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Jaime A Quintero,1– 3 Camilo A Medina,1,4,5 Federico Penagos,3,4 Jaime Andres Montesdeoca,3,4 Gildardo Antonio Orozco,1,4 Juan Saavedra-Castrillón,3,4 Julio Diez-Sepulveda1,3,4 1Departamento de Medicina de Emergencias y Cuidado Crítico, Fundación Valle del Lili, Cali, Colombia; 2Centro de Investigaciones Clínicas (CIC), Fundación Valle del Lili, Cali, Colombia; 3Semillero de Investigación en Medicina de Emergencias y Reanimación (SIMER), Facultad de Ciencias de la Salud, Cali, Colombia; 4Universidad Icesi, Facultad de Ciencia de la Salud, Cali, Colombia; 5Departamento de Medicina Interna, Fundación Valle del Lili, Cali, ColombiaCorrespondence: Jaime A Quintero, Email jaime.quintero.ra@fvl.org.coIntroduction: Hyperkalemia is a prevalent electrolyte disorder related to elevated serum potassium levels, resulting in diverse abnormal electrocardiographic findings and associated clinical signs and symptoms, often necessitating specific treatment. However, in some patients, these abnormal findings may not be present on the electrocardiogram even in elevated serum potassium levels. This study aims to identify electrocardiographic abnormalities related to the severity of hyperkalemia and the clinical outcomes in an emergency department in southwestern Colombia.Methodology: This is a retrospective cross-sectional descriptive study. We described the electrocardiographic findings, clinical characteristics, treatment, and outcomes related to the degrees of hyperkalemia. The potential association between the severity of hyperkalemia and electrocardiographic findings was evaluated.Results: A total of 494 patients were included. The median of the potassium level was 6.6 mEq/L. Abnormal electrocardiographic findings were reported in 61.5% of the cases. Mild and severe hyperkalemia groups reported abnormalities in 59.9% and 61.2%, respectively. The most common electrocardiography abnormalities were the peaked T wave 36.2%, followed by wide QRS 83 (16.8%). Only 1.4% of patients had adverse outcomes. The abnormal findings were registered in 61.5%. Mortality was 11.9%. The peaked T wave was the most common finding across different levels of hyperkalemia severity.Conclusion: High serum potassium levels are related with abnormal ECG. However, patients with different degrees of hyperkalemia could not describe abnormal ECG findings. In a high proportion of patients with renal chronic disease and hyperkalemia, the abnormalities in the ECG could be minimal or absent.Keywords: hyperkalemia, degree, outcomes, electrocardiographic, ECG, abnormalities

Allister Gibbons,1 Ella H Leung,1 Luis J Haddock,1 Carlos A Medina,1 Viviana Fernandez,2 Jean-Marie A Parel,1,2 Heather A Durkee,2 Guillermo Amescua,1 Eduardo C Alfonso,1 Victor L Perez1,3 1Bascom Palmer Eye Institute/University of Miami Miller School of Medicine, Miami, FL, 2Ophthalmic Biophysics Center, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, 3Ocular Surface Center, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA Purpose: To determine the indications, long-term clinical and visual outcomes, and complications of the aphakic snap-on type I Boston keratoprosthesis (KPro). Design: Retrospective, non-comparative case series. Methods: Forty-five eyes of 43 patients with type I aphakic snap-on KPros with at least 1 year of follow-up were included. The past medical histories, preoperative indications, best-corrected visual acuities (BCVAs), postoperative complications, and retention rates were analyzed. Results: The most common indication for KPro implantation was a failed corneal graft (89%). The mean preoperative BCVA was count fingers–hand motion (2.14±0.45 logarithm of minimum angle of resolution [logMAR]), which initially improved to 20/200 (1.04±0.85 logMAR; P

We categorized the dormancy and germination ofblackberry (Rubus glaucus Benth) seeds from the GermplasmBank System for Food and Agriculture of the Colombian Nation. A tetrazolium test showed normal seedling production viability, but seed coat impermeability prevented imbibition, which is considered an expression of exogenous dormancy; however, this was released by immersing the seeds in 5.25% sodium hypochlorite for 16 to 21 hours. The treatment was applied to 10 accessions of Castilla blackberry, harvested during the dry and rainy seasons. The seeds were germinated under light and dark conditions. The highest germination counts were obtained with the dry-season-collected seeds incubated in darkness and with the rainy-season seeds incubated under light conditions. Differential germination responses were also independently determined by genotype, incubation conditions (light or darkness) and collecting season. / Se categorizaron la latencia y la germinación ensemillas de mora de Castilla (Rubus glaucus Benth), provenientes del Sistema de Bancos de Germoplasma para la Alimentación y la Agricultura de la Nación Colombiana. La prueba del tetrazolio demostró que las semillas tenían la capacidad para dar origen a una plántula normal; sin embargo, al contacto con el agua la imbibición fue restringida por la impermeabilidad de la testa, lo que se considera como una expresión de latencia exógena. Ésta pudo ser removida con la inmersión de las semillas durante 16 a 21 horas en hipoclorito de sodio al 5,25%. El tratamiento fue aplicado a 10 accesiones de mora de Castila cosechadas en épocas seca y lluviosa; las semillas se germinaron bajo condiciones deluz y oscuridad, con una mayor germinación al incubar lasprovenientes de tiempo seco en condiciones de oscuridad y en aquellas de época lluviosa al ser germinadas con luz. También al aplicar el procedimiento de remoción de latencia exógena se observaron respuestas germinativas diferenciales determinadas por el genotipo, las condiciones de incubación (luz y oscuridad) y la época de recolección.

