Evaluation of Masters Choice Corn Silage on Growing Steer Performance

A growing study evaluated three corn silage hybrids on growing steer performance. Th e three hybrids were: a conventional hybrid- Farm Choice (CON) commonly grown in Eastern Nebraska which served as the control, Masters Choice hybrids MCT6365 RIB (MC1) selected to improve fi ber and starch digestion and MCT6733 GT3000 (MC2) that has been selected to improve fi ber digestion in cattle. Relative to CON, feeding hybrid MC1 resulted in similar DMI, but numerically increased ADG which significantly improved F:G compared to CON. Feeding MC2 led to greater DMI, similar ADG, and poorer (greater) F:G compared to CON. Feeding Masters Choice hybrid MCT6365 RIB (MC1) corn silage at 80% of the diet DM likely improved digestion and energy availability to the steers, which allowed greater ADG and improved F:G, while the opposite was true for MC2. Differences in hybrids exist when fed to growing cattle at 80% of the diet

Role of C-reactive protein in the bone marrow of Modic type 1 changes

Modic type 1 changes (MC1) are vertebral bone marrow lesions and associate with low back pain. Increased serum C-reactive protein (CRP) has inconsistently been associated with MC1. We aimed to provide evidence for a role of CRP in the tissue pathophysiology of MC1 bone marrow. From thirteen MC1 patients undergoing spinal fusion at MC1 levels, vertebral bone marrow aspirates from MC1 and intra-patient control bone marrow were taken. Bone marrow CRP, IL-1, and IL-6 were measured with enzyme-linked immunosorbent assays; lactate dehydrogenase (LDH) was measured with a colorimetric assay. CRP, IL-1, and IL-6 were compared between MC1 and control bone marrow. Bone marrow CRP was correlated with blood CRP and with bone marrow IL-1, IL-6, and LDH. CRP expression by marrow cells was measured with PCR. Increased CRP in MC1 bone marrow (mean difference: +0.22 mg CRP/g protein, 95% CI [-0.04, 0.47], p=0.088) correlated with blood CRP (r=0.69, p=0.018), with bone marrow IL-1β (ρ=0.52, p=0.029) and IL-6 (ρ=0.51, p=0.031). Marrow cells did not express CRP. Increased LDH in MC1 bone marrow (143.1%, 95% CI [110.7%, 175.4%], p=0.014) indicated necrosis. A blood CRP threshold of 3.2 mg/L detected with 100% accuracy increased CRP in MC1 bone marrow. In conclusion, the association of CRP with inflammatory and necrotic changes in MC1 bone marrow provides evidence for a pathophysiological role of CRP in MC1 bone marrow. This article is protected by copyright. All rights reserved

Bone marrow stromal cells in Modic type 1 changes promote neurite outgrowth

The pain in patients with Modic type 1 changes (MC1) is often due to vertebral body endplate pain, which is linked to abnormal neurite outgrowth in the vertebral body and adjacent endplate. The aim of this study was to understand the role of MC1 bone marrow stromal cells (BMSCs) in neurite outgrowth. BMSCs can produce neurotrophic factors, which have been shown to be pro-fibrotic in MC1, and expand in the perivascular space where sensory vertebral nerves are located. The study involved the exploration of the BMSC transcriptome in MC1, co-culture of MC1 BMSCs with the neuroblastoma cell line SH-SY5Y, analysis of supernatant cytokines, and analysis of gene expression changes in co-cultured SH-SY5Y. Transcriptomic analysis revealed upregulated brain-derived neurotrophic factor (BDNF) signaling-related pathways. Co-cultures of MC1 BMSCs with SH-SY5Y cells resulted in increased neurite sprouting compared to co-cultures with control BMSCs. The concentration of BDNF and other cytokines supporting neuron growth was increased in MC1 vs. control BMSC co-culture supernatants. Taken together, these findings show that MC1 BMSCs provide strong pro-neurotrophic cues to nearby neurons and could be a relevant disease-modifying treatment target

Submicrosecond comparisons of time standards via the Navigation Technology Satellites (NTS)

