The synthesis, discovery, and development of a highly promising class of microtubule stabilization agents: Curative effects of desoxyepothilones B and F against human tumor xenografts in nude mice

We have evaluated two synthetic epothilone analogues lacking the 12,13-epoxide functionality, 12,13-desoxyepothilone B (dEpoB), and 12,13-desoxyepothilone F (dEpoF). The concentrations required for 50% growth inhibition (IC50) for a variety of anticancer agents were measured in CCRF-CEM/VBL1000 cells (2,048-fold resistance to vinblastine). By using dEpoB, dEpoF, aza-EpoB, and paclitaxel, the IC50 values were 0.029, 0.092, 2.99, and 5.17 ��M, respectively. These values represent 4-, 33.5-, 1,423- and 3,133-fold resistance, respectively, when compared with the corresponding IC50 in the parent [nonmultiple drug-resistant (MDR)] CCRF-CEM cells. We then produced MDR human lung carcinoma A549 cells by continuous exposure of the tumor cells to sublethal concentrations of dEpoB (1.8 yr), vinblastine (1.2 yr), and paclitaxel (1.8 yr). This continued exposure led to the development of 2.1-, 4,848-, and 2,553-fold resistance to each drug, respectively. The therapeutic effect of dEpoB and paclitaxel was also compared in vivo in a mouse model by using various tumor xenografts. dEpoB is much more effective in reducing tumor sizes in all MDR tumors tested. Analysis of dEpoF, an analog possessing greater aqueous solubility than dEpoB, showed curative effects similar to dEpoB against K562, CCRF-CEM, and MX-1 xenografts. These results indicate that dEpoB and dEpoF are efficacious antitumor agents with both a broad chemotherapeutic spectrum and wide safety margins.

Acyl tunichlorins: a new class of nickel chlorins isolated from the Caribbean tunicate Trididemnum solidum.

A new class of nickel-containing chlorins (acyl tunichlorins) has been isolated from the Caribbean tunicate Trididemnum solidum. The structures of 28 of these nickel (II) hydroporphyrins were elucidated using mass spectrometry, one- and two-dimensional NMR spectroscopy, and chemical degradation/derivatization. Unique structural features of these compounds include the diversity of aliphatic side chains, which are derived from C14:0 to C22:6 fatty acids, and their location at an unprecedented position at C-2a on the hydroporphyrin nucleus. No chlorins with ester-linked acyl side chains at C-2a have been reported previously. Although the exact biological role that these compounds play in T. solidum remains unknown, acyl tunichlorins represent the only nickel-containing chlorins to be isolated from a living system and are the C-2a acyl derivatives of tunichlorin, a nickel chlorin reported by this laboratory in 1988.

Recombinant human uteroglobin suppresses cellular invasiveness via a novel class of high-affinity cell surface binding site.

The mechanism(s) that regulates invasion of trophoblasts through the uterine epithelium during embryo implantation and nidation in hemochorial placental mammals is poorly understood. While limited trophoblast invasion is essential for the establishment of normal pregnancy, dysregulation of this process may contribute to the pathogenesis of choriocarcinoma, a highly invasive and lethal form of cancer arising from the trophoblasts. We have previously demonstrated that rabbit uteroglobin (UG), a cytokine-like, antiinflammatory protein, produced by the endometrial epithelium during pregnancy, has a potent antichemotactic effect on neutrophils and monocytes in vitro. Here, we report that recombinant human UG (hUG) dramatically suppresses invasion of human trophoblasts and NIH 3T3 cells through an artificial basement membrane (Matrigel) in vitro but has no effect on that of human choriocarcinoma cells. We identified a previously unreported high-affinity, high molecular weight (approximately 190 kDa), nonglycosylated hUG-binding protein, readily detectable on human trophoblasts and NIH 3T3 cells but totally lacking on choriocarcinoma cells. Taken together, these results raise the possibility that (i) hUG plays a critical role in regulating cellular invasiveness, at least in part, via its previously unrecognized cell surface binding site, and (ii) some of the numerous biological activities of proteins of the UG family, reported so far, may be mediated via this binding site.

Cationic facial amphiphiles: a promising class of transfection agents.

