TTN novel splice variant in familial dilated cardiomyopathy and splice variants review: a case report.

This case report details the identification of a novel likely pathogenic splicing variant in the TTN gene, associated with dilated cardiomyopathy (DCM), in a 42-year-old male patient presenting with early-onset heart failure and reduced ejection fraction. DCM is a nonischemic heart condition characterized by left biventricular dilation and systolic dysfunction, with approximately one-third of cases being familial and often linked to genetic mutations. The TTN gene, encoding the largest human protein essential for muscle contraction and sarcomere structure, is implicated in about 25% of DCM cases through mutations, especially truncating variants. Our investigation revealed a previously unreported G > C mutation at the splice acceptor site in intron 356 of TTN, confirmed by Sanger sequencing and not found in population databases, suggesting a novel contribution to the understanding of DCM etiology. The case emphasizes the critical role of the TTN gene in cardiac function and the genetic complexity underlying DCM. A comprehensive literature review highlighted the prevalence and significance of splice variants in the TTN gene, particularly those affecting the titin A-band, which is known for its role in muscle contraction and stability. This variant's identification underscores the importance of genetic screening in patients with DCM, offering insights into the disease's familial transmission and potential therapeutic targets. Our findings contribute to the expanding knowledge of genetic factors in DCM, demonstrating the necessity of integrating genetic diagnostics in cardiovascular medicine. This case supports the growing evidence linking splicing mutations in specific regions of the TTN gene to DCM development and underscores the importance of genetic counseling and testing in managing heart disease.

AARS and CACNA1A mutations: diagnostic insights into a case report of uncommon epileptic encephalopathy phenotypes in two siblings.

Epilepsy, characterized by recurrent seizures, impacts 70-80% of patients, leading to cognitive deficits. The intricate relationship between seizure control and cognitive impairment remains complex. Epileptic encephalopathy (EE), an intensified form often rooted in genetic factors, is detectable through next-generation sequencing, aiding in precise diagnoses, family counseling, and potential treatment strategies. We present a case involving two sisters with refractory generalized seizures evolving into dysarthria, dysphagia, ataxia, and cognitive decline. Despite normal physical exams, abnormal electroencephalogram results consistent with epilepsy were noted. Whole Exome Sequencing identified heterozygous variants in the alanyl-tRNA synthetase (AARS) and Calcium Voltage-Gated Channel Subunit Alpha 1 (CACNA1A) genes. The AARS variant (c.C2083T, p.R695*) was maternal, while the CACNA1A variant (c.G7400C, p.R2467P) was paternal. Patients A and B exhibited a unique blend of neurological and psychiatric conditions, distinct from common disorders that begin adolescence, like Juvenile Myoclonic Epilepsy. Whole Exome Sequencing uncovered an AARS gene and CACNA1A gene, linked to various autosomal dominant phenotypes. Presence in both parents, coupled with familial reports of migraines and seizures, provides insight into accelerated symptom progression. This study underscores the importance of genetic testing in decoding complex phenotypes and emphasizes the value of documenting family history for anticipating related symptoms and future health risks.

HLA allelic diversity in the Waorani population of Ecuador: Its significance to their ancestry and migration.

The Waorani, an isolated indigenous tribe in Ecuador, have long been characterized by limited genetic diversity, with few studies delving into their genetic background. Human Leukocyte Antigen (HLA) genes which are located in the human major histocompatibility complex (MHC) provides valuable insights into population evolution due to its highly polymorphic nature. However, little is known about the HLA diversity and ancestry of the Waorani population. In this study, we sequenced eight HLA genes using Next Generation Sequencing (NGS) from 134 Waorani individuals and obtained up to four-field HLA allele resolution. Cluster and phylogenetic analysis show that the Waorani are genetically distant from other Ecuador populations, but instead show genetic affinities with the Puyanawa and Terena tribes from Brazil, as well as the Mixe tribe from Mexico. The identification of alleles common within the Waorani population, previously linked to specific health conditions, notably paves the way for future association analyses. This extensive study, employing Next-Generation Sequencing (NGS) technology, significantly enriches the sparse and segmented understanding of HLA diversity in the South American region. Our findings enhance the global comprehension of human genetic diversity and underscore the value of studying indigenous populations. Such research is vital for deepening our insights into human migration patterns and evolutionary processes.

