Effects of Genetic Background on Susceptibility and the Acceleration of Hearing Loss in Mice

Acquired hearing loss, which includes age-related hearing loss and noise-induced hearing loss, is a common hearing impairment and shows phenotypic variability. One reason for phenotypic variability is influence of genetic background. The modifiers underlying genetic background are modulated and advance the hearing phenotypes through gene-gene interactions with other etiological genetic factors. Moreover, the modifiers play a role in the susceptibility of environmental hearing risk factors, namely, the strength and weakness of environmental susceptibility often modulate and advance hearing phenotypes via gene-environment interactions. The complicated gene-gene and gene-environment interactions make genetic analysis of acquired hearing loss difficult. In particular, the effects of environmental factors cannot be completely excluded or controlled. Although genome-wide approaches to identify genetic modifiers have proven challenging in humans, the responsible genes and mutations are widely unknown. In this chapter, we suggest that mouse models are useful for studying genetic background effects for acquired hearing loss. The genetic analysis of mouse models identified the genetic modifiers. We review the genetic research in mouse models for acquired hearing loss to identify and confirm the modifiers by both forward and reverse genetics approaches

Life and How to Live It

The reaction of Mn^III salen-type complexes with di- and tetraanionic α-Keggin-type polyoxometalates (POMs) was performed, and three types of Coulombic aggregations containing Mn^III out-of-plane dimeric units (abbreviated as [Mn₂]²⁺) that are potentially single-molecule magnets (SMMs) with an <i>S</i>_T = 4 ground state were synthesized: [Mn₂(5-MeOsaltmen)₂(acetone)₂]­[SW₁₂O₄₀] (<b>1</b>), [Mn₂(salen)₂(H₂O)₂]₂[SiW₁₂O₄₀] (<b>2</b>), and [Mn­(5-Brsaltmen)­(H₂O)­(acetone)]₂[{Mn₂(5-Brsaltmen)₂}­(SiW₁₂O₄₀)] (<b>3</b>), where 5-Rsaltmen^2– = <i>N</i>,<i>N</i>′-(1,1,2,2-tetramethylethylene)­bis­(5-R-salicylideneiminate) with R = MeO (methoxy), Br (bromo) and salen^2– = <i>N</i>,<i>N</i>′-ethylenebis­(salicylideneiminate). Compound <b>1</b> with a dianionic POM, [SW₁₂O₄₀]^2–, is composed of a 1:1 aggregating set of [Mn₂]²⁺/POM, and <b>2</b>, with a tetraanionic POM, [SiW₁₂O₄₀]^4–, is a 2:1 set. Compound <b>3</b> with [SiW₁₂O₄₀]^4– forms a unique 1D coordinating chain with a [−{Mn₂}–POM−]^2– repeating unit, for which a hydrogen-bonded dimeric unit ([Mn­(5-Brsaltmen)­(H₂O)­(acetone)]₂²⁺) is present as a countercation. Independent of the formula ratio of [Mn₂]²⁺/POM, Mn^III dimers and POM units in <b>1</b>–<b>3</b> form respective segregated columns along a direction of the unit cell, which make an alternate packing to separate evenly identical species in a crystal. The nearest intermolecular Mn···Mn distance is found in the order <b>2</b> < <b>3</b> < <b>1</b>. The segregation of the [Mn₂]²⁺ dimer resulted in interdimer distances long enough to effectively reduce the intermolecular magnetic interaction, in particular in <b>1</b> and <b>3</b>. Consequently, an intrinsic property, SMM behavior, of Mn^III dimers has been characterized in this system, even though the interdimer interactions are still crucial in the case of <b>2</b>, where a long-range magnetic order competitively affects slow relaxation of the magnetization at low ac frequencies

HER2-Positive Metaplastic Breast Cancer with Resistance to Neoadjuvant Chemotherapy: Case Report

Introduction: Metaplastic breast carcinoma (MBC) is a rare histologic subtype of breast carcinoma, which is usually negative for estrogen receptor, progesterone receptor, and HER2. HER2-positive MBC is therefore extremely rare. Most MBCs have poor response to chemotherapy. HER2-targeted neoadjuvant chemotherapy (NAC) is widely performed and has high efficacy in treating HER2-positive breast cancer. We report an atypical case of HER2-positive breast cancer that had poor response to NAC and was diagnosed with MBC after the surgery. Case Presentation: A 73-year-old woman noticed a mass in her right breast and visited our hospital. The mass was diagnosed as hormone receptor-negative, HER2-positive invasive ductal carcinoma, T2N0M0 stage IIA. She received HER2-targeted NAC comprising trastuzumab + pertuzumab + docetaxel. Despite three courses, we observed disease progression. The next NAC regimen was composed of two courses of epirubicin + cyclophosphamide, but the cancer continued to grow. She stopped receiving NAC and underwent a unilateral mastectomy and sentinel lymph node biopsy. Although the preoperative pathological result of core needle biopsy specimen showed invasive ductal carcinoma, the postoperative pathological result of the surgical specimen was MBC. Conclusion: In this case, when the patient had undergone three courses of trastuzumab + pertuzumab + docetaxel, it would have been appropriate to review the result of the core needle biopsy with pathologists or to perform vacuum-assisted breast biopsy. This case suggests the importance of considering the possibility of special histologic subtypes such as MBC when a tumor with the diagnosis of invasive ductal carcinoma is resistant to NAC

