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Abstract
Integrin-targeted therapies are under investigation for HIV associated neuroinflammation, yet their impact on CNS anti-viral immunity remains undefined. We examined the role of α4 integrin in T cell mediated neuroimmune surveillance using SIV-infected macaques with α4 blockade and T cell-specific α4-deficient mice. In macaques, α4 blockade preserved CD4 Th1 cell access to the brain parenchyma but impaired CD8 effector recruitment, disrupting antiviral control. Despite stable cerebrospinal fluid viral loads, hippocampal SIV RNA increased under blockade. Single-cell analyses revealed α4 enrichment in CD8 effector memory (TEM) cells; blockade reduced inferred CD8 TEM-monocyte interactions and heightened innate immune activation in the hippocampus. Microscopy demonstrated persistent SIV-induced microglial simplification despite treatment. Th1 CD4 effectors correlated positively with gray matter viral RNA, whereas α4β7⁺ CD8 T cells correlated inversely, implicating impaired CD8 TEM recruitment in elevated parenchymal viral burden. In mice, α4 proved dispensable for CD4 trafficking to inflamed brain but essential for CD8 effector access across CNS compartments and for both subsets to reach skull marrow. These findings establish that α4 integrin governs CD8-mediated neuroimmune surveillance through coordinated cellular positioning, with blockade enabling viral seeding while disrupting spatially organized antiviral defense.
Authors
Pabitra B. Pal, Sonny R. Elizaldi, Giovanne B. Diniz, Ravi Prakash Rai, Yashavanth Shaan Lakshmanappa, Anil Verma, Daniel Rossmiller, Jesse Kaufman, Rahul Srivastava, Sean Ott, Carissa T. Erices, Kayla Schwartz, Danielle Beckman, Zhong-Min Ma, Alex Petkov, Daniel Newhouse, Dhivyaa Rajasundaram, John H. Morrison, Reben Raeman, Smita S. Iyer
Abstract
Mild traumatic brain injury (mTBI) from closed-head injuries (CHI) can lead to prevalent neuropsychiatric disorders, including mood disorders and an increased risk for neurodegenerative diseases and dementia. Inflammasomes are molecular complexes crucial for neuroinflammation and secondary damage after trauma, however their role in mild CHI is poorly understood. In this study, we investigate the cellular expression of inflammasome-related genes and their functional significance in CHI models. Single-cell RNA sequencing analysis of cortical tissue after trauma revealed selective expression of Asc (also known as Pycard), which encodes the inflammasome adaptor Apoptosis-associated Speck-like protein containing a Caspase recruitment domain (ASC), predominantly in microglial clusters. Sustained upregulation of inflammasome-related proteins, microglia activation and astrocyte reactivity persisted up to 21 days in a model for mTBI, with this pattern significantly reduced in Asc-/- mice. Importantly, mild cognitive impairment induced after mild CHI was largely abrogated in Asc-/- mice. These findings suggest that ASC, as the primary inflammasome adaptor, plays a critical role in sustaining neuroinflammation and contributes to cognitive deficits after mild CHI. This study provides insights into the molecular neuroinflammatory mechanisms underlying CHI, potentially informing future therapeutic strategies.
