tbuckley/cabot-search huggingface dataset:
IAMSAM: image-based analysis of molecular signatures using the Segment Anything Model
Authors: Dongjoo Lee, Jeongbin Park, Seungho Cook, Seongjin Yoo, Daeseung Lee, Hongyoon Choi
Journal: Genome biology (2024)

Spatial transcriptomics is a cutting-edge technique that combines gene expression with spatial information, allowing researchers to study molecular patterns within tissue architecture. Here, we present IAMSAM, a user-friendly web-based tool for analyzing spatial transcriptomics data focusing on morphological features. IAMSAM accurately segments tissue images using the Segment Anything Model, allowing for the semi-automatic selection of regions of interest based on morphological signatures. Furthermore, IAMSAM provides downstream analysis, such as identifying differentially expressed genes, enrichment analysis, and cell type prediction within the selected regions. With its simple interface, IAMSAM empowers researchers to explore and interpret heterogeneous tissues in a streamlined manner.
Endocisternal interfaces for minimally invasive neural stimulation and recording of the brain and spinal cord
Authors: Joshua C Chen, Abdeali Dhuliyawalla, Robert Garcia, Ariadna Robledo, Joshua E Woods, Fatima Alrashdan, Sean O'Leary, Adam Husain, Anthony Price, Scott Crosby, Michelle M Felicella, Ajay K Wakhloo, Patrick Karas, Nicole Provenza, Wayne Goodman, Sameer A Sheth, Sunil A Sheth, Jacob T Robinson, Peter Kan
Journal: Nature Biomedical Engineering (2024)
Landiolol in patients with septic shock
Authors: Vassilios Vazgiourakis, Konstantinos Mantzarlis, Demosthenes Makris
Journal: Intensive Care Medicine (2024)

We read with great interest the article by Rehberg et al. [1].The use of β-blockers during septic shock aims to control heart rate ameliorating the deleterious effects of persistent tachycardia.Until now, contradictory results exist about the effects of landiolol in septic patients [2, 3].We therefore wish to draw authors attention to some points.Sinus tachycardia at the level of > 95 bpm is not always a hallmark of sympathetic overstimulation; it may be a compensatory mechanism to excessive reduction of peripheral vascular resistances [2].Patients with any form of compensatory tachycardia were excluded according to physicians' discretion.It would be of great value to know about the criteria used to characterize the tachycardia as 'compensatory' and therefore to exclude those patients from taking landiolol.Second issue is that although primary end-point (control and maintenance of heart rate) was achieved with landiolol, no other differences between groups were observed; notably there was a tendency for higher vasopressor doses in the landiolol group.We would like the comment of the authors on this finding because it is not clear how the isolated finding of heart rate reduction could justify the use of b-blockers in septic patients.On top of this observation, although vasopressors dose in the landiolol group was not increased within 24 h, it is a question if the use of landiolol and accordingly heart rate reduction prevented vasopressors dose to be reduced.Finally, the authors concluded that heart rate control by β-blockers may be beneficial in specific subgroups of septic patients.Is there any bed-side test or parameter that could easily identify patients that are more likely to benefit from this intervention?Until now, the only promising maker to discriminate tachycardic patients with sepsis qualified for esmolol use is the systolic-dicrotic notch pressure difference [4].The question which patients' subgroups will be benefited from β-blockade remains.
Brca1 haploinsufficiency promotes early tumor onset and epigenetic alterations in a mouse model of hereditary breast cancer
Authors: Carman Man-Chung Li, Alyssa Cordes, Michael U J Oliphant, S Aidan Quinn, Mayura Thomas, Laura M Selfors, Francesca Silvestri, Nomeda Girnius, Gianmarco Rinaldi, Jason J Zoeller, Hana Shapiro, Christina Tsiobikas, Kushali P Gupta, Shailja Pathania, Aviv Regev, S Cigall Kadoch, Senthil K Muthuswamy, Joan S Brugge
Journal: Nature Genetics (2024)
The pro-oncogenic noncanonical activity of a RAS•GTP:RanGAP1 complex facilitates nuclear protein export
Authors: Brajendra K Tripathi, Nicole H Hirsh, Xiaolan Qian, Marian E Durkin, Dunrui Wang, Alex G Papageorge, Ross Lake, Yvonne A Evrard, Adam I Marcus, Suresh S Ramalingam, Mary Dasso, Karen H Vousden, James H Doroshow, Kylie J Walters, Douglas R Lowy
Journal: Nature Cancer (2024)

