Pub Date : 2025-04-04DOI: 10.1016/j.isci.2025.112353
Budimir Mirianna , Šakić Trogrlić Robert , Almeida Cinthia , Arestegui Miguel , Chuquisengo Vásquez Orlando , Cisneros Abel , Cuba Iriarte Monica , Dia Adama , Lizon Leon , Madueño Giorgio , Ndiaye Alioune , Ordoñez Caldas Miluska , Rahman Tamanna , RanaTharu Bikram , Sall Alpha , Uprety Dharam , Anderson Chris , McQuistan Colin
This perspective critically examines the challenges and opportunities of implementing people-centred Multi-Hazard Early Warning Systems (MHEWS) in the Global South. Despite global initiatives, such as the Early Warnings for All initiative, operational realities lag behind. By exploring the needs of the most vulnerable and how core concepts of multi-hazard thinking (e.g., hazard interrelationships and vulnerability dynamics) integrate into different pillars and cross-cutting components of an MHEWS, the perspective highlights a mismatch between current ambitions and realities on the ground. Drawing on extensive experience from Practical Action, we identify opportunities to move towards MHEWS through outlining potential entry points in research, policy, and practice. We emphasise a need for localised, inclusive strategies that genuinely address the needs of the most vulnerable populations and fully encompass the meaning of multi-hazards, including hazard interrelationships, the dynamics of risk components, and the complexity of multi-hazard impacts.
{"title":"Opportunities and Challenges for People-Centred Multi-Hazard Early Warning Systems: Perspectives from the Global South","authors":"Budimir Mirianna , Šakić Trogrlić Robert , Almeida Cinthia , Arestegui Miguel , Chuquisengo Vásquez Orlando , Cisneros Abel , Cuba Iriarte Monica , Dia Adama , Lizon Leon , Madueño Giorgio , Ndiaye Alioune , Ordoñez Caldas Miluska , Rahman Tamanna , RanaTharu Bikram , Sall Alpha , Uprety Dharam , Anderson Chris , McQuistan Colin","doi":"10.1016/j.isci.2025.112353","DOIUrl":"10.1016/j.isci.2025.112353","url":null,"abstract":"<div><div>This perspective critically examines the challenges and opportunities of implementing people-centred Multi-Hazard Early Warning Systems (MHEWS) in the Global South. Despite global initiatives, such as the Early Warnings for All initiative, operational realities lag behind. By exploring the needs of the most vulnerable and how core concepts of multi-hazard thinking (e.g., hazard interrelationships and vulnerability dynamics) integrate into different pillars and cross-cutting components of an MHEWS, the perspective highlights a mismatch between current ambitions and realities on the ground. Drawing on extensive experience from Practical Action, we identify opportunities to move towards MHEWS through outlining potential entry points in research, policy, and practice. We emphasise a need for localised, inclusive strategies that genuinely address the needs of the most vulnerable populations and fully encompass the meaning of multi-hazards, including hazard interrelationships, the dynamics of risk components, and the complexity of multi-hazard impacts.</div></div>","PeriodicalId":342,"journal":{"name":"iScience","volume":"28 5","pages":"Article 112353"},"PeriodicalIF":4.6,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143843244","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-03DOI: 10.1016/j.isci.2025.112339
Wenjun Luo , Mingjiu Zhao , Mengyao Gu , Jiaqi Huang , Shiyao Wu , Bin Zhao
Corona Virus Disease 2019 (COVID-19) and diabetes interact to influence disease severity, yet their combined immunological characteristics remain unclear. Here, we analyzed Tim-3+ T cells in patients with COVID-19, Type 1 Diabetes (T1D), or both conditions. COVID-19 reduced peripheral T cell subsets but increased Tim-3+ cells, while T1D and COVID-19 with T1D showed the opposite pattern. Patients with Type 2 Diabetes (T2D) exhibited no significant alterations. In human samples and mouse models, Tim-3+ T cells demonstrated impaired activation and cytokine production. RNA-seq analysis in mice and RT-PCR analysis in human samples together identified the dysregulation of the JAK-STAT pathway in Tim-3+ T cells. These findings highlight Tim-3-mediated JAK-STAT dysregulation in T-cells as a potential mechanism linking COVID-19 and T1D, offering insights for therapeutic targeting.
