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A revision of the genus Cantabrogeus Salgado, 2000, with description of three new hypogean species endemic to the Cantabrian mountains (Coleoptera, Leiodidae, Cholevinae, Leptodirini) The two previously known species of the genus Cantabrogeus (Coleoptera, Leiodidae, Cholevinae, Leptodirini) are redescribed, and three new species are described: Cantabrogeus antimachus n. sp., C. cultellus n. sp. and C. fresnedai n. sp. One of these (C. antimachus n. sp.) is tripliod (3n = 33) and the first known parthenogenetic species of Leiodidae. The relationships between the different taxa are discussed based on external morphological characters and the structure of male and female genitalia, as well as the distribution of the species in the different areas in the Cantabrian mountains (NW Iberia). Analyses of molecular data (fragments of seven mitochondrial and nuclear genes) confirms the monophyly of Cantabrogeus and its sister–group relationship with Fresnedaella, as well as its inclusion within the paraphyletic series Quaestus. The parthenogenetic species (C. antimachus n. sp.) has a derived position within Cantabrogeus, which, according to previous estimates of the molecular rate, probably diversified during the Pliocene–Pleistocene in the Cantabrian karst areas, of a high tectonic complexity.

Description of Bathysciola liqueana n. sp. from the central Pyrenees. Designation of lectotypes and distribution data for species of the B. meridionalis group (Jacquelin du Val, 1854) (Insecta, Coleoptera, Leiodidae, Cholevinae, Leptodirini) We describe a new species of the genus Bathysciola Jeannel, 1910 (B. liqueana n. sp.) belonging to the ‘meridionalis’ group. It was collected in a subterranean environment, in Liqué cave, Larroque massif, Moulis, Ariège, France. The closest species is Bathysciola meridionalis (Jacquelin du Val, 1854), also known from Ariège. The new species differs mainly in morphological characteristics of the aedeagus: short, wide, with rounded apex in B. liqueana n. sp. whereas it is long, narrow, with pointed apex in B. meridionalis. We discuss the taxonomical position of the new species and provide illustrations of structures showing the differences between the two species, along with distribution data, including for B. finismillennii Fresneda & Salgado, 2006. We designate lectotypes of B. meridionalis and B. nitidula Normand, 1907.

On the presence of Catops subfuscus Kellner, 1846 in the Pyrenees (Coleoptera, Leiodidae, Cholevinae, Catopini) We provide new distribution data for Catops subfuscus Kellner, 1846. We update the geonemy of the species and, based on recent data, we confirm its presence in the subterranean environment on both sides of the Pyrenean massif. Illustrations of the aedeagus and a distribution map are provided.

Abstract Background Cave organisms have been used as models for evolution and biogeography, as their reduced above-ground dispersal produces phylogenetic patterns of area distribution that largely match the geological history of mountain ranges and cave habitats. Most current hypotheses assume that subterranean lineages arose recently from surface dwelling, dispersive close relatives, but for terrestrial organisms there is scant phylogenetic evidence to support this view. We study here with molecular methods the evolutionary history of a highly diverse assemblage of subterranean beetles in the tribe Leptodirini (Coleoptera, Leiodidae, Cholevinae) in the mountain systems of the Western Mediterranean. Results Ca. 3.5 KB of sequence information from five mitochondrial and two nuclear gene fragments was obtained for 57 species of Leptodirini and eight outgroups. Phylogenetic analysis was robust to changes in alignment and reconstruction method and revealed strongly supported clades, each of them restricted to a major mountain system in the Iberian peninsula. A molecular clock calibration of the tree using the separation of the Sardinian microplate (at 33 MY) established a rate of 2.0% divergence per MY for five mitochondrial genes (4% for cox1 alone) and dated the nodes separating the main subterranean lineages before the Early Oligocene. The colonisation of the Pyrenean chain, by a lineage not closely related to those found elsewhere in the Iberian peninsula, began soon after the subterranean habitat became available in the Early Oligocene, and progressed from the periphery to the centre. Conclusions Our results suggest that by the Early-Mid Oligocene the main lineages of Western Mediterranean Leptodirini had developed all modifications to the subterranean life and were already present in the main geographical areas in which they are found today. The origin of the currently recognised genera can be dated to the Late Oligocene-Miocene, and their diversification can thus be traced to Miocene ancestors fully adapted to subterranean life, with no evidence of extinct epigean, less modified lineages. The close correspondence of organismal evolution and geological record confirms them as an important study system for historical biogeography and molecular evolution.

