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Phenylethylthiazolylthiourea (PETT) derivatives have been identified as a new series of non-nucleoside inhibitors of HIV-1 RT. Structure-activity relationship studies of this class of compounds resulted in the identification of N-[2-(2-pyridyl)ethyl]-N'-[2-(5-bromopyridyl)]-thiourea hydrochloride (trovirdine; LY300046.HCl) as a highly potent anti-HIV-1 agent. Trovirdine is currently in phase one clinical trials for potential use in the treatment of AIDS. Extension of these structure-activity relationship studies to identify additional compounds in this series with improved properties is ongoing. A part of this work is described here. Replacement of the two aromatic moieties of the PETT compounds by various substituted or unsubstituted heteroaromatic rings was investigated. In addition, the effects of multiple substitution in the phenyl ring were also studied. The antiviral activities were determined on wild-type and constructed mutants of HIV-1 RT and on wild-type HIV-1 and mutant viruses derived thereof, Ile100 and Cys181, in cell culture assays. Some selected compounds were determined on double-mutant viruses, HIV-1 (Ile 100/Asn103) and HIV-1 (Ile100/Cys181). A number of highly potent analogs were synthesized. These compounds displayed IC50's against wild-type RT between 0.6 and 5 nM. In cell culture, these agents inhibited wild-type HIV-1 with ED50's between 1 and 5 nM in MT-4 cells. In addition, these derivatives inhibited mutant HIV-1 RT (Ile 100) with IC50's between 20 and 50 nM and mutant HIV-1 RT (Cys 181) with IC50's between 4 and 10 nM, and in cell culture they inhibited mutant HIV-1 (Ile100) with ED50's between 9 and 100 nM and mutant HIV-1 (Cys181) with ED50's between 3 and 20 nM.

A novel series of potent specific HIV-1 inhibitory compounds is described. The lead compound in the series, N-(2-phenethyl)-N'-(2-thiazolyl)thiourea (1), inhibits HIV-1 RT using rCdG as the template with an IC50 of 0.9 microM. In MT-4 cells, compound 1 inhibits HIV-1 with an ED50 of 1.3 microM. The 50% cytotoxic dose in cell culture is > 380 microM. The chemical structure-activity relationship (SAR) was developed by notionally dividing the lead compound in four quadrants. The SAR strategy had two phases. The first phase involved optimization of antiviral activity through independent variation of quadrants 1-4. The second phase involved the preparation of hybrid structures combining the best of these substituents. Further SAR studies and pharmacokinetic considerations led to the identification of N-(2-pyridyl)-N'-(5-bromo-2-pyridyl)-thiourea (62; LY300046.HCl) as a candidate for clinical evaluation. LY300046.HCl inhibits HIV-1 RT with an IC50 of 15 nM and in cell culture has an ED50 of 20 nM.

The synthesis of 1-carba-1-dethiacephalosporin nuclei is described. The new route utilizes a readily-available penicillin derivative as starting material and features an intramolecular ring closure to form the six-membered ring.

The synthesis and antimicrobial activity of several new 1-carba-1-dethiacephalosporins is described. The discovery of unique activity of some of the analogues against methicillin-resistant Staphylococcus aureus led to the development of a structure-activity relationship designed to optimize this activity. The results of this investigation along with the pharmacokinetic characteristics of select compounds are described.

A new method for the synthesis of chiral azetidinones bearing a carbon-carbon bond at the 4-position is described. The preparation involves a stereoselective alkylation-reduction of a silylated 4-phenylsulfonyl azetidinone. The utility of this method was demonstrated by a formal total synthesis of loracarbef.

A new method for the synthesis of chiral azetidinones bearing a carbon-carbon bond at the 4-position is described. The preparation involves a stereoselective alkylation-reduction of a silylated 4-phenylsulfonyl azetidinone. The utility of this method was demonstrated by a formal total synthesis of loracarbef.

The synthesis and biological evaluation of novel 1-carba-1-dethiacephalosporins exhibiting activity against anaerobic pathogens are described. The nitrothiazole substituent was determined to be crucial to maintaining this activity. The pharmacokinetic parameters and initial toxicological profile of the lead compound are discussed.

