Top read articles in the last 30 days
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Abstract
At-home blood collection devices (ABCDs) can facilitate study participation for remote and rural cohorts. Previous studies used ABCDs to interrogate samples by proteomics and sequencing approaches. We wanted to address the question of whether this approach could be used to assess live immune cells with high-parameter flow cytometry to enable remote immune monitoring. We first compared blood from standard venipuncture with ABCD blood draws, followed by assessment of the impact of sample shipping on immune cell viability and phenotyping. We found that capillary blood collected with a Tasso+ device and concurrently drawn venipuncture blood samples had highly congruent immune cell composition and phenotype. Shipment of Tasso+ samples via the United States Postal Service altered the myeloid compartment, but T cell numbers, subsets, and phenotypes remained remarkably stable compared with non-shipped samples. Finally, we describe a flow cytometry analysis framework that allowed for direct sample comparison even when samples were stained and analyzed over a time period of 1.5 years. Overall, our data highlight the feasibility of using ABCDs combined with subsequent flow cytometry analysis for remote immune monitoring. Additionally, our study also identifies areas that could be improved to further promote the use of ABCDs for immune monitoring.
Authors
Andrew J. Konecny, Fang Yun Lim, Eva Domenjo-Vila, Erika Lovas, Rachel L. Blazevic, Louise E. Kimball, Michael Boeckh, Alpana Waghmare, Martin Prlic
Total views: 1977
Abstract
Pancreatic cancer is a highly innervated gastrointestinal disease in which sympathetic nerves play a critical role in modulating tumor growth and the tumor microenvironment (TME). While recent studies suggest that sympathetic nerves influence various TME components, including lymphoid and myeloid immune cells, their interactions with cancer-associated fibroblasts (CAFs) remain poorly understood. CAFs are a hallmark of pancreatic tumors and are known to upregulate axon guidance and neuroactive cues, suggesting a potential feedback loop with tumor-innervating nerves. Here, we investigated the bidirectional crosstalk between sympathetic nerves and CAFs in human and mouse pancreatic tumors. Using a chemo-genetic ablation model, we selectively eliminated pancreatic sympathetic nerves and found that denervation significantly reduced tumor size in female mice. To further dissect this interaction, we established coculture systems with immortalized pancreatic fibroblasts and primary sympathetic neuron explants, identifying key transcriptional changes driven by CAF–sympathetic nerve signaling. Our findings demonstrated that sympathetic signaling enhanced CAF activation and extracellular matrix remodeling, while activated CAFs, in turn, induced transcriptional programs in sympathetic neurons associated with nerve injury response. These results establish CAFs as central mediators of the tumor-supportive role of sympathetic nerves, offering further insights into the neural regulation of pancreatic cancer progression.
Authors
Ariana L. Sattler, Parham Diba, Kevin Hawthorne, Carl Pelz, Joe Grieco, Tetiana Korzun, Bryan Chong, M.J. Kuykendall, Rosalie C. Sears, Daniel L. Marks, Mara H. Sherman, Teresa A. Zimmers, S. Ece Eksi
Total views: 1683
Abstract
GLP-1 receptor (GLP-1R) agonists decrease blood glucose and body weight and reduce rates of cardiovascular and renal disease. Although GLP-1R activation lowers blood pressure (BP), the underlying mechanisms remain incompletely understood and have been attributed to weight loss and endothelial cell GLP-1R signaling. Here, we show that GLP-1Rs in vascular smooth muscle cells (VSMCs) are essential for semaglutide-mediated BP reduction in mice. In contrast, GLP-1Rs in Tie2+ endothelial or immune cells are not required for semaglutide to lower BP. The VSMC GLP-1R is dispensable for the effects of semaglutide on food intake, body weight, and blood glucose but is required for its actions to increase glomerular filtration rate and promote natriuresis. Systemic semaglutide administration resulted in proteomic changes in the renal artery and kidney in pathways related to platelet aggregation, fibrin clot formation, lipid metabolism, and proapoptotic signaling that are abolished in mice lacking VSMC GLP-1R expression. Moreover, semaglutide directly induced vasorelaxation in preconstricted mesenteric arteries ex vivo. Together, these findings identify VSMCs as a key cellular target linking GLP-1R activation to BP regulation, renal electrolyte excretion, and proteomic changes in renal artery and kidney.
