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We study the role that recourse plays in the commercial real estate loan contracts of the largest U.S. banks. We find that recourse is valued by lenders and is treated as a substitute for conventional equity. At origination, recourse loans have rate spreads that are at least 20 basis points lower and loan-to-value ratios that are around 3 percentage points higher than non-recourse loans. Dynamically, recourse affects loan modification negotiations by providing additional bargaining power to the lender. Recourse loans were half as likely to receive accommodation during the COVID-19 pandemic, and the modifications that did occur entailed a relatively smaller reduction in payments.

Unlike any other major component of GDP, private investment in nonresidential structures excluding drilling and mining (henceforth "NRS") has steadily declined since the start of 2020. Figure 1 shows the evolution of GDP as well as the main components of private domestic final demand since 2019.

Type-III CRISPR-Cas systems have recently been adopted for sequence-specific detection of SARS-CoV-2. Here, we make two major advances that simultaneously limit sample handling and significantly enhance the sensitivity of SARS-CoV-2 RNA detection directly from patient samples. First, we repurpose the type III-A CRISPR complex from Thermus thermophilus (TtCsm) for programmable capture and concentration of specific RNAs from complex mixtures. The target bound TtCsm complex primarily generates two cyclic oligoadenylates (i.e., cA3 and cA4) that allosterically activate ancillary nucleases. To improve sensitivity of the diagnostic, we identify and test several ancillary nucleases (i.e., Can1, Can2, and NucC). We show that Can1 and Can2 are activated by both cA3 and cA4, and that different activators trigger changes in the substrate specificity of these nucleases. Finally, we integrate the type III-A CRISPR RNA-guided capture technique with the Can2 nuclease for 90 fM (5x104 copies/ul) detection of SARS-CoV-2 RNA directly from nasopharyngeal swab samples.

Over 950,000 whole-genome sequences of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been determined for viruses isolated from around the world. These sequences are critical for understanding the spread and evolution of SARS-CoV-2. Using global phylogenomics, we show that mutations frequently occur in the C-terminal end of ORF7a. We isolate one of these mutant viruses from a patient sample and use viral challenge experiments to link this isolate (ORF7aΔ115) to a growth defect. ORF7a is implicated in immune modulation, and we show that the C-terminal truncation negates anti-immune activities of the protein, which results in elevated type I interferon response to the viral infection. Collectively, this work indicates that ORF7a mutations occur frequently, and that these changes affect viral mechanisms responsible for suppressing the immune response.

Over 200,000 whole genome sequences of SARS-CoV-2 have been determined for viruses isolated from around the world. These sequences have been critical for understanding the spread and evolution of SARS-CoV-2. Using global phylogenomics, we show that mutations frequently occur in the C-terminal end of ORF7a. We isolate one of these mutant viruses from a patient sample and use viral challenge experiments to demonstrate that this mutation results in a growth defect. ORF7a has been implicated in immune modulation, and we show that the C-terminal truncation results in distinct changes in interferon stimulated gene expression. Collectively, this work indicates that ORF7a mutations occur frequently and that these changes affect viral mechanisms responsible for suppressing the immune response. Declaration of Interest: B.W. is the founder of SurGene LLC, and VIRIS Detection Systems Inc. B.W., A. Nemudryi, and A. Nemudraia are inventors on patents related to CRISPR-Cas systems and applications thereof.

We introduce here the Fourier correlation (FC) method for obtaining bulk diffusion coefficients in simulations of condensed, nonideal mixtures. The method in particular allows a Fickian mutual diffusion coefficient to be calculated directly in a molecular dynamics simulation and provides for a correction of errors due to finite system sizes. It is an equilibrium method that may be performed at the same time as standard thermodynamic computations. The method is tested by simulating a binary system of LJ particles meant to approximate a nonideal liquid mixture of methane and carbon tetrafluoride. Results are validated by comparison to Green–Kubo and nonequilibrium methods and simulation at multiple system sizes.

