SGLT2 Inhibitors as Potential Anticancer Agents.

Sodium-glucose cotransporter 2 (SGLT2) serves as a critical glucose transporter that has been reported to be overexpressed in cancer models, followed by increased glucose uptake in both mice and humans. Inhibition of its expression can robustly thwart tumor development in vitro and in vivo. SGLT2 inhibitors are a comparatively new class of antidiabetic drugs that have demonstrated anticancer effects in several malignancies, including breast, liver, pancreatic, thyroid, prostate, and lung cancers. This review aims to assess the extent of SGLT involvement in different cancer cell lines and discuss the pharmacology, mechanisms of action, and potential applications of SGLT2 inhibitors to reduce tumorigenesis and its progression. Although these agents display a common mechanism of action, they exhibit distinct affinity towards the SGLT type 2 transporter compared to the SGLT type 1 transporter and varying extents of bioavailability and half-lives. While suppression of glucose uptake has been attributed to their primary mode of antidiabetic action, SGLT2 inhibitors have demonstrated several mechanistic ways to combat cancer, including mitochondrial membrane instability, suppression of ß-catenin, and PI3K-Akt pathways, increase in cell cycle arrest and apoptosis, and downregulation of oxidative phosphorylation. Growing evidence and ongoing clinical trials suggest a potential benefit of combination therapy using an SGLT2 inhibitor with the standard chemotherapeutic regimen. Nevertheless, further experimental and clinical evidence is required to characterize the expression and role of SGLTs in different cancer types, the activity of different SGLT subtypes, and their role in tumor development and progression.

Age-Dependent and Pathway-Specific Bimodal Action of Nicotine on Synaptic Plasticity in the Hippocampus of Mice Lacking the miR-132/212 Genes.

Nicotine addiction develops predominantly during human adolescence through smoking. Self-administration experiments in rodents verify this biological preponderance to adolescence, suggesting evolutionary-conserved and age-defined mechanisms which influence the susceptibility to nicotine addiction. The hippocampus, a brain region linked to drug-related memory storage, undergoes major morpho-functional restructuring during adolescence and is strongly affected by nicotine stimulation. However, the signaling mechanisms shaping the effects of nicotine in young vs. adult brains remain unclear. MicroRNAs (miRNAs) emerged recently as modulators of brain neuroplasticity, learning and memory, and addiction. Nevertheless, the age-dependent interplay between miRNAs regulation and hippocampal nicotinergic signaling remains poorly explored. We here combined biophysical and pharmacological methods to examine the impact of miRNA-132/212 gene-deletion (miRNA-132/212-/-) and nicotine stimulation on synaptic functions in adolescent and mature adult mice at two hippocampal synaptic circuits: the medial perforant pathway (MPP) to dentate yrus (DG) synapses (MPP-DG) and CA3 Schaffer collaterals to CA1 synapses (CA3-CA1). Basal synaptic transmission and short-term (paired-pulse-induced) synaptic plasticity was unaltered in adolescent and adult miRNA-132/212-/- mice hippocampi, compared with wild-type controls. However, nicotine stimulation promoted CA3-CA1 synaptic potentiation in mature adult (not adolescent) wild-type and suppressed MPP-DG synaptic potentiation in miRNA-132/212-/- mice. Altered levels of CREB, Phospho-CREB, and acetylcholinesterase (AChE) expression were further detected in adult miRNA-132/212-/- mice hippocampi. These observations propose miRNAs as age-sensitive bimodal regulators of hippocampal nicotinergic signaling and, given the relevance of the hippocampus for drug-related memory storage, encourage further research on the influence of miRNAs 132 and 212 in nicotine addiction in the young and the adult brain.

High-Yielding Flow Synthesis of a Macrocyclic Molecular Hinge.

Many molecular machines are built from modular components with well-defined motile capabilities, such as axles and wheels. Hinges are particularly useful, as they provide the minimum flexibility needed for a simple and pronounced conformational change. Compounds with multiple stable conformers are common, but molecular hinges almost exclusively operate via dihedral rotations rather than truly hinge-like clamping mechanisms. An ideal molecular hinge would better reproduce the behavior of hinged devices, such as gates and tweezers, while remaining soluble, scalable, and synthetically versatile. Herein, we describe two isomeric macrocycles with clamp-like open and closed geometries, which crystallize as separate polymorphs but interconvert freely in solution. An unusual one-pot addition cyclization reaction was used to produce the macrocycles on a multigram scale from inexpensive reagents, without supramolecular templating or high-dilution conditions. Using mechanistic information from NMR kinetic studies and at-line mass spectrometry, we developed a semicontinuous flow synthesis with maximum conversions of 85-93% and over 80% selectivity for a single isomer. The macrocycles feature voids that are sterically protected from guests, including reactive species such as fluoride ions, and could therefore serve as chemically inert hinges for adaptive supramolecular receptors and flexible porous materials.