Nine matched pairs of cephalosporins and their 1-carba-1-dethiacephalosporin analogues have been compared with regard to microbiological activity, beta-lactam carbonyl infrared absorption, and aqueous stability. In general the microbiological activity of the pairs of compounds were very similar across a broad range of bacteria. The infrared absorption bands for the beta-lactam carbonyls of the pairs indicated a general trend for the 1-carba-1-dethiacephalosporins to absorb at lower frequencies than the corresponding cephalosporins. All of the 1-carba-1-dethiacephalosporins did however present a striking stability enhancement over their cephalosporin counterparts at pH = 10 or 11 in water. This marked contrast of MIC similarity with the observed differences in chemical reactivity clearly demonstrates hydroxide ion catalyzed hydrolysis is not a good model for transpeptidase activity unless the compounds comprise a limited domain of structural type.

In the Siberian hamster, Phodopus sungorus, short-day photoperiods induce the winter phenotype, which in males includes a decrease in the production of androgens and changes in physiology to inhibit reproduction. Motoneurones of the spinal nucleus of the bulbocavernosus (SNB) and their target muscles, the bulbocavernosus and the levator ani, a neuromuscular system involved in male copulation, also display seasonal plasticity in P. sungorus. It is not known whether the plasticity seen in the SNB system of gonadally intact hamsters is due to the effects of photoperiod per se, or to the photoperiod-induced changes in androgen production. To answer this question, we castrated adult male hamsters from long days and then implanted them with capsules containing either testosterone or blanks. Half of the hamsters from each hormone condition were moved into short photoperiod (8 : 16 h light/dark cycle) while the rest were maintained under long-day conditions (15 : 9 h light/dark cycle). After 15 weeks, many measures of the SNB system, such as somata size and weight of target muscles, responded only to androgen, not to photoperiod. However, there were effects of photoperiod on the neuromuscular junctions (NMJs) that were independent of androgen status. For example, the number of synaptic zones per NMJ and the area of the NMJs were significantly increased by short days and/or testosterone treatment. The two factors exerted an additive, rather than an interactive, effect on these measures. Another striated muscle, the extensor digitorum longus, which is present in both sexes and plays no specialized role in reproduction, displayed neither an effect of androgen nor of photoperiod on fibre size or NMJ structure. These results suggest that, in addition to androgenic effects on SNB plasticity, there is also an androgen-independent effect of photoperiod on the SNB neuromuscular system.

The synthesis and biological evaluation of novel 1-carba-1-dethiacephalosporins exhibiting activity against anaerobic pathogens are described. The nitrothiazole substituent was determined to be crucial to maintaining this activity. The pharmacokinetic parameters and initial toxicological profile of the lead compound are discussed.

This special issue on steroids and glia represents the intersection of two emerging themes in the neurosciences: (a) Glia actively modulate and participate in brain function throughout life, and (b) glia are sensitive to steroid hormones. This overview begins by reviewing some of the basic principles of steroid hormone action on the brain and introducing the various glia that inhabit the peripheral and central nervous system. A prominent theme among the articles that follow is that glia may be direct targets for steroid hormones since they possess steroid receptors and the promoter region of glial-specific genes such as glutamine synthetase contain hormone-responsive elements. The articles in this special issue discuss evidence that glia may mediate steroid action on the nervous system in the context of (a) steroid metabolism, which may control the hormonal microenvironment of neurons both in the normal and injured brain; (b) brain development including sexual differentiation; (c) synaptic plasticity which may underlie the cyclic release of luteinizing hormone releasing hormone in the female rodent brain; (d) neural repair and aging; and (e) brain immune function. Another theme among these articles is that glia influence neurons via specific secreted and cell-surface molecules, and that steroids affect this mode of communication by altering the level of glial production of these signaling molecules and/or the sensitivity of neurons to such signals.

