Buckling without bending: a new paradigm in morphogenesis

A curious feature of organ and organoid morphogenesis is that in certain cases, spatial oscillations in the thickness of the growing "film" are out-of-phase with the deformation of the slower-growing "substrate," while in other cases, the oscillations are in-phase. The former cannot be explained by elastic bilayer instability, and contradict the notion that there is a universal mechanism by which brains, intestines, teeth, and other organs develop surface wrinkles and folds. Inspired by the microstructure of the embryonic cerebellum, we develop a new model of 2d morphogenesis in which system-spanning elastic fibers endow the organ with a preferred radius, while a separate fiber network resides in the otherwise fluid-like film at the outer edge of the organ and resists thickness gradients thereof. The tendency of the film to uniformly thicken or thin is described via a "growth potential". Several features of cerebellum, +blebbistatin organoid, and retinal fovea morphogenesis, including out-of-phase behavior and a film thickness amplitude that is comparable to the radius amplitude, are readily explained by our simple analytical model, as may be an observed scale-invariance in the number of folds in the cerebellum. We also study a nonlinear variant of the model, propose further biological and bio-inspired applications, and address how our model is and is not unique to the developing nervous system.Comment: version accepted by Physical Review

Characterization and performance of nucleic acid nanoparticles combined with protamine and gold

Macromolecular nucleic acids such as DNA vaccines, siRNA, and splice-site switching oligomers (SSO) have vast chemotherapeutic potential. Nanoparticulate biomaterials hold promise for DNA and RNA delivery when a means for binding is identified that retains structure-function and provides stabilization by the nanoparticles. In order to provide these benefits of binding, we combined DNA and RNA with protamine-demonstrating association to gold microparticles by electrophoretic, gel shot, fluorescence, and dynamic laser light spectroscopy (DLLS). A pivotal finding in these studies is that the Au-protamine-DNA conjugates greatly stabilize the DNA; and DNA structure and vaccine activity are maintained even after exposure to physical, chemical, and temperature-accelerated degradation. Specifically, protamine formed nanoparticles when complexed to RNA. These complexes could be detected by gel shift and were probed by high throughput absorbance difference spectroscopy (HTADS). Biological activity of these RNA nanoparticles (RNPs) was demonstrated also by a human tumor cell splice-site switching assay and by siRNA delivery against B-Raf-a key cancer target. Finally, RNA:protamine particles inhibited growth of cultured human tumor cells and bacteria. These data provide new insights into DNA and RNA nanoparticles and prospects for their delivery and chemotherapeutic activity. (C) 2009 Elsevier Ltd. All rights reserved

Morphological Variation, Karyology, and Systematic Relationships of \u3ci\u3eHeteromys gaumeri\u3c/i\u3e (Rodentia: Heteromyidae)

Morphological variation was assessed within and among populations of Heteromys gaumeri using univariate and multivariate statistical analyses of external and cranial measurements. Although patterns and amount of nongeographic variation in H. gaumeri were similar to other heteromyines, geographic variation was relatively conservative. Mean values of most characters were statistically homogeneous among localities and spatially unpatterned. Consequently, no association was found between levels of within- and among-sample variation for individual characters (the Kluge-Kerfoot phenomenon ). Populations of H. gaumeri were chromosomally monomorphic. The lack of morphological and chromosomal variation in H. gaumeri contrasts sharply with patterns in other heteromyines. Heteromys gaumeri is morphologically and chromosomally distinct from the H. desmarestianus species group (to which it is currently assigned) and appears to share some primitive characters with Liomys (the sister group of Heteromys). We recommend that H. gaumeri be removed from the H. desmarestianus group. Spanish abstract: La variación morfológica intra e interpoblacional de Heteromys gaumeri fue evaluada usando análisis estadísticos univariados y multivariados de medidas externas y craneales. A pesar de que los patrones y cantidad de variación intrapoblacional en H. gaumeri fue similar a la de otros heterominos, la variación geográfica fue relativamente conservadora. Los valores promedio de la mayoría de los caracteres fueron estadisticamente homogeneos entre las localidades, sin mostrar ningún patrón de variación espacial. En conservencia, no se encontró asociación alguna entre los niveles de variación intra e interpoblacional para caracteres individuates ( fenómena Kluge-Kerfoot ), Las poblaciones de H. gaumeri fueron monomórficas cromosómicamente. La falta de variacion tanto morfológica como cronosómica en H. gaumeri contrasta marcadamente con los patrones encontrados anteriormente para otros heteróminos. Heteromys gaumeri es morfológica y cromosómicamente distinguible del grupo H. desmarestianus (al cual se asigna actualmente) y aparentemente comparte algunos caracteres primitives con Liomys (el grupo hermano de Heteromys). Nosotros recomendamos que se remueva a H. gaumeri del grupo H. desmarestianus. Portuguese abstract: Avalia-se a variação morfológica intra- e interpopulacional de Heteromys gaumeri, através de análises estatisticas uni- e multivariadas de medidas externas e craniais. Apesar dos padrões, e da quantidade de variação intrapopulacional em H. gaumeri serem similares aos de outros heteromídeos, a variação geográfica é relativamente conservadora. Os valores médios da maior parte dos caráteres examinados são estatìsticamente homogeneos entre as localidades, e não surgiu nenhum padrão de variações locais. Consequentemente, não foram encontradas assoçiacões entre os níveis de varaiações intra- e interpopulacionais para caráteres individuais (o “fenômeno Kluge-Kerfoot”). Populações de H. gaumeri mostraram-se cromossômicamente monomórficas. A falta de variação morfológica ou cromossômica em H. gaumeri é altamente contrastante aos padrões encontrados em outros heteromídeos. Heteromys gaumeri distinguese tanto morfológica quanto cromossômicamente do grupo H. desmarestianus, ao qual está atualmente designado, e aparentemente possue caráteres primitivos em comum com Liomys—grupo irmão de Heteromys. Recomendamos que H. gaumeri seja removido do grupo H. desmarestianus