Canonical RAS signaling, including PI3K/AKT- and RAF/MEK-dependent activities, results mainly from RAS•GTP interaction with its effectors at the plasma membrane. Here, we identified a fundamental, oncogenic, noncanonical RAS•GTP activity that increases XPO1-dependent export of nuclear protein cargo into the cytoplasm and is independent of PI3K/AKT and RAF/MEK signaling. This RAS-dependent step acts downstream from XPO1 binding to nuclear protein cargo and is mediated by a perinuclear protein complex between RAS•GTP and RanGAP1 that facilitates hydrolysis of Ran•GTP to Ran•GDP, which promotes release of nuclear protein cargo into the cytoplasm. The export of nuclear EZH2, which promotes cytoplasmic degradation of the DLC1 tumor suppressor protein, is a biologically important component of this pro-oncogenic activity. Conversely, preventing nuclear protein export contributes to the antitumor activity of KRAS inhibition, which can be further augmented by reactivating the tumor suppressor activity of DLC1 or potentially combining RAS inhibitors with other cancer treatments.
TRBC1-CAR T cell therapy in peripheral T cell lymphoma: a phase 1/2 trial
Authors: Kate Cwynarski, Gloria Iacoboni, Eleni Tholouli, Tobias Menne, David A Irvine, Nivetha Balasubramaniam, Leigh Wood, Justin Shang, Eric Xue, Yiyun Zhang, Silvia Basilico, Margarida Neves, Meera Raymond, Ian Scott, Mohamed El-Kholy, Ram Jha, Heather Dainton-Smith, Rehan Hussain, William Day, Mathieu Ferrari, Simon Thomas, Koki Lilova, Wolfram Brugger, Teresa Marafioti, Pierre Lao-Sirieix, Paul Maciocia, Martin Pule
Journal: Nature Medicine (2024)

Relapsed/refractory peripheral T cell lymphomas (PTCLs) are aggressive tumors with a poor prognosis. Unlike B cell lymphomas, treatment of PTCL has not benefited from advances in immunotherapy. This is largely due to a lack of suitable target antigens that discriminate malignant from normal T cells, thus avoiding severe immunosuppression consequent to depletion of the entire T cell compartment. We recently described a targeting strategy based on the mutually exclusive expression of T cell antigen receptor beta-chain constant domain (TRBC) 1 and 2. Selective targeting of the T cell antigen receptor beta-chain expressed by the (clonal) malignancy spares normal T cells expressing the other chain. The LibraT1 study is an ongoing, multicenter, international, single-arm phase 1/2 study of TRBC1-directed autologous chimeric antigen receptor (CAR) T cells (AUTO4) in relapsed/refractory TRBC1-positive PTCL. Primary objectives were assessment of safety and tolerability of AUTO4 infusion. Key secondary endpoints included efficacy, CAR T cell expansion and persistence. Here we describe the findings from dose escalation in LibraT1 in the first ten patients, in a non-prespecified interim analysis. AUTO4 resulted in low frequency of severe immunotoxicity, with one of ten patients developing grade 3 cytokine release syndrome. Complete metabolic response was observed in four of ten evaluable patients, with remissions being durable beyond 1 year in two patients. While an absence of circulating CAR T cells was observed, CAR T cells were readily detected in lymph node biopsy samples from sites of original disease suggesting homing to tumor sites. These results support the continuing exploration of TRBC1 targeting in PTCL. ClinicalTrials.gov registration: NCT03590574 .
Chronic social stress induces p16-mediated senescent cell accumulation in mice
Authors: Carey E Lyons, Jean Pierre Pallais, Seth McGonigle, Rachel P Mansk, Charles W Collinge, Matthew J Yousefzadeh, Darren J Baker, Patricia R Schrank, Jesse W Williams, Laura J Niedernhofer, Jan M van Deursen, Maria Razzoli, Alessandro Bartolomucci
Journal: Nature Aging (2024)
TYK2 regulates tau levels, phosphorylation and aggregation in a tauopathy mouse model
Authors: Jiyoen Kim, Bakhos Tadros, Yan Hong Liang, Youngdoo Kim, Cristian Lasagna-Reeves, Jun Young Sonn, Dah-Eun Chloe Chung, Bradley Hyman, David M Holtzman, Huda Yahya Zoghbi
Journal: Nature Neuroscience (2024)