Resumen: En la actualidad tenemos el privilegio de vivir una época de importantes transformaciones para nuestra profesión. Reflexionar sobre las implicaciones que estos cambios suponen es un ejercicio racional y prudente, en el sentido más aristotélico del término, que nos permitirá afrontar el futuro asumiendo los compromisos y responsabilidades éticas y profesionales que nos correspondan.El objetivo de este trabajo es analizar algunas de las transformaciones que se han producido en los contextos académico, profesional y social en los que se desempeñan los profesionales de Enfermería y los retos éticos que suponen estos cambios para los enfermeros y enfermeras en cuanto condicionan su desarrollo futuro.Abstract: Ethical challenges for the nursing care in changing scenarios. On these days, we have the privilege of living in a time of important changes for our profession. Reflecting about the implications of these changes is a rational and prudent behaviour, in the most Aristotelian sense of the terms, and will make us able to face the future assuming our ethical and professional commitments and responsibilities. The aim of this paper is to analyse some of the transformations that have taken place in the academic, professional and social contexts where nurses perform their profession and the ethical challenges that these changes mean for their future development.

This study reports the effects of sheep and pig liquid manure, and chemical fertilizer on the phytoplankton, primary productivity and aquaculture production in the cultivation of carp in semi-rustic ponds. The total yield was 4.632 kg in two hectares. Treatment with chemical fertilizers was found to present the highest yield with 10.06 ± 0.67 (kg/Ha/day), followed by treatment with pig manure (8.27 ± 1.24 kg/Ha/day) and sheep manure (6.33 ± 1.95 kg/Ha/day). It was also found that concentrations of phytoplankton were significantly (p

Background: Tooth loss (TL) affects quality of life and general health. The literature suggesting that tamoxifen treatment in patients with breast cancer (BC) could be associated with alterations in oral health, increasing the risk of TL, is still scarce. This work aimed to determine the relationship between TL and tamoxifen consumption in patients with BC., Material and Methods: This cross-sectional observational study was carried out from July to September 2023 in the medical oncology services of the "Virgen de la Puerta" - ESSALUD High Complexity Hospital and "Dr. Luis Pinillos Ganoza" - IREN Norte - Regional Institute of Neoplastic Diseases, in Trujillo - Peru. Overall, 200 adult patients diagnosed with BC were evaluated, of which 100 consumed tamoxifen and 100 did not. Inter- and intra-rater reliability was determined with respect to TL, resulting in intra-class correlation values RHO = 0.971 and interclass RHO = 0.938. The oncologist of the corresponding service performed BC diagnosis and stage. Poisson regression was used to analyze results with a significance level of p<0.05., Results: No relationship was found between TL and tamoxifen consumption in patients with breast cancer (p= 0.221); however, greater TL was observed in women who consumed tamoxifen for more than one year compared to those who did not use it (p=0.025) and in older adult women compared to young women (p=0.030)., Conclusions: There is a relationship between TL and time of use of tamoxifen in patients with BC, concluding that patients who consumed tamoxifen for more than one year had greater TL than those who did not. Furthermore, no relationship was found between TL and cancer stages, but there was greater TL in older adult patients and also in those who consumed tamoxifen and did not receive chemotherapy or radiotherapy.

Background: To determine the relationship between temporomandibular joint dysfunction (TMJD) and tinnitus in Peruvian adult patients., Material and Methods: This observational and cross-sectional study was conducted between April and May 2023, including 76 adult patients from the Otorhinolaryngology Service of Víctor Lazarte Echegaray Essalud Hospital in Trujillo (Peru). The intra- and inter-rater reliability was determined for the clinical measurement of TMJD, obtaining Kappa values above 0.995. To diagnose tinnitus, we worked with a doctor specializing in otolaryngology. Chi-square test and logistic regression were used to analyze results, considering a significance level of p <0.05., Results: A relationship was found between TMJD and tinnitus ( p =0.022), increasing the frequency of this disorder as temporomandibular involvement was higher ( p =0.043). There was no relation between these disorders according to gender and age, nor in hypertensive patients ( p =0.131) or patients suffering from migraine ( p =0.147); however, a relationship was found between TMJD and tinnitus in patients with hearing loss ( p =0.046)., Conclusions: TMJD is associated with tinnitus in otorhinolaryngological and hypoacusis patients. However, in hypertensive and migraine patients, and according to gender and age, no relation was found between those disorders. Key words: Tinnitus, Temporomandibular Joint Disorders, Hearing Loss, Sensorineural, Audiometry, Migraine, Hypertension, Headache., Competing Interests: Conflicts of interest None declared., (Copyright: © 2024 Medicina Oral S.L.)

