The Gap Junction Inhibitor Octanol Decreases Proliferation and Increases Glial Differentiation of Postnatal Neural Progenitor Cells.

Neural precursor cells (NPCs) that persist in the postnatal/adult subventricular zone (SVZ) express connexins that form hemichannels and gap junctions. Gap junctional communication plays a role in NPC proliferation and differentiation during development, but its relevance on postnatal age remains to be elucidated. In this work we aimed to evaluate the effect of the blockade of gap junctional communication on proliferation and cell fate of NPCs obtained from the SVZ of postnatal rats. NPCs were isolated and expanded in culture as neurospheres. Electron microscopy revealed the existence of gap junctions among neurosphere cells. Treatment of cultures with octanol, a broad-spectrum gap junction blocker, or with Gap27, a specific blocker for gap junctions formed by connexin43, produced a significant decrease in bromodeoxyuridine incorporation. Octanol treatment also exerted a dose-dependent antiproliferative effect on glioblastoma cells. To analyze possible actions on NPC fate, cells were seeded in the absence of mitogens. Treatment with octanol led to an increase in the percentage of astrocytes and oligodendrocyte precursors, whereas the percentage of neurons remained unchanged. Gap27 treatment, in contrast, did not modify the differentiation pattern of SVZ NPCs. Our results indicate that general blockade of gap junctions with octanol induces significant effects on the behavior of postnatal SVZ NPCs, by reducing proliferation and promoting glial differentiation.

Understanding the Gaps in the Reporting of COPD Exacerbations by Patients: A Review.

Exacerbations of chronic obstructive pulmonary disease (COPD) are associated with loss of lung function, poor quality of life, loss of exercise capacity, risk of serious cardiovascular events, hospitalization, and death. However, patients underreport exacerbations, and evidence suggests that unreported exacerbations have similar negative health implications for patients as those that are reported. Whilst there is guidance for physicians to identify patients who are at risk of exacerbations, they do not help patients recognise and report them. Newly developed tools, such as the COPD Exacerbation Recognition Tool (CERT) have been designed to achieve this objective. This review focuses on the underreporting of COPD exacerbations by patients, the factors associated with this, the consequences of underreporting, and potential solutions.

Migration of a Contraceptive Subdermal Device Into the Lung.

Subdermal contraceptive implants are usually inserted subdermally and carry the possibility to migrate within a small range, usually less than 2 cm from the insertion sites; significant migration over 2 cm is rare. This paper discusses the case of a 38-year-old female patient with a migrated subdermal Implanon contraceptive implant in the left pulmonary artery. On chest computed tomography, roughly a 4 cm long linear hyperdensity foreign body in the left lower lobe was found and was favored to be a migrated Implanon in a subsegmental pulmonary artery branch. An interventional radiologist performed an endovascular removal of the left pulmonary artery Implanon using a right common femoral vein access. Very few cases have been reported of complications with inserting and removing the subdermal contraceptive implants as it is considered a reasonably safe procedure in the hands of physicians familiar with the technique. Therefore, if a properly trained individual had carried out the correct procedure of inserting a subdermal implant, the migration of an implant over 2 cm should not occur.

MRI and CT Fusion in Stereotactic Electroencephalography (SEEG).

Epilepsy is a neurological disorder characterized by spontaneous recurrent seizures. While 20% to 30% of epilepsy cases are untreatable with Anti-Epileptic Drugs, some of these cases can be addressed through surgical intervention. The success of such interventions greatly depends on accurately locating the epileptogenic tissue, a task achieved using diagnostic techniques like Stereotactic Electroencephalography (SEEG). SEEG utilizes multi-modal fusion to aid in electrode localization, using pre-surgical resonance and post-surgical computer tomography images as inputs. To ensure the absence of artifacts or misregistrations in the resultant images, a fusion method that accounts for electrode presence is required. We proposed an image fusion method in SEEG that incorporates electrode segmentation from computed tomography as a sampling mask during registration to address the fusion problem in SEEG. The method was validated using eight image pairs from the Retrospective Image Registration Evaluation Project (RIRE). After establishing a reference registration for the MRI and identifying eight points, we assessed the method's efficacy by comparing the Euclidean distances between these reference points and those derived using registration with a sampling mask. The results showed that the proposed method yielded a similar average error to the registration without a sampling mask, but reduced the dispersion of the error, with a standard deviation of 0.86 when a mask was used and 5.25 when no mask was used.

