Preliminary insights of the genetic diversity and invasion pathways of Cedrela odorata in the Galapagos Islands, Ecuador.

Cedrela odorata is considered the second most invasive tree species of the Galapagos Islands. Although it is listed in CITES Appendix II and there are population losses in mainland Ecuador, in Galapagos it is paradoxically a species of concern due to its invasive potential. Genetic studies can shed light on the invasion history of introduced species causing effects on unique ecosystems like the Galapagos. We analyzed nine microsatellite markers in C. odorata individuals from Galapagos and mainland Ecuador to describe the genetic diversity and population structure of C. odorata in the Galapagos and to explore the origin and invasion history of this species. The genetic diversity found for C. odorata in Galapagos (H e = 0.55) was lower than reported in the mainland (H e = 0.81), but higher than other invasive insular plant species, which could indicate multiple introductions. Our results suggest that Ecuador's northern Coastal region is the most likely origin of the Galapagos C. odorata, although further genomic studies, like Whole Genome Sequencing, Rad-Seq, and/or Whole Genome SNP analyses, are needed to confirm this finding. Moreover, according to our proposed pathway scenarios, C. odorata was first introduced to San Cristobal and/or Santa Cruz from mainland Ecuador. After these initial introductions, C. odorata appears to have arrived to Isabela and Floreana from either San Cristobal or Santa Cruz. Here, we report the first genetic study of C. odorata in the Galapagos and the first attempt to unravel the invasion history of this species. The information obtained in this research could support management and control strategies to lessen the impact that C. odorata has on the islands' local flora and fauna.

Cedrela odorata es considerada la segunda especie más invasora de árboles en las Islas Galápagos. Esta especie está catalogada en el Apéndice II de CITES y sus poblaciones se encuentran amenazadas en Ecuador continental, pero paradójicamente en Galápagos es una especie de preocupación por su potencial invasor. Estudios genéticos pueden ayudar a entender la historia de invasión de especies introducidas que causan efectos en ecosistemas únicos como Galápagos. En este estudio, analizamos 9 marcadores microsatélites en individuos de Galápagos y Ecuador continental para describir la diversidad genética y estructura poblacional de C. odorata en Galápagos y explorar el origen e historia de invasión de esta especie. La diversidad genética encontrada para C. odorata en Galápagos (H e = 0.55) fue menor que la reportada en continente (H e = 0.81), pero mayor que la de otras especies de plantas insulares invasoras, lo que podría sugerir múltiples introducciones de esta especie a Galápagos. Nuestros resultados sugieren que la costa norte ecuatoriana es el origen más probable de C. odorata en Galápagos, aunque más estudios, como secuenciación del genoma completo, Rad­Seq y/o análisis de SNPs, son necesarios para confirmar este hecho. Además, de acuerdo con los escenarios propuestos, es posible que C. odorata haya sido introducida primero a San Cristóbal y/o Santa Cruz desde Ecuador continental. Después de estas introducciones iniciales, parece haber llegado a Isabela y Floreana desde San Cristóbal o Santa Cruz. Este es el primer estudio genético de C. odorata en Galápagos y el primer intento de esclarecer la historia de invasión de esta especie. La información obtenida en esta investigación podría apoyar estrategias de manejo para disminuir el impacto que C. odorata tiene sobre la flora y fauna nativa de estas islas.

Hydrothermal liquefaction aqueous phase mycoremediation to increase inorganic nitrogen availability.