Background: In patients with large ventral hernias, botulinum toxin to external and internal oblique muscles decreases thickness and increases length. We examined the impact of botulinum toxin in the amount of loss of domain according to two ratios and in hernia size., Methods: Between October 2021 and November 2023, 20 patients with ventral hernias measuring 10 cm or more on the horizontal size underwent the administration of 50 units of botulinum toxin to each external and each internal oblique muscle 4 weeks before their surgery. Incisional hernia volume to peritoneal volume ratio, volume ratio, and hernia size were compared before and 4 weeks after the injection of botulinum toxin. Comparisons between all variables obtained before and after the administration of botulinum toxin were performed using either the paired t-test or the Wilcoxon signed-rank test. Pearson correlation coefficient was used to analyze associations between initial conditions and further changes observed after botulinum toxin injection., Results: We observed a 42% reduction in muscle amplitude, 16% increase in intra-abdominal volume, 28% decrease in herniated volume, decreases of 6% in IHV/PV ratio and of 11% in V ratio, 11% reduction of hernia width, and decrease of 10% in rectangular and elliptical hernia areas., Conclusions: In patients with large ventral hernias, botulinum toxin is associated with reduction of hernia size and decrease in loss of domain, the latter not being significant when less than 10% of the visceral block is herniated., (© 2024 International Society of Surgery/Société Internationale de Chirurgie (ISS/SIC).)

Chronic Kidney Disease (CKD) is a serious public health problem. Hyperglycemia stimulates the production of reactive oxygen species that cause oxidative damage to proteins. AOPPs constitute a group of oxidized dityrosine-containing proteins that are generated during periods of oxidative stress. They have proved to be a valuable early marker of oxidative tissue damage and active mediators of inflammation associated with the uremic state. To analyze if advanced oxidative protein products (AOPPs) have diagnostic accuracy for identifying chronic kidney disease (CKD) in the adult population. We conducted a diagnostic test validation study in 302 adults ≥20 years old, of both sexes, with and without T2D. After obtaining informed consent, a comprehensive clinical history, anthropometric measurements (weight, BMI) and blood pressure were recorded. Glucose, cholesterol, triglyceride, HDL-c, LDL-c and AOPPs were determinates. Glomerular filtration rate (GFR) was calculated using Cockcroft-Gault (C-G) corrected by body surface area (BSA, mL/min/1.73 m 2 ), CKD-EPI and MDRD equations to identify five stages of CKD. This study follows the Standards for Reporting Diagnostic Accuracy Studies (STARD). The median value of AOPPs was 198.32 µmol/L (minimum-maximum value: 113.48-522.42 µmol/L). The group with patients diagnosed with T2D exhibited higher concentrations (median: 487.39 µmol/L) compared to the non-diabetic group (median: 158.50 µmol/L, p = 0.0001). The selected cut-off point was ≥200 µmol/L using the closest to the median value of AOPPs with sensitivity and specificity as follows: C-G: sensitivity 96.58%; specificity 80%; likelihood ratio: 4.83; CKD-EPI: sensitivity 95.76%; specificity 79.89%; likelihood ratio: 4.76; MDRD: sensitivity 86.55%; specificity: 73.22%; likelihood ratio: 3.23. A difference was observed between AOPPs and chronic kidney disease stage. This study provides evidence that AOPPs ≥ 200 µmol/L have diagnostic accuracy in identifying stage 4-5 CKD by C-G, MDRD and CKD-EPI equations in adults with and without T2D.