Genetic continuity and change among the Indigenous peoples of California.

Before the colonial period, California harboured more language variation than all of Europe, and linguistic and archaeological analyses have led to many hypotheses to explain this diversity1. We report genome-wide data from 79 ancient individuals from California and 40 ancient individuals from Northern Mexico dating to 7,400-200 years before present (BP). Our analyses document long-term genetic continuity between people living on the Northern Channel Islands of California and the adjacent Santa Barbara mainland coast from 7,400 years BP to modern Chumash groups represented by individuals who lived around 200 years BP. The distinctive genetic lineages that characterize present-day and ancient people from Northwest Mexico increased in frequency in Southern and Central California by 5,200 years BP, providing evidence for northward migrations that are candidates for spreading Uto-Aztecan languages before the dispersal of maize agriculture from Mexico2-4. Individuals from Baja California share more alleles with the earliest individual from Central California in the dataset than with later individuals from Central California, potentially reflecting an earlier linguistic substrate, whose impact on local ancestry was diluted by later migrations from inland regions1,5. After 1,600 years BP, ancient individuals from the Channel Islands lived in communities with effective sizes similar to those in pre-agricultural Caribbean and Patagonia, and smaller than those on the California mainland and in sampled regions of Mexico.

Equivalent impacts of logging and beaver activities on aboveground carbon stock loss in the southernmost forest on Earth.

The conservation of forest landscapes is crucial for global climate strategies, and the forest in Tierra del Fuego, located in Patagonia, represents the southernmost example on Earth. These ecosystems are critical for Chile's roadmap toward carbon neutrality. Unfortunately, these ecosystems have been impacted by logging and beaver activities. Currently, the precise contribution of each driver to forest cover and carbon stock loss remains insufficiently quantified, impeding effective policymaking and the implementation of strategies to safeguard and enhance carbon stocks in these ecosystems. In this study, we conducted an assessment of forest carbon stock loss resulting from both logging and beaver activities in Chilean Tierra del Fuego from 1986 to 2019. While beavers have received significant attention for their substantial contribution to forest cover loss (56.1% forest cover, ≈ 1.4 MtC), our findings suggest that logging has nearly equally contributed to carbon stock depletion (43.8% forest cover, ≈ 1.2 MtC). Consequently, the prevailing focus on beavers has obscured the ongoing logging-induced carbon stock loss. The implications of our study highlight the urgency for comprehensive consideration of both drivers in Chile's climate strategy to fulfill the country's mitigation commitments.

MTSS2-related neurodevelopmental disorder: Further delineation of the phenotype.

MTSS2-related neurodevelopmental disorder (MTSS2-related NDD) (MIM 620086) is characterized by intellectual developmental disorder with ocular anomalies and distinctive facial features (IDDOF). The only existing report to date described five individuals who exhibited an identical de novo c.2011C>T (p.Arg671Trp) variant in the MTSS2 gene. Herein, we report a new case of MTSS2-related NND in a male dizygotic twin who presented with IDDOF and severe intellectual disability. This patient also displayed additional clinical features, including low functioning autism, hypothyroidism, duodenal obstruction secondary to Ladd's bands, inguinal hernias, cryptorchidism, transient subperiosteal new bone formation, and short stature with delayed bone age, which had not been previously reported in association with the MTSS2-related NDD. Exome sequencing identified the recurrent c.2011C>T (p.Arg671Trp) variant in the MTSS2 gene. The mother and the other twin tested negative for the pathogenic variant, while the father's participation in the study was unavailable. This case confirms that the MTSS2-related NDD is caused by the recurrent MTSS2 missense variant p.Arg671Trp. The novel findings identified in our patient expand the phenotypic spectrum associated with this new autosomal dominant entity, but further studies on its genetic and clinical manifestations are still needed.

EP300 as a Molecular Integrator of Fibrotic Transcriptional Programs.

