Publications

ABSTRACT We assessed the effect of voriconazole (VRC) on the expression and release of selected cytokines and chemokines in the THP-1 human monocytic cell line in response to Aspergillus fumigatus hyphal fragments (HF) by cDNA microarray analysis, reverse transcriptase (RT) PCR, and enzyme-linked immunosorbent assay. Stimulation of THP-1 cells by HF alone caused a significant up-regulation of CCL4 ( MIP1B ) and CCL16 , while CCL2 ( MCP1 ) was down-regulated. By comparison, in the presence of VRC, a large number of genes such as CCL3 ( MIP1A ), CCL4 ( MIP1B ), CCL5 ( RANTES ), CCL7 ( MCP3 ), CCL11 ( EOTAXIN ), CCL15 ( MIP1 Δ), CXCL6 , and CXCL13 were strongly up-regulated in THP-1 cells challenged by HF, whereas CCL20 ( MIP3A ) and CCL21 ( MIP2 ) were down-regulated. Among five genes differentially expressed in THP-1 cells, IL12A , IL12B , and IL-16 were down-regulated whereas IL-11 and TGFB1 were significantly up-regulated in the presence of VRC. The inflammation-related genes IFN γ, IL1R1 , and TNFA were also up-regulated in THP-1 cells exposed to HF only in the presence of VRC. RT-PCR of four selected genes validated the results of microarrays. The release of interleukin 1β (IL-1β) and IL-12 was significantly increased from monocytes stimulated either by HF alone ( P < 0.05) or in the presence of VRC ( P < 0.01 and P < 0.05, respectively). In contrast, tumor necrosis factor alpha release from monocytes was enhanced only in the presence of VRC ( P < 0.01). The chemokines monocyte chemoattractant protein 1 and macrophage inflammatory protein 1β were decreased under both conditions ( P < 0.01). These results demonstrate that in the presence of VRC, HF induces a more pronounced profile of gene expression in THP-1 cells than HF alone, potentially leading to more-efficient host resistance to A. fumigatus .

Abstract Introduction Evidence is limited on the effectiveness of a fourth vaccine dose against coronavirus disease 2019 (COVID‐19) in populations with prior severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infections. We estimated the risk of COVID‐19 deaths and SARS‐CoV‐2 infections according to vaccination status in previously infected individuals in Austria. Methods This is a nationwide retrospective observational study. We calculated age and gender adjusted Cox proportional hazard ratios (HRs) of COVID‐19 deaths (primary outcome) and SARS‐CoV‐2 infections (secondary outcome) from 1 November to 31 December 2022, primarily comparing individuals with four versus three vaccine doses. Relative vaccine effectiveness (rVE) was calculated as (1‐HR) X 100. Results Among 3,986,312 previously infected individuals, 281,291 (7,1%) had four and 1,545,242 (38.8%) had three vaccinations at baseline. We recorded 69 COVID‐19 deaths and 89,056 SARS‐CoV‐2 infections. rVE for four versus three vaccine doses was −24% (95% CI: −120 to 30) against COVID‐19 deaths, and 17% (95% CI: 14–19) against SARS‐CoV‐2 infections. This latter effect rapidly diminished over time and infection risk with four vaccinations was higher compared to less vaccinated individuals during extended follow‐up until June 2023. Adjusted HR (95% CI) for all‐cause mortality for four versus three vaccinations was 0.79 (0.74–0.85). Discussion In previously infected individuals, a fourth vaccination was not associated with COVID‐19 death risk, but with transiently reduced risk of SARS‐CoV‐2 infections and reversal of this effect in longer follow‐up. All‐cause mortality data suggest healthy vaccinee bias.

Trust management credentials directly authorize actions, rather than divide the authorization task into authentication and access control. Unlike traditional credentials, which bind keys to principals, trust management credentials bind keys to the authorization to perform certain tasks. The Distributed Credential FileSystem (DisCFS) uses trust management credentials to identify: (1) files being stored; (2) users; and (3) conditions under which their file access is allowed. Users share files by delegating access rights, issuing credentials in the style of traditional capabilities. Credentials permit, for example, access by remote users not known in advance to the file server, which simply enforces sharing policies rather than entangling itself in their management. Throughput and latency benchmarks of our prototype DisCFS implementation indicate performance roughly comparable to NFS version 2, while preserving the advantages of credentials for distributed control.

Coherent anti‐Stokes Raman spectra (1700–1100 cm −1 ) of 7,8‐dimethyl‐10‐tetraacetylisoalloxazine (tetracetylriboflavin) in chloroform and several other solvents of higher polarity and proton availability are reported. Solvent polarity has no influence on either the intensities or frequencies of the Raman modes, whereas the influence of protic solvents is more marked. As well as altering the effective mass of the particular atoms in the isoalloxazine involved, hydrogen bonding is known to change the bond hybridization throughout the entire ring system. A similarly mild electronic perturbation can be produced by changing the methyl substitution on the benzene subnucleus of the isoalloxazine, and this is shown to produce significant changes in the Raman spectrum. Isotopic substitution with 13 C and 15 N is used to mimic the effective mass changes that would occur on hydrogen bonding. For the model compounds in chloroform, the effect of isotopic substitution on some modes is different from that reported for the same substitution in riboflavin bound to riboflavin binding protein. Frequencies of the prominent bands in all spectra were determined by lineshape analysis. On the basis of these results a tentative interpretation is made of the changes that occur in the Raman spectra of flavins when they bind to flavoproteins.

Achieving high code reuse in physical design flows is challenging but increasingly necessary to build complex systems. Unfortunately, existing approaches based on parameterized Tcl generators support very limited reuse and struggle to preserve reusable code as designers customize flows for specific designs and technologies. We present a vision and framework based on modular flow generators that encapsulates coarse-grain and fine-grain reusable code in modular nodes and assembles them into complete flows. The key feature is a flow consistency and instrumentation layer embedded in Python, which supports mechanisms for rapid and early feedback on inconsistent composition. The approach gradually types the Tcl language and allows both automatic and user-annotated static assertion checks. We evaluate the design flows of successive generations of silicon prototypes designed in TSMC16, TSMC28, TSMC40, SKY130, and IBM180 technologies, showing how our approach can enable significant code reuse in future flows.