(Micro)evolutionary changes and the evolutionary potential of bird migration

Seasonal migration is the yearly long-distance movement of individuals between their breeding and wintering grounds. Individuals from nearly every animal group exhibit this behavior, but probably the most iconic migration is carried out by birds, from the classic V-shape formation of geese on migration to the amazing nonstop long-distance flights undertaken by Arctic Terns Sterna paradisaea. In this chapter, we discuss how seasonal migration has shaped the field of evolution. First, this behavior is known to turn on and off quite rapidly, but controversy remains concerning where this behavior first evolved geographically and whether the ancestral state was sedentary or migratory (Fig. 7.1d, e). We review recent work using new analytical techniques to provide insight into this topic. Second, it is widely accepted that there is a large genetic basis to this trait, especially in groups like songbirds that migrate alone and at night precluding any opportunity for learning. Key hypotheses on this topic include shared genetic variation used by different populations to migrate and only few genes being involved in its control. We summarize recent work using new techniques for both phenotype and genotype characterization to evaluate and challenge these hypotheses. Finally, one topic that has received less attention is the role these differences in migratory phenotype could play in the process of speciation. Specifically, many populations breed next to one another but take drastically different routes on migration (Fig. 7.2). This difference could play an important role in reducing gene flow between populations, but our inability to track most birds on migration has so far precluded evaluations of this hypothesis. The advent of new tracking techniques means we can track many more birds with increasing accuracy on migration, and this work has provided important insight into migration's role in speciation that we will review here

A phase II evaluation of cediranib in the treatment of recurrent or persistent endometrial cancer: An NRG Oncology/Gynecologic Oncology Group study

PURPOSE: Cediranib is a multi-tyrosine kinase inhibitor targeting vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and fibroblast growth factor (FGF) receptors. This phase II study was conducted to assess activity and tolerability of single-agent cediranib in recurrent/persistent endometrial cancer. PATIENTS AND METHODS: Eligible patients had recurrent or persistent endometrial cancer after receiving one or two prior cytotoxic regimens, measurable disease, and Gynecologic Oncology Group (GOG) performance status of ≤2 (≤1 if two prior cytotoxic regimens given). Cediranib 30mg orally daily for a 28daycycle was administered until disease progression or prohibitive toxicity. Microvessel density (MVD) was measured in tumor tissue from initial hysterectomy specimens and correlated with clinical outcome. Primary endpoints were tumor response and surviving progression-free for six months without subsequent therapy (6-month event-free survival [EFS]). RESULTS: Of 53 patients enrolled, 48 were evaluable for cediranib efficacy and toxicity. Median age was 65.5 years, 52% of patients had received prior radiation, and 73% of patients received only one prior chemotherapy regimen. A partial response was observed in 12.5%. Fourteen patients (29%) had six-month EFS. Median progression-free survival (PFS) was 3.65 months and median overall survival (OS) 12.5 months. No grade 4 or 5 toxicities were observed. A trend towards improved PFS was found in patients whose tumors expressed high MVD. CONCLUSION: Cediranib as a monotherapy treatment for recurrent or persistent endometrial cancer is well tolerated and met protocol set objectives for sufficient activity to warrant further investigation. MVD may be a useful biomarker for activity

Selective small molecule induced degradation of the BET bromodomain protein BRD4

The Bromo- and Extra-Terminal (BET) proteins BRD2, BRD3, and BRD4 play important roles in transcriptional regulation, epigenetics, and cancer and are the targets of pan-BET selective bromodomain inhibitor JQ1. However, the lack of intra-BET selectivity limits the scope of current inhibitors as probes for target validation and could lead to unwanted side effects or toxicity in a therapeutic setting. We designed Proteolysis Targeted Chimeras (PROTACs) that tether JQ1 to a ligand for the E3 ubiquitin ligase VHL, aimed at triggering the intracellular destruction of BET proteins. Compound MZ1 potently and rapidly induces reversible, long-lasting, and unexpectedly selective removal of BRD4 over BRD2 and BRD3. The activity of MZ1 is dependent on binding to VHL but is achieved at a sufficiently low concentration not to induce stabilization of HIF-1α. Gene expression profiles of selected cancer-related genes responsive to JQ1 reveal distinct and more limited transcriptional responses induced by MZ1, consistent with selective suppression of BRD4. Our discovery opens up new opportunities to elucidate the cellular phenotypes and therapeutic implications associated with selective targeting of BRD4

