tools L-Neuron and L-Measure, we are able to introduce cell-to-cell variability by generating detailed, three-dimensional granule cell morphologies that are based on biological reconstructions. Through these and other improvements, we aim to construct a more complete full-scale model of the rat dentate gyrus, to provide a better tool to delineate the functional role of cell types within the dentate gyrus and their pathological changes observed in epilepsy.

Animals display incredibly diverse color patterns yet little is known about the underlying genetic basis of these phenotypes. However, emerging results are reshaping our view of how the process of phenotypic evolution occurs. Here, we outline recent research from three particularly active areas of investigation: melanin pigmentation in Drosophila, wing patterning in butterflies, and pigment variation in lizards. For each system, we highlight (i) the function and evolution of color variation, (ii) various approaches that have been used to explore the genetic basis of pigment variation, and (iii) conclusions regarding the genetic basis of convergent evolution which have emerged from comparative analyses. Results from these studies indicate that natural variation in pigmentation is a particularly powerful tool to examine the molecular basis of evolution, especially with regard to convergent or parallel evolution. Comparison of these systems also reveals that the molecular basis of convergent evolution is heterogeneous, sometimes involving conserved mechanisms and sometimes not. In the near future, additional work in other emerging systems will substantially expand the scope of available comparisons., (© 2012 John Wiley & Sons A/S.)

Many biodiversity hotspots are located in montane regions, especially in the tropics. A possible explanation for this pattern is that the narrow thermal tolerances of tropical species and greater climatic stratification of tropical mountains create more opportunities for climate-associated parapatric or allopatric speciation in the tropics relative to the temperate zone. However, it is unclear whether a general relationship exists among latitude, climatic zonation and the ecology of speciation. Recent taxon-specific studies obtained different results regarding the role of climate in speciation in tropical versus temperate areas. Here, we quantify overlap in the climatic distributions of 93 pairs of sister species of mammals, birds, amphibians and reptiles restricted to either the New World tropics or to the Northern temperate zone. We show that elevational ranges of tropical- and temperate-zone species do not differ from one another, yet the temperature range experienced by species in the temperate zone is greater than for those in the tropics. Moreover, tropical sister species tend to exhibit greater similarity in their climatic distributions than temperate sister species. This pattern suggests that evolutionary conservatism in the thermal niches of tropical taxa, coupled with the greater thermal zonation of tropical mountains, may result in increased opportunities for allopatric isolation, speciation and the accumulation of species in tropical montane regions. Our study exemplifies the power of combining phylogenetic and spatial datasets of global climatic variation to explore evolutionary (rather than purely ecological) explanations for the high biodiversity of tropical montane regions.

Background: Comparative studies of amniotes have been hindered by a dearth of reptilian molecular sequences. With the genomic assembly of the green anole, Anolis carolinensis available, non-avian reptilian genes can now be compared to mammalian, avian, and amphibian homologs. Furthermore, with more than 350 extant species in the genus Anolis, anoles are an unparalleled example of tetrapod genetic diversity and divergence. As an important ecological, genetic and now genomic reference, it is imperative to develop a standardized Anolis gene nomenclature alongside associated vocabularies and other useful metrics., Results: Here we report the formation of the Anolis Gene Nomenclature Committee (AGNC) and propose a standardized evolutionary characterization code that will help researchers to define gene orthology and paralogy with tetrapod homologs, provide a system for naming novel genes in Anolis and other reptiles, furnish abbreviations to facilitate comparative studies among the Anolis species and related iguanid squamates, and classify the geographical origins of Anolis subpopulations., Conclusions: This report has been generated in close consultation with members of the Anolis and genomic research communities, and using public database resources including NCBI and Ensembl. Updates will continue to be regularly posted to new research community websites such as lizardbase. We anticipate that this standardized gene nomenclature will facilitate the accessibility of reptilian sequences for comparative studies among tetrapods and will further serve as a template for other communities in their sequencing and annotation initiatives.

