tbuckley/cabot-search huggingface dataset:
Innovative pathological network‐based multitarget approaches for Alzheimer's disease treatment
Authors: Paloma Mayo, Jorge Pascual, Enrique Crisman, Cristina Domínguez, Manuela G. López, Rafael León
Journal: Medicinal Research Reviews (2024)

Abstract Alzheimer's disease (AD) is the most prevalent neurodegenerative disease and is a major health threat globally. Its prevalence is forecasted to exponentially increase during the next 30 years due to the global aging population. Currently, approved drugs are merely symptomatic, being ineffective in delaying or blocking the relentless disease advance. Intensive AD research describes this disease as a highly complex multifactorial disease. Disclosure of novel pathological pathways and their interconnections has had a major impact on medicinal chemistry drug development for AD over the last two decades. The complex network of pathological events involved in the onset of the disease has prompted the development of multitarget drugs. These chemical entities combine pharmacological activities toward two or more drug targets of interest. These multitarget‐directed ligands are proposed to modify different nodes in the pathological network aiming to delay or even stop disease progression. Here, we review the multitarget drug development strategy for AD during the last decade.
A chimeric adenovirus‐vectored vaccine based on Beta spike and Delta RBD confers a broad‐spectrum neutralization against Omicron‐included SARS‐CoV‐2 variants
Authors: Weiqi Hong, Hong Lei, Dandan Peng, Yuhe Huang, Cai He, Jingyun Yang, Yanan Zhou, Jian Liu, Xiangyu Pan, Haiying Que, Aqu Alu, Li Chen, Jiayuan Ai, Furong Qin, Binhan Wang, Danyi Ao, Zhen Zeng, Ying Hao, Yu Zhang, Xiya Huang, Chunjun Ye, MinYang Fu, Xuemei He, Zhenfei Bi, Xuejiao Han, Min Luo, Hongbo Hu, Wei Cheng, Haohao Dong, Jian Lei, Lu Chen, Xikun Zhou, Wei Wang, Guangwen Lu, Guobo Shen, Li Yang, Jinliang Yang, Jiong Li, Zhenling Wang, Xiangrong Song, Qiangming Sun, Shuaiyao Lu, Youchun Wang, Ping Cheng, Xiawei Wei
Journal: MedComm (2024)

Abstract Urgent research into innovative severe acute respiratory coronavirus‐2 (SARS‐CoV‐2) vaccines that may successfully prevent various emerging emerged variants, particularly the Omicron variant and its subvariants, is necessary. Here, we designed a chimeric adenovirus‐vectored vaccine named Ad5‐Beta/Delta. This vaccine was created by incorporating the receptor‐binding domain from the Delta variant, which has the L452R and T478K mutations, into the complete spike protein of the Beta variant. Both intramuscular (IM) and intranasal (IN) vaccination with Ad5‐Beta/Deta vaccine induced robust broad‐spectrum neutralization against Omicron BA.5‐included variants. IN immunization with Ad5‐Beta/Delta vaccine exhibited superior mucosal immunity, manifested by higher secretory IgA antibodies and more tissue‐resident memory T cells (T RM ) in respiratory tract. The combination of IM and IN delivery of the Ad5‐Beta/Delta vaccine was capable of synergically eliciting stronger systemic and mucosal immune responses. Furthermore, the Ad5‐Beta/Delta vaccination demonstrated more effective boosting implications after two dosages of mRNA or subunit recombinant protein vaccine, indicating its capacity for utilization as a booster shot in the heterologous vaccination. These outcomes quantified Ad5‐Beta/Delta vaccine as a favorable vaccine can provide protective immunity versus SARS‐CoV‐2 pre‐Omicron variants of concern and BA.5‐included Omicron subvariants.
Sea Anemone Membrane Attack Complex/Perforin Superfamily Demonstrates an Evolutionary Transitional State between Venomous and Developmental Functions
Authors: Joachim M Surm, Morani Landau, Yaara Y Columbus-Shenkar, Yehu Moran
Journal: Molecular Biology and Evolution (2024)

