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Physicians diagnose subjectively the etiology of inaccessible infections where sampling is not feasible (such as, pneumonia, sinusitis, cholecystitis, peritonitis), as bacterial or viral. The diagnosis is based on their experience with some medical markers like blood counts and medical symptoms since it is harder to obtain swabs and reliable laboratory results for most cases. In this study, infrared spectroscopy with machine learning algorithms was used for the rapid and objective diagnosis of the etiology of inaccessible infections and enables an assessment of the error for the subjective diagnosis of the etiology of these infections by physicians. Our approach allows for diagnoses of the etiology of both accessible and inaccessible infections as based on an analysis of the innate immune system response through infrared spectroscopy measurements of white blood cell (WBC) samples. In the present study, we examined 343 individuals involving 113 controls, 89 inaccessible bacterial infections, 54 accessible bacterial infections, 60 inaccessible viral infections, and 27 accessible viral infections. Using our approach, the results show that it is possible to differentiate between controls and infections (combined bacterial and viral) with 95% accuracy, and enabling the diagnosis of the etiology of accessible infections as bacterial or viral with94% sensitivity and90% specificity within one hour after the collection of the blood sample with error rate6%. Based on our approach, the error rate of the physicians' subjective diagnosis of the etiology of inaccessible infections was found to be23%.

Human viral and bacterial infections are responsible for a variety of diseases that are still the main causes of death and economic burden for society across the globe. Despite the different responses of the immune system to these infections, some of them have similar symptoms, such as fever, sneezing, inflammation, vomiting, diarrhea, and fatigue. Thus, physicians usually encounter difficulties in distinguishing between viral and bacterial infections on the basis of these symptoms. Rapid identification of the etiology of infection is highly important for effective treatment and can save lives in some cases. The current methods used for the identification of the nature of the infection are mainly based on growing the infective agent in culture, which is a time-consuming (over 24 h) and usually expensive process. The main objective of this study was to evaluate the potential of the mid-infrared spectroscopic method for rapid and reliable identification of bacterial and viral infections based on simple peripheral blood samples. For this purpose, white blood cells (WBCs) and plasma were isolated from the peripheral blood samples of patients with confirmed viral or bacterial infections. The obtained spectra were analyzed by multivariate analysis: principle component analysis (PCA) followed by linear discriminant analysis (LDA), to identify the infectious agent type as bacterial or viral in a time span of about 1 h after the collection of the blood sample. Our preliminary results showed that it is possible to determine the infectious agent with high success rates of 82% for sensitivity and 80% for specificity, based on the WBC data.

Rapid identification of bacterial infection is very important and in many cases can save human life. Many pathogens can cause infections. While these infections share identical symptoms, the immune system responds differently to these pathogens. The current microbiology lab methods used to diagnose the infection type are time consuming (2-4 days). Thus, physicians may be tempted to start unnecessary antibiotic treatment, based on their wrong diagnosis (based on experience) of the infection. Uncontrolled use of antibiotics is the main driving force for the development of multi drug resistant bacteria which is considered a global health problem. We hypothesize that the different responses of the immune system to the infecting pathogens, cause some minute biochemical changes in the blood componentsthat can be detected by infrared spectroscopy which is known as a fast, accurate, sensitive and low cost method. In this study, we used infrared microscopy to measure the vibrational spectra of white blood cells (WBC) samples of 105 infected patients (69 bacterial and 36 with viral infection) and 90 controls (non-infected patients). The obtained spectra were analyzed using machine learning algorithms to identify the infection type as bacterial or viral in a time span of less than one hour after blood sample collection. Our study results showed that it is possible to determine the infection type with high success rates of 93% sensitivity and 85% specificity, based solely on WBC obtained from simple peripheral blood samples.

Correction for ‘Diagnosis of inaccessible infections using infrared microscopy of white blood cells and machine learning algorithms’ by Adam H. Agbaria et al., Analyst, 2020, DOI: 10.1039/D0AN00752H.

article i nfo Polarization of the plasma luminescence produced by both nanosecond and femtosecond laser ablation of Si(111) was analyzed under different conditions of fluence and detection geometry. It is shown that the lu- minescence is partially polarized and is directed in the plane of the crystal. The time evolution of the plasma emission signal was also investigated with the use of a streak camera. The mechanism for polarization is pro- posed to be preferential reflection of s-polarized light (i.e., light polarized normal to the plane of laser inci- dence) by the melted surface, in agreement with the Fresnel equations. Earlier reports of much stronger polarization are shown to be erroneous.

