Structural Insights to Human Immunodeficiency Virus (HIV-1) Targets and Their Inhibition.

Human immunodeficiency virus (HIV) is a deadly virus that attacks the body's immune system, subsequently leading to AIDS (acquired immunodeficiency syndrome) and ultimately death. Currently, there is no vaccine or effective cure for this infection; however, antiretrovirals that act at various phases of the virus life cycle have been useful to control the viral load in patients. One of the major problems with antiretroviral therapies involves drug resistance. The three-dimensional structure from crystallography studies are instrumental in understanding the structural basis of drug binding to various targets. This chapter provides key insights into different targets and drugs used in the treatment from a structural perspective. Specifically, an insight into the binding characteristics of drugs at the active and allosteric sites of different targets and the importance of targeting allosteric sites for design of new-generation antiretrovirals to overcome complex and resistant forms of the virus has been reviewed.

Limitations to carrier mobility and phase-coherent transport in bilayer graphene.

We present transport measurements on high-mobility bilayer graphene fully encapsulated in hexagonal boron nitride. We show two terminal quantum Hall effect measurements which exhibit full symmetry broken Landau levels at low magnetic fields. From weak localization measurements, we extract gate-tunable phase-coherence times τϕ as well as the inter- and intravalley scattering times τi and τ*, respectively. While τϕ is in qualitative agreement with an electron-electron interaction-mediated dephasing mechanism, electron spin-flip scattering processes are limiting τϕ at low temperatures. The analysis of τi and τ* points to local strain fluctuation as the most probable mechanism for limiting the mobility in high-quality bilayer graphene.

Beam-profile compensation for quantum yield characterisation of Yb-Tm codoped upconverting nanoparticles emitting at 474 nm, 650 nm and 804 nm.

Upconverting nanoparticles (UCNPs) have found widespread applications in biophotonics and energy harvesting due to their unique non-linear optical properties arising from energy transfer upconversion (ETU) mechanisms. However, accurately characterising the power density-dependent efficiency of UCNPs using the internal quantum yield (iQY) is challenging due to the lack of methods that account for excitation beam-profile distortions. This limitation hinders the engineering of optimal UCNPs for diverse applications. To address this, this work present a novel beam profile compensation strategy based on a general analytical rate-equations model, enabling the evaluation of iQY for ETU processes of arbitrary order, such as ETU2, ETU3, and beyond. The method was applied to characterise the ETU2 and ETU3 processes corresponding to the main emission peaks (474 nm, 650 nm, and 804 nm) of a Yb-Tm codoped core-shell ß-UCNP. Through this approach, the transition power density points (which delimit the distinct non-linear regimes of the upconversion luminescence (UCL)), and the saturation iQY values (which are reached at high excitation power densities above the transition points) were determined. The ETU2 process exhibits a single transition power density point, denoted as ρ2, while the ETU3 processes involve two transition points, ρ2 and ρ3. By compensating for the beam profile, we evaluate the iQY of individual lines across a wide dynamic range of excitation power densities (up to 105 W cm-2), encompassing both non-linear and linear regimes of UCL. This study introduces a valuable approach for accurately characterising the iQY of UCNPs, facilitating a deeper understanding of the upconversion and its performance. By addressing excitation beam-profile distortions, this method provides a comprehensive and reliable assessment of the power density-dependent iQY. The results highlight the applicability and effectiveness of this beam profile compensation strategy, which can be employed for a wide range of UCNPs. This advancement opens new avenues for the tailored design and application of UCNPs in various fields, especially for biophotonics.

Graphene-based charge sensors.

We discuss graphene nanoribbon-based charge sensors and focus on their functionality in the presence of external magnetic fields and high frequency pulses applied to a nearby gate electrode. The charge detectors work well with in-plane magnetic fields of up to 7 T and pulse frequencies of up to 20 MHz. By analyzing the step height in the charge detector's current at individual charging events in a nearby quantum dot, we determine the ideal operation conditions with respect to the applied charge detector bias. Average charge sensitivities of 1.3 × 10(-3)e Hz(-1/2) can be achieved. Additionally, we investigate the back action of the charge detector current on the quantum transport through a nearby quantum dot. By varying the charge detector bias from 0 to 4.5 mV, we can increase the Coulomb peak currents measured at the quantum dot by a factor of around 400. Furthermore, we can completely lift the Coulomb blockade in the quantum dot.

Fabrication of coupled graphene-nanotube quantum devices.

