Chronic Mg2+ Deficiency Does Not Impair Insulin Secretion in Mice.

Magnesium is an essential mediator of a vast number of critical enzymatic cellular reactions in the human body. Some clinical epidemiological studies suggest that hypomagnesemia accounts for declines in insulin secretion in patients with type 2 diabetes (T2D); however, the results of various experimental studies do not support this notion. To address this discrepancy, we assessed the short- and long-term effects of hypomagnesemia on ß-cell function and insulin secretion in primary mouse islets of Langerhans and in a mouse model of hypomagnesemia known as Trpm6Δ17 /fl;Villin1-Cre mice. We found that lowering the extracellular Mg2+ concentration from 1.2 mM to either 0.6 or 0.1 mM remarkably increased glucose-induced insulin secretion (GIIS) in primary islets isolated from C57BL/6 mice. Similarly, both the plasma insulin levels and GIIS rose in isolated islets of Trpm6Δ17 /fl;Villin1-Cre mice. We attribute these rises to augmented increases in intracellular Ca2+ oscillations in pancreatic ß-cells. However, the glycemic metabolic profile was not impaired in Trpm6Δ17 /fl;Villin1-Cre mice, suggesting that chronic hypomagnesemia does not lead to insulin resistance. Collectively, the results of this study suggest that neither acute nor chronic Mg2+ deficiency suppresses glucose-induced rises in insulin secretion. Even though hypomagnesemia can be symptomatic of T2D, such deficiency may not account for declines in insulin release in this disease.

Hippocampal parvalbumin interneurons play a critical role in memory development.

Episodic memories formed in early childhood rapidly decay, but their latent traces remain stored long term. These memories require the dorsal hippocampus (dHPC) and seem to undergo a developmental critical period. It remains to be determined whether the maturation of parvalbumin interneurons (PVIs), a major mechanism of critical periods, contributes to memory development. Here, we show that episodic infantile learning significantly increases the levels of parvalbumin in the dHPC 48 h after training. Chemogenetic inhibition of PVIs before learning indicated that these neurons are required for infantile memory formation. A bilateral dHPC injection of the γ-aminobutyric acid type A receptor agonist diazepam after training elicited long-term memory expression in infant rats, although direct PVI chemogenetic activation had no effect. Finally, PVI activity was required for brain-derived neurotrophic factor (BDNF)-dependent maturation of memory competence, i.e., adult-like long-term memory expression. Thus, dHPC PVIs are critical for the formation of infantile memories and for memory development.

Leveraging Expert Demonstration Features for Deep Reinforcement Learning in Floor Cleaning Robot Navigation.

In this paper, a Deep Reinforcement Learning (DRL)-based approach for learning mobile cleaning robot navigation commands that leverage experience from expert demonstrations is presented. First, expert demonstrations of robot motion trajectories in simulation in the cleaning robot domain are collected. The relevant motion features with regard to the distance to obstacles and the heading difference towards the navigation goal are extracted. Each feature weight is optimized with respect to the collected data, and the obtained values are assumed as representing the optimal motion of the expert navigation. A reward function is created based on the feature values to train a policy with semi-supervised DRL, where an immediate reward is calculated based on the closeness to the expert navigation. The presented results show the viability of this approach with regard to robot navigation as well as the reduced training time.

Differential role of neuronal glucose and PFKFB3 in memory formation during development.

The consumption of glucose in the brain peaks during late childhood; yet, whether and how glucose metabolism is differentially regulated in the brain during childhood compared to adulthood remains to be understood. In particular, it remains to be determined how glucose metabolism is involved in behavioral activations such as learning. Here we show that, compared to adult, the juvenile rat hippocampus has significantly higher mRNA levels of several glucose metabolism enzymes belonging to all glucose metabolism pathways, as well as higher levels of the monocarboxylate transporters MCT1 and MCT4 and the glucose transporters endothelial-GLUT1 and GLUT3 proteins. Furthermore, relative to adults, long-term episodic memory formation in juvenile animals requires significantly higher rates of aerobic glycolysis and astrocytic-neuronal lactate coupling in the hippocampus. Only juvenile but not adult long-term memory formation recruits GLUT3, neuronal 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) and more efficiently engages glucose in the hippocampus. Hence, compared to adult, the juvenile hippocampus distinctively regulates glucose metabolism pathways, and formation of long-term memory in juveniles involves differential neuronal glucose metabolism mechanisms.