A method for aerial rendezvous of small unmanned aircraft systems is proposed. The system includes placing a passively towed drogue into an orbit that is suitable for a small unmanned aircraft systems to follow, and a seeker guidance method for use with a monocular camera mounted on the centerline of the unmanned aircraft systems. The principle contributions of the work include a method for controlling the drogue path in moderate winds by manipulating the mothership orbit and airspeed, and a vision-based nonlinear pursuit tracking method that uses pitch rate and roll commands to guide the unmanned aircraft systems to an aerial rendezvous with the drogue. Simulation and flight-test results are presented to demonstrate the suitability of these methods.

A nonlinear guidance law for autonomously tracking a cooperative airborne target with a fixed, forward-looking camera is proposed. The method is called visual pursuit and it is intended for use with a vision sensor, but it is also compatible with inputs from other sensors like GPS. Line-of-sight angles are input into the guidance method that produces roll and flight path angle rate commands for tracking an aerial target and following it in close formation. Visual pursuit is based on the formation of a Lyapunov-based scalar system that is shown to be mathematically stable for a cooperative target. The method is shown to be effective at keeping the target in the camera field of view in strong cross winds by allowing the target position to float laterally within the camera field of view. The amount of movement of the target is governed by an optimization algorithm that keeps the line-of-sight errors within a specified region of the camera field of view. For comparison, a linear pursuit method is also implemented. Results showed effective tracking with less bank angle effort in strong winds. Simulation and flight test results are shown to demonstrate the suitability of the method.

Human aldehyde oxidase 1 (AOX1) has been subcloned into a vector suitable for expression in Escherichia coli, and the protein has been expressed. The resulting protein is active, with sulfur being incorporated in the molybdopterin cofactor. Expression levels are modest, but 1 liter of cells supplies enough protein for both biochemical and kinetic characterization. Partial purification is achieved by nickel affinity chromatography through the addition of six histidines to the amino-terminal end of the protein. Kinetic analysis, including kinetic isotope effects and comparison with xanthine oxidase, reveal similar mechanisms, with some subtle differences. This expression system will allow for the interrogation of human aldehyde oxidase structure/function relationships by site-directed mutagenesis and provide protein for characterizing the role of AOX1 in drug metabolism.

This paper discusses the design, modeling and control of a towed ight vehicle that is used in an aerial recovery system. The towed vehicle is controlled to allow for mid-air rendezvous of a trailing aircraft. A design method for the vehicle airframe is described and validated through equilibrium solutions used to verify the reachable locations of the towed vehicle. A nonlinear control law is described for relative position control. The vehicle design and control law are tested in a nonlinear simulation. Simulation results show that the towed vehicle maintains the desired position.

Cocaine abuse and toxicity remain widespread problems in the United States. Currently cocaine toxicity is treated only symptomatically, because there is no Food and Drug Administration-approved pharmacotherapy for this indication. To address the unmet need, a stabilized mutant of bacterial cocaine esterase [T172R/G173Q-CocE (DM-CocE)], which hydrolyzes cocaine into inactive metabolites and has low immunogenic potential, has been developed and previously tested in animal models of cocaine toxicity. Here, we document the rapid cocaine hydrolysis by low doses of DM-CocE in vitro and in vivo, as well as the pharmacokinetics and distribution of the DM-CocE protein in rats. DM-CocE at 50.5 μg/kg effectively eliminated 4 mg/kg cocaine within 2 min in both male and female rats as measured by mass spectrometry. We expanded on these findings by using a pharmacologically relevant dose of DM-CocE (0.32 mg/kg) in rats and monkeys to hydrolyze convulsant doses of cocaine. DM-CocE reduced cocaine to below detection limits rapidly after injection; however, elimination of DM-CocE resulted in peripheral cocaine redistribution by 30 to 60 min. Elimination of DM-CocE was quantified by using [35S] labeling of the enzyme and was found to have a half-life of 2.1 h in rats. Minor urinary output of DM-CocE was also observed. Immunohistochemistry, Western blotting, and radiography all were used to elucidate the mechanism of DM-CocE elimination, rapid proteolysis, and recycling of amino acids into all tissues. This rapid elimination of DM-CocE is a desirable property of a therapeutic for cocaine toxicity and should reduce the likelihood of immunogenic or adverse reactions as DM-CocE moves toward clinical use.