A new troglobiomorphic Trechus Clairville, 1806 and evidence of multiple colonizations in the subterranean environment of the Cantabrian mountains (Coleoptera, Carabidae, Trechinae) We describe Trechus (Trechus) valenzuelai n. sp. from the Cantabrian area of Spain: Sierra de Cuera, Asturias. The species was collected in the subterranean environment, in caves and dolines. Morphological examination revealed that the new species is sister to Trechus escalerae Abeille de Perrin, 1903 within the T. saxicola clade. A synapomorphy of the male genitalia, shared by T. valenzuelai n. sp. and T. escalerae, is described and illustrated: the endophallus has a sclerotised piece shaped like a club, elongated, robust, strongly sclerotised and with a membranous sac covered with small spicules at the base. We discuss the taxonomy of the new species and provide illustrations of structures showing the differences between T. escalerae and T. valenzuelai n. sp., along with biogeographical and distributional data and hypotheses regarding the speciation events based on previously pubished molecular data, and the geological structure and the palaeoclimatology of their geographical area. We hypothesize that in this clade, the colonization of the subterranean environment was the result of multiple, independent and simultaneous colonization processes. A lectotype is designated for T. escalerae.

New distribution data for the hypogean Cholevinae from the Moroccan Atlas (Coleoptera, Leiodidae) The authors report new findings on the distribution of Speonemadus maroccanus (Jeannel, 1936), Nargus (Demochrus) rufipennis (Lucas, 1846), Choleva (Choleva) kocheri Henrot, 1962 and Catops fuscus fuscoides Reitter, 1909. The geonemy of these species is updated and the research is illustrated with maps of their distribution.

Developmental and epileptic encephalopathies (DEEs) feature altered brain development, developmental delay and seizures, with seizures exacerbating developmental delay. Here we identify a cohort with biallelic variants in DENND5A, encoding a membrane trafficking protein, and develop animal models with phenotypes like the human syndrome. We demonstrate that DENND5A interacts with Pals1/MUPP1, components of the Crumbs apical polarity complex required for symmetrical division of neural progenitor cells. Human induced pluripotent stem cells lacking DENND5A fail to undergo symmetric cell division with an inherent propensity to differentiate into neurons. These phenotypes result from misalignment of the mitotic spindle in apical neural progenitors. Cells lacking DENND5A orient away from the proliferative apical domain surrounding the ventricles, biasing daughter cells towards a more fate-committed state, ultimately shortening the period of neurogenesis. This study provides a mechanism for DENND5A-related DEE that may be generalizable to other developmental conditions and provides variant-specific clinical information for physicians and families., (© 2024. The Author(s).)

Neurodevelopmental disorders with intellectual disability (ND/ID) are a heterogeneous group of diseases driving lifelong deficits in cognition and behavior with no definitive cure. X-linked intellectual disability disorder 105 (XLID105, #300984; OMIM) is a ND/ID driven by hemizygous variants in the USP27X gene encoding a protein deubiquitylase with a role in cell proliferation and neural development. Currently, only four genetically diagnosed individuals from two unrelated families have been described with limited clinical data. Furthermore, the mechanisms underlying the disorder are unknown. Here, we report 10 new XLID105 individuals from nine families and determine the impact of gene variants on USP27X protein function. Using a combination of clinical genetics, bioinformatics, biochemical, and cell biology approaches, we determined that XLID105 variants alter USP27X protein biology via distinct mechanisms including changes in developmentally relevant protein-protein interactions and deubiquitylating activity. Our data better define the phenotypic spectrum of XLID105 and suggest that XLID105 is driven by USP27X functional disruption. Understanding the pathogenic mechanisms of XLID105 variants will provide molecular insight into USP27X biology and may create the potential for therapy development., (© 2024 Koch et al.)