We report on the fabrication and characterization of all-carbon hybrid quantum devices based on graphene and single-walled carbon nanotubes. We discuss both carbon nanotube quantum dot devices with graphene charge detectors and nanotube quantum dots with graphene leads. The devices are fabricated by chemical vapor deposition growth of carbon nanotubes and subsequent structuring of mechanically exfoliated graphene. We study the detection of individual charging events in the carbon nanotube quantum dot by a nearby graphene nanoribbon and show that they lead to changes of up to 20% of the conductance maxima in the graphene nanoribbon, acting as a well performing charge detector. Moreover, we discuss an electrically coupled graphene-nanotube junction, which exhibits a tunneling barrier with tunneling rates in the low GHz regime. This allows us to observe Coulomb blockade on a carbon nanotube quantum dot with graphene source and drain leads.

Generalised analytical model of the transition power densities of the upconversion luminescence and quantum yield.

The quantum yield (QY) evaluation of upconverting nanoparticles (UCNPs) is an essential step in the characterisation of such materials. The QY of UCNPs is governed by competing mechanisms of populating and depopulating the electronic energy levels involved in the upconversion (UC), namely linear decay rates and energy transfer rates. As a consequence, at low excitation, the QY excitation power density (ρ) dependence obeys the power law ρn-1, where n represents the number of absorbed photons required for the emission of a single upconverted photon and determines the order of the energy transfer upconversion (ETU) process. At high power densities, the QY transits to a saturation level independent of the ETU process and the number of excitation photons, as a result of an anomalous power density dependence present in UCNPs. Despite the importance of this non-linear process for several applications (e.g., living tissue imaging and super-resolution-microscopy), little has been reported in the literature regarding theoretical studies to describe the UC QY, especially for ETUs with order higher than two. Therefore, this work presents a simple general analytical model, which introduces the concept of the transition power density points and QY saturation to characterise the QY of an arbitrary ETU process. The transition power density points determine where the power density dependence of the QY and the UC luminescence changes. The results provided in this paper from fitting the model to experimental QY data of a Yb-Tm codoped ß-UCNP for 804 nm and 474 nm emissions (ETU2 and ETU3 processes, respectively) exemplify the application of the model. The common transition points found for both processes were compared to each other showing strong agreement with theory, as well as, compared to previous reports when possible.

Electronic excited states in bilayer graphene double quantum dots.

We report tunneling spectroscopy experiments on a bilayer graphene double quantum dot device that can be tuned by all-graphene lateral gates. The diameter of the two quantum dots are around 50 nm and the constrictions acting as tunneling barriers are 30 nm in width. The double quantum dot features additional energies on the order of 20 meV. Charge stability diagrams allow us to study the tunable interdot coupling energy as well as the spectrum of the electronic excited states on a number of individual triple points over a large energy range. The obtained constant level spacing of 1.75 meV over a wide energy range is in good agreement with the expected single-particle energy spacing in bilayer graphene quantum dots. Finally, we investigate the evolution of the electronic excited states in a parallel magnetic field.

Evaluation of relative beam-profile-compensated quantum yield of upconverting nanoparticles over a wide dynamic range of power densities.

The presented work uses a discrete strategy of beam profile compensation to evaluate the local internal quantum yield (iQY) of upconverting nanoparticles (UCNPs) at the pixel level of the beam profile using a compact CMOS camera. The two-photon process of upconversion with a central emission peak at 804 nm was studied for a ß-phase core-shell Tm-codoped UCNP under 976 nm excitation. At the balancing power density point, ρb, found to be 44 ± 3 W cm-2, the iQY, ηb, was obtained as 2.3 ± 0.1%. Combining the power density dynamic range provided by the pixel depth of the camera with the dynamic range achieved using two distinct beam profiles to excite the UCNPs, the iQY was evaluated throughout a range of 104 in the iQY scale (from 0.0003% to 4.6%) and 106 in power densities of excitation (from 0.003 W cm-2 to 1050 W cm-2). To the best of our knowledge, these are the lowest values ever obtained as QY results have never been reported under 0.02% or at excitation power densities below 0.01 W cm-2.

Historical atmospheric pollution trends in Southeast Asia inferred from lake sediment records.