Authors
Tao Li, Sergio Castro-Gomez, Pablo Botella Lucena, Ana Vieira-Saecker, Stephanie Schwartz, Yingying Ding, Yushuang Deng, Maling Guo, Valentin Stein, Douglas T. Golenbock, Eicke Latz, Michael T. Heneka
Abstract
Authors
Fadil M. Hannan, Mark Stevenson, Taha Elajnaf, Hussam Rostom, Kate E. Lines, Michelle Stewart, Sara Wells, Lee Moir, Thomas J. Gardella, Rajesh V. Thakker
Abstract
Hypomorphic variants in the SEL1L-HRD1 ER-associated degradation (ERAD) complex have been linked to severe neurological syndromes in children, including neurodevelopmental delay, intellectual disability, motor dysfunction, and early death. Despite this association, its physiological importance and underlying mechanisms in neurons remain poorly understood. Here, we show that neuronal SEL1L-HRD1 ERAD is essential for maintaining one-carbon metabolism, motor function, and overall viability. Neuron-specific deletion of Sel1L in mice (Sel1LSynCre) resulted in growth retardation, severe motor impairments, and early mortality by 9 weeks of age—mirroring core clinical features observed in affected patients—despite preserved neuronal numbers and only modest ER stress. Multi-omics analyses, including single-nucleus RNA sequencing and metabolomics, revealed significant dysregulation of one-carbon metabolism in ERAD-deficient brains. This included activation of the serine, folate, and methionine pathways, accompanied by elevated levels of S-adenosylmethionine and related metabolites, likely resulted from induction of the integrated stress response (ISR). Together, these findings uncover a previously unappreciated role for neuronal SEL1L-HRD1 ERAD in coordinating ER protein quality control with metabolic adaptation, providing new insight into the molecular basis of ERAD-related neurodevelopmental disease.
Authors
Mauricio Torres, You Lu, Brent Pederson, Hui Wang, Anna Gretzinger, Liangguang Lin, Jiwon Hwang, Xinxin Chen, Alan C. Rupp, Abigail J. Tomlinson, Andrew J. Scott, Zhen Zhao, Daniel R. Wahl, Martin Myers, Jr, Costas A. Lyssiotis, Ling Qi
Abstract
SLC13A5 citrate transporter disorder is a rare epileptic encephalopathy caused by loss of function pathogenic variants in the SLC13A5 gene. Loss of sodium/citrate cotransporter (NaCT) function causes a severe early life epilepsy resulting in life-long developmental disabilities and increased extracellular citrate. Current antiseizure medications may reduce seizure frequency, yet more targeted treatments are needed to address the epileptic and neurodevelopmental SLC13A5 phenotype. We performed preclinical studies in SLC13A5 deficient mice evaluating phenotype rescue with adeno-associated virus (AAV) vector carrying a functional copy of the human SLC13A5 gene (AAV9/SLC13A5). Cerebrospinal fluid-delivery of AAV9/SLC13A5 decreased extracellular citrate levels, normalized electrophysiologic and sleep architecture abnormalities, and restored resistance to chemically induced seizures and death. Treatment benefits were achieved with administration during early brain development and in young adult mice, indicating therapeutic efficacy across developmental and post-developmental stages. Comparison of delivery routes in young adult KO mice showed that higher brain targeting achieved with intra-cisterna magna delivery resulted in greater treatment benefit as compared to intrathecal lumbar puncture delivery. Together, these results support further development of AAV9/SLC13A5 for treating SLC13A5 citrate transporter disorder.
Authors
Lauren E. Bailey, Raegan M. Adams, Morgan K. Schackmuth, Irvin T. Garza, Krishanna Knight, Sydni K. Holmes, Meghan M. Eller, MinJae Lee, Rachel M. Bailey
Abstract
Recurrent hypoglycaemia in type 1 diabetes (T1D) may culminate in impaired awareness of hypoglycaemia (IAH). While neuroimaging studies identified affected brain regions, more complex perspectives integrating vascular dynamics with endocrine profile are missing. 26 healthy adults, 30 T1D patients with normal hypoglycaemia awareness (NAH), and 25 T1D patients with IAH underwent a hyperinsulinaemic stepped clamp (euglycaemia → hypoglycaemia 50 mg.dL-1) combined with pseudo-continuous arterial spin-labelling MRI. Cerebral blood flow (CBF) and sympathetic vasomotor-range (0.02-0.05 Hz) CBF oscillations were modelled against serially sampled plasma cortisol, epinephrine, norepinephrine and glucagon. In healthy controls, hypoglycaemia evoked robust thalamo-striatal and salience–interoceptive CBF increases (mean Cohen’s d across significant clusters=0.93) and suppression of vasomotor oscillations (d=0.71). T1D retained CBF response but failed to attenuate oscillations (dT1D>controls=0.43). IAH further blunted hypoglycaemia-associated CBF increase, especially in thalamus, striatum and insula (dNAH>IAH=0.51). Hormone-CBF coupling differed quantitatively: cortisol/epinephrine–CBF correlations were positive in controls (r=0.37/0.26), negative in NAH (-0.16/-0.40) and strongly positive in IAH (0.42/0.46). Thus, our findings indicate that T1D disrupts dynamic, sympathetic modulation of CBF, whereas IAH additionally impairs perfusion reserve and shows maladaptive catecholamine-dependent CBF regulation, suggesting a qualitatively distinct neurovascular phenotype.
