Redescription of the tiger beetle Cicindelidia aeneicollis (Bates 1881) (Coleoptera: Cicindelidae) and discovery of new morphological variants from the Pacific Slope of Mexico.

The tiger beetle species, Cicindelidia aeneicollis (Bates 1881) is redescribed, as Bates original description was inadequate and did not accurately capture the character states or variation found within the species. The specific epithet aeneicollis is partially misleading as the proepisternum is mostly aeneous (bronze/copper) with the basal quarter to third being polychromatic, which the description does not convey. Some populations of this species from the western coast of Mexico exhibit significant variation in maculations, with individuals ranging from weakly marked (as in Bates description) to much more extensively marked.

Species delimitation, discovery and conservation in a tiger beetle species complex despite discordant genetic data.

In an age of species declines, delineating and discovering biodiversity is critical for both taxonomic accuracy and conservation. In recent years, there has been a movement away from using exclusively morphological characters to delineate and describe taxa and an increase in the use of molecular markers to describe diversity or through integrative taxonomy, which employs traditional morphological characters, as well as genetic or other data. Tiger beetles are charismatic, of conservation concern, and much work has been done on the morphological delineation of species and subspecies, but few of these taxa have been tested with genetic analyses. In this study, we tested morphologically based taxonomic hypotheses of polymorphic tiger beetles in the Eunota circumpicta (LaFerté-Sénectère, 1841) species complex using multilocus genomic and mtDNA analyses. We find multiple cryptic species within the previous taxonomic concept of Eunota circumpicta, some of which were historically recognized as subspecies. We found that the mtDNA and genomic datasets did not identify the same taxonomic units and that the mtDNA was most at odds with all other genetic and morphological patterns. Overall, we describe new cryptic diversity, which raises important conservation concerns, and provide a working example for testing species and subspecies validity despite discordant data.

Mutation of key signaling regulators of cerebrovascular development in vein of Galen malformations.

To elucidate the pathogenesis of vein of Galen malformations (VOGMs), the most common and most severe of congenital brain arteriovenous malformations, we performed an integrated analysis of 310 VOGM proband-family exomes and 336,326 human cerebrovasculature single-cell transcriptomes. We found the Ras suppressor p120 RasGAP (RASA1) harbored a genome-wide significant burden of loss-of-function de novo variants (2042.5-fold, p = 4.79 x 10-7). Rare, damaging transmitted variants were enriched in Ephrin receptor-B4 (EPHB4) (17.5-fold, p = 1.22 x 10-5), which cooperates with p120 RasGAP to regulate vascular development. Additional probands had damaging variants in ACVRL1, NOTCH1, ITGB1, and PTPN11. ACVRL1 variants were also identified in a multi-generational VOGM pedigree. Integrative genomic analysis defined developing endothelial cells as a likely spatio-temporal locus of VOGM pathophysiology. Mice expressing a VOGM-specific EPHB4 kinase-domain missense variant (Phe867Leu) exhibited disrupted developmental angiogenesis and impaired hierarchical development of arterial-capillary-venous networks, but only in the presence of a "second-hit" allele. These results illuminate human arterio-venous development and VOGM pathobiology and have implications for patients and their families.

A genomic test of subspecies in the Eunota togata species group (Coleoptera: Cicindelidae): Morphology masks evolutionary relationships and taxonomy.

Most of the world's biodiversity is described primarily or exclusively using morphological traits that may not always reflect the true evolutionary units. Accurate taxonomy is critical for conservation efforts and re-evaluation of traditional taxonomy may often be warranted since species and subspecies are frequently the focus of conservation and faunistic studies. Here, we test comprehensive taxonomic hypotheses of morphologically defined subspecies in the tiger beetle, Eunota togata (LaFerté-Sénectère, 1841). The four recognized subspecies were delineated based mainly on the dorsal coloration and extent of white markings termed maculations. We combine inferences from mtDNA genealogies and genome-wide multilocus data to elucidate the evolutionary relationships within the group and assess the taxonomic implications. Three of the four subspecific taxa delineated by morphology were not supported by the genomic or mtDNA data. In fact, the species-level diversity in this group was underestimated, as E. togata was found to represent three well-supported distinct species in all genetic analyses. Emerging from these analyses, we also document an intriguing example of convergent evolution in lighter colored E. togata adapting to similar white saline backgrounds. Our collective work underscores the importance of using molecular methods to reevaluate morphological based taxonomy for species and subspecies delimitation and conservation.