Hydrothermal liquefaction aqueous phase (HTL-AP) is a waste product from a thermochemical process where wet biomass is converted into biocrude oil. This nutrient-rich wastewater may be repurposed to benefit society by assisting crop growth after adequate treatment to increase inorganic nitrogen, especially NO3 -. This study aims to increase HTL-AP inorganic nitrogen, specifically NH3/NH4 + and NO3 -, through fungal remediation for further use in hydroponic systems. Trametes versicolor, a white-rot fungus known for degrading a range of organic pollutants, was used to treat a diluted (5 %) HTL-AP for 9 days. No fungal growth was observed, but T. versicolor activity was suspected by laccase activity throughout cultivation time. NO3 --N and NH3/NH4 +-N increased by 17 and 8 times after three days of fungal treatment, which was chosen as the appropriate time for HTL-AP fungal treatment as it resulted in the highest concentration of NO3 --N. The addition of nitrifying bacteria to the fungal treatment resulted in a twofold increase in NO3 --N concentration compared to the fungal treatment alone, indicating an enhancement in treatment efficacy. COD decreased by 51.33 % after 24 h, which may be related to the fungus' capacity to reduce the concentration of organics in the wastewater; nonetheless, COD increased in the following days, which may be related to the release of fungal byproducts. T. versicolor shows promise as a potential candidate for increasing inorganic nitrogen in HTL-AP. However, future studies should primarily address HTL-AP toxicity, reducing NH3/NH4 +-N while increasing NO3 --N, and hydroponics crop production after fungal treatment.

Association of Dietary Patterns with Cardiovascular Disease Risk Factors in Mexican Adults: Insights from a Cross-Sectional Descriptive Study.

Dietary patterns (DPs) are an essential tool to analyze the relationship between diet and health as they have presented an association with the incidence of chronic non-communicable diseases. Therefore, the aim of this study was the identification and characterization of DPs and their association with cardiovascular risk factors. For this purpose, a cross-sectional descriptive study was carried out in 165 Mexican adults, including dietary intakes derived from a validated food frequency questionnaire, clinical history, anthropometry, and biochemical biomarkers using standardized procedures for glucose, total cholesterol, triglycerides, LDL-c, and HDL-c. DPs were identified through principal component analysis and ordinal logistic regression was used to examine associations between DPs and cardiovascular disease risk factors. Three DPs were identified: Mexican Fast-Food, Variety-Food, and Healthy-Economic, with a high prevalence of overweight and obesity (78%). Having a high adherence to a Mexican Fast-Food pattern (OR 1.71 CI 1.4-2.8), being sedentary (OR 4.85 2.32-10.15) and smoking (0R 6.4 CI 2.40-16.9) increased the risk of having a high scale of risk factors (four or more risk factors simultaneously). In conclusion, the Mexican Fast-Food pattern showed an increase in the risk of having multiple risk factors, while a sedentary lifestyle and overeating were largely responsible for the prevalence of overweight and obesity in this group of Mexican adults.

Lenvatinib Plus Pembrolizumab Versus Sunitinib in First-Line Treatment of Advanced Renal Cell Carcinoma: Final Prespecified Overall Survival Analysis of CLEAR, a Phase III Study.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical trial updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.We present the final prespecified overall survival (OS) analysis of the open-label, phase III CLEAR study in treatment-naïve patients with advanced renal cell carcinoma (aRCC). With an additional follow-up of 23 months from the primary analysis, we report results from the lenvatinib plus pembrolizumab versus sunitinib comparison of CLEAR. Treatment-naïve patients with aRCC were randomly assigned to receive lenvatinib (20 mg orally once daily in 21-day cycles) plus pembrolizumab (200 mg intravenously once every 3 weeks) or sunitinib (50 mg orally once daily [4 weeks on/2 weeks off]). At this data cutoff date (July 31, 2022), the OS hazard ratio (HR) was 0.79 (95% CI, 0.63 to 0.99). The median OS (95% CI) was 53.7 months (95% CI, 48.7 to not estimable [NE]) with lenvatinib plus pembrolizumab versus 54.3 months (95% CI, 40.9 to NE) with sunitinib; 36-month OS rates (95% CI) were 66.4% (95% CI, 61.1 to 71.2) and 60.2% (95% CI, 54.6 to 65.2), respectively. The median progression-free survival (95% CI) was 23.9 months (95% CI, 20.8 to 27.7) with lenvatinib plus pembrolizumab and 9.2 months (95% CI, 6.0 to 11.0) with sunitinib (HR, 0.47 [95% CI, 0.38 to 0.57]). Objective response rate also favored the combination over sunitinib (71.3% v 36.7%; relative risk 1.94 [95% CI, 1.67 to 2.26]). Treatment-emergent adverse events occurred in >90% of patients who received either treatment. In conclusion, lenvatinib plus pembrolizumab achieved consistent, durable benefit with a manageable safety profile in treatment-naïve patients with aRCC.