Fibrosis is a condition characterized by the excessive accumulation of extracellular matrix proteins in tissues, leading to organ dysfunction and failure. Recent studies have identified EP300, a histone acetyltransferase, as a crucial regulator of the epigenetic changes that contribute to fibrosis. In fact, EP300-mediated acetylation of histones alters global chromatin structure and gene expression, promoting the development and progression of fibrosis. Here, we review the role of EP300-mediated epigenetic regulation in multi-organ fibrosis and its potential as a therapeutic target. We discuss the preclinical evidence that suggests that EP300 inhibition can attenuate fibrosis-related molecular processes, including extracellular matrix deposition, inflammation, and epithelial-to-mesenchymal transition. We also highlight the contributions of small molecule inhibitors and gene therapy approaches targeting EP300 as novel therapies against fibrosis.

Successful Treatment of Paecilomyces variotii Pneumonia and Lupus Nephritis With Posaconazole-Cyclophosphamide Co-administration Without Drug Interaction-Induced Toxicity.

Paecilomyces variotii is an opportunistic mold that causes pulmonary infections in immunosuppressed humans that are often treated with triazole therapy. Lupus nephritis is a major cause of progressive kidney disease in patients with systemic lupus erythematosus, often requiring cyclophosphamide-based therapies. Triazole-cyclophosphamide co-administration is challenging as triazoles increase cyclophosphamide concentrations, which can worsen cyclophosphamide toxicity. We describe herein a patient with Paecilomyces variotii pneumonia and concomitant lupus nephritis who was successfully treated with posaconazole and echinocandin-bridged interruptions to allow for cyclophosphamide therapy. This regimen was well-tolerated without cyclophosphamide toxicity and achieved improvements in both fungal pneumonia and renal function.

Minimal Residual Disease in Multiple Myeloma: Past, Present, and Future.

Responses to treatment have improved over the last decades for patients with multiple myeloma. This is a consequence of the introduction of new drugs that have been successfully combined in different clinical contexts: newly diagnosed, transplant-eligible or ineligible patients, as well as in the relapsed/refractory setting. However, a great proportion of patients continue to relapse, even those achieving complete response, which underlines the need for updated response criteria. In 2014, the international myeloma working group established new levels of response, prompting the evaluation of minimal residual disease (MRD) for those patients already in complete or stringent complete response as defined by conventional serological assessments: the absence of tumor plasma cells in 100,000 total cells or more define molecular and immunophenotypic responses by next-generation sequencing and flow cytometry, respectively. In this review, we describe all the potential methods that may be used for MRD detection based on the evidence found in the literature, paying special attention to their advantages and pitfalls from a critical perspective.

Prevalence of genetic mutations in alpha-1 antitrypsin deficiency (aatd) in patients with chronic obstructive pulmonary disease in Colombia.

BACKGROUND: Alpha-1 antitrypsin deficiency (AATD) is an underrecognized genetic disorder associated mainly with pulmonary emphysema and Chronic Obstructive Pulmonary Disease (COPD). All individuals with COPD regardless of age or ethnicity should be tested for AATD, but in Colombia its prevalence in unknown. MAIN OBJECTIVE: To determine the prevalence of the genetic mutations, present in AATD in adult patients with COPD in Colombia, using a genotyping test on cells from the oral mucosa. METHODS: This was a multicentre, observational, cross-sectional study which included adult patients attending seven COPD care centres in Colombia. Demographic data, medical history, including history of exposure to smoking and biomass smoke, most recent spirometry, pharmacological and non-pharmacological treatment received, serum AAT levels, and mutations detected by the genotyping test were recorded for all the recruited patients. For the comparison of variables between the groups with and without mutation, we used the X2 test for the qualitative variables and the Student's t-test or Mann-Whitney U test according to their distribution. MAIN FINDINGS: We collected a sample of 1,107 patients, the median age was 73.8 years (87.6-79.9). Mutations were documented in 144 patients (13.01%), the majority had the M/S mutation (78.50%), followed by M/Z (9.72%). One patient had a ZZ mutation and two patients had null alleles. In total, 23 patients had mutations associated with serum AAT deficiency (levels below 60 mg/dl). CONCLUSIONS: Genetic mutations were documented in 13.01% of patients with COPD in Colombia and 2.07% were AATD-related, showing that there is a significant number of underdiagnosed patients.

