Diurnal Preference Predicts Phase Differences in Expression of Human Peripheral Circadian Clock Genes

Background: Circadian rhythms play an integral role in human behavior, physiology and health. Individual differences in daily rhythms (chronotypes) can affect individual sleep-wake cycles, activity patterns and behavioral choices. Diurnal preference, the tendency towards morningness or eveningness among individuals, has been associated with interpersonal variation in circadian clock-related output measures, including body temperature, melatonin levels and clock gene mRNA in blood, oral mucosa, and dermal fibroblast cell cultures. Methods: Here we report gene expression data from two principal clock genes sampled from hair follicle cells, a peripheral circadian clock. Hair follicle cells from fourteen individuals of extreme morning or evening chronotype were sampled at three time points. RNA was extracted and quantitative PCR assays were used to measure mRNA expression patterns of two clock genes, 'Per3' and 'Nr1d2'. Results: We found significant differences in clock gene expression over time between chronotype groups, independent of gender or age of participants. Extreme evening chronotypes have a delay in phase of circadian clock gene oscillation relative to extreme morning types. Variation in the molecular clockwork of chronotype groups represents nearly three-hour phase differences ('Per3': 2.61 hours; 'Nr1d2': 3.08 hours, both: 2.86) in circadian oscillations of these clock genes. Conclusions: The measurement of gene expression from hair follicles at three time points allows for a direct, efficient method of estimating phase shifts of a peripheral circadian clock in real-life conditions. The robust phase differences in temporal expression of clock genes associated with diurnal preferences provide the framework for further studies of the molecular mechanisms and gene-by-environment interactions underlying chronotype-specific behavioral phenomena, including social jetlag

Drug Combination in Cancer Treatment—From Cocktails to Conjugated Combinations

It is well recognized today that anticancer drugs often are most effective when used in combination. However, the establishment of chemotherapy as key modality in clinical oncology began with sporadic discoveries of chemicals that showed antiproliferative properties and which as a first attempt were used as single agents. In this review we describe the development of chemotherapy from its origins as a single drug treatment with cytotoxic agents to polydrug therapy that includes targeted drugs. We discuss the limitations of the first chemotherapeutic drugs as a motivation for the establishment of combined drug treatment as standard practice in spite of concerns about frequent severe, dose limiting toxicities. Next, we introduce the development of targeted treatment as a concept for advancement within the broader field of small-molecule drug combination therapy in cancer and its accelerating progress that was boosted by recent scientific and technological progresses. Finally, we describe an alternative strategy of drug combinations using drug-conjugates for selective delivery of cytotoxic drugs to tumor cells that potentiates future improvement of drug combinations in cancer treatment. Overall, in this review we outline the development of chemotherapy from a pharmacological perspective, from its early stages to modern concepts of using targeted therapies for combinational treatment

The effects of terminal-link fixed-interval and variable-interval schedules on responding under concurrent chained schedules

Previous work using variable-interval schedules in the terminal links of concurrent chained schedules suggested that relative choice proportion in the initial links equalled relative rate of reinforcement in the terminal links. With fixed-interval terminal-link schedules, however, matching was not obtained. The present study held pairs of fixed-interval terminal-link schedules in a constant ratio but varied absolute sizes. Relative choice for the smaller terminal-link fixed-interval schedule was a negatively accelerated, increasing function of absolute size of the fixed-interval pairs. Matching was found only with the fixed-interval pair of 5 and 10 sec. When pairs of variable-interval schedules were arranged so that the harmonic mean of the intervals equalled the fixed-interval parameter values, relative choice functions were like those for fixed-interval schedules

Un Análisis Multi-Escalar del Sistema Forestal Peruano

Perú tiene 67 millones de hectáreas de bosque, que viene a ser más del 53% de la superficie total del país (OIMT, 2010). La extracción maderera es la propulsora principal de la economía dentro de la Amazonía Peruana, generando empleos para comunidades rurales y urbanas (Sears y Pinedo-Vásquez, 2011). Sin embargo, a menudo los empresarios madereros explotan a sus trabajadores a través de un sistema de préstamos (De la Rosa Tincopa, 2009). Alrededor de 1354 comunidades indígenas poseen títulos de propiedad en la región (OIMT, 2010), pero muchas comunidades no tienen los títulos para su territorio que muchas veces se sobrepone a concesiones madereras (Salisbury et al. 2011).https://scholarship.richmond.edu/geography-posters/1008/thumbnail.jp