An interim demonstration was performed of the time transfer capability of the NAVSTAR GPS system using a single NTS satellite. Measurements of time difference (pseudo-range) are made from the NTS tracking network and at the participating observatories. The NTS network measurements are used to compute the NTS orbit trajectory. The central NTS tracking station has a time link to the Naval Observatory UTC (USNO,MC1) master clock. Measurements are used with the NTS receiver at the remote observatory, the time transfer value UTC (USNO,MC1)-UTC (REMOTE, VIA NTS) is calculated. Intercomparisons were computed using predicted values of satellite clock offset and ephemeus

Pro-fibrotic phenotype of bone marrow stromal cells in Modic type 1 changes

Modic type 1 changes (MC1) are painful vertebral bone marrow lesions frequently found in patients suffering from chronic low-back pain. Marrow fibrosis is a hallmark of MC1. Bone marrow stromal cells (BMSCs) are key players in other fibrotic bone marrow pathologies, yet their role in MC1 is unknown. The present study aimed to characterise MC1 BMSCs and hypothesised a pro-fibrotic role of BMSCs in MC1. BMSCs were isolated from patients undergoing lumbar spinal fusion from MC1 and adjacent control vertebrae. Frequency of colony-forming unit fibroblast (CFU-F), expression of stem cell surface markers, differentiation capacity, transcriptome, matrix adhesion, cell contractility as well as expression of pro-collagen type I alpha 1, α-smooth muscle actin, integrins and focal adhesion kinase (FAK) were compared. More CFU-F and increased expression of C-X-C-motif-chemokine 12 were found in MC1 BMSCs, possibly indicating overrepresentation of a perisinusoidal BMSC population. RNA sequencing analysis showed enrichment in extracellular matrix proteins and fibrosis-related signalling genes. Increases in pro-collagen type I alpha 1 expression, cell adhesion, cell contractility and phosphorylation of FAK provided further evidence for their pro-fibrotic phenotype. Moreover, a leptin receptor high expressing (LEPRhigh) BMSC population was identified that differentiated under transforming growth factor beta 1 stimulation into myofibroblasts in MC1 but not in control BMSCs. In conclusion, pro-fibrotic changes in MC1 BMSCs and a LEPRhigh MC1 BMSC subpopulation susceptible to myofibroblast differentiation were found. Fibrosis is a hallmark of MC1 and a potential therapeutic target. A causal link between the pro-fibrotic phenotype and clinical characteristics needs to be demonstrated

FGF2 overrides key pro-fibrotic features of bone marrow stromal cells isolated from Modic type 1 change patients

Extensive extracellular matrix production and increased cell-matrix adhesion by bone marrow stromal cells (BMSCs) are hallmarks of fibrotic alterations in the vertebral bone marrow known as Modic type 1 changes (MC1). MC1 are associated with non-specific chronic low-back pain. To identify treatment targets for MC1, in vitro studies using patient BMSCs are important to reveal pathological mechanisms. For the culture of BMSCs, fibroblast growth factor 2 (FGF2) is widely used. However, FGF2 has been shown to suppress matrix synthesis in various stromal cell populations. The aim of the present study was to investigate whether FGF2 affected the in vitro study of the fibrotic pathomechanisms of MC1-derived BMSCs. Transcriptomic changes and changes in cell-matrix adhesion of MC1-derived BMSCs were compared to intra-patient control BMSCs in response to FGF2. RNA sequencing and quantitative real-time polymerase chain reaction revealed that pro-fibrotic genes and pathways were not detectable in MC1-derived BMSCs when cultured in the presence of FGF2. In addition, significantly increased cell-matrix adhesion of MC1-derived BMSCs was abolished in the presence of FGF2. In conclusion, the data demonstrated that FGF2 overrides key pro-fibrotic features of MC1 BMSCs in vitro. Usage of FGF2-supplemented media in studies of fibrotic mechanisms should be critically evaluated as it could override normally dominant biological and biophysical cues

