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    Effect of Electrical Stimulation on PC12 Cells Cultured in Different Hydrogels: Basis for the Development of Biomaterials in Peripheral Nerve Tissue Engineering
    (MDPI, 2023-12) Olguín, Yusser; Selva, Mónica; Benavente, Diego; Orellana, Nicole; Montenegro, Ivan; Madrid, Alejandro; Jaramillo-Pinto, Diego; Otero, María Carolina; Corrales, Tomas P.; Acevedo, Cristian A.
    Extensive damage to peripheral nerves is a health problem with few therapeutic alternatives. In this context, the development of tissue engineering seeks to obtain materials that can help recreate environments conducive to cellular development and functional repair of peripheral nerves. Different hydrogels have been studied and presented as alternatives for future treatments to emulate the morphological characteristics of nerves. Along with this, other research proposes the need to incorporate electrical stimuli into treatments as agents that promote cell growth and differentiation; however, no precedent correlates the simultaneous effects of the types of hydrogel and electrical stimuli. This research evaluates the neural differentiation of PC12 cells, relating the effect of collagen, alginate, GelMA, and PEGDA hydrogels with electrical stimulation modulated in four different ways. Our results show significant correlations for different cultivation conditions. Electrical stimuli significantly increase neural differentiation for specific experimental conditions dependent on electrical frequency, not voltage. These backgrounds allow new material treatment schemes to be formulated through electrical stimulation in peripheral nerve tissue engineering. © 2023 by the authors.
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    Epigenetic Changes and Chromatin Reorganization in Brain Function: Lessons from Fear Memory Ensemble and Alzheimer’s Disease
    (MDPI, 2022-10) van Zundert, Brigitte; Montecino, Martin
    Healthy brain functioning in mammals requires a continuous fine-tuning of gene expression. Accumulating evidence over the last three decades demonstrates that epigenetic mechanisms and dynamic changes in chromatin organization are critical components during the control of gene transcription in neural cells. Recent genome-wide analyses show that the regulation of brain genes requires the contribution of both promoter and long-distance enhancer elements, which must functionally interact with upregulated gene expression in response to physiological cues. Hence, a deep comprehension of the mechanisms mediating these enhancer–promoter interactions (EPIs) is critical if we are to understand the processes associated with learning, memory and recall. Moreover, the onset and progression of several neurodegenerative diseases and neurological alterations are found to be strongly associated with changes in the components that support and/or modulate the dynamics of these EPIs. Here, we overview relevant discoveries in the field supporting the role of the chromatin organization and of specific epigenetic mechanisms during the control of gene transcription in neural cells from healthy mice subjected to the fear conditioning paradigm, a relevant model to study memory ensemble. Additionally, special consideration is dedicated to revising recent results generated by investigators working with animal models and human postmortem brain tissue to address how changes in the epigenome and chromatin architecture contribute to transcriptional dysregulation in Alzheimer’s disease, a widely studied neurodegenerative disease. We also discuss recent developments of potential new therapeutic strategies involving epigenetic editing and small chromatin-modifying molecules (or epidrugs).
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    c-Abl Tyrosine Kinase Is Required for BDNF-Induced Dendritic Branching and Growth
    (2023-02) Chandía-Cristi, América; Stuardo, Nicolás; Trejos, Cristian; Leal, Nancy; Urrutia, Daniela; Bronfman, Francisca C.; Álvarez Rojas, Alejandra
    Brain-derived neurotrophic factor (BDNF) induces activation of the TrkB receptor and several downstream pathways (MAPK, PI3K, PLC-γ), leading to neuronal survival, growth, and plasticity. It has been well established that TrkB signaling regulation is required for neurite formation and dendritic arborization, but the specific mechanism is not fully understood. The non-receptor tyrosine kinase c-Abl is a possible candidate regulator of this process, as it has been implicated in tyrosine kinase receptors’ signaling and trafficking, as well as regulation of neuronal morphogenesis. To assess the role of c-Abl in BDNF-induced dendritic arborization, wild-type and c-Abl-KO neurons were stimulated with BDNF, and diverse strategies were employed to probe the function of c-Abl, including the use of pharmacological inhibitors, an allosteric c-Abl activator, and shRNA to downregulates c-Abl expression. Surprisingly, BDNF promoted c-Abl activation and interaction with TrkB receptors. Furthermore, pharmacological c-Abl inhibition and genetic ablation abolished BDNF-induced dendritic arborization and increased the availability of TrkB in the cell membrane. Interestingly, inhibition or genetic ablation of c-Abl had no effect on the classic TrkB downstream pathways. Together, our results suggest that BDNF/TrkB-dependent c-Abl activation is a novel and essential mechanism in TrkB signaling.
