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Abstract Pacific bluefin tuna (Thunnus orientalis) remains heavily depleted due to overexploitation. Aquaculture and stock enhancement based on artificial seedlings could be effective solutions to this problem. However, widespread adoption of seedling production is limited because spawning in captivity of bluefin tuna, a large pelagic top predator, requires much space, time, cost, and labour. To downsize and shorten their generation time, here, we show that xenogeneic germ cell transplantation enables a surrogate production of functional bluefin tuna sperm in hybrid little tuna (genus: Euthynnus), which attain sexual maturity at a smaller body size and shorter time. Intraperitonially transplanted bluefin tuna germ cells migrate towards and are incorporated into the gonads of little tuna larvae. These recipients produce functional donor-derived bluefin tuna sperm at a mere 8 months of age and 1 kg of body size. This result represents an advance toward compact, low-cost, and time-efficient seedling production that will improve the efficiency of bluefin tuna aquaculture.

In recent years, rapid advances in research methods have made single cell analysis possible. Systemic sclerosis (SSc), a disease characterized by the triad of immune abnormalities, fibrosis, and vasculopathy, has also been the subject of various analyses. To summarize the results of single cell analysis in SSc accumulated to date and to deepen our understanding of SSc. Four databases were used to perform a database search on 23rd June 2023. Assessed Grading of Recommendations Assessment, Development and Evaluation certainty of evidence were performed according to PRISMA guidelines. The analysis was completed on July 2023. 17 studies with 358 SSc patients were included. Three studies used PBMCs, six used skin, nine used lung with SSc-interstitial lung diseases (ILDs), and one used lung with SSc-pulmonary arterial hypertension (PAH). The cells studied included immune cells such as T cells, natural killer cells, monocytes, macrophages, and dendritic cells, as well as endothelial cells, fibroblasts, keratinocytes, alveolar type I cells, basal epithelial cells, smooth muscle cells, mesothelial cells, etc. This systematic review revealed the results of single cell analysis, suggesting that PBMCs, skin, SSc-ILD, and SSc-PAH show activation and dysfunction of cells associated with immune-abnormalities, fibrosis, and vasculopathy, respectively.

Abstract Introduction Activation of the MAPK pathway by genetic mutations (such as BRAF and RET) initiates and accelerates the growth of papillary thyroid carcinoma (PTC). However, the correlation between genetic mutations and clinical features remains to be established. Therefore, this study aimed to retrospectively analyze major genetic mutations, specifically BRAF mutations and RET rearrangements, and develop a treatment algorithm by comparing background and clinical characteristics. Method One hundred thirteen patients with primary PTC were included in this study. BRAF mutations were detected via Sanger sequencing and RET rearrangements were detected via fluorescence in situ hybridization (FISH) analysis, and reverse transcription polymerase chain reaction (RT-PCR). The patients were categorized into two groups based on the presence of BRAF mutations and RET rearrangements and their clinical characteristics (age, sex, TNM, stage, extratumoral extension, tumor size, unifocal/multifocal lesions, vascular invasion, differentiation, chronic thyroiditis, preoperative serum thyroglobulin level, and 18F-fluorodeoxyglucose (FDG) uptake) were compared subsequently. Result After excluding unanalyzable specimens, 80 PTC patients (22 males and 58 females, mean age: 57.2 years) were included in the study. RET rearrangements were positive in 8 cases (10%), and BRAF mutation was positive in 63 (78.6%). The RET rearrangement group was significantly associated with younger age (p = 0.024), multifocal lesion (p = 0.048), distant metastasis (p = 0.025) and decreased 18F-fluorodeoxyglucose uptake (p

Postnatal cell fate is postulated to be primarily determined by the local tissue microenvironment. Here, we find that Mediator 1 (Med1) dependent epigenetic mechanisms dictate tissue-specific lineage commitment and progression of dental epithelia. Deletion of Med1, a key component of the Mediator complex linking enhancer activities to gene transcription, provokes a tissue extrinsic lineage shift, causing hair generation in incisors. Med1 deficiency gives rise to unusual hair growth via primitive cellular aggregates. Mechanistically, we find that MED1 establishes super-enhancers that control enamel lineage transcription factors in dental stem cells and their progenies. However, Med1 deficiency reshapes the enhancer landscape and causes a switch from the dental transcriptional program towards hair and epidermis on incisors in vivo, and in dental epithelial stem cells in vitro. Med1 loss also provokes an increase in the number and size of enhancers. Interestingly, control dental epithelia already exhibit enhancers for hair and epidermal key transcription factors; these transform into super-enhancers upon Med1 loss suggesting that these epigenetic mechanisms cause the shift towards epidermal and hair lineages. Thus, we propose a role for Med1 in safeguarding lineage specific enhancers, highlight the central role of enhancer accessibility in lineage reprogramming and provide insights into ectodermal regeneration.