No small-molecule therapeutic is available to treat cocaine addiction, but enzyme-based therapy to accelerate cocaine hydrolysis in serum has gained momentum. Bacterial cocaine esterase (CocE) is the fastest known native enzyme that hydrolyzes cocaine. However, its lability at 37°C has limited its therapeutic potential. Cross-linking subunits through disulfide bridging is commonly used to stabilize multimeric enzymes. Herein we use structural methods to guide the introduction of two cysteine residues within dimer interface of CocE to facilitate intermolecular disulfide bond formation. The disulfide-crosslinked enzyme displays improved thermostability, particularly when combined with previously described mutations that enhance stability (T172R-G173Q). The newly modified enzyme yielded an extremely stable form of CocE (CCRQ-CocE) that retained greater than 90% of its activity after 41 days at 37°C, representing an improvement of more than 4700-fold over the wild-type enzyme. CCRQ-CocE could also be modified by polyethylene glycol (PEG) polymers, which improved its in vivo residence time from 24 to 72 h, as measured by a cocaine lethality assay, by self-administration in rodents, and by measurement of inhibition of cocaine-induced cardiovascular effects in rhesus monkeys. PEG-CCRQ elicited negligible immune response in rodents. Subunit stabilization and PEGylation has thus produced a potential protein therapeutic with markedly higher stability both in vitro and in vivo.

Cocaine toxicity is a widespread problem in the United States, responsible for more than 500,000 emergency department visits a year. There is currently no U.S. Food and Drug Administration-approved pharmacotherapy to directly treat cocaine toxicity. To this end, we have developed a mutant bacterial cocaine esterase (DM-CocE), which has been previously shown to rapidly hydrolyze cocaine into inert metabolites, preventing and reversing toxicity with limited immunogenic potential. Herein we describe the ability of DM-CocE to hydrolyze the active cocaine metabolites norcocaine and cocaethylene and its inability to hydrolyze benzoylecgonine. DM-CocE hydrolyzes norcocaine and cocaethylene with 58 and 45% of its catalytic efficiency for cocaine in vitro as measured by a spectrophotometric assay. We have developed a mass spectrometry method to simultaneously detect cocaine, benzoylecgonine, norcocaine, and ecgonine methyl ester to quantify the effect of DM-CocE on normal cocaine metabolism in vivo. DM-CocE administered to rats 10 min after a convulsant dose of cocaine alters the normal metabolism of cocaine, rapidly decreasing circulating levels of cocaine and norcocaine while increasing ecgonine methyl ester formation. Benzoylecgonine was not hydrolyzed in vivo, but circulating concentrations were reduced, suggesting that DM-CocE may bind and sequester this metabolite. These findings suggest that DM-CocE may reduce cocaine toxicity by eliminating active and toxic metabolites along with the parent cocaine molecule.

This paper describes a guidance method that enables an unmanned aircraft to execute a mid-air rendezvous with another aircraft flying along a known path. The method uses a vector field approach for following time-optimal, 3-dimensional Dubins airplane paths to a desired location. The desired flight path is mathematically defined as the intersection of two surface functions. The paper describes a method for deriving surface functions that result in the inclined straight line and helical flight paths that are required to fly these time optimal paths. A low computation cost, unconstrained optimization routine is presented that can be used to determine a time-optimal path that will result in the interception of another aircraft. Simulation results are provided for the intercept of an aircraft flying along an elliptical path.