Multiple layers of GaN/AlN quantum dot (QD) ensembles were grown by the Stranski-Krastanov method on Si(111) using molecular beam epitaxy. During the subsequent cooling from growth temperature, the thermal expansion coefficient mismatch between the Si substrate and GaN/AlN film containing the vertically stacked QDs leads to an additional biaxial tensile stress of 20–30 kbar in the III-nitride film. We have selectively modified the thermal stress in the QD layers by etching a cross-hatched pattern into the as-grown sample using inductively coupled Cl2/Ar plasma reactive ion etching. The results show that a suitable choice of stripe width from ∼2 to 10 μm and orientation along [11-20] and [1-100] can create regions of in-plane uniaxial stress that enable a selective and local control of the polarized luminescence from ensembles of QDs which were probed with cathodoluminescence. A theoretical modelling of the effects of carrier filling on the polarization anisotropy and the excitonic transition energy was performed, as based on three dimensional self-consistent solutions of the Schrodinger and Poisson equations using the 6 × 6 k·p method (© 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)

The Mn-doped CdS nanocrystals encapsulated by carbon (Cd1−xMnxS/C) were synthesized by a one-step, kinetically controlled, solid-state reaction under autogenic pressure at elevated temperatures. The ∼50 nm wurtzite Cd1−xMnxS core was encapsulated by a 5−11 nm disordered carbon shell, and with the increase in Mn concentration, a gradual change from isotropic nanocrystals to one-dimensional nanorods was observed. Electron paramagnetic resonance studies showed that Mn2+ could be efficiently doped into the CdS lattice up to a Mn:Cd atomic ratio of 0.012. The 0.9−1.8 atomic % manganese-doped CdS samples were found to be ferromagnetic at room temperature, and the magnetic moment did not saturate even at 2 K, likely due to the coexistence of superparamagnetic fractions and antiferromagnetic coupling between the Mn2+ spins. The lowest-doped samples (Mn:Cd = 0.009 and 0.012) display the highest magnetic moments (4.43 ± 0.04 and 4.52 ± 0.04 μB/Mn), respectively. The more concentrated samples exhibit weaker magnetic...

Zn(x)Cd(1-x)Se/C core/shell nanocrystals with 31-39 nm semiconducting core and 11-25 nm carbon shell were synthesized from solid state precursors in large scale amounts. A mixture of spherical and tripod nanostructures were obtained only in the one-step reaction (ZC3), where the Zn- and Cd-precursors were reacted simultaneously, rather than in the two step reactions (ZC1 and ZC2), where largely spherical nanostructures were observed. Rietveld analysis of the X-ray diffraction patterns of the samples prepared in three different ways, all under their autogenic pressure, reveal varying compositions of the Zn(x)Cd(1-x)Se nanocrystal core, where the cubic phases with higher Zn content were dominant compared to the hexagonal phases. Carbon encapsulation offers excellent protection to the nanocrystal core and is an added advantage for biological applications. Cathodoluminescence (CL) measurements with spatially integrated and highly localized excitations show distinct peaks and sharp lines at various wavelengths, representing emissions from single nanostructures possessing different compositions, phases, and sizes. Transmission electron microscopy (TEM) showed striations in the nanocrystals that are indicative of a composition modulation, and possibly reveal a phase separation and spinodal decomposition within the nanocrystals. Thermal quenching of the luminescence for both the near band-edge and defect related emissions were observed in the range 60-300 K. The measured activation energies of ∼50-70 meV were related to the presence of shallow donors or acceptors, deep level emissions, and thermal activation and quenching of the luminescence due to the thermal release of electrons from shallow donors to the conduction band or a thermal release of holes from shallow acceptors to the valence band. Spatially integrated CL spectra revealed the existence of broadening and additional components that are consistent with the presence of a composition modulation in the nanocrystals. Spatial localization of the emission in isolated single nanocrystals was studied using monochromatic CL imaging and local CL spectroscopy. CL spectra acquired by a highly localized excitation of individual nanocrystals showed energy shifts in the excitonic luminescence that are consistent with a phase separation into Zn- and Cd-rich regions. The simultaneous appearance of both structural and compositional phase separation for the synthesis of Zn(x)Cd(1-x)Se nanocrystals reveals the complexity and uniqueness of these results.

Molecular mechanics calculations of the cyclic tetrapeptide ring system for the cis, trans, cis, trans amide bond sequences for cyclo tetraglycine and cyclo tetraalanine have been carried out. A systematic search of conformational space was carried out by using Still's RINGMAKER in an attempt to find the global minimum for each amide bond sequence. Ring system structures were optimized by using the BAKMOD program. A comparison of 11 experimentally determined cyclic tetrapeptide conformations with the lowest energy calculated conformations showed that only 4 of 11 known cyclic tetrapeptides adopted the lowest energy conformation. However, when the destabilization energy between cyclo tetraalanine and cyclo tetraglycine was calculated, 10 of the 11 experimentally determined conformations for cyclic tetrapeptides with alternating cis, trans, cis, trans amide bond sequences adopted the conformations with the least de-stabilization energy. The relationship between the molecular mechanics calculations and empirical rules for predicting cyclic tetrapeptide conformations is discussed.

