Effects of mesenchymal stromal cells versus serum on tendon healing in a controlled experimental trial in an equine model

Abstract Background Mesenchymal stromal cells (MSC) have shown promising results in the treatment of tendinopathy in equine medicine, making this therapeutic approach seem favorable for translation to human medicine. Having demonstrated that MSC engraft within the tendon lesions after local injection in an equine model, we hypothesized that they would improve tendon healing superior to serum injection alone. Methods Quadrilateral tendon lesions were induced in six horses by mechanical tissue disruption combined with collagenase application 3 weeks before treatment. Adipose-derived MSC suspended in serum or serum alone were then injected intralesionally. Clinical examinations, ultrasound and magnetic resonance imaging were performed over 24 weeks. Tendon biopsies for histological assessment were taken from the hindlimbs 3 weeks after treatment. Horses were sacrificed after 24 weeks and forelimb tendons were subjected to macroscopic and histological examination as well as analysis of musculoskeletal marker expression. Results Tendons injected with MSC showed a transient increase in inflammation and lesion size, as indicated by clinical and imaging parameters between week 3 and 6 (p < 0.05). Thereafter, symptoms decreased in both groups and, except that in MSC-treated tendons, mean lesion signal intensity as seen in T2w magnetic resonance imaging and cellularity as seen in the histology (p < 0.05) were lower, no major differences could be found at week 24. Conclusions These data suggest that MSC have influenced the inflammatory reaction in a way not described in tendinopathy studies before. However, at the endpoint of the current study, 24 weeks after treatment, no distinct improvement was observed in MSC-treated tendons compared to the serum-injected controls. Future studies are necessary to elucidate whether and under which conditions MSC are beneficial for tendon healing before translation into human medicine

Mitochondrial Substrate-Level Phosphorylation as Energy Source for Glioblastoma: Review and Hypothesis

Glioblastoma multiforme (GBM) is the most common and malignant of the primary adult brain cancers. Ultrastructural and biochemical evidence shows that GBM cells exhibit mitochondrial abnormalities incompatible with energy production through oxidative phosphorylation (OxPhos). Under such conditions, the mitochondrial F0-F1 ATP synthase operates in reverse at the expense of ATP hydrolysis to maintain a moderate membrane potential. Moreover, expression of the dimeric M2 isoform of pyruvate kinase in GBM results in diminished ATP output, precluding a significant ATP production from glycolysis. If ATP synthesis through both glycolysis and OxPhos was impeded, then where would GBM cells obtain high-energy phosphates for growth and invasion? Literature is reviewed suggesting that the succinate-CoA ligase reaction in the tricarboxylic acid cycle can substantiate sufficient ATP through mitochondrial substrate-level phosphorylation (mSLP) to maintain GBM growth when OxPhos is impaired. Production of high-energy phosphates would be supported by glutaminolysis-a hallmark of GBM metabolism-through the sequential conversion of glutamine -> glutamate -> alpha-ketoglutarate -> succinyl CoA -> succinate. Equally important, provision of ATP through mSLP would maintain the adenine nucleotide translocase in forward mode, thus preventing the reverse-operating F0-F1 ATP synthase from depleting cytosolic ATP reserves. Because glucose and glutamine are the primary fuels driving the rapid growth of GBM and most tumors for that matter, simultaneous restriction of these two substrates or inhibition of mSLP should diminish cancer viability, growth, and invasion

Brief of Intellectual Property Law Scholars As Amici Curiae in Support of Neither Party, WesternGeco LLC v. Ion Geophysical Corp., No. 16-1011, US Supreme Court