Metabolomic profiling reveals a differential role for hippocampal glutathione reductase in infantile memory formation.

The metabolic mechanisms underlying the formation of early-life episodic memories remain poorly characterized. Here, we assessed the metabolomic profile of the rat hippocampus at different developmental ages both at baseline and following episodic learning. We report that the hippocampal metabolome significantly changes over developmental ages and that learning regulates differential arrays of metabolites according to age. The infant hippocampus had the largest number of significant changes following learning, with downregulation of 54 metabolites. Of those, a large proportion was associated with the glutathione-mediated cellular defenses against oxidative stress. Further biochemical, molecular, and behavioral assessments revealed that infantile learning evokes a rapid and persistent increase in the activity of neuronal glutathione reductase, the enzyme that regenerates reduced glutathione from its oxidized form. Inhibition of glutathione reductase selectively impaired long-term memory formation in infant but not in juvenile and adult rats, confirming its age-specific role. Thus, metabolomic profiling revealed that the hippocampal glutathione-mediated antioxidant pathway is differentially required for the formation of infantile memory.

CIM6P/IGF-2 Receptor Ligands Reverse Deficits in Angelman Syndrome Model Mice.

Angelman syndrome (AS), a genetic disorder that primarily affects the nervous system, is characterized by delayed development, intellectual disability, severe speech impairment, and problems with movement and balance (ataxia). Most affected children also have recurrent seizures (epilepsy). No existing therapies are capable of comprehensively treating the deficits in AS; hence, there is an urgent need to identify new treatments. Here we show that insulin-like growth factor 2 (IGF-2) and mannose-6-phosphate (M6P), ligands of two independent binding sites of the cation-independent M6P/IGF-2 receptor (CIM6P/IGF-2R), reverse most major deficits of AS modeled in mice. Subcutaneous injection of IGF-2 or M6P in mice modeling AS restored cognitive impairments as assessed by measurements of contextual and recognition memories, motor deficits assessed by rotarod and hindlimb clasping, and working memory/flexibility measured by Y-maze. IGF-2 also corrected deficits in marble burying and significantly attenuated acoustically induced seizures. An observational battery of tests confirmed that neither ligand changed basic functions including physical characteristics, general behavioral responses, and sensory reflexes, indicating that they are relatively safe. Our data provide strong preclinical evidence that targeting CIM6P/IGF-2R is a promising approach for developing novel therapeutics for AS. LAY SUMMARY: There is no effective treatment for the neurodevelopmental disorder Angelman syndrome (AS). Using a validated AS mouse model, the Ube3am-/p+ , in this study we show that systemic administration of ligands of the cation independent mannose-6-phosphate receptor, also known as insulin-like growth factor 2 receptor (CIM6P/IGF-2R) reverses cognitive impairment, motor deficits, as well as seizures associated with AS. Thus, ligands that activate the CIM6P/IGF-2R may represent novel, potential therapeutic targets for AS.

Artificial Intelligence for COVID-19 Drug Discovery and Vaccine Development.

SARS-COV-2 has roused the scientific community with a call to action to combat the growing pandemic. At the time of this writing, there are as yet no novel antiviral agents or approved vaccines available for deployment as a frontline defense. Understanding the pathobiology of COVID-19 could aid scientists in their discovery of potent antivirals by elucidating unexplored viral pathways. One method for accomplishing this is the leveraging of computational methods to discover new candidate drugs and vaccines in silico. In the last decade, machine learning-based models, trained on specific biomolecules, have offered inexpensive and rapid implementation methods for the discovery of effective viral therapies. Given a target biomolecule, these models are capable of predicting inhibitor candidates in a structural-based manner. If enough data are presented to a model, it can aid the search for a drug or vaccine candidate by identifying patterns within the data. In this review, we focus on the recent advances of COVID-19 drug and vaccine development using artificial intelligence and the potential of intelligent training for the discovery of COVID-19 therapeutics. To facilitate applications of deep learning for SARS-COV-2, we highlight multiple molecular targets of COVID-19, inhibition of which may increase patient survival. Moreover, we present CoronaDB-AI, a dataset of compounds, peptides, and epitopes discovered either in silico or in vitro that can be potentially used for training models in order to extract COVID-19 treatment. The information and datasets provided in this review can be used to train deep learning-based models and accelerate the discovery of effective viral therapies.