The conformations of chlamydocin and cyclo (Ala-Aib-Phe-D-Pro) (Ala4-chlamydocin) in chloroform have been investigated by nuclear magnetic resonance, infrared and circular dichroism spectroscopy. The data obtained from these experiments establish an all transoid, bis gamma-turn conformation for both compounds in chloroform with the following torsional angles (+/- 20 degrees): Ala4-chlamydocin: Aib, phi + 60 degrees, psi - 50 degrees; omega + 160 degrees; Phe phi - 120 degrees, psi + 120 degrees, omega - 160 degrees; D-Pro phi + 60 degrees, psi - 55 degrees, omega + 160 degrees; Ala phi - 110 degrees, psi + 110 degrees, omega - 160 degrees. Chlamydocin adopts a closely related conformation in neat chloroform. Nuclear Overhauser Effect (NOE) data are utilized to assign amide bond geometries in the cyclic tetrapeptide ring system.

Botulinum neurotoxin (BoNT) metalloproteases and related proteases are the most selective proteases known. X-ray crystal structures suggest that the active sites of the native enzymes exist in catalytically incompetent forms that must be activated by substrate binding. In order to characterize the postulated substrate-induced conformational changes for enzyme activation, we synthesized a series of transition-state analog inhibitors in which the dipeptide cleavage site is replaced by tetrahedral intermediate analogs within the minimal substrate peptide sequence. In this paper, we report our efforts to design inhibitors of BoNT/A metalloprotease. We confirm that an effective substrate sequence for BoNT/A metalloprotease is a 17-mer peptide corresponding to residues 187-203 of SNAP-25. A more stable substrate, Nle202SNAP-25 [187-203] was synthesized in order to develop an assay for proteolytic activity of BoNT/A metalloprotease that can be used to monitor time-dependent inhibition. Alpha-thiol amide analogs of Gln-197 were incorporated via solid-phase peptide synthesis into both 17-mer minimal peptide substrate sequences. The synthesis, characterization and inhibition kinetics for the alpha-thiol amide analogs of holotoxin A substrate are described. These substrate-derived inhibitors were shown to be submicromolar inhibitors of BoNT/A catalytic activity.

The carbon-encapsulated, Mn-doped ZnSe (Zn1−xMnxSe@C) nanowires, nanorods, and nanoparticles are synthesized by the solvent-free, one-step RAPET (reactions under autogenic pressure at elevated temperature) approach. The aspect ratio of the nanowires/nanorods is altered according to the Mn/Zn atomic ratio, with the maximum being observed for Mn/Zn = 1:20. A 10–20 nm amorphous carbon shell is evidenced from electron microscopy analysis. The replacement of Zn by Mn in the Zn1−xMnxSe lattice is confirmed by the hyperfine splitting values in the electron paramagnetic resonance (EPR) experiments. Raman experiments reveal that the Zn1−xMnxSe core is highly crystalline, while the shell consists of disordered graphitic carbon. Variable-temperature cathodoluminescence measurements are performed for all samples and show distinct ZnSe near-band-edge and Mn-related emissions. An intense and broad Mn-related emission at the largest Mn alloy composition of 19.9% is further consistent with an efficient incorporation of Mn within the host ZnSe lattice. The formation of the core/shell nanowires and nanorods in the absence of any template or structure-directing agent is controlled kinetically by the Zn1−xMnxSe nucleus formation and subsequent carbon encapsulation. Mn replaces Zn mainly in the (111) plane and catalyzes the nanowire growth in the [111] direction.

Spatially, spectrally, and depth-resolved cathodoluminescence (CL) measurements were performed for high-quality thin AlN films grown on Si(111). Cl spectra exhibited a sharp peak at 5.960 eV, corresponding to the near-band-edge excitonic emission of AlN. Depth-resolved CL analysis showed that deep level oxygen and carbon impurities are localized primarily at the AlN/Si interface and AlN outer surface. Monochromatic CL imaging of the near-band-edge emission exhibits a spotty pattern, which corresponds to high concentrations of threading dislocations and thermally induced microcracks in the thin layers. We have examined relief of the thermal stress in close proximity to single microcracks and intersecting microcracks. Local CL spectra acquired with a focused e-beam show blue-shifts as large as ∼82 meV in the AlN near-band edge excitonic peaks, reflecting defect-induced reductions in the biaxial thermal stress, which has a maximum value of ∼47 kbar.

[structure: see text] The protected Gln-Phe hydroxyethylene dipeptide isostere 1 was synthesized as a precursor for preparation of potential inhibitors of Botulinum neurotoxin B metalloprotease. The method allows for the synthesis of additional hydroxyethylene dipeptide isosteres such as 2 with functionalized P1 side chains. The isosteres prepared were coupled with a dipeptide to produce protected pseudotetrapeptide derivatives.

We have examined in detail the optical properties of InGaN quantum wells (QWs) grown on pyramidal GaN mesas prepared by lateral epitaxial overgrowth (LEO) in a metalorganic chemical vapor deposition system that resulted in QWs on {1-101} facets. The effects of In migration during growth on the resulting QW thickness and composition were examined with transmission electron microscopy (TEM) and various cathodoluminescence (CL) imaging techniques, including CL wavelength imaging and activation energy imaging. Spatial variations in the luminescence efficiency, QW interband transition energy, thermal activation energy, and exciton binding energy were probed at various temperatures. Cross-sectional TEM was used to examine thickness variations of the InGaN/GaN QW grown on a pyramidal mesa. CL imaging revealed a marked improvement in the homogeneity of CL emission of the LEO sample relative to a reference sample for a conventionally grown In0.15Ga0.85N/GaN QW. The characteristic phase separation that resulted in ...

