Genetic diversity and historical demography of underutilised goat breeds in North-Western Europe.

In the last decade, several studies aimed at dissecting the genetic architecture of local small ruminant breeds to discover which variations are involved in the process of adaptation to environmental conditions, a topic that has acquired priority due to climate change. Considering that traditional breeds are a reservoir of such important genetic variation, improving the current knowledge about their genetic diversity and origin is the first step forward in designing sound conservation guidelines. The genetic composition of North-Western European archetypical goat breeds is still poorly exploited. In this study we aimed to fill this gap investigating goat breeds across Ireland and Scandinavia, including also some other potential continental sources of introgression. The PCA and Admixture analyses suggest a well-defined cluster that includes Norwegian and Swedish breeds, while the crossbred Danish landrace is far apart, and there appears to be a close relationship between the Irish and Saanen goats. In addition, both graph representation of historical relationships among populations and f4-ratio statistics suggest a certain degree of gene flow between the Norse and Atlantic landraces. Furthermore, we identify signs of ancient admixture events of Scandinavian origin in the Irish and in the Icelandic goats. The time when these migrations, and consequently the introgression, of Scandinavian-like alleles occurred, can be traced back to the Viking colonisation of these two isles during the Viking Age (793-1066 CE). The demographic analysis indicates a complicated history of these traditional breeds with signatures of bottleneck, inbreeding and crossbreeding with the improved breeds. Despite these recent demographic changes and the historical genetic background shaped by centuries of human-mediated gene flow, most of them maintained their genetic identity, becoming an irreplaceable genetic resource as well as a cultural heritage.

Data on the cytotoxicity of chlorogenic acid in 3D cultures of HT-29 cells.

Functional foods, beyond basic nutrition, offer health benefits to consumers thanks to the presence of bioactive compounds such as some phytochemicals [1,2]. Today, these foods are of particular interest in biomedical research due to their chemopreventive potential, as they have been shown to induce various biological effects on tumor cells, including the ability to inhibit cell proliferation, induce apoptosis, arrest cell cycle progression, and increase reactive oxygen species [3,4]. Multiple studies have confirmed the relationship between diet and the onset and progression of colorectal cancer (CRC), a malignant neoplasm that arises in the lining of the colon and/or rectum. Therefore, finding foods that can intervene in the carcinogenesis process is an important avenue of research [5,6]. Chlorogenic acid (CGA) is one of the most abundant phenolic compounds in coffee and is also found in fruits and vegetables. Scientific evidence suggests that CGA has chemopreventive potential on CRC cells [7], [8], [9]. For example, in previous studies conducted by our research group, green and roasted coffee extracts were characterized, and this compound was identified as the most abundant [7]. In addition, it was found to significantly decrease cell viability, reduce migration capacity, cause DNA fragmentation, and induce the production of reactive oxygen species in colorectal adenocarcinoma cells cultured in monolayer and treated with different doses of CGA. Furthermore, the mechanism underlying this biological activity has been related to CGA's ability to modulate the Wnt- /ß-catenin pathway, which is implicated in the development and progression of CRC [7,10,11]. This paper presents data on the cytotoxic response of CGA treatments on HT-29 cells cultured in a 3D model. To this end, morphological changes in cell spheroids, propidium iodide and DiOC6 uptake, quantification of reactive oxygen species (ROS) production, phosphatidylserine exposure, and cell cycle progression were evaluated by flow cytometry.

In Vitro and In Silico Study on the Impact of Chlorogenic Acid in Colorectal Cancer Cells: Proliferation, Apoptosis, and Interaction with ß-Catenin and LRP6.