Transient Thermomechanical Simulation of 7075 Aluminum Contraction around a SiO2 Microparticle.

One important challenge that faces the metallurgic industry turns around the constant increment in the mechanical resistance of certain finished products. Metallurgic advantages can be obtained from the inclusion of microparticles in metallic materials, but this inclusion involves complex challenges as the internal stress distribution can be modified. In this work, the simulation of a cooling sequence in 7075 aluminum with a SiO2 microparticle is presented. Two models of two-dimensional (2D) type were constructed in ANSYS®2019 with circular and oval shape microparticles located inside the aluminum. Both models were subjected to the same thermomechanical transient analysis to compare the remaining stress distributions around the microparticles after the thermal load and to observe the effect of the geometrical shape. The results show remaining stresses increased in the oval model as a consequence of the geometrical shape modification. After applying a tension load in the analyzed specimens, shear stress concentrations were observed with a higher magnitude around the covertex of the oval shape. The results can be very useful for the creation of materials with controlled remnant stress located in specific or desired locations in the matrix.

Enantioselective Total Synthesis of Cannabinoids-A Route for Analogue Development.

A practical synthetic approach to Δ9-tetrahydrocannabinol (1) and cannabidiol (2) that provides scalable access to these natural products and should enable the generation of novel synthetic analogues is reported.

Astrocyte glycogen and lactate: New insights into learning and memory mechanisms.

Memory, the ability to retain learned information, is necessary for survival. Thus far, molecular and cellular investigations of memory formation and storage have mainly focused on neuronal mechanisms. In addition to neurons, however, the brain comprises other types of cells and systems, including glia and vasculature. Accordingly, recent experimental work has begun to ask questions about the roles of non-neuronal cells in memory formation. These studies provide evidence that all types of glial cells (astrocytes, oligodendrocytes, and microglia) make important contributions to the processing of encoded information and storing memories. In this review, we summarize and discuss recent findings on the critical role of astrocytes as providers of energy for the long-lasting neuronal changes that are necessary for long-term memory formation. We focus on three main findings: first, the role of glucose metabolism and the learning- and activity-dependent metabolic coupling between astrocytes and neurons in the service of long-term memory formation; second, the role of astrocytic glucose metabolism in arousal, a state that contributes to the formation of very long-lasting and detailed memories; and finally, in light of the high energy demands of the brain during early development, we will discuss the possible role of astrocytic and neuronal glucose metabolisms in the formation of early-life memories. We conclude by proposing future directions and discussing the implications of these findings for brain health and disease. Astrocyte glycogenolysis and lactate play a critical role in memory formation. Emotionally salient experiences form strong memories by recruiting astrocytic ß2 adrenergic receptors and astrocyte-generated lactate. Glycogenolysis and astrocyte-neuron metabolic coupling may also play critical roles in memory formation during development, when the energy requirements of brain metabolism are at their peak.

Dynamic expression of FKBP5 in the medial prefrontal cortex regulates resiliency to conditioned fear.

The factors influencing resiliency to the development of post-traumatic stress disorder (PTSD) remain to be elucidated. Clinical studies associate PTSD with polymorphisms of the FK506 binding protein 5 (FKBP5). However, it is unclear whether changes in FKBP5 expression alone could produce resiliency or susceptibility to PTSD-like symptoms. In this study, we used rats as an animal model to examine whether FKBP5 in the infralimbic (IL) or prelimbic (PL) medial prefrontal cortex regulates fear conditioning or extinction. First, we examined FKBP5 expression in IL and PL during fear conditioning or extinction. In contrast to the stable expression of FKBP5 seen in PL, FKBP5 expression in IL increased after fear conditioning and remained elevated even after extinction suggesting that IL FKBP5 levels may modulate fear conditioning or extinction. Consistent with this possibility, reducing basal FKBP5 expression via local infusion of FKBP5-shRNA into IL reduced fear conditioning. Furthermore, reducing IL FKBP5, after consolidation of the fear memory, enhanced extinction memory indicating that IL FKBP5 opposed formation of the extinction memory. Our findings demonstrate that lowering FKBP5 expression in IL is sufficient to both reduce fear acquisition and enhance extinction, and suggest that lower expression of FKBP5 in the ventral medial prefrontal cortex could contribute to resiliency to PTSD.

