Membrane-Based, Liquid–Liquid Separator with Integrated Pressure Control

We describe the development and application of an improved, membrane-based, liquid–liquid separator. Membrane-based separation relies on the exploitation of surface forces and the use of a membrane wetted by one of the phases; however, successful separation requires accurate control of pressures, making the operation and implementation cumbersome. Here we present an improved separator design that integrates a pressure control element to ensure that adequate operating conditions are always maintained. Additionally, the integrated pressure control decouples the separator from downstream unit operations. A detailed examination of the controlling physical equations shows how to design the device to allow operation across a wide range of conditions. Easy to implement, multistage separations such as solvent swaps and countercurrent extractions are demonstrated. The presented design significantly simplifies applications ranging from multistep synthesis to complex multistage separations.Novartis-MIT Center for Continuous ManufacturingUnited States. Defense Advanced Research Projects Agency (Grant N66001-11-C-4147

Averaging level control to reduce off-spec material in a continuous pharmaceutical pilot plant

The judicious use of buffering capacity is important in the development of future continuous pharmaceutical manufacturing processes. The potential benefits are investigated of using optimal-averaging level control for tanks that have buffering capacity for a section of a continuous pharmaceutical pilot plant involving two crystallizers, a combined filtration and washing stage and a buffer tank. A closed-loop dynamic model is utilized to represent the experimental operation, with the relevant model parameters and initial conditions estimated from experimental data that contained a significant disturbance and a change in setpoint of a concentration control loop. The performance of conventional proportional-integral (PI) level controllers is compared with optimal-averaging level controllers. The aim is to reduce the production of off-spec material in a tubular reactor by minimizing the variations in the outlet flow rate of its upstream buffer tank. The results show a distinct difference in behavior, with the optimal-averaging level controllers strongly outperforming the PI controllers. In general, the results stress the importance of dynamic process modeling for the design of future continuous pharmaceutical processes

Rapid Flow-Based Peptide Synthesis

A flow-based solid-phase peptide synthesis methodology that enables the incorporation of an amino acid residue every 1.8 min under automatic control or every 3 min under manual control is described. This is accomplished by passing a stream of reagent through a heat exchanger into a low volume, low backpressure reaction vessel, and through a UV detector. These features enable continuous delivery of heated solvents and reagents to the solid support at high flow rate, thereby maintaining maximal concentration of reagents in the reaction vessel, quickly exchanging reagents, and eliminating the need to rapidly heat reagents after they have been added to the vessel. The UV detector enables continuous monitoring of the process. To demonstrate the broad applicability and reliability of this method, it was employed in the total synthesis of a small protein, as well as dozens of peptides. The quality of the material obtained with this method is comparable to that for traditional batch methods, and, in all cases, the desired material was readily purifiable by RP-HPLC. The application of this method to the synthesis of the 113-residue Bacillus amyloliquefaciens RNase and the 130-residue DARPin pE59 is described in the accompanying manuscript.MIT Faculty Start-up FundMassachusetts Institute of Technology (Charles E. Reed Faculty Initiative Fund)Deshpande Center for Technological InnovationDamon Runyon-Rachleff (Innovation Award)Sontag Foundation (Distinguished Scientist Award)C. P. Chu and Y. Lai FellowshipDaniel S. Kemp Summer FellowshipNational Institute of General Medical Sciences (U.S.). Biotechnology Training Program (Grant 5T32GM008334-25)National Institutes of Health (U.S.) (Fellowship F32GM101762

Rhinovirus-induced epithelial RIG-I inflammasome suppresses antiviral immunity and promotes inflammation in asthma and COVID-19.

Rhinoviruses and allergens, such as house dust mite are major agents responsible for asthma exacerbations. The influence of pre-existing airway inflammation on the infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is largely unknown. We analyse mechanisms of response to viral infection in experimental in vivo rhinovirus infection in healthy controls and patients with asthma, and in in vitro experiments with house dust mite, rhinovirus and SARS-CoV-2 in human primary airway epithelium. Here, we show that rhinovirus infection in patients with asthma leads to an excessive RIG-I inflammasome activation, which diminishes its accessibility for type I/III interferon responses, leading to their early functional impairment, delayed resolution, prolonged viral clearance and unresolved inflammation in vitro and in vivo. Pre-exposure to house dust mite augments this phenomenon by inflammasome priming and auxiliary inhibition of early type I/III interferon responses. Prior infection with rhinovirus followed by SARS-CoV-2 infection augments RIG-I inflammasome activation and epithelial inflammation. Timely inhibition of the epithelial RIG-I inflammasome may lead to more efficient viral clearance and lower the burden of rhinovirus and SARS-CoV-2 infections

