Audiovestibular Involvement in Patients With Systemic Sclerosis.

INTRODUCTION: Audiovestibular dysfunction has been reported in many autoimmune connective tissue diseases, including systemic sclerosis (SSc). OBJECTIVE: To assess the prevalence and features of audiological and vestibular disturbances in SSc patients and evaluate their relationship with disease duration, clinical features, nailfold videocapillaroscopy pattern, and immunologic profiles. METHOD: A matched case-control study was conducted in a rheumatology clinic of a second-level hospital over 24 months. All patients underwent a detailed ear, nose, and throat examination, as well as audiometric and vestibular assessments, including pure tone audiometry, speech audiometry, immittance tests, and the Video Head Impulse Test. RESULTS: Thirty-five SSc patients and 24 healthy controls were included in the study. In the SSc group, subjective hearing loss was reported by 17.1% of patients, vertigo by 14.3%, tinnitus by 11.4%, and dizziness by 5.7%. Sensorineural hearing loss was identified in 42.9% of SSc patients, significantly higher than in the control group (p = 0.013). There was no correlation between audiological manifestations and clinical symptoms, organ involvement, immunologic characteristics, and treatment. Vestibular dysfunction was detected in 60% of SSc patients, significantly higher than the control group (p = 0.05). A significant correlation was found between abnormal Video Head Impulse Test and the presence of anti-RNA polymerase III and anti-Th/To antibodies (p = 0.05 and p = 0.034, respectively). CONCLUSION: Our study revealed an increased prevalence of sensorineural hearing loss and vestibulopathy in SSc patients.

Hotspots of biogeochemical activity linked to aridity and plant traits across global drylands.

Perennial plants create productive and biodiverse hotspots, known as fertile islands, beneath their canopies. These hotspots largely determine the structure and functioning of drylands worldwide. Despite their ubiquity, the factors controlling fertile islands under conditions of contrasting grazing by livestock, the most prevalent land use in drylands, remain virtually unknown. Here we evaluated the relative importance of grazing pressure and herbivore type, climate and plant functional traits on 24 soil physical and chemical attributes that represent proxies of key ecosystem services related to decomposition, soil fertility, and soil and water conservation. To do this, we conducted a standardized global survey of 288 plots at 88 sites in 25 countries worldwide. We show that aridity and plant traits are the major factors associated with the magnitude of plant effects on fertile islands in grazed drylands worldwide. Grazing pressure had little influence on the capacity of plants to support fertile islands. Taller and wider shrubs and grasses supported stronger island effects. Stable and functional soils tended to be linked to species-rich sites with taller plants. Together, our findings dispel the notion that grazing pressure or herbivore type are linked to the formation or intensification of fertile islands in drylands. Rather, our study suggests that changes in aridity, and processes that alter island identity and therefore plant traits, will have marked effects on how perennial plants support and maintain the functioning of drylands in a more arid and grazed world.

Naturally occurring genetic diseases caused by de novo variants in domestic animals.

With the advent of next-generation sequencing, an increasing number of cases of de novo variants in domestic animals have been reported in scientific literature primarily associated with clinically severe phenotypes. The emergence of new variants at each generation is a crucial aspect in understanding the pathology of early-onset diseases in animals and can provide valuable insights into similar diseases in humans. With the aim of collecting deleterious de novo variants in domestic animals, we searched the scientific literature and compiled reports on 42 de novo variants in 31 genes in domestic animals. No clear disease-associated phenotype has been established in humans for three of these genes (NUMB, ANKRD28 and KCNG1). For the remaining 28 genes, a strong similarity between animal and human phenotypes was recognized from available information in OMIM and OMIA, revealing the importance of comparative studies and supporting the use of domestic animals as natural models for human diseases, in line with the One Health approach.

Meta-analysis of 46,000 germline de novo mutations linked to human inherited disease.

BACKGROUND: De novo mutations (DNMs) are variants that occur anew in the offspring of noncarrier parents. They are not inherited from either parent but rather result from endogenous mutational processes involving errors of DNA repair/replication. These spontaneous errors play a significant role in the causation of genetic disorders, and their importance in the context of molecular diagnostic medicine has become steadily more apparent as more DNMs have been reported in the literature. In this study, we examined 46,489 disease-associated DNMs annotated by the Human Gene Mutation Database (HGMD) to ascertain their distribution across gene and disease categories. RESULTS: Most disease-associated DNMs reported to date are found to be associated with developmental and psychiatric disorders, a reflection of the focus of sequencing efforts over the last decade. Of the 13,277 human genes in which DNMs have so far been found, the top-10 genes with the highest proportions of DNM relative to gene size were H3-3 A, DDX3X, CSNK2B, PURA, ZC4H2, STXBP1, SCN1A, SATB2, H3-3B and TUBA1A. The distribution of CADD and REVEL scores for both disease-associated DNMs and those mutations not reported to be de novo revealed a trend towards higher deleteriousness for DNMs, consistent with the likely lower selection pressure impacting them. This contrasts with the non-DNMs, which are presumed to have been subject to continuous negative selection over multiple generations. CONCLUSION: This meta-analysis provides important information on the occurrence and distribution of disease-associated DNMs in association with heritable disease and should make a significant contribution to our understanding of this major type of mutation.

