Human β-Cell Proliferation and Intracellular Signaling: Driving in the Dark Without a Road Map

A major goal in diabetes research is to find ways to enhance the mass and function of insulin secreting β-cells in the endocrine pancreas to prevent and/or delay the onset or even reverse overt diabetes. In this Perspectives in Diabetes article, we highlight the contrast between the relatively large body of information that is available in regard to signaling pathways, proteins, and mechanisms that together provide a road map for efforts to regenerate β-cells in rodents versus the scant information in human β-cells. To reverse the state of ignorance regarding human β-cell signaling, we suggest a series of questions for consideration by the scientific community to construct a human β-cell proliferation road map. The hope is that the knowledge from the new studies will allow the community to move faster towards developing therapeutic approaches to enhance human β-cell mass in the long-term goal of preventing and/or curing type 1 and type 2 diabetes

Construction of Empirical Care Pathways Process Models from Multiple Real-World Datasets

Care pathways (CPWs) are "multidisciplinary care plans that detail essential care steps for patients with specific clinical problems." While CPWs impact on health or cost outcomes is vastly studied, an in-depth analysis of the real-world implementation of the CPWs is an area that still remains underexplored. The present work describes how to apply an existing process mining methodology to construct the empirical CPW process models. These process models are a unique piece of information for health services research: for example to evaluate their conformance against the theoretical CPW described on clinical guidelines or to evaluate the impact of the process in health outcomes. To this purpose, this work relies on the design and implementation of a solution that a) synthesizes the expert knowledge on how health care is delivered within and across providers as an activity log, and b) constructs the CPW process model from that activity log using process mining techniques. Unlike previous research based on ad hoc data captures, current approach is built on the linkage of various heterogeneous real-world data (RWD) sets that share a minimum semantic linkage. RWD, defined as secondary use of routinely collected data as opposite to ad hoc data extractions, is a unique source of information for the CPW analysis due to its coverage of the caregiving activities and its wide availability. The viability of the solution is demonstrated by constructing the CPW process model of Code Stroke (Acute Stroke CPW) in the Aragon region (Spain)

Spectrophotometric Study of Polymeric DyesGels After a Gamma Irradiation Process for its Possible Use as a Radiation Dosimeter

This work aims to evaluate a dosimetric system composed of green malachite supported in agarose. Previous work showed that solutions of green malachite irradiated at 1 to 40 kGy present a linear behavior. This system is a gel composed of green malachite (2.5×10–3 M), sodium benzoate (1%),and agarose (1%) that was exposed tovarious doses of gamma irradiation. The irradiated systems were measured with a UV-V is spectrophotometer at 619 nm. Experimental parameters (such as dose rate, doses, and temperature) were controlled and optimized for reproducible and reliable results. More studies are needed to propose a dosimeter in the system in the range of 1.8 to 4.0 kGy

Quantitative ultrasound spectroscopy for screening cylindrical lithium-ion batteries for second-life applications

Diagnosing lithium-ion battery degradation is a crucial part of managing energy storage systems. Recent research has explored ultrasonic testing for non-invasive health assessment as an alternative to traditional, time-consuming, electrical-only methods. Assessing the state of health is vital for determining quality at end of ‘first’ life, with retired batteries at 70–80 % health still holding value for secondlife applications. Over the coming years, tens of GWh of salvaged batteries will hit the market, requiring rapid noninvasive methods to classify retired batteries according to their state of health. This study uses a 64 – element ultrasonic array to obtain mid-band quantitative ultrasound spectroscopy parameters – including mid-band fit, spectral slope, and intercept – from circumferential waves around cylindrical batteries. Thirteen cylindrical cells were used to evaluate the methodology: three pristine and ten retired from the same source. The mid-band fit showed the ability to track the state of charge and discriminate between the state of health levels in accelerated degradation experiments both with pristine batteries, and also with recovered secondlife batteries with unknown historical use. Linear-array ultrasonic transducers, coupled with quantitative spectral parameters, show promise for future non-destructive battery health screening methods, offering valuable insights for the emerging used battery market

Effect of Continuous Positive Airway Pressure on Inflammatory, Antioxidant, and Depression Biomarkers in Women With Obstructive Sleep Apnea: A Randomized Controlled Trial