Abstract Gene duplication is a major force driving evolutionary innovation. A classic example is generating new animal toxins via duplication of physiological protein-encoding genes and recruitment into venom. While this process drives the innovation of many animal venoms, reverse recruitment of toxins into nonvenomous cells remains unresolved. Using comparative genomics, we find members of the Membrane Attack Complex and Perforin Family (MAC) have been recruited into venom-injecting cells (cnidocytes), in soft and stony corals and sea anemones, suggesting that the ancestral MAC was a cnidocyte expressed toxin. Further investigation into the model sea anemone Nematostella vectensis reveals that three members have undergone Nematostella-specific duplications leading to their reverse recruitment into endomesodermal cells. Furthermore, simultaneous knockdown of all three endomesodermally expressed MACs leads to mis-development, supporting that these paralogs have nonvenomous function. By resolving the evolutionary history and function of MACs in Nematostella, we provide the first proof for reverse recruitment from venom to organismal development.
Long-term consequences on stigmatization and disease burden during adulthood among patients with childhood or adolescence-onset atopic dermatitis
Authors: Bruno Halioua, Charbel Skayem, Stéphanie Merhand, Yaron Ben Hayoun, Charles Taieb
Journal: British Journal of Dermatology (2024)

The World Health Organization is calling on governments to take action to reduce the stigmatization of patients with skin diseases, highlighting the significant psychosocial burden experienced by patients with atopic dermatitis (AD) from childhood onwards. This cross-sectional study reveals that stigma experienced in childhood or adolescence increases the risk of disease burden, stress and stigma in adulthood, underlining the importance of reinforced psychological support. It highlights the need for dermatologists to target these patients, in order to improve their quality of life.
Comparative analysis of maternal gene expression patterns unravels evolutionary signatures across reproductive modes
Authors: Ferenc Kagan, Andreas Hejnol
Journal: Molecular Biology and Evolution (2024)

Maternal genes have a pivotal role in regulating metazoan early development. As such their functions have been extensively studied since the dawn of developmental biology. The temporal and spatial dynamics of their transcripts have been thoroughly described in model organisms and their functions have been undergoing heavy investigations. Yet, less is known about the evolutionary changes shaping their presence within diverse oocytes. Due to their unique maternal inheritance pattern, a high degree is predicted to be present when it comes to their expression. Insofar only limited and conflicting results have emerged around it. Here, we set out to elucidate which evolutionary changes could be detected in the maternal gene expression patterns using phylogenetic comparative methods on RNAseq data from 43 species. Using normalized gene expression values and fold change information throughout early development we set out to find the best-fitting evolutionary model. Through modeling, we find evidence supporting both the high degree of divergence and constraint on gene expression values, together with their temporal dynamics. Furthermore, we find that maternal gene expression alone can be used to explain the reproductive modes of different species. Together, these results suggest a highly dynamic evolutionary landscape of maternal gene expression. We also propose a possible functional dichotomy of maternal genes which is influenced by the reproductive strategy undertaken by examined species.
A GGC-repeat expansion in ZFHX3 encoding polyglycine causes spinocerebellar ataxia type 4 and impairs autophagy
Authors: Karla P. Figueroa, Caspar Gross, Elena Buena-Atienza, Sharan Paul, Mandi Gandelman, Naseebullah Kakar, Marc Sturm, Nicolas Casadei, Jakob Admard, Joohyun Park, Christine Zühlke, Yorck Hellenbroich, Jelena Pozojevic, Saranya Balachandran, Kristian Händler, Simone Zittel, Dagmar Timmann, Friedrich Erdlenbruch, Laura Herrmann, Thomas Feindt, Martin Zenker, Thomas Klopstock, Claudia Dufke, Daniel R. Scoles, Arnulf Koeppen, Malte Spielmann, Olaf Riess, Stephan Ossowski, Tobias B. Haack, Stefan M. Pulst
Journal: Nature Genetics (2024)
Feature-selective responses in macaque visual cortex follow eye movements during natural vision
Authors: Will Xiao, Saloni Sharma, Gabriel Kreiman, Margaret S. Livingstone
Journal: Nature Neuroscience (2024)