Objective: The metabolic benefits of GLP-1 receptor (GLP-1R) agonists on glycemic and weight control are well established as therapy for type 2 diabetes and obesity. Glucagon's ability to increase energy expenditure is well described, and the combination of these mechanisms-of-actions has the potential to further lower hepatic steatosis in metabolic disorders and could therefore be attractive for the treatment for non-alcoholic steatohepatitis (NASH). Here, we have investigated the effects of a dual GLP-1/glucagon receptor agonist NN1177 on hepatic steatosis, fibrosis, and inflammation in a preclinical mouse model of NASH. Having observed strong effects on body weight loss in a pilot study with NN1177, we hypothesized that direct engagement of the hepatic glucagon receptor (GCGR) would result in a superior effect on steatosis and other liver related parameters as compared to the GLP-1R agonist semaglutide at equal body weight., Methods: Male C57Bl/6 mice were fed a diet high in trans-fat, fructose, and cholesterol (Diet-Induced Obese (DIO)-NASH) for 36 weeks. Following randomization based on the degree of fibrosis at baseline, mice were treated once daily with subcutaneous administration of a vehicle or three different doses of NN1177 or semaglutide for 8 weeks. Hepatic steatosis, inflammation and fibrosis were assessed by immunohistochemistry and morphometric analyses. Plasma levels of lipids and liver enzymes were determined, and hepatic gene expression was analyzed by RNA sequencing., Results: NN1177 dose-dependently reduced body weight up to 22% compared to vehicle treatment. Plasma levels of ALT, a measure of liver injury, were reduced in all treatment groups with body weight loss. The dual agonist reduced hepatic steatosis to a greater extent than semaglutide at equal body weight loss, as demonstrated by three independent methods. Both the co-agonist and semaglutide significantly decreased histological markers of inflammation such as CD11b and Galectin-3, in addition to markers of hepatic stellate activation (αSMA) and fibrosis (Collagen I). Interestingly, the maximal beneficial effects on above mentioned clinically relevant endpoints of NN1177 treatment on hepatic health appear to be achieved with the middle dose tested. Administering the highest dose resulted in a further reduction of liver fat and accompanied by a massive induction in genes involved in oxidative phosphorylation and resulted in exaggerated body weight loss and a downregulation of a module of co-expressed genes involved in steroid hormone biology, bile secretion, and retinol and linoleic acid metabolism that are also downregulated due to NASH itself., Conclusions: These results indicate that, in a setting of overnutrition, the liver health benefits of activating the fasting-related metabolic pathways controlled by the glucagon receptor displays a bell-shaped curve. This observation is of interest to the scientific community, due to the high number of ongoing clinical trials attempting to leverage the positive effects of glucagon biology to improve metabolic health., Competing Interests: Declaration of competing interest Thomas Monfeuga, Jenny Norlin, Anne Bugge, Elisabeth D. Gaalsgaard, Cesar A. Prada-Medina, Markus Latta, Sanne S. Veidal and Dorte Holst are employees of Novo Nordisk A/S and shareholders in Novo Nordisk A/S. Pia S. Petersen is currently employee at Ascendis Pharma A/S and Michael Feigh is employee at Gubra A/S., (Copyright © 2023 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Background: Xicotli data is the short name given to the dataset generated within the project framework "Integration of Biodiversity Data for the Management and Conservation of Wild Bee-Plant Interactions in Mexico (2021-2023)", as xicotli is the generic word for a bee in Nahuatl. The team comprised eco-informaticians, ecologists and taxonomists of both native bees and flora. The generated dataset contains so far 4,532 curated records of the plants, which are potential hosts of species of three focal families of bees native to Mexico: Apidae, Halictidae and Megachilidae and morphological and ecological data of the plant-bee interactions. This dataset was integrated and mobilised from citizen observations available at naturalista.mx (iNat), which were compiled through the iNaturalist project., New Information: The new information obtained with the Xicotli data project was: Taxonomic information about bee species curated by taxonomists based on the information contained in iNaturalist;Taxonomic identification of the host plants by a botanist from the photos compiled by the Xicotli Data project;Data on the ecomorphological traits of bees and plants based on expert knowledge and literature. All the data were integrated into the Xicotli Data Project via the creation of new "observation fields". The visibility of the information originally contained in iNaturalist was maximized and can be consulted directly on the iNaturalist platform., (Juan M Barrios, Brenda Y Bedolla-García, Paola A González-Vanegas, Andrés Lira-Noriega, Juan C López-Enriquez, Jorge A Mérida-Rivas, Daniel Madrigal-González, Pilar Rodríguez, Matthias Rös, Remy Vandame, Raúl Sierra-Alcocer, Carlos A. Cultid-Medina.)

Background: The global scientific literature in dentistry has shown important advances in the field, with major contributions ranging from the analysis of the basic epidemiological aspects of prevention to specialised results in the field of dental treatments. The present investigation aimed to analyse the current state of the scientific literature on dentistry hosted in the Web of Science database. Methods: The methodology included two phases in the analysis of articles and indexed reviews in all thematic areas. During the first phase, the following variables were analysed: scientific production by the publisher, the evolution of scientific output published by publishers, the factors associated with the impact of scientific production, and the modelling of the impact of scientific production on dentistry. During the second phase, associations, evolutions, and trends in the use of keywords in the scientific literature in dentistry were analysed. Results: The first phase shows that scientific production in dentistry will increase between 2010 and 2021, reaching 12,126 articles in 2021. Publishers such as Wiley and Elsevier stand out, but Quintessence Publishing has the most citations. Factors such as pages, authors, and references influence the number of citations. Phase 2 analyzes trends in the dental literature using the WoS database. Topics such as "dental education", "pediatric dentistry", and "pandemic" stand out. The intersection of technology and dentistry and the importance of evidence-based education are highlighted. Conclusions: In conclusion, the study shows that the most studied topics include the association of dental education and the curriculum, the association of pediatric dentistry with oral health, and dental care. The findings show that more recently emphasised topics also stand out, such as evidence-based dentistry, the COVID-19 pandemic, infection control, and endodontics, as well as the need for future research to expand current knowledge based on emerging topics in the scientific literature on dentistry., Competing Interests: No competing interests were disclosed., (Copyright: © 2023 Millones-Gómez PA et al.)

Introduction: The publication of articles on the circular economy has different associated factors to explain the citations registered in the Web of Science., Method: Articles from the publishers Elsevier, MDPI, Taylor & Francis, Wiley, and Springer Nature were evaluated., Results: It was expected that the older the article was, the more citations it had received, but this was not always the case. It was also recognized that there was a lower number of citations if the articles were too large or if they had too many references., Discussion: This analysis helps to establish the factors that must be addressed in order to publish in journals that have a high citation rate. Conclusion: Based on speci?c articles and with speci?c references, it will be possible to increase the probability of citations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Minchón-Medina, Timaná-Palacios, Alvarez-Risco, Del-Aguila-Arcentales and Yáñez.)