Very-Long-Chain Acyl-CoA Dehydrogenase Deficiency (VLCADD) is a fatty acid oxidation disorder characterized by the decreased ability of the enzyme very-long-chain acyl-CoA dehydrogenase to break down fatty acids with 14 to 20-long carbon chains. The resulting clinical manifestations are variable in severity and include hypoketotic hypoglycemia, rhabdomyolysis, and cardiomyopathy. Treatment can consist of limiting the dietary intake of long-chain fatty acids, the prevention of fasting, and the supplementation of medium-chain fats. This study, conducted in the context of a 5-year long-term follow-up on VLCADD, evaluates how the diagnosis of this fatty acid disorder impacts the family, specifically as it relates to the medical diet and barriers to care. Caregivers ( n = 10) of individuals with VLCADD responded to a survey about how VLCADD potentially impacts their family. The review included the clinical outcomes of the patients ( n = 11), covering instances of rhabdomyolysis, cardiomyopathy, and hospitalizations related to VLCADD. Families affected by VLCADD experience barriers to care, including difficulties with finances, ability to work, and access to nutrition.

Progressive encephalopathy with brain atrophy and thin corpus callosum (PEBAT) is a severe and rare progressive neurodegenerative disease (OMIM 617913). This condition has been described in individuals with pathogenic variants affecting tubulin-specific chaperone protein D (TBCD), which is responsible for proper folding and assembly of tubulin subunits. Here we describe two unrelated infants from Central America presenting with worsening neuromuscular weakness, respiratory failure, polyneuropathy, and neuroimaging findings of severe cerebral volume loss with thin corpus callosum. These individuals harbored the same homozygous variant of uncertain significance in the TBCD gene on whole exome sequencing (WES). Predicted protein modeling of this variant confirmed disruption of the protein helix at the surface of TBCD. The goal of this report is to emphasize the importance of rapid WES, careful interpretation of uncertain variants, prognostication, and family counseling especially when faced with a neurodegenerative clinical course., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Nonketotic hyperglycinemia (NKH) is caused by deficient glycine cleavage enzyme activity and characterized by elevated brain glycine. Metabolism of glycine is connected enzymatically to serine through serine hydroxymethyltransferase and shares transporters with serine and threonine. We aimed to evaluate changes in serine and threonine in NKH patients, and relate this to clinical outcome severity. Age-related reference values were developed for cerebrospinal fluid (CSF) serine and threonine from 274 controls, and in a cross-sectional study compared to 61 genetically proven NKH patients, categorized according to outcome. CSF d-serine and l-serine levels were stereoselectively determined in seven NKH patients and compared to 29 age-matched controls. In addition to elevated CSF glycine, NKH patients had significantly decreased levels of CSF serine and increased levels of CSF threonine, even after age-adjustment. The CSF serine/threonine ratio discriminated between NKH patients and controls. The CSF glycine/serine aided in discrimination between severe and attenuated neonates with NKH. Over all ages, the CSF glycine, serine and threonine had moderate to fair correlation with outcome classes. After age-adjustment, only the CSF glycine level provided good discrimination between outcome classes. In untreated patients, d-serine was more reduced than l-serine, with a decreased d/l-serine ratio, indicating a specific impact on d-serine metabolism. We conclude that in NKH the elevation of glycine is accompanied by changes in l-serine, d-serine and threonine, likely reflecting a perturbation of the serine shuttle and metabolism, and of one-carbon metabolism. This provides additional guidance on diagnosis and prognosis, and opens new therapeutic avenues to be explored., (© 2022 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)

Background: The coronavirus pandemic has led to a situation without precedent in modern history. The aim of this study is to analyse the consequences after one year of the pandemic on a group of children and adolescents assessed at the beginning of the pandemic in 2020 and to determine the most effective ways of psychologically coping with this pandemic., Method: Two different, but equivalent, groups with a total of 604 (study I, 2020) and 743 (study II, 2021) children and adolescents in residential care, foster families, kinship families or family strengthening programs in Spain were evaluated using the SDQ (mental health measure), KIDSCREEN-10 index (quality of life measure) and Kidcope (coping behaviour measure). An independent sample t-test and a decision tree analysis were used., Results: The mental health of children and adolescents decreased by 9.7%, and Self-Perceived quality of life did not change after one year of the COVID-19 pandemic. Nonactive coping strategies predicted worse mental health and worse quality of life. Problem solving served as a protective factor., Conclusion: One year after, the COVID-19 pandemic has an effect on the psychological wellbeing of children and adolescents, and the consequences can be reduced if proper coping strategies are used.