Authors
Kyle D. Medak, Jacqueline A. Koehler, Laurie L. Baggio, Maria J. Gonzalez-Rellan, Chi Kin Wong, Xiemin Cao, Vivikta Rao, Sean Kao, Yu Cui, Jiayi Fu, Easton Liaw, M. Golam Kabir, Jie Zhang, Jin Wei, Daniel J. Drucker
Total views: 1676
Abstract
We generated a comparative spatial proteomic atlas of the human and mouse retina using a highly multiplexed immunohistochemistry technique called iterative bleaching extends multiplexity (IBEX). We refined the IBEX workflow by integrating an antibody dissociation option alongside chemical bleaching. This dual strategy enabled removal of the entire antibody complex, permitting the flexible use of antibodies from the same host species across iterative cycles. We coupled this workflow with super-resolution imaging via deconvolution and applied it to the retina of healthy humans and WT mice and the Crb1rd8 mouse model. We successfully imaged over 25 protein markers on human and mouse tissue sections, generating spatial atlases of the major retinal cell populations. Cross-species protein expression was compared to scRNA-seq datasets to identify protein and transcript disparities. Super-resolution IBEX delineated the ultrastructural features of the outer limiting membrane (OLM), identifying CD44 as a core structural component tightly colocalized with a highly organized F-actin belt within Müller glial endfeet. Using the Crb1rd8 mouse model, disruption of this complex was spatially associated with rosette formation and OLM structural failure. In summary, spatial proteomic atlases of the human and mouse retina were used to reveal insights into the arrangement of major retinal cell populations and OLM structure.
Authors
Yuxuan Meng, Jakub Kubiak, Zuzanna Dzieniak, Lorna Fowler, Rose Avient, Jason Hopley, Linyulong Li, Chaoran Li, Yuan Tian, Bruno Charbit, Colin J. Chu
Total views: 1656
Abstract
Short QT syndrome is a heritable arrhythmia disorder linked to sudden cardiac death. We recently identified that individuals with alternating hemiplegia of childhood (AHC), a rare neurodevelopmental disorder, can exhibit shortened corrected QT intervals and elevated risk for ventricular fibrillation. This is especially true for patients with AHC heterozygous for the recurrent ATP1A3-D801N variant, though the underlying cardiac mechanism remains unclear. We hypothesized that the D801N missense impairs Na+/K+-ATPase function, causing Ca2+ overload, shortened action potential duration (APD), and arrhythmias. Using in silico modeling and patient-derived induced pluripotent stem cell cardiomyocytes (iPSC-CMsD801N), we observed shorter APD, elevated intracellular and sarcoplasmic reticulum Ca2+ levels, and delayed afterdepolarizations (DADs) compared with WT. Additionally, increased Ca²+ influx via the Na+/Ca2+ exchanger (NCX1) during depolarization was observed in iPSC-CMsD801N. Simulations and in vitro experiments suggest that reduced ATPase function accelerated inactivation of L-type Ca2+ channels. Pharmacologic inhibition of NCX1 with ORM-10103 normalized APD and reduced DADs. These findings support a Ca2+-mediated mechanism for arrhythmogenesis in ATP1A3-D801N carriers and identify NCX1 as a potential therapeutic target.