Super-enhancer hijacking drives ectopic expression of hedgehog pathway ligands in meningiomas.

Hedgehog signaling mediates embryologic development of the central nervous system and other tissues and is frequently hijacked by neoplasia to facilitate uncontrolled cellular proliferation. Meningiomas, the most common primary brain tumor, exhibit Hedgehog signaling activation in 6.5% of cases, triggered by recurrent mutations in pathway mediators such as SMO. In this study, we find 35.6% of meningiomas that lack previously known drivers acquired various types of somatic structural variations affecting chromosomes 2q35 and 7q36.3. These cases exhibit ectopic expression of Hedgehog ligands, IHH and SHH, respectively, resulting in Hedgehog signaling activation. Recurrent tandem duplications involving IHH permit de novo chromatin interactions between super-enhancers within DIRC3 and a locus containing IHH. Our work expands the landscape of meningioma molecular drivers and demonstrates enhancer hijacking of Hedgehog ligands as a route to activate this pathway  in neoplasia.

A new species of tiger beetle (Coleoptera: Cicindelidae) from the Death Valley ecosystem.

A new tiger beetle species, Cicindela timbisha Duran, Chambers, Nelson & Roman n. sp., of the tribe Cicindelini, is described from the Death Valley ecoregion of eastern California, USA. It is most similar to C. senilis G.Horn, 1866 but is distinguished on the basis of multiple morphological characteristics, including differences in maculations, chaetotaxy of the antennae and a statistically significant difference in body size (P<0.001). The new species also differs from C. senilis in that it is found in an isolated freshwater spring in an inland basin east of the Sierra Nevada mountains, whereas C. senilis is found in saline soils, primarily coastal areas and inland plains, west of the Sierra Nevada range.

Genetic dysregulation of an endothelial Ras signaling network in vein of Galen malformations.

To elucidate the pathogenesis of vein of Galen malformations (VOGMs), the most common and severe congenital brain arteriovenous malformation, we performed an integrated analysis of 310 VOGM proband-family exomes and 336,326 human cerebrovasculature single-cell transcriptomes. We found the Ras suppressor p120 RasGAP ( RASA1 ) harbored a genome-wide significant burden of loss-of-function de novo variants (p=4.79×10 -7 ). Rare, damaging transmitted variants were enriched in Ephrin receptor-B4 ( EPHB4 ) (p=1.22×10 -5 ), which cooperates with p120 RasGAP to limit Ras activation. Other probands had pathogenic variants in ACVRL1 , NOTCH1 , ITGB1 , and PTPN11 . ACVRL1 variants were also identified in a multi-generational VOGM pedigree. Integrative genomics defined developing endothelial cells as a key spatio-temporal locus of VOGM pathophysiology. Mice expressing a VOGM-specific EPHB4 kinase-domain missense variant exhibited constitutive endothelial Ras/ERK/MAPK activation and impaired hierarchical development of angiogenesis-regulated arterial-capillary-venous networks, but only when carrying a "second-hit" allele. These results illuminate human arterio-venous development and VOGM pathobiology and have clinical implications.

Berberis microphylla G. Forst Intake Reduces the Cardiovascular Disease Plasmatic Markers Associated with a High-Fat Diet in a Mice Model.