The evolution of the amniotic egg was one of the great evolutionary innovations in the history of life, freeing vertebrates from an obligatory connection to water and thus permitting the conquest of terrestrial environments. Among amniotes, genome sequences are available for mammals and birds, but not for non-avian reptiles. Here we report the genome sequence of the North American green anole lizard, Anolis carolinensis. We find that A. carolinensis microchromosomes are highly syntenic with chicken microchromosomes, yet do not exhibit the high GC and low repeat content that are characteristic of avian microchromosomes. Also, A. carolinensis mobile elements are very young and diverse-more so than in any other sequenced amniote genome. The GC content of this lizard genome is also unusual in its homogeneity, unlike the regionally variable GC content found in mammals and birds. We describe and assign sequence to the previously unknown A. carolinensis X chromosome. Comparative gene analysis shows that amniote egg proteins have evolved significantly more rapidly than other proteins. An anole phylogeny resolves basal branches to illuminate the history of their repeated adaptive radiations., (© 2011 Macmillan Publishers Limited. All rights reserved)

Crossbred yearling steers (n=80; 406 ± 2.7 kg of BW) were used to evaluate the effects of S concentration in dried distillers grains with solubles (DDGS) on growth performance, carcass characteristics, and ruminal concentrations of CH(4) and H(2)S in finishing steers fed diets based on steam-flaked corn (SFC) or dry-rolled corn (DRC) and containing 30% DDGS (DM basis) with moderate S (0.42% S, MS) or high S (0.65% S, HS). Treatments consisted of SFC diets containing MS (SFC-MS), SFC diets containing HS (SFC-HS), DRC diets containing MS (DRC-MS), or DRC diets containing HS (DRC-HS). High S was achieved by adding H(2)SO(4) to DDGS. Ruminal gas samples were analyzed for concentrations of H(2)S and CH(4). Steers were fed once daily in quantities that resulted in traces of residual feed in the bunk the following day for 140 d. No interactions (P ≥ 0.15) between dietary S concentration and grain processing were observed with respect to growth performance or carcass characteristics. Steers fed HS diets had 8.9% less DMI (P < 0.001) and 12.9% less ADG (P=0.006) than steers fed diets with MS, but S concentration had no effect on G:F (P=0.25). Cattle fed HS yielded 4.3% lighter HCW (P = 0.006) and had 16.2% less KPH (P=0.009) than steers fed MS. Steers fed HS had decreased (P=0.04) yield grades compared with steers fed MS. No differences were observed among treatments with respect to dressing percentage, liver abscesses, 12th-rib fat thickness, LM area, or USDA quality grades (P ≥ 0.18). Steers fed SFC had less DMI (P < 0.001) than steers fed DRC. Grain processing had no effect (P > 0.05) on G:F or carcass characteristics. Cattle fed HS had greater (P < 0.001) ruminal concentrations of H(2)S than cattle fed MS. Hydrogen sulfide concentration was inversely related (P ≤ 0.01) to ADG (r=-0.58) and DMI (r=-0.67) in cattle fed SFC, and to DMI (r=-0.40) in cattle fed DRC. Feeding DDGS that are high in dietary S may decrease the DMI of beef steers and compromise the growth performance and carcass characteristics of feedlot cattle., (© 2011 American Society of Animal Science. All rights reserved.)

