Aggregated chromosomes/chromatin transfer: a novel approach for mitochondrial replacement with minimal mitochondrial carryover: the implications of mouse experiments for human aggregated chromosome transfer.

Nuclear transfer techniques, including spindle chromosome complex (SC) transfer and pronuclear transfer, have been employed to mitigate mitochondrial diseases. Nevertheless, the challenge of mitochondrial DNA (mtDNA) carryover remains unresolved. Previously, we introduced a method for aggregated chromosome (AC) transfer in human subjects, offering a potential solution. However, the subsequent rates of embryonic development have remained unexplored owing to legal limitations in Japan, and animal studies have been hindered by a lack of AC formation in other species. Building upon our success in generating ACs within mouse oocytes via utilization of the phosphodiesterase inhibitor 3-isobutyl 1-methylxanthine (IBMX), this study has established a mouse model for AC transfer. Subsequently, a comparative analysis of embryo development rates and mtDNA carryover between AC transfer and SC transfer was conducted. Additionally, the mitochondrial distribution around SC and AC structures was investigated, revealing that in oocytes at the metaphase II stage, the mitochondria exhibited a relatively concentrated arrangement around the spindle apparatus, while the distribution of mitochondria in AC-formed oocytes appeared to be independent of the AC position. The AC transfer approach produced a marked augmentation in rates of fertilization, embryo cleavage, and blastocyst formation, especially as compared to scenarios without AC transfer in IBMX-treated AC-formed oocytes. No significant disparities in fertilization and embryo development rates were observed between AC and SC transfers. However, relative real-time PCR analyses revealed that the mtDNA carryover for AC transfers was one-tenth and therefore significantly lower than that of SC transfers. This study successfully accomplished nuclear transfers with ACs in mouse oocytes, offering an insight into the potential of AC transfers as a solution to heteroplasmy-related challenges. These findings are promising in terms of future investigation with human oocytes, thus advancing AC transfer as an innovative approach in the field of human nuclear transfer methodology.

Dermoscopy of glomus tumour: a cross-sectional study of 86 cases.

BACKGROUND: Glomus tumours (GTs) are benign cutaneous neoplasms derived from the neuromyoarterial apparatus with a strong predilection for acral sites, especially the subungual space. Current data regarding dermoscopy of these lesions are very limited. OBJECTIVES: To analyse the dermoscopic structures and patterns seen in a large series of subungual (SUGTs) and extraungual glomus tumours (EUGTs) and to determine their diagnostic significance. METHODS: Clinical and dermoscopic images of 86 histopathologically proven cases of GTs (47 SUGTs and 39 EUGTs) collected from 9 hospitals in Spain, France, Italy, and Brazil were evaluated for the presence of dermoscopic structures and patterns. Similarly, 189 and 185 dermoscopic images of other ungual tumours and other extraungual non-pigmented tumours, respectively, were evaluated for the same structures and patterns. Finally, we evaluate diagnostic testing accuracy calculating sensitivity (S), specificity (Sp), and positive and negative predictive values of the different patterns for the diagnosis of GT. RESULTS: Regarding SUGTs, four patterns were built from the combination of different structures. The pattern composed of a structureless purplish/red subungual spot with or without vessels reached the highest S (S1, 78.8%). The combination of a structureless purplish/red subungual spot and longitudinal erythronychia (LE) (S2) is highly specific (96.3%). Patterns S3 (proximal purplish/red subungual spot, LE, and distal notch) and S4 (bed subungual spot and onycholysis) are the most specific and exclusive of matrix and bed tumours, respectively. The most consistent pattern in EUGTs is composed of a structureless purplish-white to reddish-white homogeneous area and linear unfocused vessels (E) (S: 61.5%, Sp: 95.7%). EUGTs did not show lacunae, unlike other vascular tumours. CONCLUSIONS: Dermoscopy is helpful in improving the diagnostic accuracy of GTs, not only in SUGTs but also when these lesions arise out of the ungual apparatus.

Professional dental care provision systems for persons with disabilities by prefecture in Japan.