Cocaine toxicity is a prevalent problem in the Unites States for which there is currently no FDA-approved pharmacotherapy. We have developed a bacterial cocaine esterase (CocE) towards this indication. A thermostabilized mutant of CocE (DM-CocE) retains the hydrolytic activity of the wild-type esterase, rapidly hydrolyzing cocaine into the inactive metabolites ecgonine methyl ester and benzoic acid, and can prevent cocaine toxicities in rodent and non-human primate models. To advance DM-CocE towards clinical use, we examine here how the hydrolytic activity of DM-CocE is altered by some drugs commonly co-administered with cocaine.We employed a spectrophotometric cocaine hydrolysis assay to evaluate whether pharmacologically relevant doses of alcohol, nicotine, morphine, phencyclidine, ketamine, methamphetamine, naltrexone, naloxone, or midazolam would alter the Michaelis-Menten kinetics of DM-CocE for cocaine. Mass spectrometry was used to evaluate interaction with diazepam as this drug interferes with the absorbance spectra of cocaine critical for the spectrophotometric assay.Alcohol, nicotine, morphine, phencyclidine, ketamine, methamphetamine, naltrexone, naloxone, and midazolam did not alter cocaine hydrolysis by DM-CocE. However, diazepam significantly slowed DM-CocE cocaine hydrolysis at very high concentrations, most likely through interaction of the phenyl ring of the benzodiazepine with the active site of DM-CocE.DM-CocE does not display significant drug interactions, with the exception of diazepam, which may warrant further study as DM-CocE progresses towards a clinically used pharmacotherapy for cocaine toxicity. Alternate benzodiazepines, e.g., midazolam could be used to avoid this potential interaction.

A long-acting mutant form of a naturally occurring bacterial cocaine esterase (T172R/G173Q CocE; double mutant CocE (DM CocE)) has previously been shown to antagonize the reinforcing, convulsant, and lethal effects of cocaine in rodents. However, the effectiveness and therapeutic characteristics of DM CocE in nonhuman primates, in a more clinically relevant context, are unknown. The current studies were aimed at (1) characterizing the cardiovascular effects of cocaine in freely moving rhesus monkeys, (2) evaluating the capacity of DM CocE to ameliorate these cocaine-induced cardiovascular effects when administered 10 min after cocaine, and (3) assessing the immunological responses of monkeys to DM CocE following repeated administration. Intravenous administration of cocaine produced dose-dependent increases in mean arterial pressure (MAP) and heart rate (HR) that persisted throughout the 2-h observation period following a dose of 3.2 mg/kg cocaine. Cocaine failed to produce reliable changes in electrocardiograph (ECG) parameters, body temperature, and locomotor activity. DM CocE produced a rapid and dose-dependent amelioration of the cardiovascular effects, with saline-like MAP measures restored within 5–10 min, and saline-like HR measures restored within 20–40 min of DM CocE administration. Although administration of DM CocE produced increases in anti-CocE antibodies, they did not appear to have a neutralizing effect on the capacity of DM CocE to reverse the cardiovascular effects of cocaine. In conclusion, these findings in monkeys provide strong evidence to suggest that highly efficient cocaine esterases, such as DM CocE, can provide a potential therapeutic option for treatment of acute cocaine intoxication in humans.

Background A longer acting, double mutant bacterial cocaine esterase (CocE T172R/G173Q; DM CocE) has been shown to protect mice from cocaine-induced lethality, inhibit the reinforcing effects of cocaine in rats, and reverse cocaine's cardiovascular effects in rhesus monkeys. The current studies evaluated the effectiveness of DM CocE to protect against, and reverse cocaine's cardiovascular, convulsant, and lethal effects in male and female rats. Methods Pretreatment studies were used to determine the effectiveness and in vivo duration of action for DM CocE to protect rats against the occurrence of cardiovascular changes, convulsion and lethality associated with acute cocaine toxicity. Posttreatment studies were used to evaluate the capacity of DM CocE to rescue rats from the cardiovascular and lethal effects of large doses of cocaine. In addition, male and female rats were studied to determine if there were any potential effects of sex on the capacity of DM CocE to protect against, or reverse acute cocaine toxicity in rats. Results Pretreatment with DM CocE dose-dependently protected rats against cocaine-induced cardiovascular changes, convulsion and lethality, with higher doses active for up to 4 h, and shifting cocaine-induced lethality at least 10-fold to the right. In addition to dose-dependently recovering rats from an otherwise lethal dose of cocaine, post-treatment with DM CocE also reversed the cardiovascular effects of cocaine. There were no sex-related differences in the effectiveness of DM CocE to protect against, or reverse acute cocaine toxicity. Conclusions Together, these results support the development of DM CocE for the treatment of acute cocaine toxicity.