The past and present role of peptidomimetics to drug discovery and protein design is summarized. The historical evolution of this area of research and the current state-of-the-art research strategies are described. A detailed description of each of the peptidomimetics types that have appeared in the literature so far is discussed. Some examples are used to illustrate the drug design process that proceeds from the native peptide to a completely non-peptide peptidomimetic structure. Special attention is given to important pharmaceutical targets such as the cysteine, metallo, serineor aspartic proteases, integrins, G-protein–coupled receptors, etc. The principles currently used are highlighted in the discussions of some of the most successful examples. It is obvious that major progress in this area is primarily derived of recent advances in all aspects of science. Molecular modeling, X-ray crystallography, and high field NMR have greatly contributed to this endeavor. Peptidomimetic inhibitors were traditionally developed by modifying peptide bonds, by mimicking the transition states for enzyme-catalyzed reactions, or by constraining the conformational mobility of a peptide-derived chain; the latter was used to overcome some of the pharmacokinetic barriers encountered in using peptides as drugs. Lately, these difficulties have been partially solved with rational drug design of de novo compounds. Several methods have been successfully applied, with noteworthy examples currently in clinical trials, and many others are expected in the near future. It would be wrong, however, to imply that this process is a universal panacea. New ideas are urgently needed to produce clinical candidates faster and to solve some of the undesired pharmacokinetic issues. Keywords: peptidomimetic; conformationally restricted; template; isosteres; transition state; drug design; GRAB peptidomimetic; peptidase inhibitor; GPCR inhibitors

[reaction: see text]. General stereocontrolled synthesis of all four (2,3)-stereoisomers of 2-substituted statines is described. The 2,3-syn and 2,3-anti isomers were synthesized via beta-ketoester reduction and aldol reactions, respectively. Peptides containing 2-substituted statines inhibit porcine pepsin with nanomolar IC50 values.

Novel tripeptide-derived peptidomimetics 1, 7ab, and 8ab, inspired by templates generated by the structure-generating program GrowMol, were synthesized, shown to inhibit Rhizopus chinensis pepsin, and found by X-ray crystallography to bind to the enzyme in the GrowMol-predicted mode. Repetitive evaluation of the computer-generated templates for synthetic feasibility and optimal enzyme interactions led to the designed compounds.

[reaction: see text] The 3-alkoxy-4-arylpiperidine inhibitors of aspartic peptidases are shown to be a new type of non-peptide peptidomimetic inhibitor. These piperidines can be designed from peptide-derived inhibitors by use of a structure-generating program but only after the enzyme active site conformation has been modified in a mechanistically related fashion. New enantioselective syntheses of 3-alkoxy-4-arylpiperidine analogues are described.

InGaN/GaN quantum wells (QW) were grown by metalorganic chemical vapor deposition (MOCVD) on pyramids of epitaxial lateral overgrown (ELO) GaN samples. The ELO GaN samples were grown by MOCVD on sapphire (0001) substrates that were patterned with a SiNx mask. Scanning electron microscopy and cathodoluminescence (CL) imaging experiments were performed to examine lateral variations in structure and QW luminescence energy. CL wavelength imaging (CLWI) measurements show that the QW peaks on the top of the grooves are red-shifted in comparison with the QW emission from the side walls. The results show that In atoms have migrated to the top of the pyramids during the QW growth. The effects of V/III ratio, growth temperature as well as ELO GaN stripe orientation on the QW properties are also studied.

[formula: see text] Two syntheses of a model system of the DEF ring system of complestatin and chloropeptin are described. The key step in both of these syntheses involves the formation of the biaryl linkage using a palladium-catalyzed Suzuki cross-coupling reaction and a catalytic enantioselective ene reaction to form the 6-bromo-D-tryptophan. Additionally, ring contraction of the 17-membered DEF ring system of complestatin generates the 16-membered DEF ring system of chloropeptin in a biomimetic fashion.

A new method to obtain pure zymogen-derived peptidases is presented. The key strategy is to install a polyhistidine peptide tag on the N-terminus of the propeptide sequence of a zymogen. After expression, purification, and folding of the protein, autocatalytic posttranslational cleavage and filtration through a nickel affinity column gives pure, functional peptidase. This method takes advantage of the nickel affinity chromatography system that removes both zymogen peptide and nonfunctional folded peptidase without the need to use external enzymes to remove, often incompletely, the resulting fusion peptide. This technique was used to prepare the aspartic peptidase rhizopuspepsin. His-tagged rhizopuspepsinogen was expressed, and the desired protein was isolated as inclusion bodies and refolded. The proenzyme was purified by normal methods and then the relatively pure proenzyme was activated via intramolecular proteolysis at low pH. The propeptide and any inactive rhizopuspepsinogen were removed via affinity chromatography. This procedure yields a highly active rhizopuspepsin in 99% purity, which was demonstrated by PAGE, protein sequencing, and X-ray crystallography (1.5 A) of the isolated peptidase. A new fluorescent assay system is introduced for rhizopuspepsin, utilizing the substrate KPVSY(4-NO(3)-F)RL. The kinetics constants were K(m) = 3.4 microM +/- 0.31 and k(cat) = 55 +/- 1.0 s(-1).