Diagnosis challenges in CHARGE syndrome: A novel variant and clinical description.

Introduction: In resource-limited settings, patients with uncommon phenotypes often face prolonged diagnostic journeys and potential misdiagnoses. Coloboma, heart defects, atresia choanae, restricted growth and development, genital and ear abnormalities syndrome (CHARGE) syndrome, a congenital condition affecting various body parts such as the heart, ears, eyes, and genitals, exemplifies this challenge. Case presentation: We present the case of a 21-year-old male patient from Ecuador who exhibited hypogonadism, facial deformities, and stunted growth. Due to the scarcity of genetic specialists and limited access to genetic testing in Ecuador, the patient received a misdiagnosis of Noonan syndrome. However, a correct diagnosis of CHARGE syndrome was ultimately reached after eight years, facilitated by genetic sequencing that identified a novel mutation in the Chromodomain helicase DNA binding protein 7 gene. Conclusion: This case highlights the critical role of meticulously assessing patients' symptoms and emphasizes the necessity for enhanced collaboration among physicians and researchers. Such efforts are pivotal in advancing healthcare access and equity for individuals in developing nations.

Development and evaluation of ciprofloxacin local controlled release materials based on molecularly imprinted polymers.

The aim of this study was the molecular imprinting polymers (MIPs) assessment as a controlled release system of ciprofloxacin. The MIPs synthesis was performed by three different methods: emulsion, bulk, and co-precipitation. Lactic acid (LA) and methacrylic acid (MA) were used as functional monomers and ethylene glycol dimethacrylate as crosslinker. Also, nonimprinted polymers (NIPs) were synthesized. MIPs and NIPs were characterized by scanning electron microscopy, Fourier Transform Infrared Reflection, specific surface area, pore size, and release kinetics. Their efficiency against Staphylococcus aureus and Escherichia coli, and their cytotoxicity in dermal fibroblast cells were proven. Results show that MIPs are mesoporous materials with a pore size between 10 and 20 nm. A higher adsorption with the co-precipitation MIP with MA as a monomer was found. The release kinetics proved that a non-Fickian process occurred and that the co-precipitation MIP with LA presented the highest release rate (90.51 mg/L) in 8 h. The minimum inhibitory concentration was found between 0.031 and 0.016 mg/L for Staphylococcus aureus and between 0.004 and 0.031 mg/L for the Escherichia coli. No cytotoxicity in cellular cultures was found; also, cellular growth was favored. This study demonstrated that MIPs present promising properties for drug administration and their application in clinical practice.

Unmet needs in countries participating in the undiagnosed diseases network international: an international survey considering national health care and economic indicators.