Clinical, molecular, and histological characteristics of severely necrotic and fatal mpox in HIV-infected patients.

BACKGROUND: This case series of 5 patients with severely necrotic mpox highlights the predominantly necrotic nature of lesions seen in cases of severe mpox as shown by skin and lung biopsy, as well as the extensive dissemination of the infection, as shown by polymerase chain reaction (PCR) assessment in different body sites. CASE PRESENTATIONS: Patients were male, the median age was 37, all lived with HIV (2 previously undiagnosed), the median CD4+ cell count was 106 cells/mm3, and 2/5 were not receiving antiretroviral treatment. The most common complication was soft tissue infection. Skin and lung biopsies showed extensive areas of necrosis. Mpox PCR was positive in various sites, including skin, urine, serum, and cerebrospinal fluid. The initiation of antiretroviral treatment, worsened the disease, like that seen in immune reconstitution syndrome. Three patients died due to multiple organ failure, presumably associated with mpox since coinfections and opportunistic pathogens were ruled out. CONCLUSIONS: Severely necrotic manifestations of mpox in people living with advanced and untreated HIV are related to adverse outcomes.

LITESPARK-012: pembrolizumab plus lenvatinib with or without belzutifan or quavonlimab for advanced renal cell carcinoma.

Combination treatment with immunotherapy agents and/or vascular endothelial growth factor tyrosine kinase inhibitors are a standard of care for patients with advanced clear cell renal cell carcinoma (ccRCC). Novel therapeutic combinations that include the hypoxia-inducible factor 2α inhibitor belzutifan and the cytotoxic T-lymphocyte-associated protein 4 inhibitor quavonlimab are being investigated for their potential to further improve patient outcomes. This protocol describes the rationale and design of the randomized, phase III LITESPARK-012 study, which will evaluate the efficacy and safety of pembrolizumab plus lenvatinib with or without belzutifan or quavonlimab as first-line treatment for advanced ccRCC. Results from this study may support triplet combination therapies as a potential new standard of care for advanced ccRCC. Clinical trial registry: NCT04736706 (ClinicalTrials.gov).

Subungual Keratoacanthoma: Typical and Atypical Presentations of an Uncommon Nail Tumor.

Introduction: Keratoacanthoma (KA) is a group of tumors of epidermal origin with controversial nature. Subungual keratoacanthoma (SUKA) is a rare and destructive variant with more aggressive behavior. SUKA appears as a rapidly growing, painful tumor beneath the nail plate that rapidly progresses to a mass that can measure up to 2 cm. The toe location is unusual. The diagnosis must be made based on the correlation of clinical, radiological, and histopathological findings. Case Presentation: We present two cases of patients diagnosed with SUKAs with different clinical presentations which ranged from very typical to uncommon one. Both cases were treated with simple excision without recurrences. Conclusion: SUKA is a rare subungual tumor. Nail bed location represents a more difficult diagnostic challenge. SUKA should be suspected in the context of persistent and progressive pain on a finger or toe, once more frequent painful tumors have been ruled out.

Solid Lipid Nanoparticles (SLN) and Nanostructured Lipid Carriers (NLC) Prepared by Microwave and Ultrasound-Assisted Synthesis: Promising Green Strategies for the Nanoworld.

Many pharmaceutically active molecules are highly lipophilic, which renders their administration and adsorption in patients extremely challenging. Among the countless strategies to overcome this problem, synthetic nanocarriers have demonstrated superb efficiency as drug delivery systems, since encapsulation can effectively prevent a molecules' degradation, thus ensuring increased biodistribution. However, metallic and polymeric nanoparticles have been frequently associated with possible cytotoxic side effects. Solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC), which are prepared with physiologically inert lipids, therefore emerged as an ideal strategy to bypass toxicities issues and avoid the use of organic solvents in their formulations. Different approaches to preparation, using only moderate amounts of external energy to facilitate a homogeneous formation, have been proposed. Greener synthesis strategies have the potential to provide faster reactions, more efficient nucleation, better particle size distribution, lower polydispersities, and furnish products with higher solubility. Particularly microwave-assisted synthesis (MAS) and ultrasound-assisted synthesis (UAS) have been utilized in the manufacturing of nanocarrier systems. This narrative review addresses the chemical aspects of those synthesis strategies and their positive influence on the characteristics of SLNs and NLCs. Furthermore, we discuss the limitations and future challenges for the manufacturing processes of both types of nanoparticles.

