Life Science Alliance最新文献_第9页

The type of DNA damage response after decitabine treatment depends on the level of DNMT activity. 地西他滨治疗后的 DNA 损伤反应类型取决于 DNMT 的活性水平。

IF 3.3 2区生物学

Life Science Alliance Pub Date : 2024-06-21 Print Date: 2024-09-01 DOI: 10.26508/lsa.202302437

Tina Aumer, Maike Däther, Linda Bergmayr, Stephanie Kartika, Theodor Zeng, Qingyi Ge, Grazia Giorgio, Alexander J Hess, Stylianos Michalakis, Franziska R Traube

{"title":"The type of DNA damage response after decitabine treatment depends on the level of DNMT activity.","authors":"Tina Aumer, Maike Däther, Linda Bergmayr, Stephanie Kartika, Theodor Zeng, Qingyi Ge, Grazia Giorgio, Alexander J Hess, Stylianos Michalakis, Franziska R Traube","doi":"10.26508/lsa.202302437","DOIUrl":"10.26508/lsa.202302437","url":null,"abstract":"Decitabine and azacytidine are considered as epigenetic drugs that induce DNA methyltransferase (DNMT)-DNA crosslinks, resulting in DNA hypomethylation and damage. Although they are already applied against myeloid cancers, important aspects of their mode of action remain unknown, highly limiting their clinical potential. Using a combinatorial approach, we reveal that the efficacy profile of both compounds primarily depends on the level of induced DNA damage. Under low DNMT activity, only decitabine has a substantial impact. Conversely, when DNMT activity is high, toxicity and cellular response to both compounds are dramatically increased, but do not primarily depend on DNA hypomethylation or RNA-associated processes. By investigating proteome dynamics on chromatin, we show that decitabine induces a strictly DNMT-dependent multifaceted DNA damage response based on chromatin recruitment, but not expression-level changes of repair-associated proteins. The choice of DNA repair pathway hereby depends on the severity of decitabine-induced DNA lesions. Although under moderate DNMT activity, mismatch (MMR), base excision (BER), and Fanconi anaemia-dependent DNA repair combined with homologous recombination are activated in response to decitabine, high DNMT activity and therefore immense replication stress induce activation of MMR and BER followed by non-homologous end joining.","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"7 9","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11192838/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141437115","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Correction: Apolipoprotein E intersects with amyloid-β within neurons. 更正：载脂蛋白 E 与神经元内的淀粉样蛋白-β有交集。

IF 3.3 2区生物学

Life Science Alliance Pub Date : 2024-06-21 Print Date: 2024-09-01 DOI: 10.26508/lsa.202402875

Sabine C Konings, Emma Nyberg, Isak Martinsson, Laura Torres-Garcia, Oxana Klementieva, Claudia Guimas Almeida, Gunnar K Gouras

引用次数: 0

Activation of the Keap1/Nrf2 pathway suppresses mitochondrial dysfunction, oxidative stress, and motor phenotypes in C9orf72 ALS/FTD models. 激活 Keap1/Nrf2 通路可抑制 C9orf72 ALS/FTD 模型中的线粒体功能障碍、氧化应激和运动表型。

IF 3.3 2区生物学

Life Science Alliance Pub Date : 2024-06-21 Print Date: 2024-09-01 DOI: 10.26508/lsa.202402853

Wing Hei Au, Leonor Miller-Fleming, Alvaro Sanchez-Martinez, James Ak Lee, Madeleine J Twyning, Hiran A Prag, Laura Raik, Scott P Allen, Pamela J Shaw, Laura Ferraiuolo, Heather Mortiboys, Alexander J Whitworth