Background: Patients, families, the healthcare system, and society as a whole are all significantly impacted by rare diseases (RDs). According to various classifications, there are currently up to 9,000 different rare diseases that have been recognized, and new diseases are discovered every month. Although very few people are affected by each uncommon disease individually, millions of people are thought to be impacted globally when all these conditions are considered. Therefore, RDs represent an important public health concern. Although crucial for clinical care, early and correct diagnosis is still difficult to achieve in many nations, especially those with low and middle incomes. Consequently, a sizeable amount of the overall burden of RD is attributable to undiagnosed RD (URD). Existing barriers and policy aspects impacting the care of patients with RD and URD remain to be investigated. Methods: To identify unmet needs and opportunities for patients with URD, the Developing Nations Working Group of the Undiagnosed Diseases Network International (DNWG-UDNI) conducted a survey among its members, who were from 20 different nations. The survey used a mix of multiple choice and dedicated open questions covering a variety of topics. To explore reported needs and analyze them in relation to national healthcare economical aspects, publicly available data on (a) World Bank ranking; (b) Current health expenditure per capita; (c) GDP per capita; (d) Domestic general government health expenditure (% of GDP); and (e) Life expectancy at birth, total (years) were incorporated in our study. Results: This study provides an in-depth evaluation of the unmet needs for 20 countries: low-income (3), middle-income (10), and high-income (7). When analyzing reported unmet needs, almost all countries (N = 19) indicated that major barriers still exist when attempting to improve the care of patients with UR and/or URD; most countries report unmet needs related to the availability of specialized care and dedicated facilities. However, while the countries ranked as low income by the World Bank showed the highest prevalence of referred unmet needs across the different domains, no specific trend appeared when comparing the high, upper, and low-middle income nations. No overt trend was observed when separating countries by current health expenditure per capita, GDP per capita, domestic general government health expenditure (% of GDP) and life expectancy at birth, total (years). Conversely, both the GDP and domestic general government health expenditure for each country impacted the presence of ongoing research. Conclusion: We found that policy characteristics varied greatly with the type of health system and country. No overall pattern in terms of referral for unmet needs when separating countries by main economic or health indicators were observed. Our findings highlight the importance of identifying actionable points (e.g., implemented orphan drug acts or registries where not available) in order to improve the care and diagnosis of RDs and URDs on a global scale.

Undiagnosed diseases: Needs and opportunities in 20 countries participating in the Undiagnosed Diseases Network International.

Introduction: Rare diseases (RD) are a health priority worldwide, overall affecting hundreds of millions of people globally. Early and accurate diagnosis is essential to support clinical care but remains challenging in many countries, especially the low- and medium-income ones. Hence, undiagnosed RD (URD) account for a significant portion of the overall RD burden. Methods: In October 2020, the Developing Nations Working Group of the Undiagnosed Diseases Network International (DNWG-UDNI) launched a survey among its members, belonging to 20 countries across all continents, to map unmet needs and opportunities for patients with URD. The survey was based on questions with open answers and included eight different domains. Conflicting interpretations were resolved in contact with the partners involved. Results: All members responded to the survey. The results indicated that the scientific and medical centers make substantial efforts to respond to the unmet needs of patients. In most countries, there is a high awareness of RD issues. Scarcity of resources was highlighted as a major problem, leading to reduced availability of diagnostic expertise and research. Serious equity in accessibility to services were highlighted both within and between participating countries. Regulatory problems, including securing informed consent, difficulties in sending DNA to foreign laboratories, protection of intellectual property, and conflicts of interest on the part of service providers, remain issues of concern. Finally, most respondents stressed the need to strengthen international cooperation in terms of data sharing, clinical research, and diagnostic expertise for URD patients in low and medium income countries. Discussion: The survey highlighted that many countries experienced a discrepancy between the growing expertise and scientific value, the level of awareness and commitment on the part of relevant parties, and funding bodies. Country-tailored public health actions, including general syllabus of medical schools and of the education of other health professionals, are needed to reduce such gaps.

Novel SRY-box transcription factor 9 variant in campomelic dysplasia and the location of missense and nonsense variants along the protein domains: A case report.

Background: Campomelic dysplasia (CD) is a rare disorder that involves the skeletal and genital systems. This condition has been associated with a diverse set of mutations in the SRY-box transcription factor 9 (SOX9) gene. Case presentation: We herein report a case involving a 4-year-old female patient with CD, female sex reversal, type 1 Arnold-Chiari malformation, and bilateral conductive hearing loss and investigate the causal mutation. Whole-exome sequencing analysis detected a novel Trp115X* variant in the SOX9 gene. We performed a literature review of the reported cases and demonstrated that the missense variants were located only in the self-dimerization domain (DIM) and high-mobility group box domains. We also reported that variants in the DIM domain do not cause sex reversal and identified that the amino acid sequences that were mutated in the patients with campomelic dysplasia are evolutionarily conserved among primates. Conclusions: We suggest that missense variants cannot be located in the K2, PQA, and PQS given that these domains function critically for transcriptional activation or repression of target genes and evolve under purifying selection.

