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The administration of spike monoclonal antibody treatment to patients with mild to moderate COVID-19 is very challenging. This article summarizes essential components and processes in establishing an effective spike monoclonal antibody infusion program. Rapid identification of a dedicated physical infrastructure was essential to circumvent the logistical challenges of caring for infectious patients while maintaining compliance with regulations and ensuring the safety of our personnel and other patients. Our partnerships and collaborations among multiple different specialties and disciplines enabled contributions from personnel with specific expertise in medicine, nursing, pharmacy, infection prevention and control, electronic health record (EHR) informatics, compliance, legal, medical ethics, engineering, administration, and other critical areas. Clear communication and a culture in which all roles are welcomed at the planning and operational tables are critical to the rapid development and refinement needed to adapt and thrive in providing this time-sensitive beneficial therapy. Our partnerships with leaders and providers outside our institutions, including those who care for underserved populations, have promoted equity in the access of monoclonal antibodies in our regions. Strong support from institutional leadership facilitated expedited action when needed, from a physical, personnel, and system infrastructure standpoint. Our ongoing real-time assessment and monitoring of our clinical program allowed us to improve and optimize our processes to ensure that the needs of our patients with COVID-19 in the outpatient setting are met.

Resume Objectif L’objectif etait d’evaluer les performances de localisation sonore spatiale azimutale dans differentes conditions pour l’optimisation d’un protocole de localisation sonore spatiale de routine. Materiel et methode Deux groupes de sujets sains ont ete testes de facon identique. Le premier groupe devait garder la tete fixe alors que le deuxieme groupe etait autorise a tourner la tete. La localisation sonore spatiale etait testee oreilles nues, puis avec un bouchon d’oreille droit (asymetrie auditive aigue) pour chacun des stimuli sonores suivants : bande etroite centree sur 250 Hz pulse, bandes etroites centrees sur 2000 Hz, 4000 Hz et 8000 Hz continus, wobule 4000 Hz continu, bruit blanc pulse et mot (« lac »). L’erreur quadratique moyenne ou RMS Error (Root Mean Square Error) permettait de calculer la performance de localisation. Resultats Tete fixe, la localisation sonore etait significativement perturbee apres bouchon d’oreille pour l’ensemble des stimuli (p Conclusion Le test realise chez un sujet tete fixe est plus sensible. L’utilisation d’un bruit en bande etroite centre sur 4000 Hz et continu explore la difference d’intensite interaurale. Un bruit en bande etroite centre sur 250 Hz et pulse permet d’explorer la difference de temps interaurale. Le test tete mobile, plus proche des conditions de vie reelle, est optimise avec un bruit en bande etroite centre sur 2000 Hz et continu.

A set of derivatives of 11β-(4-oxyphenyl)estradiol were prepared as potential fluorescent imaging agents for the evaluation of the estrogen receptor. The compounds were designed based on the established affinity and selectivity of 11β-[4-(dimethylethoxy)phenyl]estradiol (RU39411) as an estrogen receptor (ER) antagonist. The 5-(dimethylamino) naphathalene-1-sulfonyl (dansyl) and 7-nitrobenzo[c][1,2,5] oxadiaol-4-yl (NBD) moieties were selected based on their fluorescent and physicochemical properties. A convergent synthesis was developed that culminated in the [3 + 2] copper (I) assisted alkyne-azide cycloaddition coupling of the steroidal and fluorescent components. Good yields were obtained for the intermediates and final products, and the structural variations in the steroid component will permit evaluation of ER affinity and selectivity.

The development of fluorescent ligands for the estrogen receptor (ER) continues to be of interest. Over the past 20 years, most efforts have focused on appending an expanding variety of fluorophores to the B-, C- and D-rings of the steroidal scaffold. This review highlights the synthesis and evaluation of derivatives substituted primarily at the 6-, 7α- and 17α-positions, culminating with our recent work on 11β-substituted estradiols, and proposes an approach to new fluorescent imaging agents that retain high ER affinity.

A series consisting of substituted benzoylbenzamide derivatives of 17α-E-vinyl estradiol 6a-i and 7a-d was prepared in good overall yields from the corresponding novel iodinated benzoylbenzamide precursors using Pd(0)-catalyzed Stille coupling. Biological evaluation using competitive binding assays indicated that all compounds were effective ligands for the ERα- and ERβ-LBD (RBA = 0.5-10.0% of estradiol). Most of the compounds expressed lower stimulatory (agonist) potency (RSA

Background: Real-world clinical data to support the use of casirivimab-imdevimab for the treatment of outpatients with mild to moderate coronavirus disease-19 (COVID-19) is needed. This study aimed to assess the outcomes of casirivimab-imdevimab treatment of mild to moderate COVID-19. Methods: A retrospective cohort of 696 patients who received casirivimab-imdevimab between December 4, 2020 and April 9, 2021 was compared to a propensity-matched control of 696 untreated patients with mild to moderate COVID-19 at Mayo Clinic sites in Arizona, Florida, Minnesota, and Wisconsin. Primary outcome was rate of hospitalization at days 14, 21 and 28 after infusion. Findings: The median age of the antibody-treated cohort was 63 years (interquartile range, 52-71); 45·5% were ≥65 years old; 51·4% were female. High-risk characteristics were hypertension (52·4%), body mass index ≥35 (31·0%), diabetes mellitus (24·6%), chronic lung disease (22·1%), chronic renal disease (11·4%), congestive heart failure (6·6%), and compromised immune function (6·7%). Compared to the propensity-matched untreated control, patients who received casirivimab-imdevimab had significantly lower all-cause hospitalization rates at day 14 (1·2% vs 3·4%; Odds Ratio [OR], 0·26; 95% confidence interval (CI): 0·11-0·64), day 21 (1·2% vs 4·2%; OR, 0·22; 95% CI: 0·09-0·52), and day 28 (1·3% vs 4·9%; OR, 0·21; 95% CI: 0·09-0·48). Rates of intensive care unit admission and mortality at days 14, 21 and 28 were similarly low for antibody-treated and untreated groups. Interpretation:Among high-risk patients with mild to moderate COVID-19, casirivimab-imdevimab treatment was associated with a significantly lower rate of hospitalization. Funding Information: This work was funded by an intramural grant from Mayo Clinic to RRR. Declaration of Interests: CP, AP, AV, and PL are employees of nference and have financial interests in the company. JCO is supported by grants from nference, and is a paid consultant for Elsevier, Inc. and Bates College. ADB is supported by grants from NIAID (grants AI110173 and AI120698) Amfar (#109593) and Mayo Clinic (HH Shieck Khalifa Bib Zayed Al-Nahyan Named Professorship of Infectious Diseases). ADB is a paid consultant for Abbvie and Flambeau Diagnostics, is a paid member of the DSMB for Corvus Pharmaceuticals and Equilium, owns equity for scientific advisory work in Zentalis and Nference, and is founder and President of Splissen therapeutics. RRR is supported by research grants from Regeneron, Roche, Gilead and the Mayo Clinic, and is a member of DSMB for Novartis. All other have nothing to disclose. Ethics Approval Statement: The Mayo Clinic Institutional Review Board approved this study. Informed consent was waived and patients without research authorization were excluded.

