Computer engineering

Control Flow Integrity (CFI) is an effective technique to mitigate threats such as code-injection and code-reuse attacks in programs by protecting indirect transfers. For stripped binaries, a CFI policy has to be made conservatively due to the lack of source code level semantics. Existing binary-only CFI solutions such as BinCFI and CCFIR demonstrate the ability to protect stripped binaries, but the policies they apply are too permissive, allowing sophisticated code-reuse attacks. In this paper, we propose a new binary-only CFI protection scheme called BinCC, which applies static binary rewriting to provide finer-grained protection for x86 stripped ELF binaries. Through code duplication and static analysis, we divide the binary code into several mutually exclusive code continents. We further classify each indirect transfer within a code continent as either an Intra-Continent transfer or an Inter-Continent transfer, and apply separate, strict CFI polices to constrain these transfers. To evaluate BinCC, we introduce new metrics to estimate the average amount of legitimate targets of each kind of indirect transfer as well as the difficulty to leverage call preceded gadgets to generate ROP exploits. Compared to the state of the art binary-only CFI, BinCFI, the experimental results show that BinCC significantly reduces the legitimate transfer targets by 81.34% and increases the difficulty for adversaries to bypass CFI restriction to launch sophisticated ROP attacks. Also, BinCC achieves a reasonable performance, around 14% of the space overhead decrease and only 4% runtime overhead increase as compared to BinCFI.

Most patients with acute myeloid leukemia (AML) die from progressive disease after relapse, which is associated with clonal evolution at the cytogenetic level 1,2. To determine the mutational spectrum associated with relapse, we sequenced the primary tumor and relapse genomes from 8 AML patients, and validated hundreds of somatic mutations using deep sequencing; this allowed us to precisely define clonality and clonal evolution patterns at relapse. Besides discovering novel, recurrently mutated genes (e.g. WAC, SMC3, DIS3, DDX41, and DAXX) in AML, we found two major clonal evolution patterns during AML relapse: 1) the founding clone in the primary tumor gained mutations and evolved into the relapse clone, or 2) a subclone of the founding clone Users may view, print, copy, download and text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

Interactions between bone and the reproductive system have until now been thought to be limited to the regulation of bone remodeling by the gonads. We now show that, in males, bone acts as a regulator of fertility. Using coculture assays, we demonstrate that osteoblasts are able to induce testosterone production by the testes, though they fail to influence estrogen production by the ovaries. Analyses of cellspecific loss-and gain-of-function models reveal that the osteoblast-derived hormone osteocalcin performs this endocrine function. By binding to a G protein-coupled receptor expressed in the Leydig cells of the testes, osteocalcin regulates in a CREBdependent manner the expression of enzymes that is required for testosterone synthesis, promoting germ cell survival. This study expands the physiological repertoire of osteocalcin and provides the first evidence that the skeleton is an endocrine regulator of reproduction.

Hyperactivation, a swimming pattern of mammalian sperm in the oviduct, is essential for fertilization. It is characterized by asymmetrical flagellar beating and an increase of cytoplasmic Ca 2+. We observed that some mouse sperm swimming in the oviduct produce high-amplitude pro-hook bends (bends in the direction of the hook on the head), whereas other sperm produce high-amplitude anti-hook bends. Switching direction of the major bends could serve to redirect sperm toward oocytes. We hypothesized that different Ca 2+ signaling pathways produce high-amplitude pro-hook and anti-hook bends. In vitro, sperm that hyperactivated during capacitation (because of activation of CATSPER plasma membrane Ca 2+ channels) developed highamplitude pro-hook bends. The CATSPER activators procaine and 4-aminopyridine (4-AP) also induced high-amplitude prohook bends. Thimerosal, which triggers a Ca 2+ release from internal stores, induced high-amplitude anti-hook bends. Activation of CATSPER channels is facilitated by a pH rise, so both Ca 2+ and pH responses to treatments with 4-AP and thimerosal were monitored. Thimerosal triggered a Ca 2+ increase that initiated at the base of the flagellum, whereas 4-AP initiated a rise in the proximal principal piece. Only 4-AP triggered a flagellar pH rise. Proteins were extracted from sperm for examination of phosphorylation patterns induced by Ca 2+ signaling. Procaine and 4-AP induced phosphorylation of proteins on threonine and serine, whereas thimerosal primarily induced dephosphorylation of proteins. Tyrosine phosphorylation was unaffected. We concluded that hyperactivation, which is associated with capacitation, can be modulated by release of Ca 2+ from intracellular stores to reverse the direction of the dominant flagellar bend and, thus, redirect sperm.