The use of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) is well-established for the treatment of advanced non-small cell lung cancer (NSCLC) patients with activating EGFR mutations. In this study, we report the long-term efficacy of EGFR-TKI therapy in a patient with postoperative recurrent NSCLC. A 58-year-old Japanese woman experienced recurrence after surgery, and an EGFR L858R mutation was identified. The patient continued gefitinib therapy for over 13 years, achieving a long-term survival of 21 years after postoperative recurrence, and 24 years after the initial diagnosis. This is the first report of a long-term response to EGFR-TKI therapy in an NSCLC patient with an L858R mutation. This case suggests the potential effectiveness of combining local therapy with EGFR-TKI treatment for metachronous oligometastatic disease.

AbstractPurpose c-Jun N-terminal kinases (JNKs) comprise a subfamily of mitogen-activated protein kinases (MAPKs). The JNK group is known to be activated by a variety of stimuli. However, the molecular mechanism underlying heat-induced JNK activation is largely unknown. The aim of this study was to clarify how JNK activity is stimulated by heat.Methods and materials The expression levels of various MAPK members in HeLa cells, with or without hyperthermia treatment, were evaluated via western blotting. The kinase activity of MAPK members was assessed through in vitro kinase assays. Cell death was assessed in the absence or presence of siRNAs targeting MAPK-related members.Results Hyperthermia decreased the levels of MAP3Ks, such as ASK1 and MLK3 which are JNK kinase kinase members, but not those of the downstream MAP2K/SEK1 and MAPK/JNK. Despite the reduced or transient phosphorylation of ASK1, MLK3, or SEK1, downstream JNK was phosphorylated in a temperature-dependent manner. In vitro kinase assays demonstrated that heat did not directly stimulate SEK1 or JNK. However, the expression levels of DUSP16, a JNK phosphatase, were decreased upon hyperthermia treatment. DUSP16 knockdown enhanced the heat-induced activation of ASK1–SEK1–JNK pathway and apoptosis.Conclusion JNK was activated in a temperature-dependent manner despite reduced or transient phosphorylation of the upstream MAP3K and MAP2K. Hyperthermia-induced degradation of DUSP16 may induce activation of the ASK1–SEK1–JNK pathway and subsequent apoptosis.

Skin aging is a multifaceted process influenced by genetic, environmental, and immunological factors, resulting in visible changes such as wrinkles, pigmentation, and alterations in skin texture. Despite its high relevance, there is a paucity of large-scale studies focusing on visible age-related changes in facial skin among Japanese populations, particularly by region. This study aims to address these gaps by examining age- and sex-specific skin changes in a large cohort of 2,543 Japanese subjects using advanced skin imaging techniques. The study included subjects aged 17–71 years who provided informed consent. The imaging system captures facial images using standard light, UV light, and two types of polarized light, applying deep learning techniques to analyze various skin parameters. Statistical analysis was performed to evaluate correlations between age, gender, and skin characteristics. Results indicated significant correlations between age and skin color across all domains, with large pores on the nose showing the highest correlation with age. Sebum and porphyrin levels exhibited a decreasing trend with age, though correlation coefficients were low. Cheek gloss, both in area and color, showed relatively high correlation coefficients. Pigmentation-related items, such as spots and melanin, demonstrated significant age correlations, particularly in areas like the corners of the eyes, under the eyes, and cheeks. Wrinkles and fine wrinkles correlated with age in various regions, though not on the forehead. The findings highlight the importance of understanding regional and demographic variations in skin aging to develop effective anti-aging treatments.