The climatic variability hypothesis predicts the evolution of species with wide thermal tolerance ranges in environments with variable temperatures, and the evolution of thermal specialists in thermally stable environments. In caves, the extent of spatial and temporal thermal variability experienced by taxa decreases with their degree of specialization to deep subterranean habitats. We use phylogenetic generalized least squares to model the relationship among thermal tolerance (upper lethal limits), subterranean specialization (estimated using ecomorphological traits), and habitat temperature in 16 beetle species of the tribe Leptodirini (Leiodidae). We found a significant, negative relationship between thermal tolerance and the degree of subterranean specialization. Conversely, habitat temperature had only a marginal effect on lethal limits. In agreement with the climatic variability hypothesis and under a climate change context, we show that the specialization process to live in deep subterranean habitats involves a reduction of upper lethal limits, but not an adjustment to habitat temperature. Thermal variability seems to exert a higher evolutionary pressure than mean habitat temperature to configure the thermal niche of subterranean species. Our results provide novel insights on thermal physiology of species with poor dispersal capabilities and on the evolutionary process of adaptation to subterranean environments. We further emphasize that the pathways determining vulnerability of subterranean species to climate change greatly depend on the degree of specialization to deep subterranean environments., (© 2022 The Ecological Society of America.)

The genetic causes of global developmental delay (GDD) and intellectual disability (ID) are diverse and include variants in numerous ion channels and transporters. Loss-of-function variants in all five endosomal/lysosomal members of the CLC family of Cl - channels and Cl - /H + exchangers lead to pathology in mice, humans, or both. We have identified nine variants in CLCN3, the gene encoding CIC-3, in 11 individuals with GDD/ID and neurodevelopmental disorders of varying severity. In addition to a homozygous frameshift variant in two siblings, we identified eight different heterozygous de novo missense variants. All have GDD/ID, mood or behavioral disorders, and dysmorphic features; 9/11 have structural brain abnormalities; and 6/11 have seizures. The homozygous variants are predicted to cause loss of ClC-3 function, resulting in severe neurological disease similar to the phenotype observed in Clcn3 -/- mice. Their MRIs show possible neurodegeneration with thin corpora callosa and decreased white matter volumes. Individuals with heterozygous variants had a range of neurodevelopmental anomalies including agenesis of the corpus callosum, pons hypoplasia, and increased gyral folding. To characterize the altered function of the exchanger, electrophysiological analyses were performed in Xenopus oocytes and mammalian cells. Two variants, p.Ile607Thr and p.Thr570Ile, had increased currents at negative cytoplasmic voltages and loss of inhibition by luminal acidic pH. In contrast, two other variants showed no significant difference in the current properties. Overall, our work establishes a role for CLCN3 in human neurodevelopment and shows that both homozygous loss of ClC-3 and heterozygous variants can lead to GDD/ID and neuroanatomical abnormalities., (Copyright © 2021 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

We redefine the genus Troglocharinus Reitter, 1908 based on a phylogenetic analysis with a combination of mitochondrial and molecular data. We recovered the current Speonomites mengeli (Jeannel, 1910) and S. mercedesi (Zariquiey, 1922) as valid, separate species within the Troglocharinus clade, not directly related to Speonomites Jeannel, 1910, a finding corroborated by a detailed study of the male and female genitalia. In consequence, we reinstate Speonomus mercedesi Zariquiey, 1922 stat. nov. as a valid species, transfer both of them to the genus Troglocharinus, T. mengeli (Jeannel, 1910) comb. nov. and T. mercedesi (Zariquiey, 1922) comb. nov., and redescribe the genus. The study of new material from the distribution area of the former S. mengeli revealed the presence of two undescribed species, T. sendrai sp. nov. and T. fadriquei sp. nov., which we describe herein. We designate the lectotype of Speonomus vinyasi Escolà, 1971 to fix its identity, as among its syntypes there are two different species. In agreement with the results of the phylogenetic analyses we establish the synonymy between the genus Speonomites and Pallaresiella Fresneda, 1998 syn. nv.

Background: A pandemic disaster has specific effects on mental health, however, little is known about those specific effects in children and adolescents. Thus, the aim of this study is to describe the psychological impact of the COVID-19 pandemic on a sample of children and adolescents and to compare the results with previous national data and other studies to determine variations., Method: A total of 459 children and adolescents in residential care, foster families, kinship families, or family strengthening programs under SOS Children's Villages Spain were evaluated using the SDQ to measure internalizing and externalizing problems and using KIDSCREEN-10 index to measure heath related quality of life. An independent sample t-test, one-way ANOVA and the chi-square test were used., Results: The children and adolescents in this study had worse psychological wellbeing than those in the 2017 Spanish reference, that is, before the COVID-19 outbreak. Quality of life remained the same. No differences between care modalities were found., Conclusion: It is necessary to monitor the mental health status of children and adolescents to prevent possible problems. Additionally, it is necessary to use well-known assessment instruments because it is essential to have a reference to other situations and populations.

