Novel decay dynamics revealed for virus-mediated drug activation in cytomegalovirus infection

Human cytomegalovirus (CMV) infection is a substantial cause of morbidity and mortality in immunocompromised hosts and globally is one of the most important congenital infections. The nucleoside analogue ganciclovir (GCV), which requires initial phosphorylation by the viral UL97 kinase, is the mainstay for treatment. To date, CMV decay kinetics during GCV therapy have not been extensively investigated and its clinical implications not fully appreciated. We measured CMV DNA levels in the blood of 92 solid organ transplant recipients with CMV disease over the initial 21 days of ganciclovir therapy and identified four distinct decay patterns, including a new pattern exhibiting a transient viral rebound (Hump) following initial decline. Since current viral dynamics models were unable to account for this Hump profile, we developed a novel multi-level model, which includes the intracellular role of UL97 in the continued activation of ganciclovir, that successfully described all the decline patterns observed. Fitting the data allowed us to estimate ganciclovir effectiveness in vivo (mean 92%), infected cell half-life (mean 0.7 days), and other viral dynamics parameters that determine which of the four kinetic patterns will ensue. An important clinical implication of our results is that the virological efficacy of GCV operates over a broad dose range. The model also raises the possibility that GCV can drive replication to a new lower steady state but ultimately cannot fully eradicate it. This model is likely to be generalizable to other anti-CMV nucleoside analogs that require activation by viral enzymes such as UL97 or its homologues

High power RF input couplers and test stand for the BERLinPro Project

The bERLinPro project [1], under construction at HZB, is a 100 mA, 50 MeV superconducting RF SRF energy recovery linac ERL being built to study the accelerator technology and physics of operating a high current SRF ERL. For this high current operation, coaxial RF power couplers capable of handling 115 kW of power per coupler, dual couplers per cavity , continuous wave cw at 1.3 GHz are required for both the SRF photo injector and booster cavities. In order to sustain this power level a coupler has been designed based on the high power coupler currently in use at the KEK cERL. Two key changes that were made to the coupler were the modification of the coupler tip, termed a golf tee, as well as increased cooling of the inner conductor. This former modification is incorporated so as to achieve the desired coupling, Qext 105, with minimal coupler penetration into the beam pipe. Herein, we discuss the RF design and properties of the high power coaxial coupler for the photo injector as well as booster cavities of bERLinPro, along with the design of the test stand for conditioning a pair of coupler

Software for Dataset-wide XAI: From Local Explanations to Global Insights with Zennit, CoRelAy, and ViRelAy

Deep Neural Networks (DNNs) are known to be strong predictors, but their prediction strategies can rarely be understood. With recent advances in Explainable Artificial Intelligence, approaches are available to explore the reasoning behind those complex models' predictions. One class of approaches are post-hoc attribution methods, among which Layer-wise Relevance Propagation (LRP) shows high performance. However, the attempt at understanding a DNN's reasoning often stops at the attributions obtained for individual samples in input space, leaving the potential for deeper quantitative analyses untouched. As a manual analysis without the right tools is often unnecessarily labor intensive, we introduce three software packages targeted at scientists to explore model reasoning using attribution approaches and beyond: (1) Zennit - a highly customizable and intuitive attribution framework implementing LRP and related approaches in PyTorch, (2) CoRelAy - a framework to easily and quickly construct quantitative analysis pipelines for dataset-wide analyses of explanations, and (3) ViRelAy - a web-application to interactively explore data, attributions, and analysis results.Comment: 10 pages, 3 figure

RF input power couplers for high current SRF applications

present day accelerator science. The bERLinPro project is presently being built at HZB to address the challenges involved in high current SRF machines with the goal of generating and accelerating a 100 mA electron beam to 50 MeV in continuous wave cw mode at 1.3 GHz. One of the main challenges in this project is that of handling the high input RF power required for the photo injector as well as booster cavities where there is no energy recovery process. A high power co axial input power coupler is being developed to be used for the photo injector and booster cavities at the nominal beam current. The coupler is based on the KEK cERL design and has been modified to minimise the penetration of the coupler tip in the beam pipe without compromising on beam power coupling Qext 105 . Herein we report on the RF design of the high power 115 kW per coupler, dual couplers per cavity bERLinPro BP coupler along with initial results on thermal calculations. We summarise the RF conditioning of the TTF III couplers modified for cw operation performed in the past at BESSY HZB. A similar conditioning is envisaged in the near future for the low current SRF photo injector and the bERLinPro main linac cryomodule

Spontaneous breathing with airway pressure release ventilation favors ventilation in dependent lung regions and counters cyclic alveolar collapse in oleic-acid-induced lung injury: a randomized controlled computed tomography trial

