Effects of RANKL-Targeted Therapy in Immunity and Cancer.

The role of the receptor activator of nuclear factor-κB ligand (RANKL)/RANK system is well characterized within bone, where RANKL/RANK signaling mediates osteoclastogenesis and bone resorption. However, this system has also been shown to influence biologic processes beyond the skeletal system, including in the immune system and in cancer. RANKL/RANK signaling is important in lymph-node development, lymphocyte differentiation, dendritic cell survival, T-cell activation, and tolerance induction. The RANKL/RANK axis may also have direct, osteoclast-independent effects on tumor cells. Indeed, activity of the RANKL/RANK pathway in cancer cells has been correlated with tumor progression and advanced disease. Denosumab, a fully human monoclonal antibody against RANKL, inhibits osteoclastogenesis and is widely used not just for the treatment of osteoporosis, but for the prevention of skeletal-related events from bone metastases in solid malignancies such as breast and prostate cancer. The potential effects of denosumab on the immune system have been largely ignored. Nevertheless, with the emergence of immunotherapies for cancer, denosumab may impact the effectiveness of these therapies, especially if they are given in combination. In this article, we review the role of RANKL/RANK in bone, immunity, and cancer. Examining the potential effects of routine treatment with denosumab beyond the bone represents an important area of investigation

Some Introductory Notes on the Development and Characteristics of Sabah Malay

This is a preliminary description of the Malay variety used as a lingua franca in the Malaysian state of Sabah at the northernmost top of Borneo. The paper discusses a number of common linguistic features that distinguish Sabah Malay from other Malay varieties and analyses these features from a historical linguistic perspective. While it is argued that Sabah Malay has a close historical relation with other Malay dialects spoken in Borneo, especially Brunei Malay, the vernacular is also influenced phonologically and lexically by Sabah\u27s indigenous and immigrant speech communities. Words and sentences recorded or elicited during fieldwork in various parts of Sabah illustrate these points

Bending and Breathing Modes of the Galactic Disk

We explore the hypothesis that a passing satellite or dark matter subhalo has excited coherent oscillations of the Milky Way's stellar disk in the direction perpendicular to the Galactic midplane. This work is motivated by recent observations of spatially dependent bulk vertical motions within ~ kpc of the Sun. A satellite can transfer a fraction of its orbital energy to the disk stars as it plunges through the Galactic midplane thereby heating and thickening the disk. Bulk motions arise during the early stages of such an event when the disk is still in an unrelaxed state. We present simple toy-model calculations and simulations of disk-satellite interactions, which show that the response of the disk depends on the relative velocity of the satellite. When the component of the satellite's velocity perpendicular to the disk is small compared with that of the stars, the perturbation is predominantly a bending mode. Conversely, breathing and higher order modes are excited when the vertical velocity of the satellite is larger than that of the stars. We argue that the compression and rarefaction motions seen in three different surveys are in fact breathing mode perturbations of the Galactic disk.Comment: 12 pages, 12 figure

State-Regularized Recurrent Neural Networks to Extract Automata and Explain Predictions

Recurrent neural networks are a widely used class of neural architectures. They have, however, two shortcomings. First, they are often treated as black-box models and as such it is difficult to understand what exactly they learn as well as how they arrive at a particular prediction. Second, they tend to work poorly on sequences requiring long-term memorization, despite having this capacity in principle. We aim to address both shortcomings with a class of recurrent networks that use a stochastic state transition mechanism between cell applications. This mechanism, which we term state-regularization, makes RNNs transition between a finite set of learnable states. We evaluate state-regularized RNNs on (1) regular languages for the purpose of automata extraction; (2) non-regular languages such as balanced parentheses and palindromes where external memory is required; and (3) real-word sequence learning tasks for sentiment analysis, visual object recognition and text categorisation. We show that state-regularization (a) simplifies the extraction of finite state automata that display an RNN's state transition dynamic; (b) forces RNNs to operate more like automata with external memory and less like finite state machines, which potentiality leads to a more structural memory; (c) leads to better interpretability and explainability of RNNs by leveraging the probabilistic finite state transition mechanism over time steps.Comment: To appear at IEEE Transactions on Pattern Analysis and Machine Intelligence. The extended version of State-Regularized Recurrent Neural Networks [arXiv:1901.08817

Interseismic deformation above the Sunda Megathrust recorded in coral microatolls of the Mentawai islands, West Sumatra

The geomorphology and internal stratigraphy of modern coral microatolls show that all the outer arc Mentawai islands of West Sumatra have been subsiding over the past several decades. These same islands rose as much as 3 m during the giant megathrust earthquakes of 1797 and 1833, and the current subsidence probably reflects strain accumulation that will lead to future large earthquakes. Average subsidence rates over the past half century vary from 2 to 14 mm yr^(−1) and increase southwestward, toward the subduction trench. The pattern is consistent with rates of subsidence measured by a sparse network of continuously recording Global Positioning System (cGPS) stations and with locking of a 400-km-long section of the underlying subduction megathrust, between about 1°S and 4°S. This record of subsidence and tilting, extending nearly a century into the past, implies that the region is advancing toward the occurrence of another giant earthquake. However, evidence of episodic rather than steady subsidence reflects a behavior that is more complex than simple elastic strain accumulation and relief. Most prominent of these episodes is an extensive emergence/subsidence couplet in about 1962, which may be the result of rapid, aseismic slip on the megathrust, between the islands and the trench. Lower subsidence rates recorded by the corals since about 1985 may reflect failure on many small patches within the locked section of the megathrust

Perspectives on testicular sex cord-stromal tumors and those composed of both germ cells and sex cord-stromal derivatives with a comparison to corresponding ovarian neoplasms

Sex cord-stromal tumors (SCSTs) are the second most frequent category of testicular neoplasms, accounting for approximately 2–5% of cases. Both genetic and epigenetic factors account for the differences in frequency and histologic composition between testicular and ovarian SCSTs. For example, large cell calcifying Sertoli cell tumor and intratubular large cell hyalinizing Sertoli cell neoplasia occur in the testis but have not been described in the ovary. In this article, we discuss recently described diagnostic entities as well as inconsistencies in nomenclature used in the recent World Health Organization classifications of SCSTs in the testis and ovary. We also thoroughly review the topic of neoplasms composed of both germ cells and sex cord derivatives with an emphasis on controversial aspects. These include “dissecting gonadoblastoma” and testicular mixed germ cell-sex cord stromal tumor (MGC-SCST). The former is a recently described variant of gonadoblastoma that sometimes is an immediate precursor of germinoma in the dysgenetic gonads of patients with a disorder of sex development. Although the relationship of “dissecting gonadoblastoma” to the previously described undifferentiated gonadal tissue is complex and not entirely resolved, we believe that it is preferable to continue to use the term undifferentiated gonadal tissue for those cases that are not neoplastic and are considered to be the precursor of classical gonadoblastoma. Although the existence of testicular MGC-SCST has been challenged, the most recent evidence supports its existence; however, testicular MGC-SCST differs significantly from ovarian examples due to both genetic and epigenetic factors