OMA1-Mediated Mitochondrial Dynamics Balance Organellar Homeostasis Upstream of Cellular Stress Responses.

In response to cellular metabolic and signaling cues, the mitochondrial network employs distinct sets of membrane-shaping factors to dynamically modulate organellar structures through a balance of fission and fusion. While these organellar dynamics mediate mitochondrial structure/function homeostasis, they also directly impact critical cell-wide signaling pathways such as apoptosis, autophagy, and the integrated stress response (ISR). Mitochondrial fission is driven by the recruitment of the cytosolic dynamin-related protein-1 (DRP1), while fusion is carried out by mitofusins 1 and 2 (in the outer membrane) and optic atrophy-1 (OPA1) in the inner membrane. This dynamic balance is highly sensitive to cellular stress; when the transmembrane potential across the inner membrane (Δψm) is lost, fusion-active OPA1 is cleaved by the overlapping activity with m-AAA protease-1 (OMA1 metalloprotease, disrupting mitochondrial fusion and leaving dynamin-related protein-1 (DRP1)-mediated fission unopposed, thus causing the collapse of the mitochondrial network to a fragmented state. OMA1 is a unique regulator of stress-sensitive homeostatic mitochondrial balance, acting as a key upstream sensor capable of priming the cell for apoptosis, autophagy, or ISR signaling cascades. Recent evidence indicates that higher-order macromolecular associations within the mitochondrial inner membrane allow these specialized domains to mediate crucial organellar functionalities.

Ketoconazole Reverses Imatinib Resistance in Human Chronic Myelogenous Leukemia K562 Cells.

Chronic myeloid leukemia (CML) is a hematologic disorder characterized by the oncogene BCR-ABL1, which encodes an oncoprotein with tyrosine kinase activity. Imatinib, a BCR-ABL1 tyrosine kinase inhibitor, performs exceptionally well with minimal toxicity in CML chemotherapy. According to clinical trials, however, 20-30% of CML patients develop resistance to imatinib. Although the best studied resistance mechanisms are BCR-ABL1-dependent, P-glycoprotein (P-gp, a drug efflux transporter) may also contribute significantly. This study aimed to establish an imatinib-resistant human CML cell line, evaluate the role of P-gp in drug resistance, and assess the capacity of ketoconazole to reverse resistance by inhibiting P-gp. The following parameters were determined in both cell lines: cell viability (as the IC50) after exposure to imatinib and imatinib + ketoconazole, P-gp expression (by Western blot and immunofluorescence), the intracellular accumulation of a P-gp substrate (doxorubicin) by flow cytometry, and the percentage of apoptosis (by the Annexin method). In the highly resistant CML cell line obtained, P-gp was overexpressed, and the level of intracellular doxorubicin was low, representing high P-gp activity. Imatinib plus a non-toxic concentration of ketoconazole (10 µM) overcame drug resistance, inhibited P-gp overexpression and its efflux function, increased the intracellular accumulation of doxorubicin, and favored greater apoptosis of CML cells. P-gp contributes substantially to imatinib resistance in CML cells. Ketoconazole reversed CML cell resistance to imatinib by targeting P-gp-related pathways. The repurposing of ketoconazole for CML treatment will likely help patients resistant to imatinib.

Differentiation activates mitochondrial OPA1 processing in myoblast cell lines.

