Homogeneous immunoconjugates for boron neutron-capture therapy: Design, synthesis, and preliminary characterization

The application of immunoprotein-based targeting strategies to the boron neutron-capture therapy of cancer poses an exceptional challenge, because viable boron neutron-capture therapy by this method will require the efficient delivery of 103 boron-10 atoms by each antigen-binding protein. Our recent investigations in this area have been focused on the development of efficient methods for the assembly of homogeneous immunoprotein conjugates containing the requisite boron load. In this regard, engineered immunoproteins fitted with unique, exposed cysteine residues provide attractive vehicles for site-specific modification. Additionally, homogeneous oligomeric boron-rich phosphodiesters (oligophosphates) have been identified as promising conjugation reagents. The coupling of two such boron-rich oligophosphates to sulfhydryls introduced to the CH2 domain of a chimeric IgG3 has been demonstrated. The resulting boron-rich immunoconjugates are formed efficiently, are readily purified, and have promising in vitro and in vivo characteristics. Encouragingly, these studies showed subtle differences in the properties of the conjugates derived from the two oligophosphate molecules studied, providing a basis for the application of rational design to future work. Such subtle details would not have been as readily discernible in heterogeneous conjugates, thus validating the rigorous experimental design employed here.

Is there a Population II analogy to the F star lithium dip?

Observers have found a small number of lithium-depleted halo stars in the temperature range of the Spite plateau. The current status of the mass-loss hypothesis for producing the observed lithium dip in Population (Pop) I stars is briefly discussed and extended to Pop II stars as a possible explanation for these halo objects. Based on detections of F-type main-sequence variables, mass loss is assumed to occur in a narrow temperature region corresponding to this “instability strip.” As Pop II main-sequence stars evolve to the blue, they enter this narrow temperature region, then move back through the lower temperature area of the Spite plateau. If 0.05 M⊙ (solar mass) or more have been lost, they will show lithium depletion. This hypothesis affects the lithium-to- beryllium abundance, the ratio of high- to low-lithium stars, and the luminosity function. Constraints on the mass-loss hypothesis due to these effects are discussed. Finally, mass loss in this temperature range would operate in stars near the turnoff of metal-poor globular clusters, resulting in apparent ages 2 to 3 Gyr (gigayears) older than they actually are.

Synthesis and in vivo murine evaluation of Na4[1-(1′-B10H9)-6-SHB10H8] as a potential agent for boron neutron capture therapy

Reaction of the normal isomer of [B20H18]2− and the protected thiol anion, [SC(O)OC(CH3)3]−, produces an unexpected isomer of [B20H17SC(O)OC(CH3)3]4− directly and in good yield. The isomer produced under mild conditions is characterized by an apical–apical boron atom intercage connection as well as the location of the thiol substituent on an equatorial belt adjacent to the terminal boron apex. Although the formation of this isomer from nucleophilic attack of the normal isomer of [B20H18]2− has not been reported previously, the isomeric assignment has been unambiguously confirmed by one-dimensional and two-dimensional 11B NMR spectroscopy. Deprotection of the thiol substituent under acidic conditions produces a protonated intermediate, [B20H18SH]3−, which can be deprotonated with a suitable base to yield the desired product, [B20H17SH]4−. The sodium salt of the resulting [B20H17SH]4− ion has been encapsulated in small, unilamellar liposomes, which are capable of delivering their contents selectively to tumors in vivo, and investigated as a potential agent for boron neutron capture therapy. The biodistribution of boron was determined after intravenous injection of the liposomal suspension into BALB/c mice bearing EMT6 mammary adenocarcinoma. At low injected doses, the tumor boron concentration increased throughout the time-course experiment, resulting in a maximum observed boron concentration of 46.7 μg of B per g of tumor at 48 h and a tumor to blood boron ratio of 7.7. The boron concentration obtained in the tumor corresponds to 22.2% injected dose (i.d.) per g of tissue, a value analogous to the most promising polyhedral borane anions investigated for liposomal delivery and subsequent application in boron neutron capture therapy.

Helioseismology: Probing the interior of a star

Helioseismology offers, for the first time, an opportunity to probe in detail the deep interior of a star (our Sun). The results will have a profound impact on our understanding not only of the solar interior, but also neutrino physics, stellar evolution theory, and stellar population studies in astrophysics.