Use of Opportunistic Clinical Data and a Population Pharmacokinetic Model to Support Dosing of Clindamycin for Premature Infants to Adolescents

Clindamycin is commonly prescribed to treat children with skin and skin structure infections (including those caused by community-acquired methicillin-resistant Staphylococcus aureus [CA-MRSA]), yet little is known about the pharmacokinetics (PK) across pediatric age groups. A population PK analysis was performed in NONMEM using samples collected in an opportunistic study from children receiving intravenous clindamycin per standard of care. The final model was used to optimize pediatric dosing to match adult exposure proven effective against CA-MRSA. A total of 194 plasma PK samples collected from 125 children were included in the analysis. Median age (range) was 3.3 years (0–20). Median dosing was 9.9 mg/kg/dose (3.8–15.1). A 1-compartment model described the data well. The final model included body weight and a sigmoidal maturation relationship between postmenstrual age (PMA) and clearance (CL): CL (L/h)=13.7*(weight/70)0.75*(PMA3.1/(43.63.1+PMA3.1)); V (L)=61.8*(weight/70). Maturation reached 50% adult CL values at ~44 weeks PMA. Our findings support age-based dosing

Effects of zilpaterol hydrochloride and zinc methionine on growth performance and carcass characteristics of beef bulls

Sixty beef bulls with a body weight (BW) of 314.79 16.2 kg were used to evaluate the effects of zilpaterol hydrochloride (ZH) and zinc methionine (ZM) on growth performance and carcass characteristics. The experimental design was a randomized complete block, with a factorial 22 arrangement of treatments (ZH: 0 and 0.15 mg kg 1 BW; ZM: 0 and 80 mg kg 1 dry matter). The ZH increased (PB0.05) the final BW, average daily gain, feed conversion, carcass yield and longissimus dorsi area. Bulls fed ZH plus ZM had less (PB0.01) backfat thickness and intramuscular fat (IMF) compared with those fed ZH or ZM alone. The ZH increased (PB0.02) the meat crude protein content and cooking loss. It is therefore concluded that ZH increases growth performance, carcass yield, longissimus dorsi area, and meat crude protein. The interaction of ZM and ZH did not present additional advantages. The reason for the reduction in backfat thickness and IMF by ZH plus ZM is unclear, and implies that our knowledge of b-agonistic adrenergic substances and their interactions with minerals is incomplete

Effects of feeding zilpaterol hydrochloride for twenty to forty days on carcass cutability and subprimal yield of calf-fed Holstein steers

El presente trabajo de investigación se realizó con el propósito de Determinar la relación de los estilos de aprendizaje en el rendimiento académico- área de Ingles- en estudiantes de cuarto grado de secundaria del C.P.M. "San Pedro Chanel", Sullana- Piura, 2017. Para el desarrollo de la investigación se utilizó un diseño Correlacional, No Experimental Transversal, así como una población de 1700 estudiantes del nivel secundaria y una muestra No probabilística de 36 estudiantes de cuarto grado de secundaria del aula ?B?. Para la recopilación de la información se utilizó como técnica a la encuesta y como instrumento un cuestionario con escala valorativa referido a la variable Estilos de aprendizaje y para la variables Rendimiento académico se utilizó como técnica al análisis documental y como instrumento una ficha de análisis documental. La información recopilada se registró y procesó utilizando el programa SPSS V19, a partir de lo cual se presentan los resultados en tablas, así como también se realizó el análisis correlacional a través del coeficiente de Pearson. Según los resultados obtenidos existe relación moderada entre las dimensiones estilo de aprendizaje activo y estilo de aprendizaje pragmático en el rendimiento académico en los estudiantes con un coeficiente de Pearson de (0.480 y 0.561); existe relación alta entre el estilo de aprendizaje reflexivo y el rendimiento académico en los estudiantes con un coeficiente de Pearson de (0.634) y existe relación baja entre el estilo de aprendizaje teórico y el rendimiento académico en los estudiantes con un coeficiente de Pearson de (0.382).Tesi