Kirkwood-Buff (KB) solution theory is a means to obtain certain thermodynamic derivatives from knowledge of molecular distributions. In actual practice the required integrals over radial distribution functions suffer inaccuracies due to finite-distance truncation effects and their use in closed systems. In this work we discuss how best to minimize these inaccuracies under traditional KB theory. In addition we implement a method for calculating KB quantities in molecular simulations with periodic boundary conditions and particularly within the canonical ensemble. The method is based on a finite-Fourier-series expansion of molecular concentration fluctuations and leads to more reliable results for a given computational effort. The procedure is validated and compared to the original method for a nonideal liquid mixture of Lennard-Jones particles intended to imitate a real system, carbon tetrafluoride, and methane.

Colloque avec actes et comité de lecture. Internationale.; International audience; The physical origin of spiral vortex breakdown is investigated using the direct and adjoint Navier-Stokes equations linearized around axisymmetric vortex breakdown. The wave modes region, defined as the overlap region between adjoint and direct global mode, allows us to determine whether the wake of the recirculation region or the recirculation region itself causes the spiral vortex breakdown.

This paper presents a model developed to explain the life-cycle patterns in both homeownership and portfolio allocation, and the relationship between them, using a model of rational agents. Two key innovations are incorporated into this model. First, housing is explicitly modeled as both a consumption and investment good, as opposed to examining just one aspect in isolation from the other. Second, traditional mortgage contracts are also explicitly introduced into the model. A finite horizon life-cycle model including both of these innovations is then solved and calibrated using data from the Health and Retirement Survey. As a result, the model proves that the “over-investment” of housing is not inconsistent with the behavior of rational, forward-looking agents. The model is also able to capture the negative correlation between the housing share and risky asset share of portfolio. The results show how the desire to consume large homes contributes both to an increase in the portfolio share of housing and a decrease in the portfolio share of risky assets. This model demonstrates the close link between the housing “over-investment” and the stock “under-investment” puzzles

Deriving electrical energy from glucose and other carbohydrates under mild conditions is an important research objective because these biomolecules are abundant, renewable, have high energy density, and are convenient as fuels. This rich promise has not been realized because stable, inexpensive, and efficient catalysts are not available to oxidize carbohydrates and transfer all or nearly all of their electrons to fuel cell anodes. We report here that viologen catalysts meet these demanding criteria by catalytically oxidizing glucose and other carbohydrates in a mildly alkaline solution, making possible a direct carbohydrate fuel cell. Formate and carbonate are major products of carbohydrate oxidation, demonstrating that extensive carbon-carbon bond breaking has occurred. A rudimentary fuel cell utilizing viologen catalysts and glucose or dihydroxyacetone as fuels demonstrated electrical power production at up to 20 mA/cm 2 superficial current density. Improved catalyst function and cell design should significantly advance the efficiency and viability of direct carbohydrate fuel cell technology as a means of generating electrical energy from renewable biomass.

The effects of two different polymeric wound dressings and a new collagen matrix (CM) implant on the healing and scarring of full-thickness excision wounds were studied in swine. The synthetic polymers comprised an occlusive O2-impermeable hydrocolloid dressing (HCD) and an occlusive O2-permeable polyurethane film (PUF). The CM implant consisted of an acellular collagen sponge fabricated from purified bovine tendon type I collagen. Wounds were evaluated for granulation tissue--production capacity by measuring 14C proline incorporation into collagenase-sensitive protein. Epidermal resurfacing and wound contraction were measured by computerized morphometric image analysis of wounds made on a tattooed grid. In comparison with air-exposed wounds, the relative collagen synthetic capacity was greater in the granulation tissue of wounds treated with HCD, PUF, or CM with occlusion. Both HCD and PUF accelerated by 40% the epidermal resurfacing over the granulating wound bed. Wound contraction was significantly reduced by CM but was not altered by the occlusive dressings.

