Background: The nuclear-encoded enzyme polymerase gamma (Pol-γ) is crucial in the replication of the mitochondrial genome (mtDNA), which in turn is vital for mitochondria and hence numerous metabolic processes and energy production in eukaryotic cells. Variants in the POLG gene, which encodes the catalytic subunit of Pol-γ, can significantly impair Pol-γ enzyme function. Pol-γ-associated disorders are referred to as POLG-spectrum disorders (POLG-SDs) and are mainly autosomal-recessively inherited. Clinical manifestations include muscle weakness and fatigue, and severe forms of the disease can lead to premature death in infancy, childhood, and early adulthood, often associated with seizures, liver failure, or intractable epilepsy. Here, we analyzed fibroblasts from a compound heterozygous patient with the established pathogenic variant c.2419C>T; p.(Arg807Cys) and a previously undescribed variant c.678G>C; p.(Gln226His) with a clinical manifestation compatible with POLG-SDs, sensory ataxic neuropathy, and infantile muscular atrophy. We conducted a battery of functional studies for Pol-γ and mitochondrial dysfunction on the patient’s fibroblasts, to test whether the novel variant c.678G>C; p.(Gln226His) may be causative in human disease. Aims/Methods: We analyzed skin-derived fibroblasts in comparison to a first-degree relative (the mother of the patient), an asymptomatic carrier harboring only the established c.2419C>T; p.(Arg807Cys) mutation. Assessments of mitochondrial function included measurements of mtDNA content, mRNA levels of mitochondrial genes, mitochondrial mass, and mitochondrial morphology. Case Presentation and Results: A 13-year-old male presented with symptoms starting at three years of age, including muscle weakness and atrophy in the lower extremities and facial muscles, which later extended to the upper limbs, voice, and back muscles, without further progression. The patient also reported fatigue and muscle pain after physical activity, with no sensory deficits. Extensive diagnostic tests such as electromyography, nerve conduction studies, muscle biopsy, and MRI were unremarkable. Exome sequencing revealed that he carried the compound heterozygous variants in POLG c.678G>C; p.(Gln226His) and c.2419C>T; p.(Arg807Cys), but no other potential genetic pathogenic causes. In comparison to a first-degree relative (his mother) who only carried the c.2419C>T; p.(Arg807Cys) pathogenic mutation, in vitro analyses revealed a significant reduction in mtDNA content (~50%) and mRNA levels of mtDNA-encoded proteins. Mitochondrial mass was reduced by approximately 20%, and mitochondrial interconnectivity within cells was impaired, as determined by fluorescence microscopy and mitochondrial staining. Conclusions: Our findings suggest that the c.678G>C; p.(Gln226His) variant, in conjunction with the c.2419C>T; p.(Arg807Cys) mutation, may compromise mtDNA replication and mitochondrial function and could result in clinically significant mitochondriopathy. As this study is based on one patient compared to a first-degree relative (but with an identical mitochondrial genome), the pathogenicity of c.678G>C; p.(Gln226His) of POLG should be confirmed in future studies, in particular, in conjunction with other POLG-variants.

• Book : 16(2)
• Pub. Date : 2025
• Page : pp.198-198
• Keyword :

이 연구는 니가타현에 위치한 도쿄전력 가시와자키 가리와 원전 재가동을 둘러싼 원전 입지 지역의 현황을 희생의 시스템 논의를 토대로 검토했다. 원전 입지 지역에 대해서는 위험을 감수하는 희생을 강요당하는 반면, 그에 응당한 경제적인 혜택을 받는다는 등 쟁점이 존재하기 때문에, 사회적인 갈등을 야기하고 있는 해당 원전과 지역의 현황을 논할 필요가 있다. 주요 결과로는 첫 번째, 전력생산과 소비 측면에서 가시와자키 가리와 원전 입지 지역과 그 주변 지역에서는 불평등을 인식하고 있었으며, 원전에 대한 영향력이 제한된 상황에서 이를 극복하기 위한 움직임이 지역 정치와 시민사회 차원에서 관찰되었다. 두 번째, 일본 정부는 해당 원전의 안전성을 강조하며 재가동을 추진하려 하지만 원전의 위험은 이미 가시화된 상태이며, 이는 지자체와 시민들이 원전 관련 의사결정에 대한 참여를 요구하는 기제가 되고 있다. 세 번째, 원전이 지역경제에 어떠한 영향을 주는가에 대해서는 논쟁이 전개되고 있으며 지역 시민들의 인식도 혼란이 있었다. 이는 경제적 혜택과의 비교대상이 위험이라는 특성에서 기인한다. 이 연구에서는 원전 입지 지역과 주변 지역을 포함하여 ‘원전 영향 지역’이라는 개념을 제안했고, 가시와자키 가리와 원전 영향 지역 사례를 통해 지역과 주민 차원에서 기존의 수동적인 위치를 탈피하려는 실천이 이루어지고 있음을 확인할 수 있었다.

• Pub. Date : 2025
• Page : pp.280-311
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• Book : 34()
• Pub. Date : 2025
• Page :
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Abstract In the case of neonates, especially low birth weight preterm and high-risk infants, portable X-rays are frequently used. However, the image quality of portable X-rays is significantly lower compared to standard adult or pediatric X-rays, leading to considerable challenges in identifying abnormalities. Although attempts have been made to introduce deep learning to address these image quality issues, the poor quality of the images themselves hinders the training of deep learning models, further emphasizing the need for image enhancement. Additionally, since neonates have a high cell division rate and are highly sensitive to radiation, increasing radiation exposure to improve image quality is not a viable solution. Therefore, it is crucial to enhance image quality through preprocessing before training deep learning models. While various image enhancement methods have been proposed, Contrast Limited Adaptive Histogram Equalization (CLAHE) has been recognized as an effective technique for contrast-based image improvement. However, despite extensive research, the process of setting CLAHE’s hyperparameters still relies on a brute force, manual approach, making it inefficient. To address this issue, we propose a method called Bayesian Optimization CLAHE(BO-CLAHE), which leverages Bayesian optimization to automatically select the optimal hyperparameters for X-ray images used in diagnosing lung diseases in preterm and high-risk neonates. The images enhanced by BO-CLAHE demonstrated superior performance across several classification models, with particularly notable improvements in diagnosing Transient Tachypnea of the Newborn (TTN). This approach not only reduces radiation exposure but also contributes to the development of AI-based diagnostic tools, playing a crucial role in the early diagnosis and treatment of preterm and high-risk neonates.