Epigenetic targeting of Hedgehog pathway transcriptional output through BET bromodomain inhibition

Hedgehog signaling drives oncogenesis in several cancers and strategies targeting this pathway have been developed, most notably through inhibition of Smoothened. However, resistance to Smoothened inhibitors occurs via genetic changes of Smoothened or other downstream Hedgehog components. Here, we overcome these resistance mechanisms by modulating GLI transcription via inhibition of BET bromodomain proteins. We show the BET bromodomain protein, BRD4, regulates GLI transcription downstream of SMO and SUFU and chromatin immunoprecipitation studies reveal BRD4 directly occupies GLI1 and GLI2 promoters, with a substantial decrease in engagement of these sites upon treatment with JQ1, a small molecule inhibitor targeting BRD4. Globally, genes associated with medulloblastoma-specific GLI1 binding sites are downregulated in response to JQ1 treatment, supporting direct regulation of GLI activity by BRD4. Notably, patient- and GEMM-derived Hedgehog-driven tumors (basal cell carcinoma, medulloblastoma and atypical teratoid/rhabdoid tumor) respond to JQ1 even when harboring genetic lesions rendering them resistant to Smoothened antagonists

Systems-pharmacology dissection of a drug synergy in imatinib-resistant CML

Occurrence of the BCR-ABL[superscript T315I] gatekeeper mutation is among the most pressing challenges in the therapy of chronic myeloid leukemia (CML). Several BCR-ABL inhibitors have multiple targets and pleiotropic effects that could be exploited for their synergistic potential. Testing combinations of such kinase inhibitors identified a strong synergy between danusertib and bosutinib that exclusively affected CML cells harboring BCR-ABL[superscript T315I]. To elucidate the underlying mechanisms, we applied a systems-level approach comprising phosphoproteomics, transcriptomics and chemical proteomics. Data integration revealed that both compounds targeted Mapk pathways downstream of BCR-ABL, resulting in impaired activity of c-Myc. Using pharmacological validation, we assessed that the relative contributions of danusertib and bosutinib could be mimicked individually by Mapk inhibitors and collectively by downregulation of c-Myc through Brd4 inhibition. Thus, integration of genome- and proteome-wide technologies enabled the elucidation of the mechanism by which a new drug synergy targets the dependency of BCR-ABL[superscript T315I] CML cells on c-Myc through nonobvious off targets

Rapid niche expansion by selection on functional genomic variation after ecosystem recovery

It is well recognized that environmental degradation caused by human activities can result in dramatic losses of species and diversity. However, comparatively little is known about the ability of biodiversity to re-emerge following ecosystem recovery. Here, we show that a European whitefish subspecies, the gangfisch Coregonus lavaretus macrophthalmus, rapidly increased its ecologically functional diversity following the restoration of Lake Constance after anthropogenic eutrophication. In fewer than ten generations, gangfisch evolved a greater range of gill raker numbers (GRNs) to utilize a broader ecological niche. A sparse genetic architecture underlies this variation in GRN. Several co-expressed gene modules and genes showing signals of positive selection were associated with GRN and body shape. These were enriched for biological pathways related to trophic niche expansion in fishes. Our findings demonstrate the potential of functional diversity to expand following habitat restoration, given a fortuitous combination of genetic architecture, genetic diversity and selection