Adrenocorticotropin-Dependent Ectopic Cushing's Syndrome: A Case Report.

Paraneoplastic syndromes are rare and diverse conditions caused by either an abnormal chemical signaling molecule produced by tumor cells or a body's immune response against the tumor itself. These syndromes can manifest in a variable, multisystemic and often nonspecific manner posing a diagnostic challenge. We report the case of an 81-year-old woman who exhibited severe hypokalemia, metabolic alkalosis, and worsening hyperglycemia. The investigation was consistent with adrenocorticotropin (ACTH)-dependent Cushing's syndrome and, eventually, the patient was diagnosed with stage IV primary small-cell lung cancer (SCLC). SCLC is known to be associated with paraneoplastic syndromes, including Cushing's syndrome caused by ectopic adrenocorticotropin (ACTH) secretion. Despite being associated with very poor outcomes, managing these syndromes can be challenging and may hold prognostic significance.

First evidence of gonadal hybrid dysgenesis in Chagas disease vectors (Hemiptera, Triatominae): gonad atrophy prevents events of interspecific gene flow and introgression.

BACKGROUND: Hybridization events between Triatoma spp. have been observed under both natural and laboratory conditions. The ability to produce hybrids can influence different aspects of the parent species, and may even result in events of introgression, speciation and extinction. Hybrid sterility is caused by unviable gametes (due to errors in chromosomal pairing [meiosis]) or by gonadal dysgenesis (GD). All of the triatomine hybrids analyzed so far have not presented GD. We describe here for the first time GD events in triatomine hybrids and highlight these taxonomic and evolutionary implications of these events. METHODS: Reciprocal experimental crosses were performed between Triatoma longipennis and Triatoma mopan. Intercrosses were also performed between the hybrids, and backcrosses were performed between the hybrids and the parent species. In addition, morphological and cytological analyzes were performed on the atrophied gonads of the hybrids. RESULTS: Hybrids were obtained only for the crosses T. mopan♀ × T. longipennis♂. Intercrosses and backcrosses did not result in offspring. Morphological analyses of the male gonads of the hybrids confirmed that the phenomenon that resulted in sterility of the hybrid was bilateral GD (the gonads of the hybrids were completely atrophied). Cytological analyses of the testes of the hybrids also confirmed GD, with no germ cells observed (only somatic cells, which make up the peritoneal sheath). CONCLUSIONS: The observations made during this study allowed us to characterize, for the first time, GD in triatomines and demonstrated that gametogenesis does not occur in atrophied gonads. The characterization of GD in male hybrids resulting from the crossing of T. mopan♀ × T. longipennis♂ highlights the importance of evaluating both the morphology and the cytology of the gonads to confirm which event resulted in the sterility of the hybrid: GD (which results in no gamete production) or meiotic errors (which results in non-viable gametes).

Using plants in forensics: State-of-the-art and prospects.

The increasing use of plant evidence in forensic investigations gave rise to a powerful new discipline - Forensic Botany - that analyses micro- or macroscopic plant materials, such as the totality or fragments of an organ (i.e., leaves, stems, seeds, fruits, roots) and tissue (i.e., pollen grains, spores, fibers, cork) or its chemical composition (i. e., secondary metabolites, isotopes, DNA, starch grains). Forensic botanists frequently use microscopy, chemical analysis, and botanical expertise to identify and interpret evidence crucial to solving civil and criminal issues, collaborating in enforcing laws or regulations, and ensuring public health safeguards. The present work comprehensively examines the current state and future potential of Forensic Botany. The first section conveys the critical steps of plant evidence collection, documentation, and preservation, emphasizing the importance of these initial steps in maintaining the integrity of the items. It explores the different molecular analyses, covering the identification of plant species and varieties or cultivars, and discusses the limitations and challenges of these techniques in forensics. The subsequent section covers the diversity of Forensic Botany approaches, examining how plant evidence exposes food and pharmaceutical frauds, uncovers insufficient or erroneous labeling, traces illegal drug trafficking routes, and combats the illegal collection or trade of protected species and derivatives. National and global security issues, including the implications of biological warfare, bioterrorism, and biocrime are addressed, and a review of the contributions of plant evidence in crime scene investigations is provided, synthesizing a comprehensive overview of the diverse facets of Forensic Botany.

