Peripheral innervation plays an important role in regulating tissue repair and regeneration. Here we provide evidence that injured peripheral nerves provide a reservoir of mesenchymal precursor cells ...that can directly contribute to murine digit tip regeneration and skin repair. In particular, using single-cell RNA sequencing and lineage tracing, we identify transcriptionally distinct mesenchymal cell populations within the control and injured adult nerve, including neural crest-derived cells in the endoneurium with characteristics of mesenchymal precursor cells. Culture and transplantation studies show that these nerve-derived mesenchymal cells have the potential to differentiate into non-nerve lineages. Moreover, following digit tip amputation, neural crest-derived nerve mesenchymal cells contribute to the regenerative blastema and, ultimately, to the regenerated bone. Similarly, neural crest-derived nerve mesenchymal cells contribute to the dermis during skin wound healing. These findings support a model where peripheral nerves directly contribute mesenchymal precursor cells to promote repair and regeneration of injured mammalian tissues.
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•Peripheral nerves contain four transcriptionally distinct mesenchymal populations•Endoneurial Pdgfra-positive cells have mesenchymal precursor properties•Nerve mesenchymal cells contribute to bone formation during digit tip regeneration•Transplanted and endogenous nerve mesenchymal cells contribute to dermal repair
Carr et al. demonstrate that peripheral nerves contain mesenchymal precursor-like cells that participate in repair of damaged mesenchymal tissues. Utilizing scRNA-seq, lineage tracing, and transplantation approaches, the authors show that neural crest-derived endoneurial mesenchymal precursor cells generate bone and dermal cells during digit tip regeneration and skin wound healing.
•Dedifferentiated Schwann cells are required for the regeneration of multiple tissues in mammals and amphibians.•Dedifferentiated Schwann cells originate from injured nerves and migrate into damaged ...tissues.•Dedifferentiated Schwann cells promote regeneration through paracrine growth factor secretion.•Sox2 expression regulates dedifferentiated Schwann cell activity during tissue repair and regeneration.
Current evidence suggests that peripheral nerve-associated Schwann cells possess the capacity to promote the repair and regeneration of multiple tissue types, in addition to peripheral nervous system axons. These findings shed light on the nerve-dependent nature of regeneration that has been well documented in various organs. This review outlines recent advances in knowledge surrounding endogenous regenerative functions of Schwann cells across species and tissue types, with a specific focus on the role of Sox2+ dedifferentiated Schwann cells in regulating the proliferation of surrounding tissue-resident mesenchymal precursors.
Adult mammals have lost multi-tissue regenerative capacity, except for the distal digit, which is able to regenerate via mechanisms that remain largely unknown. Here, we show that, after adult mouse ...distal digit removal, nerve-associated Schwann cell precursors (SCPs) dedifferentiate and secrete growth factors that promote expansion of the blastema and digit regeneration. When SCPs were dysregulated or ablated, mesenchymal precursor proliferation in the blastema was decreased and nail and bone regeneration were impaired. Transplantation of exogenous SCPs rescued these regeneration defects. We found that SCPs secrete factors that promote self-renewal of mesenchymal precursors, and we used transcriptomic and proteomic analysis to define candidate factors. Two of these, oncostatin M (OSM) and platelet-derived growth factor AA (PDGF-AA), are made by SCPs in the regenerating digit and rescued the deficits in regeneration caused by loss of SCPs. As all peripheral tissues contain nerves, these results could have broad implications for mammalian tissue repair and regeneration.
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•Schwann cell precursors (SCPs) enter the regenerating digit tip•Ablation of SCPs by inducible deletion or denervation inhibits regeneration•SCPs secrete growth factors to promote mesenchymal cell proliferation•Oncostatin M and PDGF-AA can rescue regeneration in a denervated digit tip
Johnston et al. show that, during regeneration of the mouse digit tip, nerve-associated Schwann cell precursors dedifferentiate and move into the injured tissue, where they secrete paracrine factors, including oncostatin M and PDGF-AA, to promote mesenchymal cell proliferation, expansion of the blastema, and regeneration.
The first part of the review contrasts the main drawbacks of silica-based packings such as their relative thermal and chemical instability with excellent stability of metal oxides. The paper concerns ...mainly ZrO
2, TiO
2 and Al
2O
3. Methods of preparation of spherical particles for HPLC are described. Surface chemistry of the oxides is, however, very different from that of silica. Ability of the oxides to ion- and ligand exchange is discussed from a chromatographic point of view.
Endometriosis is a chronic, estrogen-dependent condition that causes dysmenorrhea and pelvic pain. Elagolix, an oral, nonpeptide, gonadotropin-releasing hormone (GnRH) antagonist, produced partial to ...nearly full estrogen suppression in previous studies.