Study objectives: The effect of continuous positive airway pressure (CPAP) on mediators of cardiovascular disease and depression in women with obstructive sleep apnea (OSA) is unknown. We aimed to assess the effect of CPAP therapy on a variety of biomarkers of inflammation, antioxidant activity, and depression in women with OSA. Methods: We conducted a multicenter, randomized controlled trial in 247 women diagnosed with moderate-to-severe OSA (apnea-hypopnea index [AHI] ? 15). Women were randomized to CPAP (n = 120) or conservative treatment (n = 127) for 12 weeks. Changes in tumor necrosis factor ? (TNF?), interleukin 6 (IL-6), C-reactive protein (CRP), intercellular adhesion molecule 1 (ICAM-1), catalase (CAT), superoxide dismutase (SOD), and brain-derived neurotrophic factor (BDNF) were assessed. Additional analyses were conducted in subgroups of clinical interest. Results: Women had a median (25th-75th percentiles) age of 58 (51-65) years, body mass index 33.5 (29.0-38.3) kg/m2, and AHI 33.3 (22.8-49.3). No differences were found between groups in the baseline levels of the biomarkers. After 12 weeks of follow-up, there were no changes between groups in any of the biomarkers assessed. These results did not change when the analyses were restricted to sleepy women or to those with severe OSA. In women with CPAP use at least 5 hours per night, only TNF? levels decreased compared to the control group (-0.29 ± 1.1 vs -0.06 ± 0.53, intergroup difference -0.23 [95% CI = -0.03 to -0.50]; p = 0.043). Conclusions: Twelve weeks of CPAP therapy does not improve biomarkers of inflammation, antioxidant activity, or depression compared to conservative treatment in women with moderate-to-severe OSA

A novel PKC activating molecule promotes neuroblast differentiation and delivery of newborn neurons in brain injuries

Neural stem cells are activated within neurogenic niches in response to brain injuries. This results in the production of neuroblasts, which unsuccessfully attempt to migrate toward the damaged tissue. Injuries constitute a gliogenic/non-neurogenic niche generated by the presence of anti-neurogenic signals, which impair neuronal differentiation and migration. Kinases of the protein kinase C (PKC) family mediate the release of growth factors that participate in different steps of the neurogenic process, particularly, novel PKC isozymes facilitate the release of the neurogenic growth factor neuregulin. We have demonstrated herein that a plant derived diterpene, (EOF2; CAS number 2230806-06-9), with the capacity to activate PKC facilitates the release of neuregulin 1, and promotes neuroblasts differentiation and survival in cultures of subventricular zone (SVZ) isolated cells in a novel PKC dependent manner. Local infusion of this compound in mechanical cortical injuries induces neuroblast enrichment within the perilesional area, and noninvasive intranasal administration of EOF2 promotes migration of neuroblasts from the SVZ towards the injury, allowing their survival and differentiation into mature neurons, being some of them cholinergic and GABAergic. Our results elucidate the mechanism of EOF2 promoting neurogenesis in injuries and highlight the role of novel PKC isozymes as targets in brain injury regeneration

Cytogenetic and molecular characterization in gonadal tissue of patients with ovotesticular syndrome and gonadal dysgenesis 46,XY and 46,XX