Cytogenetic Key to Identification of Triatominae Species Reported in an Outbreak Region of Oral Transmission of Chagas Disease in the Brazilian Northeast.

Oral transmission from the consumption of processed food with triatomines and/or their feces infected with Trypanosoma cruzi prevails among recent cases of Chagas disease in Brazil. In Paraíba, a state of the Brazilian northeast, there was an outbreak caused by the consumption of sugarcane juice that resulted in 26 cases of infection and one death. Until now, 10 species of triatomines have been reported in this Brazilian state. Thus, we developed a dichotomous key to assist in the correct identification of Paraíba triatomines based on cytogenetic data. The dichotomous key allowed the differentiation of all the species in this state. Although the purpose of CytoKeys is not to replace dichotomous keys based on morphological data, the use of these complementary keys can help to solve taxonomic problems, preventing identification errors, especially between similar species such as Triatoma brasiliensis and Triatoma petrocchiae, both present in the Brazilian northeast.

Climate and Environmental Changes and Their Potential Effects on the Dynamics of Chagas Disease: Hybridization in Rhodniini (Hemiptera, Triatominae).

Chagas disease affects about eight million people. In view of the issues related to the influence of anthropogenic changes in the dynamics of the distribution and reproductive interaction of triatomines, we performed experimental crosses between species of the Rhodniini tribe in order to evaluate interspecific reproductive interactions and hybrid production capacity. Reciprocal crossing experiments were conducted among Rhodnius brethesi × R. pictipes, R. colombiensis × R. ecuadoriensis, R. neivai × R. prolixus, R. robustus × R. prolixus, R. montenegrensis × R. marabaensis; R. montenegrensis × R. robustus, R. prolixus × R. nasutus and R. neglectus × R. milesi. With the exception of crosses between R. pictipes ♀ × R. brethesi ♂, R. ecuadoriensis ♀ × R. colombiensis ♂ and R. prolixus ♀ × R. neivai ♂, all experimental crosses resulted in hybrids. Our results demonstrate that both allopatric and sympatric species produce hybrids, which can generate concern for public health agencies in the face of current anthropogenic events. Thus, we demonstrate that species of the Rhodniini tribe are capable of producing hybrids under laboratory conditions. These results are of great epidemiological importance and raise an important discussion about the influence of climatic and environmental interactions on Chagas disease dynamics.

LOCUS (LOng Covid-Understanding Symptoms, events and use of services in Portugal): A three-component study protocol.

Approximately 10% of patients experience symptoms of Post COVID-19 Condition (PCC) after a SARS-CoV-2 infection. Akin acute COVID-19, PCC may impact a multitude of organs and systems, such as the cardiovascular, respiratory, musculoskeletal, and neurological systems. The frequency and associated risk factors of PCC are still unclear among both community and hospital settings in individuals with a history of COVID-19. The LOCUS study was designed to clarify the PCC's burden and associated risk factors. LOCUS is a multi-component study that encompasses three complementary building blocks. The "Cardiovascular and respiratory events following COVID-19" component is set to estimate the incidence of cardiovascular and respiratory events after COVID-19 in eight Portuguese hospitals via electronic health records consultation. The "Physical and mental symptoms following COVID-19" component aims to address the community prevalence of self-reported PCC symptoms through a questionnaire-based approach. Finally, the "Treating and living with Post COVID-19 Condition" component will employ semi-structured interviews and focus groups to characterise reported experiences of using or working in healthcare and community services for the treatment of PCC symptoms. This multi-component study represents an innovative approach to exploring the health consequences of PCC. Its results are expected to provide a key contribution to the optimisation of healthcare services design.

A partial duplication of an X-linked gene exclusive of a primate lineage (Macaca).

Gene duplication plays a significant role in evolution. Paralogous gene copies may be lost due to the successive accumulation of deleterious mutations or remain active in the genome. In this work, a partial duplication of an X-linked region in the Macaca genus is identified and explored. Genomic comparisons reveal that the duplication encompasses the genes encoding ornithine transcarbamylase (OTC) and retinitis pigmentosa GTPase regulator (RPGR), spanning over 0.1 Mb on the chromosome 9 of Macaca. According to our analyses, the duplicated region of chromosome 9 involves partial coding sequences of both OTC and RPGR genes. Analyses of the selective pressures did not reveal significant differences in the ratio between nonsynonymous and synonymous mutations (w<1), suggesting that no selective pressures were acting in the evolutionary process. Reports for a biological role regarding some partial duplications exist in the literature, therefore, although being rare events, partial duplications of functionally important genes are worthy of study so that their impact can be explored.