OBJECTIVE: The number of persons with disabilities has increased and aged. Although it is important to maintain good oral health to extend healthy life expectancy, it is difficult for such people. This study aimed to analyze regional disparities in dental care provision systems for disabled people and to propose measures for the establishment of an appropriate system. BASIC RESEARCH DESIGN: To examine regional disparities in dental care provision systems for persons with disabilities, the number of practicing dentists and dental clinics per 100,000 population, dentists certified by the Japanese Society for Disability and Oral Health, and institutions with certified dentists per 100,000 disabled persons for each prefecture were calculated. The Gini coefficient of each was also calculated to visualize and analyze regional disparities. RESULT: The Gini coefficients were 0.09 and 0.07 for practicing dentists and dental clinics and 0.32 and 0.28 for the certified dentists and institutions with the certified dentists, respectively. Dental institutions for the disabled abounded in the three metropolitan areas: Tokyo, Aichi, and Osaka, and their density tended to be lower in northern and southern Japan. In prefectures with few such institutions, there was no correlation between the number of institutions and prefectural residents' income, and some prefectures had similar incomes but had many institutions. CONCLUSION: The distribution of dental care to the disabled is highly uneven in Japan, therefore, a system needs to be established to address this issue.

NWChem: Past, present, and future.

Specialized computational chemistry packages have permanently reshaped the landscape of chemical and materials science by providing tools to support and guide experimental efforts and for the prediction of atomistic and electronic properties. In this regard, electronic structure packages have played a special role by using first-principle-driven methodologies to model complex chemical and materials processes. Over the past few decades, the rapid development of computing technologies and the tremendous increase in computational power have offered a unique chance to study complex transformations using sophisticated and predictive many-body techniques that describe correlated behavior of electrons in molecular and condensed phase systems at different levels of theory. In enabling these simulations, novel parallel algorithms have been able to take advantage of computational resources to address the polynomial scaling of electronic structure methods. In this paper, we briefly review the NWChem computational chemistry suite, including its history, design principles, parallel tools, current capabilities, outreach, and outlook.

Tumour necrosis factor α augments the inhibitory effects of CTLA-4-Ig on osteoclast generation from human monocytes via induction of CD80 expression.

Cytotoxic T lymphocyte antigen-4-immunoglobulin (CTLA-4-Ig) exerts anti-rheumatic action via negative regulation of the co-stimulation process between antigen-presenting cells and T cells. CTLA-4-Ig also binds to CD80/CD86 on monocytes of osteoclast precursors. However, little is known about the effect of CTLA-4-Ig on osteoclastogenesis in rheumatoid arthritis (RA). In this study we evaluated the effects of CTLA-4-Ig on osteoclast generation from human blood monocytes (PBM) and rheumatoid synovial fluid monocytes (RSFM). Highly purified monocytes were cultured with receptor activator of nuclear factor kappa-B ligand (RANKL) and macrophage colony-stimulating factor (M-CSF) in the presence of CTLA-4-Ig. CTLA-4-Ig inhibited RANKL-induced osteoclast generation in PBM and RSFM, as determined by tartrate-resistant acid phosphatase (TRAP) staining and bone resorption assay using osteo assay surface plates. In addition, CTLA-4-Ig reduced the gene and protein expressions of nuclear factor of activated T cells, cytoplasmic 1 (NFATc1) and cathepsin K during osteoclastogenesis. Furthermore, CTLA-4-Ig significantly inhibited cell proliferation during osteoclastogenesis. Interestingly, the gene expression of indoleamine 2,3-dioxygenase-1, an inducer of apoptosis, was enhanced by CTLA-4-Ig. We next examined the effect of tumour necrosis factor (TNF)-α, a major inflammatory cytokine in rheumatoid synovium, on the expression of CD80 and CD86 by flow cytometric analysis. TNF-α potently induced the surface expression of CD80, which is known to have much higher affinity to CTLA-4-Ig than CD86, and this induction was observed at mRNA levels. Interestingly, freshly prepared rheumatoid synovial monocytes also expressed CD80 as much as TNF-α-treated PBM. Furthermore, TNF-α enhanced CTLA-4-Ig-induced inhibition of osteoclastogenesis and cell proliferation. Taken together, the TNF-α-induced CD80 may augment CTLA-4-Ig-induced inhibition of osteoclastogenesis, suggesting that CTLA-4-Ig potently inhibits osteoclast differentiation and protects bone destruction in rheumatoid inflamed joints.