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    Prostaglandin E2 Exposure Disrupts E-Cadherin/Caveolin-1-Mediated Tumor Suppression to Favor Caveolin-1-Enhanced Migration, Invasion, and Metastasis in Melanoma Models
    (MDPI, 2023-12) Lobos-González, Lorena; Oróstica, Lorena; Díaz-Valdivia, Natalia; Rojas-Celis, Victoria; Campos, America; Duran-Jara, Eduardo; Farfán, Nicole; Leyton, Lisette; Quest, Andrew F. G.
    Caveolin-1 (CAV1) is a membrane-bound protein that suppresses tumor development yet also promotes metastasis. E-cadherin is important in CAV1-dependent tumor suppression and prevents CAV1-enhanced lung metastasis. Here, we used murine B16F10 and human A375 melanoma cells with low levels of endogenous CAV1 and E-cadherin to unravel how co-expression of E-cadherin modulates CAV1 function in vitro and in vivo in WT C57BL/6 or Rag−/− immunodeficient mice and how a pro-inflammatory environment generated by treating cells with prostaglandin E2 (PGE2) alters CAV1 function in the presence of E-cadherin. CAV1 expression augmented migration, invasion, and metastasis of melanoma cells, and these effects were abolished via transient co-expression of E-cadherin. Importantly, exposure of cells to PGE2 reverted the effects of E-cadherin expression and increased CAV1 phosphorylation on tyrosine-14 and metastasis. Moreover, PGE2 administration blocked the ability of the CAV1/E-cadherin complex to prevent tumor formation. Therefore, our results support the notion that PGE2 can override the tumor suppressor potential of the E-cadherin/CAV1 complex and that CAV1 released from the complex is phosphorylated on tyrosine-14 and promotes migration/invasion/metastasis. These observations provide direct evidence showing how a pro-inflammatory environment caused here via PGE2 administration can convert a potent tumor suppressor complex into a promoter of malignant cell behavior.
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    Effect of exercise on the memory of overweight or obese older adults: Systematic review
    (Republica del Paraguay Ministry of Public Health and Social, 2022-06) Curilem Gatica, Cristian; Guandalini Valdete, Regina; Liabeuf Altamirano, Gianella; Liabeuf Altamirano, G.; Bahamondes Ávila, Carlos; Bruneau Chávez, José; Berral de la Rosa, Francisco José
    Obesity and overweight in older adults are associated with an increased risk of cognitive diseases, contributing to decreased functional performance. The objective of this review is to analyze the effect of exercise on memory in older adults with obesity or overweight. The methodology uses the words MESH: Population = aged, overweight, obesity; Intervention = exercise; Comparison = control groups; Result = Memory; Design: randomized controlled trial. Searching until December 2021 in PUBMED, SCIELO, BVSALUD, LILACS, TRIP DATABASE, and MEDLINE. Six thousand eight hundred thirty-two items are identified. We analyzed five studies with 214 participants. The mean body mass index is 28.6 ± 1.1 kg/m2, and the initial average Mini mental is 23.6 ± 2.1 points. The intervention with exercise is from twelve to twenty-six weeks. In the random-effects model, exercise improves the mean Mini Mental by MD = 2.6 points (1.7 to 3.4) p < 0.01. Heterogeneity (87.7 %). Exercise improves cognitive function (memory) in older adults who are overweight or obese. © 2022, Republica del Paraguay Ministry of Public Health and Social Welfare. All rights reserved.