[Myocardial infarction, stroke, and psoriasis: A systematic review of observational studies]. / Infarctus du myocarde, accident vasculaire cérébral et psoriasis : une revue systématique des études observationnelles.

Patients with psoriasis can have higher rates of hypertension, diabetes mellitus 2, and dyslipidemia. This study aimed to assess the association between psoriasis, myocardial infarction (MI), and stroke. A systematic review was carried out using PubMed/Medline, EMBASE, and LILACS databases searching for observational studies that assessed stroke and/or MI in patients diagnosed with psoriasis vulgaris compared to non-psoriatic patients. A total of 649 articles were identified but only 15 were included in the study. Although there were studies that have observed a significant positive association between psoriasis and MI or stroke, an almost equal number of studies showed no statistically significant association. The relationship between psoriasis and ischemic cardiovascular events is still controversial and it is difficult to establish psoriasis as the etiology of these events.

Non-B DNA conformations analysis through molecular dynamics simulations.

BACKGROUND: Non-B DNA conformations are molecular structures that do not follow the canonical DNA double helix. Mutagenetic instability in nuclear and mitochondrial DNA (mtDNA) genomes has been associated with simple non-B DNA conformations, as hairpins or more complex structures, as G-quadruplexes. One of these structures is Structure A, a cloverleaf-like non-B conformation predicted for a 93-nt (nucleotide) stretch of the mtDNA control region 5'-peripheral domain. Structure A is embedded in a hot spot for the 3' end of human mtDNA deletions revealing its importance in influencing the mutational instability of the mtDNA genome. METHODS: To better characterize Structure A, we predicted its 3D conformation using state-of-art methods and algorithms. The methodologic workflow consisted in the prediction of non-B conformations using molecular dynamics simulations. The conservation scores of alignments of the Structure A region in humans, primates, and mammals, was also calculated. RESULTS: Our results show that these computational methods are able to measure the stability of non-B conformations by using the level of base pairing during molecular dynamics. Structure A showed high stability and low flexibility correlated with high conservation scores in mammalian, more specifically in primate lineages. CONCLUSIONS: We showed that 3D non-B conformations can be predicted and characterized by our methodology. This allowed the in-depth analysis of the structure A, and the main results showed the structure remains stable during the simulations. GENERAL SIGNIFICANCE: The fine-scale atomic molecular determination of this type of non-B conformation opens the way to perform computational molecular studies that can show their involvement in mtDNA cellular mechanisms.

A wide range of South American inselberg floras reveal cohesive biome patterns.

Inselbergs are azonal formations found scattered in different biomes globally. The first floristic list focusing on an inselberg in the Brazilian Amazon is presented here. We aimed to investigate floristic and phylogenetic connections among Neotropical inselbergs and analyze whether environmental variables act as a filter of plant lineages. We used a database compiled from 50 sites spanning three main Neotropical biomes (Amazon, 11 sites, Atlantic Forest, 14 sites, and Caatinga, 25 sites) comprising 2270 Angiosperm species. Our data highlight the vastly different inselberg flora found in each biome. The inselberg floras of the Atlantic Forest and Caatinga show closer phylogenetic ties than those seen in the other biome pairs. The phylogenetic lineages found in all three biomes are also strongly divergent, even within plant families. The dissimilarity between biomes suggests that distinct biogeographical histories might have unfolded even under comparable environmental filtering. Our data suggest that the inselberg flora is more related to the biome where it is located than to other factors, even when the microclimatic conditions in the outcrops differ strongly from those of the surrounding matrix. Relative to the other biomes, the flora of the Caatinga inselbergs has the highest level of species turnover. There is a possibility that plants colonized these rather distant inselbergs even when they were found under very different climatic conditions than those in the Amazonian and Atlantic Forest biomes. It is worth noting that none of the studied inselbergs found in the Caatinga biome is protected. In view of the uniqueness and drought-resilient lineages present in each group of inselbergs, along with their vulnerability to destruction or disturbance and their strong connection with water availability, we stress the need to protect this ecosystem not only to conserve plants potentially useful for ecological restoration but also to preserve the balance of this ecosystem and its connections.

Molecular Markers: An Overview of Data Published for Fungi over the Last Ten Years.

