Advances in Hyaluronan Biology: Signaling, Regulation, and Disease Mechanisms

Hyaluronan is an extracellular glycosaminoglycan polymer consisting of linear disaccharide units containing alternating glucuronate and N-acetylglucosamine.Many cell types make hyaluronan, which unlike most other macromolecules is assembled at the plasmamembrane and concurrently translocated through the hyaluronan synthase enzyme. The normal function of large hyaluronan polymers (\u3e1MDa) in tissue cushioning, hydration, and lubrication is well established. The aberrant accumulation and degradation of hyaluronan and the receptor-mediated signaling of smaller hyaluronan fragments have also been extensively implicated in a variety of pathological states including inflammation and cancer. More recently, the discovery that hyaluronan can either be a structural matrix component or appear as smaller processed polymers and oligomers that differentially engage a diverse range of signaling receptors has created an exciting paradigm shift and reenergized hyaluronan research in a broad range of fields. In this special issue, eight review articles focus on summarizing the latest contributions to understanding hyaluronan synthesis and catabolism and the regulation of hyaluronan functions. Seven novel primary research articles also investigate multiple roles of hyaluronan in disease progression and targeting

Advances in Hyaluronan Biology: Signaling, Regulation, and Disease Mechanisms

Hyaluronan is an extracellular glycosaminoglycan polymer consisting of linear disaccharide units containing alternating glucuronate and N-acetylglucosamine.Many cell types make hyaluronan, which unlike most other macromolecules is assembled at the plasmamembrane and concurrently translocated through the hyaluronan synthase enzyme. The normal function of large hyaluronan polymers (\u3e1MDa) in tissue cushioning, hydration, and lubrication is well established. The aberrant accumulation and degradation of hyaluronan and the receptor-mediated signaling of smaller hyaluronan fragments have also been extensively implicated in a variety of pathological states including inflammation and cancer. More recently, the discovery that hyaluronan can either be a structural matrix component or appear as smaller processed polymers and oligomers that differentially engage a diverse range of signaling receptors has created an exciting paradigm shift and reenergized hyaluronan research in a broad range of fields. In this special issue, eight review articles focus on summarizing the latest contributions to understanding hyaluronan synthesis and catabolism and the regulation of hyaluronan functions. Seven novel primary research articles also investigate multiple roles of hyaluronan in disease progression and targeting

The protein kinase R modifies gut physiology to limit colitis

Here we investigate the function of the innate immune molecule protein kinase R (PKR) in intestinal inflammation. To model a colitogenic role of PKR, we determine the physiological response to dextran sulfate sodium (DSS) of wild-type and two transgenic mice strains mutated to express either a kinase-dead PKR or to ablate expression of the kinase. These experiments recognize kinase-dependent and -independent protection from DSS-induced weight loss and inflammation, against a kinase-dependent increase in the susceptibility to DSS-induced injury. We propose these effects arise through PKR-dependent alteration of gut physiology, evidenced as altered goblet cell function and changes to the gut microbiota at homeostasis that suppresses inflammasome activity by controlling autophagy. These findings establish that PKR functions as both a protein kinase and a signaling molecule in instituting immune homeostasis in the gut

Landing Error Scoring System (LESS) Items are Associated with the Incidence Rate of Lower Extremity Stress Fracture

Objectives: Lower-extremity stress fracture injuries are a major cause of morbidity in physically active populations. The ability to efficiently screen for modifiable risk factors associated with injury is critical in developing and implementing effective injury prevention programs. The purpose of this study was to determine if baseline Landing Error Scoring System (LESS) scores were associated with the incidence rate of lower-extremity stress fracture during four years of follow-up. Methods: To accomplish this objective we conducted a prospective cohort study at a US Service Academy. A total of 1772 eligible subjects with complete baseline data and no history of lower-extremity stress fracture were included in this study. At baseline we conducted motion analysis during a jump landing task using the LESS. Incident lower-extremity stress fracture cases were identified during the four year follow-up period using the injury surveillance systems at our institution. The primary outcome of interest was the incidence rate of lower-extremity stress fracture during follow-up. The electronic medical records of each potential incident case were reviewed and case status was determined by an adjudication committee consisting of two sports medicine fellowship-trained orthopaedic surgeons who were blinded to baseline LESS data. The association between baseline LESS scores and the incidence rate of lower-extremity stress fracture was examined for total LESS score and for each individual LESS item. Univariate and multivariable Poisson regression models were used to estimate the association between baseline LESS scores and the incidence rate of lower-extremity stress fracture during follow-up. Results: During the follow-up period, 94 incident lower-extremity stress fractures were documented in the study cohort and the cumulative incidence of stress fracture was 5.3% (95%CI: 4.3%, 6.5%). In univariate analyses total LESS score at baseline was associated with the incidence rate of lower-extremity stress fracture during follow-up. For every additional movement error documented at baseline there was a 15% increase in the incidence rate of lower-extremity stress fracture during follow-up (IRR=1.15; 95%CI: 1.02, 1.31, p=0.025). Based on univariate analyses, several individual LESS items at baseline were also associated with the incidence rate of stress fracture during follow-up. Ankle flexion at initial contact (p=0.055), stance width at initial contact (p=0.026), asymmetrical landing at initial contact (p=0.003), trunk flexion at initial contact (p=0.036), and overall impression (p=0.021) were significantly associated with the incidence rate of stress fracture. In multivariable analyses controlling for sex and year of entry into the cohort, subjects who consistently landed flat-footed or heel-to-toe were 2.33 times (IRR=2.33; 95%CI: 1.36, 3.97, p=0.002) more likely to sustain a lower-extremity stress fracture during follow-up. Similarly, subjects who consistently demonstrated asymmetric landing at initial contact were 2.53 times (IRR=2.53; 95%CI: 1.34, 4.74, p=0.004) more likely to sustain a stress fracture during follow-up. Conclusion: These data suggest that specific LESS items may be predictive of lower-extremity stress fracture risk and may be helpful in injury screening and prevention