BackgroundChronic kidney disease (CKD) is characterized by a decreased glomerular filtration rate or renal injury (especially proteinuria) for at least 3 months. The early detection and treatment of CKD, a major global public health concern, before the onset of symptoms is important. This study aimed to develop machine learning models to predict the risk of developing CKD within 1 and 5 years using health examination data.MethodsData were collected from patients who underwent annual health examinations between 2017 and 2022. Among the 30,273 participants included in the study, 1,372 had CKD. Demographic characteristics, body mass index, blood pressure, blood and urine test results, and questionnaire responses were used to predict the risk of CKD development at 1 and 5 years. This study examined three outcomes: incident estimated glomerular filtration rate (eGFR) 0.8 for predicting the onset of CKD in 1 year when the outcome was eGFR 0.9. With LR and a neural network, the specificities were 0.749 and 0.739 and AUROCs were 0.889 and 0.890, respectively, for predicting onset within 5 years. The AUROCs of most models were approximately 0.65 when the outcome was eGFR

Avaliamos alguns aspectos provenientes da interação entre estudantes de um programa de pós-graduação e mestres oriundos de povos e comunidades tradicionais no transcurso de uma disciplina baseada no Encontro de Saberes (ES). Adaptamos o método de avaliação qualitativa preconizado pela Avaliação de Quarta Geração de modo a captar as principais questões apontadas pelos participantes. O ES apresentou potencialidades políticas e intersubjetivas, na medida em que o diálogo cuidadoso entre diferentes epistemes colocou em perspectiva a noção de ciência única e ocasionou o desvelamento e a retomada reflexiva de aspectos da ascendência direta e da ancestralidade presentes nas trajetórias particulares dos estudantes.

Hyperthermia is a promising anticancer treatment that induces heat stress, thereby stimulating various signal transduction pathways to maintain cellular homeostasis. Mitogen-activated protein kinases (MAPKs) associate various extracellular stimuli with cytoplasmic and nuclear mediators through a three-tiered cascade of kinases, including MAPKs, MAP2Ks, and MAP3Ks. In mammals, three major groups of MAPKs have been characterized: extracellular signal-regulated protein kinases (ERK1/2), p38 MAPKs (α, β, γ, and δ), and c-Jun NH2-terminal kinases (JNK1/2/3). Each group of MAPKs is activated by heat and exhibits distinct biological functions. Recent studies have indicated that in hyperthermia, MAPK signaling pathways regulate cell survival and death in unique ways. This review offers a concise overview of the MAPK signaling pathway, specifically ERK and JNK, focusing on their relevance in cancer, interplay with heat shock proteins or phosphatases, and current understanding of the MAPK signaling pathway in hyperthermia.

Abstract Sex bias is known in the prevalence/pathology of neurodevelopmental disorders. Sex-dependent differences of the certain brain areas are known to emerge perinatally through the exposure to sex hormones, while gene expression patterns in the rodent embryonic brain does not seem to be completely the same between male and female. To investigate potential sex differences in gene expression and cortical organization during the embryonic period in mice, we conducted a comprehensive analysis of gene expression for the telencephalon at embryonic day (E) 11.5 (a peak of neural stem cell expansion) and E14.5 (a peak of neurogenesis) using bulk RNA-seq data. As a result, our data showed the existence of notable sex differences in gene expression patterns not obviously at E11.5, but clearly at E14.5 when neurogenesis has become its peak. These data can be useful for exploring potential contribution of genes exhibiting sex differences to the divergence in brain development. Additionally, our data underscore the significance of studying the embryonic period to gain a deeper understanding of sex differences in brain development.

Abstract Despite high vaccination rates globally, countries are still grappling with new COVID infections, and patients diagnosed as mild dying at home during outpatient treatment. Hence, this study aim to identify, then validate, biomarkers that could predict if newly infected COVID-19 patients would subsequently require hospitalization or could recover safely with medication as outpatients. Serum cytokine/chemokine data from 129 COVID-19 patients within 7 days after the onset of symptoms in Bangladesh were used as training data. The majority of patients were infected with the Omicron variant and over 88% were vaccinated. Patients were divided into those with mild symptoms who recovered, and those who deteriorated to moderate or severe illness. Using the Lasso method, 15 predictive markers were identified and used to classify patients into these two groups. The biomarkers were then validated in a cohort of 194 Covid patients in Japan with a predictive accuracy that exceeded 80% for patients infected with Delta and Omicron variants, and 70% for Wuhan and Alpha variants. In an environment of widespread vaccination, these biomarkers could help medical practitioners determine if newly infected COVID-19 patients will improve and can be managed on an out-patient basis, or if they will deteriorate and require hospitalization.