The Role of Intervertebral Disc Cartilage Catabolites in Modic Type 1 Changes

The thesis investigates the pathobiology of Modic changes (MCs), specifically focusing on Modic type 1 changes (MC1), emphasizing the complexity of the disease. Although MCs manifest as vertebral bone marrow lesions, the inflammation and degeneration observed in the neighboring intervertebral disc and cartilage endplate (CEP) are also closely linked to MCs. However, the underlying mechanisms and how the tissues crosstalk to induce MC development are unclear to this point. Yet, comprehending these pathobiological mechanisms is crucial for the development of targeted therapies, which are currently nonexistent. The thesis explores various aspects of MC1 addressing pathologic processes seen within the MC1 bone marrow, the CEP and the disc. Finally, the project's findings suggest a new disease mechanism for MC1 development initiated through MC1 specific disc degeneration. Chapter three investigated the impact of bone marrow stromal cells (BMSC) from MC1 on neurite outgrowth, using an in-vitro co-culture system. Multiple studies have reported an elevated presence of nerve fibers in the MC1 bone marrow and endplate, a definitive connection to the underlying cause has not been established. For the first time, the dysregulated MC1 BMSCs were directly linked to increased neurite outgrowth. With this knowledge, an important treatment target has been identified, paving the way for further studies to explore how to mitigate this effect. The fourth chapter explores the concept of a disc microbiome, particularly focusing on the MC1 and MC2 microbiomes, using metagenomic analysis. The disc microbiome challenges the conventional notion of disc sterility, necessitating clear methodological definitions for further investigation. Although our analysis confirmed the presence of a disc microbiome, the findings deviated from those of previous studies on degenerated MC discs, even after aligning the parameters of bioinformatic analysis to the previous studies. This study underscores the importance of not only standardizing bioinformatic analysis approaches but also further investigating factors that influence the bacterial composition of the disc microbiome. Differences could stem from sample preparation techniques or variations in the geographical and ethnic backgrounds of patients. Once clarified, the exploration of the disc microbiome will unlock numerous opportunities for diagnostic and treatment applications. The fifth chapter of the thesis highlights the to this point overlooked biological role of CEP cells. The experiments were able to confirm the presence of Toll-like receptors (TLRs) on CEP cells and particularly emphasized the presence of TLR2 as it was the only TLR that was upregulated through direct stimulation. The discovery of TLRs on CEP cells is noteworthy due to their high density compared to the cells in the adjacent disc and their ability to induce inflammation and promote the production of catabolic enzymes, potentially leading to endplate degeneration. This not only enhances our understanding of CEP cells but also reveals novel treatment targets. The sixth chapter presents the main project of the thesis, which focuses on understanding MC1 pathobiology and proposes a new mechanism for MC1 development beginning with MC1-specific disc degeneration. It is grounded in the fact that although disc degeneration is often observed in the disc adjacent to MC1, not all degenerated discs progress to MC1. The proposed MC1-specific disc degeneration is hypothesized to generate more fragments, triggering inflammation in the adjacent endplate, causing endplate destruction. This ultimately breaches the CEP barrier between the disc and bone marrow, allowing pro-inflammatory fragments (damage associated molecular patterns (DAMPs)) and inflammatory cytokines to spill over into the bone marrow, inducing MC1. Although the study is ongoing, significant discoveries have been made. MC1 discs were found to have a higher abundance of extracellular matrix derived fragments as well a greater abundance of the protease high temperature requirement serine protease 1 (HTRA1) than degenerated nonMC discs. In a subsequent phase, the abundant cartilage intermediate layer protein 1 (CILP1) fragments were successfully replicated by exposure to HTRA1 and were demonstrated to possess pro-inflammatory properties via TLR4 signaling activation, thereby classifying them as DAMPs. A CEP explant model was used to show that TLR activation can induce CEP tissue destruction, connecting the DAMP abundance in the disc to CEP damage. However, further experiments are necessary to address the gaps within the proposed mechanism. MC1 is a pathology associated with distinct inflammatory and pain-related processes, suggesting it could and should be treated specifically. This thesis demonstrates this and thus marks an important step towards targeted therapy for MC1

Anti-tau conformational scFv MC1 antibody efficiently reduces pathological tau species in adult JNPL3 mice.