Reductions of a series of highly hindered α,α-disubstituted amino esters to the corresponding amino alcohols were accomplished using the BuLi-DIBAl “ate complex”. In addition, the novel amino acid a-benzyl histidine was reduced via α persilylation/LAH reduction protocol.

We have examined the optical properties of self-assembled InAs quantum dots (QDs) grown on prepatterned GaAs(001) substrates with polarization sensitive and time-resolved cathodoluminescence (CL) imaging and spectroscopy techniques. The InAs QDs were formed using a novel application in self-assembled molecular beam epitaxial growth, which entailed the growth of InAs on preformed [110]-oriented stripe mesas. Interfacet In adatom migration occurred along the stripe side-walls during growth, enabling the selective formation of linear arrays of InAs QDs on the stripe mesas. The total InAs deposition needed to induce the two-dimensional to three-dimensional morphology change on the stripes is less than that required to initiate QD formation on the unpatterned substrates. The QDs formed on the mesa top were found with a luminescence distribution redshifted relative to QDs in the valley region, indicating that QDs with a larger average size were formed on the mesa top. The lower density of QDs in the valley region led to a weaker emission and sharper δ-like transitions at lower beam currents, relative to emission from QDs on the mesa. CL imaging was employed to study the spatial distribution of luminescence and identified the presence of relatively small QDs situated near the edges of the valley region along the lower surface of the stripe edges. An excitation- and energy-dependent polarization anisotropy relative to the 〈110〉 directions was observed in CL emission. A polarization anisotropy reversal was found between CL from QDs on the mesa and in the valley regions, revealing the importance of the stress anisotropy in both the formation of QDs and their subsequent optical properties. The CL was examined as a function of temperature to evaluate the thermal re-emission of carriers and the associated activation energies. The carrier relaxation kinetics were studied with time-resolved CL to measure differences in the CL onset and decay rates for QDs in the valley and mesa regions.

(3R)-amino-(2S)-hydroxy heptanoic acid (AHHpA) was synthesized via asymmetric aminohydroxylation and coupled with di-and tripeptides to form three compounds that inhibit MetAP-1 with IC50 values in the low micromolar range.

Defect formation and In segregation in InGaN/GaN quantum wells grown at various temperatures and with various well thicknesses were studied using cathodoluminescence, transmission electron microscopy (TEM) and high-resolution transmission electron microscopy (HR-TEM). In 0.16 Ga 0.84 N quantum wells with In compositional nonuniformity and a small number of structural defects originating at the InGaN/GaN interface showed sharp and intense InGaN emission in cathodoluminescence (CL). Increasing the In composition caused surface roughness in the InGaN layer and the formation of stacking faults/dislocations originating at InGaN/GaN interface. This resulted in a reduction of the InGaN emission peak intensity. ( 1998 Elsevier Science B.V. All rights reserved.

We have examined the optical properties of self-assembled InAs quantum dots (QDs) with polarization sensitive and time-resolved cathodoluminescence (CL) techniques. The InAs QDs were formed via self-assembly during molecular beam epitaxial growth of InAs on unpatterned GaAs(001). CL spectra exhibited a two-component line shape whose linewidth, intensity, and peak positions were found to be temperature and excitation dependent. The two components are found to be consistent with state filling of the QDs, resulting in emission involving ground state and excited state excitonic transitions. The luminescence intensities and lineshapes of the QD and wetting layer (WL) excitonic transitions were analyzed with constant excitation and time-resolved CL for various temperatures and excitation levels to study the thermal activation, re-emission, and recombination kinetics of carriers. Thermal quenching of the QD ground state and excited state components in the 105–175 K range is correlated with a rise in the WL emiss...

GaAs/AlGaAs quantum wells (QWs), selectively disordered using an AlAs native oxide and thermal annealing technique, were studied using spectrally, spatially, and temporally resolved cathodoluminescence (CL). The spectral shift of the QW luminescence was determined as a function of annealing temperature in the oxide and nonoxide regions. Time-resolved CL was used to assess the impact of defects and the built-in field near the oxide/nonoxide transition region on the carrier lifetime. Spatially resolved CL spectroscopy was used to examine changes in the QW luminescence intensity near the transition region. The carrier lifetime was found to increase in the transition region, owing to the enhanced spatial separation of electrons and holes in this region. From CL images and line scans of three samples annealed at different temperatures, a partial dead region is found between oxide and nonoxide regions. Details of the native oxide formation are discussed.

