Pre-Existing Adenovirus Immunity Modifies a Complex Mixed Th1 and Th2 Cytokine Response to an Ad5/HIV-1 Vaccine Candidate in Humans

The results of the recent Step Study highlight a need to clarify the effects of pre-existing natural immunity to a vaccine vector on vaccine-induced T-cell responses. To investigate this interaction, we examined the relationship between pre-existing Ad5 immunity and T-cell cytokine response profiles in healthy, HIV-uninfected recipients of MRKAd5 HIV-1 gag vaccine (HVTN 050, ClinicalTrials.gov #NCT00849732). Participants were grouped by baseline Ad5 neutralizing antibody titer as either Ad5-seronegative (titer ≤18; n = 36) or Ad5-seropositive (titer >200; n = 34). Samples from vaccine recipients were analyzed for immune responses to either HIV-1 Gag peptide pools or Ad5 empty vector using an ex vivo assay that measures thirty cytokines in the absence of long-term culture. The overall profiles of cytokine responses to Gag and Ad5 had similar combinations of induced Th1- and Th2-type cytokines, including IFN-γ, IL-2, TNF-α, IP-10, IL-13, and IL-10, although the Ad5-specific responses were uniformly higher than the Gag-specific responses (p<0.0001 for 9 out of 11 significantly expressed analytes). At the peak response time point, PBMC from Ad5-seronegative vaccinees secreted significantly more IP-10 in response to Gag (p = 0.008), and significantly more IP-10 (p = 0.0009), IL-2 (p = 0.006) and IL-10 (p = 0.05) in response to Ad5 empty vector than PBMC from Ad5-seropositive vaccinees. Additionally, similar responses to the Ad5 vector prior to vaccination were observed in almost all subjects, regardless of Ad5 neutralizing antibody status, and the levels of secreted IFN-γ, IL-10, IL-1Ra and GM-CSF were blunted following vaccination. The cytokine response profile of Gag-specific T cells mirrored the Ad5-specific response present in all subjects before vaccination, and included a number of Th1- and Th2-associated cytokines not routinely assessed in current vaccine trials, such as IP-10, IL-10, IL-13, and GM-CSF. Together, these results suggest that vector-specific humoral responses may reduce vaccine-induced T-cell responses by previously undetected mechanisms

Effects of Low-Quality Audit Disclosure on Audit Effort and Informativeness

We provide evidence that audit quality disclosure increases auditors’ efforts and audit reports’ informativeness to equity investors only when audit clients’ underlying financial reporting quality is low. We find that auditors with restatement-announcing clients have greater audit lag on their concurrent, non-restating clients only when those clients have material weaknesses in internal controls. This finding is consistent with auditors taking action to decrease the insurance value, and increase the informativeness value, of audit reports following the revelation that they are low quality auditors. We find that these actions result in lower bid-ask spreads, lower stock illiquidity, and higher long-term operating performance of the affected audit clients, consistent with greater audit effort leading to greater financial reporting informativeness. Our audit effort results are more pronounced for Big N auditors, which have greater ability to reallocate audit resources between clients. Our operating performance results are more pronounced for financially-constrained and capital-issuing audit clients, consistent with these clients being more reliant on informed investor decisions. Taken together, our results are informative to the audit quality indicator project currently being evaluated by the Public Company Accounting Oversight Board and to the growing literature on audit quality

Filtering false alarms of buffer overflow analysis using SMT solvers

Buffer overflow detection using static analysis can provide a powerful tool for software programmers to find difficult bugs in C programs. Sound static analysis based on abstract interpretation, however, often suffers from false alarm problem. Although more precise abstraction can reduce the number of the false alarms in general, the cost to perform such analysis is often too high to be practical for large software. On the other hand, less precise abstraction is likely to be scalable in exchange for the increased false alarms. In order to attain both precision and scalability, we present a method that first applies less precise abstraction to find buffer overflow alarms fast, and selectively applies a more precise analysis only to the limited areas of code around the potential false alarms. In an attempt to develop the precise analysis of alarm filtering for large C programs, we perform a symbolic execution over the potential alarms found in the previous analysis, which is based on the abstract interpretation. Taking advantage of a state-of-art SMT solver, our precise analysis efficiently filters out a substantial number of false alarms. Our experiment with the test cases from three open source programs shows that our filtering method can reduce about 68% of false alarms on average. (C) 2009 Elsevier B.V. All rights reserved

Expression of uncharacterized male germ cell-specific genes and discovery of novel sperm-tail proteins in mice.