We documented the ontogeny of androgen receptor (AR) immunoreactivity for rat lumbar motoneurons of the sexually dimorphic motor pools, the spinal nucleus of the bulbocavernosus (SNB) and the dorsolateral nucleus (DLN), and for the sexually monomorphic retrodorsolateral nucleus (RDLN). We also assessed the ontogeny of AR immunoreactivity in the rat sexually dimorphic levator ani (LA), which is a target muscle for SNB motoneurons. Lumbar spinal cords and LA muscles from gonadally intact males at ages postnatal days (P)7, P10, and P14 and as adults were incubated with the rabbit antiserum PG-21. Half of the prepubertal males (P7-P14) received 200 micrograms of testosterone propionate (TP) 2 hours prior to death to enhance immunodetection of ARs. We found that SNB motoneurons developed AR immunoreactivity at first and achieved adult levels by P10. In contrast, the number of RDLN motoneurons with AR-immunopositive nuclei during development remained well below the adult number. Development of AR immunoreactivity in the DLN shared characteristics with both the SNB and the RDLN. AR immunoreactivity developed in some DLN motoneurons by P10, although the percentage of labelled motoneurons remained below that in adulthood. Acute TP treatment significantly increased the number of SNB motoneurons with AR-positive nuclei at P7. The LA showed a robust pattern of AR immunostaining from P7 to adulthood. Immunostaining was present only in nuclei and constituted only a subpopulation of the nuclei present in muscle. The present results confirm and extend previous results based on steroid autoradiography and steroid binding assays regarding regional and developmental differences in the expression of ARs.

In adult skeletal muscles, exogenous ciliary neurotrophic factor (CNTF) induces axons and their nerve terminals to sprout. CNTF also regulates the amount of multiple innervation in developing skeletal muscles during synapse elimination, maintaining multiple innervation of muscle fibers. While CNTF may maintain multiple innervation by regulating developmental synapse elimination, it is also possible that CNTF induces the formation of new multiple innervation through a sprouting response. In this study I examined morphologically the effects of CNTF during synapse elimination in the extensor digitorum longus (EDL) muscle. Rat pups received injections of CNTF in one leg and vehicle in the other either early [postnatal day 7 (P7)-P13] or late (P14-P20) in development. The early treatment period corresponds to that time when the pattern of innervation in the EDL is converted from predominantly multiple to single innervation. The late treatment period is at the end of synapse elimination for the EDL but corresponds to the major period of synapse elimination in the levator ani (LA), allowing a comparison of effects on these two muscles from the same animals. On the day after the final injection, EDL muscles were dissected and stained with tetranitroblue tetrazolium and the resulting pattern of innervation was assessed. The present findings indicate that only the early CNTF treatment regulates the level of multiple innervation in the EDL. Moreover, the effect o early CNTF treatment was local, affecting multiple innervation only in the EDL from the CNTF-treated leg. CNTF injected during the late treatment period had no apparent effects on the EDL but had a potent effect on the pattern of innervation in the LA, significantly increasing the level of multiple innervation in this muscle. Thus, CNTF affected multiple innervation in these two muscles only if provided during the period when single innervation normally develops. There was no evidence to indicate that CNTF induced axons or their terminals to sprout during either treatment period. In conclusion, CNTF increases the level of multiple innervation, probably by regulating synapse elimination, and skeletal muscles themselves may be an important target site for CNTF action. Presumably, the sprouting response to CNTF found in adult muscle develops sometime after P21.

A series of over 70 difluoropurine analogs was synthesized by varying the C-2, 6 and 8 substituents about the purine ring system. After initial in vitro and in vivo screening, testing concentrated on the 2,6-diaminopurine analog (dFdAP) and the guanosine analog (dFdG). dFDAP appears to be a prodrug for dFdG. Both compounds significantly inhibited mammary tumor growth in mice, caused a moderate inhibition in ovarian and lymphosarcoma models, and demonstrated no activity in lung and melanoma models. This is a narrower spectrum of activity than that of gemcitabine (dFdC). The antitumor activity of dFdAP in human xenografts that are refractory to standard clinical agents was comparable or superior to that of gemcitabine. However, during the preliminary toxicology testing, dFdG was associated with several deaths caused by cardiac toxicity. Therefore, although dFdG is a potentially useful oncolytic, further investigation is required.

Cross sections for inclusive inelastic electron scattering from H, D, Be, Al, Cu and Au have been measured at 6° for incident energies up to 19.5 GeV. Within the stated errors, the cross sections were found to be directly proportional to the sum of the constituent nucleon cross sections.

Summaries of ship observations for four marine areas off the west coast of Africa have been used to describe the diurnal variation of precipitation in the eastern tropical Atlantic. These long-term means show a definitive early morning maximum in precipitation frequency throughout the year, in agreement with findings in most tropical ocean areas. In contrast, data for the nearby GATE area, which are limited to summer months, show late afternoon-early evening maxima in precipitation frequency and amount. Support for differences of this type is offered by the patterns of convective activity over the tropical Atlantic shown by satellite IR data during GATE as presented by Murakami (1979).