{"title":"Activation of the Keap1/Nrf2 pathway suppresses mitochondrial dysfunction, oxidative stress, and motor phenotypes in C9orf72 ALS/FTD models.","authors":"Wing Hei Au, Leonor Miller-Fleming, Alvaro Sanchez-Martinez, James Ak Lee, Madeleine J Twyning, Hiran A Prag, Laura Raik, Scott P Allen, Pamela J Shaw, Laura Ferraiuolo, Heather Mortiboys, Alexander J Whitworth","doi":"10.26508/lsa.202402853","DOIUrl":"10.26508/lsa.202402853","url":null,"abstract":"Mitochondrial dysfunction is a common feature of C9orf72 amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD); however, it remains unclear whether this is a cause or consequence of the pathogenic process. Analysing multiple aspects of mitochondrial biology across several Drosophila models of C9orf72-ALS/FTD, we found morphology, oxidative stress, and mitophagy are commonly affected, which correlated with progressive loss of locomotor performance. Notably, only genetic manipulations that reversed the oxidative stress levels were also able to rescue C9orf72 locomotor deficits, supporting a causative link between mitochondrial dysfunction, oxidative stress, and behavioural phenotypes. Targeting the key antioxidant Keap1/Nrf2 pathway, we found that genetic reduction of Keap1 or pharmacological inhibition by dimethyl fumarate significantly rescued the C9orf72-related oxidative stress and motor deficits. Finally, mitochondrial ROS levels were also elevated in C9orf72 patient-derived iNeurons and were effectively suppressed by dimethyl fumarate treatment. These results indicate that mitochondrial oxidative stress is an important mechanistic contributor to C9orf72 pathogenesis, affecting multiple aspects of mitochondrial function and turnover. Targeting the Keap1/Nrf2 signalling pathway to combat oxidative stress represents a therapeutic strategy for C9orf72-related ALS/FTD.","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"7 9","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11192839/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141437111","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Recent approaches in computational modelling for controlling pathogen threats. 控制病原体威胁的计算建模最新方法。

IF 3.3 2区生物学

Life Science Alliance Pub Date : 2024-06-21 Print Date: 2024-09-01 DOI: 10.26508/lsa.202402666

John A Lees, Timothy W Russell, Liam P Shaw, Joel Hellewell

引用次数: 0

p53 ensures the normal behavior and modification of G1/S-specific histone H3.1 in the nucleus. p53 可确保细胞核中 G1/S 特异性组蛋白 H3.1 的正常行为和修饰。

IF 3.3 2区生物学

Life Science Alliance Pub Date : 2024-06-21 Print Date: 2024-09-01 DOI: 10.26508/lsa.202402835

Tsukasa Oikawa, Junya Hasegawa, Haruka Handa, Naomi Ohnishi, Yasuhito Onodera, Ari Hashimoto, Junko Sasaki, Takehiko Sasaki, Koji Ueda, Hisataka Sabe

{"title":"p53 ensures the normal behavior and modification of G1/S-specific histone H3.1 in the nucleus.","authors":"Tsukasa Oikawa, Junya Hasegawa, Haruka Handa, Naomi Ohnishi, Yasuhito Onodera, Ari Hashimoto, Junko Sasaki, Takehiko Sasaki, Koji Ueda, Hisataka Sabe","doi":"10.26508/lsa.202402835","DOIUrl":"10.26508/lsa.202402835","url":null,"abstract":"H3.1 histone is predominantly synthesized and enters the nucleus during the G1/S phase of the cell cycle, as a new component of duplicating nucleosomes. Here, we found that p53 is necessary to secure the normal behavior and modification of H3.1 in the nucleus during the G1/S phase, in which p53 increases C-terminal domain nuclear envelope phosphatase 1 (CTDNEP1) levels and decreases enhancer of zeste homolog 2 (EZH2) levels in the H3.1 interactome. In the absence of p53, H3.1 molecules tended to be tethered at or near the nuclear envelope (NE), where they were predominantly trimethylated at lysine 27 (H3K27me3) by EZH2, without forming nucleosomes. This accumulation was likely caused by the high affinity of H3.1 toward phosphatidic acid (PA). p53 reduced nuclear PA levels by increasing levels of CTDNEP1, which activates lipin to convert PA into diacylglycerol. We moreover found that the cytosolic H3 chaperone HSC70 attenuates the H3.1-PA interaction, and our molecular imaging analyses suggested that H3.1 may be anchored around the NE after their nuclear entry. Our results expand our knowledge of p53 function in regulation of the nuclear behavior of H3.1 during the G1/S phase, in which p53 may primarily target nuclear PA and EZH2.","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"7 9","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11192845/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141437113","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Congress of multiple dimers is needed for cross-phosphorylation of IRE1α and its RNase activity. IRE1α 的交叉磷酸化及其 RNase 活性需要多个二聚体的共同作用。

IF 3.3 2区生物学

Life Science Alliance Pub Date : 2024-06-17 Print Date: 2024-09-01 DOI: 10.26508/lsa.202302562

Andrea Orsi, Eelco van Anken, Milena Vitale, Moreno Zamai, Valeria R Caiolfa, Roberto Sitia, Anush Bakunts