Precision Analysis of the

We present a precision analysis of the ^{136}Xe two-neutrino ßß electron spectrum above 0.8 MeV, based on high-statistics data obtained with the KamLAND-Zen experiment. An improved formalism for the two-neutrino ßß rate allows us to measure the ratio of the leading and subleading 2νßß nuclear matrix elements (NMEs), ξ_{31}^{2ν}=-0.26_{-0.25}^{+0.31}. Theoretical predictions from the nuclear shell model and the majority of the quasiparticle random-phase approximation (QRPA) calculations are consistent with the experimental limit. However, part of the ξ_{31}^{2ν} range allowed by the QRPA is excluded by the present measurement at the 90% confidence level. Our analysis reveals that predicted ξ_{31}^{2ν} values are sensitive to the quenching of NMEs and the competing contributions from low- and high-energy states in the intermediate nucleus. Because these aspects are also at play in neutrinoless ßß decay, ξ_{31}^{2ν} provides new insights toward reliable neutrinoless ßß NMEs.

Geographic distribution of dental specialists permitted to advertise dental practices in Japan.

OBJECTIVE: The purpose of this study was to determine the geographic distribution of dental specialists permitted to advertise dental practices in Japan. METHOD: We identified the populations of 349 secondary medical zones nationwide from the 2015 population census, as well as the number of dentists in five specialties, namely oral surgeons, pedodontists, periodontists, dental anesthesiologists, and dental radiologists, who had been permitted to advertise dental practices, from a 2016 survey of physicians, dentists, and pharmacists. We determined the placement rate, Lorenz curve, and Gini coefficient for dentists in each specialty in order to describe their geographic distributions. RESULTS: The placement rates of at least one of these types of dentist in each secondary medical zone were 73.9% for oral surgeons, 66.2% for pedodontists, 60.5% for periodontists, 31.8% for dental anesthesiologists, and 18.3% for dental radiologists. The Gini coefficients were 0.397, 0.400, 0.491, 0.650, and 0.761, respectively. CONCLUSION: The dentists in each specialty were few in number and were unequally distributed among the zones, but less so for oral surgeons and pedodontists. Dental anesthesiologists and radiologists were located primarily at university hospitals in urban areas and, therefore, were more unequally distributed.

Efficacy and safety of anti-CD20 antibody rituximab for patients with refractory systemic lupus erythematosus.

Objective We examined the efficacy and safety of rituximab in patients with refractory systemic lupus erythematosus (SLE). Methods The study enrolled 63 SLE patients who were treated with rituximab between 2002 and 2015. The participants underwent a battery of tests before treatment and at one year. Treatment ranged from two to four times at 500 or 1000 mg. Results Baseline characteristics were males:females = 6:57, age 33.9 years, and disease duration 87.2 months. The primary endpoint: The rate of major clinical response (MCR) was 60% while the partial clinical response (PCR) was 25%. Thirty of 36 (83%) patients with lupus nephritis (WHO II: 2, III: 5, IV: 22, V: 4, IV+V: 2, not assessed: 1) and 22 of 24 patients (92%) with neuropsychiatric SLE, who could be followed at one year, showed changes from BILAG A or B score to C or D score at one year. Multivariate analysis identified high anti-dsDNA antibody and shorter disease duration as significant determinants of MCR at one year. Repeat examination was conducted at five years. Primary failure was recorded in 8.8% and secondary failure in 32.4% (time to relapse: 24.4 months). Rituximab was well tolerated although 65 adverse events, mostly infections, were recorded within one year. Conclusion Rituximab is potentially efficacious for the treatment of patients with refractory SLE.