Resume La localisation sonore spatiale est primordiale pour le confort de vie. Elle permet de definir la position d’une source sonore dans les trois dimensions de l’espace (azimut, hauteur et distance). Elle repose sur trois types d’indices differents : deux indices binauraux (difference de temps interaurale et difference d’intensite interaurale) et 1’indice monaural spectral (fonction de transfert liee a la tete). Ces indices sont complementaires et varient selon les caracteristiques acoustiques du son incident. L’objectif de cette mise au point est de realiser une synthese des connaissances actuelles sur les fondements physiques de la localisation sonore spatiale.

Sound source localization is paramount for comfort of life, determining the position of a sound source in 3 dimensions: azimuth, height and distance. It is based on 3 types of cue: 2 binaural (interaural time difference and interaural level difference) and 1 monaural spectral cue (head-related transfer function). These are complementary and vary according to the acoustic characteristics of the incident sound. The objective of this report is to update the current state of knowledge on the physical basis of spatial sound localization.

A series of three 1,1-bis(4-hydroxyphenyl)-2-(3-hydroxyphenyl)-ethylene derivatives was prepared and evaluated as potential estrogen receptor imaging agents. The compounds display high binding affinity compared to estradiol, with the 2-iodo and 2-bromo-derivatives expressing higher affinity than the parent 2-nonhalogenated derivative. Evaluation in immature female rats also indicate that the compounds were all full estrogenic agonists with potencies in the same order of activity (I ∼ Br > H). Computational analysis of the interactions between the ligands and ERα-LBD demonstrated positive contribution of halide to binding properties. In preparation for studies using the radiohalogenated analogs, the corresponding protected 2-(tributylstannyl) derivative was prepared and converted to the corresponding 2-iodo-product.

A series of unsymmetrically substituted biphenyl compounds was designed as alpha helical proteomimetics with the aim of inhibiting the binding of coactivator proteins to the nuclear hormone receptor coactivator binding domain. These compounds were synthesized in good overall yields in seven steps starting from 2-bromoanisole. The final products were evaluated using cotransfection reporter gene assays and mammalian two-hybrid competitive inhibition assays to demonstrate their effectiveness as competitive binding inhibitors. The results from this study indicate that these proteomimetics possess the ability to inhibit coactivator–receptor interactions, but via a mixed mode of inhibition.

A series of bipolar biphenyl compounds was synthesized as proteomimetic analogs of the LXXLL penta-peptide motif responsible for the binding of coactivator proteins to the nuclear hormone receptor coactivator binding domain. These compounds were subjected to multiple in vitro assays to evaluate their effectiveness as competitive binding inhibitors. The results from this initial study indicate that these proteomimetics possess the ability to inhibit this protein-protein interaction.

As part of our ongoing project to develop new molecular probes for estrogen receptor-alpha, we are exploring the utility of internally-substituted asymmetric biphenyls as a proteomimetic scaffold. In this study, we describe synthetic methods for preparing the requisite substituted-bromophenol precursors, their further elaboration, and the subsequent Suzuki–Miyaura coupling of these sterically-hindered and electronically-rich aromatic systems. The results provide an efficient route with which to generate further libraries of novel asymmetric biphenyl compounds as potential proteomimetics.

As part of our program to explore the influence of small structural modifications on the biological response of the estrogen receptor-α (ERα), we prepared and evaluated a series of mono-and di-substituted phenyl vinyl estradiols. The target compounds were prepared in 45 -80 % yields using the Stille coupling reaction and evaluated using competitive binding analysis with the ERα-ligand binding domain (hERα-LBD) and estrogenic activity (induction of alkaline phosphatase in Ishikawa cells). Results indicated that the 2,4- and 2,5-dimethyl derivatives, 5b and 5c, had the highest relative binding affinity (RBA= 20.5 and 37.3%) and relative stimulatory activity (RSA = 101.0 and 12.3%) of the di-methyl series.

The preparation and characterization of a novel nitroxide spin probe based on a steroidal anti-estrogen is described. The probe 5 demonstrated very high binding affinity for both the alpha and beta isoforms of the estrogen receptor–ligand binding domain. EPR spectrometric studies demonstrate conformational constraints for the ligand, consistent with the nitroxyl moiety occupying a position just beyond the receptor-solvent interface.

The preparation of the novel isomeric 6- and 7-propargyloxy derivatives of 4-(3-fluoroanilino)-quinazoline was achieved using a six-step process. An alternate method to the 7-propargyloxy derivative and analogous 7-propargyloxy containing compounds is also described.

Soy isoflavones exert inconsistent bone density-preserving effects, but the bone strength-preserving effects in humans are unknown. Our double-blind randomized controlled trial examined 2 soy isoflavone doses (80 or 120mg/d) vs placebo tablets on volumetric bone mineral density (vBMD) and strength (by means of peripheral quantitative computed tomography) in healthy postmenopausal women (46-63yr). We measured 3-yr changes in cortical BMD (CtBMD), cortical thickness (CtThk), periosteal circumference (PC), endosteal circumference (EC), and strength-strain index (SSI) at 1/3 midshaft femur (N=171), and trabecular BMD (TbBMD), PC, and SSI at 4% distal tibia (N=162). We found no treatment effect on femur CtThk, PC, or EC, or tibia TbBMD or PC. The strongest predictors (negative) of tibia TbBMD and SSI and femur CtBMD were timepoint and bone resorption; whole-body fat mass was protective of SSI. As time since last menstrual period (TLMP) increased (p=0.012), 120-mg/d dose was protective of CtBMD. The strongest predictors of femur SSI were timepoint, bone resorption, and TLMP (protective). Isoflavone tablets were negative predictors of SSI, but 80-mg/d dose became protective as bone turnover increased (p=0.011). Soy isoflavone treatment for 3yr was modestly beneficial for midshaft femur vBMD as TLMP increased and for midshaft femur SSI as bone turnover increased.