Cdh23 and Prepulse Inhibition

We previously identified quantitative trait loci (QTL) for prepulse inhibition (PPI), an endophenotype of schizophrenia, on mouse chromosome 10 and reported Fabp7 as a candidate gene from an analysis of F2 mice from inbred strains with high (C57BL/6N; B6) and low (C3H/HeN; C3H) PPI levels. Here, we reanalyzed the previously reported QTLs with increased marker density. The highest logarithm of odds score (26.66) peaked at a synonymous coding and splice-site variant, c.753G>A (rs257098870), in the Cdh23 gene on chromosome 10; the c.753G (C3H) allele showed a PPI-lowering effect. Bayesian multiple QTL mapping also supported the same variant with a posterior probability of 1. Thus, we engineered the c.753G (C3H) allele into the B6 genetic background, which led to dampened PPI. We also revealed an e-QTL (expression QTL) effect imparted by the c.753G>A variant for the Cdh23 expression in the brain. In a human study, a homologous variant (c.753G>A; rs769896655) in CDH23 showed a nominally significant enrichment in individuals with schizophrenia. We also identified multiple potentially deleterious CDH23 variants in individuals with schizophrenia. Collectively, the present study reveals a PPI-regulating Cdh23 variant and a possible contribution of CDH23 to schizophrenia susceptibility

A new genotype of bovine leukemia virus in South America identified by NGS-based whole genome sequencing and molecular evolutionary genetic analysis

Background: Bovine leukemia virus (BLV) is a member of retroviridae family, together with human T cell leukemia virus types 1 and 2 (HTLV-1 and -2) belonging to the genes deltaretrovirus, and infects cattle worldwide. Previous studies have classified the env sequences of BLV provirus from different geographic locations into eight genetic groups. To investigate the genetic variability of BLV in South America, we performed phylogenetic analyses of whole genome and partial env gp51 sequences of BLV strains isolated from Peru, Paraguay and Bolivia, for which no the molecular characteristics of BLV have previously been published, and discovered a novel BLV genotype, genotype-9, in Bolivia. Results: In Peru and Paraguay, 42.3 % (139/328) and over 50 % (76/139) of samples, respectively, were BLV positive. In Bolivia, the BLV infection rate was up to 30 % (156/507) at the individual level. In Argentina, 325/420 samples were BLV positive, with a BLV prevalence of 77.4 % at the individual level and up to 90.9 % at herd level. By contrast, relatively few BLV positive samples were detected in Chile, with a maximum of 29.1 % BLV infection at the individual level. We performed phylogenetic analyses using two different approaches, maximum likelihood (ML) tree and Bayesian inference, using 35 distinct partial env gp51 sequences from BLV strains isolated from Peru, Paraguay, and Bolivia, and 74 known BLV strains, representing eight different BLV genotypes from various geographical locations worldwide. The results indicated that Peruvian and Paraguayan BLV strains were grouped into genotypes-1, -2, and -6, while those from Bolivia were clustered into genotypes-1, -2, and -6, and a new genotype, genotype-9. Interestingly, these results were confirmed using ML phylogenetic analysis of whole genome sequences obtained by next generation sequencing of 25 BLV strains, assigned to four different genotypes (genotypes-1, -2, -6, and -9) from Peru, Paraguay, and Bolivia. Comparative analyses of complete genome sequences clearly showed some specific substitutions, in both structural and non-structural BLV genes, distinguishing the novel genotype-9 from known genotypes. Conclusions: Our results demonstrate widespread BLV infection in South American cattle and the existence of a new BLV genotype-9 in Bolivia. We conclude that at least seven BLV genotypes (genotypes-1, -2, -4, -5, -6, -7, and -9) are circulating in South America.Facultad de Ciencias VeterinariasInstituto de Genética Veterinari

Real-Time PCR Assay for the Diagnosis and Quantification of Co-infections by Diaporthe batatas and Diaporthe destruens in Sweet Potato

Foot rot disease caused by Diaporthe destruens (formerly Plenodomus destruens) has become a major concern for the production of sweet potato [Ipomoea batatas (L.) Lam.] in Japan. A related fungus Diaporthe batatas, which causes dry rot disease of sweet potato, is native and is widespread in fields in Japan. The similar characteristics of these two pathogens pose a challenge for conventional disease diagnosis. Currently, there are no effective molecular measures for identifying and distinguishing D. destruens and D. batatas. Here, we demonstrate a real-time PCR assay that distinguishes and quantifies D. batatas and D. destruens from co-infected sweet potato. The assay was performed with various simulated DNA combinations of D. batatas and D. destruens ranging from 1:1 to 1:100000. The assay was also used with the ratios of D. batatas: D. destruens: sweet potato DNA ranging from 1:1:1 to 1:1:100000. These assays produced a specific amplification product for each of the pathogens, and quantified the fungal biomass over the entire range tested without detecting false positives. The assay was validated by using infected sweet potato collected from various fields; it showed sufficient sensitivity and specificity to quantify and distinguish D. batatas and D. destruens from these field samples. Thus, our real-time PCR assay would be a useful tool for diagnosis of D. batatas and D. destruens and is expected to provide the foundation for the design of integrated disease management strategies for foot rot disease in sweet potato