Potocki-Lupski Syndrome (PTLS, MIM 610883), or duplication of chromosome 17p11.2, is a clinically recognizable condition characterized by infantile hypotonia, failure to thrive, developmental delay, intellectual disability, and congenital anomalies. Short stature, classified as greater than two standard deviations below the mean, has not previously been considered a major feature of PTLS. Retrospective chart review on a cohort of 37 individuals with PTLS was performed to investigate the etiology of short stature. Relevant data included anthropometric measurements, insulin growth factor-1 (IGF-1), insulin-like growth factor binding protein 3 (IGFBP-3), growth hormone (GH) stimulation testing, blood glucose levels, brain MRI, and bone age. Approximately 25% (9/37) of individuals with PTLS had short stature. Growth hormone deficiency (GHD) was definitively identified in two individuals. These two PTLS patients with growth hormone deficiency, as well as three others with short stature and no documented GHD, received growth hormone and obtained improvement in linear growth. One individual was identified to have pituitary abnormalities on MRI and had complications of hypoglycemia due to unrecognized GHD. Individuals with PTLS can benefit from undergoing evaluation for GHD should they present with short stature or hypoglycemia. Early identification of GHD could facilitate potential therapeutic benefit for individuals with PTLS, including linear growth, musculoskeletal, and in cases of hypoglycemia, potentially cognitive development as well., (© 2020 Wiley Periodicals LLC.)

The genus Speonemadus Jeannel, 1922 currently includes 12 species distributed in the Western Mediterranean (Iberian Peninsula, North Africa, Sicily and continental Italy). Two new species are described from Morocco, S. brusteli sp. n. from the Rif and S. comasi sp. n. from the High Atlas, the first in the S. vandalitiae-group of species and the second with an isolated position within the genus. Two species are also resurrected from synonymy, S. pulchellus (Reitter, 1885) stat. rest. (former synonym of S. orchesioides (Fairmaire, 1879)) and S. gracilis (Kraatz, 1870) stat. rest. (former synonym of S. vandalitiae (Heyden, 1870)), raising the total number of species of the genus to 16. Lectotypes are designated for Anemadus pulchellus Reitter, 1885, and Anemadus tenuipes Peyerimhoff, 1917. A molecular phylogeny of the genus Speonemadus is presented, based on a combination of mitochondrial and nuclear genes and including seven of the currently recognised species, one of the newly described (S. brusteli sp. n.) and the two reinstated taxa. The genus is estimated to have diversified from the late Miocene (Tortonian), with successive cladogenetic events related to the isolation of landmasses between Iberia and North Africa, including the opening of the Strait of Gibraltar at the end of the Messinian. The distribution of some of the species of Speonemadus remains still uncertain, due to their frequent misidentification and the problems with their taxonomic status.

Aphaobius haraldi sp. n. from the mesovoid shallow substratum (MSS) of the Austrian Alps is described, illustrated, and compared with the closest species of the genus. The new species belongs to the A. kraussi species group, formerly including five species. It can be readily separated from other species of the genus by the large parameres, with an enlarged apical part, a unique feature among species of Aphaobius. The phylogenetic position of the new species is clarified using mitochondrial and nuclear data of four related species of Aphaobius, plus some representatives of related genera from the same geographic area. The diversification of the group was estimated to be recent, dating from the Pleistocene. New records and molecular data are provided regarding the enigmatic monospecific genus of the Austrian Alps, Lotharia Mandl, 1944, which was found to be sister to the studied species of Aphaobius.

For management strategies in the context of global warming, accurate predictions of species response are mandatory. However, to date most predictions are based on niche (bioclimatic) models that usually overlook biotic interactions, behavioral adjustments or adaptive evolution, and assume that species can disperse freely without constraints. The deep subterranean environment minimises these uncertainties, as it is simple, homogeneous and with constant environmental conditions. It is thus an ideal model system to study the effect of global change in species with poor dispersal capabilities. We assess the potential fate of a lineage of troglobitic beetles under global change predictions using different approaches to estimate their thermal niche: bioclimatic models, rates of thermal niche change estimated from a molecular phylogeny, and data from physiological studies. Using bioclimatic models, at most 60% of the species were predicted to have suitable conditions in 2080. Considering the rates of thermal niche change did not improve this prediction. However, physiological data suggest that subterranean species have a broad thermal tolerance, allowing them to stand temperatures never experienced through their evolutionary history. These results stress the need of experimental approaches to assess the capability of poor dispersal species to cope with temperatures outside those they currently experience.