• Book : 15(1)
• Pub. Date : 2025
• Page :
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AbstractHair follicle neural crest stem cells reside in the bulge region of the outer root sheath of hair follicles, originate from the ectoderm, and have multidirectional differentiation potential, making them ideal candidates for tissue engineering applications. These cells mainly reside in a hypoxic microenvironment that favors the maintenance of stemness. Recently, many studies have elucidated the involvement of the Hippo pathway in the regulation of stem cell fate. However, few studies have investigated whether the Hippo signaling pathway regulates the growth of hair follicle neural crest stem cells in hypoxic environments. In the present study, we investigated the role of the Hippo pathway in the regulation of hair follicle neural crest stem cells under hypoxic conditions. We identified neural crest‐derived stem cells from single‐cell RNA‐seq data of skin organoids in a public database, and reported that the Hippo pathway was activated in the cell population. Hair follicle neural crest stem cells were isolated from rat hair follicles and cultured under hypoxic (3% oxygen) and normoxic (20% oxygen) conditions. Cell viability was assessed via the CCK8 assay. The expression levels of several key genes, including Hif2α, Nestin, Sox10, Oct4, Nanog, Sox2, and Klf4, were evaluated via quantitative real‐time PCR, after which we treated the cells with verteporfin, a small molecule inhibitor of the Hippo pathway. Changes in the subcellular localization of the hair follicle neural crest stem cell‐specific marker SOX10 were assessed via immunofluorescence. Western blotting was used to analyze the expression levels of proteins associated with stemness and hypoxia responses, including HIF2α, SOX10, OCT4, NANOG, SOX2, and KLF4. The results showed that hypoxic conditions facilitated the maintenance of stemness in hair follicle neural crest stem cells, including the promotion of proliferation and the expression of multipotential markers. Inhibition of the Hippo pathway results in a significant decrease in cell proliferation. The protein expression of HIF2α, SOX10, OCT4, NANOG, SOX2, and KLF4 was also reduced under hypoxic conditions.

• Book : ()
• Pub. Date : 2025
• Page :
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• Book : ()
• Pub. Date : 2025
• Page :
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• Book : ()
• Pub. Date : 2025
• Page :
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• Book : ()
• Pub. Date : 2025
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Background: The registry-based collection of detailed cancer and late effect (LE) data in childhood and adolescent cancer (CAC) is rarely explored. Aim: We aimed to provide an overview of CAC registration practices in Europe and share a Slovenian example. Methods: We distributed a questionnaire among European cancer registries on disease, treatment and LE registration and present the system at the Slovenian Cancer Registry along with an example of retrospectively collected LE data from a cohort of central nervous system tumour survivors from 1983 to 2000. Kaplan–Meier and Cox regression were used to calculate the LE incidence. Results: Out of 27 responding registries, over 80% registered cancer type, vital status, death and second primary cancer data. Less than 20% registered cumulative doses of radiation and systemic therapy or progressions. Only three registered LEs. The obstacles in setting up LE collection in registries are a lack of standardization in the variable sets, definitions and methods of collection. In the retrospective cohort, neurological and endocrine LEs were most common. Females had a higher risk of endocrine LEs (HR of 1.89; 95% CI of 1.08–3.31), while patients treated with radiotherapy had higher risks of endocrine (3.47; 1.80–6.69), musculoskeletal and skin LEs (3.16; 1.60–6.26) and second primary cancers (2.85; 1.18–6.75). Conclusions: Standardization and harmonization are necessary to promote detailed CAC and LE registration.

• Book : 17(4)
• Pub. Date : 2025
• Page : pp.580-580
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Abstract Acute ionizing radiation (IR) causes severe DNA damage, leading to cell cycle arrest, cell death, and activation of the innate immune system. The role and signaling pathway of stimulator of interferon genes (STING) in IR-induced tissue damage and cell death are not well understood. This study revealed that STING is crucial for promoting apoptosis in response to DNA damage caused by acute IR both in vitro and in vivo. STING binds to poly (ADP‒ribose) (PAR) produced by activated poly (ADP‒ribose) polymerase-1 (PARP1) upon IR. Compared with that in WT cells, apoptosis was suppressed in Sting gt-/gt- cells. Excessive PAR production by PARP1 due to DNA damage enhances STING phosphorylation, and inhibiting PARP1 reduces cell apoptosis after IR. In vivo, IR-induced crypt cell death was significantly lower in Sting gt-/gt- mice or with low-dose PARP1 inhibitor, PJ34, resulting in substantial resistance to abdominal irradiation. STING deficiency or inhibition of PARP1 function can reduce the expression of the proapoptotic gene PUMA, decrease the localization of Bax on the mitochondrial membrane, and thus reduce cell apoptosis. Our findings highlight crucial roles for STING and PAR in the IR-mediated induction of apoptosis, which may have therapeutic implications for controlling radiation-induced apoptosis or acute radiation symptoms.

• Book : ()
• Pub. Date : 2025
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