Transport coefficients like shear, bulk and longitudinal viscosities are sensitive to the intermolecular interaction potential and finite size effects when are numerically determined. For the hard-sphere (HS) fluid, such transport properties are determined almost exclusively with computer simulations. However, their systematic determination and analysis throughout shear stress correlation functions and the Green-Kubo formalism can not be done due to discontinuous nature of the interaction potential. Here, we use the pseudo hard-sphere (PHS) potential to determine pressure correlation functions as a function of volume fraction in order to compute mentioned viscosities. Simulation results are compared to available event-driven molecular dynamics of the HS fluid and also used to propose empirical corrections for the Chapman-Enskog zero density limit of shear viscosity. Moreover, we show that PHS potential is a reliable representation of the HS fluid and can be used to compute transport coefficients. The molecular simulation results of the present work are valuable for further exploration of HS-type fluids or extend the approach to compute transport properties of hard-colloid suspensions., (Creative Commons Attribution license.)

Background: Defining Andean anurans through their altitudinal limits has been a common practice in species lists, studies of responses to climate change among others, especially in the northern Andes. At least three proposals to differentiate Andean anurans from lowland anurans through elevation and at least one to differentiate Andean anurans from high mountain anurans have been formulated. However, the most frequently used altitudinal limits are not based on theoretical or numerical support, but on observations or practical definitions. Additionally, these proposals have been applied equally to different portions of the Andes, ignoring the fact that even between slopes of the same mountain, environmental conditions (and therefore the distribution of species) may differ. The objective of this work was to evaluate the concordance between the altitudinal distribution of anurans in the Colombian Andes and four different altitudinal delimitation proposals., Methods: We constructed our study area in a manner that allowed us to include species from the Andean region (as traditionally defined) and adjacent lowlands, because if the boundaries criteria were applied they would separate the species of the latter by themselves. We divided the study area into eight entities according to the watershed and the course of the most important rivers. We conducted a bibliographic search for all anurans in the cordilleras and inter-Andean valleys of Colombia and complemented the search with information on anurans for the region available in the GBIF. After curing the species distribution points, we generated elevation bands of 200 m amplitude for both the study area and for each Andean entity. Subsequently, we performed a cluster analysis to evaluate the grouping of the elevation bands according to their species composition., Results: In none of the cases (neither for the entire study area nor for any of the entities) we found a correspondence of any of the traditionally used boundaries and the altitudinal distribution of Anurans in the Andean region of Colombia. Instead, on average, the altitudinal delimitation proposals arbitrarily spanned the altitudinal distribution of about one third of the species distributed in the study area., Conclusions: We suggest that, although, based on our results, some Andean entities can be divided according to the altitudinal composition of the species that occur in them, we did not find any results that support the idea of a generalizable altitudinal limit for the Colombian Andes. Thus, to avoid biases in studies that may later be used by decision makers, the selection of anuran species in studies in the Colombian Andes should be based on biogeographic, phylogenetic or natural history criteria and not on altitudinal limits as they have been used., Competing Interests: The authors declare that they have no competing interests., (© 2023 Herrera-Lopera et al.)

As primarily sessile organisms, plants often show a non-random spatial distribution of genotypes over distance. This process known as fine-scale spatial genetic structure (FSGS) has been suggested through systematic reviews to depend on life form, mating system, and pollen and seed dispersal vectors, while there is no consensus on its behaviour due to external factors, such as anthropogenic habitat changes. By conducting a systematic review and global meta-analysis of empirical FSGS studies, we aimed to evaluate how anthropogenic habitat fragmentation and degradation influence the strength of FSGS in plant populations by means of the Sp statistic. Moreover, we tested how pollination and seed dispersal vectors contribute to the variation of the Sp statistic. We retrieved 243 FSGS studies from 1960 to 2020 of which only 65 were informative for the systematic review. Most empirical studies comprised outcrossers (84%) and trees (67%), with few herbs (23%) and scarce annual species (2%). In weighted meta-analyses for 116 plant populations (31 studies), we did not detect significant effects in the magnitude of effect sizes for the Sp statistic among undisturbed, degraded and fragmented habitats. Results showed significant effects for seed dispersal vectors, but not for pollination. Overall, we observed high variation among the effect sizes (not related to the goodness-of-fit of mixed models) of habitat status, pollination and seed dispersal categories, which precludes identifying biological trends on the Sp statistic. More empirical studies are needed that contrast multiple plant populations in disturbed versus undisturbed habitats, and by increasing the taxonomic groups, such as herbs and annual plants., Competing Interests: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Annals of Botany Company.)