Star scientists and institutional transformation: Patterns of invention and innovation in the formation of the biotechnology industry

The most productive (“star”) bioscientists had intellectual human capital of extraordinary scientific and pecuniary value for some 10–15 years after Cohen and Boyer’s 1973 founding discovery for biotechnology [Cohen, S., Chang, A., Boyer, H. & Helling, R. (1973) Proc. Natl. Acad. Sci. USA 70, 3240–3244]. This extraordinary value was due to the union of still scarce knowledge of the new research techniques and genius and vision to apply them in novel, valuable ways. As in other sciences, star bioscientists were very protective of their techniques, ideas, and discoveries in the early years of the revolution, tending to collaborate more within their own institution, which slowed diffusion to other scientists. Close, bench-level working ties between stars and firm scientists were needed to accomplish commercialization of the breakthroughs. Where and when star scientists were actively producing publications is a key predictor of where and when commercial firms began to use biotechnology. The extent of collaboration by a firm’s scientists with stars is a powerful predictor of its success: for an average firm, 5 articles coauthored by an academic star and the firm’s scientists result in about 5 more products in development, 3.5 more products on the market, and 860 more employees. Articles by stars collaborating with or employed by firms have significantly higher rates of citation than other articles by the same or other stars. The U.S. scientific and economic infrastructure has been particularly effective in fostering and commercializing the bioscientific revolution. These results let us see the process by which scientific breakthroughs become economic growth and consider implications for policy.

Internal molecular motions of bacteriorhodopsin: hydration-induced flexibility studied by quasielastic incoherent neutron scattering using oriented purple membranes.

Quasielastic incoherent neutron scattering from hydrogen atoms, which are distributed nearly homogeneously in biological molecules, allows the investigation of diffusive motions occurring on the pico- to nanosecond time scale. A quasielastic incoherent neutron scattering study was performed on the integral membrane protein bacteriorhodopsin (BR), which is a light-driven proton pump in Halobacterium salinarium. BR is embedded in lipids, forming patches in the cell membrane of the organism, which are the so called purple membranes (PMs). Measurements were carried out at room temperature on oriented PM-stacks hydrated at two different levels (low hydration, h = 0.03 g of D2O per g of PM; high hydration, h = 0.28 g of D2O per g of PM) using time-of-flight spectrometers. From the measured spectra, different diffusive components were identified and analyzed with respect to the influence of hydration. This study supports the idea that a decrease in hydration results in an appreciable decrease in internal molecular flexibility of the protein structure. Because it is known from studies on the function of BR that the pump activity is reduced if the hydration level of the protein is insufficient, we conclude that the observed diffusive motions are essential for the function of this protein. A detailed analysis and classification of the different kinds of diffusive motions, predominantly occurring in PMs under physiological conditions, is presented.

Preparation and properties of nido-carborane-specific monoclonal antibodies for potential use in boron neutron capture therapy for cancer.

As the first step of a research program aimed at developing a bispecific monoclonal antibody system for the delivery of boron-rich molecules to tumor cells for boron neutron capture therapy, monoclonal antibodies (mAbs) were produced against an anionic nido-carborane derivative, 4-[7,8-dicarbadodecahydroundecaborat(-1)-7-yl]butanoic acid. Two IgG subclass mAbs, designated HAW101 and HAW102, were identified that specifically bound the anionic nido-carborane hapten, as well as a variety of other anionic nido-carborane cage derivatives. By using surface plasmon resonance technology, the affinity constants of HAW101 and HAW102 were determined to be 1.9 x 10(9) and 6.8 x 10(8) M-1, respectively. A diverse array of 7-substituted and 7,8-disubstituted anionic nido-carborane derivatives reacted with the mAb HAW101 in competition ELISA, whereas anionic closo-polyhedral boranes showed negligible binding, suggesting a role for the open nido-carborane cage structure. These results suggest that mAbs such as HAW101, which bind anionic nido-carboranes, are useful in the development of bispecific mAbs for specific targeting and enhanced boron delivery to tumor sites.