Background: Our previous study indicated that soy protein with isoflavones lessened lumbar spine bone loss in midlife women. Objective: We examined the efficacy of isoflavones (extracted from soy protein) on bone mineral density (BMD) in nonosteoporotic postmenopausal women. We hypothesized that isoflavone tablets would spare BMD, with biological (age, body weight, serum 25hydroxyvitamin D) and lifestyle (physical activity, dietary intake) factors modulating BMD loss. Design: Our double-blind, randomized controlled trial (36 mo) included healthy postmenopausal women (aged 45.8‐65.0 y) with intent-to-treat (n = 224) and compliant (n = 208) analyses. Treatment groups consisted of a placebo control group and 2 soy isoflavone groups (80 compared with 120 mg/d); women received 500 mg calcium and 600 IU vitamin D3. Outcomes included lumbar spine, total proximal femur, femoral neck, and whole-body BMD. Results: Analysis of variance for intent-to-treat and compliant (80%) models, respectively, showed no treatment effect for spine (P = 0.46, P = 0.21), femur (P = 0.86, P = 0.46), neck (P = 0.17, P= 0.14), or whole-body (P= 0.86,P= 0.78) BMD.From baseline to 36 mo, BMD declined regardless of treatment. In intent-to-treat and compliant models, respectively, BMD decreases were as follows: spine (22.08%, 21.99%), femur (21.43%, 21.38%), neck (22.56%, 22.51%), and whole body (21.66%, 21.62%). Regression analysis (compliant model) indicated that age, whole-body fat mass, and bone resorption were common predictors of BMD change. After adjustment for these factors, 120 mg (compared with placebo) was protective (P = 0.024) for neck BMD. We observed no treatment effect on adverse events, endometrial thickness, or bone markers. Conclusion: Our results do not show a bone-sparing effect of extractedsoyisoflavones,exceptforamodesteffectatthefemoralneck. This trial was registered at clinicaltrials.gov as NCT00043745. Am J Clin Nutr 2010;91:218‐30.

Human immunodeficiency virus type 1 minus strand transfer was measured using a genomic donor-acceptor template system in vitro. Donor RNA D199, having the minimum region required for minus strong stop DNA synthesis, was previously shown to transfer with 35% efficiency to an acceptor RNA representing the 3' repeat region. Donor D520, having an additional 321-nucleotide segment extending into gag, transferred at 75% efficiency. In this study each transfer step was analyzed to account for the difference. Measurement of terminal transfer indicated that the 3' terminus of the cDNA generated using D520 is more accessible for transfer than that of D199. Nevertheless, acceptor competition experiments demonstrated that D520 has a greater preference for invasion-driven versus terminal transfer than D199. Competition mapping showed that the base of the transactivation response element is the primary invasion site for D520, important for efficient acceptor invasion. Acceptors complementary to the invasion and terminal transfer sites, but not the region between, allowed assessment of the significance of hybrid propagation by branch migration. These bipartite acceptors showed that with D520, invasion raises the local concentration of the acceptor for efficient terminal transfer by a proximity effect. However, with D199, invasion is relatively inefficient, and the cDNA 3' terminus is not very accessible. For most transfers that occurred, the acceptor accessed the cDNA 3' end by branch migration. Results suggest that both proximity and branch migration mechanisms contribute to transfers, with the proportion determined by donor-cDNA structure. D520 transfers better because it has greater accessibility for both invasion and terminus transfer.

The article of record as published may be located at http://dx.doi.org/10.1016/j.infrared.2006.10.021 This paper presents the design, fabrication and characterization of a QWIP photodetector capable of detecting simultaneously infrared radiation within near infrared (NIR), mid wavelength infrared (MWIR) and long wavelength infrared (LWIR). The NIR detection was achieved using interband transition while MWIR and LWIR were based on intersubband transition in the conduction band. The quantum well structure was designed using a computational tool developed to solve self-consistently the Schro¨dinger–Poisson equation with the help of the shooting method. Intersubband absorption in the sample was measured for the MWIR and LWIR using Fourier transform spectroscopy (FTIR) and the measured peak positions were found at 5.3 lm and 8.7 lm which agree well with the theoretical values obtained 5.0 lm and 9.0 lm for the two infrared bands which indicates the accuracy of the self-consistent model. The photodetectors were fabricated using a standard photolithography process with exposed middle contacts to allow separate bias and readout of signals from the three wavelength bands. The measured photoresponse gave three peaks at 0.84 lm, 5.0 lm and 8.5 lm wavelengths with approximately 0.5 A/W, 0.03 A/W and 0.13 A/W peak responsivities for NIR, MWIR and LWIR bands, respectively. This work demonstrates the possibility of detection of widely separated wavelength bands using interband and intersubband transitions in quantum wells. The work is supported in part by a grant through the Research Office of the Naval Postgraduate School.

Background: Soy protein or its components may protect against the atherosclerotic cardiovascular disease (CVD) risk factors total homocysteine (tHcy), C-reactive protein (CRP), and excess body iron, which generally increase with menopause. Objective: The primary objective of this study was to determine the independent effect of the soy protein components isoflavones and phytate on CVD risk factors in postmenopausal women. The secondary objective was to identify factors [blood lipids, oxidative stress indexes, serum ferritin, plasma folate, plasma vitamin B-12, and body mass index (BMI)] contributing to tHcy and CRP concentrations. Design: In a double-blind, 6-wk study, 55 postmenopausal women aged 47-72 y were randomly assigned to 1 of 4 soy protein (40 g/d) isolate treatments: native phytate and native isoflavone (n = 14), native phytate and low isoflavone (n = 13), low phytate and native isoflavone (n = 14), or low phytate and low isoflavone (n = 14). We measured iron indexes, tHcy, CRP, and BMI. Results: Soy protein with native phytate significantly reduced tHcy (P = 0.017), transferrin saturation (P = 0.027), and ferritin (P = 0.029), whereas soy protein with native isoflavones had no effect on any variables. At baseline, BMI was highly correlated with tHcy (r = 0.39, P = 0.003) and CRP (r = 0.55, P < 0.0001), whereas HDL cholesterol was correlated with CRP (r = -0.30, P = 0.02). Multiple regression analysis showed that LDL cholesterol and BMI contributed significantly (R 2 = 19.9%, P = 0.003) to the overall variance in tHcy. Conclusion: Consuming phytate-rich foods and maintaining a healthy weight may reduce atherosclerotic CVD risk factors in postmenopausal women.

