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The Ufm1 conjugation system is a novel ubiquitin-like modification system, consisting of Ufm1, Uba5 (E1), Ufc1 (E2) and poorly characterized E3 ligase(s). RCAD/Ufl1 (also known as KIAA0776, NLBP and Maxer) was reported to function as a Ufm1 E3 ligase in ufmylation (Ufm1-mediated conjugation) of DDRGK1 and ASC1 proteins. It has also been implicated in estrogen receptor signaling, unfolded protein response (UPR) and neurodegeneration, yet its physiological function remains completely unknown. In this study, we report that RCAD/Ufl1 is essential for embryonic development, hematopoietic stem cell (HSC) survival and erythroid differentiation. Both germ-line and somatic deletion of RCAD/Ufl1 impaired hematopoietic development, resulting in severe anemia, cytopenia and ultimately animal death. Depletion of RCAD/Ufl1 caused elevated endoplasmic reticulum stress and evoked UPR in bone marrow cells. In addition, loss of RCAD/Ufl1 blocked autophagic degradation, increased mitochondrial mass and reactive oxygen species, and led to DNA damage response, p53 activation and enhanced cell death of HSCs. Collectively, our study provides the first genetic evidence for the indispensable role of RCAD/Ufl1 in murine hematopoiesis and development. The finding of RCAD/Ufl1 as a key regulator of cellular stress response sheds a light into the role of a novel protein network including RCAD/Ufl1 and its associated proteins in regulating cellular homeostasis.

Billions of dollars are spent annually on software-related cost. It is estimated that up to 45 percent of software cost is due to the difficulty in understanding existing systems when performing maintenance tasks (i.e., adding features, removing bugs, etc.). One of the root causes is that software products often come with poor, incomplete, or even without any documented specifications. In an effort to improve program understanding, Lo et al. have proposed iterative pattern mining which outputs patterns that are repeated frequently within a program trace, or across multiple traces, or both. Frequent iterative patterns reflect frequent program behaviors that likely correspond to software specifications. To reduce the number of patterns and improve the efficiency of the algorithm, Lo et al. have also introduced mining closed iterative patterns, i.e., maximal patterns without any superpattern having the same support. In this paper, to technically deepen research on iterative pattern mining, we introduce mining iterative generators, i.e., minimal patterns without any subpattern having the same support. Iterative generators can be paired with closed patterns to produce a set of rules expressing forward, backward, and in-between temporal constraints among events in one general representation. We refer to these rules as representative rules. A comprehensive performance study shows the efficiency of our approach. A case study on traces of an industrial system shows how iterative generators and closed iterative patterns can be merged to form useful rules shedding light on software design. © 2006 IEEE.

Plasmids may have unique advantages as a gene delivery system. However, a major obstacle is the low in vivo transduction efficiency. In this study, an electroporation-based gene transduction approach was taken to study the effect of interleukin (IL)-2 or IL-12 gene transduction on the growth of experimental murine tumors. Significant intratumoral gene transduction was achieved by electroporation of tumors that had been injected with naked plasmids encoding reporter genes and cytokine genes (IL-2 and IL-12) under the control of a constitutive cytomegalovirus promoter. In addition, significant tumor growth delay could be achieved in a murine melanoma line B16.F10 with the cytokine genes. Most importantly, systemic transgene levels were negligible when compared with intratumoral adenovirus-mediated IL-12 gene delivery, which leads to significantly higher systemic cytokine levels. Therefore, naked plasmid- and in vivo electroporation-mediated cancer gene therapy may be therapeutically efficacious while maintaining low systemic toxicity.

Social network users connect and interact with one another to fulfil different kinds of social and information needs.When interaction ceases between two users, we say that their tie becomes dormant. While there are different underlying reasons of dormant ties, it is important to find means to revive such ties so as to maintain vibrancy in the relationships. In this work, we thus focus on designing an online experiment to evaluate the effectiveness of personalized social messages to revive dormant ties. The experiment carefully selects users with dormant ties so that no user gets mixed treatments and be affected by the responses of other users undergoing treatment. Our results show that personalized message content plays an important part in reviving dormant ties. Specifically, we find the message containing friend's recent activity information is more effective than that containing inter-friend activity information. We observe that the quality of engagement of at least 50% of the revived ties can effectively be restored to the level before the ties become dormant. We also observe that it is easier to revive dormant ties that involve users from the same country than those involving users from different countries.

Transgenic mice that express the influenza virus hemagglutinin (HA) on pancreatic islet beta cells (ins-HA) demonstrate tolerance of HA even after immunization with influenza virus. Surprisingly, when Ins-HA mice were mated with a transgenic mouse expressing a TCR specific for an epitope of HA that is restricted by MHC class I H-2Kd (Clone-4 TCR), the resulting double transgenic (Ins-HA x Clone-4 TCR)F1 neonates developed spontaneous autoimmune diabetes immediately after birth and died within 10 days. This represents a unique situation in which all safeguards within the immune system that normally maintain tolerance of self-antigens in the neonate are insufficient.

Tumor growth is rarely associated with a strong specific CTL response, suggesting that the immune system is ignorant of the presence of tumor because the Ags are not readily available to or are sequestered from potential effector cells. We studied the in vivo activation of naive TCR transgenic hemagglutinin (HA)-specific CD8+ T cells adoptively transferred into mice bearing HA-expressing tumor using 5,6-carboxy-succinimidyl-fluorescein-ester labeling, which allows the identification of proliferating HA-specific T cells. We demonstrate that tumor Ags are constitutively presented in the lymph nodes draining tumors and are powerfully mitogenic for responding T cells despite the absence of anti-tumor CTL responses. Importantly, this proliferative signal occurs throughout tumor growth and is still detectable 6 mo after tumor inoculation when tumor is not palpable. These results provide the first evidence that there is constitutive presentation of tumor Ags in draining lymph nodes.

Many software design and verification techniques assume the availability of some kind of behavioral models of the systems under analysis [2,4,10,11,28]. Unfortunately, manually specifying and maintaining behavioral models is expensive and error prone, and requires specific skills that are not always available in development teams. This reduces the applicability of model-based approaches in industrial projects. The problem of generating behavioral models can be solved with techniques that automatically generate behavioral models by mining program executions and thus reducing the effort required to generate models [3, 5, 18,20,24]