In vivo Confocal Laser Microscopy for monitoring of actinic keratosis treatment: a comparison with histopathologic assessment after treatment with topical 5% 5-fluorouracil.

BACKGROUND: Histological examination is the gold standard for actinic keratosis diagnosis; however, it is not always a feasible approach. Reflectance confocal microscopy (RCM) is a non-invasive technique that may be an alternative for monitoring actinic keratoses treatment response. Topical 5-fluorouracil is indicated for actinic keratosis multiple lesions and for field cancerization treatment. OBJECTIVES: To assess the RCM accuracy, sensibility and specificity for actinic keratosis, considering as a gold standard the histopathological examination; as well as to evaluate the efficacy of 5% 5-fluorouracil treatment. METHODS: This is a prospective study in actinic keratosis patients between August 2014 and November 2015. RCM analyses were performed in one randomly selected actinic keratosis lesion of the upper limbs by two independent observers before and after 5% 5-fluorouracil treatment. At the end of treatment and with clinical bleaching of treated lesions, histological examination was performed by two pathologists. RESULTS: A total of 50 lesions were enroled, and 40 lesions presented complete clinical bleaching after treatment and were included in the final analysis. Accuracy, sensibility and specificity means among observers were 83.8%, 84.6% and 83.3%, respectively. After 5-fluorouracil treatment, actinic keratosis was diagnosed in 45.0% (observer 1) and 32.5% (observer 2) of subjects according to RCM and in 32.5% of subjects according to histological examination. Considering RCM observers diagnosis, the concordance was substantial (k 0.637, P < 0.001). 5-fluorouracil led to a reduction in 55.0%-67.5% of actinic keratoses according to RCM analysis. CONCLUSION: This study allows to validate RCM as a non-invasive method capable of monitoring actinic keratosis therapeutic response to 5-fluorouracil, presenting efficacy comparable to histological examination. Additionally, the results suggest that 5-fluorouracil may be a satisfactory option for therapeutic control of this condition.

Chimpanzee Personality and the Arginine Vasopressin Receptor 1A Genotype.

Polymorphisms of the arginine vasopressin receptor 1a (AVPR1a) gene have been linked to various measures related to human social behavior, including sibling conflict and agreeableness. In chimpanzees, AVPR1a polymorphisms have been associated with traits important for social interactions, including sociability, joint attention, dominance, conscientiousness, and hierarchical personality dimensions named low alpha/stability, disinhibition, and negative emotionality/low dominance. We examined associations between AVPR1a and six personality domains and hierarchical personality dimensions in 129 chimpanzees (Pan troglodytes) living in Japan or in a sanctuary in Guinea. We fit three linear and three animal models. The first model included genotype, the second included sex and genotype, and the third included genotype, sex, and sex × genotype. All personality phenotypes were heritable. Chimpanzees possessing the long form of the allele were higher in conscientiousness, but only in models that did not include the other predictors; however, additional analyses suggested that this may have been a consequence of study design. In animal models that included sex and sex × genotype, chimpanzees homozygous for the short form of the allele were higher in extraversion. Taken with the findings of previous studies of chimpanzees and humans, the findings related to conscientiousness suggest that AVPR1a may be related to lower levels of impulsive aggression. The direction of the association between AVPR1a genotype and extraversion ran counter to what one would expect if AVPR1a was related to social behaviors. These results help us further understand the genetic basis of personality in chimpanzees.

A case of maxillary sarcoma in a chimpanzee (Pan troglodytes).

Oral malignancy is rare in chimpanzees. A 34-year-old female chimpanzee (Pan troglodytes) at Kumamoto Sanctuary, Japan, had developed it. Treatment is technically difficult for chimpanzees while malignant neoplasm is seemingly rising in captive populations. Widespread expert discussion, guidelines for treatment, especially for great apes in terminal stages is urgently needed.

Trends in the geographic distribution of dental clinics in Japan.