Background Postmenopausal women are at risk of cardiovascular disease (CVD) as a result of unfavorable blood lipid profiles and increased oxidative stress. Soy protein consumption may help protect against these risk factors. Objective Our objective was to ascertain the effect of the soy protein components isoflavones and phytate on CVD risk in postmenopausal women. Design In a double-blind 6-wk study, 55 postmenopausal women were randomly assigned to 1 of 4 treatments with soy protein (40 g/d) isolate (SPI): low phytate/low isoflavone (LP/LI); normal phytate/low isoflavone (NP/LI); low phytate/normal isoflavone (LP/NI); or normal phytate/normal isoflavone (NP/NI). Blood lipids (total, LDL, and HDL cholesterol and triacylglycerol) and oxidative stress indexes (protein carbonyls, oxidized LDLs, and 8-iso-prostaglandin-F(2alpha)) were measured at baseline and 6 wk. Results The oxidative stress indexes were not significantly affected by either phytate or isoflavones. Phytate treatment had a minimal but nonsignificant effect in reducing protein carbonyls and 8-iso-prostaglandin-F(2alpha); the reductions were 6-8% and 4-6% in the NP/LI and NP/NI groups and 1-4% and 3-4% in the LP/LI and LP/NI groups, respectively. Similarly, circulating lipids were not significantly affected by either phytate or isoflavones. The decline in total (6%-7% compared with 2%-4%) and LDL (10%-11% compared with 3%-7%) cholesterol did not differ significantly between the normal- and low-isoflavone groups, respectively. Conclusion In postmenopausal women, neither phytate nor isoflavones in SPI have a significant effect of reducing oxidative damage or favorably altering blood lipids.

Laboratory experiments on the branching, symbiont-bearing coral genus Porites and Acropora have been carried out to determine the dependence of the skeletal boron isotopic composition (δ11B) on the pH of seawater. The results show a clear relationship similar to previously established empirical calibrations for planktonic foraminifera and inorganic calcite. A −0.6‰ offset exists between P. cylindrica and A. nobilis which is systematic over the pH range of 7.7–8.2. To test whether the δ11B of coral skeletons changes with physiological processes such as photosynthesis and respiration, corals were grown along a depth transect in their natural environment and under controlled conditions in the laboratory at varying light intensities and food supply. Although we also observe an isotopic offset between P. compressa and Montipora verrucosa, neither experimental treatment systematically changed the δ11B of the two species. These findings are encouraging for using the boron isotope paleo-pH proxy in corals, because it appears that seawater pH is the dominant control on the boron isotopic composition in corals.

The purpose of this contribution is to show that it is possible to obtain accurate depositional U–Pb ages and original marine 87Sr/86Sr values from the same sample of marine cement. Altered marine aragonite cements from algal mounds of the Late Carboniferous (Bursum Stage) Laborcita Formation yield a U–Pb age of 300.2±3.8 Ma, consistent with the existing chronostratigraphic framework. We use fluid rock interaction models to extrapolate to original seawater 87Sr/86Sr values based on Sr isotope and trace element analyses of multiple petrographically identified components that should represent mixes of primary and diagenetic fluids. Such modeling provides a range of 0.70807–0.70820 for the 87Sr/86Sr value of the marine end member. These data, combined with a 87Sr/86Sr value of 0.70849±0.00001 for unaltered aragonite from algal plates and bivalves in the underlying Holder Formation, show a decreasing trend in 87Sr/86Sr toward the end of the Carboniferous. Whereas the range in 87Sr/86Sr values from the Laborcita Formation is consistent with existing Sr curves, the 87Sr/86Sr values of the aragonite are appreciably higher than these curves (at least 0.0001). The aragonite from the Holder Formation has greater than 6000 ppm Sr, and thus these components should reflect the original marine value. Data from marine cements and biogenic aragonite from other sections are necessary to evaluate whether the 87Sr/86Sr values from the Sacramento Mountains truly record the global value.

We examined whether early injury-associated activation of cyclic AMP response element binding protein (CREB) in the spinal dorsal horn was mediated by the cyclic AMP-dependent protein kinase A (PKA) pathway. Significant increases in the levels of phosphorylated CREB (pCREB), phosphorylated PKAIIalpha regulatory subunit (pPKA), and PKAalpha catalytic subunit (PKAalpha cat) were elicited 2 h after loose ligation of the sciatic nerve. These injury-elicited increases were significantly reduced by dorsal horn application of the cell-permeable PKA inhibitor Rp-8-Br-cAMPS. The cell-permeable PKA activator Sp-8-Br-cAMPS significantly increased the levels of pCREB, pPKA and PKAalpha cat 2 h after application onto the dorsal horn of control, uninjured animals. Our data lent further support to the notion that activation of PKA may play an important role in the early stages of nerve injury-elicited plasticity in the dorsal horn.

As part of our program to develop novel ligands for the estrogen receptor, we synthesized the series of isomeric 17alpha-(trifluoromethyl)phenylvinyl estradiols using our solid-phase organic synthesis methodology. The compounds were evaluated for their relative binding affinity (RBA) using the ERalpha-LBD and in vivo potency using the immature rat uterotrophic growth assay. The ortho-isomer had the highest RBA values, 48-223, and the highest estrogenicity in vivo. The other isomers had significantly lower affinities and were weaker agonists in the uterotrophic assay. The results suggest that introduction of substituents at the 17alpha-position of estradiol is tolerated by the ER-LBD and permit agonist responses in the intact animal, however, the effect is sensitive to the position of groups on the phenyl ring. This study demonstrates that the 17alpha-position of estradiol is a reasonable site for modification but the position and physicochemical properties of such modifications may significantly affect the affinity and efficacy of the ligand.

