Background Prevalent non‐motor symptoms of Parkinson’s disease (PD) include gastrointestinal motor impairments and advanced stage PD displays pathological aggregates of α‐synuclein in colonic ...enteric neurons. We previously showed that 12 months old mice overexpressing human wild type (WT) α‐synuclein under the Thy1 promoter (Thy1‐aSyn) displayed colonic motor dysfunction. We investigated functional gut alterations at earlier ages and histological correlates.
Methods Defecation, gastric emptying (GE), and immunostaining for α‐synuclein, peripheral choline acetyltransferase (pChAT), tyrosine hydroxylase (TH), neuronal nitric oxide synthase (nNOS), and vasoactive intestinal peptide (VIP) in distal colon myenteric plexuses were assessed in male Thy1‐aSyn compared to littermate WT mice.
Key Results Thy1‐aSyn mice aged 2.5–3 or 7–8 months old had 81% and 55% reduction in fecal pellet output, respectively, in the first 15 min of exposure to a novel environment. The reduction remained significant in the older group for 2‐h, and subsequent refeeding resulted also in a 60% and 69% reduction of defecation in the first hour, respectively. Thy1‐aSyn mice (8–10 months) displayed increased α‐synuclein in the myenteric plexuses with abundant varicose terminals surrounding pChAT‐immunoreactive (ir) neurons, and only a few, nNOS‐ir neurons. There were no conspicuous changes in pChAT‐ and nNOS‐ir neurons, or TH‐ and VIP‐ir nerve fibers. Thy1‐aSyn mice aged 4–18 months had normal GE.
Conclusions & Inferences The occurrence of over‐production of pre‐synaptic α‐synuclein in colonic myenteric ganglia several months before the loss of striatal dopamine may provide an anatomical basis for interference with cholinergic neuronal activation, causing an early impairment in defecation to stimuli.
Gene-expression programs define shared and species-specific phenotypes, but their evolution remains largely uncharacterized beyond the transcriptome layer
. Here we report an analysis of the ...co-evolution of translatomes and transcriptomes using ribosome-profiling and matched RNA-sequencing data for three organs (brain, liver and testis) in five mammals (human, macaque, mouse, opossum and platypus) and a bird (chicken). Our within-species analyses reveal that translational regulation is widespread in the different organs, in particular across the spermatogenic cell types of the testis. The between-species divergence in gene expression is around 20% lower at the translatome layer than at the transcriptome layer owing to extensive buffering between the expression layers, which especially preserved old, essential and housekeeping genes. Translational upregulation specifically counterbalanced global dosage reductions during the evolution of sex chromosomes and the effects of meiotic sex-chromosome inactivation during spermatogenesis. Despite the overall prevalence of buffering, some genes evolved faster at the translatome layer-potentially indicating adaptive changes in expression; testis tissue shows the highest fraction of such genes. Further analyses incorporating mass spectrometry proteomics data establish that the co-evolution of transcriptomes and translatomes is reflected at the proteome layer. Together, our work uncovers co-evolutionary patterns and associated selective forces across the expression layers, and provides a resource for understanding their interplay in mammalian organs.
ABSTRACT
With approximately 7000 species, snakes and lizards, collectively known as squamates, are by far the most species‐rich group of reptiles. It was from reptile‐like ancestors that mammals and ...birds evolved and squamates can be viewed as phylogenetically positioned between them and fishes. Hence, their hearts have been studied for more than a century yielding insights into the group itself and into the independent evolution of the fully divided four‐chambered hearts of mammals and birds. Structurally the heart is complex and debates persist on rudimentary issues such as identifying structures critical to understanding ventricle function. In seeking to resolve these controversies we have generated three‐dimensional (3D) models in portable digital format (pdf) of the anaconda and anole lizard hearts (‘typical’ squamate hearts) and the uniquely specialized python heart with comprehensive annotations of structures and cavities. We review the anatomy and physiology of squamate hearts in general and emphasize the unique features of pythonid and varanid lizard hearts that endow them with mammal‐like blood pressures. Excluding pythons and varanid lizards it is concluded that the squamate heart has a highly consistent design including a disproportionately large right side (systemic venous) probably due to prevailing pulmonary bypass (intraventricular shunting). Unfortunately, investigations on rudimentary features are sparse. We therefore point out gaps in our knowledge, such as the size and functional importance of the coronary vasculature and of the first cardiac chamber, the sinus venosus, and highlight areas with implications for vertebrate cardiac evolution.
This study demonstrates hydrogen production in a membrane-less continuous flow microbial electrolysis cell (MEC) with a gas-phase cathode. The MEC used a carbon felt anode and a gas diffusion cathode ...with a Pt loading of 0.5
mg
cm
−2. No proton exchange membrane (PEM) was used in the setup. Instead, the electrodes were separated by a J-cloth. The absence of a PEM as well as a short distance maintained between the electrodes (0.3
mm) resulted in a low internal resistance of 19
Ω. Due to an improved design, the volumetric hydrogen production rate reached 6.3
L
STP
L
A
−
1
d
−1. In spite of the PEM absence, methane concentration in the gas collection chamber was below 2.1% and the presence of hydrogen in the anodic chamber was never observed.
Abnormal remodeling of subchondral bone (SB) induced by estrogen deficiency has been shown to be involved in osteoarthritis (OA). Raloxifene (RAL) is commonly used to treat postmenopausal ...osteoporosis (OP). However, little is known about its effects on OA combined with estrogen deficiency. This study was performed to evaluate the efficacy of RAL on patella baja-induced patellofemoral joint OA (PFJOA) in an ovariectomized rat model.