Fossil fuel combustion leads to increased levels of air pollution, which negatively affects human health as well as the environment. Documented data for Southeast Asia (SEA) show a strong increase in fossil fuel consumption since 1980, but information on coal and oil combustion before 1980 is not widely available. Spheroidal carbonaceous particles (SCPs) and heavy metals, such as mercury (Hg), are emitted as by-products of fossil fuel combustion and may accumulate in sediments following atmospheric fallout. Here we use sediment SCP and Hg records from several freshwater lentic ecosystems in SEA (Malaysia, Philippines, Singapore) to reconstruct long-term, region-wide variations in levels of these two key atmospheric pollution indicators. The age-depth models of Philippine sediment cores do not reach back far enough to date first SCP presence, but single SCP occurrences are first observed between 1925 and 1950 for a Malaysian site. Increasing SCP flux is observed at our sites from 1960 onward, although individual sites show minor differences in trends. SCP fluxes show a general decline after 2000 at each of our study sites. While the records show broadly similar temporal trends across SEA, absolute SCP fluxes differ between sites, with a record from Malaysia showing SCP fluxes that are two orders of magnitude lower than records from the Philippines. Similar trends in records from China and Japan represent the emergence of atmospheric pollution as a broadly-based inter-region environmental problem during the 20th century. Hg fluxes were relatively stable from the second half of the 20th century onward. As catchment soils are also contaminated with atmospheric Hg, future soil erosion can be expected to lead to enhanced Hg flux into surface waters.

Size quantization of Dirac fermions in graphene constrictions.

Quantum point contacts are cornerstones of mesoscopic physics and central building blocks for quantum electronics. Although the Fermi wavelength in high-quality bulk graphene can be tuned up to hundreds of nanometres, the observation of quantum confinement of Dirac electrons in nanostructured graphene has proven surprisingly challenging. Here we show ballistic transport and quantized conductance of size-confined Dirac fermions in lithographically defined graphene constrictions. At high carrier densities, the observed conductance agrees excellently with the Landauer theory of ballistic transport without any adjustable parameter. Experimental data and simulations for the evolution of the conductance with magnetic field unambiguously confirm the identification of size quantization in the constriction. Close to the charge neutrality point, bias voltage spectroscopy reveals a renormalized Fermi velocity of ∼1.5 × 10(6) m s(-1) in our constrictions. Moreover, at low carrier density transport measurements allow probing the density of localized states at edges, thus offering a unique handle on edge physics in graphene devices.

MADSTRESS: a linear approach for evaluating scattering and absorption coefficients of samples measured using time-resolved spectroscopy in reflection.

Time-resolved spectroscopy is a powerful technique permitting the separation of the scattering properties from the chemical absorption properties of a sample. The reduced scattering coefficient and the absorption coefficient are usually obtained by fitting diffusion or Monte Carlo models to the measured data using numerical optimization techniques. However, these methods do not take the spectral dimension of the data into account during the evaluation procedure, but evaluate each wavelength separately. A procedure involving multivariate methods may seem more appealing for people used to handling conventional near-infrared data. In this study we present a new method for processing TRS spectra in order to compute the absorption and reduced scattering coefficients. This approach, MADSTRESS, is based on linear regression and a two-dimensional (2D) interpolation procedure. The method has allowed us to calculate absorption and scattering coefficients of apples and fructose powder. The accuracy of the method was good enough to provide the identification of fructose absorption peaks in apple absorption spectra and the construction of a calibration model predicting the sugar content of apples.

In vitro measurements of optical properties of porcine brain using a novel compact device.

Knowledge of the optical properties of tissues can be applied in numerous medical and scientific fields, including cancer diagnostics and therapy. There are many different ways of determining the optical properties of turbid media. The paper describes measurements of the optical properties of porcine brain tissue using novel instrumentation for simultaneous absorption and scattering characterisation of small turbid samples. Integrating sphere measurements are widely used as a reference method for determination of the optical properties of relatively thin turbid samples. However, this technique is associated with bulky equipment, complicated measuring techniques, interference compensation techniques and inconvenient sample handling. It is believed that the sphere for some applications can be replaced by a new, compact device, called the combined angular and spatially resolved head sensor, to measure the optical properties of thin turbid samples. The results compare very well with data obtained with an integrating sphere for well-defined samples. The instrument was shown to be accurate to within 12% for microa and 1% for micro's in measurements of intralipid-ink samples. The corresponding variations of data were 17% and 2%, respectively. The reduced scattering coefficient for porcine white matter was measured to be 100 cm(-1) at 633 nm, and the value for coagulated brain tissue was 65 cm(-1). The corresponding absorption coefficients were 2 and 3 cm(-1), respectively.