This paper presents the results of the analysis of a single-arm inelastic-electron-scattering experiment at an angle of 4\ifmmode^\circ\else\textdegree\fi{}. We present data on the turnon of scaling in the low-${q}^{2}$ region $0.1l{q}^{2}l1.8$, the neutron-proton comparison at large values of the scaling variable $\ensuremath{\omega}$, resonance excitation, and the shadowing in scattering from heavy nuclei.

A spiral-shaped radar echo, apparently of non-tornadic origin, was observed over southwestern Alabama on the afternoon of July 1, 1959. A series of scope photographs of the CPS-9 radar at Maxwell Air Force Base shows that this feature persisted for well over an hour and suggests that the pattern was experiencing anticyclonic rotation.

The space variability of sea surface temperature, as indicated by observations from individual merchant ships and research vessels, is considered in investigating the question of the existence of mesoscale patterns in the sea surface temperature field in the tropical Atlantic. This approach offers strong evidence that mesoscale patterns are considerably weaker than those indicated in an article previously published in this journal. DOI: 10.1111/j.2153-3490.1967.tb01463.x

Physical review letters 19(15), 869 - 872 (1967). doi:10.1103/PhysRevLett.19.869, Published by APS, College Park, Md.

The surface wind-speed reports in tropical cyclones given by aircraft-reconnaissance observers are based almost exclusively on state-of-sea observations. The reliability of wind estimates prepared in this manner is considered along with some of the practical difficulties involved in making observations from reconnaissance aircraft.

Differential cross sections for electron scattering from hydrogen and deuterium in the deep-inelastic region show that the neutron cross section is significantly smaller than the proton cross section over a large part of the kinematic region studied. Although $\ensuremath{\nu}{{W}_{2}}^{d}$ differs in magnitude from $\ensuremath{\nu}{{W}_{2}}^{p}$, it exhibits a similar scaling behavior.

Radiosonde observations made at Kusaie in the eastern Caroline Islands on May 15–16, 1956, reported tropopause temperatures colder than −86° C. in several instances with an extreme value of −96° C. This series of soundings is examined and compared with those made at other stations in the equatorial Pacific area.

The physical review 161(5), 1344 - 1355 (1967). doi:10.1103/PhysRev.161.1344, Published by Lancaster, Pa. [u.a.]

Differential cross sections for electrons scattered inelastically from hydrogen have been measured at 18\ifmmode^\circ\else\textdegree\fi{}, 26\ifmmode^\circ\else\textdegree\fi{}, and 34\ifmmode^\circ\else\textdegree\fi{}. The range of incident energy was 4.5 to 18 GeV, and the range of four-momentum transfer squared was 1.5 to 21 ${(\frac{\mathrm{GeV}}{c})}^{2}$. With the use of these data in conjunction with previously measured data at 6\ifmmode^\circ\else\textdegree\fi{} and 10\ifmmode^\circ\else\textdegree\fi{}, the contributions from the longitudinal and transverse components of the exchanged photon have been separately determined. The values of the ratio of the photoabsorption cross sections $\frac{{\ensuremath{\sigma}}_{S}}{{\ensuremath{\sigma}}_{T}}$ are found to lie in the range 0 to 0.5. The question of scaling of $2{M}_{p}{W}_{1}$ and $\ensuremath{\nu}{W}_{2}$ as a function of $\ensuremath{\omega}$ is discussed, and scaling is verified for a large kinematic range. Also, a new scaling variable which reduces to $\ensuremath{\omega}$ in the Bjorken limit is introduced which extends the scaling region. The behavior of ${\ensuremath{\sigma}}_{T}$ and ${\ensuremath{\sigma}}_{S}$ is also discussed as a function of $\ensuremath{\nu}$ and ${q}^{2}$. Various weighted sum rules of $\ensuremath{\nu}{W}_{2}$ are evaluated.

Rawin observations made at Kindley AFB, Bermuda on 28 March 1955 reported unusually strong winds in the lower troposphere at two successive observation times. A maximum reported speed of 222 kn was shown at 9000 ft at the top of a strong frontal inversion. The credibility of these observations is examined along with aspects of the general problem of evaluating cases of extremely strong rawin reports.

Physical review letters 20(5), 227 - 230 (1968). doi:10.1103/PhysRevLett.20.227, Published by APS, College Park, Md.