INTRODUCTION: Experimental and clinical studies have shown a reduction in intrapulmonary shunt with spontaneous breathing during airway pressure release ventilation (APRV) in acute lung injury. This reduction was related to reduced atelectasis and increased aeration. We hypothesized that spontaneous breathing will result in better ventilation and aeration of dependent lung areas and in less cyclic collapse during the tidal breath. METHODS: In this randomized controlled experimental trial, 22 pigs with oleic-acid-induced lung injury were randomly assigned to receive APRV with or without spontaneous breathing at comparable airway pressures. Four hours after randomization, dynamic computed tomography scans of the lung were obtained in an apical slice and in a juxtadiaphragmatic transverse slice. Analyses of regional attenuation were performed separately in nondependent and dependent halves of the lungs on end-expiratory scans and end-inspiratory scans. Tidal changes were assessed as differences between inspiration and expiration of the mechanical breaths. RESULTS: Whereas no differences were observed in the apical slices, spontaneous breathing resulted in improved tidal ventilation of dependent lung regions (P < 0.05) and less cyclic collapse (P < 0.05) in the juxtadiaphragmatic slices. In addition, with spontaneous breathing, the end-expiratory aeration increased and nonaerated tissue decreased in dependent lung regions close to the diaphragm (P < 0.05 for the interaction ventilator mode and lung region). CONCLUSION: Spontaneous breathing during APRV redistributes ventilation and aeration to dependent, usually well-perfused, lung regions close to the diaphragm, and may thereby contribute to improved arterial oxygenation. Spontaneous breathing also counters cyclic collapse, which is a risk factor for ventilation-associated lung injury

Booster cavity and fundamental power coupler design issues for bERLinPro

HZB has started building the 50 MeV, 100mA demonstrator energy recovery linac ERL facility bERLinPro. The high power injector system needs to deliver this beam at 6.5 MeV by combining the energy gain of a 1.4 cell SRF photo injector and three Cornell style 2 cell booster cavities. One booster cavity will be operated at zero crossing for bunch energy chirping. Thus two booster cavities have to deliver 2MV each requiring a strong coupling with a loaded Q of 105. To house the two envisaged KEK fundamental power couplers FPC with the cavity, the geometry was slightly modified. Further, to increase coupling and reduce transverse kick effects to the beam, a golf tee antenna tip was designed. This paper summarizes the SRF challenges for the booster cavities, the operational conditions and the modification to the KEK couplers, including tracking calculations to estimate the coupler kick effect to higher orde

bERLinPro Booster Cavity Design, Fabrication and Test Plans

The bERLinPro project, a 100 mA, 50 MeV superconducting RF SRF Energy Recovery Linac ERL is under construction at Helmholtz Zentrum Berlin for the purpose of studying the technical challenges and physics of operating a high current, c.w., 1.3 GHz ERL. This machine will utilize three unique SRF cryomodules for the injector, booster and linac module respectively. The booster cryomodule will contain three 2 cell SRF cavities, based on the original design by Cornell University, and will be equipped with twin 115 kW RF power couplers in order to provide the appropriate acceleration to the high current electron beam. This paper will review the status of the fabrication of the 4 booster cavities that have been built for this project by Jefferson Laboratory and look at the challenges presented by the incorporation of fundamental power couplers capable of delivering 115 kW. The test plan for the cavities and couplers will be given along with a brief overview of the cryomodule desig

First Horizontal Test Results of the HZB SRF Photoinjector for bERLinPro

The bERLinPro project, a small superconducting RF SRF c.w. energy recovery linac ERL is being built at Helmholtz Zentrum Berlin in order to develop the technology required for operation of a high current, 100 mA, 50 MeV ERL. The electron source for the accelerator is a 1.4 cell SRF photoinjector fitted with a multi alkali photocathode. As part of the HZB photoinjector development program three different SRF photoinjectors will be fabricated and tested. The photoinjector described herein is the second cavity that has been fabricated, and the first photoinjector designed for use with a multi alkali photocathode. The photoinjector has been built and tested at JLab and subsequently shipped to HZB for testing in the horizontal test cryostat HoBiCaT prior to installation in the photoinjector cryomodule. This cryomodule will be used to measure the photocathode operation in a dedicated experiment called GunLab, the precursor to installation in the bERLinPro hall. This paper will report on the final results of the cavity installed in the helium vessel in the vertical testing dewar at Jefferson Lab as well as the first horizontal test in HoBiCa

Results and Performance Simulations of the Main Linac Design for BERLinPro

The Berlin Energy Recovery Linac Project BERLinPro is designed to develop and demonstrate CW LINAC technology for 100 mA class ERLs. High current operation requires an effective damping of higher ordermodes HOMs of the 1.3 GHz main linac cavities. We have studied elliptical seven cell cavities damped by five waveguides at the adjacent beam tubes. Eigenmode calculations for geometrical figures of merit show that the present design should allow successful cw linac operation at the maximum beam current of 100 mA 77pC bunch charge. In this paper the progress in HOM calculations to avoid beam breakup instabilities for the favored cavity structure is presente

RF Measurements of the 1.6 cell Lead Niobium Photoinjector in HoBiCat

The development of a simple and robust SRF photoinjector capable of delivering 1 mA average current in c.w. operation continues to advance with the horizontal RF testing of the 1.6 cell Pb Nb hybrid photoinjector. This injector utilizes a sputtered lead coating on a removable Nb cathode plug as the photoelectron source and has recently been tested in the horizontal test cryostat facility, HoBiCaT, at Helmholtz Zentrum Berlin. In this paper we will report on the status of these RF measurements and compare the performance to previous vertical RF tests performed at Jefferson Laboratory. We will also provide a summary of the cavity tuning range and microphonics measurements now that it has been installed into a helium vessel equipped with a Saclay style tuner