A promising class of compounds for DNA transfection have been designed by conjugating various polyamines to bile-acid-based amphiphiles. Formulations containing these compounds were tested for their ability to facilitate the uptake of a beta-galactosidase reporter plasmid into COS-7 cells. Dioleoyl phosphatidyl ethanolamine (DOPE) formulations of some of the compounds were several times better than Lipofectin at promoting DNA uptake. The most active compounds contained the most hydrophilic bile acid components. The activity is clearly not related to affinity for DNA: the hydrophobic bile acid conjugates were found to form stable complexes with DNA at lower charge ratios than the hydrophilic conjugates. We suggest that the high activity of the best compounds is related to their facial amphiphilicity, which may confer an ability to destabilize membranes. The success of these unusual cationic transfection agents may inspire the design of even more effective gene delivery agents.

Molecular organization of histidine-tagged biomolecules at self-assembled lipid interfaces using a novel class of chelator lipids.

In molecular biology, the expression of fusion proteins is a very useful and well-established technique for the identification and one-step purification of gene products. Even a short fused sequence of five or six histidines enables proteins to bind to an immobilized metal ion chelate complex. By synthesis of a class of chelator lipids, we have transferred this approach to the concept of self-assembly. The specific interaction and lateral organization of a fluorescent fusion molecule containing a C-terminal oligohistidine sequence was studied by film balance techniques in combination with epifluorescence microscopy. Due to the phase behavior of the various lipid mixtures used, the chelator lipids can be laterally structured, generating two-dimensional arrays of histidine-tagged biomolecules. Because of the large variety of fusion proteins already available, this concept represents a powerful technique for orientation and organization of proteins at lipid interfaces with applications in biosensing, biofunctionalization of nanostructured interfaces, two-dimensional crystallization, and studies of lipid-anchored proteins.

A class of single-stranded telomeric DNA-binding proteins required for Rap1p localization in yeast nuclei.

We have identified a class of proteins that bind single-stranded telomeric DNA and are required for the nuclear organization of telomeres and/or telomere-associated proteins. Rlf6p was identified by its sequence similarity to Gbp1p, a single-stranded telomeric DNA-binding protein from Chlamydomonas reinhardtii. Rlf6p and Gbp1p bind yeast single-stranded G-strand telomeric DNA. Both proteins include at least two RNA recognition motifs, which are found in many proteins that interact with single-stranded nucleic acids. Disruption of RLF6 alters the distribution of repressor/activator protein 1 (Rap1p), a telomere-associated protein. In wild-type yeast cells, Rap1p localizes to a small number of perinuclear spots, while in rlf6 cells Rap1p appears diffuse and nuclear. Interestingly, telomere position effect and telomere length control, which require RAP1, are unaffected by rlf6 mutations, demonstrating that Rap1p localization can be uncoupled from other Rap1p-dependent telomere functions. In addition, expression of Chlamydomonas GBP1 restores perinuclear, punctate Rap1p localization in rlf6 mutant cells. The functional complementation of a fungal gene by an algal gene suggests that Rlf6p and Gbp1p are members of a conserved class of single-stranded telomeric DNA-binding proteins that influence nuclear organization. Furthermore, it demonstrates that, despite their unusual codon bias, C. reinhardtii genes can be efficiently translated in Saccharomyces cerevisiae cells.

CC-1065 and the duocarmycins: unraveling the keys to a new class of naturally derived DNA alkylating agents.

Key studies defining the DNA alkylation properties and selectivity of a new class of exceptionally potent, naturally occurring antitumor antibiotics including CC-1065, duocarmycin A, and duocarmycin SA are reviewed. Recent studies conducted with synthetic agents containing deep-seated structural changes and the unnatural enantiomers of the natural products and related analogs have defined the structural basis for the sequence-selective alkylation of duplex DNA and fundamental relationships between chemical structure, functional reactivity, and biological properties. The agents undergo a reversible, stereoelectronically controlled adenine-N3 addition to the least substituted carbon of the activated cyclopropane within selected AT-rich sites. The preferential AT-rich non-covalent binding selectivity of the agents within the narrower, deeper AT-rich minor groove and the steric accessibility to the alkylation site that accompanies deep AT-rich minor groove penetration control the sequence-selective DNA alkylation reaction and stabilize the resulting adduct. For the agents that possess sufficient reactivity to alkylate DNA, a direct relationship between chemical or functional stability and biological potency has been defined.