Key Message: The use of multi-environment trials to test yield-related traits in a diverse alfalfa panel allowed to find multiple molecular markers associated with complex agronomic traits. Yield is one of the most important target traits in alfalfa breeding; however, yield is a complex trait affected by genetic and environmental factors. In this study, we used multi-environment trials to test yield-related traits in a diverse panel composed of 200 alfalfa accessions and varieties. Phenotypic data of maturity stage measured as mean stage by count (MSC), dry matter content, plant height (PH), biomass yield (Yi), and fall dormancy (FD) were collected in three locations in Idaho, Oregon, and Washington from 2018 to 2020. Single-trial and stagewise analyses were used to obtain estimated trait means of entries by environment. The plants were genotyped using a genotyping by sequencing approach and obtained a genotypic matrix with 97,345 single nucleotide polymorphisms. Genome-wide association studies identified a total of 84 markers associated with the traits analyzed. Of those, 29 markers were in noncoding regions and 55 markers were in coding regions. Ten significant SNPs at the same locus were associated with FD and they were linked to a gene annotated as a nuclear fusion defective 4-like (NFD4). Additional SNPs associated with MSC, PH, and Yi were annotated as transcription factors such as Cysteine3Histidine (C3H), Hap3/NF-YB family, and serine/threonine-protein phosphatase 7 proteins, respectively. Our results provide insight into the genetic factors that influence alfalfa maturity, yield, and dormancy, which is helpful to speed up the genetic gain toward alfalfa yield improvement., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Recent declines of insect populations at high rates have resulted in the need to develop a quick method to determine their diversity and to process massive data for the identification of species of highly diverse groups. A short sequence of DNA from COI is widely used for insect identification by comparing it against sequences of known species. Repositories of sequences are available online with tools that facilitate matching of the sequences of interest to a known individual. However, the performance of these tools can differ. Here we aim to assess the accuracy in identification of insect taxonomic categories from two repositories, BOLD Systems and GenBank. This was done by comparing the sequence matches between the taxonomist identification and the suggested identification from the platforms. We used 1,160 COI sequences representing eight orders of insects from Colombia. After the comparison, we reanalyzed the results from a representative subset of the data from the subfamily Scarabaeinae (Coleoptera). Overall, BOLD systems outperformed GenBank, and the performance of both engines differed by orders and other taxonomic categories (species, genus and family). Higher rates of accurate identification were obtained at family and genus levels. The accuracy was higher in BOLD for the order Coleoptera at family level, for Coleoptera and Lepidoptera at genus and species level. Other orders performed similarly in both repositories. Moreover, the Scarabaeinae subset showed that species were correctly identified only when BOLD match percentage was above 93.4% and a total of 85% of the samples were correctly assigned to a taxonomic category. These results accentuate the great potential of the identification engines to place insects accurately into their respective taxonomic categories based on DNA barcodes and highlight the reliability of BOLD Systems for insect identification in the absence of a large reference database for a highly diverse country., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Baena-Bejarano et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Heterotopic ossification is a disorder caused by abnormal mineralization of soft tissues in which signaling pathways such as BMP, TGFβ and WNT are known key players in driving ectopic bone formation. Identifying novel genes and pathways related to the mineralization process are important steps for future gene therapy in bone disorders. In this study, we detect an inter-chromosomal insertional duplication in a female proband disrupting a topologically associating domain and causing an ultra-rare progressive form of heterotopic ossification. This structural variant lead to enhancer hijacking and misexpression of ARHGAP36 in fibroblasts, validated here by orthogonal in vitro studies. In addition, ARHGAP36 overexpression inhibits TGFβ, and activates hedgehog signaling and genes/proteins related to extracellular matrix production. Our work on the genetic cause of this heterotopic ossification case has revealed that ARHGAP36 plays a role in bone formation and metabolism, outlining first details of this gene contributing to bone-formation and -disease., (© 2023. The Author(s).)

Split-Hand/Foot Malformation type 3 (SHFM3) is a congenital limb malformation associated with tandem duplications at the LBX1/FGF8 locus. Yet, the disease patho-mechanism remains unsolved. Here we investigate the functional consequences of SHFM3-associated rearrangements on chromatin conformation and gene expression in vivo in transgenic mice. We show that the Lbx1/Fgf8 locus consists of two separate, but interacting, regulatory domains. Re-engineering of a SHFM3-associated duplication and a newly reported inversion in mice results in restructuring of the chromatin architecture. This leads to ectopic activation of the Lbx1 and Btrc genes in the apical ectodermal ridge (AER) in an Fgf8-like pattern induced by AER-specific enhancers of Fgf8. We provide evidence that the SHFM3 phenotype is the result of a combinatorial effect on gene misexpression in the developing limb. Our results reveal insights into the molecular mechanism underlying SHFM3 and provide conceptual framework for how genomic rearrangements can cause gene misexpression and disease., (© 2023. The Author(s).)