Smith-Magenis syndrome (SMS) and Potocki-Lupski syndrome (PTLS) are reciprocal contiguous gene syndromes within the well-characterized 17p11.2 region. Approximately 3.6 Mb microduplication of 17p11.2, known as PTLS, represents the mechanistically predicted homologous recombination reciprocal of the SMS microdeletion, both resulting in multiple congenital anomalies. Mouse model studies have revealed that the retinoic acid-inducible 1 gene (RAI1) within the SMS and PTLS critical genomic interval is the dosage-sensitive gene responsible for the major phenotypic features in these disorders. Even though PTLS and SMS share the same genomic region, clinical manifestations and behavioral issues are distinct and in fact some mirror traits may be on opposite ends of a given phenotypic spectrum. We describe the neurobehavioral phenotypes of SMS and PTLS patients during different life phases as well as clinical guidelines for diagnosis and a multidisciplinary approach once diagnosis is confirmed by array comparative genomic hybridization or RAI1 gene sequencing. The main goal is to increase awareness of these rare disorders because an earlier diagnosis will lead to more timely developmental intervention and medical management which will improve clinical outcome.

Background: A key question in evolutionary biology is the relationship between species traits and their habitats. Caves offer an ideal model to test the adjustment of species to their surrounding temperature, as they provide homogeneous and simple environments. We compared two species living under different thermal conditions within a lineage of Pyrenean beetles highly modified for the subterranean life since the Miocene. One, Troglocharinus fonti, is found in caves at 4-11°C in the ancestral Pyrenean range. The second, T. ferreri, inhabits the coastal area of Catalonia since the early Pliocene, and lives at 14-16°C., Results: We found no differences in their short term upper thermal limit (ca. 50°C), similar to that of most organisms, or their lower thermal limit (ca. -2.5°C), higher than for most temperate insects and suggesting the absence of cryoprotectants. In longer term tests (7 days) survival between 6-20°C was almost 100% for both species plus two outgroups of the same lineage, but all four died between 23-25°C, without significant differences between them., Conclusions: Our results suggest that species in this lineage have lost some of the thermoregulatory mechanisms common in temperate insects, as their inferred default tolerance range is larger than the thermal variation experienced through their whole evolutionary history.

In insects, whilst variations in life cycles are common, the basic patterns typical for particular groups remain generally conserved. One of the more extreme modifications is found in some subterranean beetles of the tribe Leptodirini, in which the number of larval instars is reduced from the ancestral three to two and ultimately one, which is not active and does not feed. We analysed all available data on the duration and size of the different developmental stages and compared them in a phylogenetic context. The total duration of development was found to be strongly conserved, irrespective of geographical location, habitat type, number of instars and feeding behaviour of the larvae, with a single alteration of the developmental pattern in a clade of cave species in southeast France. We also found a strong correlation of the size of the first instar larva with adult size, again regardless of geographical location, ecology and type of life cycle. Both results suggest the presence of deeply conserved constraints in the timing and energy requirements of larval development. Past focus on more apparent changes, such as the number of larval instars, may mask more deeply conserved ontogenetic patterns in developmental timing., (© 2014 The Author(s) Published by the Royal Society. All rights reserved.)

Research on subterranean organisms has focused on the colonization process and some of the associated phenotypic changes, but little is known on the long-term evolutionary dynamics of subterranean lineages and the origin of some highly specialized complex characters. One of the most extreme modifications is the reduction of the number of larval instars in some Leptodirini beetles from the ancestral 3 to 2 and ultimately a single instar. This reduction is usually assumed to have occurred independently multiple times within the same lineage and geographical area, but its evolution has never been studied in a phylogenetic framework. Using a comprehensive molecular phylogeny, we found a low number of independent origins of the reduction in the number of instars, with a single transition, dated to the Oligocene-Miocene, from 3 to 2 and then 1 instar in the Pyrenees, the best-studied area. In the Pyrenees, the 1-instar lineage had a diversification rate (0.22 diversification events per lineage per million years) significantly higher than that of 3- or 2-instar lineages (0.10), and similar to that seen in other Coleopteran radiations. Far from being evolutionary dead-ends, ancient lineages fully adapted to subterranean life seem able to persist and diversify over long evolutionary periods.

