The prefrontal cortex (PFC) is responsible for integrating cortical and subcortical inputs to execute essential cognitive functions such as attention, working memory planning and decision-making. The ...importance of this brain region in regulating complex cognitive processes is underscored by a decline in PFC-mediated ability observed in aging and disease. The cholinergic system plays a vital role in cognitive function and treatments (e.g., cholinesterase inhibitors) to improve cholinergic neurotransmission provide the standard-of-care for diseases such as Alzheimer's. Nicotinic receptors (nAChRs) are a primary site of action for acetylcholine (ACh), and the resulting pro-cognitive effects observed by stimulating nAChRs with nicotine has long been appreciated by tobacco users, prompting investigation of therapeutic development for diseases (e.g., schizophrenia, Alzheimer or attention-deficit-hyperactivity disorder) by targeting the neuronal nAChR system. Noteworthy, improvements in attention, working memory and executive processes mediated by the PFC have been reported following nicotinic agonist exposure. Relevance of these ligand gated channels in higher brain function is further supported by the association of cognitive deficits reported in humans with mutations in CHRNB2 or CHRNA7 the genes encoding for the nicotinic receptor β2 and α7 subunits, respectively. In this work we review, in light of the latest findings, how nicotinic agonists may be acting in the PFC to influence cognitive function.
There are many marine protected areas (MPAs) containing coral reef aggregations in the eastern Pacific region. However, the connectivity of corals between MPAs is still poorly known, especially in ...the Marine Conservation Corridor of the Eastern Tropical Pacific (MCCETP). Here, we assess the potential connectivity of corals across equatorial eastern Pacific MPAs through a Lagrangian particle-tracking algorithm coupled offline with an ocean-circulation numerical model. Connectivity metrics and graph theory were used to analyze the networks and highlight those MPAs that are critical for maintaining the connectivity of corals across the region. Our results show that the equatorial eastern Pacific MPAs form a relatively well-connected network, at least 40% of coral larvae released per year end up within the boundaries of an MPA. MPAs like Malpelo and Gorgona islands included in the MCCETP were found to be critical for connectivity of corals because of their high betweenness centrality and potential role as stepping-stones between coastal MPAs and offshore MPAs such as the Galapagos Islands. Two pelagic larval duration (PLD) scenarios (40 and 130 days) indicate a quasi-unidirectional larval flow from coastal MPAs toward oceanic MPAs, where the only resilient MPAs (Coiba and Malpelo islands) depend mostly on subsidiary recruitment from MPAs located along the coast of Costa Rica, Panama and Colombia. In the two PLD scenarios, Cocos Island maintains a very low resilience potential. Our results indicate the imperative need to include coastal MPAs in the MCCETP network initiative, since connectivity and resilience of coral reefs in the equatorial eastern Pacific region rely heavily on coastal MPAs.
The divalent cation, zinc is the second most abundant metal in the human body and is indispensable for life. Zinc concentrations must however, be tightly regulated as deficiencies are associated with ...multiple pathological conditions while an excess can be toxic.
Zinc plays an important role as a cofactor in protein folding and function, e.g. catalytic interactions, DNA recognition by zinc finger proteins and modulation ion channel activity. There are 24 mammalian proteins specific for zinc transport that are subdivided in two groups with opposing functions: ZnT proteins reduce cytosolic zinc concentration while ZIP proteins increase it. The mammalian brain contains a significant amount of zinc, with 5–15% concentrated in synaptic vesicles of glutamatergic neurons alone. Accumulated in these vesicles by the ZnT3 transporter, zinc is released into the synaptic cleft at concentrations from nanomolar at rest to high micromolar during active neurotransmission.
Low concentrations of zinc modulate the activity of a multitude of voltage- or ligand-gated ion channels, indicating that this divalent cation must be taken into account in the analysis of the pathophysiology of CNS disorders including epilepsy, schizophrenia and Alzheimer's disease.
In the context of the latest findings, we review the role of zinc in the central nervous system and discuss the relevance of the most recent association between the zinc transporter, ZIP8 and schizophrenia. An enhanced understanding of zinc transporters in the context of ion channel modulation may offer new avenues in identifying novel therapeutic entities that target neurological disorders.
This work proposes a generic method for modeling scanned ion beam delivery systems, without simulation of the treatment nozzle and based exclusively on beam data library (BDL) measurements required ...for treatment planning systems (TPS). To this aim, new tools dedicated to treatment plan simulation were implemented in the Gate Monte Carlo platform. The method was applied to a dedicated nozzle from IBA for proton pencil beam scanning delivery. Optical and energy parameters of the system were modeled using a set of proton depth-dose profiles and spot sizes measured at 27 therapeutic energies. For further validation of the beam model, specific 2D and 3D plans were produced and then measured with appropriate dosimetric tools. Dose contributions from secondary particles produced by nuclear interactions were also investigated using field size factor experiments. Pristine Bragg peaks were reproduced with 0.7 mm range and 0.2 mm spot size accuracy. A 32 cm range spread-out Bragg peak with 10 cm modulation was reproduced with 0.8 mm range accuracy and a maximum point-to-point dose difference of less than 2%. A 2D test pattern consisting of a combination of homogeneous and high-gradient dose regions passed a 2%/2 mm gamma index comparison for 97% of the points. In conclusion, the generic modeling method proposed for scanned ion beam delivery systems was applicable to an IBA proton therapy system. The key advantage of the method is that it only requires BDL measurements of the system. The validation tests performed so far demonstrated that the beam model achieves clinical performance, paving the way for further studies toward TPS benchmarking. The method involves new sources that are available in the new Gate release V6.1 and could be further applied to other particle therapy systems delivering protons or other types of ions like carbon.