Neurochemical Aftermath of Repetitive Mild Traumatic Brain Injury

IMPORTANCE: Evidence is accumulating that repeated mild traumatic brain injury (mTBI) incidents can lead to persistent, long-term debilitating symptoms and in some cases a progressive neurodegenerative condition referred to as chronic traumatic encephalopathy. However, to our knowledge, there are no objective tools to examine to which degree persistent symptoms after mTBI are caused by neuronal injury. OBJECTIVE: To determine whether persistent symptoms after mTBI are associated with brain injury as evaluated by cerebrospinal fluid biochemical markers for axonal damage and other aspects of central nervous system injury. DESIGN, SETTINGS, AND PARTICIPANTS: A multicenter cross-sectional study involving professional Swedish ice hockey players who have had repeated mTBI, had postconcussion symptoms for more than 3 months, and fulfilled the criteria for postconcussion syndrome (PCS) according to the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) matched with neurologically healthy control individuals. The participants were enrolled between January 2014 and February 2016. The players were also assessed with Rivermead Post Concussion Symptoms Questionnaire and magnetic resonance imaging. MAIN OUTCOMES AND MEASURES: Neurofilament light protein, total tau, glial fibrillary acidic protein, amyloid β, phosphorylated tau, and neurogranin concentrations in cerebrospinal fluid. RESULTS: A total of 31 participants (16 men with PCS; median age, 31 years; range, 22-53 years; and 15 control individuals [11 men and 4 women]; median age, 25 years; range, 21-35 years) were assessed. Of 16 players with PCS, 9 had PCS symptoms for more than 1 year, while the remaining 7 returned to play within a year. Neurofilament light proteins were significantly increased in players with PCS for more than 1 year (median, 410 pg/mL; range, 230-1440 pg/mL) compared with players whose PCS resolved within 1 year (median, 210 pg/mL; range, 140-460 pg/mL) as well as control individuals (median 238 pg/mL, range 128-526 pg/mL; P = .04 and P = .02, respectively). Furthermore, neurofilament light protein concentrations correlated with Rivermead Post Concussion Symptoms Questionnaire scores and lifetime concussion events (ρ = 0.58, P = .02 and ρ = 0.52, P = .04, respectively). Overall, players with PCS had significantly lower cerebrospinal fluid amyloid-β levels compared with control individuals (median, 1094 pg/mL; range, 845-1305 pg/mL; P = .05). CONCLUSIONS AND RELEVANCE: Increased cerebrospinal fluid neurofilament light proteins and reduced amyloid β were observed in patients with PCS, suggestive of axonal white matter injury and amyloid deposition. Measurement of these biomarkers may be an objective tool to assess the degree of central nervous system injury in individuals with PCS and to distinguish individuals who are at risk of developing chronic traumatic encephalopathy

Effects of limonene on ruminal fusobacterium necrophorum concentrations, fermentation, and lysine degradation in cattle