Tumour vessel damage resulting from laser-induced hyperthermia alone and in combination with photodynamic therapy.

This study examined tumour vessel injury resulting from laser-induced hyperthermia alone and in combination with photodynamic therapy (PDT) in the treatment of rat liver tumours by means of scanning electron microscopy. A total of 18 Wistar rats were divided into three groups. Group I (six animals) underwent hyperthermia for 15 min (15-min hyperthermia). Group II (six animals) underwent hyperthermia for 30 min (30-min hyperthermia). Group III (six animals) received the combined treatment of PDT and 30-min hyperthermia. For PDT, delta-amino laevulinic acid at a dose of 60 mg/kg of body weight was intravenously administered 60 min before irradiation at 635 nm. The morphological results indicated that 15-min hyperthermia gave rise to an increase in permeability of the vessels in the treated tumour. Thirty-min hyperthermia caused extreme oedema of vascular endothelial cells and restrictive openings of tumour branch vessels. The combined therapy of PDT and hyperthermia destroyed tumour vasculature. Large breaks of the inner wall of the treated tumour vessels were deeply involved in the basement membrane of the vessel. The results indicate that there may be a close link between inhibition of tumour growth and degree of damage to tumour vessels.

Pharmacokinetic studies on 5-aminolevulinic acid-induced protoporphyrin IX accumulation in tumours and normal tissues.

Laser-induced fluorescence (LIF) for in vivo point monitoring and fluorescence microscopy incorporating a CCD camera were used to study the fluorescence distribution of 5-aminolevulinic acid (ALA)-induced protoporphyrin IX (PpIX) in tumours. Fluorescence in a chemically-induced adenocarcinoma in the liver of rats and in an aggressive basal cell carcinoma in a patient were studied after intravenous injection of ALA at a dose of 30 mg/kg body weight. The LIF technique demonstrated slightly more ALA-induced PpIX fluorescence in the tumour than in the surrounding normal liver and abdominal muscle of rats. The visible parts of the human basal cell carcinoma exhibited strong ALA-induced fluorescence, while this fluorescence was much weaker in the necrotic areas of the tumour and in the surrounding normal skin.

Laser-based spectroscopic methods in tissue characterization.

Laser-based spectroscopic techniques were developed for tumor tissue characterization utilizing different tumor-localizing substances. In particular, sensitization with the heme precursor delta-amino levulinic acid (ALA) administered topically, orally or intravenously was used for the induction of protoporphyrin IX (PpIX). The autofluorescence as well as the PpIX-related fluorescence signals were monitored, and tumor demarcation functions were calculated for different human malignant tumors, such as tumors in the urinary bladder and the prostatic gland, in the head and neck region, in the breast and in the gastrointestinal tract. In the gastrointestinal tract, colon tumors were examined as well as tumors and dysplastic lesions in the esophagus, where patients with Barrett's esophagus were examined. Time-integrated laser-induced fluorescence measurements utilizing a point monitoring fluorosensor and a multicolor fluorescence imaging system were performed in vivo in patients in different clinical specialities.

Sequential MR imaging and proton MR spectroscopy in patients who underwent recent detoxification for chronic alcoholism: correlation with clinical and neuropsychological data.

BACKGROUND AND PURPOSE: Chronic alcohol abuse may cause neuropsychological disorders and result in brain atrophy. The purpose of this study was to evaluate the metabolic, morphologic, and functional cerebral changes in the early stage of abstinence from chronic alcoholism. METHODS: Seventeen alcohol-dependent patients underwent MR imaging and MR spectroscopy on days 1 through 3 and days 36 through 39 of abstinence. In addition, psychological performance measures testing intelligence, concentration, attention, and memory were applied. Neuropsychological data were correlated with spectroscopic and volumetric results by using a Pearson's product moment correlation. The same measurements were also performed in 12 healthy, age-matched control subjects. Peak integral values for N-acetylaspartate (NAA) and choline (Cho) were referred to the peak integral value of creatine (Cr) as the internal reference. RESULTS: NAA/Cr was decreased in the patients in both the frontal lobes and cerebellum immediately after cessation of drinking (days 1 through 3). After 36 to 39 days of abstinence, NAA/Cr had significantly increased in the patients and corresponded to performance on psychological tests. The Cho/Cr ratio was decreased in the cerebellum during early abstinence but was recovered on days 36 through 39. The patients had enlarged CSF spaces 1 to 3 days after detoxification, which decreased during sobriety. The extent of brain atrophy did not correspond to performance on psychological performance tests. CONCLUSION: Regression of brain atrophy and metabolic recovery occurs at an early stage after abstinence from chronic alcohol abuse. MR spectroscopy findings return to normal metabolic levels within weeks after detoxification. The recovery of NAA/Cr is associated with improved performance on neuropsychological tests.