Developmental changes in plasticity, synaptic, glia and connectivity protein levels in rat dorsal hippocampus.

Thus far the identification and functional characterization of the molecular mechanisms underlying synaptic plasticity, learning, and memory have not been particularly dissociated from the contribution of developmental changes. Brain plasticity mechanisms have been largely identified and studied using in vitro systems mainly derived from early developmental ages, yet they are considered to be general plasticity mechanisms underlying functions -such as long-term memory- that occurs in the adult brain. Although it is possible that part of the plasticity mechanisms recruited during development is then re-recruited in plasticity responses in adulthood, systematic investigations about whether and how activity-dependent molecular responses differ over development are sparse. Notably, hippocampal-dependent memories are expressed relatively late in development, and the hippocampus undergoes and extended developmental post-natal structural and functional maturation, suggesting that the molecular mechanisms underlying hippocampal neuroplasticity may actually significantly change over development. Here we quantified the relative basal expression levels of sets of plasticity, synaptic, glia and connectivity proteins in rat dorsal hippocampus, a region that is critical for the formation of long-term explicit memories, at two developmental ages, postnatal day 17 (PN17) and PN24, which correspond to a period of relative functional immaturity and maturity, respectively, and compared them to adult age. We found that the levels of numerous proteins and/or their phosphorylation, known to be critical for synaptic plasticity underlying memory formation, including immediate early genes (IEGs), kinases, transcription factors and AMPA receptor subunits, peak at PN17 when the hippocampus is not yet able to express long-term memory. It remains to be established if these changes result from developmental basal activity or infantile learning. Conversely, among all markers investigated, the phosphorylation of calcium calmodulin kinase II α (CamKII α and of extracellular signal-regulated kinases 2 (ERK-2), and the levels of GluA1 and GluA2 significantly increase from PN17 to PN24 and then remain similar in adulthood, thus representing correlates paralleling long-term memory expression ability.

Contextual fear conditioning depresses infralimbic excitability.

Patients with posttraumatic stress disorder (PTSD) show hypo-active ventromedial prefrontal cortices (vmPFC) that correlate with their impaired ability to discriminate between safe and dangerous contexts and cues. Previously, we found that auditory fear conditioning depresses the excitability of neurons populating the homologous structure in rodents, the infralimbic cortex (IL). However, it is undetermined if IL depression was mediated by the cued or contextual information. The objective of this study was to examine whether contextual information was sufficient to depress IL neuronal excitability. After exposing rats to context-alone, pseudoconditioning, or contextual fear conditioning, we used whole-cell current-clamp recordings to examine the excitability of IL neurons in prefrontal brain slices. We found that contextual fear conditioning reduced IL neuronal firing in response to depolarizing current steps. In addition, neurons from contextual fear conditioned animals showed increased slow afterhyperpolarization potentials (sAHPs). Moreover, the observed changes in IL excitability correlated with contextual fear expression, suggesting that IL depression may contribute to the encoding of contextual fear.

Infralimbic EphB2 Modulates Fear Extinction in Adolescent Rats.

Adolescent rats are prone to impaired fear extinction, suggesting that mechanistic differences in extinction could exist in adolescent and adult rats. Since the infralimbic cortex (IL) is critical for fear extinction, we used PCR array technology to identify gene expression changes in IL induced by fear extinction in adolescent rats. Interestingly, the ephrin type B receptor 2 (EphB2), a tyrosine kinase receptor associated with synaptic development, was downregulated in IL after fear extinction. Consistent with the PCR array results, EphB2 levels of mRNA and protein were reduced in IL after fear extinction compared with fear conditioning, suggesting that EphB2 signaling in IL regulates fear extinction memory in adolescents. Finally, reducing EphB2 synthesis in IL with shRNA accelerated fear extinction learning in adolescent rats, but not in adult rats. These findings identify EphB2 in IL as a key regulator of fear extinction during adolescence, perhaps due to the increase in synaptic remodeling occurring during this developmental phase.