Colorectal cancer mortality rate and highly altered proteins from the Wnt/ß-catenin pathway increase the scientific community's interest in finding alternatives for prevention and treatment. This study aims to determine the biological effect of chlorogenic acid (CGA) on two colorectal cancer cell lines, HT-29 and SW480, and its interactions with ß-catenin and LRP6 to elucidate a possible modulatory mechanism on the Wnt/ß-catenin pathway. These effects were determined by propidium iodide and DiOC6 for mitochondrial membrane permeability, MitoTracker Red for mitochondrial ROS production, DNA content for cell distribution on cell cycle phases, and molecular docking for protein-ligand interactions and binding affinity. Here, it was found that CGA at 2000 µM significantly affects cell viability and causes DNA fragmentation in SW480 cells rather than in HT-29 cells, but in both cell lines, it induces ROS production. Additionally, CGA has similar affinity and interactions for LRP6 as niclosamide but has a higher affinity for both ß-catenin sites than C2 and iCRT14. These results suggest a possible modulatory role of CGA over the Wnt/ß-catenin pathway in colorectal cancer.

Discovering novel clues of natural selection on four worldwide goat breeds.

In goat breeds, the domestication followed by artificial selection for economically important traits have shaped genetic variation within populations, leading to the fixation of specific alleles for specific traits. This led to the formation and evolution of many different breeds specialised and raised for a particular purpose. However, and despite the intensity of artificial selection, natural selection continues acting, possibly leaving a more diluted contribution over time, whose traces may be more difficult to capture. In order to explore selection footprints as response of environmental adaptation, we analysed a total of 993 goats from four transboundary goats breeds (Angora, Boer, Nubian and Saanen) genotyped with the SNP chip 50 K using outlier detection, runs of homozygosity and haplotype-based detection methods. Our results showed that all methods identified footprints on chromosome 6 (from 30 to 49 Mb) for two specific populations of Nubian goats sampled in Egypt. In Angora and Saanen breeds, we detected two selective sweeps using HapFLK, on chromosome 21 (from 52 to 55 Mb) and chromosome 25 (from 1 to 5 Mb) respectively. The analysis of runs of homozygosity showed some hotspots in all breeds. The overall investigation of the selected regions detected combining the different approaches and the gene ontology exploration revealed both novel and well-known loci related to adaptation, especially for heat stress. Our findings can help to better understand the balance between the two selective pressures in commercial goat breeds providing new insights on the molecular mechanisms of adaptation.

Heat stress on breeding value prediction for milk yield and composition of a Brazilian Holstein cattle population.

Due to the high milk production of Holstein cows, many countries have chosen to import semen to improve local dairy herds. This strategy would be more effective if this semen was used in the same environment conditions in which the bulls were selected. If the effect of genotype by environment (G × E) interaction is not considered, the estimated breeding values (EBVs) may vary, potentially reducing the selection response. We evaluate the impact of heat stress on selection for milk yield and composition of Holstein cows using random regression models. To verify the interference of heat stress in milk yield (MY) and composition traits (fat, protein, total saturated, and total unsaturated fatty acids content in milk), temperature-humidity index (THI) on test-day milk records was used. The threshold value to divide the environments using test-day information from Brazilian Holstein cows was 72 units of THI, i.e., < 72 represented no heat stress and > 72 represented heat stress. Legendre polynomials of second-order (Leg 2) model and two lactation points (33 and 122 DIM) were used to estimate heritabilities and EBVs for five important dairy traits. The heritabilities of milk components and fatty acids were low (0.09-0.29), regardless of lactation period and degree of heat stress, with the exception of protein content (0.30-0.35). Fat content was the only milk component that was reduced according to the degree of heat stress and lactation period. The EBVs tended to decrease in heat stress conditions, thus animals with high genetic potential demonstrated evidence of G × E interaction. However, acclimatization of dairy cows to heat stress in the farm production systems may have been responsible for the low differences among genetic parameters and EBVs with and without heat stress found in this study.

Modulatory Effect of Chlorogenic Acid and Coffee Extracts on Wnt/ß-Catenin Pathway in Colorectal Cancer Cells.