Mean aerological data for the West Indies area have been prepared from ten-year records for three stations. Mean monthly height, temperature and relative humidity data are tabulated for constant pressure surfaces. More detailed information, including density, potential temperature and specific humidity, is shown for the mean annual and the mean “hurricane season” soundings. The mean data are compared with those previously presented and some of the interesting climatological features are discussed.

The cross sections for single-arm inelastic electron-proton scattering were measured near the one-pion threshold for six values of q/sup 2/ between 0.23 and 1.84 GeVd. We determined the cross sections for nonresonant pion production and, using a particular fonnulation of soft-pion theory, extracted the normalized axial-vector form factor of the nucleon, G/sub A// G/sub A/(0) (auth)

Dropsonde data from the eyes of tropical cyclones are used for testing old and deriving new empirical relationships between the surface pressure and the heights of constant-pressure surfaces. The derived regressions are used for the preparation of a nomogram which can be used for estimating surface pressure in the eye of a tropical cyclone from aircraft pressure-height data at any level between the surface and 500 mb. The regressions also provide a basis for some comments on the mean thermal structure of the eye.

Surface pressure observations at stations along the Texas coast during the approach of hurricane Carla of 1961 have been examined in an attempt to determine the extent to which the storm as a whole participated in the irregular motion indicated by the track of the storm center as followed by radar. The pressure variations at coastal stations were found, in general, to correlate rather poorly with changes in the direction and speed of motion of the storm center. The best agreement was shown by the Galveston observations which were made some 100–150 mi. to the right of the storm track.

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Physical review letters 19(15), 865 - 868 (1967). doi:10.1103/PhysRevLett.19.865, Published by APS, College Park, Md.

An unusually large collection of aircraft-reconnaissance data was made in hurricane Daisy on 27 August 1958. These data consist primarily of detailed flight-level information collected by the research aircraft of the National Hurricane Research Project and radar films taken from the operational reconnaissance aircraft of the U. S. Navy. At this time, hurricane Daisy was a small, slow-moving storm off the Florida east coast with winds in excess of 100 kn in the lower troposphere. The concentrated nature of this vortex is clearly shown by the flight-level wind and temperature data and by the weather patterns shown on the radar films. The films from the search radar show a central, ring-like echo only a few miles wide which corresponds closely with the area of maximum observed winds. The height-finding radar shows this central echo—which is associated with the wall cloud surrounding the hurricane eye—to be nearly vertical and to extend above 60,000 ft.

We have measured the large-angle asymmetrical electron-positron pair yields of the reaction γ + C → C + e + + e − and γ + Pd → Pd + e + +e − . As a means of determining the phase and magnitude of virtual Compton scattering amplitude at high energies (4–6 GeV) on complex nuclei. The first reaction was studied at an invariant pair mass m = m ϱ , the mass of ϱ O ; the second reaction over a mass interval 300 ⩽ m ⩽ 550 MeV.

We have measured the yield of electron-positron pairs from the reaction $\ensuremath{\gamma}+\mathrm{C}\ensuremath{\rightarrow}{e}^{+}+{e}^{\ensuremath{-}}+\mathrm{C}$ as a test of the validity of quantum electrodynamics at very small distances. Our results show that first-order quantum electrodynamics correctly predicts the ${e}^{+}{e}^{\ensuremath{-}}$ pair yield up to an invariant pair mass of 900 MeV/${\mathit{c}}^{2}$.

DOI: 10.1111/j.2153-3490.1955.tb01151.x

Prior to the extensive exploration of the upper air, short-range forecasting was based on the polar-front theory of wave cyclones developed by the Norwegians during World War I. According to this theory, extratropical cyclones are regarded as waves travelling along sloping fronts between cold air masses of polar origin and warm air masses originating in tropical regions. As a result of shearing instability along the fronts, these waves increase in amplitude and eventually develop into closed vortices.

In the two years that have passed since completion of the preceding chapters, active research on the jet stream has continued in many countries. The observational evidence of jet stream structure has drawn the widest attention. It is particularly gratifying to note that measurements in jet streams by means of research aircraft traverses have been begun in Great Britain and by the United States military forces. Harding [125] has described the Navy’s program, and Widger et al. [153] that of the Air Force. These flights are eliminating the most serious deficiency of past research efforts, namely that wind profiles or cross sections had to be based mainly on geostrophic or gradient wind calculations and that reliable winds to check these calculations were seldom available.