Portland Cement-Based Grouts Enhanced with Basalt Fibers for Post-Tensioned Concrete Duct Filling.

In post-tensioned systems, grouts act as a last line of defense to prevent the penetration of harmful compounds such as chlorides, moisture and other substances that cause corrosion in the prestressing steel. For this reason, improving grouts results in the enhancement of the overall durability of the structure. In this study, the physical properties of grouts with basalt microfiber additions in the amounts of 0.03, 0.07 and 0.10% with respect to the mix volume were evaluated. The fresh properties included flowability and unit mass. Specimens were fabricated to evaluate drying shrinkage, compressive strength, air permeability and rapid permeability to chloride ions. The incorporation of basalt microfibers showed a beneficial effect on the physical properties of the grout by increasing the drying shrinkage resistance and decreasing the permeability compared to the reference mix and two commercial dry prepackaged grouts. The optimal grout mix was the one with a percentage of basalt microfibers of 0.10%, which decreased drying shrinkage by 15.98% at 14 days compared to the reference mix, and permeability to chloride ions decreased by 10.82% compared to the control mix.

MIDO GDM: an innovative artificial intelligence-based prediction model for the development of gestational diabetes in Mexican women.

Given the barriers to early detection of gestational diabetes mellitus (GDM), this study aimed to develop an artificial intelligence (AI)-based prediction model for GDM in pregnant Mexican women. Data were retrieved from 1709 pregnant women who participated in the multicenter prospective cohort study 'Cuido mi embarazo'. A machine-learning-driven method was used to select the best predictive variables for GDM risk: age, family history of type 2 diabetes, previous diagnosis of hypertension, pregestational body mass index, gestational week, parity, birth weight of last child, and random capillary glucose. An artificial neural network approach was then used to build the model, which achieved a high level of accuracy (70.3%) and sensitivity (83.3%) for identifying women at high risk of developing GDM. This AI-based model will be applied throughout Mexico to improve the timing and quality of GDM interventions. Given the ease of obtaining the model variables, this model is expected to be clinically strategic, allowing prioritization of preventative treatment and promising a paradigm shift in prevention and primary healthcare during pregnancy. This AI model uses variables that are easily collected to identify pregnant women at risk of developing GDM with a high level of accuracy and precision.

Perspectives on socio-ecological studies in the Northern and Southern Hemispheres.

Socio-ecology studies the relationships between human activities and natural systems and their importance in management and public policy. Our objective was to analyse how published papers in countries with a high Human Development Index (HDI) perform socio-ecological studies and compare them between the Northern and Southern Hemispheres. To do this, we used the Scopus platform as a source for searching and obtaining scientific papers about socio-ecological studies conducted in countries from the Northern and Southern Hemispheres. We calculated the number (n) of papers published per year and classified them using the main subject areas of the SCImago Journal & Country Rank database. Then, we analysed whether papers included specific recommendations for natural system management, nature conservation, policies or governance structures, or science in general. Besides, we studied whether the papers addressed socio-ecological studies related to flora and fauna and from what specific group of organisms or systems. Data were compared using the chi-square (χ 2) test (Pearson p < 0.005). A total of 467 papers were analysed, where 34% were from the Southern Hemisphere (mainly Argentina, Australia, Chile, and South Africa) and 66% from the Northern Hemisphere (mainly the USA, Canada, and Spain). The Northern Hemisphere (mainly North America and Europe) played a major role in the socio-ecological knowledge exchange than the Southern Hemisphere (South America and Africa). The results showed socio-ecological studies focused mainly on generating management recommendations in social and environmental science fields. The number of studies coming from the Northern Hemisphere was significantly higher than those from the Southern Hemisphere. Most of them were conducted at a local level (e.g., watersheds or human settlements) in three different systems (i) terrestrial (e.g., forests or grasslands), (ii) freshwater (e.g., rivers or streams) and (iii) marine (e.g., coastlines or seas). Most of the studies (70%) were conducted in production systems, where the majority included livestock (mainly bovine) and aquatic fisheries (e.g., salmon, artisanal coastal fishing, or trout). Most vegetation papers (65%) were on native forests. Papers on wildlife made up 30% of all animal-related studies, with mammals, birds, and marine invertebrates (such as collars) being the most extensively researched species. This work highlighted the socio-ecological approach that was used in the analysed countries with greater HDI to develop management options for natural systems.