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Modern developments in organic chemistry, molecular biology, virology, and genetics have opened new, exciting possibilities to better understand physiology and to create innovative, ...robust therapeutics. One such possibility is the burgeoning field of chemogenetics, a sub-field of chemical genetics that encompasses engineering macromolecules (particularly proteins) to modify how they interact with endogenous and exogenous ligands (particularly small molecules).
Early efforts in chemogenetics were focused on parsing the function of a specific enzyme within a closely-related family by creating orthogonal enzyme-ligand pairs (e.g. kinases paired with antagonists). This powerful concept quickly expanded into engineered G-protein-coupled receptors (e.g. DREADDs/RASSL), and more recently into engineered ligand-gated ion channels (eLGIC). The modifications to the receptor focused on eliminating their activation by endogenous ligands, while preserving or enhancing their interaction with pharmacological agents (e.g. small molecule agonist). Creation of such an engineered receptor and delivering it selectively to specific cell types opens new possibilities of accurately and precisely controlling cellular activity. Control of this activity then increases our understanding of the cells function in normal physiology, while also creating the possibility of using it as a therapeutic to address pathophysiology. The DREADDs/RASSL and eLGIC approaches have been particularly impactful in neurosciences but have applications in multiple fields.
In this work we introduce the history of the chemogenetic approach, review the seminal work with DREADDs/RASSLs and eLGIC, highlight the breadth of applications, and discuss the strengths and weaknesses associated with this technology, especially in the context of its development into a therapeutic.
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The discovery of the chemical synapse was a seminal finding in Neurobiology but the large body of microscopic interactions involved in synaptic transmission could hardly have been ...foreseen at the time of these first discoveries. Characterization of the molecular players at work at synapses and the increased granularity at which we can now analyze electrical and chemical signal processing that occur in even the simplest neuronal system are shining a new light on receptor interactions. The aim of this review is to discuss the complexity of some representative interactions between excitatory and inhibitory ligand-gated ion channels and/or G protein coupled receptors, as well as other key machinery that can impact neurotransmission and to explain how such mechanisms can be an important determinant of nervous system function.
Background and purpose: Smoking cessation trials with three high‐affinity partial agonists of α4β2 neuronal nicotinic acetylcholine receptors (nAChRs) have demonstrated differences in their clinical ...efficacy. This work examines the origin of the differences by taking into account brain exposure and pharmacological effects at human α4β2 nAChRs.
Experimental approach: Rat plasma and brain pharmacokinetics were characterized and used to predict human steady‐state plasma and brain concentrations following recommended doses of each of the three compounds. The pharmacological characterization included in vitro affinities at different nAChR subtypes, functional efficacies and potencies at the human α4β2 nAChR, as well as in vivo effects on rat mesolimbic dopamine turn‐over.
Key results: A comparison of predicted human brain concentrations following therapeutic doses demonstrated that varenicline and nicotine, but not dianicline and cytisine, can extensively desensitize and, to a lesser extent, activate α4β2 nAChRs. The limited clinical efficacy of dianicline may be accounted for by a combination of weak functional potency at α4β2 nAChRs and moderate brain penetration, while recommended doses of cytisine, despite its high in vitro potency, are predicted to result in brain concentrations that are insufficient to affect α4β2 nAChRs.
Conclusions and implications: The data provide a plausible explanation for the higher abstinence rate in smoking cessation trials following treatment with varenicline than with the two other α4β2 nAChR partial agonists. In addition, this retrospective analysis demonstrates the usefulness of combining in vitro and in vivo parameters with estimated therapeutic human brain concentrations for translation to clinical efficacy.
The aim of this study (ClinicalTrials.gov, NCT01744470) was to determine the efficacy and safety of two different doses of extended‐release tacrolimus (TacER) in kidney transplant recipients (KTRs) ...between 4 and 12 mo after transplantation. Stable steroid‐free KTRs were randomized (1:1) after 4 mo: Group A had a 50% reduction in TacER dose with a targeted TacER trough level (C0) >3 μg/L; group B had no change in TacER dose (TacER C0 7–12 μg/L). The primary outcome was estimated GFR at 1 year. Of 300 patients, the intent‐to‐treat analysis included 186 patients (group A, n = 87; group B, n = 99). TacER C0 was lower in group A than in group B at 6 mo (4.1 ± 2.7 vs. 6.7 ± 3.9 μg/L, p < 0.0001) and 12 mo (5.6 ± 2.0 vs. 7.4 ± 2.1 μg/L, p < 0.0001). Estimated GFR was similar in both groups at 12 mo (group A, 56.0 ± 17.5 mL/min per 1.73 m²; group B, 56.0 ± 22.1 mL/min per 1.73 m²). More rejection episodes occurred in group A than group B (11 vs. 3; p = 0.016). At 1 year, subclinical inflammation occurred more frequently in group A than group B (inflammation score i >0: 21.4% vs. 8.8%, p = 0.047; tubulitis score t >0: 19.6% vs. 8.7%, p = 0.076; i + t: 1.14 ± 1.21 vs. 0.72 ± 1.01, p = 0.038). Anti‐HLA donor‐specific antibodies appeared only in group A (6 vs. 0 patients, p = 0.008). TacER C0 should be maintained >7 μg/L during the first year after transplantation in low‐immunological‐risk, steroid‐free KTRs receiving a moderate dose of mycophenolic acid.
This randomized clinical trial compares two different doses of extended‐released tacrolimus 4 months after kidney transplantation in stable steroid‐free recipients and shows that reduction of the tacrolimus dose increases the risk of acute rejection and the appearance of de novo donor‐specific antibodies.
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