Cytological characteristics of premalignant cervical epithelial lesions in postmenopausal women based on endocrine indices and parakeratosis.

Objective: To identify useful cytological findings for detecting premalignant lesions in postmenopausal women, cervicovaginal smear samples were analyzed and compared between women with or without premalignant lesions based on endocrine indices and presence of parakeratosis (PK).

Methods: The cervicovaginal smear samples of postmenopausal women with premalignant lesions (n = 94) and those who were without (n = 344), who were diagnosed between 2012 and 2014 were retrieved and analyzed. Women cytologically diagnosed with malignancy or those with suspicion of malignancy were excluded from this study.

Selective binding and transport of protocadherin 15 isoforms by stereocilia unconventional myosins in a heterologous expression system.

During hair cell development, the mechanoelectrical transduction (MET) apparatus is assembled at the stereocilia tips, where it coexists with the stereocilia actin regulatory machinery. While the myosin-based tipward transport of actin regulatory proteins is well studied, isoform complexity and built-in redundancies in the MET apparatus have limited our understanding of how MET components are transported. We used a heterologous expression system to elucidate the myosin selective transport of isoforms of protocadherin 15 (PCDH15), the protein that mechanically gates the MET apparatus.

Designing AAV Vectors for Monitoring the Subtle Calcium Fluctuations of Inferior Olive Network .

Adeno-associated viral (AAV) vectors, used as vehicles for gene transfer into the brain, are a versatile and powerful tool of modern neuroscience that allow identifying specific neuronal populations, monitoring and modulating their activity. For consistent and reproducible results, the AAV vectors must be engineered so that they reliably and accurately target cell populations. Furthermore, transgene expression must be adjusted to sufficient and safe levels compatible with the physiology of studied cells.

Co-expression of low-risk HPV E6/E7 and EBV LMP-1 leads to precancerous lesions by DNA damage.

Background: Low-risk human papillomavirus (HPV), such as types 6 and 11, is considered non-oncogenic, but these types have been detected in oral cancer tissue samples, suggesting their possible involvement in oral carcinogenesis. Because double infection of high-risk HPV and Epstein-Barr virus (EBV) is known to be involved in oral carcinogenesis, we hypothesized that low-risk HPV and EBV co-infection can transform the oral cells. To verify our hypothesis, we evaluated the transformation activity of cell lines expressing both low-risk HPV E6/E7 and EBV LMP-1.

Expression of a TMC6-TMC8-CIB1 heterotrimeric complex in lymphocytes is regulated by each of the components.

The genes encode a set of homologous transmembrane proteins whose functions are not well understood. Biallelic mutations in either or are detected in more than half of cases of the pre-malignant skin disease epidermodysplasia verruciformis (EV). It is controversial whether EV induced by mutations in TMC6 or TMC8 originates from keratinocyte or lymphocyte defects.

Systemic Fluorescent Gentamicin Enters Neonatal Mouse Hair Cells Predominantly Through Sensory Mechanoelectrical Transduction Channels.

Systemically administered aminoglycoside antibiotics can enter inner ear hair cells and trigger apoptosis. However, the in vivo route(s) by which aminoglycoside antibiotics enter hair cells remains controversial. Aminoglycosides can enter mouse hair cells by endocytosis or by permeation through transmembrane ion channels such as sensory mechanoelectrical transduction (MET) channels, transient receptor potential (TRP) channels, P2X channels, Piezo2-containing ion channels, or a combination of these routes.

Multiparametric assessment of the impact of opsin expression and anesthesia on striatal cholinergic neurons and auditory brainstem activity.

Recent developments in genetic engineering have established murine models that permit the selective control of cholinergic neurons via optical stimulation. Despite copious benefits granted by these experimental advances, the sensory physiognomy of these organisms has remained poorly understood. Therefore, the present study evaluates sensory and neuronal response properties of animal models developed for the study of optically induced acetylcholine release regulation.

K1 gene transformation activities in AIDS-related and classic type Kaposi's sarcoma: Correlation with clinical presentation.

Kaposi's sarcoma-associated herpesvirus (KSHV) causes both AIDS-related Kaposi's sarcoma (KS) and classic KS, but their clinical presentations are different, and respective mechanisms remain to be elucidated. The KSHV K1 gene is reportedly involved in tumorigenesis through the immunoreceptor tyrosine-based activation motif (ITAM). Since we found the sequence variations in the K1 gene of KSHV isolated from AIDS-related KS and classic KS, we hypothesized that the transformation activity of the K1 gene contributes to the different clinical presentations.