We demonstrate that single-crystal hexagonal GaN can be grown by metal-organic chemical vapor deposition on an aluminum oxide compound (AlO x ) layer utilized as an intermediate layer between GaN and a Si(1 1 1) substrate. The surface morphology of GaN grown on the AlO x /Si(1 1 1) substrate is found to be very sensitive to both the GaN buffer-layer thickness and the AlO x thickness. Contact mode atomic force microscopy (C-AFM) observation indicates that the AlO x surface is composed of domain-like features with varying surface heights. A possible clue for a mechanism by which single crystal GaN grows on AlO x is discussed by comparing the domain-like surface features observed by C-AFM.

Cyclophilins are a family of proteins that bind cyclosporin A (CsA) and possess peptidyl-prolyl cis-trans isomerase activity. In addition, they are secreted by activated cells and act in a cytokine-like manner, presumably via signaling through a cell surface cyclophilin receptor. More recently, host-derived cyclophilin A (CyPA) has been shown to be incorporated into HIV-1 virions and its incorporation essential for viral infectivity. Here we present evidence supporting a role for viral-associated CyPA in the early events of HIV-1 infection. We report that HIV-1 infection of primary peripheral blood mononuclear cells can be inhibited by: (i) an excess of exogenously added CyPA; (ii) a CsA analogue unable to enter the cells; (iii) neutralizing antibodies to CyPA. Taken together with our observations that recombinant CyPA-induced mobilization of calcium in immortalized, as well as primary, CD4+T lymphocytes, and that incubation of T cells with iodinated CyPA, followed by chemical cross-linking, resulted in the formation of a high molecular mass complex on the cell surface, these results suggest that HIV-1-associated CyPA mediates an early event in viral infection via interaction with a cellular receptor. This interaction may present a target for anti-HIV therapies and vaccines.

We have studied time-resolved cathodoluminescence (CL) and electron beam induced current (EBIC) on AlGaAs/GaAs/InGaAs heterojunction phototransistors under operating conditions, i.e., at room temperature and under bias. Devices from four wafers, with a different amount of lattice relaxation, were tested. It is shown that the CL intensity increases more than one order of magnitude as the voltage is increased and the current gain of the device turns on. The voltage dependence of the CL signal is analogous to the current–voltage curve of the transistor. The buildup in CL intensity was found to be much less in devices with low current gain showing that the CL intensity correlates to the electrical gain of the device. Time resolved CL showed two distinct CL decay times, one very short, a few nanoseconds, and one long, of the order of microseconds. This indicates that two fundamental recombination processes are present, which we attribute to a spatially direct recombination between carriers in the base and a sp...

Intramolecular nucleophilic aromatic substitution (SNAr) of preformed ruthenium cyclopentadienyl cationic peptidyl π-complexes forms cyclic biphenyl ethers in convenient, high-yielding reactions. The utility of the method was demonstrated by the efficient convergent total synthesis of two natural products, K-13 and OF4949-III. Several analogs of K-13 and OF4949-I−IV were synthesized in high yields, and one ring system that could not be prepared by a macrolactamization method was formed in high yield by biaryl ether formation from peptidyl ruthenium complexes. Direct comparisons between these two approaches are provided. Transition metal π-complexes of either N-protected or carboxyl-protected amino acids can be used as coupling partners in peptide coupling reactions. Preformed peptidyl ruthenium complexes can be used to synthesize cyclic biphenyl ethers in a combinatorial fashion.

The optical properties of (InP)2/(GaP)2 bilayer superlattice (BSL) structures have been examined with linearly polarized cathodoluminescence (CL), time-resolved CL spectroscopy, and cathodoluminescence wavelength imaging. An In and Ga composition modulation of ∼18% forms during the metalorganic chemical vapor deposition growth of short period (InP)2/(GaP)2 bilayer superlattices. Transmission electron microscopy showed a period of ∼800 A along the [110] direction, resulting in coherently strained quantum wires. A strong excitation dependence of the polarization anisotropy and energy of excitonic luminescence from the quantum wires was found. The results are consistent with a phase-space and band filling model that is based on a k⋅p and two dimensional quantum confinement calculation which takes the coherency strain into account. CL images reveal that defects in the BSL originate from the GaAs substrate and/or the initial stages of InGaP growth. The effects of defects on the band filling, carrier relaxation...

We report on (a) the effect of growth interruption on the growth profile evolution in growth on non-planar patterned mesa tops via substrate-encoded size-reducing epitaxy (SESRE) and (b) the optical behavior of isolated 3D-confined GaAs volumes as well as 3D-confined GaAs volumes coupled with 1D-confined quantum wells (QWs) fabricated by SESRE. Steady-state excitation and time-resolved cathodoluminescence (CL) are used for these optical studies.

We have examined the kinetics of carrier relaxation in GaAs/AlGaAs quantum wells (QWs), quantum wires (QWRs), and quantum boxes (QBs) with time-resolved cathodoluminescence (CL). In the cases of QWRs and QBs, the nanostructures were grown via a size-reducing growth approach on pre-patterned GaAs(001) substrates composed of stripes and mesas, respectively. The growth involved deposition of multiple GaAs/AlGaAs layers in order to establish both structural and optical markers which facilitated the identification of important features in transmission electron microscopy (TEM) and CL experiments. In TEM measurements, the lateral dimensions of the top-most GaAs layers in typical stripe and mesa structures comprising the QWRs and QBs delineate GaAs regions expected to exhibit 2D and 3D quantum confinement effects, respectively. Time-delayed CL spectra of all three structures reveal that the initial capture of carriers in the active regions occurs on a time scale less than the temporal resolution of the CL system...