The star formation history of CALIFA galaxies: Radial structures

We have studied the radial structure of the stellar mass surface density (μ∗) and stellar population age as a function of the total stellar mass and morphology for a sample of 107 galaxies from the CALIFA survey. We applied the fossil record method based on spectral synthesis techniques to recover the star formation history (SFH), resolved in space and time, in spheroidal and disk dominated galaxies with masses from 10^9 to 10^12 M_⊙. We derived the half-mass radius, and we found that galaxies are on average 15% more compact in mass than in light. The ratio of half-mass radius to half-light radius (HLR) shows a dual dependence with galaxy stellar mass; it decreases with increasing mass for disk galaxies, but is almost constant in spheroidal galaxies. In terms of integrated versus spatially resolved properties, we find that the galaxy-averaged stellar population age, stellar extinction, and μ_∗ are well represented by their values at 1 HLR. Negative radial gradients of the stellar population ages are present in most of the galaxies, supporting an inside-out formation. The larger inner (≤1 HLR) age gradients occur in the most massive (10^11 M_⊙) disk galaxies that have the most prominent bulges; shallower age gradients are obtained in spheroids of similar mass. Disk and spheroidal galaxies show negative μ∗ gradients that steepen with stellar mass. In spheroidal galaxies, μ∗ saturates at a critical value (~7 × 10^2 M_⊙/pc^2 at 1 HLR) that is independent of the galaxy mass. Thus, all the massive spheroidal galaxies have similar local μ_∗ at the same distance (in HLR units) from the nucleus. The SFH of the regions beyond 1 HLR are well correlated with their local μ_∗, and follow the same relation as the galaxy-averaged age and μ_∗; this suggests that local stellar mass surface density preserves the SFH of disks. The SFH of bulges are, however, more fundamentally related to the total stellar mass, since the radial structure of the stellar age changes with galaxy mass even though all the spheroid dominated galaxies have similar radial structure in μ_∗. Thus, galaxy mass is a more fundamental property in spheroidal systems, while the local stellar mass surface density is more important in disks.

Mass-metallicity relation explored with CALIFA I. Is there a dependence on the star-formation rate?

We studied the global and local ℳ-Z relation based on the first data available from the CALIFA survey (150 galaxies). This survey provides integral field spectroscopy of the complete optical extent of each galaxy (up to 2−3 effective radii), with a resolution high enough to separate individual H II regions and/or aggregations. About 3000 individual H II regions have been detected. The spectra cover the wavelength range between [OII]3727 and [SII]6731, with a sufficient signal-to-noise ratio to derive the oxygen abundance and star-formation rate associated with each region. In addition, we computed the integrated and spatially resolved stellar masses (and surface densities) based on SDSS photometric data. We explore the relations between the stellar mass, oxygen abundance and star-formation rate using this dataset. We derive a tight relation between the integrated stellar mass and the gas-phase abundance, with a dispersion lower than the one already reported in the literature (σ_Δlog (O/H) = 0.07 dex). Indeed, this dispersion is only slightly higher than the typical error derived for our oxygen abundances. However, we found no secondary relation with the star-formation rate other than the one induced by the primary relation of this quantity with the stellar mass. The analysis for our sample of ~3000 individual H II   regions confirms (i) a local mass-metallicity relation and (ii) the lack of a secondary relation with the star-formation rate. The same analysis was performed with similar results for the specific star-formation rate. Our results agree with the scenario in which gas recycling in galaxies, both locally and globally, is much faster than other typical timescales, such like that of gas accretion by inflow and/or metal loss due to outflows. In essence, late-type/disk-dominated galaxies seem to be in a quasi-steady situation, with a behavior similar to the one expected from an instantaneous recycling/closed-box model.

Pathways to quiescence: SHARDS view on the star formation histories of massive quiescent galaxies at 1.0 < z < 1.5

We present star formation histories (SFHs) for a sample of 104 massive (stellar mass M > 10^10 M_⊙) quiescent galaxies (MQGs) at z = 1.0–1.5 from the analysis of spectrophotometric data from the Survey for High-z Absorption Red and Dead Sources (SHARDS) and HST/WFC3 G102 and G141 surveys of the GOODS-North field, jointly with broad-band observations from ultraviolet (UV) to far-infrared (far-IR). The sample is constructed on the basis of rest-frame UVJ colours and specific star formation rates (sSFRs = SFR/Mass). The spectral energy distributions (SEDs) of each galaxy are compared to models assuming a delayed exponentially declining SFH. A Monte Carlo algorithm characterizes the degeneracies, which we are able to break taking advantage of the SHARDS data resolution, by measuring indices such as MgUV and D4000. The population of MQGs shows a duality in their properties. The sample is dominated (85 per cent) by galaxies with young mass-weighted ages, t_M t_M < 2 Gyr, short star formation time-scales, 〈τ〉 ∼ 60–200 Myr, and masses log(M/M_⊙) ∼ 10.5. There is an older population (15 per cent) with t_M t_M = 2–4 Gyr, longer star formation time-scales, 〈τ〉∼ 400 Myr, and larger masses, log(M/M_⊙) ∼ 10.7. The SFHs of our MQGs are consistent with the slope and the location of the main sequence of star-forming galaxies at z > 1.0, when our galaxies were 0.5–1.0 Gyr old. According to these SFHs, all the MQGs experienced a luminous infrared galaxy phase that lasts for ∼500 Myr, and half of them an ultraluminous infrared galaxy phase for ∼100 Myr. We find that the MQG population is almost assembled at z ∼ 1, and continues evolving passively with few additions to the population.