Alzheimer's disease is one of at least 26 diseases characterized by tau-positive accumulation in neurons, glia or both. However, it is still unclear what modifications cause soluble tau to transform into insoluble aggregates. We previously performed genetic screens that identified tyrosine kinase 2 (TYK2) as a candidate regulator of tau levels. Here we verified this finding and found that TYK2 phosphorylates tau at tyrosine 29 (Tyr29) leading to its stabilization and promoting its aggregation in human cells. We discovered that TYK2-mediated Tyr29 phosphorylation interferes with autophagic clearance of tau. We also show that TYK2-mediated phosphorylation of Tyr29 facilitates pathological tau accumulation in P301S tau-transgenic mice. Furthermore, knockdown of Tyk2 reduced total tau and pathogenic tau levels and rescued gliosis in a tauopathy mouse model. Collectively, these data suggest that partial inhibition of TYK2 could thus be a strategy to reduce tau levels and toxicity.
Toward advances in retinoblastoma genetics in Kenya
Authors: Helen Dimaras, Beatrice Omweri, Daniel Muema, Loice Kanda, Rosaline Wanjiru Macharia, John Gitau, Catherine Mutinda, Kahaki Kimani, Wairimu Waweru, Stephen Gichuhi, Marianne W Mureithi, Lucy Njambi
Journal: Nature Genetics (2024)
Personalized positive end-expiratory pressure in spontaneously breathing patients with acute respiratory distress syndrome by simultaneous electrical impedance tomography and transpulmonary pressure monitoring: a randomized crossover trial
Authors: Tommaso Mauri, Domenico L Grieco, Elena Spinelli, Marco Leali, Joaquin Perez, Valentina Chiavieri, Tommaso Rosà, Pierluigi Ferrara, Gaetano Scaramuzzo, Massimo Antonelli, Savino Spadaro, Giacomo Grasselli
Journal: Intensive Care Medicine (2024)