MRI Features and Their Association With Outcomes in Children With Anti-NMDA Receptor Encephalitis.

OBJECTIVES: How brain MRI lesions associate with outcomes in pediatric anti-NMDA receptor encephalitis (pNMDARE) is unknown. In this study, we correlate T2-hyperintense MRI brain lesions with clinical outcomes in pNMDARE. METHODS: This was a multicenter retrospective cohort study from 11 institutions. Children younger than 18 years with pNMDARE were included. One-year outcomes were assessed by the modified Rankin Score (mRS) with good (mRS ≤2) and poor (mRS ≥3) outcomes. RESULTS: A total of 175 pNMDARE subjects were included, with 1-year mRS available in 142/175 (81%) and 60/175 (34%) had abnormal brain MRIs. The most common T2-hyperintense lesion locations were frontal, temporal, and parietal. MRI features that predicted poor 1-year outcomes included abnormal MRI, particularly T2 lesions in the frontal and occipital lobes. After adjusting for treatment within 4 weeks of onset, improvement within 4 weeks, and intensive care unit admission, MRI features were no longer associated with poor outcomes, but after multiple imputation for missing data, T2 frontal and occipital lesions associated with poor outcomes. DISCUSSION: Abnormal frontal and occipital lesions on MRI may associate with 1-year mRS in pNMDARE. MRI of the brain may be a helpful prognostication tool that should be examined in future studies.

Impact of the 2021 north american winter storms on children with epilepsy.

Purpose: In February 2021 a series of winter storms caused power outages for nearly 10 million people in the United States, Northern Mexico and Canada. In Texas, the storms caused the worst energy infrastructure failure in state history, leading to shortages of water, food and heat for nearly a week. Impacts on health and well-being from natural disasters are greater in vulnerable populations such as individuals with chronic illnesses, for example due to supply chain disruptions. We aimed to determine the impact of the winter storm on our patient population of children with epilepsy (CWE). Methods: We conducted a survey of families with CWE that are being followed at Dell Children's Medical Center in Austin, Texas. Results: Of the 101 families who completed the survey, 62% were negatively affected by the storm. Twenty-five percent had to refill antiseizure medications during the week of disruptions, and of those needing refills, 68% had difficulties obtaining the medications, leading to nine patients-or 36% of those needing a refill-running out of medications and two emergency room visits because of seizures and lack of medications. Conclusions: Our results demonstrate that close to 10% of all patients included in the survey completely ran out of antiseizure medications, and many more were affected by lack of water, heat, power and food. This infrastructure failure emphasizes the need for adequate disaster preparation for vulnerable populations such as children with epilepsy for the future.

Survival by Depth of Response and Efficacy by International Metastatic Renal Cell Carcinoma Database Consortium Subgroup with Lenvatinib Plus Pembrolizumab Versus Sunitinib in Advanced Renal Cell Carcinoma: Analysis of the Phase 3 Randomized CLEAR Study.