Cold DUst around NEarby Stars (DUNES). First results. A resolved exo-Kuiper belt around the solar-like star ζ2 Ret

We present the first far-IR observations of the solar-type stars δ Pav, HR 8501, 51 Peg and ζ^2 Ret, taken within the context of the DUNES Herschel open time key programme (OTKP). This project uses the PACS and SPIRE instruments with the objective of studying infrared excesses due to exo-Kuiper belts around nearby solar-type stars. The observed 100 μm fluxes from δ Pav, HR 8501, and 51 Peg agree with the predicted photospheric fluxes, excluding debris disks brighter than L_dust/L_* ~ 5 x 10^-7 (1σ level) around those stars. A flattened, disk-like structure with a semi-major axis of ~100 AU in size is detected around ζ2 Ret. The resolved structure suggests the presence of an eccentric dust ring, which we interpret as an exo-Kuiper belt with L_dust/L_* ≈ 10^-5.

Caught in the act: gas and stellar velocity dispersions in a fast Quenching compact star-forming galaxy at z ~ 1.7

We present Keck I MOSFIRE spectroscopy in the Y and H bands of GDN-8231, a massive, compact, star-forming galaxy at a redshift of z ~ 1.7. Its spectrum reveals both Hα and [Nii] emission lines and strong Balmer absorption lines. The Hα and Spitzer MIPS 24 μm fluxes are both weak, thus indicating a low star-formation rate of SFR≲5-10 M_⨀ yr−1. This, added to a relatively young age of ~700 Myr measured from the absorption lines, provides the first direct evidence for a distant galaxy being caught in the act of rapidly shutting down its star formation. Such quenching allows GDN-8231 to become a compact, quiescent galaxy, similar to three other galaxies in our sample, by z ~ 1.5. Moreover, the color profile of GDN-8231 shows a bluer center, consistent with the predictions of recent simulations for an early phase of inside-out quenching. Its line-of-sight velocity dispersion for the gas, σ_LOG^gas = 127 ± 32 km s^−1, is nearly 40% smaller than that of its stars, σ_LOG^* = 215 ± 35 km s^−1. High-resolution hydro-simulations of galaxies explain such apparently colder gas kinematics of up to a factor of ~1.5 with rotating disks being viewed at different inclinations and/or centrally concentrated star-forming regions. A clear prediction is that their compact, quiescent descendants preserve some remnant rotation from their star-forming progenitors.

Spatially resolved star formation main sequence of galaxies in the CALIFA survey

The "main sequence of galaxies"—defined in terms of the total star formation rate ψ versus the total stellar mass M *—is a well-studied tight relation that has been observed at several wavelengths and at different redshifts. All earlier studies have derived this relation from integrated properties of galaxies. We recover the same relation from an analysis of spatially resolved properties, with integral field spectroscopic (IFS) observations of 306 galaxies from the CALIFA survey. We consider the SFR surface density in units of log(M_⊙ yr^−1 Kpc^−2) and the stellar mass surface density in units of log(M_⊙ Kpc^−2) in individual spaxels that probe spatial scales of 0.5–1.5 Kpc. This local relation exhibits a high degree of correlation with small scatter (σ = 0.23 dex), irrespective of the dominant ionization source of the host galaxy or its integrated stellar mass. We highlight (i) the integrated star formation main sequence formed by galaxies whose dominant ionization process is related to star formation, for which we find a slope of 0.81 ± 0.02; (ii) for the spatially resolved relation obtained with the spaxel analysis, we find a slope of 0.72 ± 0.04; and (iii) for the integrated main sequence, we also identified a sequence formed by galaxies that are dominated by an old stellar population, which we have called the retired galaxies sequence.

Multiwavelength study of star-forming galaxies in the local Universe

We have studied in detail the properties of local active star-forming galaxies from the UCM survey, and in particular their star-formation histories. We have quantified the relative importance of the current episode of star formation in comparison to the underlying older stellar populations. We have also determined the total stellar mass function and burst mass function for the UCM sample using the M/L calculated for each galaxy. Integrating this mass function we obtained the contribution of the star-forming galaxies to the total stellar mass density of the local Universe.