Authors
Pavel Filip, Antonietta Canna, Heidi Grohn, Amir A. Moheet, Anjali F. Kumar, Xiufeng Li, Yuan Zhang, Lynn E. Eberly, Elizabeth R. Seaquist, Silvia Mangia
Abstract
Skeletal muscle frequently experiences oxygen depletion, especially during exercise, and the alpha subunit of the hypoxia-inducible factors (HIF1α and HIF2α) plays a crucial role in mediating cellular adaptation to low oxygen levels. However, although significant, the absence of an appropriate experimental mouse model leaves the precise roles of HIFα in myofibers unclear. Therefore, this study developed mice with myofiber-specific knockouts of prolyl hydroxylase proteins (PHDs), in which HIFα is stabilized, and inducible myofiber-specific overexpression of stable HIF1α or HIF2α to explore the role of HIFα in myofibers. Using three distinct mouse models, we found that HIF1α increased the number of oxidative fibers but paradoxically impaired exercise performance and mitochondrial function. Comparatively, HIF2α exerted protection mechanisms against glucose intolerance and diet-induced obesity. Notably, HIF2α stabilization in skeletal muscle markedly elevated erythropoietin (EPO) levels in muscle and serum but not in the kidney and liver, suggesting skeletal muscle is a previously unrecognized site of EPO production in the body. Thus, this study demonstrates the distinct roles of HIF1α and HIF2α in skeletal muscle, newly uncovering that the PHD-HIF2α axis produces EPO from myofibers.
Authors
Junhyeong Lee, Merc Emil Matienzo, Sangyi Lim, Edzel Evallo, Yeongsin Kim, Sujin Jang, Keon Kim, Chang Hyeon Choi, Youn Ho Han, Chang-Min Lee, Tae-Il Jeon, Sang-Ik Park, Jun Wu, Dong-il Kim, Min-Jung Park
Abstract
Metabolic-inflammatory crosstalk orchestrates muscle repair. Although pyroptosis typically aggravates sterile injury, we demonstrated that GSDME-dependent pyroptotic signaling associated with recruited myeloid cells paradoxically supported regeneration. GSDME expression was induced in post-surgical human muscle injury and murine damage models. Gsdme deficiency delayed functional recovery and exacerbated injury-induced myosteatosis, a pathological form of intramuscular ectopic fat deposition. Time-series and single-cell RNA-sequencing analyses revealed that GSDME loss shifted the transcriptional program from oxidative metabolism toward lipid storage and adipogenesis. Lipidomics confirmed aberrant accumulation of triacylglycerols and sphingolipids in Gsdme-deficient muscle. Single-cell profiling further identified divergent fibro-adipogenic progenitors (FAPs) states skewed toward adipogenesis, accompanied by impaired expansion of restorative Lyve1⁺Cd163⁺Txnip⁺ tissue-resident macrophages (TRMs)—validated by multiplex flow cytometry. Blocking CCR2-dependent monocyte recruitment produced regenerative defects comparable to those caused by Gsdme deficiency. Myeloid-specific Gsdme reintroduction rescued TRM expansion and function, curbed FAP adipogenic reprogramming, whereas FAP-specific expression proved ineffective. Mechanistically, IL-18 downstream of GSDME-dependent signaling engaged KLF4/JUN signaling in TRMs, sustaining their reparative and lipid-clearing capacity. This GSDME–IL-18–TRMs axis was compromised in aged muscle, yet exogenous IL-18 reversed myosteatosis and accelerated regeneration. Together, these findings suggest that GSDME-dependent pyroptotic signaling can act as a metabolic checkpoint that sustains TRM-driven lipid homeostasis to support muscle regeneration.
