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Liquid-liquid phase separation (LLPS) is a process that results in the formation of a polymer-rich liquid phase coexisting with a polymer-depleted liquid phase. LLPS plays a critical role in the cell through the formation of membrane-less organelles, but it also has a number of biotechnical and biomedical applications such as drug confinement and its targeted delivery. In this chapter, we present a computational efficient methodology that uses field-theoretic simulations (FTS) with complex Langevin (CL) sampling to characterize polymer phase behavior and delineate the LLPS phase boundaries. This approach is a powerful complement to analytical and explicit-particle simulations, and it can serve to inform experimental LLPS studies. The strength of the method lies in its ability to properly sample a large ensemble of polymers in a saturated solution while including the effect of composition fluctuations on LLPS. We describe the approaches that can be used to accurately construct phase diagrams of a variety of molecularly designed polymers and illustrate the method by generating an approximation-free phase diagram for a classical symmetric diblock polyampholyte.

Published literature on musculoskeletal coccidioidomycosis is sparse and limited to case reports and case series. This is one of the largest case series to describe the clinical presentation, diagnosis, medical and surgical management and outcomes of pediatric musculoskeletal coccidioidomycosis at a tertiary care hospital.A retrospective case review was performed on patients ≤ 21 years old who were followed at a tertiary care center with a diagnosis of musculoskeletal coccidioidomycosis from January 1, 2007, to December 31, 2020. Descriptive data are expressed as medians and interquartile range (IQR) for continuous variables or as frequency and percentage for categorical variables. Categorical values were compared using the χ2 test.Forty-one patients were identified. The median age was 12.8 years, and most were male (71%), Latinx (66%) and healthy (71%). Limb swelling (66%), bone pain (54%) and joint pain (46%) were the most common presenting symptoms. Multiple bone involvement was present in 29% while 12% had the joint disease, and craniofacial (n = 10) and metacarpal/metatarsal bones (n=9) were the most commonly involved sites. Elevated Coccidioides complement fixation (CF) titers ≥1:32 were seen in 90% of the patients. Thirty-three patients (81%) required surgical interventions and of these 16 (48%) required additional surgical procedures. Eleven patients (27%) had disease relapse. Children13 years of age were more likely to have1 organ involvement (16 vs. 7, P = 0.04), multiple bone involvement (10 vs. 2, P = 0.004) and maximum Coccidioides CF titers1:128 (13 vs. 6, P = 0.02).In endemic areas, musculoskeletal coccidioidomycosis causes a substantial disease burden in children and should be considered in the differential diagnosis of those presenting with bone and joint pain or swelling. Early diagnosis and treatment are essential to minimize long-term morbidity and mortality.

The cell wall is a critical extracellular barrier for bacteria and many other organisms. In bacteria, this structural layer consists of peptidoglycan, which maintains cell shape and structural integrity and provides a scaffold for displaying various protein factors. To attach proteins to the cell wall, Gram-positive bacteria utilize sortase enzymes, which are cysteine transpeptidases that recognize and cleave a specific sorting signal, followed by ligation of the sorting signal-containing protein to the peptidoglycan precursor lipid II (LII). This mechanism is the subject of considerable interest as a target for therapeutic intervention and as a tool for protein engineering, where sortases have enabled sortase-mediated ligation or sortagging strategies. Despite these uses, there remains an incomplete understanding of the stereochemistry of substrate recognition and ligation product formation. Here, we solved the first structures of sortase A from Streptococcus pyogenes bound to two substrate sequences, LPATA and LPATS. In addition, we synthesized a mimetic of the product of sortase-mediated ligation involving LII (LPAT-LII) and solved the complex structure in two ligand conformations. These structures were further used as the basis for molecular dynamics simulations to probe sortase A-ligand dynamics and to construct a model of the acyl-enzyme intermediate, thus providing a structural view of multiple key states in the catalytic mechanism. Overall, this structural information provides new insights into the recognition of the sortase substrate motif and LII ligation partner and will support the continued development of sortases for protein engineering applications.

International audience; Protein misfolding and aggregation is observed in many amyloidogenic diseases affecting either the central nervous system or a variety of peripheral tissues. Structural and dynamic characterization of all species along the pathways from monomers to fibrils is challenging by experimental and computational means because they involve intrinsically disordered proteins in most diseases. Yet understanding how amyloid species become toxic is the challenge in developing a treatment for these diseases. Here we review what computer, in vitro, in vivo and pharmacological experiments tell us about the accumulation and deposition of the oligomers of the (Aβ, tau), α-synuclein, IAPP and superoxide dismutase 1 proteins, which have been the mainstream concept underlying Alzheimer's disease (AD), Parkinson's disease (PD), type II diabetes (T2D) and amyotrophic lateral sclerosis (ALS) research, respectively for over many years.

