Rapid Development of the Seeker Free-Flying Inspector Guidance, Navigation, and Control System

Seeker is an automated extravehicular free-flying inspector CubeSat designed and built in-house at the Johnson Space Center (JSC). As a Class 1E project funded by the International Space Station (ISS) Program, Seeker had a stream-lined process to flight certification, but the vehicle had to be designed, developed, tested, and delivered within approximately one year after authority to proceed (ATP) and within a $1.8 million budget. These constraints necessitated an expedited Guidance, Navigation, and Control (GNC) development schedule. Development began with a navigation sensor trade study using Linear Covariance (LinCov) analysis and a rapid sensor down-selection process, resulting in the use of commercial off-the-shelf (COTS) sensors which could be procured quickly and subjected to in-house environmental testing to qualify them for flight. A neural network was used to enable a COTS camera to provide bearing measure-ments for visual navigation. The GNC flight software (FSW) algorithms utilized lean development practices and leveraged the Core Flight Software (CFS) architecture to rapidly develop the GNC system, tune the system parameters, and verify performance in simulation. This pace was anchored by several Hardware-Software Integration (HSI) milestones, which forced the Seeker GNC team to develop the interfaces both between hardware and software and between the GNC domains early in the project and to enable a timely delivery

An African-Specific Variant of TP53 Reveals PADI4 as a Regulator of p53-Mediated Tumor Suppression

TP53 is the most frequently mutated gene in cancer, yet key target genes for p53-mediated tumor suppression remain unidentified. Here, we characterize a rare, African-specific germline variant of TP53 in the DNA-binding domain Tyr107His (Y107H). Nuclear magnetic resonance and crystal structures reveal that Y107H is structurally similar to wild-type p53. Consistent with this, we find that Y107H can suppress tumor colony formation and is impaired for the transactivation of only a small subset of p53 target genes; this includes the epigenetic modifier PADI4, which deiminates arginine to the nonnatural amino acid citrulline. Surprisingly, we show that Y107H mice develop spontaneous cancers and metastases and that Y107H shows impaired tumor suppression in two other models. We show that PADI4 is itself tumor suppressive and that it requires an intact immune system for tumor suppression. We identify a p53–PADI4 gene signature that is predictive of survival and the efficacy of immune-checkpoint inhibitors. Significance: We analyze the African-centric Y107H hypomorphic variant and show that it confers increased cancer risk; we use Y107H in order to identify PADI4 as a key tumor-suppressive p53 target gene that contributes to an immune modulation signature and that is predictive of cancer survival and the success of immunotherapy

β2microglobulin mRNA expression levels are prognostic for lymph node metastasis in colorectal cancer patients

Colorectal cancer (CRC) is the fourth most common non-cutaneous malignancy in the United States and the second most frequent cause of cancer-related death. One of the most important determinants of CRC survival is lymph node metastasis. To determine whether molecular markers might be prognostic for lymph node metastases, we measured by quantitative real-time RT–PCR the expression levels of 15 cancer-associated genes in formalin-fixed paraffin-embedded primary tissues derived from stage I–IV CRC patients with (n=20) and without (n=18) nodal metastases. Using the mean of the 15 genes as an internal reference control, we observed that low expression of β2microglobulin (B2M) was a strong prognostic indicator of lymph node metastases (area under the curve (AUC)=0.85; 95% confidence interval (CI)=0.69–0.94). We also observed that the expression ratio of B2M/Spint2 had the highest prognostic accuracy (AUC=0.87; 95% CI=0.71–0.96) of all potential two-gene combinations. Expression values of Spint2 correlated with the mean of the entire gene set at an R2 value of 0.97, providing evidence that Spint2 serves not as an independent prognostic gene, but rather as a reliable reference control gene. These studies are the first to demonstrate a prognostic role of B2M at the mRNA level and suggest that low B2M expression levels might be useful for identifying patients with lymph node metastasis and/or poor survival