Differential subcellular mRNA targeting: deletion of a single nucleotide prevents the transport to axons but not to dendrites of rat hypothalamic magnocellular neurons.

It has previously been shown that mRNA encoding the arginine vasopressin (AVP) precursor is targeted to axons of rat magnocellular neurons of the hypothalamo-neurohypophyseal tract. In the homozygous Brattle-boro rat, which has a G nucleotide deletion in the coding region of the AVP gene, no such targeting is observed although the gene is transcribed. RNase protection and heteroduplex analyses demonstrate that, in heterozygous animals, which express both alleles of the AVP gene, the wild-type but not the mutant transcript is subject to axonal compartmentation. In contrast, wild-type and mutant AVP mRNAs are present in dendrites. These data suggest the existence of different mechanisms for mRNA targeting to the two subcellular compartments. Axonal mRNA localization appears to take place after protein synthesis; the mutant transcript is not available for axonal targeting because it lacks a stop codon preventing its release from ribosomes. Dendritic compartmentation, on the other hand, is likely to precede translation and, thus, would be unable to discriminate between the two mRNAs.

Codominance and toxins: a path to drugs of nearly unlimited selectivity.

The effectiveness of drugs is often limited by their insufficient selectivity. I propose designs of therapeutic agents that address this problem. The key feature of these reagents, termed comtoxins (codominance-mediated toxins), is their ability to utilize codominance, a property characteristic of many signals in proteins, including degradation signals (degrons) and nuclear localization signals. A comtoxin designed to kill cells that express intracellular proteins P1 and P2 but to spare cells that lack P1 and/or P2 is a multidomain fusion containing a cytotoxic domain and two degrons placed within or near two domains P1* and P2* that bind, respectively, to P1 and P2. In a cell containing both P1 and P2, these proteins would bind to the P1* and P2* domains of the comtoxin and sterically mask the nearby (appropriately positioned) degrons, resulting in a long-lived and therefore toxic drug. By contrast, in a cell lacking P1 and/or P2, at least one of the comtoxin's degrons would be active (unobstructed), yielding a short-lived and therefore nontoxic drug. A comtoxin containing both a degron and a nuclear localization signal can be designed to kill exclusively cells that contain P1 but lack P2. Analogous strategies yield comtoxins sensitive to the presence (or absence) of more than two proteins in a cell. Also considered is a class of comtoxins in which a toxic domain is split by a flexible insert containing binding sites for the target proteins. The potentially unlimited, combinatorial selectivity of comtoxins may help solve the problem of side effects that bedevils present-day therapies, for even nonselective delivery of a comtoxin would not affect cells whose protein "signatures" differ from the targeted one.

An Acceptance and Commitment Approach to Issues of Behavioral Health Care in Soldiers

For over a decade, the U.S. military has been engaged in two distinct, yet equally deadly conflicts: Operation Iraqi Freedom (OIF) and Operation Enduring Freedom (OEF). There are many physical and psychological effects of war necessitating the activation and interventions of a myriad of behavioral health professionals. The purpose of the paper was to understand how and if contemporary military culture may work to support or hinder application of an Acceptance and Commitment Therapy (ACT) approach to issues of psychological health among Soldiers. While the empirical research on efficacy with Soldiers is limited, a review of military culture revealed the promotion of rigid rule following, although effective in combat, influences the emotional control agenda and stigma while in garrison. However, empirical research demonstrating the clinical benefits and flexibility of ACT is rapidly emerging with civilian and Veteran populations. Suggested as a prevention technique utilized early in Soldier's training to increase psychological flexibility, ACT appears to demonstrate much promise in ameliorating the psychological consequences of war.