Phosphor imaging is a type of digital autoradiography that has been widely used in biochemistry to examine radioactively tagged proteins. We used phosphor imaging to map in situ U and Th in polished slabs of geological materials including carbonates, phosphates, and silicate-rich rocks. We examined samples containing between 2 and >500 ppm U and ∼700 ppm Th to evaluate the applicability of the technique to geological samples. Resolution of 1 mm or better was obtained even for low concentration (∼10 ppm) samples. These analyses are routine and only require a light box, phosphor screen, and access to a phosphor imager. The technique is nondestructive, relatively inexpensive, and requires very little processing time. We used this technique to identify U- and Th-enriched carbonates and phosphates, and to find “hot spots” of U- and Th-rich minerals in a granodiorite. These high-resolution maps of U and Th allow us to effectively sample for geochronology and identify potentially interesting samples for synchrotron X-radiation studies. The maps produced by phosphor imaging also have great potential for investigating the details of adsorption of radionuclides to rocks and minerals in contaminated areas.

Release of viral particles from a host cell is an important step in the viral life cycle. This has been well studied in a variety of viral systems, but quantitative data on the exact timing of viral release and potential cell-to-cell variations is still needed. This data could shed light on the underlying mechanisms that affect the timing and rate of viral production. In this poster, we explain the experimental setup that will allow us to gather this data using viral like particles produced in the HIV-1 test system.HIV-1 is an important and extensively studied retrovirus. Transfecting cells with only the structural protein Gag produces viral like particles (VLPs). The budding and release of these VLPs is similar to viruses produced from cells transfected with the full viral genome. There is a temporal distribution in the release of viral like particles from transfected cells, but the exact distribution and its cause are not fully known. We are developing an experimental setup that combines microfluidics and fluorescence to determine these.Here, we summarize previous microfluidic designs and elaborate on the design fabrication and testing process specific to the adherent mammalian cells needed to produce VLPs. These adherent cells are grown inside a PDMS/glass based microfluidic device. They are transiently transfected with HIV-1 Gag-YFP. A very slow flow of medium is established and a narrow channel section is observed downstream from the cell colony. A CCD camera is used to detect each VLP and a histogram of observed VLP vs. post transfection time is made. We explain the testing of our detection system limits using fluorescent beads as a model. Finally, we discuss the design and initial testing of microfluidic devices for single cell VLP production studies.

The Messinian evaporites in Nijar Basin, southeastern Spain are composed of coarse-crystalline Yesares selenites and Feos laminated fine-crystalline gypsum. These primary Yesares selenites, Feos gypsum, and secondary vein gypsum were analyzed for trace elements (Na, Mg, and Sr) in order to understand gypsum origin. Trace-element concentrations from the three types of gypsum differ significantly. The consistency of the Yesares data with natural marine and modeled marine results suggests that Yesares selenites were deposited from marine-dominated environments. Within the entire Yesares Formation or within one single-gypsum bed, Sr, Mg, and Na concentrations increase upward while crystal size decreases, probably indicating an increase of brine concentration as Yesares selenites were accumulating. The Sr, Na, and Mg concentrations from the Feos gypsum are partially overlapped with, but also significantly higher than those of the Yesares selenites. These Feos data are inconsistent with natural marine and modeled marine data. One interpretation for the inconsistency is that diagenetic alteration occurred to primary marine Feos gypsum. An alternative scenario is that the Feos gypsum was deposited from mixed nonmarine fluids with marine brine during the late Messinian. The latter interpretation is consistent with the stratigraphic, sedimentary, and O, S, and Sr isotopic data.

A conjugate of a C11-β-derivative of estradiol and an asymmetric tetraphenylporphyrin was synthesized to study its potential selective uptake by breast cancer cells naturally over-expressing the nuclear receptor for estrogen (ER). Competitive radioligand binding assays of this conjugate with recombinant ER showed that the conjugate bound to ER in a dose-dependent manner with an EC50 of 274 nM, compared with 1 nM for estradiol, the natural ligand. Cellular uptake studies with ER-positive MCF-7 and ER-negative HS578t human breast cancer cells revealed that, the conjugate was taken up by MCF-7 cells in a dose-dependent manner, which was obliterated by co-incubation with a large excess of estradiol. On the other hand there was very little uptake of the un-conjugated porphyrin by MCF-7 and Hs578t cells. HS578t cells also showed insignificant uptake of the conjugate under the conditions of our experiment. These results strongly suggested that specific interaction between the endogenous ER in MCF-7 cells and the estrogen part of the conjugate enabled these cells to selectively internalize the conjugate over the un-conjugated porphyrin. Therefore, ER-binding conjugates of estradiol and porphyrins could potentially be used for ER-targeted photodynamic therapy of hormone-sensitive cancers of breast, ovary, gonads etc.

Organic-rich calcite laminated with gypsum in the evaporitic, non-fossiliferous Castile Formation of the Delaware Basin, southwest USA, yields a Total Pb/U isochron age of 251.5±2.8 Ma (MSWD=1.3). The Castile Formation is almost certainly Late Permian based on its 87 Sr/ 86 Sr value of 0.706923, identical to the distinct minimum in the late Permian Sr curve. In this paper we explore the potential for using U–Pb calcite ages to date traditionally undatable sections and show how this southern-midcontinent USA (far west Texas and southeast New Mexico) deposit can be correlated to the type section in China. We accept that diagenetic alteration can bias U–Pb results, but the data set we present shows no evidence for such alteration. Clearly with alteration the age we present would represent a minimum age for the Castile Formation. If the age actually dates the Castile Formation then it requires the Permian–Triassic boundary to be younger than 251.5±2.8 Ma.

Previous work from this laboratory identified a polysome-associated endonuclease whose activation by estrogen correlates with the coordinate destabilization of serum protein mRNAs. This enzyme, named polysomal ribonuclease 1, or PMR-1, is a novel member of the peroxidase gene family. A characteristic feature of PMR-1 is its ability to generate in vitro degradation intermediates by cleaving within overlapping APyrUGA elements in the 5′-coding region of albumin mRNA. The current study sought to determine whether the in vivo destabilization of albumin mRNA following estrogen administration involves the generation of decay intermediates that could be identified as products of PMR-1 cleavage. A sensitive ligation-mediated polymerase chain reaction technique was developed to identify labile decay intermediates, and its validity in identifying PMR-1-generated decay intermediates of albumin mRNA was confirmed by primer extension experiments performed with liver RNA that was isolated from estrogen-treated frogs or digestedin vitro with the purified endonuclease. Ligation-mediated polymerase chain reaction was also used to identify decay intermediates from the 3′-end of albumin mRNA, and as a final proof of principle it was employed to identify in vivo decay intermediates of the c-myc coding region instability determinant corresponding to sites of in vitro cleavage by a polysome-associated endonuclease.