NSD1 gene evolves under episodic selection within primates and mutations of specific exons in humans cause Sotos syndrome.

BACKGROUND: Modern human brains and skull shapes differ from other hominids. Brain growth disorders as micro- (ASPM, MCPH1) and macrocephaly (NFIX, GLI3) have been highlighted as relevant for the evolution in humans due to the impact in early brain development. Genes associated with macrocephaly have been reported to cause this change, for example NSD1 which causes Sotos syndrome. RESULTS: In this study we performed a systematic literature review, located the reported variants associated to Sotos syndrome along the gene domains, compared the sequences with close primates, calculated their similarity, Ka/Ks ratios, nucleotide diversity and selection, and analyzed the sequence and structural conservation with distant primates. We aimed to understand if NSD1 in humans differs from other primates since the evolution of NSD1 has not been analyzed in primates, nor if the localization of the mutations is limited to humans. Our study found that most variations causing Sotos syndrome are in exon 19, 22 and 10. In the primate comparison we did not detect Ka/Ks ratios > 1, but a high nucleotide diversity with non-synonymous variations in exons 10, 5, 9, 11 and 23, and sites under episodic selection in exon 5 and 23, and human, macaque/colobus/tarsier/galago and tarsier/lemur/colobus. Most of the domains are conserved in distant primates with a particular progressive development from a simple PWWP1 in O. garnetti to a complex structure in Human. CONCLUSION: NSD1 is a chromatin modifier that suggests that the selection could influence brain development during modern human evolution and is not present in other primates; however, nowadays the nucleotide diversity is associated with Sotos syndrome.

Evaluación de la exposición a Hidrocarburos Aromáticos Policíclicos, salud renal y respiratoria en población indígena de Tocoy, San Antonio, S. L. P, México / Evaluation of exposure to polycyclic aromatic hydrocarbons, renal and respiratory health in the indigenous population of Tocoy, San Antonio, S. L. P, México

Resumen La contaminación del aire interior es un problema de salud pública, ya que afecta a unos 2.600 millones de personas en todo el mundo que siguen cocinando con combustibles sólidos como la madera, los residuos de las cosechas, etc. Esta exposición aumenta el factor de riesgo de desarrollo de enfermedades crónicas. La población indígena es muy susceptible a estar expuesta a mezclas de contaminantes del humo de leña como los Hidrocarburos Aromáticos Policíclicos (HAPs) debido a los métodos tradicionales de cocción. El objetivo de este trabajo fue evaluar la exposición a HAPs por medio de 10 metabolitos hidroxilados en orina de la población indígena de la Huasteca Potosina, mediante cromatografía de gases acoplada a espectrometría de masas; por otro lado, la salud renal y pulmonar fueron evaluadas con una prueba general de orina y la toxina urémica Indoxil sulfato, esta fue evaluada por medio cromatografía líquida de alto rendimiento, y la función pulmonar con una espirometría. Los resultados indican la presencia de metabolitos hidroxilados en el 89,47% de las muestras de orina, los más frecuentes fueron el 1-OH-PIRENO, el 1,2-OH-NAFTALENO. El Indoxil sulfato se presentó en el 100% de las muestras y la media era de 193,4 ± 91,85 gg/L En cuanto a la salud pulmonar, los resultados indican que algunos sujetos presentan patrones respiratorios regulares e irregulares. Estos resultados indican que la población se encuentra expuesta de manera crónica a una mezcla de contaminantes en el aire que podría producir el desarrollo de daño en los pulmones y los riñones y aumentar el riesgo al desarrollo de enfermedades crónicas.