Herschel discovery of a new class of cold, faint debris discs

We present Herschel PACS 100 and 160 ��m observations of the solar-type stars �� Men, HD 88230 and HD 210277, which form part of the FGK stars sample of the Herschel open time key programme (OTKP) DUNES (DUst around NEarby Stars). Our observations show small infrared excesses at 160 ��m for all three stars. HD 210277 also shows a small excess at 100 ��m, while the 100 ��m fluxes of �� Men and HD 88230 agree with the stellar photospheric predictions. We attribute these infrared excesses to a new class of cold, faint debris discs. Both �� Men and HD 88230 are spatially resolved in the PACS 160 ��m images, while HD 210277 is point-like at that wavelength. The projected linear sizes of the extended emission lie in the range from ~115 to ��� 250 AU. The estimated black body temperatures from the 100 and 160 ��m fluxes are ���22 K, and the fractional luminosity of the cold dust is L_dust/L_��� ~ 10^-6, close to the luminosity of the solar-system���s Kuiper belt. These debris discs are the coldest and faintest discs discovered so far around mature stars, so they cannot be explained easily invoking ���classical��� debris disc models.

Asperger's Disorder in College Students: Application of Acceptance and Commitment Therapy

College students with Asperger's Disorder (AD) are likely to face significant challenges as they encounter the unpredictable and socially demanding environment of their university setting. Acceptance and Commitment Therapy (ACT) can be a valuable approach to addressing many of these struggles. This paper will explore the application of ACT to problems that are commonly associated with individuals diagnosed with AD. Utilizing ACT and the Hexaflex Model as a guide for working with AD students can assist in establishing a greater understanding and acceptance of their unique internal experience, as well as their interaction with the external world. ACT can offer these students the ability to be more present in the moment, to recognize efforts to avoid negative experiences, and to move in directions in life that are personally meaningful.

On the Result of Invariance of the Closure Set of the Real Projections of the Zeros of an Important Class of Exponential Polynomials

In this paper we provide the proof of a practical point-wise characterization of the set RP defined by the closure set of the real projections of the zeros of an exponential polynomial P(z) = ��n j=1 cjewjz with real frequencies wj linearly independent over the rationals. As a consequence, we give a complete description of the set RP and prove its invariance with respect to the moduli of the c��� js, which allows us to determine exactly the gaps of RP and the extremes of the critical interval of P(z) by solving inequations with positive real numbers. Finally, we analyse the converse of this result of invariance.

Diplomas from Harvard College and Yale University, 1750

The diplomas are accompanied by a silver case in which the documents were stored.

Harvard Library bookplate collection, 1764-1960

This collection contains samples of bookplate labels that were pasted into books held in the libraries of Harvard University, dating from 1764 to 1960. The collection includes bookplates arranged chronologically and bookplates of the Harvard College Library and departmental libraries arranged alphabetically. The collection also contains correspondence related to bookplates, dating from 1918 to 1921, and a list of printed seals used in Harvard College Library. Some of the bookplates include handwritten inscriptions, while others are blank. There are six 18th century bookplates with inscriptions documenting gifts and bequests made following the 1764 fire that destroyed the bulk of Harvard's Library from Marblehead, Massachusetts, minister John Barnard (1681-1770; Harvard AB 1700); New Hampshire Governor Benning Wentworth (1696-1770; Harvard AB 1715); Portsmouth, New Hampshire, merchant Thomas Wibird (1706-1765; Harvard AB 1728); and merchant Thomas Lee (died 1787) of Cambridge, Massachusetts.

Letter from Samuel Willard, Harvard College, Cambridge, Massachusetts, to Catherine Willard, Petersham, Massachusetts, May 1, 1801

Willard alludes to a situation regarding his father and praises him profusely.

Letter from Samuel Willard, Harvard College, Cambridge, Massachusetts, to Abigail Willard, Petersham, Massachusetts, May 1, 1801

Willard thanks his sister for writing to him and asks her to write as often as possible. He also mentions his cousin Sophia Chadwick, who has been living with President Willard.