Patellar ligament shortening (PLS) and ovariectomy (OVX) were performed simultaneously in 3-month-old female Sprague–Dawley rats, which were treated with RAL (10 mg/kg/day) or vehicle at 72 h postoperatively for 10 weeks. PFJOA was assessed by immunohistochemistry (IHC), real-time polymerase chain reaction (PCR), tartrate-resistant acid phosphatase (TRAP) staining, enzyme-linked immunosorbent assay (ELISA), micro-computed tomography (μCT), histomorphology and behavioral analyses.
X-ray examinations showed that patella baja was successfully established by PLS. Histomorphological analysis revealed that PFJOA was significantly exacerbated by OVX and markedly alleviated by RAL. Moreover, RAL improved cartilage metabolism by decreasing MMP-13, ADAMTS-4, and caspase-3 and increasing Col-II and aggrecan at both the protein and mRNA levels. Furthermore, RAL markedly improved bone mass and SB microarchitecture and reduced osteoclast numbers and the serum osteocalcin and CTX-I levels. Although RAL showed a trend toward reducing pain sensitivity based on mechanical allodynia testing, this result was not statistically significant.
These findings demonstrate that RAL treatment retards PFJOA progression in an ovariectomized rat model, suggesting that it may be a potential candidate for amelioration of the progression of PFJOA accompanied by postmenopausal OP.
Excessive activation of G-protein-coupled receptor (GPCR) and receptor tyrosine kinase (RTK) pathways has been linked to prostate cancer metastasis. Rac activation by guanine nucleotide exchange ...factors (GEFs) plays an important role in directional cell migration, a critical step of tumor metastasis cascades. We found that the upregulation of P-Rex1, a Rac-selective GEF synergistically activated by Gbetagamma freed during GPCR signaling, and PIP3, generated during either RTK or GPCR signaling, strongly correlates with metastatic phenotypes in both prostate cancer cell lines and human prostate cancer specimens. Silencing endogenous P-Rex1 in metastatic prostate cancer PC-3 cells selectively inhibited Rac activity and reduced cell migration and invasion in response to ligands of both epidermal growth factor receptor and G-protein-coupled CXC chemokine receptor 4. Conversely, expression of recombinant P-Rex1, but not its 'GEF-dead' mutant, in non-metastatic prostate cancer cells, such as CWR22Rv1, increased cell migration and invasion through Rac-dependent lamellipodia formation. More importantly, using a mouse xenograft model, we showed that the expression of P-Rex1, but not its mutant, induced lymph node metastasis of CWR22Rv1 cells without an effect on primary tumor growth. Thus, by functioning as a coincidence detector of chemotactic signals from both GPCRs and RTKs, P-Rex1-dependent activation of Rac promotes prostate cancer metastasis.
We demonstrate efficient terahertz (THz) modulation by coupling graphene strongly with a broadband THz metasurface device. This THz metasurface, made of periodic gold slit arrays, shows near unity ...broadband transmission, which arises from coherent radiation of the enhanced local-field in the slits. Utilizing graphene as an active load with tunable conductivity, we can significantly modify the local-field enhancement and strongly modulate the THz wave transmission. This hybrid device also provides a new platform for future nonlinear THz spectroscopy study of graphene.
Abstract
CRISPR/Cas9 is an attractive platform to potentially correct dominant genetic diseases by gene editing with unprecedented precision. In the current proof-of-principle study, we explored the ...use of CRISPR/Cas9 for gene-editing in myotonic dystrophy type-1 (DM1), an autosomal-dominant muscle disorder, by excising the CTG-repeat expansion in the 3′-untranslated-region (UTR) of the human myotonic dystrophy protein kinase (DMPK) gene in DM1 patient-specific induced pluripotent stem cells (DM1-iPSC), DM1-iPSC-derived myogenic cells and DM1 patient-specific myoblasts. To eliminate the pathogenic gain-of-function mutant DMPK transcript, we designed a dual guide RNA based strategy that excises the CTG-repeat expansion with high efficiency, as confirmed by Southern blot and single molecule real-time (SMRT) sequencing. Correction efficiencies up to 90% could be attained in DM1-iPSC as confirmed at the clonal level, following ribonucleoprotein (RNP) transfection of CRISPR/Cas9 components without the need for selective enrichment. Expanded CTG repeat excision resulted in the disappearance of ribonuclear foci, a quintessential cellular phenotype of DM1, in the corrected DM1-iPSC, DM1-iPSC-derived myogenic cells and DM1 myoblasts. Consequently, the normal intracellular localization of the muscleblind-like splicing regulator 1 (MBNL1) was restored, resulting in the normalization of splicing pattern of SERCA1. This study validates the use of CRISPR/Cas9 for gene editing of repeat expansions.
Non-Newtonian fluids are extensively employed in many different industries, such as the processing of plastics, the creation of electrical devices, lubricating flows, and the production of medical ...supplies. A theoretical analysis is conducted to examine the stagnation point flow of a 2nd-grade micropolar fluid into a porous material in the direction of a stretched surface under the magnetic field effect, which is stimulated by these applications. The stratification boundary conditions are imposed on the surface of the sheet. Generalized Fourier and Fick's laws with activation energy is also considered to discuss the heat and mass transportation. To obtain the dimensionless version of the flow modeled equations, an appropriate similarity variables are used. These transfer version of equations is solved numerically by the implement of the BVP4C technique on MATLAB. The graphical and numerical results are obtained for various emerging dimensionless parameters and discussed. It is noted that by the more accurate predictions of Formula: see text and M, the velocity sketch is decreased due to occurrence of resistance effect. Further, it is seen that larger estimation of micropolar parameter improves the angular velocity of the fluid.
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