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    Babesia vogeli in dogs in Chile
    (Blackwell Publishing Ltd, 2020-11) Di Cataldo, Sophia; Ulloa-Contreras, Claudia; Cevidanes, Aitor; Hernández, Claudia; Millán, Javier
    We report the presence of Babesia vogeli in dogs in Chile. During two surveillance campaigns separated by a year, sixty-three blood samples from free-ranging rural dogs in Coquimbo, Chile, were analysed through conventional PCR screening of the 18S rRNA for Babesia species. Sequencing confirmed the presence of Babesia vogeli in 6.3% of the tested animals, with positive cases in both years. All the sequences showed 100% nucleotide sequence identity among them and 99.8% with other previously published sequences from dogs. No clinical signs or haematological abnormalities other than thrombocytopenia were found in the parasitized individuals. This is the first report of a canine piroplasmid in Chile.
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    New Evidence on BPA’s Role in Adipose Tissue Development of Proinflammatory Processes and Its Relationship with Obesity
    (MDPI, 2023-05) González-Casanova, Jorge Enrique; Bermúdez, Valmore; Caro Fuentes, Nelson Javier; Angarita, Lissé Chiquinquirá; Caicedo, Nelson Hernando; Rivas Muñoz, Jocelyn; Rojas-Gómez, Diana Marcela
    Bisphenol A (BPA) is a xenobiotic with endocrine disruptor properties which interacts with various receptors, eliciting a cellular response. In the plastic industry, BPA is widely used in the production of polycarbonate and epoxy-phenolic resins to provide elastic properties. It can be found in the lining of canned foods, certain plastic containers, thermal printing papers, composite dental fillings, and medical devices, among other things. Therefore, it is a compound that, directly or indirectly, is in daily contact with the human organism. BPA is postulated to be a factor responsible for the global epidemic of obesity and non-communicable chronic diseases, belonging to the obesogenic and diabetogenic group of compounds. Hence, this endocrine disruptor may be responsible for the development of metabolic disorders, promoting in fat cells an increase in proinflammatory pathways and upregulating the expression and release of certain cytokines, such as IL6, IL1β, and TNFα. These, in turn, at a systemic and local level, are associated with a chronic low-grade inflammatory state, which allows the perpetuation of the typical physiological complications of obesity. © 2023 by the authors.
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    In Vivo Efficacy of Purified Quillaja Saponin Extracts in Protecting against Piscirickettsia salmonis Infections in Atlantic Salmon (Salmo salar)
    (Multidisciplinary Digital Publishing Institute (MDPI), 2023-09) Cortés, Hernán; Castillo-Ruiz, Mario; Cañon-Jones, Hernán; Schlotterbeck, Trinidad; San Martín, Ricardo; Padilla, Leandro
    Piscirickettsiosis, the main infectious disease affecting salmon farming in Chile, still has no efficient control measures. Piscirickettsia salmonis is a facultative intracellular bacterium that can survive and replicate within the host macrophages, evading the immune response. Triterpenic saponins obtained from the Quillaja saponaria tree have been widely studied, and have been shown to be immunomodulatory agents, suitable for feed and vaccine applications for veterinary and human uses. The impact of the oral administration of two extracts of Quillaja saponins on the infection of P. salmonis in Salmo salar and the corresponding gene expressions of immunomarkers were studied under three in vivo models. In the intraperitoneal challenge model, the group fed with Quillaja extracts showed lower mortality (29.1% treated vs. 37.5% control). Similar results were obtained in the cohabitation model trial (36.3% vs. 60.0%). In the commercial pilot trial, the results showed a significant reduction of 71.3% in mortality caused by P. salmonis (0.51% vs. 1.78%) and antibiotic use (reduction of 66.6% compared to untreated control). Also, Quillaja extracts significantly modulated the expression of IFN-II and CD8. These results represent evidence supporting the future use of purified Quillaja extracts as a natural non-pharmacological strategy for the prevention and control of P. salmonis infections in salmon. © 2023 by the authors.