{"title":"Congress of multiple dimers is needed for cross-phosphorylation of IRE1α and its RNase activity.","authors":"Andrea Orsi, Eelco van Anken, Milena Vitale, Moreno Zamai, Valeria R Caiolfa, Roberto Sitia, Anush Bakunts","doi":"10.26508/lsa.202302562","DOIUrl":"10.26508/lsa.202302562","url":null,"abstract":"The unfolded protein response can switch from a pro-survival to a maladaptive, pro-apoptotic mode. During ER stress, IRE1α sensors dimerize, become phosphorylated, and activate XBP1 splicing, increasing folding capacity in the ER protein factory. The steps that turn on the IRE1α endonuclease activity against endogenous mRNAs during maladaptive ER stress are still unknown. Here, we show that although necessary, IRE1α dimerization is not sufficient to trigger phosphorylation. Random and/or guided collisions among IRE1α dimers are needed to elicit cross-phosphorylation and endonuclease activities. Thus, reaching a critical concentration of IRE1α dimers in the ER membrane is a key event. Formation of stable IRE1α clusters is not necessary for RNase activity. However, clustering could modulate the potency of the response, promoting interactions between dimers and decreasing the accessibility of phosphorylated IRE1α to phosphatases. The stepwise activation of IRE1α molecules and their low concentration at the steady state prevent excessive responses, unleashing full-blown IRE1 activity only upon intense stress conditions.","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"7 9","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11184514/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141419739","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Calaxin is a key factor for calcium-dependent waveform control in zebrafish sperm. 钙调蛋白是斑马鱼精子中钙依赖性波形控制的关键因素。

IF 3.3 2区生物学

Life Science Alliance Pub Date : 2024-06-14 Print Date: 2024-09-01 DOI: 10.26508/lsa.202402632

Motohiro Morikawa, Hiroshi Yamaguchi, Masahide Kikkawa

{"title":"Calaxin is a key factor for calcium-dependent waveform control in zebrafish sperm.","authors":"Motohiro Morikawa, Hiroshi Yamaguchi, Masahide Kikkawa","doi":"10.26508/lsa.202402632","DOIUrl":"10.26508/lsa.202402632","url":null,"abstract":"Calcium is critical for regulating the waveform of motile cilia and flagella. Calaxin is currently the only known molecule involved in the calcium-dependent regulation in ascidians. We have recently shown that Calaxin stabilizes outer arm dynein (OAD), and the knockout of Calaxin results in primary ciliary dyskinesia phenotypes in vertebrates. However, from the knockout experiments, it was not clear which functions depend on calcium and how Calaxin regulates the waveform. To address this question, here, we generated transgenic zebrafish expressing a mutant E130A-Calaxin deficient in calcium binding. E130A-Calaxin restored the OAD reduction of calaxin -/- sperm and the abnormal movement of calaxin -/- left-right organizer cilia, showing that Calaxin's stabilization of OADs is calcium-independent. In contrast, our quantitative analysis of E130A-Calaxin sperms showed that the calcium-induced asymmetric beating was not restored, linking Calaxin's calcium-binding ability with an asymmetric flagellar beating for the first time. Our data show that Calaxin is a calcium-dependent regulator of the ciliary beating and a calcium-independent OAD stabilizer.","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"7 9","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11178939/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141321064","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Single-housing-induced islet epigenomic changes are related to polymorphisms in diabetic KK mice. 单一饲养诱导的胰岛表观基因组变化与糖尿病 KK 小鼠的多态性有关。

IF 3.3 2区生物学

Life Science Alliance Pub Date : 2024-06-14 Print Date: 2024-08-01 DOI: 10.26508/lsa.202302099

Takao Nammo, Nobuaki Funahashi, Haruhide Udagawa, Junji Kozawa, Kenta Nakano, Yukiko Shimizu, Tadashi Okamura, Miho Kawaguchi, Takashi Uebanso, Wataru Nishimura, Masaki Hiramoto, Iichiro Shimomura, Kazuki Yasuda

