Demographic and clinical variables affecting mid‐ to late‐life trajectories of plasma ceramide and dihydroceramide species

It has been increasingly recognized at the basic science level that perturbations in ceramide metabolism are associated with the development and progression of many age‐related diseases. However, the translation of this work to the clinic has lagged behind. Understanding the factors longitudinally associated with plasma ceramides and dihydroceramides (DHCer) at the population level and how these lipid levels change with age, and by sex, is important for the clinical development of future therapeutics and biomarkers focused on ceramide metabolism. We, therefore, examined factors cross‐sectionally and longitudinally associated with plasma concentrations of ceramides and DHCer among Baltimore Longitudinal Study of Aging participants (n = 992; 3960 total samples), aged 55 years and older, with plasma at a mean of 4.1 visits (range 2–6). Quantitative analyses were performed on a high‐performance liquid chromatography‐coupled electrospray ionization tandem mass spectrometer. Linear mixed models were used to assess the relationships between plasma ceramide and DHCer species and demographics, diseases, medications, and lifestyle factors. Women had higher plasma concentrations of most ceramide and DHCer species and showed steeper trajectories of age‐related increases compared to men. Ceramides and DHCer were more associated with waist–hip ratio than body mass index. Plasma cholesterol and triglycerides, prediabetes, and diabetes were associated with ceramides and DHCer, but the relationship showed specificity to the acyl chain length and saturation. These results demonstrate the importance of examining the individual species of ceramides and DHCer, and of establishing whether intra‐individual age‐ and sex‐specific changes occur in synchrony to disease onset and progression.     

Morphological study of alar androconia in Celastrina butterflies

Morphological studies of androconia were performed for 13 Celastrina species using a digital microscope with Z‐stacking mode. Whereas C. ladon lacked androconia, the remaining 12 species were found to possess fan‐shaped androconia on the dorsal wing surfaces. The androconia of these species shared the following common features: smaller size than standard color‐producing scales, absence of dentate termini and presence of crossrib perforations. In addition, some species were characterized by unique microstructures in their androconia. The androconia of C. argiolus iynteana possessed a rounded lamellar contour, while those of C. lavendularis himilcon and C. echo cinerea were tapered on the basal end. The average number of longitudinal ridges of C. argiolus ladonides and C. filipjevi (17.1) were greater than the average number of 12 species (14.3). These results suggest that the morphological traits of androconia in microdomain, such as the shape of the lamellar form and the average number of longitudinal ridges, are useful to identify species in the genus Celastrina.     

Vitamin D supplementation worsens Alzheimer's progression: Animal model and human cohort studies

Vitamin D deficiency has been epidemiologically linked to Alzheimer''s disease (AD) and other dementias, but no interventional studies have proved causality. Our previous work revealed that the genomic vitamin D receptor (VDR) is already converted into a non‐genomic signaling pathway by forming a complex with p53 in the AD brain. Here, we extend our previous work to assess whether it is beneficial to supplement AD mice and humans with vitamin D. Intriguingly, we first observed that APP/PS1 mice fed a vitamin D‐sufficient diet showed significantly lower levels of serum vitamin D, suggesting its deficiency may be a consequence not a cause of AD. Moreover, supplementation of vitamin D led to increased Aβ deposition and exacerbated AD. Mechanistically, vitamin D supplementation did not rescue the genomic VDR/RXR complex but instead enhanced the non‐genomic VDR/p53 complex in AD brains. Consistently, our population‐based longitudinal study also showed that dementia‐free older adults (n = 14,648) taking vitamin D₃ supplements for over 146 days/year were 1.8 times more likely to develop dementia than those not taking the supplements. Among those with pre‐existing dementia (n = 980), those taking vitamin D₃ supplements for over 146 days/year had 2.17 times the risk of mortality than those not taking the supplements. Collectively, these animal model and human cohort studies caution against prolonged use of vitamin D by AD patients.     

A three‐dimensional placoderm (stem‐group gnathostome) pharyngeal skeleton and its implications for primitive gnathostome pharyngeal architecture

The pharyngeal skeleton is a key vertebrate anatomical system in debates on the origin of jaws and gnathostome (jawed vertebrate) feeding. Furthermore, it offers considerable potential as a source of phylogenetic data. Well‐preserved examples of pharyngeal skeletons from stem‐group gnathostomes remain poorly known. Here, we describe an articulated, nearly complete pharyngeal skeleton in an Early Devonian placoderm fish, Paraplesiobatis heinrichsi Broili, from Hunsrück Slate of Germany. Using synchrotron light tomography, we resolve and reconstruct the three‐dimensional gill arch architecture of Paraplesiobatis and compare it with other gnathostomes. The preserved pharyngeal skeleton comprises elements of the hyoid arch (probable ceratohyal) and a series of branchial arches. Limited resolution in the tomography scan causes some uncertainty in interpreting the exact number of arches preserved. However, at least four branchial arches are present. The final and penultimate arches are connected as in osteichthyans. A single median basihyal is present as in chondrichthyans. No dorsal (epibranchial or pharyngobranchial) elements are observed. The structure of the pharyngeal skeleton of Paraplesiobatis agrees well with Pseudopetalichthys from the same deposit, allowing an alternative interpretation of the latter taxon. The phylogenetic significance of Paraplesiobatis is considered. A median basihyal is likely an ancestral gnathostome character, probably with some connection to both the hyoid and the first branchial arch pair. Unpaired basibranchial bones may be independently derived in chondrichthyans and osteichthyans.     