Magnitud del riesgo por accidentes con objetos cortopunzantes en la consulta odontológica / Magnitude of isk for Accidents with Sharps in the Dental Practice / Magnitude do risco para acidentes com perfurocortantes na prática odontológica

Antecedentes: El personal del área de la salud está constantemente expuesto a sangre y fluidos provenientes de los pacientes durante su jornada laboral. Por lo tanto, el personal de odontología corre el riesgo de contraer enfermedades infecciosas. Objetivo: Conocer la frecuencia del riesgo laboral por objetos punzocortantes en odontólogos de primer nivel de atención de los Centros de Salud urbano y rural de los Servicios de Salud de Nuevo León Monterrey Nuevo León, México. Métodos: diseño del estudio no experimental, descriptivo, transversal y prospectivo. Población de estudio: odontólogos aplicativos de los Servicios de Salud de Nuevo León con un muestreo probabilístico 108 odontólogos. Se utilizó un cuestionario diseñado con 12 preguntas relacionadas con los accidentes punzocortantes, con una confiabilidad de un alfa de Cronbach de .832. Resultados: el 38.8 % de los masculinos informó haber presentado accidente laboral y femeninas el 67.2 % señalaron haber sufrido un accidente con punzocortante. En relación al conocer si habían sufrido algún accidente por objetos punzocortantes, solo el 59.3 % lo reportó y un 40.7 % no había sufrido accidente; un 49 % si recibió capacitación en bioseguridad y un 51 % no ha recibido capacitación. Conclusión: Con base a estos resultados podemos concluir que aún falta por mejorar las capacitaciones y ampliar la cobertura de capacitación a los odontólogos en materia de normativas de bioseguridad y manejo de residuos peligrosos biológicos infecciosos, así como actualizar el conocimiento de infecciones transmitidas por objetos punzocortantes.

Background: The staff of the health area is constantly exposed to blood and / or fluids coming from patients during their workday. Therefore, dentistry personnel run the risk of contracting infectious diseases. Purpose: To know the frequency of occupational risk due to sharp objects in top-level dentists of the urban and rural Health Centers of the Health Services of Nuevo León. Methods: design of the non-experimental, descriptive, cross-sectional and prospective study. Study population: applicative dentists of the Health Services of Nuevo Leon with a probabilistic sampling 108 of dentists. A questionnaire designed with 12 questions related to sharps accidents with a reliability of a Cronbach's alpha of .832 was used. Results: 38.8 % of the men reported having presented an accident at work and 67.2 % of the women reported having suffered an accident with a sharp cut. In relation to knowing if they had suffered an infection due to an accident by sharp objects, 59.3 % had suffered an accident and 40.7 % had not suffered an accident; 49 % were trained in biosecurity and 51 % have not received training. Conclusion: Based on these results we can conclude that there is still a need to improve the training and expand the coverage of training to the dentist in matters of biosafety regulations and management of infectious biological dangerous wastes as well as to update the knowledge of puncture-borne infections.

Antecedentes: A equipe da área de saúde é constantemente exposta ao sangue e / ou fluidos provenientes dos pacientes durante o dia de trabalho. Portanto, o pessoal de odontologia corre o risco de contrair doenças infecciosas. Objetivo: Conhecer a frequência do risco ocupacional por objetos pontiagudos em dentistas de nível superior dos Centros de Saúde urbanos e rurais dos Serviços de Saúde de Nuevo León. Métodos: delineamento do estudo não experimental, descritivo, transversal e prospectivo. População do estudo: dentistas aplicativos dos Serviços de Saúde de Nuevo León com amostragem probabilística 108 de cirurgiões-dentistas. Foi utilizado um questionário elaborado com 12 questões relacionadas aos acidentes com perfurocortantes, com confiabilidade de um alfa de Cronbach de 0,832. Resultados: 38,8% dos homens relataram ter sofrido acidente no trabalho e 67,2% das mulheres relataram ter sofrido acidente com um corte acentuado. Em relação a saber se sofreram infecção por acidente por objetos pontiagudos, 59,3% sofreram acidente e 40,7% não sofreram acidente; 49% foram treinados em biossegurança e 51% não receberam treinamento. Conclusão: Com base nesses resultados, podemos concluir que ainda há uma necessidade de melhorar o treinamento e ampliar a cobertura do treinamento para o dentista em questões de regulamentos de biossegurança e gestão de resíduos infecciosos biológicos perigosos, bem como atualizar o conhecimento sobre punção. infecções suportadas.

The measurement of consciousness: a framework for the scientific study of consciousness.

Scientists studying consciousness are attempting to identify correlations between measurements of consciousness and the physical world. Consciousness can only be measured through first-person reports, which raises problems about the accuracy of first-person reports, the possibility of non-reportable consciousness and the causal closure of the physical world. Many of these issues could be resolved by assuming that consciousness is entirely physical or functional. However, this would sacrifice the theory-neutrality that is a key attraction of a correlates-based approach to the study of consciousness. This paper puts forward a different solution that uses a framework of definitions and assumptions to explain how consciousness can be measured. This addresses the problems associated with first-person reports and avoids the issues with the causal closure of the physical world. This framework is compatible with most of the current theories of consciousness and it leads to a distinction between two types of correlates of consciousness.

