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PURPOSE: Down syndrome (DS) is caused by trisomy 21 (Ts21) and results in skeletal deficits including shortened stature, low bone mineral density and a predisposition to early onset osteoporosis. Ts21 causes significant alterations in skeletal development, morphology of the appendicular skeleton, bone homeostasis, age-related bone loss, and bone strength. However, the genetic or cellular origins of DS skeletal phenotypes remain unclear. RECENT FINDINGS: New studies reveal a sexual dimorphism in characteristics and onset of skeletal deficits that differ between DS and typically developing individuals. Age-related bone loss occurs earlier in the DS as compared to general population. SUMMARY: Perturbations of DS skeletal quality arise from alterations in cellular and molecular pathways affected by the overexpression of trisomic genes. Sex-specific alterations occur in critical developmental pathways that disrupt bone accrual, remodeling, and homeostasis and are compounded by aging, resulting in increased risks for osteopenia, osteoporosis and fracture in individuals with DS.

Trisomy 21 (Ts21) causes alterations in skeletal development resulting in decreased bone mass, shortened stature and weaker bones in individuals with Down syndrome (DS). There is a sexual dimorphism in bone mineral density (BMD) deficits associated with DS with males displaying earlier deficits than females. The relationships between causative trisomic genes, cellular mechanisms, and influence of sex in DS skeletal abnormalities remain unknown. One hypothesis is that the low bone turnover phenotype observed in DS results from attenuated osteoblast function, contributing to impaired trabecular architecture, altered cortical geometry, and decreased mineralization. DYRK1A, found in three copies in humans with DS, Ts65Dn, and Dp1Tyb DS model mice, has been implicated in the development of postnatal skeletal phenotypes associated with DS. Reduced copy number of Dyrk1a to euploid levels from conception in an otherwise trisomic Ts65Dn mice resulted in a rescue of appendicular bone deficits, suggesting DYRK1A contributes to skeletal development and homeostasis. We hypothesized that reduction of Dyrk1a copy number in trisomic osteoblasts would improve cellular function and resultant skeletal structural anomalies in trisomic mice. Female mice with a floxed Dyrk1a gene (Ts65Dn,Dyrk1afl/wt) were mated with male Osx-Cre+ (expressed in osteoblasts beginning around E13.5) mice, resulting in reduced Dyrk1a copy number in mature osteoblasts in Ts65Dn,Dyrk1a+/+/Osx-Cre P42 male and female trisomic and euploid mice, compared with littermate controls. Male and female Ts65Dn,Dyrk1a+/+/+ (3 copies of DYRK1A in osteoblasts) and Ts65Dn,Dyrk1a+/+/Osx-Cre (2 copies of Dyrk1a in osteoblasts) displayed similar defects in both trabecular architecture and cortical geometry, with no improvements with reduced Dyrk1a in osteoblasts. This suggests that trisomic DYRK1A does not affect osteoblast function in a cell-autonomous manner at or before P42. Although male Dp1Tyb and Ts65Dn mice exhibit similar skeletal deficits at P42 in both trabecular and cortical bone compartments between euploid and trisomic mice, female Ts65Dn mice exhibit significant cortical and trabecular deficits at P42, in contrast to an absence of genotype effect in female Dp1Tyb mice in trabecular bone. Taken together, these data suggest skeletal deficits in DS mouse models and are sex and age dependent, and influenced by strain effects, but are not solely caused by the overexpression of Dyrk1a in osteoblasts. Identifying molecular and cellular mechanisms, disrupted by gene dosage imbalance, that are involved in the development of skeletal phenotypes associated with DS could help to design therapies to rescue skeletal deficiencies seen in DS.