{"title":"The role of Tim-3+T cell subsets in the peripheral blood of patients with COVID-19 and diabetes","authors":"Wenjun Luo , Mingjiu Zhao , Mengyao Gu , Jiaqi Huang , Shiyao Wu , Bin Zhao","doi":"10.1016/j.isci.2025.112339","DOIUrl":"10.1016/j.isci.2025.112339","url":null,"abstract":"<div><div>Corona Virus Disease 2019 (COVID-19) and diabetes interact to influence disease severity, yet their combined immunological characteristics remain unclear. Here, we analyzed Tim-3+ T cells in patients with COVID-19, Type 1 Diabetes (T1D), or both conditions. COVID-19 reduced peripheral T cell subsets but increased Tim-3+ cells, while T1D and COVID-19 with T1D showed the opposite pattern. Patients with Type 2 Diabetes (T2D) exhibited no significant alterations. In human samples and mouse models, Tim-3+ T cells demonstrated impaired activation and cytokine production. RNA-seq analysis in mice and RT-PCR analysis in human samples together identified the dysregulation of the JAK-STAT pathway in Tim-3+ T cells. These findings highlight Tim-3-mediated JAK-STAT dysregulation in T-cells as a potential mechanism linking COVID-19 and T1D, offering insights for therapeutic targeting.</div></div>","PeriodicalId":342,"journal":{"name":"iScience","volume":"28 5","pages":"Article 112339"},"PeriodicalIF":4.6,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143854498","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-03DOI: 10.1016/j.isci.2025.112346
Christopher Playter , Rosela Golloshi , Joshua H. Garretson , Alvaro Rodriguez Gonzalez , Taiwo Habeeb Olajide , Ahmed Saad , Samuel John Benson , Rachel Patton McCord
Metastatic cancer cells traverse constricted spaces that exert forces on their nucleus and the genomic contents within. Cancerous tumors are highly heterogeneous and not all cells within them can achieve such a feat. Here, we investigated what initial genome architecture characteristics favor the constricted migratory ability of cancer cells and which arise only after passage through multiple constrictions. We identified a cell surface protein (ITGB4) whose expression correlates with increased initial constricted migration ability in human melanoma A375 cells. Sorting out this subpopulation allowed us to identify cellular and nuclear features that pre-exist and favor migration, as well as alterations that only appear after cells have passed through constrictions. We identified specific genomic regions that experienced altered genome spatial compartment profiles only after constricted migration. Our study reveals 3D genome structure contributions to both selection and induction mechanisms of cell fate change during cancer metastasis.
{"title":"Deciphering pre-existing and induced 3D genome architecture changes involved in constricted melanoma migration","authors":"Christopher Playter , Rosela Golloshi , Joshua H. Garretson , Alvaro Rodriguez Gonzalez , Taiwo Habeeb Olajide , Ahmed Saad , Samuel John Benson , Rachel Patton McCord","doi":"10.1016/j.isci.2025.112346","DOIUrl":"10.1016/j.isci.2025.112346","url":null,"abstract":"<div><div>Metastatic cancer cells traverse constricted spaces that exert forces on their nucleus and the genomic contents within. Cancerous tumors are highly heterogeneous and not all cells within them can achieve such a feat. Here, we investigated what initial genome architecture characteristics favor the constricted migratory ability of cancer cells and which arise only after passage through multiple constrictions. We identified a cell surface protein (ITGB4) whose expression correlates with increased initial constricted migration ability in human melanoma A375 cells. Sorting out this subpopulation allowed us to identify cellular and nuclear features that pre-exist and favor migration, as well as alterations that only appear after cells have passed through constrictions. We identified specific genomic regions that experienced altered genome spatial compartment profiles only after constricted migration. Our study reveals 3D genome structure contributions to both selection and induction mechanisms of cell fate change during cancer metastasis.</div></div>","PeriodicalId":342,"journal":{"name":"iScience","volume":"28 5","pages":"Article 112346"},"PeriodicalIF":4.6,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143847415","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-03DOI: 10.1016/j.isci.2025.112357