BACKGROUND: The extent of tumor shrinkage has been deemed a predictor of survival for advanced/metastatic renal cell carcinoma (RCC), a disease with historically poor survival. OBJECTIVE: To perform an exploratory analysis of overall survival (OS) by tumor response by 6 mo, and to assess the efficacy and survival outcomes in specific subgroups. DESIGN, SETTING, AND PARTICIPANTS: CLEAR was an open-label, multicenter, randomized, phase 3 trial of first-line treatment of advanced clear cell RCC. INTERVENTION: Patients were randomized 1:1:1 to lenvatinib 20 mg orally daily with pembrolizumab 200 mg intravenously once every 3 wk, lenvatinib plus everolimus (not included in this analysis), or sunitinib 50 mg orally daily for 4 wk on treatment/2 wk of no treatment. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Landmark analyses were conducted to assess the association of OS with tumor shrinkage and progressive disease status by 6 mo. Progression-free survival, duration of response, and objective response rate (ORR) were analyzed by the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk subgroup and by the presence of target kidney lesions. Efficacy was assessed by an independent review committee as per Response Evaluation Criteria in Solid Tumors version 1.1. RESULTS AND LIMITATIONS: Landmark analyses by tumor shrinkage showed that patients enrolled to lenvatinib plus pembrolizumab arm with a confirmed complete response or >75% target-lesion reduction by 6 mo had a 24-mo OS probability of ≥91.7%. A landmark analysis by disease progression showed that patients with no progression by 6 mo had lower probabilities of death in both arms. Patients with an IMDC risk classification of intermediate/poor had longer median progression-free survival (22.1 vs 5.9 mo) and a higher ORR (72.4% vs 28.8%) with lenvatinib plus pembrolizumab versus sunitinib. Similarly, results favored lenvatinib plus pembrolizumab in IMDC-favorable patients and those with/without target kidney lesions. Limitations of the study are that results were exploratory and not powered/stratified. CONCLUSIONS: Lenvatinib plus pembrolizumab showed improved efficacy versus sunitinib for patients with advanced RCC; landmark analyses showed that tumor response by 6 mo correlated with longer OS. PATIENT SUMMARY: In this report of the CLEAR trial, we explored the survival of patients with advanced renal cell carcinoma by assessing how well they initially responded to treatment. We also explored how certain groups of patients responded to treatment overall. Patients were assigned to cycles of either lenvatinib 20 mg daily plus pembrolizumab 200 mg every 3 wk or sunitinib 50 mg daily for 4 wk (followed by a 2-wk break). Patients who either had a "complete response" or had their tumors shrunk by >75% within 6 mo after starting treatment with lenvatinib plus pembrolizumab had better survival than those with less tumor reduction by 6 mo. Additionally, patients who had more severe disease (as per the International Metastatic Renal Cell Carcinoma Database Consortium) at the start of study treatment survived for longer without disease progression with lenvatinib plus pembrolizumab than with sunitinib.

Treatment of refractory ascites: Current strategies and new landscape of non-selective beta-blockers / Tratamiento de ascitis refractaria: estrategias actuales y nuevo panorama de los betabloqueadores no selectivos

Ascites is the fluid accumulation in the peritoneal cavity, and it is the consequence of a wide variety of entities, being liver cirrhosis the most common one. In this kind of patients, the development of ascites results from splanchnic vasodilation; decreased effective circulating volume; the activation of the sympathetic nervous system and the renin–angiotensin–aldosterone system; and a systemic inflammatory process. Its management is diverse and depends on the severity of the hemodynamic disturbance and other clinical manifestations. In recent years, therapeutic strategies have been developed, but they tend to result unconventional, so new evidence demonstrates the advantages of non-selective beta-blockers for the survival rate of patients with end-stage cirrhosis and ascites.(AU)

La ascitis es la acumulación de líquido en la cavidad peritoneal, y es consecuencia de una amplia variedad de entidades, siendo la cirrosis la más frecuente. En este tipo de pacientes, el desarrollo de ascitis resulta de la vasodilatación esplácnica, el volumen circulante efectivo disminuido, la activación del sistema nervioso simpático y el sistema renina-angiotensina-aldosterona, así como un proceso inflamatorio sistémico. Su tratamiento es diverso, y depende de la gravedad de la alteración hemodinámica y otras manifestaciones clínicas. En años recientes se han desarrollado estrategias terapéuticas poco convencionales, así como nueva evidencia demuestra los beneficios de los betabloqueadores no selectivos en la tasa de supervivencia de los pacientes con cirrosis en etapa terminal y ascitis.(AU)

Bioethics and public health policies in Mexico.