Personalized positive end-expiratory pressure (PEEP) might foster lung and diaphragm protection in patients with acute respiratory distress syndrome (ARDS) who are undergoing pressure support ventilation (PSV). We aimed to compare the physiologic effects of personalized PEEP set according to synchronized electrical impedance tomography (EIT) and driving transpulmonary pressure (∆PL) monitoring against a classical lower PEEP/FiO
Genetic architecture of cerebrospinal fluid and brain metabolite levels and the genetic colocalization of metabolites with human traits
Authors: Ciyang Wang, Chengran Yang, Daniel Western, Muhammad Ali, Yueyao Wang, Chia-Ling Phuah, John Budde, Lihua Wang, Priyanka Gorijala, Jigyasha Timsina, Agustin Ruiz, Pau Pastor, Maria Victoria Fernandez, Daniel J Panyard, Corinne D Engelman, Yuetiva Deming, Merce Boada, Amanda Cano, Pablo Garcia-Gonzalez, Neill R Graff-Radford, Hiroshi Mori, Jae-Hong Lee, Richard J Perrin, Laura Ibanez, Yun Ju Sung, Carlos Cruchaga
Journal: Nature Genetics (2024)
Proteogenomic analysis of human cerebrospinal fluid identifies neurologically relevant regulation and implicates causal proteins for Alzheimer’s disease
Authors: Daniel Western, Jigyasha Timsina, Lihua Wang, Ciyang Wang, Chengran Yang, Bridget Phillips, Yueyao Wang, Menghan Liu, Muhammad Ali, Aleksandra Beric, Priyanka Gorijala, Pat Kohlfeld, John Budde, Allan I Levey, John C Morris, Richard J Perrin, Agustin Ruiz, Marta Marquié, Mercè Boada, Itziar de Rojas, Jarod Rutledge, Hamilton Oh, Edward N Wilson, Yann Le Guen, Lianne M Reus, Betty Tijms, Pieter Jelle Visser, Sven J van der Lee, Yolande A L Pijnenburg, Charlotte E Teunissen, Marta Del Campo Milan, Ignacio Alvarez, Miquel Aguilar, Michael D Greicius, Pau Pastor, David J Pulford, Laura Ibanez, Tony Wyss-Coray, Yun Ju Sung, Carlos Cruchaga
Journal: Nature Genetics (2024)
Identification of pathological pathways centered on circRNA dysregulation in association with irreversible progression of Alzheimer’s disease
Authors: Feng Wang, Yangping Li, Huifeng Shen, Paula Martinez-Feduchi, Xingyu Ji, Peng Teng, Siddharth Krishnakumar, Jian Hu, Li Chen, Yue Feng, Bing Yao
Journal: Genome Medicine (2024)

Circular RNAs (circRNAs) are highly stable regulators, often accumulated in mammalian brains and thought to serve as "memory molecules" that govern the long process of aging. Mounting evidence demonstrated circRNA dysregulation in the brains of Alzheimer's disease (AD) patients. However, whether and how circRNA dysregulation underlies AD progression remains unexplored. We combined Poly(A)-tailing/RNase R digestion experimental approach with CARP, our published computational framework using pseudo-reference alignment for more sensitive and accurate circRNA detection to identify genome-wide circRNA dysregulation and their downstream pathways in the 5xFAD mouse cerebral cortex between 5 and 7 months of age, a critical window marks the transition from reversible to irreversible pathogenic progression. Dysregulated circRNAs and pathways associated with disease progression in 5xFAD cortex were systematically compared with circRNAs affected in postmortem subcortical areas of a large human AD cohort. A top-ranked circRNA conserved and commonly affected in AD patients and 5xFAD mice was depleted in cultured cells to examine AD-relevant molecular and cellular changes. We discovered genome-wide circRNA alterations specifically in 5xFAD cortex associated with AD progression, many of which are commonly dysregulated in the subcortical areas of AD patients. Among these circRNAs, circGigyf2 is highly conserved and showed the highest net reduction specifically in the 7-month 5xFAD cortex. CircGIGYF2 level in AD patients' cortices negatively correlated with dementia severity. Mechanistically, we found multiple AD-affected splicing factors that are essential for circGigyf2 biogenesis. Functionally, we identified and experimentally validated the conserved roles of circGigyf2 in sponging AD-relevant miRNAs and AD-associated RNA binding proteins (RBPs), including the cleavage and polyadenylation factor 6 (CPSF6). Moreover, circGigyf2 downregulation in AD promoted silencing activities of its sponged miRNAs and enhanced polyadenylation site processing efficiency of CPSF6 targets. Furthermore, circGigyf2 depletion in a mouse neuronal cell line dysregulated circGigyf2-miRNA and circGigyf2-CPSF6 axes and potentiated apoptotic responses upon insults, which strongly support the causative roles of circGigyf2 deficiency in AD neurodegeneration. Together, our results unveiled brain circRNAs associated with irreversible disease progression in an AD mouse model that is also affected in AD patients and identified novel molecular mechanisms underlying the dysregulation of conserved circRNA pathways contributing to AD pathogenesis.
Astrocyte transcriptomic changes along the spatiotemporal progression of Alzheimer’s disease
Authors: Alberto Serrano-Pozo, Huan Li, Zhaozhi Li, Clara Muñoz-Castro, Methasit Jaisa-Aad, Molly A Healey, Lindsay A Welikovitch, Rojashree Jayakumar, Annie G Bryant, Ayush Noori, Theresa R Connors, Miwei Hu, Karen Zhao, Fan Liao, Gen Lin, Timothy Pastika, Joseph Tamm, Aicha Abdourahman, Taekyung Kwon, Rachel E Bennett, Maya E Woodbury, Astrid Wachter, Robert V Talanian, Knut Biber, Eric H Karran, Bradley T Hyman, Sudeshna Das
Journal: Nature Neuroscience (2024)