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    Selective Concurrence of the Long Non-Coding RNA MALAT1 and the Polycomb Repressive Complex 2 to Promoter Regions of Active Genes in MCF7 Breast Cancer Cells
    (MDPI, 2023-06) Arratia, Felipe; Fierro, Cristopher; Blanco, Alejandro; Fuentes, Sebastián; Nahuelquen, Daniela; Montecino, Martin; Rojas, Adriana; Aguilar, Rodrigo
    In cancer cells, the long non-coding RNA (lncRNA) MALAT1 has arisen as a key partner for the Polycomb Repressive Complex 2 (PRC2), an epigenetic modifier. However, it is unknown whether this partnership occurs genome-wide at the chromatin level, as most of the studies focus on single genes that are usually repressed. Due to the genomic binding properties of both macromolecules, we wondered whether there are binding sites shared by PRC2 and MALAT1. Using public genome-binding datasets for PRC2 and MALAT1 derived from independent ChIP- and CHART-seq experiments performed with the breast cancer cell line MCF7, we searched for regions containing PRC2 and MALAT1 overlapping peaks. Peak calls for each molecule were performed using MACS2 and then overlapping peaks were identified by bedtools intersect. Using this approach, we identified 1293 genomic sites where PRC2 and MALAT1 concur. Interestingly, 54.75% of those sites are within gene promoter regions ([removed]
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    Prevalence of the Bifid Mandibular Condyle and Its Relationship with Pathologies of the Temporomandibular Joint: A Systematic Review and Meta-Analysis
    (MDPI, 2023-10) Valenzuela-Fuenzalida, Juan José; Navarro, Kora-lle Keller; Urbina, Pia; Trujillo-Riveros, Martin; Nova-Baeza, Pablo; Orellana-Donoso, Mathias; Rodriguez-Luengo, Macarena; Beccerra Farfan, Alvaro; Sanchis-Gimeno, Juan A.
    The aim of this study was to describe the prevalence of anatomical variants in the bifid mandibular condyle (BMC) and report its association with temporomandibular joint (TMJ) pathology. Methods: We searched the Medline, Scopus, Web of Science, Google Scholar, CINAHL, and LILACS databases from their inception up to September 2023. Two authors independently performed the search, study selection, and data extraction, and they also assessed the methodological quality with an assurance tool for anatomical studies (AQUA). Finally, the pooled prevalence was estimated using a random effects model. Results: A total of 50 studies met the eligibility criteria. Twenty studies, with a total of 88,625 subjects, were included in the meta-analysis. The overall prevalence of the bifid mandibular condyle (BMC) variant was 1% (95% CI = 1% to 2%). Conclusions: The correlation between the BMC and TMJ pathologies has a relatively low prevalence in studies that present a considerable number of subjects. From a clinical point of view, a direct association cannot be made between the presence of the BMC and TMJ pathologies or symptoms.
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    Neuropathic Pain Induces Interleukin-1β Sensitive Bimodal Glycinergic Activity in the Central Amygdala
    (MDPI, 2022-07-01) Oliva, Carolina A.; Stehberg, Jimmy; Barra, Rafael; Mariqueo, Trinidad
    Neuropathic pain reduces GABA and glycine receptor (GlyR)-mediated activity in spinal and supraspinal regions associated with pain processing. Interleukin-1β (IL-1β) alters Central Amygdala (CeA) excitability by reducing glycinergic inhibition in a mechanism that involves the auxiliary β-subunit of GlyR (βGlyR), which is highly expressed in this region. However, GlyR activity and its modulation by IL-1β in supraspinal brain regions under neuropathic pain have not been studied. We performed chronic constriction injury (CCI) of the sciatic nerve in male Sprague Dawley rats, a procedure that induces hind paw plantar hyperalgesia and neuropathic pain. Ten days later, the rats were euthanized, and their brains were sliced. Glycinergic spontaneous inhibitory currents (sIPSCs) were recorded in the CeA slices. The sIPSCs from CeA neurons of CCI animals show a bimodal amplitude distribution, different from the normal distribution in Sham animals, with small and large amplitudes of similar decay constants. The perfusion of IL-1β (10 ng/mL) in these slices reduced the amplitudes within the first five minutes, with a pronounced effect on the largest amplitudes. Our data support a possible role for CeA GlyRs in pain processing and in the neuroimmune modulation of pain perception. © 2022 by the authors. Licensee MDPI, Basel, Switzerland.