Authors
Qi Cao, Jian Liu, Gang Huang, Su-Yuan Wang, Guo-Dong Lu, Yong Huang, Yi-Ting Chen, Zhen Zhang, Jiang-Tao Fu, Si-Jia Sun, Xiaofei Chen, Chunlin Zhuang, Chunquan Sheng, Fu-Ming Shen, Dong-Jie Li, Pei Wang
Abstract
Interstitial lung disease (ILD) is a major cause of morbidity and mortality in systemic sclerosis (SSc); however, the immunopathologic mechanisms driving lung disease in SSc are unclear. T cells have been implicated as a likely driver of lung injury in SSc. Here, we have evaluated T cells in the blood of patients with SSc-ILD and identified a specific population of cytotoxic CD8 T cells that is expanded in SSc-ILD patients. Cytotoxic effector memory CD8 T cells marked by CD57 expression are preferentially expanded in SSc-ILD patients compared to SSc patients without ILD and controls and show prominent clonal expansion. These CD57+ T effector memory (TEM) cells differ from T effector memory cells re-expressing CD45RA (TEMRA) transcriptomically and functionally, with cytotoxic function that is enhanced by CD155 engagement of the costimulatory receptor CD226. We performed immunostaining of lung tissue samples obtained from independent SSc-ILD patients (biopsy or explant) and confirmed the presence of CD57+ TEM. In parallel, we analyzed publicly available lung scRNA-seq datasets from multiple ILD cohorts and identified endothelial cells as a likely source of CD155 to activate CD57+ cytotoxic T cells. Together, the results implicate a CD57+ cytotoxic CD8 T cell population as a potential mediator of lung injury in SSc-ILD.
Authors
Takanori Sasaki, Ye Cao, John M. Sowerby, Kazuhiko Higashioka, Kathryne E. Marks, Mehreen Elahee, Mari Kamiya, Paul F. Dellaripa, Richard I. Ainsworth, Kimberly E. Taylor, Nunzio Bottini, Paul Wolters, Edy Y. Kim, Francesco Boin, Deepak A. Rao
Abstract
Stereotactic arrhythmia radiotherapy (STAR) is emerging as a highly effective treatment for ventricular tachycardia (VT). Growing evidence indicates that STAR favorably reprograms the electrical substrate by speeding conduction and/or prolonging repolarization via modulating ion channel expression, though the mechanisms whereby single-fraction radiation mediates durable changes in gene expression are incompletely understood. Here, we identify dynamic changes in the cardiomyocyte epigenome and transcriptome after irradiation (IR) in vivo and in vitro, including durably increased expression and chromatin accessibility of Scn5a (encoding the alpha subunit of the sodium channel, NaV1.5), demonstrating a role for epigenetic memory in conduction velocity (CV) increases observed after STAR. Transcriptomic and epigenetic sequencing further identify dynamic changes to gene expression and regulatory regions involved in cellular repolarization, calcium handling, and metabolism after IR. These changes are mirrored by dose-dependent and cell-autonomous changes in repolarization, calcium flux, and mitochondrial respiration, highlighting important cellular processes which may mediate therapeutic effects of STAR. Overall, we find that cardiomyocytes exposed to a single fraction of high-dose IR exhibit epigenetic reprogramming that mediates broad and dynamic physiologic responses.