Citation: Samii, S. S., Wallace, N., Nagaraja, T. G., Engstrom, M. A., Miesner, M. D., Armendariz, C. K., & Titgemeyer, E. C. (2016). Effects of limonene on ruminal fusobacterium necrophorum concentrations, fermentation, and lysine degradation in cattle. Journal of Animal Science, 94(8), 3420-3430. doi:10.2527/jas2016-0455Previous in vitro data showed that Fusobacterium necrophorum was inhibited by limonene. We further evaluated effects of limonene on growth of F. necrophorum in vitro as well as on ruminal concentrations of F. necrophorum in vivo. With in vitro cultivation in anaerobic brain-heart infusion broth, limonene decreased growth of F. necrophorum. Thymol also reduced growth of F. necrophorum, but it was less effective than limonene. Tylosin effectively reduced growth of F. necrophorum in vitro. Although the response over fermentation times and concentrations of antimicrobials differed somewhat between tylosin and limonene, the 2 antimicrobial agents yielded similar inhibitory effects on growth of F. necrophorum at concentrations ranging from 6 to 24 mg/L. The effects of limonene on ruminal F. necrophorum concentration in vivo were tested in 7 ruminally cannulated heifers (225 kg initial BW) used in a 7 × 4 Youden square design. Treatments included: 1) control, 2) limonene at 10 mg/kg diet DM, 3) limonene at 20 mg/kg diet DM, 4) limonene at 40 mg/kg diet DM, 5) limonene at 80 mg/kg diet DM, 6) CRINA-L (a blend of essential oil components) at 180 mg/kg diet DM, and 7) tylosin at 12 mg/kg diet DM. Each period included 11 d with 10 d washouts between periods. Samples of ruminal contents were collected before treatment initiation and after 4, 7, and 10 d of treatment for measuring F. necrophorum by the most probable number method using selective culture medium. Limonene linearly decreased (P = 0.03) ruminal F. necrophorum concentration, with the lowest concentration achieved with 40 mg of limonene/kg dietary DM. Limonene tended (P ? 0.07) to linearly reduce ruminal molar proportions of propionate and valerate while tending to linearly increase (P ? 0.10) those of butyrate and 2-methyl butyrate. Limonene did not affect ruminal NH3 concentrations or degradation rates of lysine. Neither CRINA-L (P = 0.52) nor tylosin (P = 0.19) affected ruminal F. necrophorum concentrations. CRINA-L significantly decreased ruminal concentrations of NH3 and molar proportions of 3-methyl butyrate, whereas tylosin significantly decreased molar proportions of propionate while increasing those of butyrate and tending to increase those of acetate. Limonene supplementation reduced ruminal concentrations of F. necrophorum suggesting that it may have the potential to reduce the prevalence of liver abscesses, although further research is needed to assess the effect of limonene in feedlot cattle. © 2016 American Society of Animal Science. All rights reserved

Comment: Cultural eutrophication of natural lakes in the United States is real and widespread

This is the published version

Gene-environment interaction between lead and Apolipoprotein E4 causes cognitive behavior deficits in mice

Abstract Background Alzheimer’s disease (AD) is characterized by progressive cognitive decline and memory loss. Environmental factors and gene-environment interactions (GXE) may increase AD risk, accelerate cognitive decline, and impair learning and memory. However, there is currently little direct evidence supporting this hypothesis. Methods In this study, we assessed for a GXE between lead and ApoE4 on cognitive behavior using transgenic knock-in (KI) mice that express the human Apolipoprotein E4 allele (ApoE4-KI) or Apolipoprotein E3 allele (ApoE3-KI). We exposed 8-week-old male and female ApoE3-KI and ApoE4-KI mice to 0.2% lead acetate via drinking water for 12 weeks and assessed for cognitive behavior deficits during and after the lead exposure. In addition, we exposed a second (cellular) cohort of animals to lead and assessed for changes in adult hippocampal neurogenesis as a potential underlying mechanism for lead-induced learning and memory deficits. Results In the behavior cohort, we found that lead reduced contextual fear memory in all animals; however, this decrease was greatest and statistically significant only in lead-treated ApoE4-KI females. Similarly, only lead-treated ApoE4-KI females exhibited a significant decrease in spontaneous alternation in the T-maze. Furthermore, all lead-treated animals developed persistent spatial working memory deficits in the novel object location test, and this deficit manifested earlier in ApoE4-KI mice, with female ApoE4-KI mice exhibiting the earliest deficit onset. In the cellular cohort, we observed that the maturation, differentiation, and dendritic development of adult-born neurons in the hippocampus was selectively impaired in lead-treated female ApoE4-KI mice. Conclusions These data suggest that GXE between ApoE4 and lead exposure may contribute to cognitive impairment and that impaired adult hippocampal neurogenesis may contribute to these deficits in cognitive behavior. Together, these data suggest a role for GXE and sex differences in AD risk