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    Workers with suspected diagnosis of Silicosis: a case study of sarcoidosis versus Siderosis
    (MDPI, 2023-06) Delgado-García, Diemen; Miranda-Astorga, Patricio; Delgado-Cano, Ashley; Gómez-Salgado, Juan; Ruiz-Frutos, Carlos
    Silicosis is one of the most important occupational respiratory diseases worldwide, hence the importance of making a correct diagnosis. Diagnosis is commonly based on radiological findings according to the ILO International Classification of Radiographs of Pneumoconioses and occupational exposure. High-resolution computed tomography is indicated for differential diagnosis. This article presents two cases with an initial diagnosis of silicosis that ended up being diagnosed as sarcoidosis and siderosis, respectively. The first case was a 42-year-old male who worked as a crushing operator in an underground copper and molybdenum mine for 22 years. He had a history of exposure to silicon dioxide and was asymptomatic. X-rays did not distinguish silicosis or siderosis, but histological findings (open lung biopsy) allowed for a diagnosis of sarcoidosis. The second case was a 50-year-old male who had worked as a welder in a molybdenum filter plant, an open pit mine since 2013; he spent the previous 20 years as a welder in an underground copper mine, with exposure to silicon dioxide and was symptomatic. The first radiograph showed opacities that were compatible with pulmonary silicosis. A subsequent high-resolution computed tomography and lung biopsy showed a pattern of pulmonary siderosis. Due to the similarities in the radiographs of these three diseases, greater emphasis must be placed on the differential diagnosis, for which a complete occupational and clinical history is important in order to provide clues for the performance of complementary tests to avoid misdiagnosing.
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    Effects of ascending and descending direct current on grip strength assessed through dynamometry and myofeedback: A randomized controlled trial
    (University School of Physical Education in Wroclaw, 2020) de la Barra Ortiz, Hernán Andrés; Opazo Cancino, Jaime; Minzer Goluboff, Nicole; Andrade Obando, Ghyslaing; Herrera Jara, Macarena; González Vera, María Fernanda
    Introduction. To investigate effects of ascending and descending direct current (ADC and DD C) on muscle strength evaluated with dynamometry. Muscle strength values in kilograms were compared in 3 groups (ADC, DD C, and control) before and after galvanic electrical intervention. Methods. A randomized clinical trial was performed in the Physiotherapy Laboratory of Andres Bello University among 83 healthy volunteers. The intervention was a direct current session at an intensity of 4 mA for 12 minutes with 48-cm2 electrodes (dose: 48 mA · min;current density: 0.04 mA/cm2). The difference between the groups was galvanic therapy type applied. Current application followed a hand dynamometric test and myofeedback evaluation. The main outcome was maximum strength difference (MSdif) and its corresponding value in microvolts (μV-MSdif) obtained with myofeedback. Results. There were statistically significant changes regarding MSdif in groups who received direct current (p = 0.0001). These variations were also seen when comparing the 3 groups with the consideration of men (p = 0.0012) and women (p = 0.0021) separately. No statistically significant changes were observed in the μV-MSdif values (p = 0.9409). Conclusions. ADC can generate variations in grip strength after an intervention session, with an increase in strength of 8.9%. The increase in strength was observed both in men (6.7%) and in women (9%) of the ADC group.