Tau protein in vitro can undergo liquid liquid phase separation (LLPS); however, observations of this phase transition in living cells are limited. To investigate protein state transitions in living cells we found that Cry2 can optogentically increase the association of full lengh tau with microtubules. To probe this mechanism, we identified tau domains that drive tau clustering on microtubules in living cells. The polyproline rich domain (PRD) drives LLPS and does so under the control of phosphorylation. These readily observable cytoplasmic condensates underwent fusion and fluorescence recovery after photobleaching consistent with the ability of the PRD to undergo LLPS in vitro. In absence of the MTBD, the tau PRD co-condensed with EB1, a regulator of plus-end microtubule dynamic instability. The specific domain properties of the MTBD and PRD serve distinct but mutually complementary roles that utilize LLPS in a cellular context to implement emergent functionalities that scale their relationship from binding alpha-beta tubulin heterodimers to the larger proportions of microtubules.

Coarse-graining (CG) approaches are becoming essential tools in the study of complex systems because they can considerably speed up computer simulations, with the promise of determining properties in a range of length scales and time scales never before possible. While much progress in this field has been achieved in recent years, application of CG methods is still inhibited by the limited understanding of a number of conceptual points that need to be resolved to open up the field of CG to a wide range of applications in material science and biology. In this paper, we present some of the key findings that emerged from the development of the integral equation theory of coarse-graining (IECG), which addresses some of the fundamental questions in coarse-graining. Although the IECG method pertains to the CG of polymer liquids, and specifically homopolymer melts are illustrated here, many of the results that emerge from the study of the IECG approach are general and apply to the CG of any molecular liquid. Through this method, we developed a formal relation between the statistical mechanics of CG and a number of predicted physical properties. On the basis of the theory of liquids, the IECG affords the analytical solution of the intermolecular potential for macromolecules represented by a Markov chain of CG sites, thus providing a transparent tool for analysis of the properties in coarse-graining. We identify three key requirements that render a CG model useful: accuracy, transferability, and computational efficiency. When these three requirements are fulfilled, the CG model becomes widely applicable and useful for studying regions in the phase space that are not covered by atomistic simulations. In the process, the IECG answers formally a number of relevant questions on how structural, thermodynamic, and dynamical properties are modified during coarse-graining. It sheds light upon how the level of CG affects the shape of the CG potential and how, in turn, the shape of the potential affects the physical properties. It tests the validity of selecting the potential-of-mean force as the effective pairwise CG potential and the role of higher-order many-body corrections to the pairwise potential to recover structural and thermodynamic consistency of the CG model. Because the IECG theory can be analytically formalized, it does not suffer from the problem of transferability and, in the canonical ensemble, leads to consistent pair distribution functions, pressure, isothermal compressibility, and excess free energy at variable levels of CG from the atomistic to the ultra-CG model, where macromolecules are represented as interpenetrable soft spheres.

Background Coccidioidal meningitis is a severe form of coccidioidomycosis associated with significant morbidity and mortality. Published literature in the pediatric population is limited, particularly on coccidioidal meningitis. Here we describe a large case series of pediatric coccidioidal meningitis followed at a tertiary care center in an endemic region. Methods We performed a retrospective case review of patients ≤21 years old followed at our facility with a diagnosis of coccidioidal meningitis from January 1, 2000, to December 31, 2018. Results Overall, 30 patients were identified during the study period. The median age was 10.8 years (IQR: 4.6-15). The majority of patients were previously healthy (93%) and all required hospitalization. Fever (90%), headache (70%), vomiting (53%), and fatigue (57%) were the most common clinical manifestations. More than one-third (40%) had concurrent pulmonary disease. Only 20 patients (67%) had initial Coccidioides complement fixation (CF) titers >=1:16. The majority had extra-axial brain involvement (60%) and seven (23%) had associated spinal canal disease. Over two-third required shunt placement (70%) and almost half of them (43%) underwent revision. Neurological complications including paresis/paralysis, stroke, neuropathy, seizures, and cognitive delay were observed in 20% of patients. Two-thirds (73%) of patients received fluconazole as the initial drug. However, 37% of those had fluconazole failure, requiring alternative treatment. Due to refractory disease, two patients required a novel triazole, isavuconazole, while adjunctive therapy with steroids and interferon-gamma (IFNγ) was used in 20% of patients. Most cases (83%) stabilized, 13% experienced relapses and/or progressive disease, and 3% were fatal. Conclusion Pediatric coccidioidal meningitis is an uncommon and sometimes devastating complication of disseminated coccidioidomycosis. Many patients present with relatively low CF titers, and communicating hydrocephalus and long term neurologic complications are common. Fluconazole treatment failures are common, and management remains difficult despite recent advances in therapy. Most patients do well once the disease is stabilized and require lifelong therapy. Newer therapeutic agents are needed. Disclosures All Authors: No reported disclosures

The process of freezing proteins is widely used in applications ranging from processing and storage of biopharmaceuticals to cryo-EM analysis of protein complexes. The formation of an ice-water interface is a critical destabilization factor for the protein, which can be offset by the use of cryo-protectants. Using molecular dynamics simulation, we demonstrate that the presence of the ice-water interface leads to a lowering of the free-energy barrier for unfolding, resulting in rapid unfolding of the protein. The unfolding process does not require direct adsorption of the protein to the surface, but is rather mediated by nearby liquid molecules that show an increased tendency for hydrating nonpolar groups. The observed enhancement in the cold denaturation process upon ice formation can be mitigated by addition of glucose, which acts as a cryoprotectant through preferential exclusion from side chains of the protein.