Authors
Samuel D. Jordan, Shuhua Fu, Abigail Fulkerson, Donghua Hu, Sherwin Ng, David M. Zhang, Sneha Manikandan, Jeffrey Szymanski, Nan Hu, Yuqian Xie, Anish Bedi, James J. Tabor, Lauren Boggs-Bailey, Lori Strong, Stephanie Hicks, Lavanya Aryan, Nishanth Gabriel, Geoffrey D. Hugo, Kuo-Chan Weng, Nathaniel Huebsch, Julie K. Schwarz, Bo Zhang, Stacey L. Rentschler
Abstract
Mutations in SLC26A4 are the second most common cause of hereditary hearing loss in many Asian countries, leading to DFNB4, a condition characterized by progressive hearing loss and inner ear malformations. While gene therapy holds great potential, its postnatal application has remained unexplored due to the lack of suitable animal models and the challenges of prenatal intervention. This study represents the first preclinical investigation of postnatal gene therapy for DFNB4 using a clinically relevant Slc26a4 mutant mouse model that closely replicates human auditory phenotypes. Utilizing the synthetic AAV.Anc80L65 vector, we achieved robust SLC26A4 delivery to critical cochlear regions, including the endolymphatic sac and cochlear lateral wall. Comprehensive phenotypic analyses revealed a critical therapeutic window spanning the neonatal and juvenile stages, within which AAV.Anc80L65-mediated SLC26A4 delivery significantly improved hearing, as evidenced by lower auditory brainstem response thresholds. Moreover, the therapy preserved hair cells, reduced endolymphatic sac enlargement, partially restored the endocochlear potential, and mitigated inner ear structural degeneration. These therapeutic effects persisted into adulthood, highlighting the long-term efficacy of postnatal gene therapy. Together, these findings establish a critical therapeutic window for DFNB4 and demonstrate the feasibility of targeting the endolymphatic sac and cochlear lateral wall for effective intervention.
Authors
Yi-Hsiu Tsai, Peng-Yu Wu, Yu-Chi Chuang, Chun-Ying Huang, Hiroki Takeda, Hiroshi Hibino, Chen-Chi Wu, Yen-Fu Cheng
Abstract
The gastrointestinal tract varies in structure and function by region, yet the drivers of region-specific inflammatory disease remain elusive. Here, a TNF-overexpressing murine model (TnfΔARE/+) of Crohn’s disease (CD) was used to investigate how pathobionts interact with host immune susceptibilities to drive region-specific disease. We identified the pathobiont Chlamydia muridarum, an intracellular bacterium and murine counterpart to the human sexually transmitted C. trachomatis, as a necessary and sufficient trigger for disease manifestation in the proximal/ascending colon, a common site of CD. In genetically susceptible hosts, pathobiont-triggered proximal colonic inflammation is driven by goblet cell responses, one of which through tryptophan metabolism via indoleamine 2,3-dioxygenase (IDO1). Our findings translate to human disease, where we demonstrate upregulation of epithelia-derived IDO1 in actively inflamed ascending colon specimens, but not actively inflamed terminal ileum specimens, of CD patients. Our findings mechanistically reveal how genetic and microbial factors drive the manifestation of disease in a region-specific manner and provide a unique model to study CD specific to the ascending colon.
Authors
Paige N. Spencer, Monica E. Brown, Erin P. Smith, Jiawei Wang, William Kim, Luisella Spiga, Naila Tasneem, Alan J. Simmons, Taewoo Kim, Yilin Yang, Yanwen Xu, Lin Zheng, James Ro, Harsimran Kaur, Seung Woo Kang, Matthew D. Helou, Mason A. Lee, Deronisha Arceneaux, Katherine D. Mueller, Ozge S. Kuddar, Mariah H. Harned, Jing Li, Amrita Banerjee, Nicholas O. Markham, Keith T. Wilson, Lori A. Coburn, Jeremy A. Goettel, Qi Liu, M. Kay Washington, Raphael H. Valdivia, Wenhan Zhu, Ken S. Lau
Abstract
Single-cell analysis of human triple-negative breast cancer revealed heterogeneous macrophage populations with opposing phenotypes—pro-inflammatory and pro-resolution of inflammation. Paradoxically, both subsets accumulated in therapy-refractory residual tumors but showed inverse correlations across patients, suggesting mutually exclusive resistance mechanisms. Inflammatory macrophages localized preferentially to epithelial-like tumors, whereas pro-resolution macrophages were enriched in mesenchymal-like tumors. Mouse models faithfully recapitulated these patterns. After immuno-chemotherapy, mesenchymal-like tumors expanded pro-resolution macrophages through phagocytosis/efferocytosis, ω-3 fatty-acid uptake, and resolvin production. Macrophage-secreted C1q emerged as a principal antagonist of T-cell function by targeting mitochondria and inducing metabolic dysfunction. By contrast, epithelial-like tumors accumulated inflammatory macrophages and neutrophils that produced prostaglandins via ω-6 fatty-acid pathways. Knocking down ELOVL5—an elongase involved in ω-3 and ω-6 metabolism—mitigated both neutrophil- and macrophage-mediated immunosuppression. These distinct axes, driven by dysregulated inflammation and resolution programs, converged to undermine therapy-induced immunosurveillance; however, targeting their shared upstream regulators may overcome these resistance mechanisms.