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    Fortuna and Serendipity: history of some drugs used in Pediatric Intensive Care
    (Sociedad Chilena de Pediatria, 2022-07) Donoso F., Alejandro; Neumann B., Megan; Arriagada S., Daniela
    Serendipity has played a crucial role in the history of many different areas of science, including modern medicine. This corresponds to the ability to make a discovery, which occurs accidentally or by chance, in combination with the sagacity of the observer. Many of the most important and revolutionary findings in medical science, specifically pharmacology, involved serendipitous events of a nature. Some examples related to drug discovery and pharmacological research are briefly reviewed, such as the history of benzodiazepines, chloral hydrate, clonidine, warfarin, Ringer’s solution, valproic acid, barbiturates, penicillin and insulin, in which there were events related to serendipity. All these drugs or their derivatives are currently in frequent use in Intensive Care Units. © 2022, Sociedad Chilena de Pediatria. All rights reserved.
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    Nuligest university students of childbearing age and their position about possible ways of delivery
    (Sociedad Chilena de Obstetricia y Ginecologia, 2022-07) Puchi, Alexa; Espinoza, Nicolás; Montes, Alejandra; Apablaza, Nicolás; Palazzi, Michela; Sothers, Kim
    Introduction: Both in South America and worldwide, the increase in the rate of elective caesarean sections has been overwhelming.This is considered a public health problem, since vaginal delivery is the most physiological route for birth and brings health benefits for the mother and the newborn, immediately and in the future. Objective: To evaluate the position of nulliparous women of childbearing age regarding the delivery pathways through their knowledge, perceptions, and preferences. Method: Cross-sectional study with an analytical component. A survey was applied to university students for data collection through SPSS, and analysis was made with the difference of proportions and χ2 test. Results: 210 women surveyed; 80% of them are unaware of the lower infant morbidity associated with a vaginal delivery, more than a half estimate an advantage of a cesarean section that it avoids pain, and a large percentage are unaware of the medical risks associated with cesarean sections. Conclusions: There is a high level of ignorance regarding the benefits, risks and consequences of the different delivery routes. © 2022 Sociedad Chilena de Obstetricia y Ginecología. Publicado por Permanyer. Este es un artículo open access bajo la licencia CC BY-NC-ND (https://creativecommons.org/licenses/by-nc-nd/4.0/).
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    A look at the safety of ultrasound in obstetric echotomography
    (Sociedad Chilena de Obstetricia y Ginecologia, 2022-07) Jeldes Maturana, Jorge; Ramírez Peña, Rodrigo; Zúñiga Clavijo, Patricia; Ogalde Baeza, Sebastián; Miño Cornejo, José S.; Fuentes Alburquenque, Mauricio; Pastén Avalos, Miriam; Canals Lambarri, Mauricio
    The thermal and mechanical indices are the best estimators of fetal risk in an ultrasound and their values should be controlled in order to minimize exposure as much as possible. We compared the values of the thermal and mechanical indices obtained in obstetric ultrasound examinations of pregnant patients, with the value recommended by the international community. These indices were estimated in 421 obstetric ultrasounds during 2019. The estimated values were compared with each other and with the recommended value for each index and according to the display mode (B, color Doppler and spectral Doppler). Of the total sample, for the thermal index in color Doppler mode, 0.24% exceeded the recommended standard value and 2.85%. in spectral Doppler mode. For the mechanical index, the recommended value was exceeded in B mode by 11.16%, in 8.08% in color Doppler mode and, finally, by 0.48% for spectral Doppler mode. The mechanical and thermal indices in this sample of obstetric ultrasound examinations are on average below the reference value. However, there is a significant number of cases in which the standards are exceeded, which should be a warning to the medical community. © 2022 Sociedad Chilena de Obstetricia y Ginecología. Publicado por Permanyer. Este es un artículo open access bajo la licencia CC BY-NC-ND (https://creativecommons.org/licenses/by-nc-nd/4.0/).
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    Effect of single post-ovulatory administration of mifepristone (RU486) on transcript profile during the receptive period in human endometrium
    (BioScientifica Ltd., 2016-04) Cuevas, Catherina A.; Tapia-Pizarro, Alejandro; Salvatierra, Ana María; Munroe, David J.; Velasquez, Luis; Croxatto, Horacio B.