Self-coacervation is a phenomenon in which a solution of polyampholytes spontaneously phase separates into a dense liquid coacervate phase, rich in the polyampholyte, coexisting with a dilute supernatant phase. Such coacervation results in the formation of membraneless organelles in vivo and has further been applied industrially as synthetic encapsulants and coatings. It has been suggested that coacervation is primarily driven by the entropy gain from releasing counter-ions upon complexation. Using fully fluctuating field-theoretic simulations employing complex Langevin sampling and complementary molecular dynamics simulations, we have determined that the small ions contribute only weakly to the self-coacervation behavior of charge-symmetric block polyampholytes in solution. Salt partitioning between the supernatant and coacervate is also found to be negligible in the weak-binding regime at low electrostatic strengths. Asymmetries in charge distribution along the polyampholytes can cause net-charges that lead to "tadpole" configurations in dilute solution and the suppression of phase separation at low salt content. The field and particle-based simulation results are compared with analytical predictions from the random phase approximation (RPA) and postulated scaling relationships. The qualitative trends are mostly captured by the RPA, but the approximation fails at low concentration.

The mechanism that leads to liquid-liquid phase separation (LLPS) of the tau protein, whose pathological aggregation is implicated in neurodegenerative disorders, is not well understood. Establishing a phase diagram that delineates the boundaries of phase co-existence is key to understanding whether LLPS is an equilibrium or intermediate state. We demonstrate that tau and RNA reversibly form complex coacervates. While the equilibrium phase diagram can be fit to an analytical theory, a more advanced model is investigated through field theoretic simulations (FTS) that provided direct insight into the thermodynamic driving forces of tau LLPS. Together, experiment and simulation reveal that tau-RNA LLPS is stable within a narrow equilibrium window near physiological conditions over experimentally tunable parameters including temperature, salt and tau concentrations, and is entropy-driven. Guided by our phase diagram, we show that tau can be driven toward LLPS under live cell coculturing conditions with rationally chosen experimental parameters., eLife digest Proteins make up much of the machinery of cells and perform many roles that are essential for life. Some important proteins – known as intrinsically disordered proteins – lack any stable three-dimensional structure. One such protein, called tau, is best known for its ability to form tangles in the brain, and a buildup of these tangles is a hallmark of Alzheimer’s disease and many other dementias. Tau is also one of a number of proteins that can undergo a process called liquid-liquid phase separation: essentially, a solution of tau separates into a very dilute solution interspersed with droplets of a concentrated tau solution, similar to an oil-water mixture separating into a very watery solution with drops of oil. Understanding the conditions that lead to spontaneous liquid-liquid phase separation might give insight into how the tau tangles form. However, it was not known whether it is possible in principle for liquid-liquid phase separation of tau to occur in a living brain. Lin, McCarty et al. have now used an advanced computer simulation method together with experiments to map the conditions under which a solution containing tau undergoes liquid-liquid phase separation. Temperature as well as the concentrations of salt and the tau protein all influenced how easily tau droplets formed or dissolved, and the narrow range of conditions that encouraged droplet formation fell within the normal conditions found in the body, also known as “physiological conditions”. This suggested that tau droplets might form and dissolve easily in living systems, and possibly in the brain, depending on the precise physiological conditions. To explore this possibility further, tau protein was added to a dish containing living cells. As the map suggested, slightly adjusting temperature or protein concentrations caused tau droplets to form and dissolve, all while the cells remained alive. The map provided by this study may offer guides to researchers looking for liquid-liquid phase separation in the brain. If liquid-liquid phase separation of tau occurs in living brains, it may be important for determining whether and when damaging tau tangles emerge. For example, the high concentration of tau in droplets might speed up tangle formation. Ultimately, a better understanding of the conditions and mechanism for liquid-liquid phase separation of tau can help researchers understand the role of protein droplet formation in living systems. This may be a process that promotes, or possibly a regulatory mechanism that prevents, the formation of tau tangles associated with dementia.

