Biological properties of water-soluble phosphorhydrazone dendrimers

1984-8250Dendrimers are hyperbranched and perfectly defined macromolecules, constituted of branches emanating from a central core in an iterative fashion. Phosphorhydrazone dendrimers constitute a special family of dendrimers, possessing one phosphorus atom at each branching point. The internal structure of these dendrimers is hydrophobic, but hydrophilic terminal groups can induce the solubility of the whole structure in water. Indeed, the properties of these compounds are mainly driven by the type of terminal groups their bear; this is especially true for the biological properties. For instance, positively charged terminal groups are efficient for transfection experiments, as drug carriers, as anti-prion agents, and as inhibitor of the aggregation of Alzheimer's peptides, whereas negatively charged dendrimers have anti-HIV properties and can influence the human immune system, leading to anti-inflammatory properties usable against rheumatoid arthritis. This review will give the most representative examples of the biological properties of water-soluble phosphorhydrazone dendrimers, organized depending on the type of terminal groups they bear

Syndromics: A Bioinformatics Approach for Neurotrauma Research

Substantial scientific progress has been made in the past 50 years in delineating many of the biological mechanisms involved in the primary and secondary injuries following trauma to the spinal cord and brain. These advances have highlighted numerous potential therapeutic approaches that may help restore function after injury. Despite these advances, bench-to-bedside translation has remained elusive. Translational testing of novel therapies requires standardized measures of function for comparison across different laboratories, paradigms, and species. Although numerous functional assessments have been developed in animal models, it remains unclear how to best integrate this information to describe the complete translational “syndrome” produced by neurotrauma. The present paper describes a multivariate statistical framework for integrating diverse neurotrauma data and reviews the few papers to date that have taken an information-intensive approach for basic neurotrauma research. We argue that these papers can be described as the seminal works of a new field that we call “syndromics”, which aim to apply informatics tools to disease models to characterize the full set of mechanistic inter-relationships from multi-scale data. In the future, centralized databases of raw neurotrauma data will enable better syndromic approaches and aid future translational research, leading to more efficient testing regimens and more clinically relevant findings

Extensive innate immune gene activation accompanies brain aging, increasing vulnerability to cognitive decline and neurodegeneration: a microarray study

BACKGROUND: This study undertakes a systematic and comprehensive analysis of brain gene expression profiles of immune/inflammation-related genes in aging and Alzheimer’s disease (AD). METHODS: In a well-powered microarray study of young (20 to 59 years), aged (60 to 99 years), and AD (74 to 95 years) cases, gene responses were assessed in the hippocampus, entorhinal cortex, superior frontal gyrus, and post-central gyrus. RESULTS: Several novel concepts emerge. First, immune/inflammation-related genes showed major changes in gene expression over the course of cognitively normal aging, with the extent of gene response far greater in aging than in AD. Of the 759 immune-related probesets interrogated on the microarray, approximately 40% were significantly altered in the SFG, PCG and HC with increasing age, with the majority upregulated (64 to 86%). In contrast, far fewer immune/inflammation genes were significantly changed in the transition to AD (approximately 6% of immune-related probesets), with gene responses primarily restricted to the SFG and HC. Second, relatively few significant changes in immune/inflammation genes were detected in the EC either in aging or AD, although many genes in the EC showed similar trends in responses as in the other brain regions. Third, immune/inflammation genes undergo gender-specific patterns of response in aging and AD, with the most pronounced differences emerging in aging. Finally, there was widespread upregulation of genes reflecting activation of microglia and perivascular macrophages in the aging brain, coupled with a downregulation of select factors (TOLLIP, fractalkine) that when present curtail microglial/macrophage activation. Notably, essentially all pathways of the innate immune system were upregulated in aging, including numerous complement components, genes involved in toll-like receptor signaling and inflammasome signaling, as well as genes coding for immunoglobulin (Fc) receptors and human leukocyte antigens I and II. CONCLUSIONS: Unexpectedly, the extent of innate immune gene upregulation in AD was modest relative to the robust response apparent in the aged brain, consistent with the emerging idea of a critical involvement of inflammation in the earliest stages, perhaps even in the preclinical stage, of AD. Ultimately, our data suggest that an important strategy to maintain cognitive health and resilience involves reducing chronic innate immune activation that should be initiated in late midlife

On the efficiency of placement service and programme placement at the public employment offices in Sweden