Geotrechus sarpedon sp. n., a new species of blind Trechini is described from Arbailles Massif, western Pyrenees, trance. The generic attribution of the new species was challenging as it shares morphological features of both genera Geotrechus Jeannel, 1919 and Aphaenops subgenus Hydraphaenops Jeannel, 1926, confirming their polyphyly, which has been highlighted by previous molecular studies on the group. Molecular data suggests unambiguously strong affinities between the new species and the clade Aphaenops vasconicus Jeannel, 1913-A. galani Espanol, 1968 occurring in the same geographic area, and not related with Aphaenops ehlersi (Abeille de Perrin, 1872), type species of the subgenus Hydraphaenops. The species is included in the paraphyletic genus Geotrechus until its affinities with the other species of Geotrechus and A. (Hydraphaenops) are clarified.

A molecular phylogeny of the species from the Trechus brucki clade (previously Trechus uhagoni group)based on fragments of four mitochondrial genes and one nuclear gene is given. We describe Trechus (Trechus) bouillonisp. n. from the western pre-Pyrenees: Sierras de Urbasa-Andía, Navarra, Spain. The species was collected in mesovoid shallow substratum (mss), a subterranean environment. Molecular as well as morphological evidences demonstrate that the new species belongs to the Trechus brucki clade. A narrow endemic species of high altitude in western French Pyrenees merged with Trechus brucki Fairmaire, 1862a, Trechus bruckoidessp. n., is described. A lectotype is designated for Trechus brucki and Trechus planiusculus Fairmaire, 1862b (junior synonym of Trechus brucki). The species group is redefined based on molecular and morphological characters, and renamed as the brucki group, as Trechus brucki was the first described species of the clade. A unique synapomorphy of the male genitalia, a characteristic secondary sclerotization of the sperm duct, which is shared by all the species of the brucki group sensu novo, is described and illustrated. The Trechus brucki group sensu novo is composed of Trechus beusti (Schaufuss, 1863), Trechus bouillonisp. n., Trechus brucki, Trechus bruckoidessp. n., Trechus grenieri Pandellé, 1867, T. uhagoni uhagoni Crotch, 1869, T. uhagoni ruteri Colas, 1935 and Trechus pieltaini Jeannel, 1920. We discuss the taxonomy of the group and provide illustrations of structures showing the differences between the species, along with distribution data and biogeographical comments.

Sexual dimorphism in blood pressure (BP) regulation has been observed both in humans and experimental animals, and estrogens have been shown to contribute to this epidemiological observation. A key enzyme in determining estrogen levels is aromatase cytochrome P450. The aim of this study was to evaluate the role of the gene encoding aromatase, CYP19A1, as an independent risk factor for hypertension and its relationship with systolic and diastolic BP measures. We genotyped 2 polymorphisms within the CYP19A1 gene, IVS4 rs11575899 and 3'UTR rs10046, in 3448 individuals. In quantitative analysis, we observed significant associations between the 2 polymorphisms and BP values in women, being these associations dependent on BMI and independent of menopause status. The case-control analysis revealed that the most prominent associations were found for nonobese women in diastolic hypertension (DHT): the IVS4_22 and 3'UTR_11 are risk genotypes (OR=1.61, P=0.027 and OR=1.59, P=0.012, respectively), whereas IVS4_11 and 3'UTR_22 genotypes have a protective effect against DHT (OR=0.63, P=0.009, and OR=0.61, P=0.020, respectively). Haplotype analysis confirmed the above associations: among nonobese women the haplotype 21 is overrepresented in hypertensive women (OR=1.33, P=0.004, for DHT and OR=1.25, P=0.026, for systolic hypertension, SHT) and, conversely, the haplotype 12 protects against hypertension (OR=0.78, P=0.015 for DHT and OR=0.82, P=0.04 for SHT). Our study has shown that the CYP19A1 gene may be involved in the genetic regulation of BP in women. This effect is dependent on BMI and independent of menopause status, suggesting that this action is mainly driven by aromatase activity in fat tissue.