This amici curiae brief was filed on behalf of Intellectual Property Law Scholars in WesternGeco LLC v. Ion Geophysical Corp. in the U.S. Supreme Court. The question presented is: Whether the U.S. Court of Appeals for the Federal Circuit erred in holding that lost profits arising from prohibited combinations occurring outside of the United States are categorically unavailable in cases in which patent infringement is proven under 35 U.S.C. § 271(f). In RJR Nabisco, Inc. v. European Community, 136 S. Ct. 2090 (2016), the Supreme Court articulated a two-step method for assessing the extraterritorial reach of a US statute: 1. A court should determine whether the presumption against extraterritoriality has been rebutted—that is, whether the statute gives a clear, affirmative indication that it applies extraterritorially. If the presumption is rebutted, the statute may have extraterritorial reach. 2. But even if the presumption has not been rebutted, a court should look at the focus of the statute. If the conduct relevant to the statute\u27s focus occurred in the United States, then the case involves a permissible domestic application even if other conduct occurred abroad; but if the conduct relevant to the focus occurred in a foreign country, then the case involves an impermissible extraterritorial application regardless of any other conduct that occurred in U.S. territory. The brief of amici curiae makes the follow points: 1. The Supreme Court has not squarely answered the question as to whether the presumption against extraterritoriality applies separately to remedial provisions of a statute generally (here whether it applies to § 284). We argue it does. 2. We argue that the territorial reach § 284 necessarily depends the relevant provision of § 271 used to find liability. Here, under § 271(f), the presumption is rebutted (though it would not be generally for a case under § 271(a), with NTP v. Research in Motion may be a counter-example when one looks at the focus at step 2)). 3. We also argue that the Court should offer more guidance as to what happens even if the RJR test is satisfied. RJR Nabisco seems to operate in binary fashion -- either the statute has extraterritorial reach or it doesn\u27t. But Microsoft Corp. v. AT&T Corp., and earlier Supreme Court decision also interpreting 35 U.S.C. § 271(f), suggests that the presumption may still have a role in interpreting a statute. We offer two suggestions on how the presumption should operate in this context. First, courts should seriously and formally consider issues of comity and potential conflicts with foreign law in assessing whether to apply U.S. law extraterritorially. Second, that territoriality should remain relevant in assessments of proximate cause

Testing a Social Network Intervention Using Vlogs to Promote Physical Activity Among Adolescents: A Randomized Controlled Trial

There is a need to stimulate physical activity among adolescents, but unfortunately, they are hard to reach with traditional mass media interventions. A promising alternative is to carry out social network interventions. In social network interventions, a small group of individuals (influence agents) is selected to promote health-related behaviors within their social network. This study investigates whether a social network intervention is more effective to promote physical activity, compared to a mass media intervention and no intervention. Ad

Remnant Fermi surface in the presence of an underlying instability in layered 1T-TaS_2

We report high resolution angle-scanned photoemission and Fermi surface (FS) mapping experiments on the layered transition-metal dichalcogenide 1T-TaS_2 in the quasi commensurate (QC) and the commensurate (C) charge-density-wave (CDW) phase. Instead of a nesting induced partially removed FS in the CDW phase we find a pseudogap over large portions of the FS. This remnant FS exhibits the symmetry of the one-particle normal state FS even when passing from the QC-phase to the C-phase. Possibly, this Mott localization induced transition represents the underlying instability responsible for the pseudogapped FS

Screening, Coulomb pseudopotential, and superconductivity in alkali-doped Fullerenes

We study the static screening in a Hubbard-like model using quantum Monte Carlo. We find that the random phase approximation is surprisingly accurate almost up to the Mott transition. We argue that in alkali-doped Fullerenes the Coulomb pseudopotential $\mu^\ast$ is not very much reduced by retardation effects. Therefore efficient screening is important in reducing $\mu^{\ast}$ sufficiently to allow for an electron-phonon driven superconductivity. In this way the Fullerides differ from the conventional picture, where retardation effects play a major role in reducing the electron-electron repulsion.Comment: 4 pages RevTeX with 2 eps figures, additional material available at http://www.mpi-stuttgart.mpg.de/docs/ANDERSEN/fullerene

Gut microbiome composition in the Hispanic Community Health Study/Study of Latinos is shaped by geographic relocation, environmental factors, and obesity.

Background: Hispanics living in the USA may have unrecognized potential birthplace and lifestyle influences on the gut microbiome. We report a cross-sectional analysis of 1674 participants from four centers of the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), aged 18 to 74 years old at recruitment.Results: Amplicon sequencing of 16S rRNA gene V4 and fungal ITS1 fragments from self-collected stool samples indicate that the host microbiome is determined by sociodemographic and migration-related variables. Those who relocate from Latin America to the USA at an early age have reductions in Prevotella to Bacteroides ratios that persist across the life course. Shannon index of alpha diversity in fungi and bacteria is low in those who relocate to the USA in early life. In contrast, those who relocate to the USA during adulthood, over 45 years old, have high bacterial and fungal diversity and high Prevotella to Bacteroides ratios, compared to USA-born and childhood arrivals. Low bacterial diversity is associated in turn with obesity. Contrasting with prior studies, our study of&nbsp;the Latino population shows increasing Prevotella to Bacteroides ratio with greater obesity. Taxa within Acidaminococcus, Megasphaera, Ruminococcaceae, Coriobacteriaceae, Clostridiales, Christensenellaceae, YS2 (Cyanobacteria), and Victivallaceae are significantly associated with both obesity and earlier exposure to the USA, while Oscillospira and Anaerotruncus show paradoxical associations with both obesity and late-life introduction to the USA.Conclusions: Our analysis of the gut microbiome of Latinos demonstrates unique features that might be responsible for health disparities affecting Hispanics living in the USA