Polyphenols are bioactive substances that participate in the prevention of chronic illnesses. High content has been described in Berberis microphylla G. Forst (calafate), a wild berry extensively distributed in Chilean-Argentine Patagonia. We evaluated its beneficial effect through the study of mouse plasma metabolome changes after chronic consumption of this fruit. Characterized calafate extract was administered in water, for four months, to a group of mice fed with a high-fat diet and compared with a control diet. Metabolome changes were studied using UHPLC-DAD-QTOF-based untargeted metabolomics. The study was complemented by the analysis of protein biomarkers determined using Luminex technology, and quantification of OH radicals by electron paramagnetic resonance spectroscopy. Thirteen features were identified with a maximum annotation level-A, revealing an increase in succinic acid, activation of tricarboxylic acid and reduction of carnitine accumulation. Changes in plasma biomarkers were related to inflammation and cardiovascular disease, with changes in thrombomodulin (-24%), adiponectin (+68%), sE-selectin (-34%), sICAM-1 (-24%) and proMMP-9 (-31%) levels. The production of OH radicals in plasma was reduced after calafate intake (-17%), especially for the group fed with a high-fat diet. These changes could be associated with protection against atherosclerosis due to calafate consumption, which is discussed from a holistic and integrative point of view.

Increasing precision in the management of pediatric neurosurgical cerebrovascular diseases with molecular genetics.

Recent next-generation DNA and RNA sequencing studies of congenital and pediatric cerebrovascular anomalies such as moyamoya disease, arteriovenous malformations, vein of Galen malformations, and cavernous malformations have shed new insight into the genetic regulation of human cerebrovascular development by implicating multiple novel disease genes and signaling pathways in the pathogenesis of these disorders. These diseases are now beginning to be categorized by molecular disruptions in canonical signaling pathways that impact the differentiation and proliferation of specific venous, capillary, or arterial cells during the hierarchical development of the cerebrovascular system. Here, the authors discuss how the continued study of these and other congenital cerebrovascular conditions has the potential to replace the current antiquated, anatomically based disease classification systems with a molecular taxonomy that has the potential to increase precision in genetic counseling, prognostication, and neurosurgical and endovascular treatment stratification. Importantly, the authors also discuss how molecular genetic data are already informing clinical trials and catalyzing the development of targeted therapies for these conditions historically considered as exclusively neurosurgical lesions.

Single Night Surveys of Moth Communities Can Serve as Ultra-Rapid Biodiversity Assessments.

Biodiversity conservation decisions are typically based on limited data and resources. For this reason, there is great interest in surveying taxa that may allow for a rapid assessment of the biodiversity at a site. Numerous taxa have been proposed and utilized for rapid assessments that allow for such a survey in a matter of weeks or less. Herein, we test the idea that nocturnal moths have many of the characteristics that make them ideal for such surveys, such as relative ease of identification, strong ecological association with specific plant species and habitats, high alpha diversity, extended seasonal activity, and ease of trapping. We demonstrate that even in a few hours of sampling during single night surveys, moth communities are predictive of regional forest types at sampling sites in New Jersey. We sampled moths in five different forest habitats in New Jersey, USA: Pine Barrens, Upland Deciduous Forest, Palustrine Deciduous Forest, Maritime Forest, and Ruderal/Disturbed Forests, at four sites per forest type. Non-metric multidimensional scaling (NMDS) analyses revealed that moth communities differ significantly across these four forest types (p < 0.01). We used Analysis of Similarity (ANOSIM) R tests to quantify the degree of differentiation among moth communities, and found that Tortricidae (R = 0.657) and Geometridae (R = 0.637) predict forest communities nearly as well as the total moth diversity (R = 0.668). Uncommon species (R = 0.665) were better predictors than common species (R = 0.500). Host plant generalists (R = 0.654) were better predictors than specialists (0.538), which was a surprising find.

A new genus of tiger beetle (Coleoptera: Cicindelidae) from the Nearctic and Neotropical realms.

The taxonomically problematic tiger beetle species, Cylindera lemniscata (LeConte, 1854), has been difficult to place within the Nearctic fauna because of its peculiar morphological characteristics which were noted in its description, and by subsequent workers. Molecular phylogenetic studies of the late 1990s and early 2000s were similarly unable to reach a consensus about its systematic placement. More recently, a densely sampled mtDNA genealogy recovered Cy. lemniscata as a monotypic clade that is sister to a larger clade of Nearctic tiger beetles that included species of Dromochorus Gurin-Mneville, 1845, Ellipsoptera Dokhtouroff, 1883 and Parvindela Duran Gough, 2019. In this present study, morphological characters were assessed for Cy. lemniscata and all of the above taxa, as well as members of the genus Brasiella Rivalier, 1954 and Cicindelidia cardini (Leng Mutchler, 1916), a poorly known Cuban endemic with markings that are remarkably similar to Cy. lemniscata. The consensus of molecular and morphological analyses indicates that Cy. lemniscata is not congeneric with any other species, and as such, we erect Jundlandia Duran Gough 2022, new genus, to accommodate this unique taxon. Future molecular work may determine that Ci. cardini may belong in Jundlandia.