Notch signaling during human T cell development

Notch signaling is critical during multiple stages of T cell development in both mouse and human. Evidence has emerged in recent years that this pathway might regulate T-lineage differentiation differently between both species. Here, we review our current understanding of how Notch signaling is activated and used during human T cell development. First, we set the stage by describing the developmental steps that make up human T cell development before describing the expression profiles of Notch receptors, ligands, and target genes during this process. To delineate stage-specific roles for Notch signaling during human T cell development, we subsequently try to interpret the functional Notch studies that have been performed in light of these expression profiles and compare this to its suggested role in the mouse

A code to Make Your Own Synthetic ObservaTIonS (MYOSOTIS)

We introduce our new code MYOSOTIS (Make Your Own Synthetic ObservaTIonS) which is designed to produce synthetic observations from simulated clusters. The code can synthesize observations from both ground-and spaced-based observatories, for a range of different filters, observational conditions and angular/spectral resolution. In this paper, we highlight some of the features of MYOSOTIS, creating synthetic observations from young massive star clusters. Our model clusters are simulated using NBODY6 code and have different total masses, halfmass radii, and binary fractions. The synthetic observations are made at the age of 2 Myr with Solar metallicity and under different extinction conditions. For each cluster, we create synthetic images of the Hubble Space Telescope (HST) in the visible (WFPC2/F555W) as well as Very Large Telescopes in the nearIR (SPHERE/IRDIS/Ks). We show how MYOSOTIS can be used to look at mass function (MF) determinations. For this aim we re-estimate stellar masses using a photometric analysis on the synthetic images. The synthetic MF slopes are compared to their actual values. Our photometric analysis demonstrate that depending on the adopted filter, extinction, angular resolution, and pixel sampling of the instruments, the power-law index of the underlying MFs can be shallower than the observed ones by at least ±0.25 dex which is in agreement with the observed discrepancies reported in the literature, specially for young star clusters

A phase I trial of the selective oral cyclin-dependent kinase inhibitor seliciclib (CYC202; R-Roscovitine), administered twice daily for 7 days every 21 days

Seliciclib (CYC202; R-roscovitine) is the first selective, orally bioavailable inhibitor of cyclin-dependent kinases 1, 2, 7 and 9 to enter clinical trial. Preclinical studies showed antitumour activity in a broad range of human tumour xenografts. A phase I trial was performed with a 7-day b.i.d. p.o. schedule. Twenty-one patients (median age 62 years, range: 39–73 years) were treated with doses of 100, 200 and 800 b.i.d. Dose-limiting toxicities were seen at 800 mg b.i.d.; grade 3 fatigue, grade 3 skin rash, grade 3 hyponatraemia and grade 4 hypokalaemia. Other toxicities included reversible raised creatinine (grade 2), reversible grade 3 abnormal liver function and grade 2 emesis. An 800 mg portion was investigated further in 12 patients, three of whom had MAG3 renograms. One patient with a rapid increase in creatinine on day 3 had a reversible fall in renal perfusion, with full recovery by day 14, and no changes suggestive of renal tubular damage. Further dose escalation was precluded by hypokalaemia. Seliciclib reached peak plasma concentrations between 1 and 4 h and elimination half-life was 2–5 h. Inhibition of retinoblastoma protein phosphorylation was not demonstrated in peripheral blood mononuclear cells. No objective tumour responses were noted, but disease stabilisation was recorded in eight patients; this lasted for a total of six courses (18 weeks) in a patient with ovarian cancer