Spontaneous recovery of fear reverses extinction-induced excitability of infralimbic neurons.

In rodents, the infralimbic (IL) region of the medial prefrontal cortex plays a key role in the recall of fear extinction. Previously we showed that fear conditioning decreases the intrinsic excitability of IL neurons, and that fear extinction reverses the depressed excitability. In the current study, we examined the time course of the extinction-induced changes in adolescent rats. Immediately after extinction, IL neurons continued to show depressed excitability. However 4 hours after extinction, IL neurons showed an increase in evoked spikes that correlated with a reduced fast afterhyperpolarizing potential. This suggests that acquisition of fear extinction induces an increase in spike firing 4 hours later, during the consolidation of extinction. We also examined IL excitability in a group of rats that showed spontaneous recovery of fear 17 days after extinction (SR group). Similar to neurons after fear conditioning, IL neurons from the SR group showed depressed intrinsic excitability compared to neurons 4 hours after extinction, suggesting that extinction-induced enhancement in intrinsic excitability decreases with time reverting back to a depressed state. These results suggest that plasticity in IL contributes to the spontaneous recovery of fear and preventing this depression of IL excitability could prolong fear extinction.

Astrocytic expression of HIV-1 Nef impairs spatial and recognition memory.

Despite the widespread use of antiretroviral therapy that effectively limits viral replication, memory impairment remains a dilemma for HIV infected people. In the CNS, HIV infection of astrocytes leads to the production of the HIV-1 Nef protein without viral replication. Post mortem studies have found Nef expression in hippocampal astrocytes of people with HIV associated dementia suggesting that astrocytic Nef may contribute to HIV associated cognitive impairment even when viral replication is suppressed. To test whether astrocytic expression of Nef is sufficient to induce cognitive deficits, we examined the effect of implanting primary rat astrocytes expressing Nef into the hippocampus on spatial and recognition memory. Rats implanted unilaterally with astrocytes expressing Nef showed impaired novel location and novel object recognition in comparison with controls implanted with astrocytes expressing green fluorescent protein (GFP). This impairment was correlated with an increase in chemokine ligand 2 (CCL2) expression and the infiltration of peripheral macrophages into the hippocampus at the site of injection. Furthermore, the Nef exposed rats exhibited a bilateral loss of CA3 neurons. These results suggest that Nef protein expressed by the implanted astrocytes activates the immune system leading to neuronal damage and spatial and recognition memory deficits. Therefore, the continued expression of Nef by astrocytes in the absence of viral replication has the potential to contribute to HIV associated cognitive impairment.

Análisis experimental del desgaste entre UHMWPE y acero inoxidable 316l empleados en la manufactura de prótesis coxofemorales / Experimental wear analysis of UHMWPE and stainless 316l used in the manufacturing of coxofemoral prosthesis

La causa más común de falla en prótesis coxofemorales es el aflojamiento entre los componentes que conforman el sistema, de manera específica la copa acetabular y la cabeza femoral. En esta investigación se presenta un análisis tribológico del desgaste en los componentes mencionados, ya que cuando las superficies en contacto se desgastan, la funcionalidad mecánica del sistema se compromete, debido al cambio de geometría de los mismos, dando como resultado un juego mecánico entre la copa y la cabeza. Los materiales considerados en este estudio son el polietileno de ultra elevado peso molecular (UHMWPE, por sus siglas en inglés) para la copa acetabular, y acero inoxidable 316L para la cabeza femoral. Esta combinación de materiales representa hoy en día la recomendación más usual por parte de los cirujanos para pacientes de la tercera edad. La tasa anual de desgaste se determinó de manera experimental y se cuantificó la cantidad de material desprendido durante el contacto. Se establecieron las condiciones de carga de forma analítica, considerando las que actúan sobre la cabeza femoral a lo largo del área de desgaste durante la marcha humana. Posteriormente, se realizó el análisis experimental de desgaste utilizando una máquina tribológica de configuración perno-sobre-disco (pin-on-disk), diseñada de manera específica para este estudio. Las pruebas para determinar la pérdida volumétrica de los componentes se realizaron bajo tres condiciones de operación: en seco, lubricada con agua destilada y lubricada con suero bovino. El marco experimental considerado consistió en pernos de UHMWPE sobre discos de acero inoxidable 316l simulando el desgaste equivalente a diez años de uso de la prótesis. Finalmente, de los resultados obtenidos se puede establecer que el desgaste y la cantidad de partículas desprendidas disminuyen considerablemente cuando se utiliza suero bovino como lubricante para replicar las condiciones reales de operación del sistema...