Measurement of WγW\gamma and ZγZ\gamma Production in ppˉp\bar{p} Collisions at s\sqrt{s} = 1.96 TeV

The Standard Model predictions for $W\gamma$ and $Z\gamma$ production are tested using an integrated luminosity of 200 pb$^{-1}$ of \ppbar collision data collected at the Collider Detector at Fermilab. The cross sections are measured selecting leptonic decays of the $W$ and $Z$ bosons, and photons with transverse energy $E_T>7$ GeV that are well separated from leptons. The production cross sections and kinematic distributions for the $W\gamma$ and $Z\gamma$ are compared to SM predictions.Comment: 7 pages, 4 figures, submitted to PR

Measurement of the Lifetime Difference Between B_s Mass Eigenstates

We present measurements of the lifetimes and polarization amplitudes for B_s --> J/psi phi and B_d --> J/psi K*0 decays. Lifetimes of the heavy (H) and light (L) mass eigenstates in the B_s system are separately measured for the first time by determining the relative contributions of amplitudes with definite CP as a function of the decay time. Using 203 +/- 15 B_s decays, we obtain tau_L = (1.05 +{0.16}/-{0.13} +/- 0.02) ps and tau_H = (2.07 +{0.58}/-{0.46} +/- 0.03) ps. Expressed in terms of the difference DeltaGamma_s and average Gamma_s, of the decay rates of the two eigenstates, the results are DeltaGamma_s/Gamma_s = (65 +{25}/-{33} +/- 1)%, and DeltaGamma_s = (0.47 +{0.19}/-{0.24} +/- 0.01) inverse ps.Comment: 8 pages, 3 figures, 2 tables; as published in Physical Review Letters on 16 March 2005; revisions are for length and typesetting only, no changes in results or conclusion

Measurement of the ttbar Production Cross Section in ppbar Collisions at sqrt{s}=1.96 TeV using Lepton + Jets Events with Secondary Vertex b-tagging

We present a measurement of the ttbar production cross section using events with one charged lepton and jets from ppbar collisions at a center-of-mass energy of 1.96 TeV. In these events, heavy flavor quarks from top quark decay are identified with a secondary vertex tagging algorithm. From 162 pb-1 of data collected by the Collider Detector at Fermilab, a total of 48 candidate events are selected, where 13.5 +- 1.8 events are expected from background contributions. We measure a ttbar production cross section of 5.6^{+1.2}_{-1.1} (stat.) ^{+0.9}_{0.6} (syst.) pb.Comment: 28 pages, 20 figures. Published in Physical Review

Search for ZZ and ZW Production in ppbar Collisions at sqrt(s) = 1.96 TeV

We present a search for ZZ and ZW vector boson pair production in ppbar collisions at sqrt(s) = 1.96 TeV using the leptonic decay channels ZZ --> ll nu nu, ZZ --> l l l' l' and ZW --> l l l' nu. In a data sample corresponding to an integrated luminosity of 194 pb-1 collected with the Collider Detector at Fermilab, 3 candidate events are found with an expected background of 1.0 +/- 0.2 events. We set a 95% confidence level upper limit of 15.2 pb on the cross section for ZZ plus ZW production, compared to the standard model prediction of 5.0 +/- 0.4 pb.Comment: 7 pages, 2 figures. This version is accepted for publication by Phys. Rev. D Rapid Communication

Measurement of the Cross Section for Prompt Diphoton Production in p-pbar Collisions at sqrt(s) = 1.96 TeV

We report a measurement of the rate of prompt diphoton production in $p\bar{p}$ collisions at $\sqrt{s}=1.96 ~\hbox{TeV}$ using a data sample of 207 pb$^{-1}$ collected with the upgraded Collider Detector at Fermilab (CDF II). The background from non-prompt sources is determined using a statistical method based on differences in the electromagnetic showers. The cross section is measured as a function of the diphoton mass, the transverse momentum of the diphoton system, and the azimuthal angle between the two photons and is found to be consistent with perturbative QCD predictions.Comment: 7 pages, 3 figures,revtex4. Version accepted by PRL, but with cross section tables i