A series of polynuclear mixed-ligand tris(pyrazolyl)methane iron(II) complexes displaying high temperature spin crossover behaviour has been synthesised. These complexes are of the type [(Fe((3,5-Me(2)pz)(3)CH))(n)(μ-L)](BF(4))(2n), where μ-L is one of five bridging ligands X(CH(2)OCH(2)C(pz)(3))(n), (X = the central linking moiety, pz = pyrazolyl ring and n = 2 (ditopic), 3 (tritopic) or 4 (tetratopic)). Throughout the series the terminal tris(3,5-dimethylpyrazolyl)methane co-ligand (3,5-Me(2)pz)(3)CH and the BF(4)(-) counter anion were kept constant while variations in the central linking moiety have produced three dinuclear complexes and a trinuclear and tetranuclear complex, all isolated as solvates. The three dinuclear complexes are a 1,4-xylene-bridged complex 1·2DME, a 2,6-naphthalene-bridged complex 2·2.5MeCN.2DME and a 1,4-butene-bridged complex 3·2DME. The trinuclear complex 4·solvent (solvent undefined) has a 1,3,5-mesitylene core and the tetranuclear complex, 5·8MeCN.2(t)BuOMe, has a 1,2,4,5-tetramethylbenzene core (DME = dimethoxyethane, (t)BuOMe = tertiarybutyl-methylether). The trinuclear cluster has a "3-up" cup shape with the cups arranging themselves in pairs to form capsules that contain anion guests. All the solvated compounds have been structurally characterised and both the solvated and desolvated versions have had their magnetic and thermal properties thoroughly investigated by variable temperature magnetic susceptibility, differential scanning calorimetric and Mössbauer spectral methods. They all display typical low spin iron(II) magnetic behaviour at room temperature and all undergo a spin state transition to high spin iron(II) above room temperature. In particular, complex 1·2DME shows an abrupt spin transition which shifts, upon desolvation, to a lower value of T(1/2) and in addition displays a small thermal hysteresis., (This journal is © The Royal Society of Chemistry 2011)

Human-induced land use changes are causing extensive habitat fragmentation. As a result, many species are not able to shift their ranges in response to climate change and will likely need to adapt in situ to changing climate conditions. Consequently, a prudent strategy to maintain the ability of populations to adapt is to focus conservation efforts on areas where levels of intraspecific variation are high. By doing so, the potential for an evolutionary response to environmental change is maximized. Here, we use modeling approaches in conjunction with environmental variables to model species distributions and patterns of genetic and morphological variation in seven Ecuadorian amphibian, bird, and mammal species. We then used reserve selection software to prioritize areas for conservation based on intraspecific variation or species-level diversity. Reserves selected using species richness and complementarity showed little overlap with those based on genetic and morphological variation. Priority areas for intraspecific variation were mainly located along the slopes of the Andes and were largely concordant among species, but were not well represented in existing reserves. Our results imply that in order to maximize representation of intraspecific variation in reserves, genetic and morphological variation should be included in conservation prioritization.

Here we use nuclear and mitochondrial DNA sequence data, combined with morphometric analyses, to clarify the systematic relationships and taxonomy of two complex species of shrews, Suncus montanus and S. murinus, in Sri Lanka. We find that subspecies of S. murinus, Suncus murinus murinus from Anuaradhapura and S. m. caerulescens from Colombo, show little or no genetic difference in the mitochondrial (cytochrome-b and 16SrRNA) and nuclear (Rag 1, aldolase C and EF-1 alpha intron) genes, confirming their classification as a single species. However, two populations of S. murinus from Peradeniya and Udawalawe are identified as putative hybrids of S. murinus and S. montanus. Shrews collected from Peradeniya are best described as a population of S. murinus, but could be identified as S.m. kandianus using morphological features. Nuclear DNA sequence data places this population in a clade with other S. murinus, but mtDNA sequences of the population nests within a clade of S. montanus haplotypes. This discordant pattern of nuclear and mitochondrial genes suggests either hybridization between S. murinus and S. montanus or introgression of S. montanus mitochondrial DNA into S. m. kandianus. S. m. murinus from Udawalawe, which shows no distinct morphological difference from S. m. murinus from Anuradhapura, falls in the clade of S. murinus in both nuclear and mitochondrial trees. In the nuclear gene tree however, S. m.murinus from Udawalawe is placed as a sister taxon to the clade including other S. murinus. Rag 1 gene sequences in Udawalawe individuals suggest recombination of S. murinus and S. montanus DNA within the gene. However, additional nuclear genes are necessary to study the extent of the hybridization of S. murinus and S. montanus., (Copyright 2010 Elsevier Inc. All rights reserved.)