The stellar and sub-stellar IMF of simple and composite populations

The current knowledge on the stellar IMF is documented. It appears to become top-heavy when the star-formation rate density surpasses about 0.1Msun/(yr pc^3) on a pc scale and it may become increasingly bottom-heavy with increasing metallicity and in increasingly massive early-type galaxies. It declines quite steeply below about 0.07Msun with brown dwarfs (BDs) and very low mass stars having their own IMF. The most massive star of mass mmax formed in an embedded cluster with stellar mass Mecl correlates strongly with Mecl being a result of gravitation-driven but resource-limited growth and fragmentation induced starvation. There is no convincing evidence whatsoever that massive stars do form in isolation. Various methods of discretising a stellar population are introduced: optimal sampling leads to a mass distribution that perfectly represents the exact form of the desired IMF and the mmax-to-Mecl relation, while random sampling results in statistical variations of the shape of the IMF. The observed mmax-to-Mecl correlation and the small spread of IMF power-law indices together suggest that optimally sampling the IMF may be the more realistic description of star formation than random sampling from a universal IMF with a constant upper mass limit. Composite populations on galaxy scales, which are formed from many pc scale star formation events, need to be described by the integrated galactic IMF. This IGIMF varies systematically from top-light to top-heavy in dependence of galaxy type and star formation rate, with dramatic implications for theories of galaxy formation and evolution.Comment: 167 pages, 37 figures, 3 tables, published in Stellar Systems and Galactic Structure, Vol.5, Springer. This revised version is consistent with the published version and includes additional references and minor additions to the text as well as a recomputed Table 1. ISBN 978-90-481-8817-

Changes in Inflammatory Response after Endovascular Treatment for Type B Aortic Dissection

This present study aims to investigate the changes in the inflammatory markers after elective endovascular treatment of Type B aortic dissection with aneurysm, as related to different anatomical features of the dissection flap in the paravisceral perfusion. Consecutive patients with type B aortic dissections with elective endovascular stent graft repair were recruited and categorized into different groups. Serial plasma levels of cytokines (Interleukin-1β, -6, -8, -10, TNF-α), chemokines (MCP-1), and serum creatinine were monitored at pre-, peri- and post-operative stages. The length of stent graft employed in each surgery was retrieved and correlated with the change of all studied biochemical parameters. A control group of aortic dissected patients with conventional medication management was recruited for comparing the baseline biochemical parameters. In total, 22 endovascular treated and 16 aortic dissected patients with surveillance were recruited. The endovascular treated patients had comparable baseline levels as the non-surgical patients. There was no immediate or thirty day-mortality, and none of the surgical patients developed post-operative mesenteric ischaemia or clinically significant renal impairment. All surgical patients had detectable pro-inflammatory mediators, but none of the them showed any statistical significant surge in the peri-operative period except IL-1β and IL-6. Similar results were obtained when categorized into different groups. IL-1β and IL-6 showed maximal levels within hours of the endovascular procedure (range, 3.93 to 27.3 higher than baseline; p = 0.001), but returned to baseline 1 day post-operatively. The change of IL-1β and IL-6 at the stent graft deployment was statistically greater in longer stent graft (p>0.05). No significant changes were observed in the serum creatinine levels. In conclusion, elective endovascular repair of type B aortic dissection associated with insignificant changes in inflammatory mediators and creatinine. All levels fell toward basal levels post-operatively suggesting that thoracic endovascular aortic repair is rather less aggressive with insignificant inflammatory modulation

Proteomic Analysis of the Secretory Response of Aspergillus niger to D-Maltose and D-Xylose

Fungi utilize polysaccharide substrates through extracellular digestion catalyzed by secreted enzymes. Thus far, protein secretion by the filamentous fungus Aspergillus niger has mainly been studied at the level of individual proteins and by genome and transcriptome analyses. To extend these studies, a complementary proteomics approach was applied with the aim to investigate the changes in secretome and microsomal protein composition resulting from a shift to a high level secretion condition. During growth of A. niger on d-sorbitol, small amounts of d-maltose or d-xylose were used as inducers of the extracellular amylolytic and xylanolytic enzymes. Upon induction, protein compositions in the extracellular broth as well as in enriched secretory organelle (microsomal) fractions were analyzed using a shotgun proteomics approach. In total 102 secreted proteins and 1,126 microsomal proteins were identified in this study. Induction by d-maltose or d-xylose resulted in the increase in specific extracellular enzymes, such as glucoamylase A on d-maltose and β-xylosidase D on d-xylose, as well as of microsomal proteins. This reflects the differential expression of selected genes coding for dedicated extracellular enzymes. As expected, the addition of extra d-sorbitol had no effect on the expression of carbohydrate-active enzymes, compared to addition of d-xylose or d-maltose. Furthermore, d-maltose induction caused an increase in microsomal proteins related to translation (e.g., Rpl15) and vesicular transport (e.g., the endosomal-cargo receptor Erv14). Millimolar amounts of the inducers d-maltose and d-xylose are sufficient to cause a direct response in specific protein expression levels. Also, after induction by d-maltose or d-xylose, the induced enzymes were found in microsomes and extracellular. In agreement with our previous findings for d-xylose induction, d-maltose induction leads to recruitment of proteins involved in proteasome-mediated degradation