TMC1 Forms the Pore of Mechanosensory Transduction Channels in Vertebrate Inner Ear Hair Cells.

The proteins that form the permeation pathway of mechanosensory transduction channels in inner-ear hair cells have not been definitively identified. Genetic, anatomical, and physiological evidence support a role for transmembrane channel-like protein (TMC) 1 in hair cell sensory transduction, yet the molecular function of TMC proteins remains unclear. Here, we provide biochemical evidence suggesting TMC1 assembles as a dimer, along with structural and sequence analyses suggesting similarity to dimeric TMEM16 channels.

Tmc2 expression partially restores auditory function in a mouse model of DFNB7/B11 deafness caused by loss of Tmc1 function.

Mouse Tmc1 and Tmc2 are required for sensory transduction in cochlear and vestibular hair cells. Homozygous Tmc1 mice are deaf, Tmc2 mice have normal hearing, and double homozygous Tmc1; Tmc2 mice have deafness and profound vestibular dysfunction. These phenotypes are consistent with their different spatiotemporal expression patterns.

Gradual Symmetric Progression of DFNA34 Hearing Loss Caused by an NLRP3 Mutation and Cochlear Autoinflammation.

Objective: To characterize the audiometric phenotype of autosomal-dominant DFNA34 hearing loss (HL) caused by a missense substitution in the NLRP3 gene. NLRP3 encodes a critical component of the NLRP3 inflammasome that is activated in innate immune responses.

Study Design: This study was conducted under protocol 01-DC-0229 approved by the NIH Combined Neurosciences IRB.

Esophageal Xanthoma: Presence of M2 Macrophages Suggests Association with Late Inflammatory and Reparative Processes.

Esophageal xanthoma is a rare lesion which is an asymptomatic small yellowish polyp, and most of the reported cases were solitary lesion. Histologically, aggregations of foam cells are found under the papillary hypertrophic squamous epithelium and the foam cells express CD68. The etiology of esophageal xanthoma is unknown.

Molecular Signature of Tumors with Monoallelic 13q14 Deletion: a Case Series of Spindle Cell Lipoma and Genetically-Related Tumors Demonstrating a Link Between FOXO1 Status and p38 MAPK Pathway.

Spindle cell/pleomorphic lipomas (SCLs), cellular angiofibromas (CAFs) and mammary-type myofibroblastomas (MFBs) are rare benign mesenchymal tumors with monoallelic 13q14 deletion. They are predicted to have a common pathogenic mechanism due to shared similar histological and immunohistochemical features; however, pathological consequences of monoallelic 13q14 deletion remain unknown. We previously reported a CAF case with monoallelic 13q14 deletion in which the tumor expressed decreased levels of FOXO1 and RB1, both of which were encoded in 13q14, and increased reactive oxygen species (ROS) levels.

mutation and cochlear autoinflammation cause syndromic and nonsyndromic hearing loss DFNA34 responsive to anakinra therapy.

The NLRP3 inflammasome is an intracellular innate immune sensor that is expressed in immune cells, including monocytes and macrophages. Activation of the NLRP3 inflammasome leads to IL-1β secretion. Gain-of-function mutations of result in abnormal activation of the NLRP3 inflammasome, and cause the autosomal dominant systemic autoinflammatory disease spectrum, termed cryopyrin-associated periodic syndromes (CAPS).

Islet Culture/Preservation Before Islet Transplantation.

Although islet culture prior to transplantation provides flexibility for the evaluation of isolated islets and the pretreatment of patients, it is well known that isolated islets deteriorate rapidly in culture. Human serum albumin (HSA) is used for medium supplementation instead of fetal bovine serum (FBS), which is typically used for islet culture research, to avoid the introduction of xenogeneic materials. However, FBS contains several factors that are beneficial to islet viability and which also neutralize the endogenous pancreatic enzymes or exogenous enzymes left over from the isolation process.

Cryopreservation of Adipose-Derived Mesenchymal Stem Cells.