Tau, the main component of the neurofibrillary tangles (NFTs), is an attractive target for immunotherapy in Alzheimer\u27s disease (AD) and other tauopathies. MC1/Alz50 are currently the only antibodies targeting a disease-specific conformational modification of tau. Passive immunization experiments using intra-peritoneal injections have previously shown that MC1 is effective at reducing tau pathology in the forebrain of tau transgenic JNPL3 mice. In order to reach a long-term and sustained brain delivery, and avoid multiple injection protocols, we tested the efficacy of the single-chain variable fragment of MC1 (scFv-MC1) to reduce tau pathology in the same animal model, with focus on brain regional differences. ScFv-MC1 was cloned into an AAV delivery system and was directly injected into the hippocampus of adult JNPL3 mice. Specific promoters were employed to selectively target neurons or astrocytes for scFv-MC1 expression. ScFv-MC1 was able to decrease soluble, oligomeric and insoluble tau species, in our model. The effect was evident in the cortex, hippocampus and hindbrain. The astrocytic machinery appeared more efficient than the neuronal, with significant reduction of pathology in areas distant from the site of injection. To our knowledge, this is the first evidence that an anti-tau conformational scFv antibody, delivered directly into the mouse adult brain, is able to reduce pathological tau, providing further insight into the nature of immunotherapy strategies

Magnetohydrodynamic simulation of the interaction between two interplanetary magnetic clouds and its consequent geoeffectiveness

Numerical studies of the interplanetary "multiple magnetic clouds (Multi-MC)" are performed by a 2.5-dimensional ideal magnetohydrodynamic (MHD) model in the heliospheric meridional plane. Both slow MC1 and fast MC2 are initially emerged along the heliospheric equator, one after another with different time interval. The coupling of two MCs could be considered as the comprehensive interaction between two systems, each comprising of an MC body and its driven shock. The MC2-driven shock and MC2 body are successively involved into interaction with MC1 body. The momentum is transferred from MC2 to MC1. After the passage of MC2-driven shock front, magnetic field lines in MC1 medium previously compressed by MC2-driven shock are prevented from being restored by the MC2 body pushing. MC1 body undergoes the most violent compression from the ambient solar wind ahead, continuous penetration of MC2-driven shock through MC1 body, and persistent pushing of MC2 body at MC1 tail boundary. As the evolution proceeds, the MC1 body suffers from larger and larger compression, and its original vulnerable magnetic elasticity becomes stiffer and stiffer. So there exists a maximum compressibility of Multi-MC when the accumulated elasticity can balance the external compression. With respect to Multi-MC geoeffectiveness, the evolution stage is a dominant factor, whereas the collision intensity is a subordinate one. The magnetic elasticity, magnetic helicity of each MC, and compression between each other are the key physical factors for the formation, propagation, evolution, and resulting geoeffectiveness of interplanetary Multi-MC.Comment: 56 pages, 11 figure

Arabidopsis metacaspase MC1 localizes in stress granules, clears protein aggregates and delays senescence

Stress granules (SGs) are highly conserved cytoplasmic condensates that assemble in response to stress and contribute to maintaining protein homeostasis. These membraneless organelles are dynamic, disassembling once the stress is no longer present. Persistence of SGs due to mutations or chronic stress has been often related to age-dependent protein-misfolding diseases in animals. Here, we find that the metacaspase MC1 is dynamically recruited into SGs upon proteotoxic stress in Arabidopsis (Arabidopsis thaliana). Two predicted disordered regions, the prodomain and the 360 loop, mediate MC1 recruitment to and release from SGs. Importantly, we show that MC1 has the capacity to clear toxic protein aggregates in vivo and in vitro, acting as a disaggregase. Finally, we demonstrate that overexpressing MC1 delays senescence and this phenotype is dependent on the presence of the 360 loop and an intact catalytic domain. Together, our data indicate that MC1 regulates senescence through its recruitment into SGs and this function could potentially be linked to its remarkable protein aggregate-clearing activity