INTRODUCTION: Bioethics, as a reference framework for collective decision-making in plural societies, represents a valuable tool for the development, implementation and evaluation of public policies in order to address structural deficiencies and contexts of vulnerability that disproportionately affect certain sectors of the population. OBJECTIVE: To provide guidelines for the strengthening of actions, programs and public policies aimed at addressing the ethical dilemmas and challenges faced by health personnel. METHODS: A documentary research process was carried out on the moral context faced by health personnel at the federal level. RESULTS: Health budget programs show important gaps in their design, implementation or evaluation, which give rise to various ethical and human rights problems. CONCLUSIONS: Given the difficulty for reaching agreements or generating common understanding with regard to public health problems, bioethics contributes to a systematic approach to the challenges of the National Health System, for the safeguarding of the human rights of users, as well as of the integrity of its institutions.

INTRODUCCIÓN: La bioética como marco referencial para la toma de decisiones colectivas en sociedades plurales representa una valiosa herramienta para el desarrollo, implementación y evaluación de las políticas públicas a fin de abordar deficiencias estructurales y contextos de vulnerabilidad que afectan desproporcionalmente a ciertos sectores de la población. OBJETIVO: Brindar pautas para el fortalecimiento de las acciones, programas y políticas públicas orientadas al abordaje de los dilemas y desafíos éticos que enfrenta el personal de salud. MÉTODOS: Se llevó a cabo un proceso de investigación documental sobre el contexto moral que enfrenta el personal de salud a nivel federal. RESULTADOS: Los programas presupuestarios en salud presentan lagunas importantes en su diseño, implementación o evaluación, que dan lugar a diversos problemas éticos y de derechos humanos. CONCLUSIONES: Ante la dificultad de alcanzar acuerdos o generar entendimiento común en relación con problemas públicos en salud, la bioética contribuye al abordamiento sistemático de los desafíos del Sistema Nacional de Salud, para la salvaguarda de los derechos humanos de los usuarios, como también de la integridad de sus instituciones.

Lethal and Non-Lethal Functions of Caspases in the DNA Damage Response.

Members of the caspase family are well known for their roles in the initiation and execution of cell death. Due to their function in the removal of damaged cells that could otherwise become malignant, caspases are important players in the DNA damage response (DDR), a network of pathways that prevent genomic instability. However, emerging evidence of caspases positively or negatively impacting the accumulation of DNA damage in the absence of cell death demonstrates that caspases play a role in the DDR that is independent of their role in apoptosis. This review highlights the apoptotic and non-apoptotic roles of caspases in the DDR and how they can impact genomic stability and cancer treatment.

Bioética y políticas públicas en salud en México / Bioethics and public health policies in Mexico

Resumen Introducción: La bioética como marco referencial para la toma de decisiones colectivas en sociedades plurales representa una valiosa herramienta para el desarrollo, implementación y evaluación de las políticas públicas a fin de abordar deficiencias estructurales y contextos de vulnerabilidad que afectan desproporcionalmente a ciertos sectores de la población. Objetivo: Brindar pautas para el fortalecimiento de las acciones, programas y políticas públicas orientadas al abordaje de los dilemas y desafíos éticos que enfrenta el personal de salud. Métodos: Se llevó a cabo un proceso de investigación documental sobre el contexto moral que enfrenta el personal de salud a nivel federal. Resultados: Los programas presupuestarios en salud presentan lagunas importantes en su diseño, implementación o evaluación, que dan lugar a diversos problemas éticos y de derechos humanos. Conclusiones: Ante la dificultad de alcanzar acuerdos o generar entendimiento común en relación con problemas públicos en salud, la bioética contribuye al abordamiento sistemático de los desafíos del Sistema Nacional de Salud, para la salvaguarda de los derechos humanos de los usuarios, como también de la integridad de sus instituciones.