Fungi are amongst the most abundant and diverse organisms. Despite being widely known for their adverse role in food spoilage or as pathogens for humans, animals, or plants, they also present several beneficial effects. Fungi contribute to human well-being due to their role as decomposers, degrading decay matter into smaller molecules which can be easily used by other ecosystem members. These organisms can produce medicinal compounds or modulate protective immune responses in human intestine. Fungi intervene in diverse food processes or act as a food supply. Due to fungal diversity, the unequivocal identification of these organisms is crucial to increasing their practical applications and decreasing their adverse effects. The process of identification could be achieved through the integral sequencing of fungi genomes. However, this procedure would be time-consuming and rather cost-inefficient. Therefore, several molecular markers have been developed to overcome these limitations. The chronology of DNA-based molecular markers development can be divided into three main steps: (1) prior to the development of the PCR technique (RFLP); (2) after the development of the PCR technique (RAPD, AFLP, ISSR, VNTR, SNP, InDels, and DNA barcoding); (3) after the development of the massive parallel sequencing technique (Metabarcoding and WGS). Therefore, the present review covers an overview of the most recently developed molecular markers used for fungal detection and identification.

Complex interactions between p.His558Arg and linked variants in the sodium voltage-gated channel alpha subunit 5 (Na V 1.5).

Common genetic polymorphisms may modify the phenotypic outcome when co-occurring with a disease-causing variant, and therefore understanding their modulating role in health and disease is of great importance. The polymorphic p.His558Arg variant of the sodium voltage-gated channel alpha subunit 5 (Na V 1.5) encoded by the SCN5A gene is a case in point, as several studies have shown it can modify the clinical phenotype in a number of cardiac diseases. To evaluate the genetic backgrounds associated with this modulating effect, we reanalysed previous electrophysiological findings regarding the p.His558Arg variant and further assessed its patterns of genetic diversity in human populations. The Na V 1.5 p.His558Arg variant was found to be in linkage disequilibrium with six other polymorphic variants that previously were also associated with cardiac traits in GWAS analyses. On account of this, incongruent reports that Arg558 allele can compensate, aggravate or have no effect on Na V 1.5, likely might have arose due to a role of p.His558Arg depending on the additional linked variants. Altogether, these results indicate a major influence of the epistatic interactions between SCN5A variants, revealing also that phenotypic severity may depend on the polymorphic background associated to each individual genome.

Genetic Variability of the Functional Domains of Chromodomains Helicase DNA-Binding (CHD) Proteins.

In the past few years, there has been an increasing neuroscientific interest in understanding the function of mammalian chromodomains helicase DNA-binding (CHD) proteins due to their association with severe developmental syndromes. Mammalian CHDs include nine members (CHD1 to CHD9), grouped into subfamilies according to the presence of specific functional domains, generally highly conserved in evolutionary terms. Mutations affecting these domains hold great potential to disrupt protein function, leading to meaningful pathogenic scenarios, such as embryonic defects incompatible with life. Here, we analysed the evolution of CHD proteins by performing a comparative study of the functional domains of CHD proteins between orthologous and paralogous protein sequences. Our findings show that the highest degree of inter-species conservation was observed at Group II (CHD3, CHD4, and CHD5) and that most of the pathological variations documented in humans involve amino acid residues that are conserved not only between species but also between paralogs. The parallel analysis of both orthologous and paralogous proteins, in cases where gene duplications have occurred, provided extra information showing patterns of flexibility as well as interchangeability between amino acid positions. This added complexity needs to be considered when the impact of novel mutations is assessed in terms of evolutionary conservation.

Compensatory epistasis explored by molecular dynamics simulations.

A non-negligible proportion of human pathogenic variants are known to be present as wild type in at least some non-human mammalian species. The standard explanation for this finding is that molecular mechanisms of compensatory epistasis can alleviate the mutations' otherwise pathogenic effects. Examples of compensated variants have been described in the literature but the interacting residue(s) postulated to play a compensatory role have rarely been ascertained. In this study, the examination of five human X-chromosomally encoded proteins (FIX, GLA, HPRT1, NDP and OTC) allowed us to identify several candidate compensated variants. Strong evidence for a compensated/compensatory pair of amino acids in the coagulation FIXa protein (involving residues 270 and 271) was found in a variety of mammalian species. Both amino acid residues are located within the 60-loop, spatially close to the 39-loop that performs a key role in coagulation serine proteases. To understand the nature of the underlying interactions, molecular dynamics simulations were performed. The predicted conformational change in the 39-loop consequent to the Glu270Lys substitution (associated with hemophilia B) appears to impair the protein's interaction with its substrate but, importantly, such steric hindrance is largely mitigated in those proteins that carry the compensatory residue (Pro271) at the neighboring amino acid position.