The identification and characterization of germ cell-specific genes are essential if we hope to comprehensively understand the mechanisms of spermatogenesis and fertilization. Here, we searched the mouse UniGene databases and identified 13 novel genes as being putatively testis-specific or -predominant. Our in silico and in vitro analyses revealed that the expressions of these genes are testis- and germ cell-specific, and that they are regulated in a stage-specific manner during spermatogenesis. We generated antibodies against the proteins encoded by seven of the genes to facilitate their characterization in male germ cells. Immunoblotting and immunofluorescence analyses revealed that one of these proteins was expressed only in testicular germ cells, three were expressed in both testicular germ cells and testicular sperm, and the remaining three were expressed in sperm of the testicular stages and in mature sperm from the epididymis. Further analysis of the latter three proteins showed that they were all associated with cytoskeletal structures in the sperm flagellum. Among them, MORN5, which is predicted to contain three MORN motifs, is conserved between mouse and human sperm. In conclusion, we herein identify 13 authentic genes with male germ cell-specific expression, and provide comprehensive information about these genes and their encoded products. Our finding will facilitate future investigations into the functional roles of these novel genes in spermatogenesis and sperm functions

TeksDB: Weaving Data Structures for a High-Performance Key-Value Store

Key-value stores (KVS) are now an integral part of modern dataintensive systems.Thanks to its simplicity, scalability, and efficiency over traditional database systems. Databases such as MySQL employ KVS (in this case, RocksDB as their backend storage instead of conventional database engines because KVS is less affected by data fragmentation. OLAP and big data analytics applications often use KVS as the backend store to make use of the efficient range-query operations of LSM(Log Structured Merge Tree)-based KVS. Furthermore, the increasing use of KVS as backend stores in distributed systems diversifies the workload for each local KVS, making it necessary to design a highly-concurrent data store that simultaneously processes mixed operations. The underlying technology trends also put immense pressure on the design of KVS. Nowadays, many core servers with hundred GBs of memory are common in production environments, and this enhanced density of hardware technologies (both in terms of the number of cores and memory capacity) leads to more data items residing in memory. This phenomenon places greater emphasis on the efficiency of the in-memory data structure in KVS, as more data accesses are serviced from its memory component, which is often called the memtable. The current memtable structure of KVS, however, generally assumes a limited memory capacity that only serves as a temporary write buffer, and the use of single-Threaded writes or unscalable data structures for the memtable fails to fulfill this external demand. © 2019 Copyright is held by the owner/author(s)

Expression of uncharacterized male germ cell-specific genes and discovery of novel sperm-tail proteins in mice

<div><p>The identification and characterization of germ cell-specific genes are essential if we hope to comprehensively understand the mechanisms of spermatogenesis and fertilization. Here, we searched the mouse UniGene databases and identified 13 novel genes as being putatively testis-specific or -predominant. Our <i>in silico</i> and <i>in vitro</i> analyses revealed that the expressions of these genes are testis- and germ cell-specific, and that they are regulated in a stage-specific manner during spermatogenesis. We generated antibodies against the proteins encoded by seven of the genes to facilitate their characterization in male germ cells. Immunoblotting and immunofluorescence analyses revealed that one of these proteins was expressed only in testicular germ cells, three were expressed in both testicular germ cells and testicular sperm, and the remaining three were expressed in sperm of the testicular stages and in mature sperm from the epididymis. Further analysis of the latter three proteins showed that they were all associated with cytoskeletal structures in the sperm flagellum. Among them, MORN5, which is predicted to contain three MORN motifs, is conserved between mouse and human sperm. In conclusion, we herein identify 13 authentic genes with male germ cell-specific expression, and provide comprehensive information about these genes and their encoded products. Our finding will facilitate future investigations into the functional roles of these novel genes in spermatogenesis and sperm functions.</p></div

Localization of the novel proteins in adult testis.

<p>A. Immunofluorescence staining of paraffin sections of adult testis was conducted using specific antibodies for the four proteins. Normal rabbit serum (NRS) was used as a negative control. The red color indicates proteins and nuclei were stained with DAPI (blue). Images in the boxes are magnified in the insets in merged images. Scale bar, 100 μm. B. Localization of Mm.271255/1700013F07Rik in mature sperm. Sperm from the cauda epididymis and vas deferens were immunostained with anti-Mm.271255/1700013F07Rik. DAPI was used to stain nuclei. Mm.271255/1700013F07Rik is localized to the neck and midpiece of sperm. Scale bar, 100 μm.</p