The Wnt/ß-Catenin pathway alterations present in colorectal cancer (CRC) are of special interest in the development of new therapeutic strategies to impact carcinogenesis and the progression of CRC. In this context, different polyphenols present in natural products have been reported to have modulatory effects against the Wnt pathway in CRC. In this study, we evaluate the effect of two polyphenol-rich coffee extracts and chlorogenic acid (CGA) against SW480 and HT-29 CRC cells. This involved the use of MTT and SRB techniques for cell viability; wound healing and invasion assay for the evaluation of the migration and invasion process; T cell factor (TCF) reporter plasmid for the evaluation of transciption factor (TCF) transcriptional activity; polymerase chain reaction (PCR) of target genes and confocal fluorescence microscopy for ß-Catenin and E-Cadherin protein fluorescence levels; and subcellular localization. Our results showed a potential modulatory effect of the Wnt pathway on CRC cells, and we observed a reduction in the transcriptional activity of ß-catenin. All the results were prominent in SW480 cells, where the Wnt pathway deregulation has more relevance and implies a constitutive activation of the signaling pathway. These results establish a starting point for the discovery of a mechanism of action associated with these effects and corroborate the anticancer potential of polyphenols present in coffee, which could be explored as chemopreventive molecules or as adjunctive therapy in CRC.

Fibroblast growth factor homologous factors serve as a molecular rheostat in tuning arrhythmogenic cardiac late sodium current.

Voltage-gated sodium (Nav1.5) channels support the genesis and brisk spatial propagation of action potentials in the heart. Disruption of NaV1.5 inactivation results in a small persistent Na influx known as late Na current (I Na,L), which has emerged as a common pathogenic mechanism in both congenital and acquired cardiac arrhythmogenic syndromes. Here, using low-noise multi-channel recordings in heterologous systems, LQTS3 patient-derived iPSCs cardiomyocytes, and mouse ventricular myocytes, we demonstrate that the intracellular fibroblast growth factor homologous factors (FHF1-4) tune pathogenic I Na,L in an isoform-specific manner. This scheme suggests a complex orchestration of I Na,L in cardiomyocytes that may contribute to variable disease expressivity of NaV1.5 channelopathies. We further leverage these observations to engineer a peptide-inhibitor of I Na,L with a higher efficacy as compared to a well-established small-molecule inhibitor. Overall, these findings lend insights into molecular mechanisms underlying FHF regulation of I Na,L in pathophysiology and outline potential therapeutic avenues.

Synergistic effects of natural compounds and conventional chemotherapeutic agents: recent insights for the development of cancer treatment strategies.

Cancer is one of the leading causes of death in the world. Chemotherapy is presented as an option for treatment of this disease, however, low specificity, high resistance rates, toxicity and hypersensitivity reactions, make it necessary to search for therapeutic alternatives that increase the selectivity of treatment, reduce the side effects and enhance its antitumor potential. Natural products are accessible, inexpensive and less toxic sources; in addition, they have multiple mechanisms of action that can potentiate the outcome of chemotherapeutics. In this review, we present evidence on the beneficial effect of the interaction of dietary phytochemicals with chemotherapeutical agents for cancer treatment. This effect is generated by different mechanisms of action such as, increased tumoricidal effect via sensitization of cancer cells, reversing chemoresistance through inhibition of several targets involved in the development of drug resistance and, decreasing chemotherapy-induced toxicity in non-tumoral cells by the promotion of repair mechanisms. Studies discussed in this review will provide a solid basis for the exploration of the potential use of natural products in combination with chemotherapeutical agents, to overcome some of the difficulties that arise in the management of cancer patients.

Modulation of Oxidative Stress-Induced Senescence during Non-Alcoholic Fatty Liver Disease.

Non-alcoholic fatty liver disease is characterized by disturbed lipid metabolism and increased oxidative stress. These conditions lead to the activation of different cellular response mechanisms, including senescence. Cellular senescence constitutes an important response to injury in the liver. Recent findings show that chronic oxidative stress can induce senescence, and this might be a driving mechanism for NAFLD progression, aggravating the disturbance of lipid metabolism, organelle dysfunction, pro-inflammatory response and hepatocellular damage. In this context, the modulation of cellular senescence can be beneficial to ameliorate oxidative stress-related damage during NAFLD progression. This review focuses on the role of oxidative stress and senescence in the mechanisms leading to NAFLD and discusses the possibilities to modulate senescence as a therapeutic strategy in the treatment of NAFLD.