Immunomodulatory Activity of Diterpenes over Innate Immunity and Cytokine Production in a Human Alveolar Epithelial Cell Line Infected with Mycobacterium tuberculosis.

BACKGROUND: Mexico has the largest number of the genus salvia plant species, whose main chemical compounds of this genus are diterpenes, these chemical compounds have shown important biological activities such as: antimicrobial, anti-inflammatory and immunomodulatory. OBJECTIVE: This study aimed to evaluate the immunomodulatory activity of three diterpenes: 1) icetexone, 2) anastomosine and 3) 7,20-dihydroanastomosine, isolated from Salvia ballotiflora, over innate immunity and cytokine production in a human alveolar epithelial cell line infected with Mycobacterium tuberculosis. METHODS: The immunomodulatory activity of diterpenes over innate immunity included reactive oxygen and nitrogen species (ROS and RNS) induction in response to infection; cytokine production included TNF-α and TGF-ß induction in response to infection. RESULTS: The diterpenes anastomosine and 7,20-dihydroanastomosine showed a statically significant (p < 0.01) increase of RNS after 36 h of infection and treatment of 2.0 µg/mL. Then, the ROS induction in response to infection showed a consistent statically significant (p < 0.01) increase after 12 h of diterpenes treatments. The cell cultures showed an anti-inflammatory effect, in the case of TGF-ß induction, in response to infection when treated with the diterpenes. On the other hand, there was not any significant effect on TNF-α release. CONCLUSION: The diterpenes anastomosine and 7,20-dihydroanastomosine increased the production of RNS after 36 h of infection and treatment. Besides, the three diterpenes increased the production of ROS after 12 h. This RNS and ROS modulation can be considered as an in vitro correlation of innate immunity in response to Mycobacterium tuberculosis infection; and an indicator of the damage of epithelial lung tissue. This study also showed an anti-inflammatory immune response by means of TGF-ß modulation when compared with control group.

Epigenetic mechanisms of particulate matter exposure: air pollution and hazards on human health.

Environmental pollution nowadays has not only a direct correlation with human health changes but a direct social impact. Epidemiological studies have evidenced the increased damage to human health on a daily basis because of damage to the ecological niche. Rapid urban growth and industrialized societies importantly compromise air quality, which can be assessed by a notable accumulation of air pollutants in both the gas and the particle phases. Of them, particulate matter (PM) represents a highly complex mixture of organic and inorganic compounds of the most variable size, composition, and origin. PM being one of the most complex environmental pollutants, its accumulation also varies in a temporal and spatial manner, which challenges current analytical techniques used to investigate PM interactions. Nevertheless, the characterization of the chemical composition of PM is a reliable indicator of the composition of the atmosphere, the quality of breathed air in urbanized societies, industrial zones and consequently gives support for pertinent measures to avoid serious health damage. Epigenomic damage is one of the most promising biological mechanisms of air pollution-derived carcinogenesis. Therefore, this review aims to highlight the implication of PM exposure in diverse molecular mechanisms driving human diseases by altered epigenetic regulation. The presented findings in the context of pan-organic cancer, fibrosis, neurodegeneration and metabolic diseases may provide valuable insights into the toxicity effects of PM components at the epigenomic level and may serve as biomarkers of early detection for novel targeted therapies.

Single-Cell DNA Sequencing and Immunophenotypic Profiling to Track Clonal Evolution in an Acute Myeloid Leukemia Patient.