Plant regeneration functional groups modulate the response to fire of soil enzyme activities in a Mediterranean shrubland

Soil enzymes are critical to soil nutrient cycling function but knowledge on the factors that control their response to major disturbances such as wildfires remains very limited. We evaluated the effect of fire-related plant functional traits (resprouting and seeding) on the resistance and resilience to fire of two soil enzyme activities involved in phosphorus and carbon cycling (acid phosphatase and β-glucosidase) in a Mediterranean shrublands in SE Spain. Using experimental fires, we compared four types of shrubland microsites: SS (vegetation patches dominated by seeder species), RR (patches dominated by resprouter species), SR (patches co-dominated by seeder and resprouter species), and IP (shrub interpatches). We assessed pre- and post-fire activities of the target soil enzymes, available P, soil organic C, and plant cover dynamics over three years after the fire. Post-fire regeneration functional groups (resprouter, seeder) modulated both pre- and post-fire activity of acid phosphatase and β-glucosidase, with higher activity in RR and SR patches than in SS patches and IP. However, we found no major differences in enzyme resistance and resilience between microsite types, except for a trend towards less resilience in SS patches. Fire similarly reduced the activity of both enzymes. However, acid phosphatase and β-glucosidase showed contrasting post-fire dynamics. While β-glucosidase proved to be rather resilient to fire, fully recovering three years after fire, acid phosphatase showed no signs of recovery in that period. Overall, the results indicate a positive influence of resprouter species on soil enzyme activity that is very resistant to fire. Long-lasting decrease in acid phosphatase activity probably resulted from the combined effect of P availability and post-fire drought. Our results provide insights on how plant functional traits modulate soil biochemical and microbiological response to fire in Mediterranean fire-prone shrublands.

Deterministic mathematical morphology for CAD/CAM

Purpose – The purpose of this paper is to present a new geometric model based on the mathematical morphology paradigm, specialized to provide determinism to the classic morphological operations. The determinism is needed to model dynamic processes that require an order of application, as is the case for designing and manufacturing objects in CAD/CAM environments. Design/methodology/approach – The basic trajectory-based operation is the basis of the proposed morphological specialization. This operation allows the definition of morphological operators that obtain sequentially ordered sets of points from the boundary of the target objects, inexistent determinism in the classical morphological paradigm. From this basic operation, the complete set of morphological operators is redefined, incorporating the concept of boundary and determinism: trajectory-based erosion and dilation, and other morphological filtering operations. Findings – This new morphological framework allows the definition of complex three-dimensional objects, providing arithmetical support to generating machining trajectories, one of the most complex problems currently occurring in CAD/CAM. Originality/value – The model proposes the integration of the processes of design and manufacture, so that it avoids the problems of accuracy and integrity that present other classic geometric models that divide these processes in two phases. Furthermore, the morphological operative is based on points sets, so the geometric data structures and the operations are intrinsically simple and efficient. Another important value that no excessive computational resources are needed, because only the points in the boundary are processed.

Request to parents of students, 1809 March 21

This brief handwritten note requests a meeting with the parents of Croswell's students in order to continue the school.

[Yearly salaries for 1737 to 1795 of the Presidents, 1796]

One leaf containing a handwritten list of the salaries of Harvard presidents for the years 1737 to 1795.

[Yearly salaries for 1786 to 1796 of the Tutors and Treasurer, 1802]

One leaf containing a handwritten list of the salaries of Harvard tutors and treasurers for the years 1786 to 1796. The paper includes the inscription "Tracy."

Early considerations proposed to Corporation relative to choice of Professor, [1804]

Small leaf containing handwritten notes outlining the guidelines that should guide the selection of a new Professor. Title transcribed from verso.

No. 7 Answer from Committee of Cambridge to Memorial of President & Professors of H. College, Copy 1799 February

Four octavo-sized leaves containing a handwritten copy of a detailed response by the Committee of the Town of Cambridge (comprised of James Winthrop, William Winthrop, and Ebenezer Stedman) to the memorial of Harvard College officers to the Massachusetts General Court.

Paid to Inhabitants of Cambridge For Supplies in the Hall, [1799 June]

One octavo-sized folded leaf containing a short handwritten list of payments made to Cambridge for supplies between 1796 and 1799.

Exhortation read to 27 of the Sophomore class, 1797 July 1

9-page handwritten copy of an address by Eliphalet Pearson read to twenty-seven members of the sophomore class after an incident on June 27, 1797 in which "in direct violation of College law a majority of the sophomore class repaired to the house of Richard Boardman in this town; that they did then & there indulge to a free use of wine" that incited them to drunkenly parade through town and disturb the evening church services of the College.

L.B.'s letter respecting excuse to president of College, 1797 August 31

Brief handwritten note to Loammi Baldwin from his son requesting a written excuse to be sent to the Harvard President for his absence on election day.