Modulation of the Canonical Wnt Signaling Pathway by Dietary Polyphenols, an Opportunity for Colorectal Cancer Chemoprevention and Treatment.

In the last few decades there has been a rise in the worldwide incidence of colorectal cancer which can be traced back to the influence of well-known modifiable risk factors such as lifestyle, diet and obesity. Conversely, the consumption of fruits, vegetables and fiber decreases the risk of CRC, which is why dietary polyphenols have aroused interest in recent years as potentially anti-carcinogenic compounds. One of the driving forces of colorectal carcinogenesis, in both sporadic and hereditary CRC, is the aberrant activation/regulation of the Wnt/ß-catenin pathway. This review discusses reports of modulation of the Wnt/ß-Catenin signaling pathway by dietary polyphenols (resveratrol, avenanthramides, epigallocatechinin, curcumin, quercetin, silibinin, genistein and mangiferin) specifically focusing on CRC, and proposes a model as to how this modulation occurs. There is potential for implementing these dietary polyphenols into preventative and therapeutic therapies for CRC as evidenced by some clinical trials that have been carried out with promising results.

Estudio Descriptivo: Colposcopia en el diagnóstico de lesiones de cuello uterino en el Hospital de Especialidades José Carrasco Arteaga, Cuenca ­ Ecuador. 2015-2019 / Descriptive Study: Colposcopy as a diagnostic method for cervix lesions in Hospital de Especialidades Jose Carrasco Arteaga, Cuenca-Ecuador. 2015-2019

INTRODUCCIÓN: El cáncer de cuello uterino es un problema de salud pública, siendo una de las principales causas de morbilidad y mortalidad en países en vía de desarrollo. Para el screening y diagnóstico de las lesiones del cuello uterino se realiza citología cervical (Papanicolaou). Ante un reporte de citología sospechosa, la colposcopia es un procedimiento imprescindible en la evaluación del tracto genital inferior para detectar lesiones tempranas y cáncer. El objetivo de la presente investigación fue caracterizar los procedimientos colposcópicos realizados, como método diagnóstico y terapéutico, en las pacientes con resultados anormales del Papanicolaou. MATERIALES Y MÉTODOS: El presente es un estudio observacional, descriptivo de corte transversal, cuyo universo lo conformaron todas las pacientes con diagnóstico citológico anormal en Papanicolaou, que se realizaron un procedimiento colposcópico entre el año 2015 hasta el año 2019 en el Hospital José Carrasco Arteaga, con un total de 1 628 pacientes. RESULTADOS: Se incluyen 1 628 procedimientos colposcópicos. El 55.46% de la población estuvieron entre los 27 a 46 años de edad. El estado civil predominante fue casada (75%). El 63.45% de las mujeres iniciaron vida sexual entre los 21 a 30 años. El 95.20% de las pacientes tuvieron entre 1 y 3 parejas sexuales. Los resultados de Papanicolaou anormales representan; el 37.28% a LIE-BG, seguido de 35.81% con ASC-US y 14.18% como LIE-AG. El 67.32% de colposcopías fueron satisfactorias. Se realizó biopsia en el 71% de las pacientes, seguido de la toma de muestra de cono con ASA-LEEP (13.69%), legrado endocervical en el 11.05%. Los resultados de anatomía patológica reportaron LIE-AG en 46.56% de los casos, seguido de 22.23 % como LIE-BG y cervicitis crónica en el 16.27%, 12.28% de los resultados fueron negativos. CONCLUSIÓN: Tres cuartas partes de las colposcopias se realizaron en mujeres entre los 27 y 56 años de edad. Los resultados anormales más frecuentemente encontrados en el Papanicolaou fueron: LIE-BG, seguido de ASC-US. 67% de las colposcopias realizadas fueron satisfactorias. Tras la colposcopia, en la mayoría de pacientes se realizó biopsia, en un menor porcentaje y en orden de frecuencia: conización electro quirúrgica con asa (ASA-LEEP), legrado endocervical e histerectomía diagnóstica. Los resultados de anatomía patológica reportaron LIE-AG en el 46.56%, LIE-BG en el 22.23 % como y cervicitis crónica en el 16.27%; 12.28% de estudios fueron negativos.(au)