Tissue temperature control using a water-cooled applicator: implications for transurethral laser-induced thermotherapy of benign prostatic hyperplasia.

A prototype to a water-cooled applicator to be used in transurethral laser-induced thermotherapy of benign prostatic hyperplasia was developed. The flexible applicator was made of Teflon tubes except for the distal outer part which was made of glass, providing a transparent medium for laser radiation and enabling efficient cooling of the surrounding tissue. For heating, laser light from a Nd:YAG laser emitting at 1064 nm, which was coupled into an optical fiber with an institutionally made diffusing tip, was used. Cooling was performed by flushing water through the applicator. By using a mathematical model it was possible to connect the temperature rise of the water in the applicator to the maximum tissue temperature. Tissue light absorption was calculated using Monte Carlo simulations and the heat conduction equation was solved numerically using a finite-difference technique. Experiments on porcine liver in vitro showed that the maximum tissue temperature could be estimated with an average accuracy of 0.4 degree C by measuring the difference in outlet and inlet applicator water temperature and using the thermal model. The results presented suggest that the described method for temperature control can be used during laser prostatectomy to maximize the lesion size while preventing carbonization.

Laser-induced fluorescence in malignant and normal tissue of rats injected with benzoporphyrin derivative.

Laser-induced fluorescence was used to characterize the localization of intravenously administered benzoporphyrin derivative-monoacid (BPD-MA) 3 h postinjection in different rat tissue types, including an induced experimental malignant tumor. A comparison of the fluorescence properties and demarcation potential between the newer sensitizer BPD-MA and four other substances, hematoporphyrin (HP), polyhematoporphyrin ester (PHE), tetrasulfonated phthalocyanine (TSPc) and the commercially available Photofrin earlier investigated, is included. The fluorescence light was induced with a nitrogen laser, emitting at 337 nm. The fluorescence spectrum in the region 380-750 nm was analyzed by a polychromator equipped with a diode array detector. The demarcation potential between tumor and surrounding tissue in terms of fluorescence signal for the tumor model used was 2:1 for BPD-MA. In comparison with the other drugs, HP shows about the same demarcation potential, whereas Photofrin and PHE exhibit about 3 times better and TSPc about 1.5 times better demarcation. By also employing the endogenous tissue fluorescence signature the contrast was enhanced by a factor of about 2 for each of the five drugs.

Fluorescence imaging and point measurements of tissue: applications to the demarcation of malignant tumors and atherosclerotic lesions from normal tissue.

The possibilities of using laser-induced fluorescence for tissue diagnostics are discussed. The tissue types investigated are malignant tumors and atherosclerotic lesions. Studies with natural autofluorescence as well as with fluorescent tumor markers are included in this paper. Fluorescence emission and decay data are presented for some tissue chromophores contributing to tissue autofluorescence. Optical spectroscopic characteristics of fluorescent malignant tumor markers are analyzed and instrumental designs for clinical applications are discussed. Images recorded with a multicolor fluorescence imaging system developed in Lund are presented.

Changes in optical properties of human whole blood in vitro due to slow heating.

Optical properties of human whole blood were investigated in vitro at 633 nm using a double integrating sphere set-up. The blood flow was maintained at a constant rate through a flow cell while continuously heating the blood at 0.2-1.1 degrees C/min from approximately 25 to 55 degrees C in a heat exchanger. A small, but rather abrupt decrease in the scattering asymmetry factor (g-factor) of 1.7 +/- 0.6% and a similar increase in the scattering coefficient of 2.9 +/- 0.6% were observed at approximately 45-46 degrees C yielding an increase in the reduced scattering coefficient of 40 +/- 10%. Furthermore, a continuous, manifest increase in the absorption coefficient was seen with increasing temperature, on average 80 +/- 70% from 25 to 50 degrees C. The effect of the heating on the blood cells was also studied under a white-light transmission microscope. A sudden change in the shape of the red blood cells, from discshaped to spherical, was observed at approximately the same temperature at which the distinct changes in g-factor and scattering coefficient were observed, i.e. at 45-46 degrees C. The results indicate that this shape transformation could explain the sudden change in scattering properties.