Radial histophysiologic gradient culture uses thin walled, permeable collagen tubes to house inocula in the form of either tissue explants, aggregates of cells, or dissociated cells. The outgrowth from these inocula spreads on the inner surface of the cylindrical tube, completely lining the lumen. Metabolites are exchanged through the wall of the collagen tube by diffusion from the pool of medium surrounding the cylinder. Urothelial cells form organoid stratified epithelium. A histophysiologic gradient occurs with the basal surface of the epithelium attached to the collagen wall. At this interface, for normal bladder, the initiation of epithelial renewal is seen in the basal zone, as shown by incorporation of tritiated thymidine. The simulation of conditions in nature is attained by the exchange of metabolites between the pool of medium and the basal zone of the epithelium. NBT-II appears as two concentric stratified epithelia. Isotopic labelling is seen throughout the epithelium attached to the collagen membrane. In the superficial stratified epithelium remnants of nuclei are seen without isotopic labelling. Preparation of living cultures and, after fixation, of histologic sections is technically easy.

• Adjacent punch biopsy wounds in 20 subjects were treated with a collagen matrix or Monsel's solution. Both techniques were easy to use and were hemostatically effective. The collagen matrix produced less inflammation, had a lower incidence of wound infection, was associated with a faster reepithelialization rate, and healed with a modestly better appearance at four weeks than did Monsel's solution. ( Arch Dermatol 1986;122:546-549)

Summary.-Five neurologically normal and five apractic subjects were required to develop and maintain target intraoral pressure Levels during 5-sec. trials. The apractic subjects showed increased latencies in gaining the target and reduced maintenance time and increased variabiliry in attempts to stay at target. Results suggest that physiologically based assessment tasks provide sensitive indices of the degree of oral apraxia in pacients with left-hemisphere brain damage. Knowledge of oral apractic deficits in ~atients with left-hemisphere brain damage is based primarily on rating-scale judgements of performance on oral movement tasks. Although results from studies using rating scales have been important in establishing the high incidence of oral apraxia in Broca's aphasia and the differential effects of aphasia type on isolated compared to sequential oral movements, they have not provided the finegrained analysis necessary to make qualitative decisions regarding the severity of involvement. The purpose of this study was to investigate oral apraxia in patients with Broca's aphasia utilizing an aerodynamic monitoring task. Five subjects with Broca's aphasia and apraxia selected on the basis of performance on the Boston Diagnostic Aphasia Examination (Goodglass & Kaplan, 1972), computerized tomography and neurological examination, and five neurologically normal subjects participated in a series of tasks char required sequential coordinated movements of the respiratory apparatus and upper alru8ay Each subject was seated in a dental chair in front of a Tektronix RM 564 storage oscilloscope with dual beam trace amplifier. Two 6-in. pieces of Intramedic .070-in tubing were placed in the subject's mouth and sealed with the lips. One piece of tubing was connected to a Statham 131 TC pressure transducer and the other served as a "bleed" tube to allow airflow during the course of the tasks. The subjects were required to inspire as fully as possible and blow into the pieces of tubing with maximum force for 3 sec. Each trial was recorded on the storage oscilloscope and on a Honeywell 1858 Visicorder. The subject's mean maximum intraoral pressure was calculated over the 3-sec. trials and was used to set target levels of 25%, 50%, and 75% of mean peak intraoral pressure for the experimental tasks. The subjects were required to match and track a target cursor set at each of these target levels on a dual beam oscilloscope with another cursor which reflected the intraoral pressure applied to the transducer. The three levels were randomized for each subject and five 5-sec. trials were completed at each of the three target levels. Oscillographic records of the 15 trials of each subject were used to determine onset time, maintenance time, and variability in performance of the tasks. Onset time was measured from the triggering of the target cursor to the point at

Colloque avec actes et comité de lecture. Internationale.; International audience; Swirling flows with jet-like axial velocities are studied by means of direct numerical simulations for various control parameters. The numerical code solves the low-Mach number approximation of the Navier-Stokes equations in cylindrical coordinates which allows the incorporation of compressible and variable-density effects without the adverse effect of acoustic waves on the numerical time-step. The governing parameters, such as swirl and coflow, are varied, and their effect on the breakdown type and breakdown location is studied. The nonlinear direct numerical simulation traces the steady states of the swirling flow, and the structure of the bifurcation is described as a function of the swirl parameter, the Reynolds number and the coflow parameter. In particular, unstable branches are computed and their physical relevance is discussed. The analysis gives new insight into the prevalence of coherent states and their controllability.