Matthew Pierpoint , Warren Floyd , Amy J. Wisdom , Lixia Luo , Yan Ma , Brendan C. Dickson , Matthew S. Waitkus , David G. Kirsch
The development of a telomere maintenance mechanism is essential for immortalization in human cancer. While most cancers elongate their telomeres by expression of telomerase, 10–15% of human cancers utilize a pathway known as alternative lengthening of telomeres (ALT). ALT is commonly associated with loss-of-function mutations in ATRX. Here, we developed a genetically engineered primary mouse model of sarcoma in CAST/EiJ mice to investigate the extent to which telomerase deficiency and Atrx-inactivation lead to ALT induction. We observed increases in multiple ALT-associated phenotypic indicators in tumors with loss of function mutations of Atrx. Furthermore, we found that loss of Atrx leads to an increase in telomeric instability and telomere sister chromatid exchange. However, Atrx-deficient tumors did not show productive telomere length maintenance in the absence of telomerase. This primary mouse model of sarcoma could facilitate future investigations into the molecular features of ALT in vivo.
{"title":"Loss of function of Atrx recapitulates phenotypes of alternative lengthening of telomeres in a primary mouse model of sarcoma","authors":"Matthew Pierpoint , Warren Floyd , Amy J. Wisdom , Lixia Luo , Yan Ma , Brendan C. Dickson , Matthew S. Waitkus , David G. Kirsch","doi":"10.1016/j.isci.2025.112357","DOIUrl":"10.1016/j.isci.2025.112357","url":null,"abstract":"<div><div>The development of a telomere maintenance mechanism is essential for immortalization in human cancer. While most cancers elongate their telomeres by expression of telomerase, 10–15% of human cancers utilize a pathway known as alternative lengthening of telomeres (ALT). ALT is commonly associated with loss-of-function mutations in ATRX. Here, we developed a genetically engineered primary mouse model of sarcoma in CAST/EiJ mice to investigate the extent to which telomerase deficiency and Atrx-inactivation lead to ALT induction. We observed increases in multiple ALT-associated phenotypic indicators in tumors with loss of function mutations of <em>Atrx.</em> Furthermore, we found that loss of <em>Atrx</em> leads to an increase in telomeric instability and telomere sister chromatid exchange. However, Atrx-deficient tumors did not show productive telomere length maintenance in the absence of telomerase. This primary mouse model of sarcoma could facilitate future investigations into the molecular features of ALT <em>in vivo</em>.</div></div>","PeriodicalId":342,"journal":{"name":"iScience","volume":"28 5","pages":"Article 112357"},"PeriodicalIF":4.6,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143843118","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-03DOI: 10.1016/j.isci.2025.112347
Yangsong Xu , Man K.S. Lee , Nicole A. de Weerd , Ziyue Fu , Camilla Bertuzzo Veiga , Dragana Dragoljevic , Dmitri Sviridov , Paul J. Hertzog , Andrew J. Fleetwood , Andrew J. Murphy
Rapid hematopoietic adaptations are important for building and sustaining the biological response to β-glucan. The signals involved in these early events have not yet been fully explored. Given that type I interferons are produced in response to β-glucan and can profoundly impact hematopoietic stem cell (HSC) function, we hypothesized that this pathway may be involved in the early bone marrow response to β-glucan. In vivo administration of β-glucan led to local interferon-α production in the peritoneal cavity and bone marrow, upregulation of its receptor, IFNAR1, specifically on long-term hematopoietic stem cells (LT-HSCs), and broad expansion of downstream progenitor subpopulations. We demonstrate that intact type I interferon signaling is critical for β-glucan-mediated LT-HSC proliferation, mitochondrial activity, and glycolytic commitment. By determining that type I interferon signaling is important for LT-HSCs, which sit at the apex of the hematopoietic hierarchy, we uncover an important component of the early inflammatory response to β-glucan.