Two new extinct fossil cicadellid taxa from Eocene Baltic amber, representing the subfamily Eurymelinae (sensu lato), are described and illustrated, and their relationships to modern leafhoppers are discussed. Eoidiocerus emarginatus gen. and sp. n. is the oldest known representative of the tribe Idiocerini. The new genus resembles some modern Afrotropical and Indomalayan idiocerine genera but differs in having the gena relatively narrow. Archipedionis obscurus gen. and sp. n., is the first well-preserved fossil representative of Macropsini to be described in detail. Previous reports of this tribe from Baltic amber, while credible, included too little morphological information to assess their relationships. Additional comparative notes are provided for previously described fossil taxa belonging to Idiocerini and Macropsini from the Oligocene of Germany. The new combinations Oncopsis sepultus sepultus (Statz, 1950), comb. n. and Oncopsis sepultus austerus (Statz, 1950), comb. n. are proposed for taxa previously included in Bythoscopus Germar. The previously unplaced cicadellid fossil taxon Priscacutius denticulatus Poinar & Brown, 2018 from mid-Cretaceous Myanmar amber is newly placed in subfamily Signoretiinae, tribe Phlogisini, and represents the oldest known member of this subfamily, the only one known from the fossil record and only the second modern cicadellid subfamily confirmed by direct fossil evidence to have been present during the Cretaceous period.

Down syndrome (DS) is caused by three copies of human chromosome 21 (Hsa21) and results in phenotypes including intellectual disability and skeletal deficits. Ts65Dn mice have three copies of ~50% of the genes homologous to Hsa21 and display phenotypes associated with DS, including cognitive deficits and skeletal abnormalities. DYRK1A is found in three copies in humans with Trisomy 21 and in Ts65Dn mice, and is involved in a number of critical pathways including neurological development and osteoclastogenesis. Epigallocatechin-3-gallate (EGCG), the main polyphenol in green tea, inhibits Dyrk1a activity. We have previously shown that EGCG treatment (~10mg/kg/day) improves skeletal abnormalities in Ts65Dn mice, yet the same dose, as well as ~20mg/kg/day did not rescue deficits in the Morris water maze spatial learning task (MWM), novel object recognition (NOR) or balance beam task (BB). In contrast, a recent study reported that an EGCG-containing supplement with a dose of 2–3 mg per day (~40–60mg/kg/day) improved hippocampal-dependent task deficits in Ts65Dn mice. The current study investigated if an EGCG dosage similar to that study would yield similar improvements in either cognitive or skeletal deficits. Ts65Dn mice and euploid littermates were given EGCG [0.4 mg/mL] or a water control, with treatments yielding average daily intakes of ~50 mg/kg/day EGCG, and tested on the multivariate concentric square field (MCSF)—which assesses activity, exploratory behavior, risk assessment, risk taking, and shelter seeking—and NOR, BB, and MWM. EGCG treatment failed to improve cognitive deficits; EGCG also produced several detrimental effects on skeleton in both genotypes. In a refined HPLC-based assay, its first application in Ts65Dn mice, EGCG treatment significantly reduced kinase activity in femora but not in the cerebral cortex, cerebellum, or hippocampus. Counter to expectation, 9-week-old Ts65Dn mice exhibited a decrease in Dyrk1a protein levels in Western blot analysis in the cerebellum. The lack of beneficial therapeutic behavioral effects and potentially detrimental skeletal effects of EGCG found in Ts65Dn mice emphasize the importance of identifying dosages of EGCG that reliably improve DS phenotypes and linking those effects to actions of EGCG (or EGCG-containing supplements) in specific targets in brain and bone.

A new genus and species of pygmy grasshopper (Orthoptera: Tetrigidae) is described from Eocene Baltic amber. Danatettix hoffeinsorum gen. et sp. nov. is assigned to the subfamily Batrachideinae based on antennae with more than 19 antennomeres, sulcate mesofemora, and rectangular paranota. This species is readily distinguished from other batrachideines by a markedly produced vertex, pronotum with divergent internal and external lateral carinae, and highly setiferous female lateral basivalvular sclerite with scabrose integument. The morphology of Danatettix suggests placement within the here defined Tettigidea genus group (comprising Eutettigidea Hancock, 1914, Paurotarsus Hancock, 1900, and Tettigidea Scudder, 1862) and suggests that the latter had diverged from the new Scaria genus group (comprising Eotetrix Gorochov, 2012, Rehnidium Grant, 1956 and Scaria Bolívar, 1887) by the Early Eocene.