Abstract Interior air pollution is a public health concern, it affects about 2.6 billion people around the world who still cook using solid fuels such as wood, crop wastes, among others. This exposition increases the risk of the development of non-communicable diseases (NCDs). The indigenous population is very susceptible to being exposed to mixtures of pollutants from the wood smoke such as Polycyclic Aromatic Hydrocarbons (PAHs) due to traditional methods of cooking, heating and waste burning. Therefore, the objective of this work was to evaluate the exposure to PAHs through the application of 10 hydroxylated metabolites (OH-PAHs) in the urine of the indigenous population from the Huasteca Potosina, this by gas chromatography coupled to mass spectrometry and to assess renal health of the population at the time of the study, with a general test of urine and through the uremic toxin Indoxyl Sulfate (IS), this by high-performance liquid chromatography, and the and pulmonary health with spirometry. The results indicate the presence OH-PAHs in 89.47% of the urine samples, the most frequent metabolites were 1-OH-PYRENE, 2-OH-NAPTHALENE. IS was present in 100% of the samples in mean concentrations of 193.4 ± 91.85 gg/L. For pulmonary health, the results indicate some subjects have regular and irregular respiratory patterns. These results indicate that the population is highly exposed to a mixture of pollutants in the air that might damage the lungs and kidneys and increase the risk of NCDs development.

Aplicación de modelos metabolómicos para la identificación de EPOC en poblaciones expuestas a humo de leña en una comunidad indígena de México / Application of metabolomic models for the identificaron of coPD in populations exposed to wood smoke in an indigenous community in Mexico

Resumen Propósito: Para la evaluación metabólica de la fisiopatología pulmonar se utiliza principalmente el aliento exhalado, el cual ha tomado una gran relevancia como método de diagnóstico no invasivo, de bajo costo, rápido y seguro. El objetivo del presente estudio fue aplicar modelos metabolómicos para la identificación de la Enfermedad Pulmonar Obstructiva Crónica (EPOC) en población vulnerable expuesta a la quema de biomasa en una comunidad indígena de México. Métodos: El estudio se conformó por 142 participantes, 44 pacientes con EPOC asociado a la quema de biomasa, 60 controles y 38 población indígena expuesta a la quema de biomasa (PIE). Las muestras de aliento exhalado se analizaron mediante una nariz electrónica (HERACLES II, Alpha MOS). Con los datos obtenidos se realizó un Análisis Canónico de Coordenadas principales (CAP), que fue utilizado para la predicción de EPOC de la PIE y se determinó la concentración de 1-hidroxipireno (1-OHP) en muestras de orina. Resultados: Se logró identificar un total 59 COVs en las muestras de aliento exhalado de los grupos de estudio, los cuales se utilizaron para establecer un modelo de discriminación entre la huella química del grupo de pacientes con EPOC y el grupo control. El modelo CAP indicó una separación entre las huellas químicas de los pacientes con EPOC y sujetos sanos, con una correcta predicción de 91,34%, con una sensibilidad y especificidad de 93,2 y 96,7% respectivamente. Se encontraron 10 participantes de la PIE con patrón obstructivo y una alta concentración de 1-OHP, determinando que existe una concentración del 1,31 ± 0,67gg/mol de creatinina. Esta concentración se encuentra más de 5 veces arriba de los valores de referencia establecidos en el 2001, que es de 0,24 gg/mol de creatinina. Al comparar los resultados de la huella química de la PIE se posicionó en el grupo de EPOC. Conclusión: Se logró obtener un diagnóstico oportuno en población vulnerable mediante el uso de la metabolómica y se demostró la exposición y los efectos pulmonares en población indígena de San Luis Potosí.