Three tools for the real-time simulation of embodied spiking neural networks using GPUs.

This paper presents a toolbox of solutions that enable the user to construct biologically-inspired spiking neural networks with tens of thousands of neurons and millions of connections that can be simulated in real time, visualized in 3D and connected to robots and other devices. NeMo is a high performance simulator that works with a variety of neural and oscillator models and performs parallel simulations on either GPUs or multi-core processors. SpikeStream is a visualization and analysis environment that works with NeMo and can construct networks, store them in a database and visualize their activity in 3D. The iSpike library provides biologically-inspired conversion between real data and spike representations to support work with robots, such as the iCub. Each of the tools described in this paper can be used independently with other software, and they also work well together.

From baconian to popperian neuroscience.

The development of neuroscience over the past 50 years has some similarities with the development of physics in the 17th century. Towards the beginning of that century, Bacon promoted the systematic gathering of experimental data and the induction of scientific truth; towards the end, Newton expressed his principles of gravitation and motion in a concise set of mathematical equations that made precise falsifiable predictions. This paper expresses the opinion that as neuroscience comes of age, it needs to move away from amassing large quantities of data about the brain, and adopt a popperian model in which theories are developed that can make strong falsifiable predictions and guide future experimental work.

Informational theories of consciousness: a review and extension.

In recent years a number of people have suggested that there is a close link between conscious experience and the differentiation and integration of information in certain areas of the brain. The balance between differentiation and integration is often called information integration, and a number of algorithms for measuring it have been put forward, which can be used to make predictions about consciousness and to understand the relationships between neurons in a network. One of the key problems with the current information integration measures is that they take a lot of computer processing power, which limits their application to networks of around a dozen neurons. There are also more general issues about whether the current algorithms accurately reflect the consciousness associated with a system. This paper addresses these issues by exploring a new automata-based algorithm for the calculation of information integration. To benchmark different approaches we implemented the Balduzzi and Tononi algorithm as a plugin to the SpikeStream neural simulator, and used it to carry out some preliminary comparisons of the liveliness and Φ measures on simple four neuron networks.

Accuracy and performance of the state-based Φ and liveliness measures of information integration.

A number of people have suggested that there is a link between information integration and consciousness, and a number of algorithms for calculating information integration have been put forward. The most recent of these is Balduzzi and Tononi's state-based Φ algorithm, which has factorial dependencies that severely limit the number of neurons that can be analyzed. To address this issue an alternative state-based measure known as liveliness has been developed, which uses the causal relationships between neurons to identify the areas of maximum information integration. This paper outlines the state-based Φ and liveliness algorithms and sets out a number of test networks that were used to compare their accuracy and performance. The results show that liveliness is a reasonable approximation to state-based Φ for some network topologies, and it has a much more scalable performance than state-based Φ.

Comparison of fluoride and sapphire optical fibers for Er: YAG laser lithotripsy.

The long-pulse (200-350 micros) Holmium: YAG (Ho: YAG) laser (lambda = 2.12 microm) is used extensively in urology for laser lithotripsy. The long-pulse Erbium: YAG (Er: YAG) laser (lambda = 2.94 microm) fragments urinary calculi up to 5 times more efficiently than the Ho: YAG laser, however, no optical fibers are available to transmit efficiently 2.94 microm laser light for laser lithotripsy. We report results of a study evaluating a fluoride glass fiber to transmit Er: YAG laser light for laser lithotripsy and compare to a sapphire fiber that provides good transmission of Er: YAG light at low irradiance. The fluoride fiber provides superior light transmission efficiency over the sapphire fiber at an Er: YAG wavelength (2.94 microm). The sapphire fiber provides a more durable and robust delivery waveguide than the fluoride fiber when ablating urinary calculi in contact mode. Results of our study suggest that further development to improve performance of fluoride fibers for laser lithotripsy is warranted.

Information integration based predictions about the conscious states of a spiking neural network.

This paper describes how Tononi's information integration theory of consciousness was used to make detailed predictions about the distribution of phenomenal states in a spiking neural network. This network had approximately 18,000 neurons and 700,000 connections and it used models of emotion and imagination to control the eye movements of a virtual robot and avoid 'negative' stimuli. The first stage in the analysis was the development of a formal definition of Tononi's theory of consciousness. The network was then analysed for information integration and detailed predictions were made about the distribution of consciousness for each time step of recorded activity. This work demonstrates how an artificial system can be analysed for consciousness using a particular theory and in the future this approach could be used to make predictions about the phenomenal states associated with biological systems.

Progress in machine consciousness.

This paper is a review of the work that has been carried out on machine consciousness. A clear overview of this diverse field is achieved by breaking machine consciousness down into four different areas, which are used to understand its aims, discuss its relationship with other subjects and outline the work that has been carried out so far. The criticisms that have been made against machine consciousness are also covered, along with its potential benefits, and the work that has been done on analysing systems for signs of consciousness. Some of the social and ethical issues raised by machine consciousness are examined at the end of the paper.