Objetivos: La etiología de la disgenesia gonadal y el síndrome ovotesticular se desconoce en la mayoría de los casos. Para realizar la caracterización citogenética y molecular de un grupo de pacientes con síndrome ovotesticular y disgenesia gonadal completa a partir de muestras de sangre periférica y tejido gonadal. Material y métodos: Se incluyeron un total de 6 pacientes, 3 con diagnóstico de síndrome ovotesticular 46, XX, uno diagnosticado con 46, XY síndrome ovotesticular; uno con sospecha de disgenesia gonadal 46, XX y otro con disgenesia gonadal completa 46, XY. Resultados Todos los pacientes fueron evaluados con cariotipo, hibridación in situ fluorescente (FISH) para SRY, amplificación de sonda dependiente de ligación múltiple (MLPA) e hibridación genómica comparativa (aCGH) en muestras de sangre periférica. En los casos con tejido gonadal disponible, los niveles de expresión genética de SOX3, SRY y SOX9 se determinaron mediante PCR en tiempo real e inmunofluorescencia. Se descartaron reordenamientos relacionados con el gen SRY. No se detectaron deleciones/duplicaciones o variaciones en el número de copias (NVC) como etiología del trastorno del desarrollo sexual en ninguno de los pacientes estudiados. En un caso de síndrome ovotesticular 46, XX, el cariotipo gonadal era diferente del cariotipo en sangre periférica. Se observó expresión aberrante de SOX3 y SOX9 en tejido gonadal de un caso con síndrome ovotesticular 46, XX. Conclusiones: Se documentaron niveles más bajos de expresión de SRY y SOX9 en comparación con los niveles en líneas celulares humanas de testículo embrionario y Sertoli en el tejido gonadal de un caso con síndrome ovotesticular 46, XY. Los estudios citogenéticos y moleculares de las gónadas como complemento del estudio de sangre periférica tienen el potencial de enriquecer la comprensión de los trastornos del desarrollo sexual en pacientes que son XX o XY en sangre periférica.Q4Objectives: The etiology of gonadal dysgenesis and the ovotesticular syndrome is unknown in most cases. The aim of the study was to perform cytogenetic and molecular characterization of a group of patients with ovotesticular syndrome and complete gonadal dysgenesis from peripheral blood and gonadal tissue samples.Materials and methods: A total of 6 patients were included, 3 with 46,XX ovotesticular syndrome diagnosis, 1 diagnosed with 46,XY ovotesticular syn-drome; 1 suspected with 46,XX gonadal dysgenesis, and 1 with 46,XY complete gonadal dysgenesis. Results: All patients were evaluated with karyotype, fluorescence in situ hybridization (FISH) for SRY, multiplex ligation-dependent probe amplification (MLPA) and comparative genomic hybridization (aCGH) in peripheral blood samples. In cases with available gonadal tissue, the levels of genetic expression of SOX3, SRY, and SOX9 were determined by real-time PCR and immunofluo-rescence. Rearrangements involving SRY gene were ruled out. No deletions/duplications or copy-number variations (CNVs) were identified as the etiology for the sexual development disorder in any of the studied patients. In one case of 46,XX ovotesticular syndrome, the gonadal karyotype was different from the karyotype in peripheral blood. Aberrant expression of SOX3 and SOX9 in gonadal tissue was observed in one case of 46,XX ovotesticular syndrome. Conclusions: Lower levels of SRY and SOX9 expression were documented in the gonadal tissue of a case of 46,XY ovotesticular syndrome, in commparison with the levels in human cellular lines of embryonic testicle and Sertoli cells. Cytogenetic and molecular studies of gonads complementary to peripheral blood studies have the potential of enhancing the understanding of sexual development disorders in patients who are XX or XY in peripheral blood.https://orcid.org/0000-0002-4900-4948https://orcid.org/0000-0002-7109-3342https://orcid.org/0000-0001-8225-4394https://orcid.org/0000-0003-1555-6661https://orcid.org/0000-0002-3463-3565https://orcid.org/0000-0002-0826-6191https://orcid.org/0000-0001-6336-5347https://orcid.org/0000-0002-7856-7213https://orcid.org/0000-0003-2241-7854https://orcid.org/0000-0002-2231-4321https://orcid.org/0000-0001-8528-4433Revista Internacional - IndexadaCN

THG113.31, a specific PGF2alpha receptor antagonist, induces human myometrial relaxation and BKCa channel activation

BACKGROUND: PGF2alpha exerts a significant contractile effect on myometrium and is central to human labour. THG113.31, a specific non-competitive PGF2alpha receptor (FP) antagonist, exerts an inhibitory effect on myometrial contractility. The BKCa channel is ubiquitously encountered in human uterine tissue and plays a significant role in modulating myometrial cell membrane potential and excitability. The objective of this study was to investigate potential BKCa channel involvement in the response of human myometrium to THG113.31. METHODS: Single and whole-cell electrophysiological BKCa channel recordings from freshly dispersed myocytes, were investigated in the presence and absence of THG113.31. Functional studies investigated the effects of THG113.31 on isolated spontaneous myometrial contractions, in the presence and absence of the BKCa channel blocker, iberiotoxin. RESULTS: Single channel recordings identified the BKCa channel as a target of THG113.31. THG113.31 significantly increased the open state probability of these channels [control 0.023+/-0.006; 10 microM THG113.31 0.087+/-0.012 (P = 0.009); and 50 microM THG113.31 0.1356+/-0.018 (P = 0.001)]. In addition, THG113.31 increased whole-cell BKCa currents over a range of membrane potentials, and this effect was reversed by 100 nanoM IbTX. Isometric tension studies demonstrated that THG113.31 exerted a significant concentration-dependent relaxant effect on human myometrial tissue and pre-incubation of strips with IbTX abolished this effect on spontaneously occurring contractions. CONCLUSION: These data suggests that activation of the BKCa channel may contribute, at least partially, to the uterorelaxant effect of THG113.31

Ginzburg-Landau functional for nearly antiferromagnetic perfect and disordered Kondo lattices

Interplay between Kondo effect and trends to antiferromagnetic and spin glass ordering in perfect and disordered bipartite Kondo lattices is considered. Ginzburg-Landau equation is derived from the microscopic effective action written in three mode representation (Kondo screening, antiferromagnetic correlations and spin liquid correlations). The problem of local constraint is resolved by means of Popov-Fedotov representation for localized spin operators. It is shown that the Kondo screening enhances the trend to a spin liquid crossover and suppresses antiferromagnetic ordering in perfect Kondo lattices and spin glass ordering in doped Kondo lattices. The modified Doniach's diagram is constructed, and possibilities of going beyond the mean field approximation are discussed.Comment: 18 pages, RevTeX, 7 EPS figures include