Abstract Purpose: to evaluate metabolic disorders of the pathophysiology of the lung, the exhaled breath is mainly used, this has become highly relevant as a non-invasive, low-cost, fast and safe diagnostic method. The objective of this study is to apply metabolomic models for the identification of Chronic Obstructive Pulmonary Disease (COPD) in a vulnerable population exposed to biomass burning in an indigenous community in Mexico. Methods: The study consisted of 142 participants, 44 patients with COPD associated with biomass burning, 60 controls and 38 indigenous population exposed to biomass burning (PIE). Exhaled breath samples were analyzed using an electronic nose (HERACLES II, Alpha MOS). With the data obtained, a Canonical Analy-sis of Principal Coordinates (CAP) was performed, which was used for the prediction of COPD of IEP and the concentration of 1-hydroxypyrene (1-OHP) in urine samples was determined. Results: A total of 59 VOCs were identified in the exhaled breath samples of the study groups, which were used to establish a discrimination model between the chemical fingerprint of the COPD patient group and the control group. The CAP model indicated a separation between the chemical fingerprints of COPD patients and healthy subjects, with a correct prediction of 91,34%, with a sensitivity and specificity of 93,2 and 96,7%, respectively. 10 IEP participants with an obstructive pattern and a high concentration of 1-OHP were found, determining that there is a concentration of 1,31 ± 0,67gg/mol of creatinine. This concentration is more than 5 times above the reference values established in 2001, which is 0,24 -jg/mol of creatinine. When comparing the results of the Chemical fingerprint of the PIE, it was positioned in the COPD group. Conclusion: It was possible to obtain an opportune diagnosis in a vulnerable population using metabolomics and exposure and pulmonary effects were demonstrated in the indigenous population of San Luis Potosí.

COL1A1 novel splice variant in osteogenesis imperfecta and splicing variants review: A case report.

Background: Osteogenesis imperfecta (OI) is a rare heterogeneous genetic disorder commonly autosomal dominant with variants in the COL1A1 and COL1A2 genes. It is characterized by bone fragility and deformity, recurrent fractures, blue sclera, dentinogenesis imperfecta, short stature, and progressive deafness. Case presentation: We present a novel splicing mutation in the COL1A1 gene (c.2398-1G > C) in a 6-year-old Ecuadorian girl with fractures after light pressure and blue sclera. We identified the pathogenic variant, performed a literature review of splice variants, and recognized their location in the COL1A1 functional domains. Conclusion: We describe the first clinical description of a patient with OI type 1 caused by a splice variant in intron 34 of COL1A1 gene and identify that most of them are localized in the triple-helical region domain. We suggest that the splice variant in signal peptide, von Willebrand factor type C, and nonhelical regions maintain their functionality or that individuals affected with severe cases die early in development and are not reported.

One-Drop Serum Screening Test for Anal Cancer in Men via Infrared Attenuated Total Reflection Spectroscopy.

Rare cancers are a challenge for clinical practice, the treatment experience at major centers to which rare cancers are referred is limited and are the most difficult to diagnose. Research to identify causes or develop prevention and early detection strategies is extremely challenging. Anal cancer is an example of a rare cancer, with the human papillomavirus (HPV) infection being the most important risk factor associated. In the early stages, anal cancer does not exhibit evident symptoms. This disease is diagnosed by means of anoscopy, which diagnoses some cases of early cancer; nevertheless, sensitivity of this test ranges between 47 and 89%. Therefore, the development of new, effective, and evidence-based screening methodologies for the early detection of rare cancers is of great relevance. In this study, the potential of ATR-FTIR spectroscopy has been explored as a sensitive, nondestructive, and inexpensive analytical method for developing disease screening platforms in serum. Spectral differences were found in the regions of 1700-1100 and 1700-1400 cm-1 between the control group and the anal cancer group related to the presence of proteins and nucleic acids. The chemometric analysis presented differences in the spectral fingerprints for both spectral regions with a high sensitivity ranging from 95.2 to 99.9% and a specificity ranging from 99.2 to 100%. This is the first step that we report for a methodology that is fast, nondestructive, and easy to perform, and the high sensitivity and specificity of the method are the basis for extensive research studies to implement these technologies in the clinical field.