Authors
Liqun Yu, Charlotte Rivas, Fengshuo Liu, Yichao Shen, Ling Wu, Zhan Xu, Yunfeng Ding, Xiaoxin Hao, Weijie Zhang, Hilda L. Chan, Jun Liu, Bo Wei, Yang Gao, Luis Becerra-Dominguez, Yi-Hsuan Wu, Siyue Wang, Tobie D. Lee, Xuan Li, Xiang Chen, David G. Edwards, Xiang H.-F. Zhang
Abstract
Circulating monocyte-derived macrophages (MDMø) rapidly invade the brain after stroke, exerting both detrimental and beneficial effects. Elucidating mechanisms that mediate detrimental properties of MDMø may identify therapeutic strategies to divert MDMø from destructive phenotypes, while preserving their favorable effects. Toward this goal, the current study explores the function of Galectin-3 (GAL3) in MDMø and elucidates mechanisms whereby MDMø-derived GAL3 exacerbates stroke injury. In the acutely injured brain, GAL3 expression was upregulated primarily within MDMø. Global knockout of GAL3 reduced brain infarcts in the short-term but did not sustain long-term positive outcomes. Using bone marrow chimera mice, macrophage transplantation, and myeloid cell-specific GAL3 knockout (LysMCre+/–Lgals3f/f) mice, we demonstrated that GAL3 in MDMø mediated acute infarct expansion after stroke. Coculturing brain lysate-treated bone marrow-derived macrophages (BMDMs) with oxygen glucose deprivation-challenged neurons induced neurotoxicity that was mitigated by the cell-permeable, selective GAL3 inhibitor TD139. GAL3 triggered cathepsin induction and lysosomal leakage in BMDMs, leading to inflammasome activation. Systemic and transient TD139 treatment in the acute injury phase reduced infarcts, tempered neuroinflammation, and improved long-term neurological outcomes. Therefore, MDMø-derived GAL3 represents a drug target that could be accessed in peripheral blood to potentially mitigate post-stroke brain injury.
Authors
Miao Wang, Zhentai Huang, Zhihong Du, Jiajing Shan, Qing Ye, Lingxiao Lu, Ming Jiang, Fei Xu, Ziyang Liu, David J.R. Fulton, Rehana K. Leak, Babak Razani, Jun Chen, Xiaoming Hu
Abstract
Authors
Jana Blazkova, Brooke D. Kennedy, Jesse S. Justement, Victoria Shi, Adeline Sewack, Maegan R. Manning, Sonali S. Dasari, Kathleen Gittens, Susan Moir, Mark Connors, Stephen A. Migueles, Tae-Wook Chun
Abstract
Alternative splicing-triggered nonsense-mediated mRNA decay (AS-NMD) critically regulates gene expression, but the extent to which neuronal genes are regulated by AS-NMD remains understudied. Here, we identified more than 3,000 developmentally regulated AS-NMD exons in mouse and human brains, and validated them in cultured neurons. AS-NMD suppresses synaptic genes during brain development and differentially regulates more than 200 causal genes for neurodevelopmental disorders (NDDs). We detected an AS-NMD exon in GRIA2 and identified splice-switching antisense oligonucleotides that suppressed GRIA2 NMD and increased its functional isoforms. In summary, this study uncovers genes repressed by AS-NMD in the brain and nominates amenable splice-switching targets for treating dominant NDDs such as autism spectrum disorders and developmental epileptic encephalopathy.