Coacervation is a common phenomenon in natural polymers and has been applied to synthetic materials systems for coatings, adhesives, and encapsulants. Single-component coacervates are formed when block polyampholytes exhibit self-coacervation, phase separating into a dense liquid coacervate phase rich in the polyampholyte coexisting with a dilute supernatant phase, a process implicated in the liquid–liquid phase separation of intrinsically disordered proteins. Using fully fluctuating field-theoretic simulations using complex Langevin sampling and complementary molecular-dynamics simulations, we develop molecular design principles to connect the sequenced charge pattern of a polyampholyte with its self-coacervation behavior in solution. In particular, the lengthscale of charged blocks and number of connections between oppositely charged blocks are shown to have a dramatic effect on the tendency to phase separate and on the accessible chain conformations. The field and particle-based simulation results are compared with analytical predictions from the random phase approximation (RPA) and postulated scaling relationships. The qualitative trends are mostly captured by the RPA, but the approximation fails catastrophically at low concentration.

A number of intrinsically disordered proteins have been shown to self-assemble via liquid–liquid phase separation into protein-rich and dilute phases. The resulting coacervates can have important biological functions, and the ability to form these assemblies is dictated by the protein’s primary amino acid sequence as well as by the solution conditions. We present a complete phase diagram for the simple coacervation of a polyampholyte intrinsically disordered protein using a field-theoretic simulation approach. We show that differences in the primary amino acid sequence and in the distribution of charged amino acids along the sequence lead to differences in the phase window for coacervation, with block-charged sequences having a larger coacervation window than sequences with a random patterning of charges. The model also captures how changing solution conditions modifies the phase diagram and can serve to guide experimental studies.

We have studied the reaction dynamics of a prototypical organic reaction using a variationally optimized truncated bias to accelerate transitions between educt and product reactant states. The asymmetric SN2 nucleophilic substitution reaction of fluoromethane and chloromethane CH3F + Cl– ⇌ CH3Cl + F– is considered, and many independent biased molecular dynamics simulations have been performed at 600, 900, and 1200 K, collecting several hundred transitions at each temperature. The transition times and relative rate constants have been obtained for both reaction directions. The activation energies extracted from an Arrhenius plot compare well with standard static calculations.

Obtaining efficient sampling of multiple metastable states through molecular dynamics and hence determining free energy differences is central for understanding many important phenomena. Here we present a new biasing strategy, which employs the recent variationally enhanced sampling approach (Valsson and Parrinello Phys. Rev. Lett. 2014, 113, 090601). The bias is constructed from an intuitive model of the local free energy surface describing fluctuations around metastable minima and depends on only a few parameters which are determined variationally such that efficient sampling between states is obtained. The bias constructed in this manner largely reduces the need of finding a set of collective variables that completely spans the conformational space of interest, as they only need to be a locally valid descriptor of the system about its local minimum. We introduce the method and demonstrate its power on two representative examples.

When proteins bind to interfaces, the resulting changes in protein structure can lead to loss of protein function. We investigate the mechanism by which surfactant molecules can counteract surface-induced protein denaturation through a detailed study of the stability of the GB1 peptide at the air-water, ice-water, and silica-water interfaces using molecular dynamics simulations coupled with metadynamics. Our simulations reveal that the air-water interface and, to a lesser extent, the ice-water interface destabilize the protein by direct interactions between the protein and surface that disrupt the hydrophobic core of the protein, while the weakly interacting silica surface stabilizes the protein through confinement effects. Addition of the surfactant Tween 80 leads to stabilization of the protein at the air-water and ice-water surfaces and mild destabilization at the water-silica interface. We show that the amphiphilic nature of the surfactant is key to its stabilizing/destabilizing effect, with an orientation-dependent mechanism in which the protein is stabilized when the hydrophilic heads of the surfactant point toward the protein.

In this paper we combine two powerful computational techniques, well-tempered metadynamics and time lagged independent component analysis. The aim is to develop a new tool for studying rare events and exploring complex free energy landscapes. Metadynamics is a well-established and widely used enhanced sampling method whose efficiency depends on an appropriate choice of collective variables. Often the initial choice is not optimal leading to slow convergence. However by analyzing the dynamics generated in one such a run with a time-lagged independent component analysis and the techniques recently developed in the area of conformational dynamics, we obtain much more efficient collective variables, that are also better capable of illuminating the physics of the system. We demonstrate the power of this approach in two paradigmatic examples., 7 pages, 4 figures