Purpose: We aimed to identify the underlying genetic cause for a novel form of distal arthrogryposis., Methods: Rare variant family-based genomics, exome sequencing, and disease-specific panel sequencing were used to detect ADAMTS15 variants in affected individuals. Adamts15 expression was analyzed at the single-cell level during murine embryogenesis. Expression patterns were characterized using in situ hybridization and RNAscope., Results: We identified homozygous rare variant alleles of ADAMTS15 in 5 affected individuals from 4 unrelated consanguineous families presenting with congenital flexion contractures of the interphalangeal joints and hypoplastic or absent palmar creases. Radiographic investigations showed physiological interphalangeal joint morphology. Additional features included knee, Achilles tendon, and toe contractures, spinal stiffness, scoliosis, and orthodontic abnormalities. Analysis of mouse whole-embryo single-cell sequencing data revealed a tightly regulated Adamts15 expression in the limb mesenchyme between embryonic stages E11.5 and E15.0. A perimuscular and peritendinous expression was evident in in situ hybridization in the developing mouse limb. In accordance, RNAscope analysis detected a significant coexpression with Osr1, but not with markers for skeletal muscle or joint formation., Conclusion: In aggregate, our findings provide evidence that rare biallelic recessive trait variants in ADAMTS15 cause a novel autosomal recessive connective tissue disorder, resulting in a distal arthrogryposis syndrome., Competing Interests: Conflict of Interest J.R.L. has stock ownership in 23andMe, is a paid consultant for Regeneron Genetics Center (RGC), and is a coinventor on multiple United States and European patents related to molecular diagnostics for inherited neuropathies, eye diseases, genomic disorders, and bacterial genomic fingerprinting. The Department of Molecular and Human Genetics at Baylor College of Medicine receives revenue from clinical genetic and genomic testing conducted at Baylor Genetics; J.R.L. serves on the Scientific Advisory Board of Baylor Genetics. U.K. has been a consultant for Alexion Pharmaceuticals, Inc. All other authors declare no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Regulatory landscapes drive complex developmental gene expression, but it remains unclear how their integrity is maintained when incorporating novel genes and functions during evolution. Here, we investigated how a placental mammal-specific gene, Zfp42, emerged in an ancient vertebrate topologically associated domain (TAD) without adopting or disrupting the conserved expression of its gene, Fat1. In ESCs, physical TAD partitioning separates Zfp42 and Fat1 with distinct local enhancers that drive their independent expression. This separation is driven by chromatin activity and not CTCF/cohesin. In contrast, in embryonic limbs, inactive Zfp42 shares Fat1's intact TAD without responding to active Fat1 enhancers. However, neither Fat1 enhancer-incompatibility nor nuclear envelope-attachment account for Zfp42's unresponsiveness. Rather, Zfp42's promoter is rendered inert to enhancers by context-dependent DNA methylation. Thus, diverse mechanisms enabled the integration of independent Zfp42 regulation in the Fat1 locus. Critically, such regulatory complexity appears common in evolution as, genome wide, most TADs contain multiple independently expressed genes., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Mutations in the E3 ubiquitin ligase parkin cause autosomal recessive Parkinson's disease (PD). Together with PTEN-induced kinase 1 (PINK1), parkin regulates the clearance of dysfunctional mitochondria. New mitochondria are generated through an interplay of nuclear- and mitochondrial-encoded proteins, and recent studies suggest that parkin influences this process at both levels. In addition, parkin was shown to prevent mitochondrial membrane permeability, impeding mitochondrial DNA (mtDNA) escape and subsequent neuroinflammation. However, parkin's regulatory roles independent of mitophagy are not well described in patient-derived neurons., Objectives: We sought to investigate parkin's role in preventing neuronal mtDNA dyshomeostasis, release, and glial activation at the endogenous level., Methods: We generated induced pluripotent stem cell (iPSC)-derived midbrain neurons from PD patients with parkin (PRKN) mutations and healthy controls. Live-cell imaging, proteomic, mtDNA integrity, and gene expression analyses were employed to investigate mitochondrial biogenesis and genome maintenance. To assess neuroinflammation, we performed single-nuclei RNA sequencing in postmortem tissue and quantified interleukin expression in mtDNA/lipopolysaccharides (LPS)-treated iPSC-derived neuron-microglia co-cultures., Results: Neurons from patients with PRKN mutations revealed deficits in the mitochondrial biogenesis pathway, resulting in mtDNA dyshomeostasis. Moreover, the energy sensor sirtuin 1, which controls mitochondrial biogenesis and clearance, was downregulated in parkin-deficient cells. Linking mtDNA disintegration to neuroinflammation, in postmortem midbrain with PRKN mutations, we confirmed mtDNA dyshomeostasis and detected an upregulation of microglia overexpressing proinflammatory cytokines. Finally, parkin-deficient neuron-microglia co-cultures elicited an enhanced immune response when exposed to mtDNA/LPS., Conclusions: Our findings suggest that parkin coregulates mitophagy, mitochondrial biogenesis, and mtDNA maintenance pathways, thereby protecting midbrain neurons from neuroinflammation and degeneration. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Deterioration in the quality of a person's voice and speech is an early marker of Parkinson's disease (PD). In humans, the neural circuit that supports vocal motor control consists of a cortico-basal ganglia-thalamo-cortico loop. The basal ganglia regions, striatum and globus pallidus, in this loop play a role in modulating the acoustic features of vocal behavior such as loudness, pitch, and articulatory rate. In PD, this area is implicated in pathogenesis. In animal models of PD, the accumulation of toxic aggregates containing the neuronal protein alpha-synuclein (αsyn) in the midbrain and striatum result in limb and vocal motor impairments. It has been challenging to study vocal impairments given the lack of well-defined cortico-basal ganglia circuitry for vocalization in rodent models. Furthermore, whether deterioration of voice quality early in PD is a direct result of αsyn-induced neuropathology is not yet known. Here, we take advantage of the well-characterized vocal circuits of the adult male zebra finch songbird to experimentally target a song-dedicated pathway, the anterior forebrain pathway, using an adeno-associated virus expressing the human wild-type αsyn gene, SNCA. We found that overexpression of αsyn in this pathway coincides with higher levels of insoluble, monomeric αsyn compared to control finches. Impairments in song production were also detected along with shorter and poorer quality syllables, which are the most basic unit of song. These vocal changes are similar to the vocal abnormalities observed in individuals with PD., Competing Interests: The authors have declared no competing interests exist.