Taxonomic changes to the Neotropical species of the genus Habroscelimorpha (Coleoptera: Cicindelidae).

The taxonomy of the tiger beetle genus Habroscelimorpha Dokhtouroff, 1883 is revised based on morphology, ecology, and molecular phylogenetics. Recently, nine Nearctic species of Habroscelimorpha were transferred to Eunota Rivalier, 1954 based on the same data types, but the Neotropical species have not been formally evaluated until the present publication. Herein I propose five new combinations based on a plurality of data, including morphological traits, ecology, and the topologies of three prior molecular studies, each based on three mitochondrial gene fragments (16S, COX3 and CytB): Eunota auraria (Klug, 1834) new combination, Eunota boops (Dejean, 1831) new combination, Eunota euryscopa (Bates, 1890) new combination, Eunota wellingi (Cassola and Sawada, 1990) new combination, Microthylax schwarzi (W. Horn, 1923) new combination.

Description of a new halophilic tiger beetle in the genus Eunota (Coleoptera, Cicindelidae, Cicindelini) identified using morphology, phylogenetics and biogeography.

Tiger beetles are a popular group of insects amongst amateur naturalists, and are well-represented in museum and private collections. New species descriptions plateaued in the 19th century, but there is a recent resurgence of discoveries as integrative taxonomy methods, guided by molecular systematics, uncover "cryptic" tiger beetle diversity. In this paper, we describe a new species using multiple data types. This new species, Eunota mecocheila Duran and Roman n. sp., is in the tribe Cicindelini, and is described from specimens collected in saline muddy ditches in northern Mexico. This species is closely related to E. circumpicta (LaFerté-Sénectère, 1841), but is separated based on morphological differences, geographic range, and genetic differentiation. Little is known about the biology or distribution of this species and it has only been collected from two sites in the state of Coahuila. Given the location of this new species, and its genetic divergence from its closest relative, E. circumpicta, we discuss the historical biogeography that may have led to isolation and speciation. The male and female dorsal, lateral and frontal habitus and the male aedeagus are shown.

Cellulose biosynthesis using simple sugars available in residual cacao mucilage exudate.

Worldwide only 8% of the biomass from harvested cacao fruits is used, as cacao beans, in chocolate-based products. Cacao mucilage exudate (CME), a nutrient-rich fluid, is usually lost during cacao beans fermentation. CME's composition and availability suggest a potential carbon source for cellulose production. CME and the Hestrin and Schramm medium were used, and compared, as growth media for bacterial cellulose (BC) production with Gluconacetobacter xylinus. CME can be used to produce BC. However, the high sugar content, low pH, and limited nitrogen sources in CME hinder G. xylinus growth affecting cellulose yields. BC production increased from 0.55 ± 0.16 g L-1 up to 13.13 ± 1.09 g L-1 after CME dilution and addition of a nitrogen source. BC production was scaled up from 30 mL to 15 L, using lab-scale experiments conditions, with no significant changes in yields and production rates, suggesting a robust process with industrial possibilities.

DIAPH1 Variants in Non-East Asian Patients With Sporadic Moyamoya Disease.