BACKGROUND: Cervical cancer is a public health issue, being one of the main causes of morbidity and mortality in developing countries. Cervical cytology (Papanicolaou) is performed for screening and diagnosis of cervical lesions. In case of a suspicious cytology report, colposcopy is an essential procedure for evaluation of the lower genital tract, to detect early lesions and cancer. The aim of this study was to characterize the colposcopy procedures performed, as a diagnostic and therapeutic method, in patients with abnormal Papanicolaou results. METHODS: This is an observational, descriptive cross-sectional study, whose universe were all the patients with abnormal cytological diagnosis in pap smear, who underwent a colposcopy procedure between 2015 and 2019 at Hospital José Carrasco Arteaga, with a total of 1 628 patients. RESULTS: 1 628 colposcopic procedures were included. 55.46% of the population were between 27 to 46 years of age. The predominant marital status was married status (75%). 63.45% of women had their first sexual experience between 21 and 30 years of age. 95.20% of the patients had between 1 and 3 sexual partners. Abnormal pap smear results represent; 37.28% to LSIL, followed by ASC-US (35.81%), and HSIL (14.18%). 67.32% of colposcopies were classified as satisfactory. Biopsy was performed in 71% of the patients, followed by loop electrosurgical excision procedure (LEEP) (13.69%), endocervical curettage in 11.05%. The pathology results reported HSIL in 46.56% of the cases, followed by 22.23% as LSIL and chronic cervicitis in 16.27%, 12.28% of the results were negative. CONCLUSION: Three-quarters of all colposcopies were performed on women between 27 and 56 years of age. The most frequently abnormal Pap smear results were: LSIL, followed ASC-US. 67% of the colposcopies were satisfactory. After colposcopy, biopsy was performed in most of the patients, in lower percentage: loop electrosurgical excision procedure (LEEP), endocervical curettage and diagnostic hysterectomy. Pathology results reported HSIL in 46.56%, LSIL IN 22.23% and chronic cervicitis in 16.27%; 12.28% of studies were negative.(au)

High SARS-CoV-2 Seroprevalence in Rural Peru, 2021: a Cross-Sectional Population-Based Study.

Latin America has been severely affected by the COVID-19 pandemic. The COVID-19 burden in rural settings in Latin America is unclear. We performed a cross-sectional, population-based, random-selection SARS-CoV-2 serologic study during March 2021 in the rural population of San Martin region, northern Peru. In total, 563 persons from 288 houses across 10 provinces were enrolled, reaching 0.2% of the total rural population of San Martin. Screening for SARS-CoV-2 IgG antibodies was done using a chemiluminescence immunoassay (CLIA), and reactive sera were confirmed using a SARS-CoV-2 surrogate virus neutralization test (sVNT). Validation of the testing algorithm using prepandemic sera from two regions of Peru showed false-positive results in the CLIA (23/84 sera; 27%) but not in the sVNT, highlighting the pitfalls of SARS-CoV-2 antibody testing in tropical regions and the high specificity of the two-step algorithm used in this study. An overall 59.0% seroprevalence (95% confidence interval [CI], 55 to 63%) corroborated intense SARS-CoV-2 spread in San Martin. Seroprevalence rates between the 10 provinces varied from 41.3 to 74.0% (95% CI, 30 to 84%). Higher seroprevalence was not associated with population size, population density, surface area, mean altitude, or poverty index in Spearman correlations. Seroprevalence and reported incidence diverged substantially between provinces, suggesting regional biases of COVID-19 surveillance data. Potentially, limited health care access due to environmental, economic, and cultural factors might lead to undetected infections in rural populations. Additionally, test avoidance to evade mandatory quarantine might affect rural regions more than urban regions. Serologic diagnostics should be pursued in resource-limited settings to inform country-level surveillance and vaccination strategies and to support control measures for COVID-19. IMPORTANCE Latin America is a global hot spot of the COVID-19 pandemic. Serologic studies in Latin America have been mostly performed in urban settings. Rural populations comprise 20% of the total Latin American population. Nevertheless, information on COVID-19 spread in rural settings is scarce. Using a representative population-based seroprevalence study, we detected a high seroprevalence in rural populations in San Martin, northern Peru, in 2021, reaching 41 to 74%. However, seroprevalence and reported incidence diverged substantially between regions, potentially due to limited health care access or test avoidance due to mandatory quarantine. Our results suggest that rural populations are highly affected by SARS-CoV-2 even though they are sociodemographically distinct from urban populations and that highly specific serological diagnostics should be performed in resource-limited settings to support public health strategies of COVID-19 control.

