Vedolizumab Dose Escalation: In for a Penny,in for a Pound?

Digestive Diseases and Sciences -     

Depression: a major,unrecognized risk factor for osteoporosis?

Existing studies of the relationship between depression and osteoporosis have been heterogeneous in their design and use of diagnostic instruments for depression, which might have contributed to the different results on the comorbidity of these two conditions. Nevertheless, these studies reveal a strong association between depression and osteoporosis. Endocrine factors such as depression-induced hypersecretion of corticotropin-releasing hormone and hypercortisolism, hypogonadism, growth hormone deficiency and increased concentration of circulating interleukin 6, might play a crucial role in the bone loss observed in subjects suffering from major depression.     

Pharmacotherapeutic approaches for decompensated heart failure: a role for the calcium sensitiser,levosimendan?

Although no universal definition exists, decompensated heart failure may be regarded as either a worsening of chronic heart failure or new-onset heart failure precipitated by an acute incident. Haemodynamic management of patients hospitalised with decompensated heart failure may include the administration of diuretics, vasodilators and positive inotropic agents. Until recently, these latter agents constituted the only drug class to produce a direct increase in stroke volume via enhanced myocardial contractility. However, despite their short-term benefits, the clinical utility of inotropic agents is compromised by their potentially deleterious effects on calcium handling and oxygen consumption, resulting in an increased risk of serious ventricular arrhythmias and death. In contrast, calcium sensitisers enhance cardiac performance without affecting calcium movement and, therefore, are potentially associated with a reduced risk of rhythmic disturbances. These agents constitute a heterogeneous group of compounds with different affinities for calcium sensitisation. Levosimendan is a potent calcium sensitiser with vasodilating properties that has been shown to provide symptomatic and haemodynamic improvement with no increase in oxygen consumption. Calcium sensitisation is therefore emerging as a promising treatment approach in this challenging therapeutic area.     

DBL-1, a TGF-β, is essential for Caenorhabditis elegans aversive olfactory learning

The TGF-β superfamily is conserved throughout metazoan, and its members play essential roles in development and disease. TGF-β has also been implicated in adult neural plasticity. However, the underlying mechanisms are not well understood. Here we report that DBL-1, a Caenorhabditis elegans TGF-β homolog known to control body morphology and immunity, is essential for aversive olfactory learning of potentially harmful bacteria food. We show that DBL-1 generated by the AVA command interneurons, which are critical for sensorimotor responses, regulates aversive olfactory learning, and that the activity of the type I TGF-β receptor SMA-6 in the hypodermis is needed during adulthood to generate olfactory plasticity. These spatial and temporal mechanisms are critical for the DBL-1 signaling to achieve its diverse functions in development and adult neural plasticity. Interestingly, aversive training decreases AVA calcium response, leading to an increase in the DBL-1 signal secreted from AVA, revealing an experience-dependent change that can underlie the role of TGF-β signaling in mediating plasticity.     

Transpiration, a prerequisite for long-distance transport of minerals in plants?

The major "benefit" alleged to accrue from transpiration (the evaporative loss of water from plant surfaces) is that it is essential for the long-distance transport of mineral ions, but the possible interrelation between these two processes has rarely been tested. Transpiration was experimentally dissociated from mineral supply by growing sunflowers (Helianthus anuus) in hydroculture and providing mineral nutrients only during the nights. These plants grew as well as a control group that received nutrients only during the day and transpired 12-15 times more water during the exposure period. It thus appears that convective water transport in the xylem, brought about by root pressure and the resultant guttation, "growth water," and Münch's phloem counterflow is in itself sufficient for long-distance mineral supply and that transpiration is not required for this function.     

Channelrhodopsin-2–XXL,a powerful optogenetic tool for low-light applications

Channelrhodopsin-2 (ChR2) has provided a breakthrough for the optogenetic control of neuronal activity. In adult Drosophila melanogaster, however, its applications are severely constrained. This limitation in a powerful model system has curtailed unfolding the full potential of ChR2 for behavioral neuroscience. Here, we describe the D156C mutant, termed ChR2-XXL (extra high expression and long open state), which displays increased expression, improved subcellular localization, elevated retinal affinity, an extended open-state lifetime, and photocurrent amplitudes greatly exceeding those of all heretofore published ChR variants. As a result, neuronal activity could be efficiently evoked with ambient light and even without retinal supplementation. We validated the benefits of the variant in intact flies by eliciting simple and complex behaviors. We demonstrate efficient and prolonged photostimulation of monosynaptic transmission at the neuromuscular junction and reliable activation of a gustatory reflex pathway. Innate male courtship was triggered in male and female flies, and olfactory memories were written through light-induced associative training.Identifying causal relationships between neuronal activity and animal behavior is a fundamental goal of neuroscience. Crucially, this task requires testing whether defined neuronal populations are sufficient for eliciting behavioral modules. The development of light-gated ion channels that can be genetically targeted to specific cells has provided a unique solution to this challenge. In pioneering work, such optogenetic effectors or actuators were originally used as multicomponent approaches (1–3). The introduction of Channelrhodopsin-1 (ChR1) (4) and especially ChR2 as a light-sensitive cation channel (5) dramatically advanced the field by providing an efficient and straightforward single-component strategy for stimulating neuronal activity (6, 7).Besides cell-specific targeting of appropriate effector elements, precise neuronal control by optogenetics demands efficient light delivery to the neurons of interest. For behavioral studies, photostimulation is ideally accomplished in intact, freely moving organisms and accompanied by functional readouts. The combination of a rich, well-characterized behavioral repertoire and elegant molecular genetics has contributed to Drosophila’s strong impact on behavioral neurogenetics (8, 9). However, low light transmission through the pigmented cuticle presupposes high light intensities for using ChR2 in flies. This obstacle greatly complicates the experimental setup for freely moving animals, and the required light energies can cause heat damage when stimulation is applied over extended time periods. Moreover, limited cellular availability of all-trans-retinal (hereafter retinal for short) demands adding high retinal concentrations as a dietary supplement. If optical access to target cells is not provided by a translucent body wall (e.g., as in nematodes, zebrafish, and Drosophila larvae), an alternative solution is the implantation of an optical fiber directly into the brain. Although this approach has been used successfully in mammals (10), such an invasive procedure is infeasible for the study of intact small organisms.Due to these restrictions in Drosophila, ChR2 has not reached the popularity attained in other organisms, and instead the field has turned mainly to thermogenetic neuronal stimulation (11–13). As with all techniques, there are also drawbacks to using temperature as a stimulus, such as undesired background activity and a multitude of temperature-sensitive cellular processes and behavioral responses. Photo-liberation of caged ATP, combined with genetic targeting of ATP-gated ion channels, has been introduced as a different optogenetic technique in Drosophila (3, 14). However, its applications are constrained by invasive, time-consuming procedures for injection of caged ATP and a limited experimental time window.Here, we introduce improved ChR2 variants as an alternative approach to address these shortcomings in Drosophila. Compared with wild-type ChR2 (ChR2-wt), expression of these mutants in target cells led to strongly enhanced photocurrents. We provide the first report, to our knowledge, of ChR2-T159C (15, 16) in flies and describe a ChR2 variant, ChR2-XXL (extra high expression and long open state), that is characterized by an extended open-state lifetime, elevated cellular expression, enhanced axonal localization, and reduced dependence on retinal addition. As a consequence, this mutant does not require dietary retinal supplementation to depolarize cells, evoke synaptic transmission, and activate neuronal networks at very low irradiance. These features enabled behavioral photostimulation in freely moving flies using diffuse low-intensity light.