Importance: Moyamoya disease (MMD), a progressive vasculopathy leading to narrowing and ultimate occlusion of the intracranial internal carotid arteries, is a cause of childhood stroke. The cause of MMD is poorly understood, but genetic factors play a role. Several familial forms of MMD have been identified, but the cause of most cases remains elusive, especially among non-East Asian individuals. Objective: To assess whether ultrarare de novo and rare, damaging transmitted variants with large effect sizes are associated with MMD risk. Design, Setting, and Participants: A genetic association study was conducted using whole-exome sequencing case-parent MMD trios in a small discovery cohort collected over 3.5 years (2016-2019); data were analyzed in 2020. Medical records from US hospitals spanning a range of 1 month to 1.5 years were reviewed for phenotyping. Exomes from a larger validation cohort were analyzed to identify additional rare, large-effect variants in the top candidate gene. Participants included patients with MMD and, when available, their parents. All participants who met criteria and were presented with the option to join the study agreed to do so; none were excluded. Twenty-four probands (22 trios and 2 singletons) composed the discovery cohort, and 84 probands (29 trios and 55 singletons) composed the validation cohort. Main Outcomes and Measures: Gene variants were identified and filtered using stringent criteria. Enrichment and case-control tests assessed gene-level variant burden. In silico modeling estimated the probability of variant association with protein structure. Integrative genomics assessed expression patterns of MMD risk genes derived from single-cell RNA sequencing data of human and mouse brain tissue. Results: Of the 24 patients in the discovery cohort, 14 (58.3%) were men and 18 (75.0%) were of European ancestry. Three of 24 discovery cohort probands contained 2 do novo (1-tailed Poisson P = 1.1 × 10-6) and 1 rare, transmitted damaging variant (12.5% of cases) in DIAPH1 (mammalian diaphanous-1), a key regulator of actin remodeling in vascular cells and platelets. Four additional ultrarare damaging heterozygous DIAPH1 variants (3 unphased) were identified in 3 other patients in an 84-proband validation cohort (73.8% female, 77.4% European). All 6 patients were non-East Asian. Compound heterozygous variants were identified in ena/vasodilator-stimulated phosphoproteinlike protein EVL, a mammalian diaphanous-1 interactor that regulates actin polymerization. DIAPH1 and EVL mutant probands had severe, bilateral MMD associated with transfusion-dependent thrombocytopenia. DIAPH1 and other MMD risk genes are enriched in mural cells of midgestational human brain. The DIAPH1 coexpression network converges in vascular cell actin cytoskeleton regulatory pathways. Conclusions and Relevance: These findings provide the largest collection to date of non-East Asian individuals with sporadic MMD harboring pathogenic variants in the same gene. The results suggest that DIAPH1 is a novel MMD risk gene and impaired vascular cell actin remodeling in MMD pathogenesis, with diagnostic and therapeutic ramifications.

Coronavirus Disease 2019 and Pituitary Apoplexy: A Single-Center Case Series and Review of the Literature.

BACKGROUND: Pituitary apoplexy (PA) is a rare, but life-threatening, condition characterized by pituitary infarction and hemorrhage, most often in the setting of a preexisting adenoma. The risk factors and mechanisms associated with PA are poorly understood. Although neurovascular manifestations of coronavirus disease 2019 (COVID-19) infection have been documented, its association with PA has not yet been determined. METHODS: From a prospectively collected database of patients treated at a tertiary care center for pituitary adenoma, we conducted a retrospective medical record review of PA cases during the COVID-19 pandemic from March 2020 to December 2020. We also conducted a literature review to identify other reported cases. RESULTS: We identified 3 consecutive cases of PA and concomitant COVID-19 infection. The most common symptoms at presentation were headache and vision changes. The included patients were successfully treated with surgical decompression and medical management of the associated endocrinopathy, ultimately experiencing improvement in their visual symptoms at the latest follow-up examination. COVID-19 infection in the perioperative period was corroborated by polymerase chain reaction test results in all the patients. CONCLUSIONS: With the addition of our series to the literature, 10 cases of PA in the setting of COVID-19 infection have been confirmed. The present series was limited in its ability to draw conclusions about the relationship between these 2 entities. However, COVID-19 infection might represent a risk factor for the development of PA. Further studies are required.

Protein kinase D1 variant associated with human epilepsy and peripheral nerve hypermyelination.