In order to better understand how sperm movement is regulated in the oviduct, we mated wild-type female mice with Acr-EGFP males that produce sperm with fluorescent acrosomes. The fluorescence improved our ability to detect sperm within the oviduct. Oviducts were removed shortly before or after ovulation and placed in chambers on a warm microscope stage for video recording. Hyperactivated sperm in the isthmic reservoir detached frequently from the epithelium and then reattached. Unexpectedly, most sperm found in the ampulla remained bound to epithelium throughout the observation period of several minutes. In both regions, most sperm produced deep flagellar bends in the direction opposite the hook of the sperm head. This was unexpected, because mouse sperm incubated under capacitating conditions in vitro primarily hyperactivate by producing deep flagellar bends in the same direction as the hook of the head. In vitro, sperm that are treated with thimerosal to release Ca 2+ from internal stores produce deep anti-hook bends; however, physical factors such as viscous oviduct fluid could also have influenced bending in oviductal sperm. Some sperm detached from epithelium in both the ampulla and isthmus during strong contractions of the oviduct. Blockage of oviduct contractions with nicardipine, however, did not stop sperm from forming a storage reservoir in the isthmus or prevent sperm from reaching the ampulla. These observations indicate that sperm continue to bind to oviductal epithelium after they leave the isthmic reservoir and that sperm motility is crucial in the transport of sperm to the fertilization site.

Hyperactivation, a motility pattern of mammalian sperm in the oviduct, is essential to fertilization. Hyperactivation helps sperm to swim effectively through oviductal mucus, to escape from the sperm reservoir, and to penetrate the cumulus matrix and zona pellucida of the oocyte. There is some evidence that mammalian sperm can undergo chemotaxis; however, the relationship of chemotaxis to hyperactivation is unknown. Ca 2+ signaling is involved in hyperactivation and implicated in chemotaxis as well. In vivo, sperm hyperactivate in the lower oviduct, far from the cumulus-oocyte complex and possibly beyond the influence of chemotactic gradients emanating from the oocyte or cumulus. Thus, sperm are likely to be hyperactivated before sensing chemotactic gradients. Chemotactic signals might modulate hyperactivation to direct sperm toward oocytes as they reach a region of influence. Ca 2+ -directed modulation of hyperactivation is a potential mechanism of this process.

Chemotaxis refers to a process whereby cells move up or down a chemical gradient. Sperm chemotaxis is known to be a strategy exploited by marine invertebrates such as sea urchins to reach eggs efficiently in moving water. Less is understood about how or whether chemotaxis is used by mammalian sperm to reach eggs, where fertilization takes place within the confinement of a reproductive tract. In this report, we quantitatively assessed sea urchin and mouse sperm chemotaxis using a recently developed microfluidic model and high-speed imaging. Results demonstrated that sea urchin Arbacia punctulata sperm were chemotactic toward the peptide resact with high chemotactic sensitivity, with an average velocity V x up the chemical gradient as high as 20% of its average speed (238 mm/s), while mouse sperm displayed no statistically significant chemotactic behavior in progesterone gradients, which had been proposed to guide mammalian sperm toward eggs. This work demonstrates the validity of a microfluidic model for quantitative sperm chemotaxis studies, and reveals a biological insight that chemotaxis up a progesterone gradient may not be a universal strategy for mammalian sperm to reach eggs.

Hyperactivation, a motility pattern of mammalian sperm in the oviduct, is essential to fertilization. Hyperactivation helps sperm to swim effectively through oviductal mucus, to escape from the sperm reservoir, and to penetrate the cumulus matrix and zona pellucida of the oocyte. Hyperactivation is characterized by asymmetrical flagellar beating and an increase of cytoplasmic Ca 2+ . We observed that when mouse sperm hyperactivate during capacitation in vitro, the amplitude of the flagellar bend that forms in the same orientation as the hook of the head is greatly increased. We defined this as pro-hook beating. We established that pro-hook beating is stimulated by an influx of Ca 2+ through CATSPER channels and is associated with an increase of intracellular pH. However, an increase of flagellar bend amplitude in the opposite direction can be induced by treating sperm with thimerosal to stimulate release of Ca 2+ from internal stores. We defined this as anti-hook beating. We also demonstrated that anti-hook beating is dominant over pro-hook beating; that is, when sperm are simultaneously or sequentially subjected to treatments that stimulate prohook and anti-hook beating, then the sperm will swim using the anti-hook beating pattern. Different protein phosphorylation patterns were detected in extracts of sperm Suarez's lab for their generous support and collaboration: Dr. Osamu Kawase, Dr.

User interfaces have special characteristics that differentiate them from the rest of the software code. Typical software metrics that indicate its complexity and quality may not be able to distinguish a complex GUI or a high quality one from another that is not. This paper is about suggesting and introducing some GUI structural metrics that can be gathered dynamically using a test automation tool. Rather than measuring quality or usability, the goal of those developed metrics is to measure the GUI testability, or how much it is hard, or easy to test a particular user interface. We evaluate GUIs for several reasons such as usability and testability. In usability, users evaluate a particular user interface for how much easy, convenient, and fast it is to deal with it. In our testability evaluation, we want to automate the process of measuring the complexity of the user interface from testing perspectives. Such metrics can be used as a tool to estimate required resources to test a particular application.