快速造血适应对于建立和维持对β-葡聚糖的生物反应非常重要。这些早期事件所涉及的信号尚未得到充分探究。鉴于I型干扰素是针对β-葡聚糖产生的，并能深刻影响造血干细胞（HSC）的功能，我们推测这一途径可能参与了骨髓对β-葡聚糖的早期反应。体内给予β-葡聚糖会导致腹腔和骨髓产生局部干扰素-α，其受体IFNAR1上调，特别是在长期造血干细胞（LT-HSCs）上，以及下游祖细胞亚群的广泛扩增。我们证明，完整的I型干扰素信号传导对β-葡聚糖介导的LT-造血干细胞增殖、线粒体活性和糖酵解承诺至关重要。通过确定 I 型干扰素信号对处于造血系统顶端的 LT-HSCs 的重要性，我们发现了早期炎症反应中对β-葡聚糖的一个重要组成部分。
{"title":"Type I interferon signaling controls the early hematopoietic expansion in response to β-glucan","authors":"Yangsong Xu , Man K.S. Lee , Nicole A. de Weerd , Ziyue Fu , Camilla Bertuzzo Veiga , Dragana Dragoljevic , Dmitri Sviridov , Paul J. Hertzog , Andrew J. Fleetwood , Andrew J. Murphy","doi":"10.1016/j.isci.2025.112347","DOIUrl":"10.1016/j.isci.2025.112347","url":null,"abstract":"<div><div>Rapid hematopoietic adaptations are important for building and sustaining the biological response to β-glucan. The signals involved in these early events have not yet been fully explored. Given that type I interferons are produced in response to β-glucan and can profoundly impact hematopoietic stem cell (HSC) function, we hypothesized that this pathway may be involved in the early bone marrow response to β-glucan. <em>In vivo</em> administration of β-glucan led to local interferon-α production in the peritoneal cavity and bone marrow, upregulation of its receptor, IFNAR1, specifically on long-term hematopoietic stem cells (LT-HSCs), and broad expansion of downstream progenitor subpopulations. We demonstrate that intact type I interferon signaling is critical for β-glucan-mediated LT-HSC proliferation, mitochondrial activity, and glycolytic commitment. By determining that type I interferon signaling is important for LT-HSCs, which sit at the apex of the hematopoietic hierarchy, we uncover an important component of the early inflammatory response to β-glucan.</div></div>","PeriodicalId":342,"journal":{"name":"iScience","volume":"28 5","pages":"Article 112347"},"PeriodicalIF":4.6,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143828316","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-03DOI: 10.1016/j.isci.2025.112340
Zedong Bi , Ruiqi Fu , Guozhang Chen , Dongping Yang , Yu Zhou , Liang Tian
Training biophysical neuron models provides insights into brain circuits’ organization and problem-solving capabilities. Traditional training methods like backpropagation face challenges with complex models due to instability and gradient issues. We explore evolutionary algorithms (EAs) combined with heterosynaptic plasticity as a gradient-free alternative. Our EA models agents with distinct neuron information routes, evaluated via alternating gating, and guided by dopamine-driven plasticity. This model draws inspiration from various biological mechanisms, such as dopamine function, dendritic spine meta-plasticity, memory replay, and cooperative synaptic plasticity within dendritic neighborhoods. Neural networks trained with this model recapitulate brain-like dynamics during cognition. Our method effectively trains spiking and analog neural networks in both feedforward and recurrent architectures, it also achieves performance in tasks like MNIST classification and Atari games comparable to gradient-based methods. Overall, this research extends training approaches for biophysical neuron models, offering a robust alternative to traditional algorithms.