Authors
Minu-Tshyeto K. Bidzimou, Padmapriya Muralidharan, Zhushan Zhang, Danyal Raza, Daniel Needs, Bo Sun, Robin M. Perelli, Mary E. Moya-Mendez, P.K. Rakesh Manivannan, Arsen S. Hunanyan, Abbigail Helfer, Christine Q. Simmons, Alfred L. George Jr., Donald M. Bers, Nenad Bursac, Mohamad A. Mikati, Andrew P. Landstrom
Total views: 1538
Potentiation of fentanyl-induced respiratory depression by alcohol is not fully reversed by naloxone
Abstract
The high frequency of opioid overdose deaths often involves co-use of alcohol, which is reported in approximately 30% of fentanyl fatalities. Both substances depress respiratory function, and their combined effects can be lethal. The present study investigated physiological parameters of respiratory-depressant effects of fentanyl when coadministered with alcohol and their sensitivity to naloxone reversal using whole-body plethysmography in male and female Long-Evans rats. Administration of a high, sedative-like dose of alcohol alone or fentanyl alone resulted in no mortality, but fentanyl plus alcohol led to mortality rates of 42% and 33% in females and males, respectively. The fentanyl+alcohol combination reduced minute ventilation and increased apneic pauses compared with either drug alone. Lower, binge-like alcohol doses when combined with fentanyl also amplified respiratory depression. Pretreatment with naloxone did not fully restore normal respiration. Naloxone administered after fentanyl+alcohol transiently reversed the decrease in minute ventilation but did not reverse apneic pauses. Fentanyl-dependent rats were partially tolerant to fentanyl- and fentanyl+alcohol–induced respiratory depression, but alcohol-dependent rats exhibited sensitization to alcohol- and fentanyl+alcohol–induced apnea. These findings highlight physiological parameters of severe respiratory risks with fentanyl+alcohol co-use, which are inadequately reversed by naloxone, underscoring the need for targeted strategies to manage opioid+alcohol overdoses.
Authors
Emma V. Frye, Lyndsay E. Hastings, Aniah N. Matthews, Adriana Gregory-Flores, Janaina C.M. Vendruscolo, Lindsay A. Kryszak, Shelley N. Jackson, Aidan J. Hampson, Nora D. Volkow, Leandro F. Vendruscolo, Renata C.N. Marchette, George F. Koob
Total views: 1489
Abstract
Angiopoietin-2 (ANGPT2) is known to destabilize vascular barriers in most peripheral organs; however, its role in the brain vasculature remains poorly understood. To investigate its physiological function within the brain vasculature, we analyzed constitutive Angpt2-knockout mice in adulthood. We showed that loss of ANGPT2 leads to region-specific vascular malformations and blood-brain barrier (BBB) dysfunction, resulting in differential permeability to 1 kDa and 70 kDa fluorescent tracers. Notably, overt vascular malformations appeared only in select brain regions that allowed leakage of both tracers. These malformations were characterized by dilated, intertwined, and sprouting endothelial cells, surrounded by reactive perivascular cells, along with high levels of astrocyte- and neuron-derived vascular endothelial growth factor A (VEGFA) and elevated expression of the vascular receptors VEGF receptor 2 (KDR) and neuropilin-1 (NRP1). Other cortical areas without obvious malformations exhibited significant leakage of the 1 kDa tracer. We also demonstrated that different cell types took up the tracers after passing the BBB. Our findings identified ANGPT2 as an important factor involved in the regulation of cerebrovascular architecture, barrier integrity, and endothelial-parenchymal interactions, and uncovered surprising differences in the leakage patterns and cellular uptake of two widely used BBB tracers.
Authors
Weihan Li, Elisa Vázquez-Liébanas, Chanaëlle Fébrissy, Florent Sauvé, Jianhao Wang, Doğan E. Sayıner, Pia Buslaps, Amanda Norrén, Michael Vanlandewijck, Liqun He, Marie Jeansson, Lars Muhl, Maarja Andaloussi Mäe
Total views: 1485
Abstract
Supernumerary centrosomes are a hallmark of cancer. To maintain viability, cancer cells cluster these centrosomes during mitosis, enabling bipolar division similar to that of normal cells. Disruption of this centrosome clustering leads to multipolar anaphase and apoptosis (anaphase catastrophe), which selectively eliminates cancer cells harboring supernumerary centrosomes. In this context, because the motor protein KIFC1 contributes to centrosome clustering, we investigated whether targeting of this mechanism through KIFC1 inhibition could be exploited in small-cell lung cancer (SCLC), an aggressive malignancy with limited treatment options and poor prognosis. Through in silico and in vitro analyses, as well as IHC of clinical samples, we found that KIFC1 is overexpressed and that centrosome amplification occurs more frequently in SCLC compared with normal tissues and other cancer types. Pharmacological and genetic inhibition of KIFC1 disrupted the clustering of supernumerary centrosomes, triggered multipolar mitosis, and exerted antineoplastic effects in SCLC cells, with minimal effects on noncancerous cells. These findings were validated and extended in vivo using SCLC xenograft models. Finally, cotargeting KIFC1 and the centrosome duplication regulator PLK4 further enhanced growth suppression in SCLC cells. Together, these results suggest that disrupting centrosome clustering and triggering anaphase catastrophe via KIFC1 inhibition may represent a promising therapeutic strategy for SCLC.
