Multiple Neural Oscillators and Muscle Feedback Are Required for the Intestinal Fed State Motor Program

After a meal, the gastrointestinal tract exhibits a set of behaviours known as the fed state. A major feature of the fed state is a little understood motor pattern known as segmentation, which is essential for digestion and nutrient absorption. Segmentation manifests as rhythmic local constrictions that do not propagate along the intestine. In guinea-pig jejunum in vitro segmentation constrictions occur in short bursts together with other motor patterns in episodes of activity lasting 40–60 s and separated by quiescent episodes lasting 40–200 s. This activity is induced by luminal nutrients and abolished by blocking activity in the enteric nervous system (ENS). We investigated the enteric circuits that regulate segmentation focusing on a central feature of the ENS: a recurrent excitatory network of intrinsic sensory neurons (ISNs) which are characterized by prolonged after-hyperpolarizing potentials (AHPs) following their action potentials. We first examined the effects of depressing AHPs with blockers of the underlying channels (TRAM-34 and clotrimazole) on motor patterns induced in guinea-pig jejunum, in vitro, by luminal decanoic acid. Contractile episode durations increased markedly, but the frequency and number of constrictions within segmenting bursts and quiescent period durations were unaffected. We used these observations to develop a computational model of activity in ISNs, excitatory and inhibitory motor neurons and the muscle. The model predicted that: i) feedback to ISNs from contractions in the circular muscle is required to produce alternating activity and quiescence with the right durations; ii) transmission from ISNs to excitatory motor neurons is via fast excitatory synaptic potentials (EPSPs) and to inhibitory motor neurons via slow EPSPs. We conclude that two rhythm generators regulate segmentation: one drives contractions within segmentation bursts, the other the occurrence of bursts. The latter depends on AHPs in ISNs and feedback to these neurons from contraction of the circular muscle

Exposure and connectedness to natural environments: An examination of the measurement invariance of the Nature Exposure Scale (NES) and Connectedness to Nature Scale (CNS) across 65 nations, 40 languages, gender identities, and age groups

Detachment from nature is contributing to the environmental crisis and reversing this trend requires detailed monitoring and targeted interventions to reconnect people to nature. Most tools measuring nature exposure and attachment were developed in high-income countries and little is known about their robustness across national and linguistic groups. Therefore, we used data from the Body Image in Nature Survey to assess measurement invariance of the Nature Exposure Scale (NES) and the Connectedness to Nature Scale (CNS) across 65 nations, 40 languages, gender identities, and age groups (N = 56,968). While multi-group confirmatory factor analysis (MG-CFA) of the NES supported full scalar invariance across gender identities and age groups, only partial scalar invariance was supported across national and linguistic groups. MG-CFA of the CNS also supported full scalar invariance across gender identities and age groups, but only partial scalar invariance of a 7-item version of the CNS across national and linguistic groups. Nation-level associations between NES and CNS scores were negligible, likely reflecting a lack of conceptual clarity over what the NES is measuring. Individual-level associations between both measures and sociodemographic variables were weak. Findings suggest that the CNS-7 may be a useful tool to measure nature connectedness globally, but measures other than the NES may be needed to capture nature exposure cross-culturally

Human immunodeficiency virus type 1 (HIV-1) derived vectors: safety considerations and controversy over therapeutic applications.

The latest generation of lentiviral vectors based on HIV-1 is one of the most efficient tools for gene transduction of mammalian cells. However, the possible employment of HIV-based vectors in clinical trials is a very controversial issue, mainly due to safety and ethical concerns. HIV-1 is a lethal pathogenic agent, which induces AIDS. Genetic vectors must derive either from viruses that are not pathogenic in humans, or that eventually just cause mild illnesses. Patients exposed to HIV-based vectors will test seropositive to certain components of HIV-1. In addition, there might be other possible adverse effects in patients that cannot be predicted, as many aspects of the pathogenesis of AIDS have not been completely understood yet. On these grounds, it seems necessary to improve the design of other lentiviral vectors, which derive from viruses that are not pathogenic in humans and are distantly related to primate retroviridae

Ezh2 reduces the ability of HDAC1-dependent pRb2/p130 transcriptional repression of cyclin A.