{"title":"Evolutionary learning in neural networks by heterosynaptic plasticity","authors":"Zedong Bi , Ruiqi Fu , Guozhang Chen , Dongping Yang , Yu Zhou , Liang Tian","doi":"10.1016/j.isci.2025.112340","DOIUrl":"10.1016/j.isci.2025.112340","url":null,"abstract":"<div><div>Training biophysical neuron models provides insights into brain circuits’ organization and problem-solving capabilities. Traditional training methods like backpropagation face challenges with complex models due to instability and gradient issues. We explore evolutionary algorithms (EAs) combined with heterosynaptic plasticity as a gradient-free alternative. Our EA models agents with distinct neuron information routes, evaluated via alternating gating, and guided by dopamine-driven plasticity. This model draws inspiration from various biological mechanisms, such as dopamine function, dendritic spine meta-plasticity, memory replay, and cooperative synaptic plasticity within dendritic neighborhoods. Neural networks trained with this model recapitulate brain-like dynamics during cognition. Our method effectively trains spiking and analog neural networks in both feedforward and recurrent architectures, it also achieves performance in tasks like MNIST classification and Atari games comparable to gradient-based methods. Overall, this research extends training approaches for biophysical neuron models, offering a robust alternative to traditional algorithms.</div></div>","PeriodicalId":342,"journal":{"name":"iScience","volume":"28 5","pages":"Article 112340"},"PeriodicalIF":4.6,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143843119","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
While tactile spatial pattern recognition has been suggested to be qualitatively similar to visual recognition, our study challenges this notion, particularly under passive touch. Previous electrophysiological and behavioral research suggested that the tactile system can process complex spatial patterns in the same way as the visual system and can be modeled as a low-pass version of visual spatial perception. However, we found that when using energy-matched simple patterns, participants were highly dependent on local skin deformation and largely ineffective at distinguishing basic shape features, such as a closed triangle vs. an open arrow, or to discern the similarity of rotated versions of the same shape, regardless of whether they were presented as vibrotactile patterns or braille patterns. This study provides compelling evidence that tactile representation of spatial patterns differs not only in resolution but also in how the brain processes shape features compared to visual representation in standard passive viewing.
{"title":"Passive human touch cannot recognize the shape of a pattern imprinted on the fingertip","authors":"Scinob Kuroki (黒木忍) , Takumi Hamazaki (浜崎拓海) , Hiroyuki Kajimoto (梶本裕之) , Shin’ya Nishida (西田眞也)","doi":"10.1016/j.isci.2025.112331","DOIUrl":"10.1016/j.isci.2025.112331","url":null,"abstract":"<div><div>While tactile spatial pattern recognition has been suggested to be qualitatively similar to visual recognition, our study challenges this notion, particularly under passive touch. Previous electrophysiological and behavioral research suggested that the tactile system can process complex spatial patterns in the same way as the visual system and can be modeled as a low-pass version of visual spatial perception. However, we found that when using energy-matched simple patterns, participants were highly dependent on local skin deformation and largely ineffective at distinguishing basic shape features, such as a closed triangle vs. an open arrow, or to discern the similarity of rotated versions of the same shape, regardless of whether they were presented as vibrotactile patterns or braille patterns. This study provides compelling evidence that tactile representation of spatial patterns differs not only in resolution but also in how the brain processes shape features compared to visual representation in standard passive viewing.</div></div>","PeriodicalId":342,"journal":{"name":"iScience","volume":"28 5","pages":"Article 112331"},"PeriodicalIF":4.6,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143834200","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-03DOI: 10.1016/j.isci.2025.112344
Liuyang Zhu , Sen Liu , Ze Wang , Yueyue Yang , Pinsheng Han , Wen Tong , Tianyu Zhao , Libo Wang , Tao Cui , Long Yang , Yamin Zhang
Metabolic dysfunction-associated steatotic liver disease (MASLD) remains the most common chronic liver disease worldwide, and appropriate in vitro models are of great significance for investigating pathogenesis and drug screening of MASLD. In this study, human expandable cholangiocyte organoids were derived from adult stem cells of normal liver tissue. After differentiation, liver organoids (LOs) exhibited the functional characteristics and genomic features of mature hepatocytes. To induce steatosis, LOs were incubated with a gradient concentration oleic acid, and it was found that the model could recapitulate the development of lipid accumulation and inflammation. In addition, the drug sensitivity of the hepatic steatosis model was further verified through anti-steatosis drug testing. In summary, LOs have great potential for disease modeling, and the results indicate that the hepatic steatosis model may serve as a useful tool for exploring the molecular mechanisms and drug screening of MASLD.