The surgical correction of hammer digits offers a variety of surgical treatments ranging from arthroplasty to arthrodesis, with many options for fixation. In the present study, we compared 2 buried implants for arthrodesis of lesser digit deformities: a Smart Toe® implant and a buried Kirschner wire. Both implants were placed in a prepared interphalangeal joint, did not violate other digital or metatarsal joints, and were not exposed percutaneously. A retrospective comparative study was performed of 117 digits with either a Smart Toe® implant or a buried Kirschner wire, performed from January 1, 2007 to December 31, 2010. Of the 117 digits, 31 were excluded because of a lack of 90-day radiographic follow-up. The average follow-up was 94 to 1130 days. The average patient age was 61.47 (range 43 to 84) years. Of the 86 included digits, 48 were left digits and 38 were right. Of the digits corrected, 54 were second digits, 24 were third digits and 8 were fourth digits. Fifty-eight Smart Toe® implants were found (15 with 19-mm straight; 2 with 19-mm angulated; 34 with 16-mm straight; and 7 with 16-mm angulated). Twenty-eight buried Kirschner wires were evaluated. No statistically significant difference was found between the Smart Toe® implants and the buried Kirschner wires, including the rate of malunion, nonunion, fracture of internal fixation, and the need for revision surgery. Of the 86 implants, 87.9% of the Smart Toe® implants and 85.7% of the buried Kirschner wires were in good position (0° to 10° of transverse angulation on radiographs). Osseous union was achieved in 68.9% of Smart Toe® implants and 82.1% of buried Kirschner wires. Fracture of internal fixation occurred in 12 of the Smart Toe® implants (20.7%) and 2 of the buried Kirschner wires (7.1%). Most of the fractured internal fixation and malunions or nonunions were asymptomatic, leading to revision surgery in only 8.6% of the Smart Toe® implants and 10.7% of the buried Kirschner wires. Both the Smart Toe® implant and the buried Kirschner wire offer a viable choice for internal fixation of an arthrodesis of the digit compared with other studies using other techniques.

We present the equation of state for a coarse-grained model of polymer melts where each chain is represented as a soft colloidal particle centered on its center-of-mass. The formalism is based on the solution of the Ornstein–Zernike equation and is analytical, allowing for the formal investigation of the elements that ensure thermodynamic consistency in coarse-grained models of polymer melts. By comparing predictions from our expressions with those from computer simulations of the coarse-grained system and with atomistic polymer integral equation theory, we demonstrate that both structural and thermodynamic consistency with the atomistic level description is maintained during our coarse-graining procedures.

This paper discusses results from continued development of inverted metamorphic multijunction (IMM) solar cells with air mass zero (AM0) conversion efficiencies greater than 34%. An experimental best four-junction IMM (IMM4J) design is presented. In an effort to improve IMM performance in space radiation environments, 1-MeV electron irradiation studies are conducted on the individual IMM4J subcells. These data are used to engineer an IMM4J structure with beginning of life AM0 conversion efficiency of approximately 34% and an end of life (EOL) remaining factor greater than 82%, where EOL is defined as performance after exposure to 1-MeV electron irradiation at 1E15 e/cm $^2$ fluence. Next-generation IMM designs are explored and an avenue toward AM0 conversion efficiencies of greater than 35% is presented.

A first-principle multiscale modeling approach is presented, which is derived from the solution of the Ornstein-Zernike equation for the coarse-grained representation of polymer liquids. The approach is analytical, and for this reason is transferable. It is here applied to determine the structure of several polymeric systems, which have different parameter values, such as molecular length, monomeric structure, local flexibility, and thermodynamic conditions. When the pair distribution function obtained from this procedure is compared with the results from a full atomistic simulation, it shows quantitative agreement. Moreover, the multiscale procedure accurately captures both large and local scale properties while remaining computationally advantageous.

Therapy for cystic fibrosis (CF) has progressed during the past several decades. Much of this progress is because of advances in genetic testing to precisely identify the underlying cause of CF transmembrane regulator (CFTR) dysfunction. However, with more than 1900 mutations that can produce a faulty CFTR, the management of CF can remain a challenge. Several innovative drugs recently approved by the Food and Drug Administration, termed genetic modulators, target the underlying disease by modulating the CFTR defect. This review provides physicians with an established simple classification scheme to guide their use of these drugs. The treatment challenge of 1900 CFTR mutations has been simplified into 6 physiologic classes, each paired with an available therapy to offer patients the most functional improvement. Drug therapy monitoring, adverse effects, and indications for discontinuation must also be considered.

We propose a new method to obtain kinetic properties of infrequent events from molecular dynamics simulation. The procedure employs a recently introduced variational approach [Valsson and Parrinello, Phys. Rev. Lett. 113, 090601 (2014)] to construct a bias potential as a function of several collective variables that is designed to flood only the associated free energy surface up to a predefined level. The resulting bias potential effectively accelerates transitions between metastable free energy minima while ensuring bias-free transition states, thus allowing accurate kinetic rates to be obtained. We test the method on a few illustrative systems for which we obtain an order of magnitude improvement in efficiency relative to previous approaches, and several orders of magnitude relative to unbiased molecular dynamics. We expect an even larger improvement in more complex systems. This and the ability of the variational approach to deal efficiently with a large number of collective variables will greatly enhance the scope of these calculations. This work is a vindication of the potential that the variational principle has if applied in innovative ways, 6 pages, 3 figures, Supplemental Information