To better understand how environment shapes phenotypic and genetic variation, we explore the relationship between environmental variables across Ecuador and genetic and morphological variation in the wedge-billed woodcreeper (Glyphorynchus spirurus), a common Neotropical rainforest bird species. Generalized dissimilarity models show that variation in amplified fragment length polymorphism markers was strongly associated with environmental variables on both sides of the Andes, but could also partially be explained by geographic distance on the western side of the Andes. Tarsus, wing, tail, and bill lengths and bill depth were well explained by environmental variables on the western side of the Andes, whereas only tarsus length was well explained on the eastern side. Regions that comprise the highest rates of genetic and phenotypic change occur along steep elevation gradients in the Andes. Such environmental gradients are likely to be particularly important for maximizing adaptive diversity to minimize the impacts of climate change. Using a framework for conservation prioritization based on preserving ecological and evolutionary processes, we found little overlap between currently protected areas in Ecuador and regions we predicted to be important in maximizing adaptive variation.

Purpose: Enzastaurin is a potent, serine-threonine kinase inhibitor which selectively targets PKCβ and PI3K/AKT signaling pathways to reduce cell proliferation, induce apoptosis, and inhibit angiogenesis. As PKCbeta and PI3K/AKT signaling are both involved in breast cancer pathogenesis, this phase II study evaluated the efficacy and toxicity of enzastaurin in previously treated patients with metastatic breast cancer (MBC)., Patients and Methods: Eligible patients had histologically confirmed MBC with measurable disease, and must have received prior anthracycline and taxane chemotherapy, but not more than two prior regimens for MBC. Human epidermal growth factor 2 (HER2)-positive patients must have progressed on prior trastuzumab therapy. Enzastaurin, 1,125-mg loading dose on day 1 followed by 500 mg daily, was administered orally in 28-day cycles. Response was assessed every 2 cycles according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria., Results: Twenty-one patients enrolled between November 2006 and September 2007. Fourteen (66.7%) patients completed at least two cycles of therapy. No patients developed Grade 3/4 hematologic toxicity. Grade 3 nonhematologic toxicity was rare (<5%) and most commonly attributed to MBC progression. There were no objective responses and no patients with stable disease for >/=6 months. Median progression-free survival was 1.68 months (95%CI: 1.02, 1.74)., Conclusions: Enzastaurin monotherapy was well tolerated, but demonstrated no activity in patients with heavily pretreated MBC.

Purpose: To determine the optimal dose of the antiepidermal growth factor receptor (EGFR) monoclonal antibody cetuximab that can be safely administered in combination with a standard daily dose of erlotinib in patients with advanced solid malignancies., Patients and Methods: Patients with advanced solid malignancies who had failed standard chemotherapies received escalating doses of cetuximab without a loading dose (100, 200, 250 mg/m(2) i.v. weekly) in combination with a fixed dose of erlotinib (150 mg daily orally) until disease progression or unacceptable toxicity., Results: Twenty-two patients were treated, including 14 patients (64%) with non-small cell lung cancer. Twenty patients received combination treatment at the highest dose level for a median of 5.5 weeks (range, 1-31 weeks). One dose-limiting toxicity was observed: grade 3 skin rash. Overall, the most common adverse events (any grade, grade 3/4) were consistent with the safety profiles of the individual drugs: acneform rash (100%, 9%), diarrhea (77%, 5%), and hypomagnesemia (59%, 12%). Seven of 18 evaluable patients (38.9%) had stable disease lasting for a median of 16.6 weeks (range, 6.1-25.1 weeks)., Conclusion: Dual EGFR inhibition with cetuximab and erlotinib is feasible; the observed toxicities were manageable and consistent with the safety profiles of the individual drugs. The recommended doses for phase II studies are 250 mg/m(2) i.v. weekly for cetuximab and 150 mg daily orally for erlotinib.