Authors
Kaining Hu, Runwei Yang, Jiaming Qiu, Xinran Feng, Kayleigh J. LaPre, Jessica Tanouye, Yalan Yang, Xiaochang Zhang
Abstract
Fibroblast growth factor receptor 1 (FGFR1) is recurrently mutated at p.N546 in neuroblastoma. We here sought to examine whether mutant FGFR1 is an oncogenic driver, a predictive biomarker, and an actionable vulnerability in this malignancy. FGFR1 mutations at p.N546 were associated with high-risk disease and rapid tumor progression, resulting in dismal outcome of these patients. Ectopic expression of FGFR1N546K induced constitutive down-stream signaling and interleukin-3-independent growth in Ba/F3 cells, indicating oncogene addicted proliferation. In FGFR1N546K;MYCN transgenic mice, neuroblastoma developed within the first days of life with fatal outcome within 3 weeks, reflecting the devastating clinical phenotypes of patients with FGFR1 mutant high-risk neuroblastoma. Treatment with FGFR inhibitors impaired proliferation and pathway activation in FGFR1N546K-expressing Ba/F3 and patient-derived FGFR1N546K mutant neuroblastoma cells, and inhibited tumor growth in FGFR1N546K;MYCN transgenic mice and in a chemotherapy-resistant patient-derived xenograft mouse model. In addition, partial regression of FGFR1N546K mutant tumor lesions occurred upon treatment with the FGFR inhibitor futibatinib and low-intensity chemotherapy in a patient with refractory neuroblastoma. Together, our data demonstrate that FGFR1N546K is a strong oncogenic driver in neuroblastoma that is associated with failure of current standard chemotherapy, and suggest potential clinical benefit of FGFR-directed therapies in FGFR1 mutant high-risk patients.
Authors
Lisa Werr, Jana Boland, Josephine Petersen, Fiorella Iglesias, Stefanie Höppner, Christoph Bartenhagen, Carolina Rosswog, Anna-Maria Hellmann, Yvonne Kahlert, Nadine Hemstedt, Nadliv Ibruli, Marcel A. Dammert, Boris Decarolis, Jan-Michael Werner, Florian Malchers, Kathrin Schramm, Olaf Witt, Klaus Hermann Beiske, Anne Gro Wesenberg Rognlien, Maria Winther Gunnes, Karin P.S. Langenberg, Jan Molenaar, Marie Bernkopf, Sabine Taschner-Mandl, Debbie Hughes, Sally L. George, Louis Chesler, Johannes H. Schulte, Giuseppe Barone, Mario Capasso, Lea F. Surrey, Rochelle Bagatell, Julien Masliah-Planchon, Gudrun Schleiermacher, Holger Grüll, Frank Westermann, Anne M. Schultheis, Reinhard Büttner, Anton G. Henssen, Angelika Eggert, Martin Peifer, Neerav N. Shukla, Thorsten Simon, Barbara Hero, H. Christian Reinhardt, Roman K. Thomas, Matthias Fischer
Abstract
BACKGROUND. Susceptibility to human immunodeficiency virus type 1 (HIV-1) infection varies between individuals, but the biological determinants of acquisition risk remain poorly defined. METHODS. We conducted a case-control study nested within a high-risk cohort in Kenya. We compared the plasma extracellular RNA collected before HIV-1 acquisition with matched uninfected controls to identify immunological processes linked to infection risk. RESULTS. Individuals who later acquired HIV-1 exhibited upregulation of immune processes that facilitate viral infection, including T cell suppression, type II interferon and Th2 immune responses. In contrast, processes associated with antiviral defence and tissue repair, such as neutrophil and natural killer cell responses, type I interferon responses, wound healing, and angiogenesis, were downregulated. CONCLUSION. These findings highlight dampened antiviral immunity prior to exposure as a correlate of increased risk for subsequent HIV-1 acquisition. TRIAL NUMBERS. Not applicable. FUNDING. This work was supported by a Wellcome Trust Award (209289/Z/17/Z) and the Sub-Saharan African Network for TB/HIV Research Excellence (SANTHE) through the DELTAS Africa programme [Del-22-007], supported by the Science for Africa Foundation, Wellcome Trust, the UK Foreign, Commonwealth & Development Office, and the European Union. Additional support was provided by the Bill & Melinda Gates Foundation, Gilead Sciences Inc., Aidsfonds, and the Ragon Institute of Mass General, MIT, and Harvard. The cohort study was supported by PEPFAR through USAID. The views expressed are those of the authors.