{"title":"Modeling hepatic steatosis with human adult stem cell-derived liver organoids","authors":"Liuyang Zhu , Sen Liu , Ze Wang , Yueyue Yang , Pinsheng Han , Wen Tong , Tianyu Zhao , Libo Wang , Tao Cui , Long Yang , Yamin Zhang","doi":"10.1016/j.isci.2025.112344","DOIUrl":"10.1016/j.isci.2025.112344","url":null,"abstract":"<div><div>Metabolic dysfunction-associated steatotic liver disease (MASLD) remains the most common chronic liver disease worldwide, and appropriate <em>in vitro</em> models are of great significance for investigating pathogenesis and drug screening of MASLD. In this study, human expandable cholangiocyte organoids were derived from adult stem cells of normal liver tissue. After differentiation, liver organoids (LOs) exhibited the functional characteristics and genomic features of mature hepatocytes. To induce steatosis, LOs were incubated with a gradient concentration oleic acid, and it was found that the model could recapitulate the development of lipid accumulation and inflammation. In addition, the drug sensitivity of the hepatic steatosis model was further verified through anti-steatosis drug testing. In summary, LOs have great potential for disease modeling, and the results indicate that the hepatic steatosis model may serve as a useful tool for exploring the molecular mechanisms and drug screening of MASLD.</div></div>","PeriodicalId":342,"journal":{"name":"iScience","volume":"28 5","pages":"Article 112344"},"PeriodicalIF":4.6,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143828314","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-03DOI: 10.1016/j.isci.2025.112341
Shuai Liu , Yi Li , Lin Quan , Hai-Xia Liu , Yang Luo , Yong-Zhong Wang
Optimizing cellulase biosynthesis in Bacillus subtilis is crucial for enhancing enzymatic yield in lignocellulosic biomass conversion. However, the regulatory mechanisms linking intracellular NAD(H/+) levels to cellulase production remain elusive. In this study, we systematically screened 13 genes associated with NAD+ biosynthesis and NADH regeneration in B. subtilis Z2. Employing a modular engineering strategy with four distinct modules, we directed metabolic flux to enhance NAD+ biosynthesis and NADH regeneration. Key genes (ycel, nadV, nadM, mdh, and sucB) were identified, and their co-expression in B. subtilis Z2 resulted in a 13.09-fold increase in intracellular NADH levels and a consequential 2.24- and 2.04-fold enhancement in the filter paper-hydrolyzing (FPase [representing total cellulase]) activity and carboxymethylcellulose (CMCase [representing endoglucanase]) activity, respectively. Experimental validations, including antagonist LaCl3 treatment and spcF gene deletion, unequivocally established the calcium signaling pathway’s role in regulating cellulase gene overexpression in response to elevated intracellular NAD(H/+) levels.