Idiopathic Parkinson's disease is characterized by a progressive loss of dopaminergic neurons, but the exact disease aetiology remains largely unknown. To date, Parkinson's disease research has mainly focused on nigral dopaminergic neurons, although recent studies suggest disease-related changes also in non-neuronal cells and in midbrain regions beyond the substantia nigra. While there is some evidence for glial involvement in Parkinson's disease, the molecular mechanisms remain poorly understood. The aim of this study was to characterize the contribution of all cell types of the midbrain to Parkinson's disease pathology by single-nuclei RNA sequencing and to assess the cell type-specific risk for Parkinson's disease using the latest genome-wide association study. We profiled >41 000 single-nuclei transcriptomes of post-mortem midbrain from six idiopathic Parkinson's disease patients and five age-/sex-matched controls. To validate our findings in a spatial context, we utilized immunolabelling of the same tissues. Moreover, we analysed Parkinson's disease-associated risk enrichment in genes with cell type-specific expression patterns. We discovered a neuronal cell cluster characterized by CADPS2 overexpression and low TH levels, which was exclusively present in idiopathic Parkinson's disease midbrains. Validation analyses in laser-microdissected neurons suggest that this cluster represents dysfunctional dopaminergic neurons. With regard to glial cells, we observed an increase in nigral microglia in Parkinson's disease patients. Moreover, nigral idiopathic Parkinson's disease microglia were more amoeboid, indicating an activated state. We also discovered a reduction in idiopathic Parkinson's disease oligodendrocyte numbers with the remaining cells being characterized by a stress-induced upregulation of S100B. Parkinson's disease risk variants were associated with glia- and neuron-specific gene expression patterns in idiopathic Parkinson's disease cases. Furthermore, astrocytes and microglia presented idiopathic Parkinson's disease-specific cell proliferation and dysregulation of genes related to unfolded protein response and cytokine signalling. While reactive patient astrocytes showed CD44 overexpression, idiopathic Parkinson's disease microglia revealed a pro-inflammatory trajectory characterized by elevated levels of IL1B, GPNMB and HSP90AA1. Taken together, we generated the first single-nuclei RNA sequencing dataset from the idiopathic Parkinson's disease midbrain, which highlights a disease-specific neuronal cell cluster as well as 'pan-glial' activation as a central mechanism in the pathology of the movement disorder. This finding warrants further research into inflammatory signalling and immunomodulatory treatments in Parkinson's disease., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

It is indisputable that every day it is demonstrated that natural products present diverse therapeutic benefits, which has boosted their incorporation within various products for clinical use. However, this must be accompanied by knowledge of their effect on cell lines to ensure their use is safe. The objective of this study was to evaluate the cytotoxic effect of two ethanolic extracts based on Peruvian natural products, on three human cell lines. Cervical cancer cell lines (HeLa), human gingival fibroblasts (HGF-1 - ATCC CRL-2014) (HGF-1) and peripheral blood mononuclear cells (PBMCs) were cultured and subsequently treated with preparations of ethanolic extracts of propolis (EEP) and Psidium guajava (EEG) from a concentration of 50 mg/mL to 0.024 mg/mL, by the 3-(4,5- dimethylthiazol-2-yl)-2,5-diphenyltetrazole bromide reduction assay. At a concentration of 0.24 mg/mL EEG, viability of 99.7±1.24%, 99.8±2.2% and 99.7±2.7% was observed in HeLa, HGF-1 and PBMCs, respectively; >90% cell viability values were observed with EPP at 0.024 mg/mL, with HGF-1 showing the highest viability (96.9±1.15%). A dose-dependent effect was observed for both extracts with a decrease in cell viability as concentrations increased (up to 50 mg/mL). EEP and EEG extracts at low concentrations do not show cytotoxicity in human cell lines, these findings are an advance in the preclinical evaluation on their safety and open a continuity to further studies for their potential applications in dentistry and medicine., Competing Interests: No competing interests were disclosed., (Copyright: © 2022 Millones-Gómez PA et al.)

Objective: To correlate genital hiatus (GH) size with surgical failures in patients undergoing sacrospinous ligament fixation (SSLF) and compare anatomic outcomes after classification based on GH size., Methods: A retrospective review of 81 patients who underwent SSLF for apical prolapse from 2010 to 2016 at a teaching hospital. Anatomical outcome is reported using the Pelvic Organ Prolapse Quantifications System. A comparison of parametric continuous variables was performed using unpaired Student t test. Categorical variables were evaluated using Pearson's χ 2 test and Fisher's exact test. A P value <0.05 was considered significant., Results: Among the 81 patients, no difference in age, parity, body mass index, preoperative prolapse stage or follow-up time was noted between those whose surgery succeeded and those with failed surgery. Postoperatively, a widened GH was significantly associated with recurrent prolapse (P < 0.001). When the preoperative size of the GH was dichotomized into widened (≥4 cm) or normal (<4 cm), there was a non-significant (P = 0.444) trend of more failures in the widened GH group. A posterior colporrhaphy did not improve success., Conclusion: Both preoperative and postoperative widened GH correlated with having more surgical failures following SSLF. Importantly, postoperatively a normal size GH was significantly associated with more surgical success., (© 2021 International Federation of Gynecology and Obstetrics.)