Mesenchymal stem cells (MSCs) have the potential to differentiate into cells of mesodermal origin such as osteoblasts, adipocytes, myocytes, and chondrocytes. They possess an immunosuppressive effect, which makes them a viable cell population for the cell-based therapy of treatment-resistant immune diseases. Adipose-derived mesenchymal stem cells (ASCs) have been demonstrated to have the ability to acquire the properties of subcutaneous adipose tissue particularly easily, and cryopreservation is currently performed as a routine method for preserving ASCs to safely acquire large numbers of cells.

TMC1 and TMC2 Localize at the Site of Mechanotransduction in Mammalian Inner Ear Hair Cell Stereocilia.

Mechanosensitive ion channels at stereocilia tips mediate mechanoelectrical transduction (MET) in inner ear sensory hair cells. Transmembrane channel-like 1 and 2 (TMC1 and TMC2) are essential for MET and are hypothesized to be components of the MET complex, but evidence for their predicted spatiotemporal localization in stereocilia is lacking. Here, we determine the stereocilia localization of the TMC proteins in mice expressing TMC1-mCherry and TMC2-AcGFP.

Transmembrane channel-like (TMC) genes are required for auditory and vestibular mechanosensation.

Mutations of the transmembrane channel-like 1 (TMC1) gene can cause dominant and recessive forms of deafness in humans and mice. TMC1 is one of eight mammalian TMC genes of unknown function. The multi-pass transmembrane topologic structure of the proteins they encode suggests roles as a receptor, transporter, channel, or pump.

Mutations of TMC1 cause deafness by disrupting mechanoelectrical transduction.

Objective: Mutations of transmembrane channel-like 1 gene (TMC1) can cause dominant (DFNA36) or recessive (DFNB7/B11) deafness. In this article, we describe the characteristics of DFNA36 and DFNB7/B11 deafness, the features of the Tmc1 mutant mouse strains, and recent advances in our understanding of TMC1 function.

Methods: Publications related to TMC1, DFNA36, or DFNB7/B11 were identified through PubMed.

Hearing loss is an early consequence of Npc1 gene deletion in the mouse model of Niemann-Pick disease, type C.

Niemann-Pick disease, type C1 (NPC1) is a rare lysosomal lipidosis that is most often the result of biallelic mutations in NPC1, and is characterized by a fatal neurological degeneration. The pathophysiology is complex, and the natural history of the disease is poorly understood. Recent findings from patients with NPC1 and hearing loss suggest that multiple steps along the auditory pathway are affected.

Slc26a4-insufficiency causes fluctuating hearing loss and stria vascularis dysfunction.

SLC26A4 mutations can cause a distinctive hearing loss phenotype with sudden drops and fluctuation in patients. Existing Slc26a4 mutant mouse lines have a profound loss of hearing and vestibular function, with severe inner ear malformations that do not model this human phenotype. In this study, we generated Slc26a4-insufficient mice by manipulation of doxycycline administration to a transgenic mouse line in which all Slc26a4 expression was under the control of doxycycline.

Mechanotransduction in mouse inner ear hair cells requires transmembrane channel-like genes.

Inner ear hair cells convert the mechanical stimuli of sound, gravity, and head movement into electrical signals. This mechanotransduction process is initiated by opening of cation channels near the tips of hair cell stereocilia. Since the identity of these ion channels is unknown, and mutations in the gene encoding transmembrane channel-like 1 (TMC1) cause hearing loss without vestibular dysfunction in both mice and humans, we investigated the contribution of Tmc1 and the closely related Tmc2 to mechanotransduction in mice.

Cell type-specific transcriptome analysis reveals a major role for Zeb1 and miR-200b in mouse inner ear morphogenesis.

Cellular heterogeneity hinders the extraction of functionally significant results and inference of regulatory networks from wide-scale expression profiles of complex mammalian organs. The mammalian inner ear consists of the auditory and vestibular systems that are each composed of hair cells, supporting cells, neurons, mesenchymal cells, other epithelial cells, and blood vessels. We developed a novel protocol to sort auditory and vestibular tissues of newborn mouse inner ears into their major cellular components.

A noncoding point mutation of Zeb1 causes multiple developmental malformations and obesity in Twirler mice.

Heterozygous Twirler (Tw) mice develop obesity and circling behavior associated with malformations of the inner ear, whereas homozygous Tw mice have cleft palate and die shortly after birth. Zeb1 is a zinc finger protein that contributes to mesenchymal cell fate by repression of genes whose expression defines epithelial cell identity. This developmental pathway is disrupted in inner ears of Tw/Tw mice.