Polymorphic Type Inference for the JNI

We present a multi-lingual type inference system for checking type safety of programs that use the Java Native Interface (JNI). The JNI uses specially-formatted strings to represent class and field names as well as method signatures, and so our type system tracks the flow of string constants through the program. Our system embeds string variables in types, and as those variables are resolved to string constants during inference they are replaced with the structured types the constants represent. This restricted form of dependent types allows us to directly assign type signatures to each of the more than 200 functions in the JNI. Moreover, it allows us to infer types for user-defined functions that are parameterized by Java type strings, which we have found to be common practice. Our inference system allows such functions to be treated polymorphically by using instantiation constraints, solved with semi-unification, at function calls. Finally, we have implemented our system and applied it to a small set of benchmarks. Although semi-unification is undecidable, we found our system to be scalable and effective in practice. We discovered 155 errors 36 cases of suspicious programming practices in our benchmarks

Regional astrocyte IFN signaling restricts pathogenesis during neurotropic viral infection

Type I IFNs promote cellular responses to viruses, and IFN receptor (IFNAR) signaling regulates the responses of endothelial cells of the blood-brain barrier (BBB) during neurotropic viral infection. However, the role of astrocytes in innate immune responses of the BBB during viral infection of the CNS remains to be fully elucidated. Here, we have demonstrated that type I IFNAR signaling in astrocytes regulates BBB permeability and protects the cerebellum from infection and immunopathology. Mice with astrocyte-specific loss of IFNAR signaling showed decreased survival after West Nile virus infection. Accelerated mortality was not due to expanded viral tropism or increased replication. Rather, viral entry increased specifically in the hindbrain of IFNAR-deficient mice, suggesting that IFNAR signaling critically regulates BBB permeability in this brain region. Pattern recognition receptors and IFN-stimulated genes had higher basal and IFN-induced expression in human and mouse cerebellar astrocytes than did cerebral cortical astrocytes, suggesting that IFNAR signaling has brain region–specific roles in CNS immune responses. Taken together, our data identify cerebellar astrocytes as key responders to viral infection and highlight the existence of distinct innate immune programs in astrocytes from evolutionarily disparate regions of the CNS

Coinductive subtyping for abstract compilation of object-oriented languages into Horn formulas

In recent work we have shown how it is possible to define very precise type systems for object-oriented languages by abstractly compiling a program into a Horn formula f. Then type inference amounts to resolving a certain goal w.r.t. the coinductive (that is, the greatest) Herbrand model of f. Type systems defined in this way are idealized, since in the most interesting instantiations both the terms of the coinductive Herbrand universe and goal derivations cannot be finitely represented. However, sound and quite expressive approximations can be implemented by considering only regular terms and derivations. In doing so, it is essential to introduce a proper subtyping relation formalizing the notion of approximation between types. In this paper we study a subtyping relation on coinductive terms built on union and object type constructors. We define an interpretation of types as set of values induced by a quite intuitive relation of membership of values to types, and prove that the definition of subtyping is sound w.r.t. subset inclusion between type interpretations. The proof of soundness has allowed us to simplify the notion of contractive derivation and to discover that the previously given definition of subtyping did not cover all possible representations of the empty type

Investigating corroboration of self-perceived posttraumatic growth among Sri Lankan Tamil survivors of ethnopolitical warfare through trait, domain, and profile agreement approaches.

Though research on assessing posttraumatic growth has been severely critiqued, some evidence suggests close others can observe and report changes in individuals following traumatic life events and are sensitive to idiosyncratic ways in which changes manifest. We extended these findings by investigating corroboration of self-perceived posttraumatic growth (PTG) and depreciation (PTD) as measured by the Posttraumatic Growth Inventory–42 (PTGI-42) among Sri Lankan Tamil war survivors (n = 200). Informants slightly corroborated overall levels of PTG and PTD, while a more nuanced profile analysis procedure revealed overall—but not distinctive—profile agreement. This suggests self–other agreement is modest and may partly reflect shared narratives and collective cultural understandings about how people change after trauma. Results demonstrate further that informants were not sensitive to idiosyncratic ways in which target individuals had changed. Together, the lack of validity evidence suggests that the PTGI-42 may be inadequate in some cross-cultural contexts as a measure of nuanced posttraumatic change (i.e., as a measure of specific changes in the five theorized domains of growth and depreciation). Future work should emphasize culture- and context-sensitive measurement of posttraumatic change, particularly focusing on methods other than retrospective self-reports, such as prospective longitudinal designs

Androgen receptor signaling regulates the transcriptome of prostate cancer cells by modulating global alternative splicing

Androgen receptor (AR), is a transcription factor and a member of a hormone receptor superfamily. AR plays a vital role in the progression of prostate cancer and is a crucial target for therapeutic interventions. While the majority of advanced-stage prostate cancer patients will initially respond to the androgen deprivation, the disease often progresses to castrate-resistant prostate cancer (CRPC). Interestingly, CRPC tumors continue to depend on hyperactive AR signaling and will respond to potent second-line antiandrogen therapies, including bicalutamide (CASODEX®) and enzalutamide (XTANDI®). However, the progression-free survival rate for the CRPC patients on antiandrogen therapies is only 8–19 months. Hence, there is a need to understand the mechanisms underlying CRPC progression and eventual treatment resistance. Here, we have leveraged next-generation sequencing and newly developed analytical methodologies to evaluate the role of AR signaling in regulating the transcriptome of prostate cancer cells. The genomic and pharmacologic stimulation and inhibition of AR activity demonstrates that AR regulates alternative splicing within cancer-relevant genes. Furthermore, by integrating transcriptomic data from in vitro experiments and in prostate cancer patients, we found that a significant number of AR-regulated splicing events are associated with tumor progression. For example, we found evidence for an inadvertent AR-antagonist-mediated switch in IDH1 and PL2G2A isoform expression, which is associated with a decrease in overall survival of patients. Mechanistically, we discovered that the epithelial-specific splicing regulators (ESRP1 and ESRP2), flank many AR-regulated alternatively spliced exons. And, using 2D invasion assays, we show that the inhibition of ESRPs can suppress AR-antagonist-driven tumor invasion. Our work provides evidence for a new mechanism by which AR alters the transcriptome of prostate cancer cells by modulating alternative splicing. As such, our work has important implications for CRPC progression and development of resistance to treatment with bicalutamide and enzalutamide

Abstract Checking Type Safety of Foreign Function Calls ∗

We present a multi-lingual type inference system for checking type safety across a foreign function interface. The goal of our system is to prevent foreign function calls from introducing type and memory safety violations into an otherwise safe language. Our system targets OCaml’s FFI to C, which is relatively lightweight and illustrates some interesting challenges in multi-lingual type inference. The type language in our system embeds OCaml types in C types and vice-versa, which allows us to track type information accurately even through the foreign language, where the original types are lost. Our system uses a representational type that can model multiple OCaml types, because C programs can observe that many OCaml types have the same physical representation. Furthermore, because C has a low-level view of OCaml data, our inference system includes a dataflow analysis to track memory offsets and tag information. Finally, our type system includes garbage collection information to ensure that pointers from the FFI to the OCaml heap are tracked properly. We have implemented our inference system and applied it to a small set of benchmarks. Our results show that programmers do misuse these interfaces, and our implementation has found several bugs and questionable coding practices in our benchmarks.