Identification of β-Lactams Active against Mycobacterium tuberculosis by a Consortium of Pharmaceutical Companies and Academic Institutions

Rising antimicrobial resistance challenges our ability to combat bacterial infections. The problem is acute for tuberculosis (TB), the leading cause of death from infection before COVID-19. Here, we developed a framework for multiple pharmaceutical companies to share proprietary information and compounds with multiple laboratories in the academic and government sectors for a broad examination of the ability of β-lactams to kill Mycobacterium tuberculosis (Mtb). In the TB Drug Accelerator (TBDA), a consortium organized by the Bill & Melinda Gates Foundation, individual pharmaceutical companies collaborate with academic screening laboratories. We developed a higher order consortium within the TBDA in which four pharmaceutical companies (GlaxoSmithKline, Sanofi, MSD, and Lilly) collectively collaborated with screeners at Weill Cornell Medicine, the Infectious Disease Research Institute (IDRI), and the National Institute of Allergy and Infectious Diseases (NIAID), pharmacologists at Rutgers University, and medicinal chemists at the University of North Carolina to screen ∼8900 β-lactams, predominantly cephalosporins, and characterize active compounds. In a striking contrast to historical expectation, 18% of β-lactams screened were active against Mtb, many without a β-lactamase inhibitor. One potent cephaloporin was active in Mtb-infected mice. The steps outlined here can serve as a blueprint for multiparty, intra- and intersector collaboration in the development of anti-infective agents

Conformal quantum field theory: From Haag-Kastler nets to Wightman fields

Starting from a chiral conformal Haag-Kastler net of local observables on two-dimensional Minkowski space-time, we construct associated pointlike localizable charged fields which intertwine between the superselection sectors with finite statistics of the theory. This amounts to a proof of the spin-statistics theorem, the PCT theorem, the Bisognano-Wichmann identification of modular operators, Haag duality in the vacuum sector, and the existence of operator product expansions. Our method consists of the explicit use of the representation theory of the universal covering group of SL(2,R). A central role is played by a ''conformal cluster theorem'' for conformal two-point functions in algebraic quantum field theory. Generalizing this ''conformal cluster theorem'' to the n-point functions of Haag-Kastler theories, we can finally construct from a chiral conformal net of algebras a compelte set of conformal n-point functions fulfilling the Wightman axioms. (orig.)74 refs.Available from TIB Hannover: RA 2999(96-136) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEDEGerman

On the existence of pointlike localized fields in conformally invariant quantum physics

SIGLEAvailable from TIB Hannover: RA2999(92-156) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekDEGerman

The construction of the pointlike localized charged fields from conformal Haag-Kastler nets

Starting from a chiral conformal Haag-Kastler net on 2 dimensional Minkowski space we construct associated charged pointlike localized fields which intertwine between arbitrary superselection sectors with finite statistics of the theory. This amounts to a proof of the Spin-Statistics theorem, the PCT theorem and the existence of operator product expansions. This paper generalizes similar results of a recently published paper by Fredenhagen and the author [FrJ] from the neutral vacuum sector to the full theory with arbitrary charge and finite statistics. (orig.)27 refs.Available from TIB Hannover: RA 2999(95-105) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEDEGerman

From conformal Haag-Kastler nets to Wightman functions

Starting from a chiral conformal Haag-Kastler net on 2 dimensional Minkowski space we present a canonical construction that leads to a complete set of conformally covariant N-point-functions fulfilling the Wightman axioms. Our method consists of an explicit use of the representation theory of the universal covering group of SL(2,R) combined with a generalization of the conformal cluster theorem to N-point-functions. (orig.)Available from TIB Hannover: RA 2999(96-181) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEDEGerman

Conformal Haag-Kastler nets, pointlike localized fields and the existence of operator product expansions

Starting from a chiral conformal Haag-Kastler net on 2 dimensional Minkowski space we construct associated pointlike localized fields. This amounts to a proof of the existence of operator product expansions. We derive the result in two ways. One is based on the geometrical identification of the modular structure, the other depends on a ''conformal cluster theorem'' of the conformal two-point-functions in algebraic quantum field theory. The existence of the fields then implies important structural properties of the theory, as PCT-invariance, the Bisognano-Wichmann identification of modular operators, Haag duality and additivity. (orig.)Available from TIB Hannover: RA 2999(94-174) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEDEGerman

Crowdsourced logistics : the pickup and delivery problem with transshipments and occasional drivers

This article considers a setting in which a courier, express, and parcel service provider operates a fleet of vehicles with regular drivers (RDs) to ship parcels from pickup to delivery points. Additionally, the company uses a platform where occasional drivers (ODs) offer their willingness to take on requests that are on or near the route they had originally planned. There exist transshipment points (TPs) to better integrate these ODs. ODs or RDs may transfer load at these predetermined TPs. The problem is modeled as a mixed-integer programming model and called pickup and delivery problem with transshipments and occasional drivers (PDPTOD). We develop a solution approach based on an adaptive large neighborhood search. The article provides insights on how the number and location of TPs impact the cost advantages achieved by integrating ODs. It also shows that the cost savings are highly sensitive to the assumed flexibility and compensation scheme

On-Road NOx and Smoke Emissions of Diesel Light Commercial VehiclesCombining Remote Sensing Measurements from across Europe

Light commercial vehicles (LCVs) account for about 10-15% of road traffic in Europe. There have only been few investigations on their on-road emission performance. Here, on-road remote sensing vehicle emission measurements from 18 locations across four European countries are combined for a comprehensive analysis of NOx and smoke emission rates from diesel LCV in the past two decades. This allows differentiating the performance by emission standards, model years, curb weights, engine loads, manufacturers, vehicle age, and temperature, as well as by measurement devices. We find a general consistency between devices and countries. On-road NOx emission rates have been much higher than type approval limit values for all manufacturers, but some perform systematically better than others. Emission rates have gone down only with the introduction of Euro 6a-b emission standards since the year 2015. Smoke emission rates are considered a proxy for particulate emissions. Their emissions have decrease substantially from the year 2010 onward for all countries and size classes measured. This is consistent with the substantial tightening of the particulate matter emission limit value that typically forced the introduction of a diesel particulate filter. The average NOx emission rate increases with engine load and decreasing ambient temperatures, particularly for Euro 4 and 5 emission classes. This explains to a large extent the differences in the absolute level between the measurement sites together with differences in fleet composition. These dependencies have already been observed earlier with diesel passenger cars; they are considered part of an abnormal emission control strategy. Some limited increase of the NOx emission rate is observed for Euro 3 vehicles older than 10 years. The strong increase for the youngest Euro 6 LCVs might rather reflect technology advances with successively younger models than genuine deterioration. However, the durability of emission controls for Euro 6 vehicles should be better monitored closely. Smoke emission rates continuously increase with vehicle age, suggesting a deterioration of the after-treatment system with use