    Progesterone regulates uterine function during the luteal phase and is essential for the acquisition of endometrial receptivity. The objective of the present study was to identify endometrial transcripts whose expression is altered during the window of implantation after the administration of 200 mg of the antiprogestin mifepristone, 48 h after the LH peak (LHC2, LHC0ZLH peak), and to determine the relationship of these transcripts with those regulated during the acquisition of receptivity. Endometrial samples were obtained in LHC7 from seven women of proven fertility, each one contributing with one cycle treated with placebo and another with mifepristone. Additionally, endometrial samples were obtained in LHC2 and LHC7 during a single untreated spontaneous cycle from seven normal fertile women as a reference. DNA microarrays were used to identify transcripts significantly regulated (defined as R2.0-fold change with false discovery rate below 1% using t-test) with the administration of mifepristone vs placebo, or during the transition from pre-receptive to receptive (LHC2 vs LHC7). Approximately 2000 transcripts were significantly regulated in both comparisons (mifepristone vs placebo and LHC2 vs LHC7), but only 777 of them were coincident and displayed opposite regulation except for 25. The mRNA level for eight selected genes regulated by mifepristone was confirmed by real-time RT-PCR. We conclude that not all changes in endometrial transcript levels occurring in the transition from LHC2 to LHC7 seem to be regulated by the progesterone receptor and w37% of the genes whose transcript levels changed by effect of mifepristone could be associated with the acquisition of receptivity. Reproduction (2016) 151 331–349
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    ALS-linked protein disulfide isomerase variants cause motor dysfunction
    (EMBO Journal. Volume 35, Issue 8, Pages 845 - 865. 15 April 2016, 2016-04) Woehlbier, Ute; Colombo, Alicia; Saaranen, Mirva J; Pérez, Viviana; Ojeda, Jorge; Bustos, Fernando J.; Andreu, Catherine I.; Torres, Mauricio; Valenzuela, Vicente; Medinas, Danilo B; Rozas, Pablo; Vidal, Rene L.; Lopez-Gonzalez, Rodrigo; Salameh, Johnny; Fernandez-Collemann, Sara; Muñoz, Natalia; Matus, Soledad; Armisen, Ricardo; Sagredo, Alfredo; Palma, Karina; Irrazabal, Thergiory; Almeida, Sandra; Gonzalez-Perez, Paloma; Campero, Mario; Gao, Fen-Biao; Henny, Pablo; Van Zundert, Brigitte; Ruddock, Lloyd W; Concha, Miguel L; Henriquez, Juan P.; Brown, Robert H.; Hetz, Claudio
    Disturbance of endoplasmic reticulum (ER) proteostasis is a common feature of amyotrophic lateral sclerosis (ALS). Protein disulfide isomerases (PDIs) are ER foldases identified as possible ALS biomarkers, as well as neuroprotective factors. However, no functional studies have addressed their impact on the disease process. Here, we functionally characterized four ALS-linked mutations recently identified in two major PDI genes, PDIA1 and PDIA3/ERp57. Phenotypic screening in zebrafish revealed that the expression of these PDI variants induce motor defects associated with a disruption of motoneuron connectivity. Similarly, the expression of mutant PDIs impaired dendritic outgrowth in motoneuron cell culture models. Cellular and biochemical studies identified distinct molecular defects underlying the pathogenicity of these PDI mutants. Finally, targeting ERp57 in the nervous system led to severe motor dysfunction in mice associated with a loss of neuromuscular synapses. This study identifies ER proteostasis imbalance as a risk factor for ALS, driving initial stages of the disease.