The polycomb group (PcG) proteins are known to be involved in maintaining the silenced state of several developmentally regulated genes. Enhancer of zeste homolog 2 (Ezh2), a member of this large protein family, has also been shown to be deregulated in different tumor types and its role, both as a potential primary effector and as a mediator of tumorigenesis, has become a subject of increased interest. We observed that Ezh2 binds to pRb2/p130, a member of the retinoblastoma family; as such, we were led to consider the possible ability of Ezh2 to modulate cell cycle progression. Both Ezh2 and pRb2/p130 repress gene expression by recruiting histone deacetylase (HDAC1), which decreases DNA accessibility for activating transcription factors. Additionally, we observed that Ezh2 interacts with the C-terminal region of pRb2/p130, essential for interaction with HDAC1. We show that Ezh2 is able to reverse pRb2/p130-HDAC1-mediated repression of the cyclin A promoter. This indicates a functional role of this complex in regulating cyclin A expression, known to be crucial in mediating cell cycle advancement. We also detected a significant decrease in the retention of HDAC1 activity associated with pRb2/p130 when Ezh2 was overexpressed. Finally, electromobility shift assays (EMSA) demonstrated that overexpression of Ezh2 caused the abrogation of the pRb2/p130-HDAC1 complex on the cyclin A promoter. These data, taken together, suggest that Ezh2 competes with HDAC1 in binding to pRb2/p130, disrupting their occupancy on the cyclin A promoter. In this study, we propose a new mechanism for the functional inactivation of pRb2/p130 that ultimately contributes to cell cycle progression and malignant transformation

A small molecule based on the pRb2/p130 spacer domain leads to inhibition of cdk2 activity, cell cycle arrest and tumor growth reduction in vivo

One strategy in the development of anticancer therapeutics has been to arrest malignant proliferation through inhibition of the enzymatic activity of cyclin-dependent kinases (cdks), which are key regulatory molecules of the cell cycle. Over the past few years, numerous compounds with remarkable cdk inhibitory activity have been studied in cancer therapy, although it is very difficult to point out the best cdk to target. An excellent candidate appears to be cdk2, whose alteration is a pathogenic hallmark of tumorigenesis. The small molecule described in our study showed an inhibitory effect on the kinase activity of cdk2, a significant growth arrest observed in a colony formation assay and a reduction in the size of the tumor in nude mice, thus suggesting its potential role as a promising new type of mechanism-based antitumor drug, also for the treatment of hyperproliferative disorders

Ethylene coordinates seed germination behavior in response to low soil pH in Stylosanthes humilis

Stylosanthes humilis is known to exhibit high persistence in acid soils, however, how low soil pH controls seed germination as well as root and hypocotyl growth remains unknown. This study was carried out to evaluate the hormonal and metabolic alterations induced by low soil pH on seed germination behavior of S. humilis.Seeds of S. humilis were sown in acid soil samples or sand soaked in buffer solution with pH ranging from 4.0 to 7.0. Concentrations of indole-3-acetic acid, ethylene, 1-aminocyclopropane-1-carboxylic acid (ACC), primary metabolite profile and final seed germination were evaluated after four days.Low soil pH led to increased final seed germination, concomitantly with higher root penetration into the soil as well as higher ACC and ethylene production by seedlings. Treatment with the ethylene biosynthesis inhibitor L-α-(2-aminoethoxyvinyl)-glycine (AVG) greatly reduced final seed germination under acidic conditions. Final seed germination of seeds treated with AVG was increased by exogenous ethylene application in a dose-dependent manner. Furthermore, low soil pH promoted distinct changes in IAA concentrations, and in carbon and nitrogen metabolism in hypocotyl and roots.Low soil pH increases the final germination of S. humilis seeds through alterations in ethylene metabolism, allowing root penetration into the soil