Tauopathy is known to be a major pathognomonic finding in important neurodegenerative diseases such as progressive supranuclear palsy (PSP) and corticobasal degeneration. However, the mechanism by which tauopathy is triggered remains to be elucidated. We previously identified the point mutation c.11596C > G, p.Pro3866Ala in the Bassoon gene (BSN) in a Japanese family with PSP-like syndrome. We showed that mutated BSN may have been involved in its own insolubilization and tau accumulation. Furthermore, BSN mutations have also been related to various neurological diseases. In order to further investigate the pathophysiology of BSN mutation in detail, it is essential to study it in mouse models. We generated a mouse model with the mouse Bassoon p.P3882A mutation, which corresponds to the human BSN p.P3866A mutation, knock-in (KI) and we performed systematic behavioral and histological analyses. Behavioral analyses revealed impaired working memory in a Y-maze test at 3 months of age and decreased locomotor activity in the home cage at 3 and 12 months of age in KI mice compared to those in wild-type mice. Although no obvious structural abnormalities were observed at 3 months of age, immunohistochemical studies showed elevation of Bsn immunoreactivity in the hippocampus and neuronal loss without tau accumulation in the substantia nigra at 12 months of age in KI mice. Although our mice model did not show progressive cognitive dysfunction and locomotor disorder like PSP-like syndrome, dopaminergic neuronal loss was observed in the substantia nigra in 12-month-old KI mice. It is possible that BSN mutation may result in dopaminergic neuronal loss without locomotor symptoms due to the early disease stage. Thus, further clinical course can induce cognitive dysfunction and locomotor symptoms.

Abstract is missing (Short communication)

Abstract Background Ehlers–Danlos syndrome (EDS) is a genetic disorder that causes fragility of the systemic connective tissues. Of the 13 subtypes, vascular EDS (vEDS) is associated with abnormalities in collagen production, resulting in arterial rupture and intestinal perforation. Herein, we report the case of a man with confirmed vEDS who survived a ruptured dissected splenic artery aneurysm triggered by perforation of the sigmoid colon. Case presentation A 48-year-old man presented to our hospital with sudden severe lower abdominal pain. The patient was genetically diagnosed with vEDS at the age of 43 years. Abdominal computed tomography (CT) showed fluid and free air surrounding the sigmoid colon. These findings suggested sigmoid colon perforation, and emergency surgery was needed. Hartmann’s procedure was performed. The resected specimen showed a 2-cm-sized depression around the perforation. Histopathological findings showed an abscess and exudate in the serosa of the perforation and thinning of the intrinsic muscular layer in the depressed area. The patient was doing well postoperatively; however, on the ninth postoperative day, sudden upper abdominal pain developed. CT revealed an intra-abdominal hemorrhage due to rupture of a dissecting splenic artery aneurysm. The aneurysm was not observed on preoperative CT and was distant from the surgical site. Urgent transcatheter arterial embolization was performed. Although embolization of the splenic artery was attempted during the procedure, the arterial dissection spread to the common hepatic artery. Moreover, the proper hepatic and gastroduodenal arteries were poorly visualized, probably due to vasospasm. Although complications associated with extensive embolization were a concern, embolization of the splenic and common hepatic arteries was necessary to save the patient’s life. After embolization, angiography showed that the left hepatic blood flow was maintained from the inferior phrenic artery, and the right hepatic inflow was maintained from the superior mesenteric artery via the peribiliary vascular plexus in the hilar area. The patient recovered well and was discharged on the 19th postoperative day. Conclusions vEDS can cause arterial rupture after intestinal surgery. Therefore, careful post-operative management is necessary. Moreover, cooperation with interventional radiologists is important for prompt treatment of vascular complications.

This study investigates the contribution of magnetostriction to vibration and acoustic noise in interior permanent magnet synchronous motors using finite element analysis and experiments on two test machines. The two motors have identical dimensions but different iron core materials. The first motor is made of 6.5% high-silicon steel 10JNEX900 with a negligible magnetostriction (0.3 ppm at 1T), and the second motor is made of amorphous iron 2605SA1 with a significantly high magnetostriction (11.0 ppm at 1T). Using finite element analysis, the electromagnetic forces, equivalent magnetostrictive forces, and resultant vibrations are compared between the two motors. The results reveal a significant counteraction between magnetostrictive vibrations and those caused by electromagnetic forces at the multiples of the sixth vibration harmonic in the amorphous iron motor. This counteraction effect was then verified experimentally. In the experiment, the amorphous iron motor exhibited similar or even lower vibrations at the multiples of the sixth harmonic but significantly higher vibrations at other harmonics. These experimental observations can only be justified by considering magnetostriction. Such experimental evidence, which has not been reported in the existing literature, highlights the importance of accounting for magnetostriction when evaluating vibration and acoustic noise in motors.