As a continuation of our program to develop probes for the hormone binding domain (HBD) of the estrogen receptor (ER), we designed a series of novel 17α-E/Z-(X-phenyl)-vinyl estradiols. Based upon our experience with solution chemistry we applied solid phase synthesis using carboxylated resins to synthesize the new compounds. The Stille coupling reaction permitted the introduction of a variety of functional groups and positional isomers on the terminal phenyl group. Subsequent cleavage from the resin generated a series of novel estradiol derivatives.

Previous studies from our laboratory demonstrated separately the tolerance of the estrogen receptor for the 17 alpha-phenylselenovinyl substituent and the enhancement of affinity imparted by the 11 beta-vinyl moiety. Our recent publication suggested that the two groups could be combined within a single structure and retain high affinity for the estrogen receptor. As a result, we have prepared in good overall yields the E- and Z-isomers of 11 beta-vinyl-17 alpha-phenylselenovinyl estradiol. Evaluation of the new steroids with receptor isolated from lamb cytosol indicated that both isomers are poorer ligands than estradiol at 4 degrees C, but both are better than estradiols. at 25 degrees C. This behavior had not been observed for the 11 beta-unsubstituted 17 alpha-E/Z phenylselenovinyl estradiols. Of particular interest was the observation that, unlike previous isomer pairs, the E-isomer possessed a greater affinity than the Z-isomer. The results suggest that relatively small changes in structure may impart significant differences in the interactions with the receptor and provide the basis for further ligand design.

The time of sedimentation of rapidly deposited clastic sedimentary rocks in fluvial environments may be directly dated with an uncertainty of less than three million years using U-Pb dating of pure micritic calcite from calcretes developed in overbank deposits. This conclusion is based on results obtained for calcretes (soil calcite, caliche) formed in the late Triassic New Haven Arkose, Hartford Basin, Connecticut, USA. The paragenesis of calcrete samples from the New Haven Arkose was determined using plane-polarized light and cathodoluminesence petrography, uranium fission track analysis, as well as trace element and stable isotope geochemistry. These calcretes contain an abundance of paleosol microfabrics and diagenetic calcite. The first-generation micritic calcite and second-generation blocky calcite have characteristics consistent with soil calcite. The third generation blocky calcite is a later diagenetic calcite (post-soil calcite). The U-Pb data for pure micritic calcite (first generation) in a horizontal sheet calcrete in sedimentary rocks of Norian age gives a 238U/207Pb-206Pb/207Pb isochron age of 211.9 ± 2.1 Ma (2-sigma, and used hereafter for all ages). This age and the stratigraphic position for this sample are in excellent agreement with the ages proposed by Gradstein et al. (1994) for the Norian/Rhaetian boundary of 209.6 ± 4.1 Ma and the Carnian/Norian boundary of 220.7 ± 4.4 Ma. The U-Pb data for two samples of first generation micrite in rhizoliths with about 15% insoluble residues give “ages” of 7 ± 66 Ma and 20 ± 36 Ma. These results suggest that relatively recent events disturbed the U-Pb system of these detrital rich samples, perhaps due to redistribution of U during weathering or during chemical dissolution for analysis. The U-Pb data for a sample of pure third generation blocky calcite cement in a rhizolith yields a 206Pb/238U-207Pb/235U isochron age of 81 ± 11 Ma. This age suggests that this sample of third generation blocky calcite precipitated during the late Cretaceous perhaps over an extended period. These results suggest that by carefully selecting samples using petrographic and geochemical characteristics U-Pb dating of pure calcite found in calcrete horizons in clastic sediments can be used to precisely date the times of sedimentation and times of later diagenesis.

Purpose: The association between deep vein thrombosis (DVT) and the hypercoagulable state is a well-established entity. However, the association between saphenous vein thrombophlebitis and coagulation abnormalities has not been investigated. Although thrombosis of varicose veins typically runs a benign course, phlebitis of the saphenous system may propagate to the deep system or saphenofemoral junction that requires more aggressive therapy. Given the potential similarity in clinical outcome between saphenous vein thrombophlebitis (SVT) and DVT, we have investigated the coagulation profile of patients presenting with isolated SVT. Methods: Seventeen consecutive patients who presented to our vascular laboratory with isolated SVT had a coagulation profile performed that included antithrombin III (AT III), protein C (PC), protein S (PS) antigen and activity levels, activated protein C (APC) resistance, factor V DNA mutation, and coagulation factors II and X. All patients had duplex scans performed on both the superficial and deep venous systems. Patients with SVT only were treated with nonsteroidal antiinflammatory drugs (NSAIDs) and warm soaks as outpatients, whereas those patients found to have DVT or a clot at the saphenofemoral junction were fully anticoagulated with heparin and coumadin therapy. All 17 patients had at least one repeat coagulation profile performed up to 5 months after their SVT occurrence to ensure that the results of hypercoagulability were not transient. Results: Ten (59%) of the 17 patients with SVT had abnormal coagulation profiles on initial presentation. All 10 patients who were hypercoagulable had repeat tests and 6 (35%) remained abnormal. Four patients who had abnormal results converted to normal values. Seven patients with normal coagulation profiles on initial presentation had repeat tests and all remained normal. Conclusion: The incidence of the hypercoagulable state in patients with SVT is high. Thirty-five percent of patients with isolated SVT had consistently abnormal coagulation profiles. Patients with SVT may be prone to the development of DVT or saphenofemoral junction thrombophlebitis and should be closely followed after the initial diagnosis of hypercoagulability. (J Vasc Surg 1998;27:677-80.)