{"title":"Enhancing cellulase biosynthesis of Bacillus subtilis Z2 by regulating intracellular NADH level","authors":"Shuai Liu , Yi Li , Lin Quan , Hai-Xia Liu , Yang Luo , Yong-Zhong Wang","doi":"10.1016/j.isci.2025.112341","DOIUrl":"10.1016/j.isci.2025.112341","url":null,"abstract":"<div><div>Optimizing cellulase biosynthesis in <em>Bacillus subtilis</em> is crucial for enhancing enzymatic yield in lignocellulosic biomass conversion. However, the regulatory mechanisms linking intracellular NAD(H/<sup>+</sup>) levels to cellulase production remain elusive. In this study, we systematically screened 13 genes associated with NAD<sup>+</sup> biosynthesis and NADH regeneration in <em>B. subtilis</em> Z2. Employing a modular engineering strategy with four distinct modules, we directed metabolic flux to enhance NAD<sup>+</sup> biosynthesis and NADH regeneration. Key genes (<em>ycel</em>, <em>nadV</em>, <em>nadM</em>, <em>mdh</em>, and <em>sucB</em>) were identified, and their co-expression in <em>B. subtilis</em> Z2 resulted in a 13.09-fold increase in intracellular NADH levels and a consequential 2.24- and 2.04-fold enhancement in the filter paper-hydrolyzing (FPase [representing total cellulase]) activity and carboxymethylcellulose (CMCase [representing endoglucanase]) activity, respectively. Experimental validations, including antagonist LaCl<sub>3</sub> treatment and <em>spcF</em> gene deletion, unequivocally established the calcium signaling pathway’s role in regulating cellulase gene overexpression in response to elevated intracellular NAD(H/<sup>+</sup>) levels.</div></div>","PeriodicalId":342,"journal":{"name":"iScience","volume":"28 5","pages":"Article 112341"},"PeriodicalIF":4.6,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143828317","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-02DOI: 10.1016/j.isci.2025.112342
Saida Oubraim , Mohammad Fauzan , Keith Studholme , Chris Gordon , Sherrye T. Glaser , Roh-Yu Shen , Iwao Ojima , Martin Kaczocha , Samir Haj-Dahmane
Endocannabinoids (eCBs) regulate synaptic function via cannabinoid receptors. While eCB signaling is well understood, the mechanisms underlying eCB synaptic transport are poorly characterized. Using 2-arachidonoylglycerol (2-AG)-mediated depolarization-induced suppression of inhibition (DSI) in the hippocampus as a readout of retrograde eCB signaling, we demonstrate that the deletion of fatty acid binding protein 5 (FABP5) impairs DSI. In FABP5 KO mice, DSI was rescued by re-expressing wild-type FABP5 but not an FABP5 mutant that does not bind 2-AG. Importantly, the deletion of astrocytic FABP5 blunted DSI, which was rescued by its re-expression in the astrocytes of FABP5 KO mice. Neuronal FABP5 was dispensable for 2-AG signaling. DSI was also rescued by expressing a secreted FABP5 variant but not by FABP7, an astrocytic FABP that does not undergo secretion. Our results demonstrate that extracellular FABP5 of astrocytic origin controls 2-AG transport and that FABP5 is adapted to coordinate intracellular and synaptic eCB transport.
{"title":"Astrocytic FABP5 mediates retrograde endocannabinoid transport at central synapses","authors":"Saida Oubraim , Mohammad Fauzan , Keith Studholme , Chris Gordon , Sherrye T. Glaser , Roh-Yu Shen , Iwao Ojima , Martin Kaczocha , Samir Haj-Dahmane","doi":"10.1016/j.isci.2025.112342","DOIUrl":"10.1016/j.isci.2025.112342","url":null,"abstract":"<div><div>Endocannabinoids (eCBs) regulate synaptic function via cannabinoid receptors. While eCB signaling is well understood, the mechanisms underlying eCB synaptic transport are poorly characterized. Using 2-arachidonoylglycerol (2-AG)-mediated depolarization-induced suppression of inhibition (DSI) in the hippocampus as a readout of retrograde eCB signaling, we demonstrate that the deletion of fatty acid binding protein 5 (FABP5) impairs DSI. In FABP5 KO mice, DSI was rescued by re-expressing wild-type FABP5 but not an FABP5 mutant that does not bind 2-AG. Importantly, the deletion of astrocytic FABP5 blunted DSI, which was rescued by its re-expression in the astrocytes of FABP5 KO mice. Neuronal FABP5 was dispensable for 2-AG signaling. DSI was also rescued by expressing a secreted FABP5 variant but not by FABP7, an astrocytic FABP that does not undergo secretion. Our results demonstrate that extracellular FABP5 of astrocytic origin controls 2-AG transport and that FABP5 is adapted to coordinate intracellular and synaptic eCB transport.</div></div>","PeriodicalId":342,"journal":{"name":"iScience","volume":"28 5","pages":"Article 112342"},"PeriodicalIF":4.6,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143843247","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号