Mitochondrial optic atrophy-1 (OPA1) plays key roles in adapting mitochondrial structure to bioenergetic function. When transmembrane potential across the inner membrane (Δψm) is intact, long (L-OPA1) isoforms shape the inner membrane through membrane fusion and the formation of cristal junctions. When Δψm is lost, however, OPA1 is cleaved to short, inactive S-OPA1 isoforms by the OMA1 metalloprotease, disrupting mitochondrial structure and priming cellular stress responses such as apoptosis. Previously, we demonstrated that L-OPA1 of H9c2 cardiomyoblasts is insensitive to loss of Δψm via challenge with the protonophore carbonyl cyanide chlorophenyl hydrazone (CCCP), but that CCCP-induced OPA1 processing is activated upon differentiation in media with low serum supplemented with all-trans retinoic acid (ATRA). Here, we show that this developmental induction of OPA1 processing in H9c2 cells is independent of ATRA; moreover, pretreatment of undifferentiated H9c2s with chloramphenicol (CAP), an inhibitor of mitochondrial protein synthesis, recapitulates the Δψm-sensitive OPA1 processing observed in differentiated H9c2s. L6.C11 and C2C12 myoblast lines display the same developmental and CAP-sensitive induction of OPA1 processing, demonstrating a general mechanism of OPA1 regulation in mammalian myoblast cell settings. Restoration of CCCP-induced OPA1 processing correlates with increased apoptotic sensitivity. Moreover, OPA1 knockdown indicates that intact OPA1 is necessary for effective myoblast differentiation. Taken together, our results indicate that a novel developmental mechanism acts to regulate OMA1-mediated OPA1 processing in myoblast cell lines, in which differentiation engages mitochondrial stress sensing.

Arbona system reengineered in the Garcia-Ariz Model: a national health reform plan from an orthopedics program perspective.

During the 1950's the healthcare system of Puerto Rico was maintained exclusively by the local government. The Arbona system, as it came to be known, although it provided health care professionals on the island with multiple educational experiences, presented substantial costs for the government. In the early 1990's a program of privatization known as "La Reforma" was implemented with the ultimate goal of providing a universal coverage system for the poor and the needy. At present this program has brought other issues regarding the quality of medical services and loss of academic centers. This is a preliminary report that analyzes various aspects of both systems through the search and analysis of background resources and literature, interviews, and physician/patient satisfaction surveys (on working conditions and quality of services). The main purpose of this report is to create a model that proves to be efficient and coherent with the island's idiosyncrasies.

Modelos, sanciones y desarrollo de la finalidad educativa en el Sistema de Responsabilidad Penal para Adolescentes. Un análisis en el adolescente infractor del delito de hurto en la ciudad de Barranquilla / Models, sanctions and development of the educational purpose in the System of Criminal Responsibility for Adolescents. An analysis in the adolescent offender of the crime of theft in the city of Barranquilla / Modelos, sanções e desenvolvimento do propósito educacional no Sistema de Responsabilidade Criminal para Adolescentes. Uma análise do adolescente infrator do roubo na cidade de Barranquilla

La presente investigación jurídico-propositiva se ocupó de analizar el desarrollo de la finalidad educativa de las sanciones en el Sistema de Responsabilidad Penal para Adolescentes (SRPA), mediante la realización de entrevistas semiestructuradas a las autoridades administrativas y judiciales que imponen y vigilan las sanciones; en complemento con el análisis de los datos suministrados por los operadores del sistema sobre los adolescentes infractores de la Ley Penal, en particular de los autores del delito de hurto en la ciudad de Barranquilla (Colombia) durante el 2017 y 2018. Se encontró que 275 adolescentes ingresaron al SRPA por este delito punible; 211 cumplieron su medida no privativa de la libertad en el Centro Luz de Esperanza, donde desarrollan un proceso integrado por terapias individuales, grupales y familiares, simultáneo a los ciclos educativos, que al parecer son insuficientes para el logro de la finalidad educativa de la sanción, atendiendo los índices de reincidencia que se presentan. Se propuso un proceso educativo que desarrolle enfoques diferenciales, inclusivos y permanentes, que más allá de escolarizarlos los involucre en un proyecto de vida.

The present legal-propositional research was concerned with analyzing the development of the educational purpose of sanctions in the System of Criminal Responsibility for Adolescents (SRPA), by conducting semistructured interviews with administrative and judicial authorities who impose and monitor sanctions; in complement with the analysis of data provided by operators of the system on adolescent offenders of the Criminal Law, particularly perpetrators of the crime of theft in the city of Barranquilla (Colombia) during 2017 and 2018. It was found that 275 adolescents entered the SRPA for this punishable offense; 211 served their non-custodial measure in the Luz de Esperanza Center, where they develop a process integrated by individual, group and family therapies, simultaneous to the educational cycles, which apparently are insufficient for the achievement of the educational purpose of the sanction, attending to the recidivism rates that occur. It was proposed an educational process that develops differential, inclusive and permanent approaches, which, beyond schooling, involves them in a life project.