We have examined carrier thermalization, recombination, and band filling in GaAs/AlGaAs quantum boxes with low-temperature cathodoluminescence (CL). The temperature dependence of the quantum box CL intensity for T⩽ 90 K exhibits an Arrhenius behavior, as a result of carrier thermalization between the quantum box and surrounding barrier regions. The width of the quantum box luminescence is found to increase rapidly with an increasing excitation density and reveals an enhanced phase-space and real-space filling, in comparison to the behavior observed for quantum wells.

We have studied the influence of structural defects on the spatial variation of radiative and nonradiative recombination in an InGaAs/AlGaAs/GaAs resonant cavity enhanced npn heterojunction phototransistor (HPT) structure using cathodoluminescence (CL) and electron beam‐induced current (EBIC) imaging. Absorber layers of InGaAs/GaAs multiple quantum wells (MQWs) are used to provide the photosensitivity for light with wavelengths that are transparent to the GaAs substrate. The current gain of the HPT under an applied bias voltage depends on the hole accumulation efficiency in the base and therefore on the hole lifetime. Strain relaxation‐induced misfit dislocations in the MQWs are found to create regions of enhanced nonradiative recombination thereby reducing locally the hole accumulation efficiency and current gain. The reduction in the local EBIC signal caused by the dark line defects is less than ∼20%, suggesting that misfit dislocations in this sample have a relatively small impact on overall device per...

The effects of strain‐induced structural defects in a nipi‐doped In0.2Ga0.8As/GaAs multiple‐quantum well sample were studied with time‐resolved electron‐beam‐induced absorption modulation, in which carrier recombination lifetimes and ambipolar diffusion constants are measured with high spatial, spectral, and temporal resolution. Based on a phenomenological model, carrier lifetimes in the limit of weak excitation at room temperature were determined. The lifetime is found to be reduced by a factor of ∼1013 compared to a theoretically calculated value, owing to the presence of strain‐induced defects and alternate recombination channels. By using a two‐dimensional diffusion model, the ambipolar diffusion coefficients Da along high‐symmetry [110], [110], and [100] directions were determined and resulted in an anisotropic behavior such that D[110]a≳D[110]a ≳D[100]a. The anisotropy in diffusion is attributed to corresponding asymmetries in the misfit dislocation density.

The proteinase from HIV undergoes rapid and irreversible deactivation caused by mild mechanical stirring. Both the free enzyme and the ternary Michaelis complex disappear in two separate first-order processes, with half-times of 3.0 and 0.8 minutes, respectively. Ignoring these deactivation steps distorts the results of kinetic analyses.

The temperature dependence of the cathodoluminescence (CL) originating from In0.21Ga0.79As/GaAs multiple quantum wells has been studied between 86 and 250 K. The CL intensity exhibits an Arrenhius‐type dependence on temperature (T), characterized by two different activation energies. The influence of misfit dislocations and point defects associated with strain relaxation on the thermal quenching of luminescence has been investigated, and the spatial variation in the activation energies has been examined. The CL intensity dependence on temperature for T≲150 K is controlled by thermally activated nonradiative recombination. For T≳150 K the decrease in CL intensity is largely influenced by thermal re‐emission of carriers out of the quantum wells.

Four analogs of cyclosporin A (CsA) were synthesized to determine if the biological activities of CsA analogs generated by multiple amino acid replacements are predictable from the effects on biological activity of analogs with single residue changes. CsA analogs [Phe 7 ]CsA (8a), [D-MeAla 3 ,Phe 7 ]CsA (8b), [D-Ser 8 ,Phe 7 ]CsA (8c), and [D-MeAla 3 ,Phe 7 ,D-Ser 8 ]CsA (8d) were designed by modification of positions 3, 7, and 8, which are adjacent to one effector region of the cyclophilin-bound CsA complex. The syntheses of CsA analogs 8a-d were carried out by suitable modifications of the reported strategy. Each analog was characterized by NMR in deuterated chloroform and DMSO solutions, and their biological activities as inhibitors of cis-trans-peptidyl prolyl isomerase (PPIase), inhibitors of proliferation in BDF1 mouse spleen cells stimulated with concanavalin A (Con A), and inhibitors of IL-2 release stimulated with PMA/ionomycin by Jurkat cells were determined. Incorporation of the phenylalanine residue in position 7 diminished activities 5-8-fold. Substitution at position 3 decreased activity nearly 2-fold, and substitution at position 8 did not lower activities. However, when all three modifications (D-MeAla 3 , Phe 7 , and D-Ser8) were incorporated into one molecule, the resulting analog, 8d, was found to bind more tightly to cyclophilin than CsA (K i = 3 ± 1.5 vs 6 ± 2 nM) and to produce the full immunosuppressive effect in the other assay systems. Our structure-activity results show that combinations of substitutions that individually lower PPIase or immunosuppressive activity produce fully active analogs when combined in a single compound. These results suggest that other, multimodified CsA derivatives may be discovered that possess excellent or improved immunosuppressive activities even though they contain a substitution that otherwise reduces immunosuppressive activity

The apparent binding constant (K i ) and the first order rate constant of inactivation (k 3 ) have been obtained for EP-475 inhibition of papain at partially saturating concentrations of inhibitor and various substrate concentrations by global analysis of the data. The value of k 3 (k 3 = 0.71 ± 0.25 s −1 ) is larger whereas K i (2.4 ± 0.91 μM) is comparable to or higher than those values for most nucleofuge methylketone inhibitors.