Authors
Natsuki Nakagawa, Minemichi Toda, Akiko Kunita, Masafumi Horie, Masakatsu Tokunaga, Hiroaki Ikushima, Mirei Ka, Takahiro Iida, Manabu Shigeoka, Yukinobu Ito, Takahiro Ando, Kousuke Watanabe, Yasunori Ota, Xi Liu, Ethan Dmitrovsky, Hidenori Kage, Masanori Kawakami
Total views: 1451
Abstract
Recently, skeletal stem cells were shown to be present in the epiphyseal growth plate (epiphyseal skeletal stem cells, epSSCs), but their function in connection with linear bone growth remains unknown. Here, we explore the possibility that modulating the number of epSSCs can correct differences in leg length. First, we examined regulation of the number and activity of epSSCs by Hedgehog (Hh) signaling. Both systemic activation of Hh pathway with Smoothened agonist (SAG) and genetic activation of Hh pathway by Patched1 (Ptch1) ablation in Pthrp-creER Ptch1fl/fl tdTomato mice promoted proliferation of epSSCs and clonal enlargement. Transient intra-articular administration of SAG also elevated the number of epSSCs. When SAG-containing beads were implanted into the femoral secondary ossification center of 1 leg of rats, this leg was significantly longer 1 month later than the contralateral leg implanted with vehicle-containing beads, an effect that was even more pronounced 2 and 6 months after implantation. We conclude that Hh signaling activates growth plate epSSCs, which effectively leads to increased longitudinal growth of bones. This opens therapeutic possibilities for the treatment of differences in leg length.
Authors
Dana Trompet, Anastasiia D. Kurenkova, Baoyi Zhou, Lei Li, Ostap Dregval, Anna P. Usanova, Tsz Long Chu, Alexandra Are, Andrei A. Nedorubov, Maria Kasper, Andrei S. Chagin
Total views: 1419
Abstract
Temporomandibular joint osteoarthritis (TMJOA), a prevalent subtype of temporomandibular disorders, is characterized by progressive cartilage degradation and subchondral bone destruction. Despite advancements in understanding TMJOA pathogenesis, the molecular mechanisms underlying its progression remain unclear. In this study, elevated Slit guidance ligand 2 (SLIT2) expression was observed in TMJ tissues of unilateral anterior crossbite–induced TMJOA mice and synovial fluid from patients with TMJOA, correlating with disease severity. Furthermore, SLIT2 overexpression in transgenic mice intensified TMJOA progression, whereas heterozygous deletion of roundabout guidance receptor 1/2 (ROBO1/2) alleviated cartilage and bone damage. Mechanistically, SLIT2 promoted ROBO1-LRP6 complex formation, facilitating LRP6 phosphorylation and β-catenin nuclear translocation. This cascade upregulated matrix-degrading enzymes while downregulating cartilage structural proteins, exacerbating cartilage destruction and subchondral bone loss. These findings suggest that the SLIT2/ROBO1/LRP6 axis may represent a potential therapeutic target for TMJOA and provide mechanistic insights into disease progression.
Authors
Guan Luo, Baoyi Chen, Wenjun Chen, Huiyi Lin, Weiqi Guo, Qingbin Zhang, Jiang Li, Lijing Wang, Janak Lal Pathak, Yuhui Yang, Weijun Zhang, Xiaoyu Zhang, Beining Zheng, Ziyi Wang, Shiting Wei, Jiaxin He, Wei-Jie Zhou, Chang Liu
Total views: 1408