The most common cause of failure in coxofemoral prostheses is the loosening between the components of the system, namely the acetabular cup and the femoral head. In this work a tribologic analysis of wear suffered in the components is presented, due to when the surfaces in contact are worn, the mechanical function of the system is compromised as the wearing implies a change in the geometry of the components, thus in their dimensions, resulting on a looseness between the cup and the head. The materials considered in this study are Ultra High Molecular Weight Polyethylene (UHMWPE) for the cup and 316L Stainless Steel for the femoral head, which represent the surgeons choice for elderly patients. The annual wearing rate between these components was experimentally determined, as well as the amount of debris produced during contact. Firstly, the loading conditions were determined analytically considering those acting on the femoral head taking into consideration the wearing area during human walk. Secondly, the experimental analysis consisted in wearing tests using a tribology pin-on-disk machine, specifically built for this study. The tests to determine the volumetric loss of the components were performed under three different operational conditions: dry, lubricated with bovine serum and lubricated with destilated water. The experimental set up consisted on UHMWPE pins and 316L Stainless steel discs simulating the equivalent wear of ten years of usage of the prostheses. Lastly, the obtained results proved that using the bovine serum as lubricant the wear and debris of the components was significantly reduced when compared with other cases, being the dry scenario where more damage was produced. It is important to point out that the bovine serum was chosen to simulate the synovial fluid in which the system is embedded.

The 'Celtic cross' technique for immediate umbilical reconstruction post-laparotomy and surgical ablation of the umbilicus.

SUMMARY: We present a novel method for immediate umbilical reconstruction following surgical ablation of the umbilicus that is simple and reproducible with aesthetically satisfactory results.

The influence of social status on the rate of growth, eye color pattern and insulin-like growth factor-I gene expression in Nile tilapia, Oreochromis niloticus.

Many aspects of teleost physiology are subject to regulation by social interactions. To evaluate the relationship of social status with growth, eye color pattern and hepatic Insulin-like Growth Factor-I (IGF-I) mRNA expression, 30 Oreochromis niloticus were isolated for 10 days and were used in a social pair study. Results revealed that growth of both dominant (except 1 day after social interaction) and subordinate individuals was suppressed, but growth suppression was greater in the subordinates. The dominant fish completely inhibited the feeding of the subordinate individuals during and 1 day after they were introduced into the aquaria together. After that, a pattern of highly aggressive attacks by dominant fish only partially inhibited feeding by the subordinates. Differential alterations in growth rate between dominants and subordinates were attributed more to behavioral changes (i.e., feeding) as transduced by physiological regulators (i.e., IGF-I level and possibly serotonin and/or neuropeptide Y) but may also be due to changes in metabolism. The fish's relative position in the social hierarchy consistently influenced the levels of IGF-I mRNA in the liver and the eye color pattern. Lower social status depressed hepatic IGF-I levels while dominant status stimulated hepatic IGF-I production, possibly in response to inhibition of somatostatin release in the hypothalamus, leading to greater secretion of pituitary growth hormone (GH). A significant positive association was detected between the IGF-I mRNA expression of the dominant fish and the level of aggression (number of attacks) during the encounter. Social status also influenced the eye color pattern of the fish. During aggressive interactions, most of the fish (22 out of 24) displayed decreased eye darkening. At the later part of the encounter, all subsequent subordinates displayed eye-darkening patterns which acted as a social signal announcing social submission. After the encounter dominant fish had paler eye color pattern than subordinates.