Thirty-one species of Nearctic Perlesta Banks, 1906 (Plecoptera: Perlidae) are recognized. A new species is described from western Arkansas and eastern Oklahoma, USA, Perlestasublobata South & DeWalt, sp. nov., from the adult male, adult female, and egg. Perlestasublobata males are differentiated from other congeners by a combination of a prominent ventral caecum and a distinct dorsal extension of the lateral sclerites of the aedeagus. A preliminary molecular phylogenetic hypothesis is proposed for Perlesta based on 17 congeners and three outgroup taxa using partial mitochondrial cytochrome c oxidase subunit I sequence data. Illustrations, stereomicroscope images, and scanning electron micrographs support the description and comparison to other Perlesta.

A new genus and species of Elcanidae (Insecta: Orthoptera) is described from mid-Cretaceous Burmese amber. Elcanonympha diana gen. et sp. nov. is known from a single, complete nymph and is distinguished from other elcanids by the pronotum cut by a single transverse sulcus, the dorsal margin of the metafemoral genicula with a row of prominent apical denticles, and the distal third of the metabasitarsus bearing a row of apically directed scale-like spines on the ventral surface.

All individuals with Down syndrome (DS), which results from trisomy of human chromosome 21 (Ts21), present with skeletal abnormalities typified by craniofacial features, short stature and low bone mineral density (BMD). Differences in skeletal deficits between males and females with DS suggest a sexual dimorphism in how trisomy affects bone. Dp1Tyb mice contain three copies of all of the genes on mouse chromosome 16 that are homologous to human chromosome 21, males and females are fertile, and therefore are an excellent model to test the hypothesis that gene dosage influences the sexual dimorphism of bone abnormalities in DS. Dp1Tyb as compared to control littermate mice at time points associated with bone accrual (6 weeks) and skeletal maturity (16 weeks) showed deficits in BMD and trabecular architecture that occur largely through interactions between sex and genotype and resulted in lower percent bone volume in all female and Dp1Tyb male mice. Cortical bone in Dp1Tyb as compared to control mice exhibited different changes over time influenced by sex × genotype interactions including reduced cortical area in both male and female Dp1Tyb mice. Mechanical testing analyses suggested deficits in whole bone properties such as bone mass and geometry, but improved material properties in female and Dp1Tyb mice. Sexual dimorphisms and the influence of trisomic gene dosage differentially altered cellular properties of male and female Dp1Tyb bone. These data establish sex, gene dosage, skeletal site and age as important factors in skeletal development of DS model mice, paving the way for identification of the causal dosage-sensitive genes. Skeletal differences in developing male and female Dp1Tyb DS model mice replicated differences in less-studied adolescents with DS and established a foundation to understand the etiology of trisomic bone deficits., Highlights • Male and female Down syndrome (DS) mice have distinct differences in skeletal deficits. • Effects of trisomy on bone properties are age and sex dependent. • Different cellular mechanisms may cause bone deficits in male and female DS mice. • Findings of skeletal deficits in DS mice correlate to observations in people with DS.

A new genus and species of fossil caddisfly (Insecta: Trichoptera) from the Lower Eocene (Ypresian) Green River Formation of Colorado is described. Litholimnephilops yinani gen. et sp. nov. is the first adult caddisfly to be described from the Green River Formation, and is characterized by large adult body size, presence of ocelli, dark leg spines, and a lack of terminal crossveins in the anterior anastomosis region of the forewings. Terminal genitalia are not visible in the preserved specimen. Familial placement is uncertain, though similarities with the families Limnephilidae and Phryganeidae are observed.

A new fossil mushroom is described and illustrated from the Lower Cretaceous Crato Formation of northeast Brazil. Gondwanagaricites magnificus gen. et sp. nov. is remarkable for its exceptional preservation as a mineralized replacement in laminated limestone, as all other fossil mushrooms are known from amber inclusions. Gondwanagaricites represents the oldest fossil mushroom to date and the first fossil mushroom from Gondwana.