Purpose: Although much attention has been focused on lower extremity deep venous thrombosis (LEDVT), there is a relative paucity of data regarding the impact of upper extremity deep venous thrombosis (UEDVT) on morbidity and mortality rates. To increase our knowledge with the latter disease, we have reviewed our experience at our institution with 170 patients who had brachial, axillary, and subclavian vein thromboses. Methods: Over the past 5 years, UEDVT was diagnosed in 170 patients by duplex scanning. The indications for duplex examination were either upper extremity swelling (95%) or as part of the workup for pulmonary embolism (5%). There were 103 women (61%) and 67 men (39%), with ages ranging from 9 to 101 years (mean, 68 ± 17 years). The diagnosis was made in 152 patients (89%) while they were admitted to the hospital and in 18 patients (11%) in the outpatient clinic. Risk factors included presence of a central venous catheter or pacemaker in 110 patients (65%), malignancy in 63 patients (37%), concomitant LEDVT in 19 patients (11%), and history of LEDVT in 18 patients (11%). Fifty-six patients (33%) had multiple risk factors, whereas 36 patients (21%) had no obvious risk factor. Results: The 1-month and 3-month mortality rates for the entire study group were 16% and 34%, respectively. Patients who had concomitant LEDVT, were 75 years of age or older, and were not treated with anticoagulation medication had a significantly higher 1-month mortality rate. Patients whose diagnoses were made in the outpatient setting were statistically younger and had a lower 3-month mortality rate when compared with the patients whose diagnoses were made as inpatients. Pulmonary embolism was documented by ventilation/perfusion scan in 12 patients (7%). Although no patient in the group in which UEDVT was diagnosed on an outpatient basis was documented to have a pulmonary embolism and 12 patients (8%) in the inpatient group had pulmonary emboli, this difference was not statistically significant. Anticoagulation medication did not totally prevent pulmonary embolism in this review. All patients were followed-up for between 0 to 49 months (mean, 13 ± 1 months). No swelling of the affected arm was observed in 145 patients (94%); four patients complained of mild intermittent swelling (2%), and seven patients reported significant swelling (4%). Conclusions: Contrary to previous reports, these data suggest that UEDVT is associated with a low incidence of postthrombotic upper extremity swelling, but a significant incidence of pulmonary embolism and rate of mortality. This review suggests that UEDVT is at least as serious a disease entity as LEDVT and should be managed as aggressively as LEDVT. (J Vasc Surg 1997;26:853-60.)

A series of analogs of the N-[2-bis arylmethoxy]-N′-phenylpropyl-piperazines GBR12909 and 12935 was synthesized and evaluated as inhibitors of synaptic monoamine transporters. The data indicated that all of the new compounds demonstrated a selectivity for the dopamine transporter compared to the other monoamine transporters with IC50 values approaching 10 nM. The results suggest that the internal piperazine moiety is not required for activity and may be replaced with a more flexible diamine unit.

We have sampled paleosol horizons from a continuous core of a rapidly deposited Late Pennsylvanian-Early Permian marine shelf section in Texas, USA. The paleosols occur on the tops of shoaling upward cycles and, based on current time constraints, these cycles average 250 ka and cannot represent longer than 400 ka. As the unconformity which is represented by the paleosol can only be a fraction of the time allowed for deposition of the cycle, the age of minerals that form in the paleosol is effectively the time of sedimentation. The uncertainty on the 238U206Pb age of brown paleosol calcite from one exposure surface is only 1 Ma. Reported uncertainties on Paleozoic boundaries are greater than 10 Ma. Our early results suggest that the marine sedimentary record may be dated to a precision of 1 Ma with UPb analyses of carefully selected paleosol calcite. These results have implications for vastly improving time resolution of the rock record.

This study compares the specific uptake and retention of the Z and E isomers of 17 alpha-iodovinyl-11 beta-methoxyestradiol (IVME2) in estrogen target tissues in immature female rats following intraperitoneal injection. Estrogen receptor binding studies in vitro showed that the Z-IVME2 had greater affinity than the E-IVME2, but our initial in vivo data, comparing 125I-labeled E- or Z-IVME2 in separate studies showed no difference between the two isomers in either uptake or retention. These results were confirmed when the two isomers, labeled either with 123I or 125I, were injected simultaneously, allowing direct comparison of uptake and retention patterns in the same animal. Analysis of the nature of the radioiodinated estrogens in estrogen target tissues showed that at all time points, the estrogen target tissues contained mainly the E isomer, even at short times after injection of Z isomer. Although the Z-IVME2 was reasonably stable in the injectant, analysis of a peritoneal lavage soon after intraperitoneal injection of Z-[125I]-IVME2 showed that mainly the E isomer was present, suggesting that the conversion occurred prior to uptake by the tissues. In vitro studies with intraperitoneal fluid and serum showed that denaturing by heating at 65 degrees C substantially reduced their ability to affect the conversion of Z to E isomer, suggesting a possible enzymatic conversion.

Residues after HF leaching of detrital feldspar grains from the Early Proterozoic Chelmsford Formation of the Sudbury Basin, Ontario record isotopic compositions very close to the initial Pb isotopic composition of their Late Archean, Superior Province source. These grains have been recrystallized to albite and K-feldspar. Residues of Chelmsford feldspar grains lie within the range of reported 206 Pb 204 Pb compositions of feldspars from plutons of the adjacent Abitibi subprovince of the Superior Province, with a steep 207 Pb 206 Pb slope of 0.35 ± 0.15 (3.7 ± 0.7 Ga). Leaches are more radiogenic than residues, but leach-residue pairs do not record in situ U (and Th) decay since either the Late Archean time of feldspar crystallization in the Superior Province or the Early Proterozoic time of recrystallization in the Chelmsford Formation. Instead, leach-residue pairs lie along an average 207 Pb 206 Pb slope of 0.250 ± 0.036, representing mixing trends. Most whole-rock samples from the Chelmsford Formation lie close to a 2.7 Ga slope, collinear with detrital feldspar compositions. We interpret the Pb data from the leaches as recording the passing of altering fluids. These fluids likely carried Pb derived from rocks or minerals with relatively high U Pb , Th Pb and Th U within the sedimentary basin itself. The residues appear to record very close to initial values because they lie along the very steep trend defined by feldspars of the Superior Province.

Radioiododestannylation has been employed to prepare a series of radioiodinated vinyl alcohols, two of which were evaluated for their tissue distribution in rats. The radioiodination method utilized tri-alkylstannylvinyl intermediates that can be prepared in good yields from 1,2-bis(tributylstannyl) ethylene and the appropriate ketones or by hydrostannation of the corresponding ethynyl alcohols. The radiolabeling proceeded at the no-carrier-added level to give, after HPLC separation, the desired products in 85-95% isolated yields. Tissue distribution studies in the rat indicated that the agents were rapidly extracted by the brain and then quickly cleared. No retention of activity was observed in the nonmetabolizing or nonexcretory organs. Chemically, the use of the E-tributylstannylvinyl lithium followed by radioiodination controlled stereochemistry and eliminated the separation of E- and Z-iodovinyl isomers. Biologically, the compounds behaved as neutral, diffusible and nonmetabolized radiotracers that may be used for the evaluation of cerebral blood flow, potentially with the short-lived radionuclide I-122 or other short-lived radiohalogens.