Single-cell DNA sequencing can address the sequence of somatic genetic events during myeloid transformation in relapsed acute myeloid leukemia (AML). We present an NPM1-mutated AML patient with an initial low ratio of FLT3-ITD (low-risk ELN-2017), treated with midostaurin combined with standard chemotherapy as front-line treatment, and with salvage therapy plus gilteritinib following allogenic stem cell transplantation after relapse. Simultaneous single-cell DNA sequencing and cell-surface immunophenotyping was used in diagnostic and relapse samples to understand the clinical scenario of this patient and to reconstruct the clonal composition of both tumors. Four independent clones were present before treatment: DNMT3A/DNMT3A/NPM1 (63.9%), DNMT3A/DNMT3A (13.9%), DNMT3A/DNMT3A/NPM1/FLT3 (13.8%), as well as a wild-type clone (8.3%), but only the minor clone with FLT3-ITD survived and expanded after therapy, being the most represented one (58.6%) at relapse. FLT3-ITD was subclonal and was found only in the myeloid blast population (CD38/CD117/CD123). Our study shows the usefulness of this approach to reveal the clonal architecture of the leukemia and the identification of small subclones at diagnosis and relapse that may explain how the neoplastic cells can escape from the activity of different treatments in a stepwise process that impedes the disease cure despite different stages of complete remission.

Diagnostic Accuracy of Capillary Blood Glucometer Testing for Gestational Diabetes.

Purpose: Few pregnant women in low-resource settings are screened for gestational diabetes mellitus (GDM) using the gold standard oral glucose tolerance test (OGTT). This study compared capillary blood glucose testing with 2-h plasma glucose measurements obtained using the 75-g OGTT to screen for GDM at primary healthcare clinics in Mexico. Patients and Methods: Pregnant women who participated in a previous prospective multicenter longitudinal cohort study and who had not been previously diagnosed with diabetes were included. Participants were evaluated using the plasmatic 2-h 75-g OGTT with simultaneous capillary blood glucose measurements using a glucometer. The study endpoint was the comparability of the glucometer results to the gold standard OGTT when collected simultaneously. Sensitivity, specificity, and area under the curve of the glucose measurements obtained for capillary blood compared with venous plasma (gold standard) were calculated to determine diagnostic accuracy. Results: The study included 947 pregnant women who had simultaneous glucose measurements available (blood capillary [glucometer] and venous blood OGTT). Overall, capillary blood glucose testing was very sensitive (89.47%); the specificity was 66.58% and the area under the curve (95% confidence interval) was 0.78 (0.74-0.81). The sensitivity, specificity and area under the curve of each capillary measurement were: 89.47%, 66.58% and 0.78 (0.74-0.82) for the fasting measurement, 91.53%, 93.24% and 0.92 (0.88-0.96) for the one-hour measurement, and 89.80%, 93.32%, 0.91 (0.87-0.95) for the second-hour measurement, respectively. No adverse events were reported. Conclusion: Capillary OGTT is a valid alternative to the gold standard OGTT for screening of GDM in low-resource situations or in situations where there are other limitations to performing the OGTT as part of primary healthcare services.

Effect of Limestone and Quartz Fillers in UHPC with Calcined Clay.

Ultra-high-performance concrete (UHPC) is a material developed to maximize the engineering characteristics of hydraulic concrete, in terms of durability and mechanical properties, but the adoption of this technology in practice has not turned out as desired, mainly due to the high amounts of cement and silica fume required for its production, and for its consequences on both economic and ecological costs. As an option to improve the impact of UHPC, both on costs and on sustainability, this work evaluates four UHPC series with metakaolin additions of 5%, 10%, 15% and 20%, and the substitution of 37.5% of the Portland cement volume by limestone or quartz filler. The compressive strength, the bulk electrical resistivity and a set of tests for microstructural characterization (TGA, XRD and quantitative EDS) were utilized to better understand the role of calcite on the hydration and pozzolanic reactions in ternary Portland cement-metakaolin-limestone filler. Results indicate that the reaction of calcite is scarce and should be considered as a mere filler, as no increase in AFm phases were found. Nevertheless, the ternary mixture with 15% of metakaolin in addition to cement, and with 37.5% of the Portland cement volume substituted by limestone filler, was the one that presented the best performance in terms of compressive strength and bulk electrical resistivity. The results of the microstructural characterization indicate that the high kaolin content in the metakaolin originated the most significant hydration and pozzolanic reactions development between the ages of 7 and 28 days, as between 28 and 91 the reaction remained dormant. In general, the whole set of results included in this work indicate that limestone filler doesn't act as a better filler than other kind of powders when used in ternary Portland cement-metakaolin- filler systems.