AIM: In Japan, along with the increase in the number of dentists, the number of dental facilities has continuously increased as well. This study aimed to examine whether the increase in the number of dental clinics in Japan has led to an improvement in their geographic distribution. METHODS: We analysed the number of dental clinics and population in all municipalities in Japan as of 2000, 2005 and 2010. We obtained data on the population from the population census and data on the number of dental clinics from the Survey of Medical Institutions. The number of municipalities was 3,258 in 2000 but had dropped to 1,750 by 2010 due to municipal mergers so population and dental data for other years were recalculated based on 2010 municipal boundaries. Lorenz curves and Gini coefficients were used to assess the distribution of dental clinics per 100,000 persons. RESULTS: The mean number of dental clinics per 100,000 persons among all municipalities was 49.9 in 2000, 52.2 in 2005 and 53.4 in 2010. The Gini coefficient for the clinics in the whole country was 0.172 in 2000, 0.164 in 2005 and 0.153 in 2010. CONCLUSION: The results suggest that the regional inequalities in the availability of dentists have been reduced gradually as the number of dental clinics has increased.

Surgical repair of an unroofed coronary sinus in a dog.

A 5-year-old, 7.9 kg castrated male Miniature Dachsund presented with heart enlargement on radiography. The dog was asymptomatic. Echocardiography revealed a tubular structure running along the posterior wall of the left atrium and connecting to the right atrium on the caudal side of the left atrium and annulus, which was presumed to be a dilated coronary sinus. After confirming a shunt between the left atrium and coronary sinus by cardiovascular catheterization, an unroofed coronary sinus was diagnosed. Open-heart surgery using cardiopulmonary bypass was performed through left atriotomy. The defect between the left atrium and the coronary sinus was closed by suturing. The cardiac enlargement improved after surgery. The dog was still alive 1227 days after surgery without clinical signs.

Identification of HLA-A2-restricted CTL epitopes of a novel tumour-associated antigen, KIF20A, overexpressed in pancreatic cancer.

BACKGROUND: Identification of tumour-associated antigens (TAAs) that induce cytotoxic T lymphocytes (CTLs) specific to cancer cells is critical for the development of anticancer immunotherapy. In this study, we aimed at identifying a novel TAA of pancreatic cancer for immunotherapy. METHODS: On the basis of the genome-wide cDNA microarray analysis, we focused on KIF20A (also known as RAB6KIFL/MKlp2) as a candidate TAA in pancreatic cancer cells. The HLA-A2 (A*02:01)-restricted CTL epitopes of KIF20A were identified using HLA-A2 transgenic mice (Tgm) and the peptides were examined to check whether they could generate human CTLs exhibiting cytotoxic responses against KIF20A(+), HLA-A2(+) tumour cells in vitro. RESULTS: KIF20A was overexpressed in pancreatic cancer and in some other malignancies, but not in their non-cancerous counterparts and many normal adult tissues. We found that KIF20A-2 (p12-20, LLSDDDVVV), KIF20A-8 (p809-817, CIAEQYHTV), and KIF20A-28 (p284-293, AQPDTAPLPV) peptides could induce HLA-A2-restricted CTLs in HLA-A2 Tgm without causing autoimmunity. Peptide-reactive human CTLs were generated from peripheral blood mononuclear cells of HLA-A2(+) healthy donors by in vitro stimulation with the three peptides, and those CTLs successfully exhibited cytotoxic responses to cancer cells expressing both KIF20A and HLA-A2. CONCLUSION: KIF20A is a novel promising candidate for anticancer immunotherapeutic target for pancreatic cancers.

Loss of Ftsj1 perturbs codon-specific translation efficiency in the brain and is associated with X-linked intellectual disability.