Biological Impact of Phenolic Compounds from Coffee on Colorectal Cancer.

Colorectal cancer is one of the leading death-related diseases worldwide, usually induced by a multifactorial and complex process, including genetic and epigenetic abnormalities and the impact of diet and lifestyle. In the present study, we evaluated the biological impact of two of the main coffee polyphenols, chlorogenic acid (CGA) and caffeic acid (CA), as well as two polyphenol-rich coffee extracts (green coffee extract and toasted coffee Extract) against SW480 and SW620 colorectal cancer cells. First, the total phenolic content and the antioxidant capability of the extracts were determined. Then, cytotoxicity was evaluated by MTT and SBR. Finally, a wound healing assay was performed to determine the impact on the cell migration process. The results showed a cytotoxic effect of all treatments in a time and dose-dependent manner, which decreased the viability in both cell lines at 24 h and 48 h; likewise, the migration capability of cells decreased with low doses of treatments. These results suggest the potential of coffee to modulate biological mechanisms involved in colorectal cancer development; however, more studies are required to understand the mechanistic insights of these observations.

Elementary mechanisms of calmodulin regulation of NaV1.5 producing divergent arrhythmogenic phenotypes.

In cardiomyocytes, NaV1.5 channels mediate initiation and fast propagation of action potentials. The Ca2+-binding protein calmodulin (CaM) serves as a de facto subunit of NaV1.5. Genetic studies and atomic structures suggest that this interaction is pathophysiologically critical, as human mutations within the NaV1.5 carboxy-terminus that disrupt CaM binding are linked to distinct forms of life-threatening arrhythmias, including long QT syndrome 3, a "gain-of-function" defect, and Brugada syndrome, a "loss-of-function" phenotype. Yet, how a common disruption in CaM binding engenders divergent effects on NaV1.5 gating is not fully understood, though vital for elucidating arrhythmogenic mechanisms and for developing new therapies. Here, using extensive single-channel analysis, we find that the disruption of Ca2+-free CaM preassociation with NaV1.5 exerts two disparate effects: 1) a decrease in the peak open probability and 2) an increase in persistent NaV openings. Mechanistically, these effects arise from a CaM-dependent switch in the NaV inactivation mechanism. Specifically, CaM-bound channels preferentially inactivate from the open state, while those devoid of CaM exhibit enhanced closed-state inactivation. Further enriching this scheme, for certain mutant NaV1.5, local Ca2+ fluctuations elicit a rapid recruitment of CaM that reverses the increase in persistent Na current, a factor that may promote beat-to-beat variability in late Na current. In all, these findings identify the elementary mechanism of CaM regulation of NaV1.5 and, in so doing, unravel a noncanonical role for CaM in tuning ion channel gating. Furthermore, our results furnish an in-depth molecular framework for understanding complex arrhythmogenic phenotypes of NaV1.5 channelopathies.