'This paper is a summary of three implementation studies on the efficiency of job placement service and programme placement at public employment service offices in Sweden. By the research design 'Comparisons by pairs of offices under matched control of external independent variables' the studies aim to characterize good employment office management practices. The research design, the methods used and the results reached are presented and discussed. Specifically, the paper proposes that good office management practices are characterized by a high ability to give self-service and assistance to self-service, and to give priority to individualised service to employers.' (author's abstract)'Dieser Bericht ist eine Zusammenfassung von drei Studien zur Effizienz der Arbeitsvermittlung und Programmteilnahme in identischen Arbeitsaemtern. Durch die Untersuchungsmethode 'Paarweiser Vergleich von Arbeitsaemtern mit gleichen aeusseren Verhaeltnissen' wird ein Versuch gemacht, gute Verwaltungspraxis der Arbeitsaemter zu charakterisieren. In diesem Bericht werden Untersuchungsmethode und Ergebnisse beschrieben und eroertert. Es zeigt sich, dass die Komponenten einer guten Verwaltungspraxis von hohem Mass aus einer guten Infrastruktur zur Selbstbedienung fuer Arbeitssuchende und individualisierten Diensten an Arbeitgebern bestehen.' (Autorenreferat)German title: Die Effizienz von Arbeitsvermittlung und von Vermittlungsprogrammen der Arbeitsaemter in SchwedenAvailable from <a href=http://skylla.wz-berlin.de/pdf/2001/i01-208.pdf target=NewWindow>http://skylla.wz-berlin.de/pdf/2001/i01-208.pdf</a> / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEDEGerman

Synthesis and application of phosphorus dendrimer immobilized azabis(oxazolines)

Phosphorus dendrimer immobilized azabis(oxazoline) ligands can be efficiently synthesized up to the third generation with 48 ligand molecules being attached to the periphery using click chemistry. The so-assembled macromolecules were evaluated in copper(II)-catalyzed asymmetric benzoylations, showing good yields and enantioselectivities. Moreover, the copper(II)-catalysts could be readily recovered and reused in several cycles. The globular structure of the dendritic ligands seems to prevent interference of the triazole moieties in the catalysis, contrasting MeOPEG or polystyrene bound ligands of the same type

Three-Dimensional Directionality Is a Pivotal Structural Feature for the Bioactivity of Azabisphosphonate-Capped Poly(PhosphorHydrazone) Nanodrug Dendrimers

Dendrimers are nanosized, nonlinear, hyperbranched polymers whose overall 3D shape is key for their biological activity. Poly(PhosphorHydrazone) (PPH) dendrimers capped with aza-bisphosphonate (ABP) end groups are known to have anti-inflammatory properties enabling the control of inflammatory diseases in different mouse models. Here we screen the antiinflammatory activity of a series of PPH dendrimers bearing between 2 and 16 ABP end groups in a mouse model of arthritis and confront the biological results with atomistic simulations of the dendrimers. We show that only the PPH dendrimers capped with 10 and 12 ABP end groups can control the flare of the inflammatory disease. All-atom accelerated molecular dynamics simulations show that dendrimers with a low number of ABP end groups are directional but highly flexible/dynamic and have thereby limited efficiency in establishing multivalent interactions. The largest dendrimer appears as nondirectional, having 16 ABP end groups forming patches all over the dendrimer surface. Conversely, intermediate dendrimers having 10 or 12 ABP end groups reach the best compromise between the number of surface groups and their stable directional gathering, a real maximization of multivalency

Owyhee River intracanyon lava flows: Does the river give a dam?

Rivers carved into uplifted plateaus are commonly disrupted by discrete events from the surrounding landscape, such as lava flows or large mass movements. These disruptions are independent of slope, basin area, or channel discharge, and can dominate aspects of valley morphology and channel behavior for many kilometers. We document and assess the effects of one type of disruptive event, lava dams, on river valley morphology and incision rates at a variety of time scales, using examples from the Owyhee River in southeastern Oregon. Six sets of basaltic lava flows entered and dammed the river canyon during two periods in the late Cenozoic ca. 2 Ma–780 ka and 250–70 ka. The dams are strongly asymmetric, with steep, blunt escarpments facing up valley and long, low slopes down valley. None of the dams shows evidence of catastrophic failure; all blocked the river and diverted water over or around the dam crest. The net effect of the dams was therefore to inhibit rather than promote incision. Once incision resumed, most of the intracanyon flows were incised relatively rapidly and therefore did not exert a lasting impact on the river valley profile over time scales \u3e106 yr. The net long-term incision rate from the time of the oldest documented lava dam, the Bogus Rim lava dam (≤1.7 Ma), to present was 0.18 mm/yr, but incision rates through or around individual lava dams were up to an order of magnitude greater. At least three lava dams (Bogus Rim, Saddle Butte, and West Crater) show evidence that incision initiated only after the impounded lakes filled completely with sediment and there was gravel transport across the dams. The most recent lava dam, formed by the West Crater lava flow around 70 ka, persisted for at least 25 k.y. before incision began, and the dam was largely removed within another 35 k.y. The time scale over which the lava dams inhibit incision is therefore directly affected by both the volume of lava forming the dam and the time required for sediment to fill the blocked valley. Variations in this primary process of incision through the lava dams could be influenced by additional independent factors such as regional uplift, drainage integration, or climate that affect the relative base level, discharge, and sediment yield within the watershed. By redirecting the river, tributaries, and subsequent lava flows to different parts of the canyon, lava dams create a distinct valley morphology of flat, broad basalt shelves capping steep cliffs of Tertiary sediment. This stratigraphy is conducive to landsliding and extends the effects of intracanyon lava flows on channel geomorphology beyond the lifetime of the dams