Novel Variation in Acyl-CoA Synthetase Long Chain Family Member 6 (ACSL6) Results in Protein Structural Modification and Multiple Non-Related Neoplasia in a 46-Year-Old: Case Report.

Multiple non-related neoplasia does not have an established approach or benefits for performing whole-exome sequencing (WES) analysis. We report on a 46-year-old woman who developed astrocytoma, thyroid, and breast cancer within 10 years. The WES analysis found a novel missense variant in the ACSL6 gene, and the protein modeling showed altered secondary and tertiary structures, which modify the binding to cofactors and substrates. ACSL6 is involved in lipid metabolism, expressed in the brain, thyroid, and breast tissues, and is associated with diverse types of cancer. Our study demonstrates the benefit of WES analysis compared with commercial panels in patients with non-related neoplasia.

Design and application of molecularly imprinted polymers for adsorption and environmental assessment of anti-inflammatory drugs in wastewater samples.

In this study, a series of molecularly imprinted polymers (MIPs) have been synthesized using separately diclofenac, naproxen, and ibuprofen as templates with three different polymerization approaches. Two functional monomers, methacrylic acid (MAA) and 2-vinylpyridine (2-VP), were tested and ethylene glycol dimethacrylate (EGDMA) was used as crosslinker; also, template-free polymers (NIPs) were synthesized. It was found that the MIP with the highest retention percentage for diclofenac was the one prepared by the emulsion approach and with MAA (98.3%); for naproxen, the one prepared by the bulk polymerization with MAA (99%); and for ibuprofen, the one synthesized by bulk with 2-VP (97.7%). These three MIPs were characterized by scanning electron microscopy, thermogravimetric test, Fourier transform infrared, specific area measurements, and surface charge. It was found that the emulsion method allowed particle size control, while the bulk method gave heterogeneous particles. The three evaluated MIPs exhibited thermal stability up to 300 °C, and it was observed that 2-VP confers greater stability to the material. From the BET analysis, it was demonstrated that the MIPs and NIPs evaluated are mesoporous materials with a pore size between 10 and 20 nm. In addition, the monomer influenced the surface charge of the material, since the MAA conferred an acidic point of zero charge (PZC), while the 2-VP conferred a PZC of basic character. Through adsorption isotherms, it was determined  that there is a higher adsorption capacity of the MIPs at acidic pH following a pseudo-second-order kinetic model. Finally, the MIPs were used to determine the non-steroidal anti-inflammatory drugs (NSAIDs) understudy in San Luis Potosí, México, wastewater, finding concentrations of 0.642, 0.985, and 0.403 mg L-1 for DCF, NPX, and IBP, respectively.

The limits of clinical findings in similar phenotypes, from Carpenter to ATRX syndrome using a whole exome sequencing approach: a case review.

BACKGROUND: The diagnostic process for uncommon disorders with similar manifestations is complicated and requires newer technology, like gene sequencing for a correct diagnosis. MAIN BODY: We described two brothers clinically diagnosed with Carpenter syndrome, which is a condition characterized by the premature fusion of certain skull bones (craniosynostosis), abnormalities of the fingers and toes, and other developmental problems, for which they underwent craniotomies. However, whole exome sequencing analysis concluded a novel pathological variation in the ATRX chromatin remodeler gene and protein remodeling demonstrated structural variations that decreased the function, giving a completely different diagnosis to these patients. CONCLUSION: Our study focuses on the importance of using newer technologies, such as whole exome sequencing analysis, in patients with ambiguous phenotypes.

Risk HLA alleles in South America and potential new epitopes for SARS-CoV2.