Astrocytes are crucial to brain homeostasis, yet their changes along the spatiotemporal progression of Alzheimer's disease (AD) neuropathology remain unexplored. Here we performed single-nucleus RNA sequencing of 628,943 astrocytes from five brain regions representing the stereotypical progression of AD pathology across 32 donors spanning the entire normal aging to severe AD continuum. We mapped out several unique astrocyte subclusters that exhibited varying responses to neuropathology across the AD-vulnerable neural network (spatial axis) or AD pathology stage (temporal axis). The proportion of homeostatic, intermediate and reactive astrocytes changed only along the spatial axis, whereas two other subclusters changed along the temporal axis. One of these, a trophic factor-rich subcluster, declined along pathology stages, whereas the other increased in the late stage but returned to baseline levels in the end stage, suggesting an exhausted response with chronic exposure to neuropathology. Our study underscores the complex dynamics of astrocytic responses in AD.
Gene Therapy in Cardiovascular Disease: Recent Advances and Future Directions in Science: A Science Advisory From the American Heart Association
Authors: Yuri Kim, Andrew P. Landstrom, Svati H. Shah, Joseph C. Wu, Christine E. Seidman
Journal: Circulation (2024)

Cardiovascular disease remains the foremost cause of morbidity and mortality globally, affecting millions of individuals. Recent discoveries illuminate the substantial role of genetics in cardiovascular disease pathogenesis, encompassing both monogenic and polygenic mechanisms and identifying tangible targets for gene therapies. Innovative strategies have emerged to rectify pathogenic variants that cause monogenic disorders such as hypertrophic, dilated, and arrhythmogenic cardiomyopathies and hypercholesterolemia. These include delivery of exogenous genes to supplement insufficient protein levels caused by pathogenic variants or genome editing to correct, delete, or modify mutant sequences to restore protein function. However, effective delivery of gene therapy to specified cells presents formidable challenges. Viral vectors, notably adeno-associated viruses and nonviral vectors such as lipid and engineered nanoparticles, offer distinct advantages and limitations. Additional risks and obstacles remain, including treatment durability, tissue-specific targeting, vector-associated adverse events, and off-target effects. Addressing these challenges is an ongoing imperative; several clinical gene therapy trials are underway, and many more first-in-human studies are anticipated. This science advisory reviews core concepts of gene therapy, key obstacles, patient risks, and ongoing research endeavors to enable clinicians to understand the complex landscape of this emerging therapy and its remarkable therapeutic potential to benefit cardiovascular disease.
Adenine base editors induce off-target structure variations in mouse embryos and primary human T cells
Authors: Leilei Wu, Shutan Jiang, Meisong Shi, Tanglong Yuan, Yaqin Li, Pinzheng Huang, Yingqi Li, Erwei Zuo, Changyang Zhou, Yidi Sun
Journal: Genome biology (2024)