Esta pesquisa jurídico-propositiva preocupou-se em analisar o desenvolvimento do propósito educacional das sanções no Sistema de Responsabilidade Criminal para Adolescentes (SRPA), realizando entrevistas semi-estruturadas com autoridades administrativas e judiciais que impõem e monitoram sanções; além da análise dos dados fornecidos pelos operadores do sistema sobre adolescentes infratores do direito penal, em particular os autores do crime de furto na cidade de Barranquilla (Colômbia) durante 2017 e 2018. Foi constatado que 275 adolescentes entraram na SRPA por este delito punível; 211 serviram sua medida não-custodial no Centro Luz de Esperanza, onde desenvolvem um processo integrado por terapias individuais, grupais e familiares, simulta-neamente com os ciclos educativos, que aparentemente são insuficientes para o cumprimento do objetivo educativo da sanção, considerando as taxas de reincidência que ocorrem. Foi proposto um processo educacional que desenvolve abordagens diferenciadas, inclusivas e permanentes que vão além da escolaridade e as envolvem em um projeto de vida.

Primer registro del pez joya rosada Anthias noeli (Perciformes, Serranidae) en el litoral del Perú

En este trabajo se registra a Anthias noeli Anderson & Baldwin, 2000 por primera vez en el Perú. Entre el 2016 y 2019, se capturaron 15 ejemplares en el litoral del departamento de Tumbes, en el extremo norte del Perú. Los ejemplares fueron fotografiados en fresco, se realizaron los análisis merísticos y morfométricos para su identificación. Además, de cinco individuos se obtuvieron tejido muscular para determinar las secuencias del gen COI. Los análisis filogenéticos confirmaron su identificación como A. noeli. Las secuencias fueron depositadas en la base de datos públicos BOLD Systems, siendo las primeras secuencias depositadas de esta especie. Con este registro se amplía la distribución sur de A. noeli.

This work documents the first record of Anthias noeli Anderson & Baldwin, 2000 in Peru. Between 2016 and 2019, fifteen specimens were captured from the littoral of the Tumbes Department, located in the northernmost of Peru. Fresh photographs were taken of the specimens and meristic and morphometric analyses were conducted for species identification. Additionally, muscle tissue was extracted from five individuals to determine COI gene sequences. Phylogenetic analyses confirmed the specimens' identity as A. noeli, and the sequences were deposited in the public database BOLD Systems, representing the first deposited sequences for this species. This record expands the southern distribution of A. noeli.

Genistein selectively inhibits estrogen-induced cell proliferation and other responses to hormone stimulation in the prepubertal rat uterus.

Sex hormone replacement therapy helps improve quality of life in climacteric women. However, estrogen-induced cell proliferation in the uterus and mammary gland increases the risk for cancer in these organs. The lower incidence of mammary cancer in Asian women than in western women has been attributed to high intake of soy isoflavones, including genistein. Our previous work in the prepubertal rat uterus model showed that genistein (0.5 mg/kg body weight subcutaneously) caused an estradiol-like hypertrophy in myometrial and uterine luminal epithelial cells and an increase in RNA content in luminal epithelium; however, it did not induce cell proliferation, uterine eosinophilia, or endometrial edema. The present study investigated, in the same animal model, the effect of genistein administration (0.5 mg/kg body weight subcutaneously) before treatment with estradiol-17ß (0.33 mg/kg body weight subcutaneously) on uterine responses that were not induced by genistein. Pretreatment with this phytoestrogen completely inhibited estradiol-induced mitoses in uterine luminal epithelium, endometrial stroma, and myometrium and partially inhibited estradiol-induced uterine eosinophilia and endometrial edema. These findings indicate that genistein protects against estrogen-induced cell proliferation in the uterus and suggest that future studies should investigate the possibility of using this agent to decrease the risk for uterine cancer after hormone replacement therapy in climacteric women.