Retinoic acid affects craniofacial patterning by changing Fgf8 expression in the pharyngeal ectoderm

Retinoic acid signaling plays important roles in establishing normal patterning and cellular differentiation during embryonic development. In this study, we show that single administration of retinoic acid at embryonic day 8.5 causes homeotic transformation of the lower jaw into upper jaw-like structures. This homeosis was preceded by downregulation of Fgf8 and Sprouty expression in the proximal domain of the first pharyngeal arch. Downregulation of mesenchymal genes such as Dlx5, Hand2, Tbx1 and Pitx2 was also observed. The oropharynx in retinoic acid-treated embryos was severely constricted. Consistent with this observation, Patched expression in the arch endoderm and mesenchyme was downregulated. Thus, retinoic acid affects the expression of subsets of epithelial and mesenchymal genes, possibly disrupting the regional identity of the pharyngeal arch.     

Influence of salinomycin treatment on division and movement of individual cancer cells cultured in normoxia or hypoxia evaluated with time-lapse digital holographic microscopy

Most studies on new cancer drugs are based on population-derived data, where the absence of response of a small population may pass unnoticed. Thus, individual longitudinal tracking of cells is important for the future development of efficient cancer treatments. We have used digital holographic microscopy to track individual JIMT-1 human breast cancer cells and L929 mouse fibroblast cultivated in normoxia or hypoxia. In addition, JIMT-1 cells were treated with salinomycin, a cancer stem cell targeting compound. Three-day time-lapse movies were captured and individual cells were analysed with respect to cell division (cell cycle length) and cell movement. Comparing population-doubling time derived from population-based growth curves and individual cell cycle time data from time-lapse movies show that the former hide a sub-population of dividing cells. Salinomycin treatment increased the motility of cells, however, this motility did not result in an increased distant migration i.e. the cells increased their local movement. MCF-7 breast cancer cells showed similar motility behaviour as salinomycin-treated JIMT-1 cells. We suggest that combining features, such as motility and migration, can be used to distinguish cancer cells with mesenchymal (JIMT-1) and epithelial (MCF-7) features. The data clearly emphasize the importance of longitudinal cell tracking to understand the biology of individual cells under different conditions.     

The long-term genetic stability and individual specificity of the human gut microbiome

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Anti-apoptotic gene Bcl2 is required for stapes development and hearing

In this paper we describe novel and specific roles for the apoptotic regulators Bcl2 and Bim in hearing and stapes development. Bcl2 is anti-apoptotic while Bim is pro-apoptotic. Characterization of the auditory systems of mice deficient for these molecules revealed that Bcl2^−/− mice suffered severe hearing loss. This was conductive in nature and did not affect sensory cells of the inner ear, with cochlear hair cells and neurons present and functional. Bcl2^−/− mice were found to have a malformed, often monocrural, porous stapes (the small stirrup-shaped bone of the middle ear), but a normally shaped malleus and incus. The deformed stapes was discontinuous with the incus and sometimes fused to the temporal bones. The defect was completely rescued in Bcl2^−/−Bim^−/− mice and partially rescued in Bcl2^−/−Bim^+/− mice, which displayed high-frequency hearing loss and thickening of the stapes anterior crus. The Bcl2^−/− defect arose in utero before or during the cartilage stage of stapes development. These results implicate Bcl2 and Bim in regulating survival of second pharyngeal arch or neural crest cells that give rise to the stapes during embryonic development.     

Characterization of a novel Drosophila melanogaster cis‐regulatory module that drives gene expression to the larval tracheal system and adult thoracic musculature

In a previous bioinformatics analysis we identified 10 conserved Drosophila melanogaster sequences that reside upstream from protein coding genes (CGs). Here we characterize one of these genomic regions, which constitutes a Drosophila melanogaster cis‐regulatory module (CRM) that we denominate TT‐CRM. The TT‐CRM is 646 bp long and is located in one of the introns of CG32239 and resides about 3,500 bp upstream of CG13711 and about 620 bp upstream of CG12493. Analysis of 646 bp‐lacZ lines revealed that TT‐CRM drives gene expression not only to the larval, prepupal, and pupal tracheal system but also to the adult dorsal longitudinal muscles. The patterns of mRNA expression of the transgene and of the CGs that lie in the vicinity of TT‐CRM were investigated both in dissected trachea and in adult thoraces. Through RT‐qPCR we observed that in the tracheal system the pattern of expression of 646 bp‐lacZ is similar to the pattern of expression of CG32239 and CG13711, whereas in the thoracic muscles 646 bp‐lacZ expression accompanies the expression of CG12493. Together, these results suggest new functions for two previously characterized D. melanogaster genes and also contribute to the initial characterization of a novel CRM that drives a dynamic pattern of expression throughout development.