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    Chromosome-Level Genome Assembly of the Blue Mussel Mytilus chilensis Reveals Molecular Signatures Facing the Marine Environment
    (Multidisciplinary Digital Publishing Institute (MDPI), 2023-04) Gallardo-Escárate, Cristian; Valenzuela-Muñoz, Valentina; Nuñez-Acuña, Gustavo; Valenzuela-Miranda, Diego; Tapia, Fabian J.; Yévenes, Marco; Gajardo, Gonzalo; Toro, Jorge E.; Oyarzún, Pablo A.; Arriagada, Gloria; Novoa, Beatriz; Figueras, Antonio; Roberts, Steven; Gerdol, Marco
    The blue mussel Mytilus chilensis is an endemic and key socioeconomic species inhabiting the southern coast of Chile. This bivalve species supports a booming aquaculture industry, which entirely relies on artificially collected seeds from natural beds that are translocated to diverse physical–chemical ocean farming conditions. Furthermore, mussel production is threatened by a broad range of microorganisms, pollution, and environmental stressors that eventually impact its survival and growth. Herein, understanding the genomic basis of the local adaption is pivotal to developing sustainable shellfish aquaculture. We present a high-quality reference genome of M. chilensis, which is the first chromosome-level genome for a Mytilidae member in South America. The assembled genome size was 1.93 Gb, with a contig N50 of 134 Mb. Through Hi-C proximity ligation, 11,868 contigs were clustered, ordered, and assembled into 14 chromosomes in congruence with the karyological evidence. The M. chilensis genome comprises 34,530 genes and 4795 non-coding RNAs. A total of 57% of the genome contains repetitive sequences with predominancy of LTR-retrotransposons and unknown elements. Comparative genome analysis of M. chilensis and M. coruscus was conducted, revealing genic rearrangements distributed into the whole genome. Notably, transposable Steamer-like elements associated with horizontal transmissible cancer were explored in reference genomes, suggesting putative relationships at the chromosome level in Bivalvia. Genome expression analysis was also conducted, showing putative genomic differences between two ecologically different mussel populations. The evidence suggests that local genome adaptation and physiological plasticity can be analyzed to develop sustainable mussel production. The genome of M. chilensis provides pivotal molecular knowledge for the Mytilus complex. © 2023 by the authors.
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    Skeletal Muscle Atrophy Induced by Diabetes Is Mediated by Non-Selective Channels and Prevented by Boldine
    (MDPI, 2023-04) Cea, Luis A.; Vásquez, Walter; Hernández-Salinas, Romina; Vielma, Alejandra Z.; Castillo-Ruiz, Mario; Velarde, Victoria; Salgado, Magdiel; Sáez, Juan C.
    Individuals with diabetes mellitus present a skeletal muscle myopathy characterized by atrophy. However, the mechanism underlying this muscular alteration remains elusive, which makes it difficult to design a rational treatment that could avoid the negative consequences in muscles due to diabetes. In the present work, the atrophy of skeletal myofibers from streptozotocin-induced diabetic rats was prevented with boldine, suggesting that non-selective channels inhibited by this alkaloid are involved in this process, as has previously shown for other muscular pathologies. Accordingly, we found a relevant increase in sarcolemma permeability of skeletal myofibers of diabetic animals in vivo and in vitro due to de novo expression of functional connexin hemichannels (Cx HCs) containing connexins (Cxs) 39, 43, and 45. These cells also expressed P2X7 receptors, and their inhibition in vitro drastically reduced sarcolemma permeability, suggesting their participation in the activation of Cx HCs. Notably, sarcolemma permeability of skeletal myofibers was prevented by boldine treatment that blocks Cx43 and Cx45 HCs, and now we demonstrated that it also blocks P2X7 receptors. In addition, the skeletal muscle alterations described above were not observed in diabetic mice with myofibers deficient in Cx43/Cx45 expression. Moreover, murine myofibers cultured for 24 h in high glucose presented a drastic increase in sarcolemma permeability and levels of NLRP3, a molecular member of the inflammasome, a response that was also prevented by boldine, suggesting that, in addition to the systemic inflammatory response found in diabetes, high glucose can promote the expression of functional Cx HCs and activation of the inflammasome in skeletal myofibers. Therefore, Cx43 and Cx45 HCs play a critical role in myofiber degeneration, and boldine could be considered a potential therapeutic agent to treat muscular complications due to diabetes. © 2023 by the authors.