Abstract Introduction: Bioethics, as a reference framework for collective decision-making in plural societies, represents a valuable tool for the development, implementation and evaluation of public policies in order to address structural deficiencies and contexts of vulnerability that disproportionately affect certain sectors of the population. Objective: To provide guidelines for the strengthening of actions, programs and public policies aimed at addressing the ethical dilemmas and challenges faced by health personnel. Methods: A documentary research process was carried out on the moral context faced by health personnel at the federal level. Results: Health budget programs show important gaps in their design, implementation or evaluation, which give rise to various ethical and human rights problems. Conclusions: Given the difficulty for reaching agreements or generating common understanding with regard to public health problems, bioethics contributes to a systematic approach to the challenges of the National Health System, for the safeguarding of the human rights of users, as well as of the integrity of its institutions.

Treatment of refractory ascites: Current strategies and new landscape of non-selective beta-blockers.

Ascites is the fluid accumulation in the peritoneal cavity, and it is the consequence of a wide variety of entities, being liver cirrhosis the most common one. In this kind of patients, the development of ascites results from splanchnic vasodilation; decreased effective circulating volume; the activation of the sympathetic nervous system and the renin-angiotensin-aldosterone system; and a systemic inflammatory process. Its management is diverse and depends on the severity of the hemodynamic disturbance and other clinical manifestations. In recent years, therapeutic strategies have been developed, but they tend to result unconventional, so new evidence demonstrates the advantages of non-selective beta-blockers for the survival rate of patients with end-stage cirrhosis and ascites.

Caspase-2 regulates S-phase cell cycle events to protect from DNA damage accumulation independent of apoptosis.

In addition to its classical role in apoptosis, accumulating evidence suggests that caspase-2 has non-apoptotic functions, including regulation of cell division. Loss of caspase-2 is known to increase proliferation rates but how caspase-2 is regulating this process is currently unclear. We show that caspase-2 is activated in dividing cells in G1-phase of the cell cycle. In the absence of caspase-2, cells exhibit numerous S-phase defects including delayed exit from S-phase, defects in repair of chromosomal aberrations during S-phase, and increased DNA damage following S-phase arrest. In addition, caspase-2-deficient cells have a higher frequency of stalled replication forks, decreased DNA fiber length, and impeded progression of DNA replication tracts. This indicates that caspase-2 protects from replication stress and promotes replication fork protection to maintain genomic stability. These functions are independent of the pro-apoptotic function of caspase-2 because blocking caspase-2-induced cell death had no effect on cell division, DNA damage-induced cell cycle arrest, or DNA damage. Thus, our data supports a model where caspase-2 regulates cell cycle and DNA repair events to protect from the accumulation of DNA damage independently of its pro-apoptotic function.

Wnt1 Lineage Specific Deletion of Gpr161 Results in Embryonic Midbrain Malformation and Failure of Craniofacial Skeletal Development.

Sonic hedgehog (Shh) signaling regulates multiple morphogenetic processes during embryonic neurogenesis and craniofacial skeletal development. Gpr161 is a known negative regulator of Shh signaling. Nullizygous Gpr161 mice are embryonic lethal, presenting with structural defects involving the neural tube and the craniofacies. However, the lineage specific role of Gpr161 in later embryonic development has not been thoroughly investigated. We studied the Wnt1-Cre lineage specific role of Gpr161 during mouse embryonic development. We observed three major gross morphological phenotypes in Gpr161 cKO (Gpr161 f/f; Wnt1-Cre) fetuses; protrusive tectum defect, encephalocele, and craniofacial skeletal defect. The overall midbrain tissues were expanded and cell proliferation in ventricular zones of midbrain was increased in Gpr161 cKO fetuses, suggesting that protrusive tectal defects in Gpr161 cKO are secondary to the increased proliferation of midbrain neural progenitor cells. Shh signaling activity as well as upstream Wnt signaling activity were increased in midbrain tissues of Gpr161 cKO fetuses. RNA sequencing further suggested that genes in the Shh, Wnt, Fgf and Notch signaling pathways were differentially regulated in the midbrain of Gpr161 cKO fetuses. Finally, we determined that cranial neural crest derived craniofacial bone formation was significantly inhibited in Gpr161 cKO fetuses, which partly explains the development of encephalocele. Our results suggest that Gpr161 plays a distinct role in midbrain development and in the formation of the craniofacial skeleton during mouse embryogenesis.