(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

Individual variability and versatility in an eco-evolutionary model of avian migration

Seasonal migration is a complex and variable behaviour with the potential to promote reproductive isolation. In Eurasian blackcaps (Sylvia atricapilla), a migratory divide in central Europe separating populations with southwest (SW) and southeast (SE) autumn routes may facilitate isolation, and individuals using new wintering areas in Britain show divergence from Mediterranean winterers. We tracked 100 blackcaps in the wild to characterize these strategies. Blackcaps to the west and east of the divide used predominantly SW and SE directions, respectively, but close to the contact zone many individuals took intermediate (S) routes. At 14.0° E, we documented a sharp transition from SW to SE migratory directions across only 27 (10–86) km, implying a strong selection gradient across the divide. Blackcaps wintering in Britain took northwesterly migration routes from continental European breeding grounds. They originated from a surprisingly extensive area, spanning 2000 km of the breeding range. British winterers bred in sympatry with SW-bound migrants but arrived 9.8 days earlier on the breeding grounds, suggesting some potential for assortative mating by timing. Overall, our data reveal complex variation in songbird migration and suggest that selection can maintain variation in migration direction across short distances while enabling the spread of a novel strategy across a wide range

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

National Beef Quality Audit-2016: Transportation, mobility, and harvest-floor assessments of targeted characteristics that affect quality and value of cattle, carcasses, and by-products

The National Beef Quality Audit-2016 (NBQA-2016) was conducted to assess current transportation, mobility, and quality characteristics of U.S. fed steers and heifers. Data were collected at 17 beef processing facilities between March and November 2016. About 8,000 live cattle were evaluated for transportation and mobility, and about 25,000 carcasses were evaluated on the slaughter floor. Cattle were in transit to the slaughter facility for a mean duration of 2.7 h from a mean distance of 218.5 km using trailers with dimensions ranging from 17.84 m2 to 59.09 m2. Area allotted per animal averaged 1.13 m2 and ranged from 0.85 m2 to 2.28 m2. A total of 96.8% of cattle received a mobility score of 1 (walks easily, no apparent lameness). Identification types (35.1% had multiple) were lot visual tags (61.5%), individual tags (55.0%), electronic tags (16.9%), metal-clip tags (9.2%), bar-coded tags (0.05%), wattles (0.01%), and other (2.6%). Cattle were black-hided (57.8%), Holstein (20.4%), red-hided (10.5%), yellow-hided (4.8%), gray-hided (2.9%), brown-hided (1.3%), and white-hided (1.1%). Unbranded hides were observed on 74.3% of cattle; 18.6% had brands located on the butt, 6.3% on the side, and 1.3% on the shoulder (values exceed 100% due to multiple brands). For hide-on carcasses, 37.7% displayed no mud or manure; specific locations for mud or manure were legs (40.8%), belly (33.0%), tail region (15.5%), side (6.8%), and top-line (3.9%). Cattle without horns represented 83.3% of the sample, and cattle that did have horns measured: \u3c 2.54 cm (5.5%), 2.54 to 12.7 cm (8.3%), and \u3e 12.7 cm (2.9%). Carcasses without bruises represented 61.1% of those sampled, whereas 28.2% had 1, 8.2% had 2, 2.1% had 3, and 0.3% had 4 bruises. Of those carcasses with a bruise, the bruise was located on the loin (29.7%), round (27.8%), chuck (16.4%), rib (14.4%), and brisket/plate/flank (11.6%). Frequencies of offal condemnations were livers (30.8%), lungs (18.2%), viscera (16.3%), hearts (11.1%), heads (2.7%), and tongues (2.0%). Compared to NBQA-2011, fewer cattle were identified for traceability, fewer were black-hided, a greater number were Holstein cattle, more with no brand and no horns, fewer without bruises, more liver, lung, and viscera condemnations, and fewer heads and tongues were condemned. The NBQA remains an influential survey for the U.S. beef industry to provide benchmarks and strategic plans for continued improvement of beef quality and consistency

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

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 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

The BET inhibitor JQ1 selectively impairs tumour response to hypoxia and downregulates CA9 and angiogenesis in triple negative breast cancer

The availability of bromodomain and extra-terminal inhibitors (BETi) has enabled translational epigenetic studies in cancer. BET proteins regulate transcription by selectively recognizing acetylated lysine residues on chromatin. BETi compete with this process leading to both downregulation and upregulation of gene expression. Hypoxia enables progression of triple negative breast cancer (TNBC), the most aggressive form of breast cancer, partly by driving metabolic adaptation, angiogenesis and metastasis through upregulation of hypoxia-regulated genes (for example, carbonic anhydrase 9 (CA9) and vascular endothelial growth factor A (VEGF-A). Responses to hypoxia can be mediated epigenetically, thus we investigated whether BETi JQ1 could impair the TNBC response induced by hypoxia and exert anti-tumour effects. JQ1 significantly modulated 44% of hypoxia-induced genes, of which two-thirds were downregulated including CA9 and VEGF-A. JQ1 prevented HIF binding to the hypoxia response element in CA9 promoter, but did not alter HIF expression or activity, suggesting some HIF targets are BET-dependent. JQ1 reduced TNBC growth in vitro and in vivo and inhibited xenograft vascularization. These findings identify that BETi dually targets angiogenesis and the hypoxic response, an effective combination at reducing tumour growth in preclinical studies