Two series of intramolecularly quenched fluorogenic oligopeptide substrates with the general sequences DABCYL-Lys-Phe-Gly-Gly-Ala-Xxx-EDANS and Abz-Lys-Phe-Gly-Gly-Ala-Xxx-Tyr(m-NO2)-NH2 have been used to explore the effect of P3′ substituents and donor/acceptor pairs on the kinetic parameters for papain-catalyzed hydrolysis. The steady-state constants are moderately affected by amino acid or fluorophore/quencher replacement. No correlation between the hydrophobicity of the P3′ substituent and the kinetic parameters was found.

A novel class of mechanism-based inhibitors of the serine proteases is developed using epitaxial selection. Tripeptide boronates esterified by an alcohol or alcohols at the boron retain the tight binding to trypsin-like enzymes associated with transition-state analogs and incorporate additional groups that can be utilized for selectivity between proteases. Formed by reaction of a series of alcohols with the inhibitor boronate oxygen(s), the most structurally compatible alcohol-derivatized inhibitors are either selected by binding to the enzyme (epitaxial selection) or assembled by epitaxial reaction on the enzyme surface. Mass spectrometry of the derivatized boronates and X-ray crystallography of the complexes identify the chemical structures and the three-dimensional interactions of inhibitors generated. This scheme also engineers novel, potent (Ki approximately 7 nM), and more specific inhibitors of individual serine proteases, by derivitizations of compounds obtained by epitaxial selection.

The nonlinear optical and transport properties of a nipi‐doped InxGa1−xAs/GaAs multiple‐quantum well sample (x=0.23) has been studied using a novel approach called electron‐beam‐induced absorption modulation (EBIA). The absorption in the sample is modulated as a result of screening of the built‐in electric field in the nipi structure due to excess carrier generation. The change in field causes a Stark shift of the first quantized optical transitions in QWs which are situated in the intrinsic layers. In EBIA, a scanning electron probe is used to locally generate an electron–hole plasma that is used to study the spatial distribution of defects that impede excess carrier transport and reduce the lifetime of spatially separated carriers. The Stark shift in the MQW structure is imaged with micrometer‐scale resolution and is compared with cathodoluminescence imaging results which show dark line defects resulting from strain‐induced misfit dislocations. Theoretical calculations using Airy functions in the transf...

Analogs of the immunosuppressive cyclic undecapeptide cyclosporin A (CsA) with substitutions in positions 1, 4, 6, and/or 11 were rationally designed to possess substantially diminished or no immunosuppressive activity. When these compounds were assayed for their capacity to interfere with the replication of human immunodeficiency virus, some displayed a potent antiviral activity in newly infected cells. However, only CsA could interfere with virus replication in persistently infected cells. One CsA analog with antiviral activity costimulated the phytohemagglutinin-induced production of interleukin 2 by human lymphocytes. Human immunodeficiency virus particles from drug-exposed cells showed lower infectivity than virions from untreated cells. Thus, these nonimmunosuppressive analogs of CsA constitute a promising class of lead compounds to develop drugs for effective treatment of the acquired immunodeficiency syndrome.

Three-dimensionally confined GaAs/AlGaAs and InAs/GaAs structures on 〈100〉 oriented square mesas patterned onto GaAs(001) substrates are realized, in-situ, via size-reducing molecular beam epitaxy. Two stages of mesa top pinch-off involving ∼ {103} and subsequently {101} side facets are revealed. GaAs and InAs quantum boxes with lateral linear dimensions down to 40 nm and confined by AlGaAs and GaAs, respectively, are reported. For InAs, the strain relief in mesas is found to enhance the well known ∼ 2 ML thickness for three-dimensional island formation on unpatterned substrates to, remarkably, > 5 ML for mesa size ∼ 75 nm. Cathodoluminescence emission from the InAs on the mesa top attests to its good optical quality.

We have investigated local variations in the optical properties of ${\mathrm{In}}_{0.06}$${\mathrm{Ga}}_{0.94}$As/GaAs using linearly polarized cathodoluminescence imaging and spectroscopy. The influence of substrate misorientation on the polarization anisotropy of excitonic luminescence in the ${\mathrm{In}}_{0.06}$${\mathrm{Ga}}_{0.94}$As films was examined. Local variations in excitonic polarization anisotropy and emission energy are found to correlate spatially with dark line defects which result from the formation of interfacial misfit dislocations.