The safety of CRISPR-based gene editing methods is of the utmost priority in clinical applications. Previous studies have reported that Cas9 cleavage induced frequent aneuploidy in primary human T cells, but whether cleavage-mediated editing of base editors would generate off-target structure variations remains unknown. Here, we investigate the potential off-target structural variations associated with CRISPR/Cas9, ABE, and CBE editing in mouse embryos and primary human T cells by whole-genome sequencing and single-cell RNA-seq analyses.
Survivin promotes stem cell competence for skin cancer initiation
Authors: Sara Canato, Rahul Sarate, Sofia Carvalho-Marques, Raquel Maia Soares, Yura Song, Sara Monteiro-Ferreira, Pauline Vieugué, Mélanie Liagre, Giancarlo Grossi, Erik Cardoso, Christine Dubois, Edward M. Conway, Silvia Schenone, Adriana Sanchez-Danes, Cedric Blanpain
Journal: Cancer Discovery (2024)

Abstract Stem cells (SC) and not progenitors (P) act as cells of origin of basal cell carcinoma (BCC). The mechanisms promoting BCC formation in SCs or restricting tumor development in Ps are currently unknown. In this study, we transcriptionally profiled SCs and Ps and found that Survivin, a pleiotropic factor that promotes cell division and inhibits apoptosis, was preferentially expressed in SCs. Using genetic gain- and loss-of-function mouse models, we showed that Survivin deletion in oncogene-expressing SCs prevents BCC formation. Survivin overexpression renders Ps competent to BCC formation by promoting cell survival and division while preventing apoptosis and differentiation. We identified Serum glucocorticoid–regulated kinase 1 (Sgk1) as a key downstream factor of Survivin and that its inhibition prevents BCC formation. This study uncovers the role and mechanisms by which Survivin regulates the competence of SCs to initiate BCC formation, promoting the survival of oncogene-expressing SCs and self-renewing division while restricting differentiation and apoptosis. Significance: This study identifies Survivin as a key regulator of the different ability of SCs and Ps to initiate skin cancer. Survivin expression in oncogene-targeted SCs is essential for their survival and self-renewal and to prevent their differentiation and apoptosis, allowing SCs and not Ps to initiate skin cancer.
KleTy: integrated typing scheme for core genome and plasmids reveals repeated emergence of multi-drug resistant epidemic lineages in Klebsiella worldwide
Authors: Heng Li, Xiao Liu, Shengkai Li, Jie Rong, Shichang Xie, Yuan Gao, Ling Zhong, Quangui Jiang, Guilai Jiang, Yi Ren, Wanping Sun, Yuzhi Hong, Zhemin Zhou
Journal: Genome Medicine (2024)

Clinically important lineages in Klebsiella, especially those expressing multi-drug resistance (MDR), pose severe threats to public health worldwide. They arose from the co-evolution of the vertically inherited core genome and horizontal gene transfers by plasmids, which has not been systematically explored.
Feedback regulation of <scp>VISTA</scp> and Treg by <scp>TNF</scp>‐α controls T cell responses in drug allergy
Authors: Lele Sun, Qing Zhao, Suiting Ao, Tingting Liu, Zhenzhen Wang, Jiabao You, Zihao Mi, Yonghu Sun, Xiaotong Xue, Monday O. Ogese, Joshua Gardner, Xiaoli Meng, Dean J. Naisbitt, Hong Liu, Furen Zhang
Journal: Allergy (2024)

Severe cutaneous adverse reactions (SCARs) mediated by cytotoxic T lymphocytes are a series of life-threatening conditions with a mortality of 4%-20%. The clinical application of tumor necrosis factor-alpha (TNF-α) antagonist improves the outcome of some SCARs patients; however, this is complicated by the elusive and varied immunopathogenesis.
Bioactive Mediator Profile of Mepolizumab‐Treated Eosinophilic Granulomatosis With Polyangiitis
Authors: Yosuke Kamide, Kyuto Sonehara, Kiyoshi Sekiya, Shigeharu Ueki, Yuto Nakamura, Yukinori Okada, Masami Taniguchi
Journal: Allergy (2024)

The data that support the findings of this study are available from the corresponding author upon reasonable request. Table S1. Data S1. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.