We performed two similar, double-blind, randomized, 6-month phase 3 trials (Elaris Endometriosis I and II EM-I and EM-II) to evaluate the effects of two doses of elagolix - 150 mg once daily (lower-dose group) and 200 mg twice daily (higher-dose group) - as compared with placebo in women with surgically diagnosed endometriosis and moderate or severe endometriosis-associated pain. The two primary efficacy end points were the proportion of women who had a clinical response with respect to dysmenorrhea and the proportion who had a clinical response with respect to nonmenstrual pelvic pain at 3 months. Each of these end points was measured as a clinically meaningful reduction in the pain score and a decreased or stable use of rescue analgesic agents, as recorded in a daily electronic diary.
A total of 872 women underwent randomization in Elaris EM-I and 817 in Elaris EM-II; of these women, 653 (74.9%) and 632 (77.4%), respectively, completed the intervention. At 3 months, a significantly greater proportion of women who received each elagolix dose met the clinical response criteria for the two primary end points than did those who received placebo. In Elaris EM-I, the percentage of women who had a clinical response with respect to dysmenorrhea was 46.4% in the lower-dose elagolix group and 75.8% in the higher-dose elagolix group, as compared with 19.6% in the placebo group; in Elaris EM-II, the corresponding percentages were 43.4% and 72.4%, as compared with 22.7% (P<0.001 for all comparisons). In Elaris EM-I, the percentage of women who had a clinical response with respect to nonmenstrual pelvic pain was 50.4% in the lower-dose elagolix group and 54.5% in the higher-dose elagolix group, as compared with 36.5% in the placebo group (P<0.001 for all comparisons); in Elaris EM-II, the corresponding percentages were 49.8% and 57.8%, as compared with 36.5% (P=0.003 and P<0.001, respectively). The responses with respect to dysmenorrhea and nonmenstrual pelvic pain were sustained at 6 months. Women who received elagolix had higher rates of hot flushes (mostly mild or moderate), higher levels of serum lipids, and greater decreases from baseline in bone mineral density than did those who received placebo; there were no adverse endometrial findings.
Both higher and lower doses of elagolix were effective in improving dysmenorrhea and nonmenstrual pelvic pain during a 6-month period in women with endometriosis-associated pain. The two doses of elagolix were associated with hypoestrogenic adverse effects. (Funded by AbbVie; Elaris EM-I and EM-II ClinicalTrials.gov numbers, NCT01620528 and NCT01931670 .).
In reversed-phase chromatography (RPC), the restricted retention of “bulky” solutes can occur in one of two ways, giving rise to either “shape selectivity” or “steric interaction.” Starting with data ...for 150 solutes and 167 monomeric type-B alkylsilica columns, the present study examines the steric interaction process further and compares it with shape selectivity. The dependence of column hydrophobicity and steric interaction on column properties (ligand length and concentration, pore diameter, end-capping) was determined and compared. The role of the solute in steric interaction was found to be primarily a function of solute molecular length, with longer solutes giving increased steric interaction. We find that there are several distinct differences in the way shape selectivity and steric interaction are affected by separation conditions and the nature of the sample. Of particular interest, steric interaction exhibits a maximum effect for monomeric C
18 columns, and becomes less important for either a C
1 or C
30 column; shape selectivity appears unimportant for monomeric C
1–C
18 columns at ambient and higher temperatures, but becomes pronounced for C
30 – as well as polymeric columns with ligands ≥C
8. One hypothesis is that shape selectivity involves the presence or creation of cavities within the stationary phase that can accommodate a retained solute (a primarily enthalpic process), while steric interaction mainly makes greater use of spaces that pre-exist the retention of the solute (a primarily entropic process). The related dependence of hydrophobic interaction on column properties was also examined.
In this part of the review authors discuss methods used for modification of metal oxide surfaces. On the basis of literature data it is shown, that silanization of the surfaces do not form stable ...supports for chromatography. On the other hand, the success of polymer modified surfaces such as polybutadiene (PBD) and polystyrene (PS) is emphasized. Permanent modification of metal oxide surfaces with Lewis bases is also widely discussed. Chromatographic properties of polymer modified surfaces of zirconia are discussed in details. The perspectives of carbon-coated metal oxide surfaces in HPLC and high temperature separations are described.