Authors
Mwikali Kioko, Shaban Mwangi, Lynn Fwambah, Amin S. Hassan, Jason T. Blackard, Philip Bejon, Eduard J. Sanders, Thumbi Ndung'u, Eunice W. Nduati, Abdirahman I. Abdi
Abstract
Obesity is accompanied by increases in free fatty acids (FFAs) in the systemic circulation, and obese patients often develop cardiac hypertrophy and diastolic dysfunction, termed obesity cardiomyopathy. Proinflammatory cytokines, including IL-6, have been implicated in the pathogenesis of the cardiac dysfunction associated with obesity cardiomyopathy. Elevation of FFAs induced by high fat diet (HFD) consumption induced diastolic dysfunction in the heart as early as after one month. HFD consumption directly stimulated IL-6 production in cardiomyocytes before local inflammation developed and induced diastolic dysfunction even in the presence of macrophage depletion with clodronate in the heart. PPARα played an essential role in mediating Il6 transcription in response to HFD consumption by forming a heterodimer with p50/RelA and binding to the NFκB element in cardiomyocytes. Local production of IL-6 in cardiomyocytes, in turn, mediated the development of diastolic cardiac dysfunction. HFD-induced diastolic dysfunction was attenuated by cardiac-specific deletion of either Ppara or Il6, as well as by interference with the PPARα-NFκB heterodimer formation by a molecular decoy. These results suggest that elevated FFAs directly upregulate Il6 through the PPARα-NFκB heterodimer in cardiomyocytes and highlight autocrine production of IL-6 as a key downstream mechanism in the initial development of diastolic dysfunction.
Authors
Shin-ichi Oka, Eun-Ah Sung, Peiyong Zhai, Kevin B. Schesing, Santosh Bhat, Adave Chin, Jiyeon Park, Yeun-Jun Chung, Akihiro Shirakabe, Takanobu Yamamoto, Yoshiyuki Ikeda, Wataru Mizushima, Shohei Ikeda, Mingming Tong, Jaemin Byun, Michinari Nakamura, Samuel I. Kim, Jamie Francisco, Dominic P. Del Re, Junichi Sadoshima
Abstract
Prion diseases are a family of transmissible, neurodegenerative conditions caused by mis-folded proteins called prions. Human cerebral organoids can be infected with prions from sporadic Creutzfeldt-Jakob Disease (sCJD) brain tissue. Initial experiments indicated that the cerebral organoids may be able to differentiate biological properties of different sCJD subtypes and, if so, it would be possible to investigate the pathogenic similarities and differences. Herein, we investigated multiple infections of cerebral organoids with two sCJD subtypes, comparing hallmark features of disease as well as neuronal function and health. Our results show that while all infections produced seeding capable PrP, which increased from 90-180 days post infection, a sCJD subtype preference for protease resistant PrP deposition was observed. Both subtypes caused substantial electrophysiological dysfunction in the infected organoids, which appeared uncoupled from PrP deposition. Neuronal dysfunction was associated with changes in neurotransmitter receptors that differed between the subtypes but produced the same outcome of a shift from inhibitory toward excitatory neurotransmission. Further changes indicated shared deficits in mitochondrial dynamics, and subtype influenced alterations in intracellular signaling pathways, cytoskeletal structure, and the extracellular matrix. We conclude that cerebral organoids demonstrate both common mitochondrial deficits and sCJD subtype specific changes in neurotransmission and organoid architecture.
Authors
Katie Williams, Bradley R. Groveman, Simote T. Foliaki, Brent Race, Arielle Hay, Ryan O. Walters, Tina Thomas, Gianluigi Zanusso, James A. Carroll, Cathryn L. Haigh
Copyright © 2026 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)