Structural and thermodynamic consistency of coarse-graining models across multiple length scales is essential for the predictive role of multi-scale modeling and molecular dynamic simulations that use mesoscale descriptions. Our approach is a coarse-grained model based on integral equation theory, which can represent polymer chains at variable levels of chemical details. The model is analytical and depends on molecular and thermodynamic parameters of the system under study, as well as on the direct correlation function in the k --> 0 limit, c0. A numerical solution to the PRISM integral equations is used to determine c0, by adjusting the value of the effective hard sphere diameter, d, to agree with the predicted equation of state. This single quantity parameterizes the coarse-grained potential, which is used to perform mesoscale simulations that are directly compared with atomistic-level simulations of the same system. We test our coarse-graining formalism by comparing structural correlations, isothermal compressibility, equation of state, Helmholtz and Gibbs free energies, and potential energy and entropy using both united atom and coarse-grained descriptions. We find quantitative agreement between the analytical formalism for the thermodynamic properties, and the results of Molecular Dynamics simulations, independent of the chosen level of representation. In the mesoscale description, the potential energy of the soft-particle interaction becomes a free energy in the coarse-grained coordinates which preserves the excess free energy from an ideal gas across all levels of description. The structural consistency between the united-atom and mesoscale descriptions means the relative entropy between descriptions has been minimized without any variational optimization parameters. The approach is general and applicable to any polymeric system in different thermodynamic conditions.

In a prospective, multicenter, double-blind study, the interval to clinical relapse in patients with acute bacterial exacerbations of chronic bronchitis from whom a pretherapy pathogen was isolated was compared following treatment with ciprofloxacin or cefuroxime axetil. Clinical and microbiological responses at the end of therapy were secondary efficacy variables. Outpatients randomly received either ciprofloxacin or cefuroxime axetil (500 mg twice a day for 14 days). Three hundred seven patients with acute exacerbations of chronic bronchitis were enrolled, of whom 208 had an exacerbation due to a bacterial pathogen. Clinical resolution at the end of ciprofloxacin and cefuroxime axetil therapy for patients for whom efficacy could be evaluated was 93% and 90%, respectively. Bacteriologic eradication rates were statistically higher for ciprofloxacin recipients (96% [89 of 93]) than for cefuroxime axetil recipients (82% [80 of 97]) (P < .01). The median infection-free interval was 146 days for ciprofloxacin recipients vs. 178 days for cefuroxime axetil recipients (P = .37). In conclusion, ciprofloxacin was associated with an infection-free interval and clinical response that were similar to those associated with cefuroxime axetil, but the bacteriologic eradication rate associated with ciprofloxacin was statistically significantly higher than that associated with cefuroxime axetil.

Numerically optimized reduced descriptions of macromolecular liquids often present thermodynamic inconsistency with atomistic level descriptions even if the total correlation function, i.e. the structure, appears to be in agreement. An analytical expression for the effective potential between a pair of coarse-grained units is derived starting from the first-principles Ornstein-Zernike equation, for a polymer liquid where each chain is represented as a collection of interpenetrating blobs, with a variable number of blobs, ${n}_{b}$, of size ${N}_{b}$. The potential is characterized by a long tail, slowly decaying with characteristic scaling exponent of ${N}_{b}^{1/4}$. This general result applies to any coarse-grained model of polymer melts with units larger than the persistence length, highlighting the importance of the long, repulsive, potential tail for the model to correctly predict both structural and thermodynamic properties of the macromolecular liquid.

This paper discusses the evolution of our 2.05 eV AlGaInP top sub-cell. Although we were not successful in introducing a more optimum 1.94 eV AlGaInP alloy into the top sub-cell of our 3 or 4J-IMM (inverted metamorphic multi-junction) structure because of insufficient current density capacity, we did successfully develop a 2.05 eV AlGaInP top sub-cell structure for 5 or 6J-IMM application. To achieve the desired current capacity of 11.3mA/cm2, we fabricated 2.05 eV hetero-junctions composed of a 1.91 eV GaInP emitter and a 2.05 eV AlGaInP base. Such a hetero-junction top sub-cell incorporated in a 3J-IMM iso-type structure exhibited sufficient J sc but reduced V oc =1.466 V, being only 43 mV greater than the 1.91 eV GaInP homo-junction sub-cell. Minor modification to the emitter of our AlGaInP homo-junction permitted the fabrication of a 2.05 eV sub-cell in a 5J-IMM iso-type structure with sufficient current density and improved V oc =1.537 V. 5 and 6J-IMM cells incorporating these top sub-cells demonstrated maximum V oc s= 4.839 and 5.195 V, respectively.