HLA alleles are associated with the body's response to infection and the regulation of the immune system. HLA alleles have been reported to be involved in response to viral infections such as SARS-CoV2. Our study reviews the HLA alleles associated with protection or susceptibility to SARS-CoV2 and the prevalence of these HLA alleles in South America. Previous studies on HLA and SARS-CoV2 infection reported that HLA-A*02:02, HLA-B*15:03, and HLA-C*12:03 are protective; while HLA-A*25:01, HLA-B*46:01, and HLA-C*01:02 increase susceptibility. We identified that these alleles are not frequent in South America, confirmed that the spike protein is the most immunogenic protein of SARS-CoV2, and detected new immunogenic epitopes that bound to protective HLA alleles and to HLA alleles common in South America (binding score > 0.90). These could be used as vaccine targets.

High Order Formation and Evolution of Hornerin in Primates.

Genomic duplication or loss can accelerate evolution because the number of repeats could affect molecular pathways and phenotypes. We have previously reported that the repeated region of filaggrin (FLG), a crucial component of the outer layers of mammalian skin, had high levels of nucleotide diversity with species-specific divergence and expansion and that it evolved under the birth-and-death model. We focused on hornerin (HRNR), a member of the same gene family that harbor similar tandem repeats as FLG, and examined the formation process of repeated regions and the evolutional model that best fit the HRNR repeated region in the crab-eating macaque (Macaca fascicularis), orangutan (Pongo abelii), gorilla (Gorilla gorilla), and chimpanzee (Pan troglodytes) and compared them with the human (Homo sapiens) sequence. Paar et al. (2011) and Takaishi et al. (2005) have different theories as to the formation of the repeated region of HRNR; both groups share the longest repeat length of 1,404 bp (quartic or longest unit), but they differed in the process. We identified the formation described by Paar et al. {[("39 bp (primary) × 9" × 2 (secondary)) × 2 (tertiary)] × 5 (quartic)} to be conserved in all species except the crab-eating macaque. We detected high nucleotide diversities between the longest repeats, which fits the birth-and-death model. We concluded that the high order repeat formation of HRNR was conserved in primates except the crab-eating macaque. As previously identified in FLG, the longest repeats have high levels of nucleotide diversity, which could contribute to phenotypic differences between closely related species.

[Eco-epidemiological aspects, natural detection and molecular identification of Leishmania spp. in Lutzomyia reburra, Lutzomyia barrettoi majuscula and Lutzomyia trapidoi].

INTRODUCTION: The province of Pichincha in Ecuador is an endemic area of cutaneous leishmaniasis, where anthropophilic sand flies with natural infection by Leishmania, have been reported as vectors. However, the role in transmission of zoophilic species has not been evaluated. OBJECTIVE: To evaluate natural infection by Leishmania in two zoophilic phlebotomine sand fly species, Lutzomyia reburra and Lu. barrettoi majuscula, and one anthropophilic species, Lu. trapidoi, as well as the endophagy and synanthropism of these species in the northwest of Pichincha. MATERIALS AND METHODS: Phlebotomines were collected using CDC light traps in different habitats and altitudes with presence of cutaneous leishmaniasis. Leishmania infection was detected using genomic DNA from females of the collected sand flies. We amplified the internal transcribed spacer gene of ribosomal RNA I (ITS1), the mitochondrial topoisomerase II gene (mtTOPOII), and the nuclear topoisomerase II gene (TopoII). Percentages of positivity for Leishmania, at spatio-temporal scale, proportion of endophagy and synanthropism index were calculated. RESULTS: Natural infection was determined for Le. amazonensis in Lu. reburra (9.5%) and Lu. b. majuscula (23.8%), while in Lu. trapidoi we detected Le. amazonensis, Le. brazilienis and Le. naiffi-lainsoni. Phlebotomines were asynanthropic and with low endophagy. CONCLUSION: Natural infection with Le. amazonensis was recorded for the first time in Lu. reburra and Lu. b. majuscula, demonstrating the importance of zoophilic phlebotomines in the maintenance of the Leishmania transmission cycle in endemic foci.