{"title":"Single-housing-induced islet epigenomic changes are related to polymorphisms in diabetic KK mice.","authors":"Takao Nammo, Nobuaki Funahashi, Haruhide Udagawa, Junji Kozawa, Kenta Nakano, Yukiko Shimizu, Tadashi Okamura, Miho Kawaguchi, Takashi Uebanso, Wataru Nishimura, Masaki Hiramoto, Iichiro Shimomura, Kazuki Yasuda","doi":"10.26508/lsa.202302099","DOIUrl":"10.26508/lsa.202302099","url":null,"abstract":"A lack of social relationships is increasingly recognized as a type 2 diabetes (T2D) risk. To investigate the underlying mechanism, we used male KK mice, an inbred strain with spontaneous diabetes. Given the association between living alone and T2D risk in humans, we divided the non-diabetic mice into singly housed (KK-SH) and group-housed control mice. Around the onset of diabetes in KK-SH mice, we compared H3K27ac ChIP-Seq with RNA-Seq using pancreatic islets derived from each experimental group, revealing a positive correlation between single-housing-induced changes in H3K27ac and gene expression levels. In particular, single-housing-induced H3K27ac decreases revealed a significant association with islet cell functions and GWAS loci for T2D and related diseases, with significant enrichment of binding motifs for transcription factors representative of human diabetes. Although these H3K27ac regions were preferentially localized to a polymorphic genomic background, SNVs and indels did not cause sequence disruption of enriched transcription factor motifs in most of these elements. These results suggest alternative roles of genetic variants in environment-dependent epigenomic changes and provide insights into the complex mode of disease inheritance.","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"7 8","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11178941/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141321063","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Correction: Reduced protein-coding transcript diversity in severe dengue emphasises the role of alternative splicing. 更正：严重登革热病中蛋白质编码转录本多样性的减少强调了替代剪接的作用。

IF 3.3 2区生物学

Life Science Alliance Pub Date : 2024-06-14 Print Date: 2024-09-01 DOI: 10.26508/lsa.202402882

Priyanka Mehta, Chinky Shiu Chen Liu, Sristi Sinha, Ramakant Mohite, Smriti Arora, Partha Chattopadhyay, Sandeep Budhiraja, Bansidhar Tarai, Rajesh Pandey

引用次数: 0

The transcription factor HIF-1α in NKp46+ ILCs limits chronic intestinal inflammation and fibrosis. NKp46+ ILC 中的转录因子 HIF-1α 限制了慢性肠炎和纤维化。

IF 3.3 2区生物学

Life Science Alliance Pub Date : 2024-06-14 Print Date: 2024-09-01 DOI: 10.26508/lsa.202402593

Eric Nelius, Zheng Fan, Michal Sobecki, Ewelina Krzywinska, Shunmugam Nagarajan, Irina Ferapontova, Dagmar Gotthardt, Norihiko Takeda, Veronika Sexl, Christian Stockmann

{"title":"The transcription factor HIF-1α in NKp46+ ILCs limits chronic intestinal inflammation and fibrosis.","authors":"Eric Nelius, Zheng Fan, Michal Sobecki, Ewelina Krzywinska, Shunmugam Nagarajan, Irina Ferapontova, Dagmar Gotthardt, Norihiko Takeda, Veronika Sexl, Christian Stockmann","doi":"10.26508/lsa.202402593","DOIUrl":"10.26508/lsa.202402593","url":null,"abstract":"Innate lymphoid cells (ILCs) are critical for intestinal adaptation to microenvironmental challenges, and the gut mucosa is characterized by low oxygen. Adaptation to low oxygen is mediated by hypoxia-inducible transcription factors (HIFs), and the HIF-1α subunit shapes an ILC phenotype upon acute colitis that contributes to intestinal damage. However, the impact of HIF signaling in NKp46+ ILCs in the context of repetitive mucosal damage and chronic inflammation, as it typically occurs during inflammatory bowel disease, is unknown. In chronic colitis, mice lacking the HIF-1α isoform in NKp46+ ILCs show a decrease in NKp46+ ILC1s but a concomitant rise in neutrophils and Ly6Chigh macrophages. Single-nucleus RNA sequencing suggests enhanced interaction of mesenchymal cells with other cell compartments in the colon of HIF-1α KO mice and a loss of mucus-producing enterocytes and intestinal stem cells. This was, furthermore, associated with increased bone morphogenetic pathway-integrin signaling, expansion of fibroblast subsets, and intestinal fibrosis. In summary, this suggests that HIF-1α-mediated ILC1 activation, although detrimental upon acute colitis, protects against excessive inflammation and fibrosis during chronic intestinal damage.","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"7 9","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11178940/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141321066","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0