The NASA Solar Probe Plus (SPP) mission will fly into and study the Sun's corona, reaching as close as 8.5 solar radii from the surface of the Sun. Power generation for the spacecraft will be provided by two solar array wings, which are being designed and built by Johns Hopkins University Applied Physics Laboratory and Emcore Photovoltaics. SPP will get closer to the Sun than any previous mission, and the solar array will therefore need to operate reliably under unusually high irradiances, temperatures, and angles of incidence, a situation that introduces intriguing challenges for the array design. This paper presents an overview of the array-geometry optimization method we have developed, the goal of which is to allow for the most benign nominal operating conditions possible, given the mission requirements for minimum power generation and maximum heat dissipation. We also outline the engineering trade-offs associated with the available options for cell lay-down onto the panel, including the non-standard material choices necessary for optimal thermal, mechanical, optical and electrical performance and robustness of the array. We conclude by presenting the near-term test plan included in the SPP array-development program, and summarize the data from preliminary measurements performed to date.

This paper discusses results from continued development of inverted metamorphic multi-junction (IMM) solar cells with air mass zero (AM0) conversion efficiencies greater than 34%. An experimental best four-junction IMM (IMM4J) design is presented. In an effort to improve IMM performance in space radiation environments, 1-MeV electron irradiation studies are conducted on the individual IMM4J subcells. This data is used to engineer an IMM4J structure with beginning of life (BOL) AM0 conversion efficiency of approximately 34% and an end of life (EOL) remaining factor greater than 82%, where EOL is defined as performance after exposure to 1-MeV electron irradiation at 1E15 e/cm2 fluence. Next generation IMM designs are explored and an avenue toward AM0 conversion efficiencies of greater than 35% is presented.

We present a theoretical approach to scale the artificially fast dynamics of simulated coarse-grained polymer liquids down to its realistic value. As coarse-graining affects entropy and dissipation, two factors enter the rescaling: inclusion of intramolecular vibrational degrees of freedom, and rescaling of the friction coefficient. Because our approach is analytical, it is general and transferable. Translational and rotational diffusion of unentangled and entangled polyethylene melts, predicted from mesoscale simulations of coarse-grained polymer melts using our rescaling procedure, are in quantitative agreement with united atom simulations and with experiments., Comment: 6 pages, 2 figures, 2 tables

The Epstein-Barr virus (EBV)-induced diseases of males with X-linked lymphoproliferative disease (XLP) include fatal infectious mononucleosis (IM), non-Hodgkin lymphoma (ML), agammaglobulinemia, and aplastic anemia. These phenotypes also occur as sporadic cases in families, and EBV seronegative males in these families must be considered at risk for XLP until they seroconvert normally to EBV. Given that 50% of males inheriting the defective XLP gene die following primary EBV infection, it is vital that they be identified pre-EBV infection. Here we report result using molecular genetic techniques to provide information as to the relative risks of EBV negative males and potential carrier females in ten families wherein a single male had died of IM. © 1993 Wiley-Liss, Inc.

Mesoscopic molecular dynamics simulations are used to determine the large scale structure of several binary polymer mixtures of various chemical architecture, concentration, and thermodynamic conditions. By implementing an analytical formalism, which is based on the solution to the Ornstein-Zernike equation, each polymer chain is mapped onto the level of a single soft colloid. From the appropriate closure relation, the effective, soft-core potential between coarse-grained units is obtained and used as input to our mesoscale simulations. The potential derived in this manner is analytical and explicitly parameter dependent, making it general and transferable to numerous systems of interest. From computer simulations performed under various thermodynamic conditions the structure of the polymer mixture, through pair correlation functions, is determined over the entire miscible region of the phase diagram. In the athermal regime mesoscale simulations exhibit quantitative agreement with united atom simulations. Furthermore, they also provide information at larger scales than can be attained by united atom simulations and in the thermal regime approaching the phase transition., 19 pages, 11 figures, 3 tables

Background. Currently, there is no single-dose therapy that is effective in the treatment of urethral or endocervical infections with Chlamydia trachomatis. Azithromycin is a new azalide antibiotic that has substantial activity against C. trachomatis, is concentrated intracellularly, and has a long half-life in serum and tissue. Methods. We conducted a trial in which 299 female patients and 158 male patients with uncomplicated genital infection and a positive C. trachomatis antigen test were randomly assigned to receive either azithromycin (1 g once orally) or doxycycline (100 mg orally twice daily for seven days). Only patients subsequently determined to have a culture positive for C. trachomatis at base line were included in the evaluation of efficacy. Results. Among the patients who could be evaluated, 5 of the 141 patients (4 percent) treated with azithromycin did not respond to treatment, as compared with 3 of the 125 patients (2 percent) treated with doxycycline (difference between groups, ...