FtsJ RNA 2'-O-methyltransferase 1 (FTSJ1) gene has been implicated in X-linked intellectual disability (XLID), but the molecular pathogenesis is unknown. We show that Ftsj1 is responsible for 2'-O-methylation of 11 species of cytosolic transfer RNAs (tRNAs) at the anticodon region, and these modifications are abolished in Ftsj1 knockout (KO) mice and XLID patient-derived cells. Loss of 2'-O-methylation in Ftsj1 KO mouse selectively reduced the steady-state level of tRNAPhe in the brain, resulting in a slow decoding at Phe codons. Ribosome profiling showed that translation efficiency is significantly reduced in a subset of genes that need to be efficiently translated to support synaptic organization and functions. Ftsj1 KO mice display immature synaptic morphology and aberrant synaptic plasticity, which are associated with anxiety-like and memory deficits. The data illuminate a fundamental role of tRNA modification in the brain through regulation of translation efficiency and provide mechanistic insights into FTSJ1-related XLID.

Prevalence of acquired melanocytic naevi in Brazilian schoolchildren.

BACKGROUND: The prevalence of acquired melanocytic naevi (AMN) is one of the most important known risk factors for malignant melanoma (MM) in homogeneous white populations. However, there are few studies on AMN in heterogeneous populations. Insight into the causes of AMN in heterogeneous populations in a country with intense ultraviolet radiation should lead to successful strategies in the prevention of MM. AIM: To evaluate the frequency and anatomical distribution of AMN and to observe the influence of environmental and constitutional variables. METHODS: A cross-sectional study on the prevalence of AMN was performed on 1279 Brazilian schoolchildren, aged 2-8 years, according to an international protocol. RESULTS: Both girls and boys had the same number of AMN. The number of AMN was higher on sun-exposed body sites, such as shoulders, thorax/upper abdomen, face/ears and back. A high number of AMN was associated with lighter skin type, greater sun exposure, age, number of sunburns and presence of freckles. CONCLUSIONS: In genetically predisposed people, the body-site distribution of AMN in a heterogeneous population (mixed ethnic backgrounds) is similar to that in a homogeneous population and has the same tendency toward potential proliferation of melanocytes in the presence of ultraviolet radiation. Strategies to reduce the incidence of MM should start at an early age. We believe that these findings will have a direct effect on concepts for preventive strategies. Studies in different populations may serve as a starting point for research into the mechanism underlying increasing rates of AMN.

[Solitary fibrous tumor of the visceral pleura being suspected of chest wall origin: report of a case].

We report a case of a solitary fibrous tumor (SFT) of the pleura which is suspected of chest wall tumor. A 52-year-old female was admitted to our hospital because of epigastralgia and body weight loss. Chest X-ray and computed tomography showed a circumscribed mass of 35 x 22 mm in diameter arising from the parietal pleura. Positron emission tomography showed uptake valve of 1.5. SFT of chest wall origin was suspected and performed video-assisted thoracic surgery. The pedunculated tumor attached to the visceral pleura. The tumor was diagnosed as a benign SFT in intraoperative diagnosis. Long term clinical follow-up is recommended for patients with SFT, because the tumor recurrence and malignant transformation may occur in tumors with benign histological features.

Large-vessel vasculitis associated with PEGylated granulocyte-colony stimulating factor.

A 71-year-old female with advanced endometrial cancer was treated with pegfilgrastim. She developed a fever within seven days, and contrast-enhanced computed tomography scans repeated within three days revealed rapidly progressive thickening of the aortic wall. When clinicians administer PEGylated granulocyte-colony stimulating factor (G-CSF) to cancer patients, drug-associated vasculitis should be suspected. This report discusses the manifestation of G-CSF-associated large-vessel vasculitis (LVV).

Neuroblastoma presenting with dilated cardiomyopathy.

We report an infant with neuroblastoma who presented with dilated cardiomyopathy. A 3-month-old girl presented with dilated cardiomyopathy diagnosed as stage III neuroblastoma. Since total resection was impossible, chemotherapy was started. Cardiomyopathy was normalized by improvement of neuroblastoma. The prompt improvement of cardiac function following treatment of neuroblastoma suggested that cardiomyopathy in this patient was caused by the increase in catecholamines secreted by neuroblastoma and that reduction in catecholamines by treatment of neuroblastoma led to improvement in the cardiomyopathy.