The STAT5-regulated miR-193b locus restrains mammary stem and progenitor cell activity and alveolar differentiation.

The transcription factor STAT5 mediates prolactin signaling and controls functional development of mammary tissue during pregnancy. This study has identified the miR-193b locus, also encoding miRNAs 365-1 and 6365, as a STAT5 target in mammary epithelium. While the locus was characterized by active histone marks in mammary tissue, STAT5 binding and expression during pregnancy, it was silent in most non-mammary cells. Inactivation of the miR-193b locus in mice resulted in elevated mammary stem/progenitor cell activity as judged by limiting dilution transplantation experiments of primary mammary epithelial cells. Colonies formed by mutant cells were larger and contained more Ki-67 positive cells. Differentiation of mammary epithelium lacking the miR-193b locus was accelerated during puberty and pregnancy, which coincided with the loss of Cav3 and elevated levels of Elf5. Normal colony development was partially obtained upon ectopically expressing Cav3 or upon siRNA-mediated reduction of Elf5 in miR-193b-null primary mammary epithelial cells. This study reveals a previously unknown link between the mammary-defining transcription factor STAT5 and a microRNA cluster in controlling mammary epithelial differentiation and the activity of mammary stem and progenitor cells.

Genome-Wide Transcriptional Roles of KSHV Viral Interferon Regulatory Factors in Oral Epithelial Cells.

The viral interferon regulatory factors (vIRFs) of KSHV are known to dysregulate cell signaling pathways to promote viral oncogenesis and to block antiviral immune responses to facilitate infection. However, it remains unknown to what extent each vIRF plays a role in gene regulation. To address this, we performed a comparative analysis of the protein structures and gene regulation of the four vIRFs. Our structure prediction analysis revealed that despite their low amino acid sequence similarity, vIRFs exhibit high structural homology in both their DNA-binding domain (DBD) and IRF association domain. However, despite this shared structural homology, we demonstrate that each vIRF regulates a distinct set of KSHV gene promoters and human genes in epithelial cells. We also found that the DBD of vIRF1 is essential in regulating the expression of its target genes. We propose that the structurally similar vIRFs evolved to possess specialized transcriptional functions to regulate specific genes.

MiR-193b and miR-365-1 are not required for the development and function of brown fat in the mouse.

Generating heat and maintaining body temperature is the primary function of brown adipose tissue (BAT). Previous studies have implicated microRNAs, including miR-193b and miR-365-1, in BAT differentiation. We used mouse genetics to further understand the specific contributions of these two miRs. BAT function in mice with an inactivated miR-193b-365-1 locus, as determined by their response to the selective ß3 adrenergic receptor agonist CL316.243 and their tolerance to cold exposure, was normal and expression of genes associated with functional BAT, including Prdm16 and Ucp1, was unaffected. In addition, genome-wide expression profiles of miRNAs and mRNAs in BAT in the presence and absence of miR-193b-365-1 were determined. In summary, these data demonstrate, in contrast to earlier work, that the development, differentiation, and function of BAT do not require the presence of miR-193b and miR-365-1.

Factors Related to Failure of Conservative Treatment in Volar Plate Avulsion Fractures of the Proximal Interphalangeal Joint.

BACKGROUD: Volar plate avulsion fractures of the proximal interphalangeal (PIP) joint are a common hand injury and have been treated conservatively with favorable results. We assumed that conservative treatment of volar plate avulsion fractures of the PIP joint would be unsuccessful if the fracture fragment, even if small, was much displaced or rotated and that delayed excision of the avulsion fractures would result in good outcomes. We report clinical and radiological outcomes of conservative treatment of volar plate avulsion fractures of the PIP joint and risk factors for failure of conservative treatment. METHODS: We retrospectively reviewed the clinical and radiological outcomes of 88 volar plate avulsion fractures (85 patients) treated conservatively at first. In 18 of these fractures, delayed excision of the fracture fragment was required after an average of 75 days of conservative treatment for limited motion or pain of the joint. We compared parameters between failed cases and successful cases after conservative treatment. RESULTS: Compared to the successful cases, the failed cases had a higher prevalence of joint dislocation at the time of injury and greater pain, larger flexion contracture, and less further flexion after conservative treatment. The shape, comminution, and size of the fracture fragments were not related with the need for operation, but the operative cases had greater displacement and rotation of the fracture fragments than the conservative cases. After fragment excision, postoperative protection of the joint was not necessary, pain was reduced, and the mean range of motion increased. CONCLUSIONS: The presence of joint dislocation and greater displacement and rotation of the fragments may be associated with the failure of conservative treatment of volar plate avulsion fractures. Failed cases after conservative treatment could be resolved by delayed fragment excision with favorable results. Therefore, it might be appropriate to consider conservative treatment at first in almost all volar plate avulsion fractures of stable PIP joints.

Comparative analysis of the viral interferon regulatory factors of KSHV for their requisite for virus production and inhibition of the type I interferon pathway.

Unique among human viruses, Kaposi's sarcoma-associated herpesvirus (KSHV) encodes several homologs of cellular interferon regulatory factors (vIRFs). Since KSHV expresses multiple factors that can inhibit interferon (IFN) signaling to promote virus production, it is still unclear to what extent vIRFs contribute to these specific processes during KSHV infection. To study the function of vIRFs during viral infection, we engineered 3xFLAG-tagged-vIRF and vIRF-knockout recombinant KSHV clones, which were utilized to test vIRF expression, as well as their requirement for viral replication, virus production, and inhibition of the type I IFN pathway in different models of lytic KSHV infection. Our data show that all vIRFs can be expressed as lytic viral proteins, yet were dispensable for KSHV production and inhibition of type I IFN. Nevertheless, as vIRFs were able to suppress IFN-stimulated antiviral genes, vIRFs may still promote the KSHV lytic cycle in the presence of an ongoing antiviral response.

Evaluation of performance of several established pitch detection algorithms in pathological voices.

Robust pitch estimation is important in many areas of speech processing. In voice pathology, diverse statistics extracted form pitch estimation were commonly used to test voice quality. In this study, we compared several established pitch detection algorithms (PDAs) for verification of adequacy of the PDAs. In the database of total pathological voices of 99 and normal voices of 30, an analysis of errors related with pitch detection was evaluated between pathological and normal voices, or among the types of pathological voices. Pitch errors of all PDAs used in this study more or less showed some changes between pathological and normal voices. According to the results of pitch errors, gross pitch error showed some increases in cases of pathological voices; especially excessive increase in PDA based on nonlinear time-series. In an analysis of types of pathological voices classified by aperiodicity and the degree of chaos, the more voice has aperiodic and chaotic, the more growth of pitch errors increased. Consequently, it is required to survey the severity of tested voice in order to obtain accurate pitch estimates.