Loracarbef (LY163892), a member of the class of beta-lactam antibiotics known as carbacephems, is characterized by a high level of chemical stability and a broad spectrum of antibacterial activity that persists in the presence of beta-lactamase. The efficacy and safety of loracarbef, 200 mg (twice daily), and cefaclor, 250 mg (three times daily) (one patient received 178 mg of cefaclor suspension, three times daily), were compared in a randomized, double-blind, multicenter trial conducted in adults with skin and skin-structure infections due predominantly to Staphylococcus aureus. Examination within 72 hours after the completion of therapy indicated a favorable clinical response in 84 (93.3%) of the 90 loracarbef-treated patients evaluable for efficacy and in 79 (95.2%) of the 83 evaluable patients treated with cefaclor. Pathogens were eradicated in 83 (92.2%) of the patients in the loracarbef group and 74 (89.2%) of those in the cefaclor group. Only four adverse events--headache/migraine, diarrhea, abdominal pain, and nausea--occurred in greater than 2% of the total study population. The overall incidence of adverse events in the 201 loracarbef-treated and 192 cefaclor-treated patients evaluated for safety was 19.9% and 24.5%, respectively. Adverse events that required hospitalization or discontinuation of treatment occurred in four patients in the cefaclor group but in none of those treated with loracarbef. There were no statistically significant differences in the clinical or bacteriologic response or the incidence of side effects between the two treatment groups. These findings indicate that loracarbef given twice daily is comparable in safety and efficacy to cefaclor given three times daily in the treatment of adults with skin and skin-structure infections.

This paper outlines the derivation of an analytical pair potential in a coarse grained description of polymer melts where each chain is represented as a collection of soft spheres. Each particle is located at the center of mass of a polymer subchain, while the polymer is divided into an arbitrary number of identical chain subsections, each comprised of a large number of monomers. It is demonstrated that the soft effective pair potentials acting between these center-of-mass sites is described by a soft repulsive region at separation distances less than the average size of each coarse grained unit and a long repulsive tail, with a small attractive component. The attractive component is located at a length scale beyond the size of the coarse grained unit and its form varies with the level of interpenetration between the coarse-grained units. Consistent with numerically derived potentials, it is found that the short range features of the potential dominate the liquid structure, while the long-tail features dominate the virial-route thermodynamics of the system. It follows that the accurate determination of the effective potential in both short and large separation distances is relevant for ensuring structural and thermodynamic consistency in the coarse-grained description of the macromolecular liquid. It is further shown that due to the sensitivity of thermodynamic properties to the large-scale features of the potential, which are irrelevant to the reproducibility of structural correlations, the determination of thermodynamically accurate potentials by numerical optimization of structure alone is not a reliable strategy in the high-density regime for high levels of coarse-graining.

Obtaining a rigorous and reliable method for linking computer simulations of polymer blends and composites at different length scales of interest is a highly desirable goal in soft matter physics. In this paper a multiscale modeling procedure is presented for the efficient calculation of the static structural properties of binary homopolymer blends. The procedure combines computer simulations of polymer chains on two different length scales, using a united atom representation for the finer structure and a highly coarse-grained approach on the meso-scale, where chains are represented as soft colloidal particles interacting through an effective potential. A method for combining the structural information by inverse mapping is discussed, allowing for the efficient calculation of partial correlation functions, which are compared with results from full united atom simulations. The structure of several polymer mixtures is obtained in an efficient manner for several mixtures in the homogeneous region of the phase diagram. The method is then extended to incorporate thermal fluctuations through an effective chi parameter. Since the approach is analytical, it is fully transferable to numerous systems., Comment: in press, 13 pages, 7 figures, 6 tables

Loracarbef, a member of the carbacephem class of β-lactam antibiotics, is a potent antibacterial agent. In a double-blind, randomized clinical trial to assess the efficacy and safety of loracarbef in the treatment of streptococcal pharyngitis and tonsillitis, 107 adult patients were treated with loracarbef (200 mg capsules twice a day or 15 mg/kg/day suspension) and 111 patients were treated with penicillin VK (250 mg capsules four times a day or 20 mg/kg/day suspension) for 10 days. In the loracarbef treatment group, 96.6% of the evaluable patients had a favorable clinical response 3–5 days after therapy, a result that compared favorably with the 93.9% response rate achieved in the penicillin group. The clinical failure/relapse rates were 3.4% for loracarbef-treated patients and 6.1% for patients receiving penicillin. Bacteriologic response data approximated the clinical results, with a successful response in 89.9% of the loracarbef-treated patients and 91.5% of the penicillin recipients. Two (1.9%) loracarbef-treated patients with rash and one (0.9%) penicillin-treated patient with diarrhea discontinued the study early because of these adverse events. The incidence of adverse events was comparable in the two treatment groups except for increased cough, which was reported by 3.7% of the loracarbef-treated patients and none of the penicillin recipients. These data support the conclusion that loracarbef is comparable to penicillin VK in the treatment of streptococcal pharyngitis and tonsillitis in adults.