A recently developed treatment of reversed-phase column selectivity (the hydrophobic-subtraction model) is reviewed and extended, including its characterization of the selectivity of different column ...types (e.g., C
1–C
30, cyano, phenyl, etc.). The application of this model to retention data for various solutes and columns has provided new insights into the nature of different solute–column interactions and their relative importance in affecting sample retention and separation. Reversed-phase columns can be characterized by five selectivity parameters (
H
,
S
*,
A
,
B
and
C
), values of which are summarized here for more than 300 different columns. The selection of columns of either equivalent or different selectivity is readily achievable on the basis of their values of
H
,
S
*, etc. The development of the hydrophobic-subtraction model, its use in characterizing the selectivity of different reversed-phase liquid chromatography (RP-LC) columns, and its application to various practical problems as described here began in 1998. The original inspiration for this project owes much to Jack Kirkland, who also contributed actively to the initial studies that laid the foundation of this model; he has since provided other important support to this project. Jack and one of the authors (LRS) have enjoyed a strong professional relationship and personal friendship for the past 35 years, and it is the privilege of the authors to dedicate this paper and the work that it represents to Jack. His contributions to HPLC column technology have extended from the mid-1960s into the present century, and it is impossible to conceive of present day HPLC practice without Jack's contributions over the years. In this and other ways, his position as a pioneer and key implementer of HPLC is widely recognized. We wish Jack well in the years to come.
The methoxymethyl radical, CH3OCH2, is an important intermediate in the low temperature combustion of dimethyl ether. The kinetics and yields of OH from the reaction of the methoxymethyl radical with ...O2 have been measured over the temperature and pressure ranges of 195-650 K and 5-500 Torr by detecting the hydroxyl radical using laser-induced fluorescence following the excimer laser photolysis (248 nm) of CH3OCH2Br. The reaction proceeds via the formation of an energized CH3OCH2O2 adduct, which either dissociates to OH + 2 H2CO or is collisionally stabilized by the buffer gas. At temperatures above 550 K, a secondary source of OH was observed consistent with thermal decomposition of stabilized CH3OCH2O2 radicals. In order to quantify OH production from the CH3OCH2 + O2 reaction, extensive relative and absolute OH yield measurements were performed over the same (T, P) conditions as the kinetic experiments. The reaction was studied at sufficiently low radical concentrations (∼10(11) cm(-3)) that secondary (radical + radical) reactions were unimportant and the rate coefficients could be extracted from simple bi- or triexponential analysis. Ab initio (CBS-GB3)/master equation calculations (using the program MESMER) of the CH3OCH2 + O2 system were also performed to better understand this combustion-related reaction as well as be able to extrapolate experimental results to higher temperatures and pressures. To obtain agreement with experimental results (both kinetics and yield data), energies of the key transition states were substantially reduced (by 20-40 kJ mol(-1)) from their ab initio values and the effect of hindered rotations in the CH3OCH2 and CH3OCH2OO intermediates were taken into account. The optimized master equation model was used to generate a set of pressure and temperature dependent rate coefficients for the component nine phenomenological reactions that describe the CH3OCH2 + O2 system, including four well-skipping reactions. The rate coefficients were fitted to Chebyshev polynomials over the temperature and density ranges 200 to 1000 K and 1 × 10(17) to 1 × 10(23) molecules cm(-3) respectively for both N2 and He bath gases. Comparisons with an existing autoignition mechanism show that the well-skipping reactions are important at a pressure of 1 bar but are not significant at 10 bar. The main differences derive from the calculated rate coefficient for the CH3OCH2OO → CH2OCH2OOH reaction, which leads to a faster rate of formation of O2CH2OCH2OOH.
Objectives
A relationship between Meniere's disease and migraine has been postulated previously. This study investigates this relationship further and determines the most influential factors for ...developing Meniere's disease.
Design
Epidemiological study.
Setting
Two tertiary referral Neuro‐Otological centres in Sheffield and Sydney.
Participants
Adult patients referred to the Neuro‐Otology clinic between 2003 and 2010.
Main outcome measures
Past history and family history of Meniere's disease and migraine. Logistic regression analysis to determine the most influential factors for Meniere's disease.
Results
One hundred and eighty‐one patients were included in the study, 102 with Meniere's disease and 79 with other balance disorders. Three significant findings were demonstrated. Firstly, a family history of Meniere's disease (33.3% versus 6.3%) or migraine (21.6% versus 9%) is more common in the Meniere's disease group than in the other balance disorders group. Secondly, a history of migrainous headaches is more common in the Meniere's disease group than in the other balance disorders group (45.1% versus 9%). Thirdly, patients with a past history or a family history of Meniere's disease or migraine have a higher likelihood of suffering from Meniere's disease.
Conclusions
There is an overall relationship between Meniere's disease and migraine. A family history of Meniere's disease or migraine is more common in Meniere's disease. A history of migrainous headache is more common in Meniere's disease. Patients with a past history or family history of Meniere's disease or migraine have a higher likelihood of suffering from Meniere's disease.
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