Current Progress In Understanding Research Articles

Osteocyte Remodeling of the Lacunar-Canalicular System: What's in a Name?

Osteocytes directly modify the bone surrounding the expansive lacunar-canalicular system (LCS) through both resorption and deposition. The existence of this phenomenon is now widely accepted, but is referred to as "osteocyte osteolysis," "LCS remodeling," and "perilacunar remodeling," among other names. The uncertainty in naming this physiological process reflects the many persistent questions about why and how osteocytes interact with local bone matrix. The goal of this review is to examine the purpose and nature of LCS remodeling and its impacts on multiscale bone quality. While LCS remodeling is clearly important for systemic calcium mobilization, this process may have additional potential drivers and may impact the ability of bone to resist fracture. There is abundant evidence that the osteocyte can resorb and replace bone mineral and does so outside of extreme challenges to mineral homeostasis. The impacts of the osteocyte on organic matrix are less certain, especially regarding whether osteocytes produce osteoid. Though multiple lines of evidence point towards osteocyte production of organic matrix, definitive work is needed. Recent high-resolution imaging studies demonstrate that LCS remodeling influences local material properties. The role of LCS remodeling in the maintenance and deterioration of bone matrix quality in aging and disease are active areas of research. In this review, we highlight current progress in understanding why and how the osteocyte removes and replaces bone tissue and the consequences of these activities to bone quality. We posit that answering these questions is essential for evaluating whether, how, when, and why LCS remodeling may be manipulated for therapeutic benefit in managing bone fragility.

Lost in Translation: Ribosome-Associated mRNA and Protein Quality Controls.

Aberrant, misfolded, and mislocalized proteins are often toxic to cells and result in many human diseases. All proteins and their mRNA templates are subject to quality control. There are several distinct mechanisms that control the quality of mRNAs and proteins during translation at the ribosome. mRNA quality control systems, nonsense-mediated decay, non-stop decay, and no-go decay detect premature stop codons, the absence of a natural stop codon, and stalled ribosomes in translation, respectively, and degrade their mRNAs. Defective truncated polypeptide nascent chains generated from faulty mRNAs are degraded by ribosome-associated protein quality control pathways. Regulation of aberrant protein production, a novel pathway, senses aberrant proteins by monitoring the status of nascent chain interactions during translation and triggers degradation of their mRNA. Here, we review the current progress in understanding of the molecular mechanisms of mRNA and protein quality controls at the ribosome during translation.

Molecular functions of human endogenous retroviruses in health and disease.

Human endogenous retroviruses (HERVs) and related genetic elements form 504 distinct families and occupy ~8% of human genome. Recent success of high-throughput experimental technologies facilitated understanding functional impact of HERVs for molecular machinery of human cells. HERVs encode active retroviral proteins, which may exert important physiological functions in the body, but also may be involved in the progression of cancer and numerous human autoimmune, neurological and infectious diseases. The spectrum of related malignancies includes, but not limits to, multiple sclerosis, psoriasis, lupus, schizophrenia, multiple cancer types and HIV. In addition, HERVs regulate expression of the neighboring host genes and modify genomic regulatory landscape, e.g., by providing regulatory modules like transcription factor binding sites (TFBS). Indeed, recent bioinformatic profiling identified ~110,000 regulatory active HERV elements, which formed at least ~320,000 human TFBS. These and other peculiarities of HERVs might have played an important role in human evolution and speciation. In this paper, we focus on the current progress in understanding of normal and pathological molecular niches of HERVs, on their implications in human evolution, normal physiology and disease. We also review the available databases dealing with various aspects of HERV genetics.

Host factors involved in resistance to retroviral infection

Viral replication requires the help of host cell factors, whose species specificity may affect viral tropism. On the other hand, there exist host factors that restrict viral replication. The anti-viral system mediated by some of these restriction factors, which is termed intrinsic immunity and is distinguished from conventional innate and adaptive immunity, has been described as playing an important role in making species-specific barriers against viral infection. Here, we describe the current progress in understanding of such restriction factors against retroviral replication, focusing on TRIM5alpha and APOBEC, whose anti-retroviral effects have recently been recognized. Additionally, we mention cyclophilin A, which is essential for HIV-1 replication in human cells and may affect viral tropism. Understanding of these host factors would contribute to identification of the determinants for viral tropism.

Chess-Playing Programs and the Problem of Complexity

This paper traces the development of digital computer programs that play chess. The work of Shannon, Turing, the Los Alamos group, Bernstein, and the authors is treated in turn. The efforts to program chess provide an indication of current progress in understanding and constructing complex and intelligent mechanisms.