Pectic Galactan Polysaccharide-Based Gene Delivery System for Targeting Neuroinflammation

Treating neuroinflammation-related injuries and disorders through manipulation of neuroinflammation functions is being heralded as a new therapeutic strategy. In this study, a novel pectic galactan (PG) polysaccharide based gene therapy approach is developed for targeting reactive gliosis in neuroinflammation. Galectin-3 (Gal-3) is a cell protein with a high affinity to β-galactoside sugars and is highly expressed in reactive gliosis. Since PG carries galactans, it can target reactive gliosis via specific carbohydrate interaction between galactan and Gal-3 on the cell membrane, and therefore can be utilized as a carrier for delivering genes to these cells. The carrier is synthesized by modifying quaternary ammonium groups on the PG. The resulting quaternized PG (QPG) is found to form complexes with plasmid DNA with a mean diameter of 100 nm and have the characteristics required for targeted gene therapy. The complexes efficiently condense large amounts of plasmid per particle and successfully bind to Gal-3. The in vivo study shows that the complexes are biocompatible and safe for administration and can selectively transfect reactive glial cells of an induced cortical lesion. The results confirm that this PG-based delivery system is a promising platform for targeting Gal-3 overexpressing neuroinflammation cells for treating neuroinflammation-related injuries and neurodegenerative diseases.     

Quantifying the limits of CAR T-cell delivery in mice and men

CAR (Chimeric Antigen Receptor) T cells have demonstrated clinical success for the treatment of multiple lymphomas and leukaemias, but not for various solid tumours, despite promising data from murine models. Lower effective CAR T-cell delivery rates to human solid tumours compared to haematological malignancies in humans and solid tumours in mice might partially explain these divergent outcomes. We used anatomical and physiological data for human and rodent circulatory systems to calculate the typical perfusion of healthy and tumour tissues, and estimated the upper limits of immune cell delivery rates across different organs, tumour types and species. Estimated maximum delivery rates were up to 10 000-fold greater in mice than humans yet reported CAR T-cell doses are typically only 10–100-fold lower in mice, suggesting that the effective delivery rates of CAR T cells into tumours in clinical trials are far lower than in corresponding mouse models. Estimated delivery rates were found to be consistent with published positron emission tomography data. Results suggest that higher effective human doses may be needed to drive efficacy comparable to mouse solid tumour models, and that lower doses should be tested in mice. We posit that quantitation of species and organ-specific delivery and homing of engineered T cells will be key to unlocking their potential for solid tumours.     

Discovery of Affinity-Based Probes for Btk Occupancy Assays

Bruton's tyrosine kinase (Btk) is an attractive target for the treatment of a wide array of B-cell malignancies and autoimmune diseases. Small-molecule covalent irreversible Btk inhibitors targeting Cys481 have been developed for the treatment of such diseases. In clinical trials, probe molecules are required in occupancy studies to measure the level of engagement of the protein by these covalent irreversible inhibitors. The result of this pharmacodynamic (PD) activity provides guidance for appropriate dosage selection to optimize inhibition of the drug target and correlation of target inhibition with disease treatment efficacy. This information is crucial for successful evaluation of drug candidates in clinical trials. Based on the pyridine carboxamide scaffold of a novel solvent-accessible pocket (SAP) series of covalent irreversible Btk inhibitors, we successfully developed a potent and selective affinity-based biotinylated probe 12 (2-[(4-{4-[5-(1-{5-[(3aS,4S,6aR)-2-oxo-hexahydro-1H-thieno[3,4-d]imidazol-4-yl]pentanamido}-3,6,9,12-tetraoxapentadecan-15-amido)pentanoyl]piperazine-1-carbonyl}phenyl)amino]-6-[1-(prop-2-enoyl)piperidin-4-yl]pyridine-3-carboxamide). Compound 12 has been used in Btk occupancy assays for preclinical studies to determine the therapeutic efficacy of Btk inhibition in two mouse lupus models driven by TLR7 activation and type I interferon.     

Analysis of volatiles evolved during high-temperature treatment of thermally stable polymers. I. Nitrogen-containing acetylene-terminated resin

Cured samples of a nitrogen-containing acetylene-terminated resin, N,N′-(1,3-phenylene-dimethylidene)bis(3-ethynylaniline), have been heated at 10°C/min up to 900°C in a pyroprobe attached to a gas chromatograph/mass spectrometer (GC/MS). Analysis of the volatiles evolved during heating identified both gases and higher boiling compounds. The major higher boiling compounds are benzene, toluene, xylene, aniline, benzonitrile, m-methylaniline, and m-methylbenzonitrile; the gases include ammonia, methane, and traces of carbon dioxide. Correlations between sample temperature and the evolution of each of these compounds have been made. The onset of all volatile formation occurs between 450 and 500°C. The higher boiling volatiles peak, then end by approximately 700°C, while the gases peak then fall off but are still being evolved at 900°C. Average weight loss measurements of 13.6% at 700°C and 15.7% at 900°C agree with previously published thermogravimetric analysis (TGA) data. © 1993 John Wiley & Sons, Inc.     

Should industrial/organizational psychologists be licensed?

A historical review of licensing among industrial/organizational (I/O) psychologists demonstrates that the American Psychological Association (APA) policy on such licensing is inconsistent. Arguments for and against licensure for this group are presented. Job analysis and APA data are drawn upon to show that few I/O activities may pose the personal risk that would seem to require the protection of a license. Alternatives are discussed for changes in present APA policy and state licensing requirements. (16 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The need for style systems in ODA

Many advanced document systems provide a formatting mechanism called ‘style sheets’ Style sheets provide a great deal of flexibility in describing a document's format, and allow easy maintenance of different house styles for a collection of documents. In this paper, we describe the basics of general style sheet systems, argue that successful document interchange must include the exchange of style sheet information, and evaluate ODA's style mechanism against this requirement.     

A simple handling technique for mammalian oocytes and embryos during preparation for transmission electron microscopy

Due to their small size, mammalian oocytes and embryos pose unique problems during preparation for transmission electron microscopy. This paper outlines a method which combines protein embedding with centrifugation to locate the specimens on the face of a Beem capsule mould. This method facilitates both the processing of oocytes with minimal loss and rapid location of the specimens within the block for simultaneous sectioning, staining and examination.     

Denial in the aftermath of traumatic head injury: Its manifestations, measurement, and treatment.

Reviews available research on the meaning and measurement of denial and strategies for treating maladaptive denial, with special reference to its occurrence in traumatic head injuries. Questionnaire or interview measures, rather than behavioral indices, are used to assess denial. Denial may be manifested with respect to past, present, or future status; and it may have both positive and negative consequences for coping, motivation, and rehabilitation. Where denial limits a patient's functioning or recovery, several treatment strategies are possible. Intervention should involve a balance between supportive and confrontational elements, with a focus on behaviors rather than verbalizations. Computer feedback, videotaping, focused group therapy, and supervised activities are possible interventions for confronting maladaptive forms of denial. (PsycINFO Database Record (c) 2010 APA, all rights reserved)