We report the case of a patient with severe progressive epilepsy and peripheral neuropathy and a novel de novo inactivating variant (p.E79X) in Protein Kinase D1 (PKD1). Using CRISPR/Cas9, we engineered the homologous variant in mice and showed that in the homozygote mouse, it recapitulated the patient peripheral nerve hypermyelination pathology. The lethality of the homozygote mouse prevented us from performing an assessment of locomotor behavior. The mutant heterozygote mouse; however, exhibited a significant increase in kainate-induced seizure activity over wild-type mice, supporting the hypothesis that the PKD1 variant is a candidate for the cause of the patient epilepsy. Because PKD1 was previously identified in a kinomic screen as an interacting partner of the K-Cl cotransporter 3 (KCC3), and since KCC3 is involved in peripheral nerve disease and brain hyperexcitability, one possible mechanism of action of PKD1 in disease is through KCC3. We show that catalytically inactive PKD1 stimulates KCC3 activity, consistent with tonic relief of inhibitory phosphorylation. Our findings implicate a novel role for PKD1 in the human nervous system, and uncover a mechanism that could serve as a potential target to promote nervous system myelination.

A new tiger beetle from the Gulf Coast of Texas (Coleoptera, Cicindelidae, Cicindelini).

A new tiger beetle species, Eunota albicauda Duran, Roman Huber n. sp., of the tribe Cicindelini, is described from the Gulf Coast of southern Texas. It is superficially most similar to E. togata (LaFert-Snectre, 1841) and E. circumpicta (LaFert-Snectre, 1841) but is distinguished on the basis of multiple character states not shared with either species. We reconstructed a phylogeny for Eunota to address the placement of this new taxon. Little is known about the biology or distribution of this exceedingly rare species. Despite extensive tiger beetle collecting from this region, only two specimens of E. albicauda n. sp. are known, collected in the mid-20th century. Future efforts to locate additional specimens should focus on coastal salt flats and marshes in southern Texas, including areas near the United States-Mexico border, late in the season (September-October).

Associations of meningioma molecular subgroup and tumor recurrence.

BACKGROUND: We and others have identified mutually exclusive molecular subgroups of meningiomas; however, the implications of this classification for clinical prognostication remain unclear. Integrated genomic and epigenomic analyses implicate unique oncogenic processes associated with each subgroup, suggesting the potential for divergent clinical courses. The aim of this study was to understand the associated clinical outcomes of each subgroup, as this could optimize treatment for patients. METHODS: We analyzed outcome data for 469 meningiomas of known molecular subgroup, including extent of resection, postoperative radiation, surveillance imaging, and time to recurrence, when applicable. Statistical relationships between outcome variables and subgroup were assessed. Features previously associated with recurrence were further investigated after stratification by subgroup. We used Kaplan-Meier analyses to compare progression-free survival, and identified factors significantly associated with recurrence using Cox proportional hazards modeling. RESULTS: Meningioma molecular subgroups exhibited divergent clinical courses at 2 years of follow-up, with several aggressive subgroups (NF2, PI3K, HH, tumor necrosis factor receptor-associated factor 7 [TRAF7]) recurring at an average rate of 22 times higher than others (KLF4, POLR2A, SMARCB1). PI3K-activated tumors recurred earlier than other subgroups but had intermediate long-term outcome. Among low-grade tumors, HH and TRAF7 meningiomas exhibited elevated recurrence compared with other subgroups. Recurrence of NF2 tumors was associated with male sex, high grade, and elevated Ki-67. Multivariate analysis identified molecular subgroup as an independent predictor of recurrence, along with grade and previous recurrence. CONCLUSION: We describe distinct clinical outcomes and recurrence rates associated with meningioma molecular subgroups. Our findings emphasize the importance of genomic characterization to guide postoperative management decisions for meningiomas.

A new tiger beetle from the Trans-Mexican Volcanic Belt (Coleoptera, Cicindelidae, Cicindelini).

A new tiger beetle species, Cicindelidia cyanipleura Duran and Roman n. sp., of the tribe Cicindelini, is described from the southwestern section of the Trans-Mexican Volcanic Belt. Superficially, it appears to be most closely related to C. rufiventris (Dejean, 1825) but is distinguished on the basis of multiple morphological characters and behavior. Given the rock-loving natural history of the species, escape behavior, polished pronotum, and small body size, it may be more closely related to the petrophiles C. laetipennis (Horn, 1913) or C. politula (LeConte, 1875), from which it is distinguished on the basis of multiple morphological characters and biogeography.