Previous studies from our laboratory using 17 alpha-E- and 17 alpha-Z-halovinyl estradiols demonstrated a marked enhancement of receptor binding by the Z-isomers. This suggested tolerance at the 17 alpha-position was not previously observed by investigations using 16 alpha and 17 alpha-substituted estradiols. Because of the synthetic access provided by vinyl tin chemistry, we prepared the 17 alpha-E and Z-phenylthiovinyl and phenylselenovinyl estradiols and compared their binding characteristics to those of the previously reported 16 alpha/17 alpha-phenylseleno and methylseleno estradiols. The results, in addition to demonstrating a facile preparation of the target compounds, indicated that significant receptor affinity was retained by these compounds (relative binding affinity = 24.5-117). The highest affinity was demonstrated by the 17 alpha-Z-phenylthiovinyl estradiol 5a, which, by molecular modeling, exhibited a significantly different molecular conformation from the corresponding 17 alpha-E-phenylthiovinyl isomer or the 17 alpha-phenyl-thioethynyl analog. The current series possessed better binding characteristics than the phenylseleno and methylseleno estradiols but somewhat poorer binding than the 17 alpha-E/Z-halovinyl series. The observations suggest that some steric limitations exist in a portion of the 17 alpha-region, and that the region is better accessed by compounds possessing Z-vinyl stereochemistry.

A new, efficient selection predicate indexing scheme for active database systems is introduced. The selection predicate index proposed uses an interval index on an attribute of a relation or object collection when one or more rule condition clauses are defined on that attribute. The selection predicate index uses a new type of interval index called the interval skip list (IS-list). The IS-list is designed to allow efficient retrieval of all intervals that overlap a point, while allowing dynamic insertion and deletion of intervals. IS-list algorithms are described in detail. The IS-list allows efficient on-line searches, insertions, and deletions, yet is much simpler to implement than other comparable interval index data structures such as the priority search tree and balanced interval binary search tree (IBS-tree). IS-lists require only one third as much code to implement as balanced IBS-trees. The combination of simplicity, performance, and dynamic updateability of the IS-list is unmatched by any other interval index data structure. This makes the IS-list a good interval index structure for implementation in an active database predicate index. ‡

Brain-derived neurotrophic factor (BDNF) and cyclic AMP response element binding protein (CREB) may critically contribute to injury-associated plasticity and thus to the development of persistent pain. In the present study we examined the potential interaction between CREB and BDNF in the spinal dorsal horn. Significant CREB phosphorylation was elicited by local application of BDNF (1 microg) onto the spinal dorsal horn of control, uninjured animals. The degree of phosphorylation was similar to that elicited by loose ligation of the sciatic nerve. The tyrosine kinase (Trk) blocker K252a (2 microg) significantly reduced the CREB phosphorylation elicited either by BDNF or the sciatic ligation. These data provided further support for the notion that at least some of the injury-associated activation of CREB in the spinal dorsal horn may be dependent upon BDNF-mediated activation of Trk receptors.

U-Pb isotope analyses on major and accessory minerals from pelitic schists in of southwestern Connecticut are used to date metamorphism and deformation. Most of the major minerals have 206 Pb/ 204 Pb ratios less than 100. However, U-Pb mineral isochron and mineral-whole rock isochrons, constructed using aliquots of the same mineral, yield concordant ages with uncertainties as low as 5 Ma. Staurolite, kyanite, and garnet are older than metamorphic monazites and zircons. These data are summarized below: 5 . mineral 206 Pb/ 204 Pb System The Straits Schist Trap Falls Fm. monazite, zircon — 207 Pb- 206 Pb 379–384 Ma 380 ± 2 Ma staurolite 48–623 238 U- 206 Pb 394–400 Ma 398 ± 5 Ma garnet 22–46 238 U- 206 Pb 383 Ma 414 ± 10 Ma 235 U- 207 Pb 418 Ma — 207 Pb- 206 Pb 623 Ma — kyanite 21–27 238 U- 206 Pb 399 Ma — chlorite, anatase, ilmenite 20–27 238 U- 206 Pb 350–370 Ma — apatite, quartz, Kspar 18–19 — — Transposed pegmatitic intrusions in The Straits Schist yield monazites with U-Pb ages analytically indistinguishable from those of metamorphic monazites and zircons in the schists. Growth of monazite and zircon in the schists may be related to high- T fluid influx associated with pegmatite intrusion. Age discordance in the garnets from The Straits Schist is most consistent with continuous loss of intermediate daughter products of the 238 U decay chain from about 420 Ma to 380 Ma. Garnets from the adjacent Trap Falls Formation do not display this behavior.

Aragonite, high-Mg calcite, and Mg-free calcite have been grown under monitored laboratory conditions to investigate mineral-fluid partitioning and isotopic fractionation of boron into carbonates. At pH ≈ 8, both polymorphs have boron isotopic compositions I6.5%0 lower than the boron isotopic composition of the experimental fluid (δ11B = 0 ± 0.7ℵ.). The isotopic composition of the synthetic minerals is identical to the calculated boron isotopic composition of the B(OH)4− species in the parent solutions, consistent with only B(OH)4− interacting with the crystal surface. The fractionation factor calculated from this isotopic offset is within analytical error of that measured between seawater and modern marine carbonates. The boron concentrations of the experimentally grown aragonite are 13.4, 85.1, and 379 ppm for total fluid boron concentrations of 0.59, 5.1, and 37.0 ppm, respectively. High-Mg calcite (HMC) coprecipitating with the aragonite has bulk boron concentrations of 5.6, 56.2, 260, and 1771 ppm for fluid boron concentrations of 0.59, 5.1, 37, and 272 ppm, respectively. Calcite boron concentrations are 1.78, 14.0, 137.7, and 1228 ppm for fluid boron concentrations of 0.45, 4.0, 44.l, and 499 ppm, respectively. Boron uptake by aragonite is greater than boron uptake by calcite grown under nearly identical conditions, while boron uptake by HMC is intermediate. Synthetic calcite crystals grown in solutions with greater than 4 ppm boron exhibit habit modification with the appearance of a subordinate form {1120} in addition to the dominant {1014}, the perfect cleavage rhombohedron, found in low-boron calcites. This is evidence of strong interaction of the borate with the crystal surface.