Abstract In natural vision, primates actively move their eyes several times per second via saccades. It remains unclear whether, during this active looking, visual neurons exhibit classical retinotopic properties, anticipate gaze shifts or mirror the stable quality of perception, especially in complex natural scenes. Here, we let 13 monkeys freely view thousands of natural images across 4.6 million fixations, recorded 883 h of neuronal responses in six areas spanning primary visual to anterior inferior temporal cortex and analyzed spatial, temporal and featural selectivity in these responses. Face neurons tracked their receptive field contents, indicated by category-selective responses. Self-consistency analysis showed that general feature-selective responses also followed eye movements and remained gaze-dependent over seconds of viewing the same image. Computational models of feature-selective responses located retinotopic receptive fields during free viewing. We found limited evidence for feature-selective predictive remapping and no viewing-history integration. Thus, ventral visual neurons represent the world in a predominantly eye-centered reference frame during natural vision.
Advancing genomics to improve health equity
Authors: Ebony B. Madden, Lucia A. Hindorff, Vence L. Bonham, Tabia Henry Akintobi, Esteban G. Burchard, Kellan E. Baker, Rene L. Begay, John D. Carpten, Nancy J. Cox, Valentina Di Francesco, Denise A. Dillard, Faith E. Fletcher, Stephanie M. Fullerton, Nanibaa’ A. Garrison, Catherine M. Hammack-Aviran, Vanessa Y. Hiratsuka, James E. K. Hildreth, Carol R. Horowitz, Chanita A. Hughes Halbert, Michael Inouye, Amber Jackson, Latrice G. Landry, Rick A. Kittles, Jeff T. Leek, Nita A. Limdi, Nicole C. Lockhart, Elizabeth O. Ofili, Eliseo J. Pérez-Stable, Maya Sabatello, Loren Saulsberry, Lorjetta E. Schools, Jennifer L. Troyer, Benjamin S. Wilfond, Genevieve L. Wojcik, Judy H. Cho, Sandra S.-J. Lee, Eric D. Green
Journal: Nature Genetics (2024)
Long noncoding RNAs underlie multiple domestication traits and leafhopper resistance in soybean
Authors: Weidong Wang, Jingbo Duan, Xutong Wang, Xingxing Feng, Liyang Chen, Chancelor B Clark, Stephen A Swarm, Jinbin Wang, Sen Lin, Randall L Nelson, Blake C Meyers, Xianzhong Feng, Jianxin Ma
Journal: Nature Genetics (2024)
AI-enabled electrocardiography alert intervention and all-cause mortality: a pragmatic randomized clinical trial
Authors: Chin-Sheng Lin, Wei-Ting Liu, Dung-Jang Tsai, Yu-Sheng Lou, Chiao-Hsiang Chang, Chiao-Chin Lee, Wen-Hui Fang, Chih-Chia Wang, Yen-Yuan Chen, Wei-Shiang Lin, Cheng-Chung Cheng, Chia-Cheng Lee, Chih-Hung Wang, Chien-Sung Tsai, Shih-Hua Lin, Chin Lin
Journal: Nature Medicine (2024)
Defining Criteria for Disease Activity States in Systemic Juvenile Idiopathic Arthritis Based on the Systemic Juvenile Arthritis Disease Activity Score
Authors: Silvia Rosina, Ana I. Rebollo‐Giménez, Letizia Tarantola, Angela Pistorio, Yulia Vyzhga, Yasser El Miedany, Hala M. Lotfy, Hend Abu‐Shady, Mervat Eissa, Naglaa S. Osman, Waleed Hassan, Marwa Y. Mahgoub, Nermeen A. Fouad, Doaa M. Mosa, Yasmin Adel, Sheren E. M. Mohamed, Ahmed R. Radwan, Mohamed H. Abu‐Zaid, Samar A. A. Tabra, Radwa H. Shalaby, Samah I. Nasef, Raju Khubchandani, Archana Khan, Naziya P. Maldar, Seza Ozen, Yagmur Bayindir, Motasem Alsuweiti, Raed Alzyoud, Hiba Almaaitah, Soamarat Vilaiyuk, Butsabong Lerkvaleekul, Ekaterina Alexeeva, Tatyana Dvoryakovskaya, Ivan Kriulin, Claudia Bracaglia, Manuela Pardeo, Fabrizio De Benedetti, Francesco Licciardi, Davide Montin, Francesca Robasto, Francesca Minoia, Giovanni Filocamo, Martina Rossano, Gabriele Simonini, Edoardo Marrani, Sarah Abu‐Rumeileh, Mikhail M. Kostik, Konstantin E. Belozerov, Priyankar Pal, Jigna N. Bathia, María M. Katsicas, Giselle Villarreal, Achille Marino, Stefania Costi, Flavio Sztajnbok, Rodrigo M. Silva, Maria C. Maggio, Dalia H. El‐Ghoneimy, Rasha El Owaidy, Adele Civino, Federico Diomeda, Sulaiman M. Al‐Mayouf, Fuad Al‐Sofyani, Zane Dāvidsone, Elisa Patrone, Claudia Saad‐Magalhães, Alessandro Consolaro, Angelo Ravelli
Journal: Arthritis & Rheumatology (2024)

Our objective was to develop and validate cutoff values in the systemic Juvenile Arthritis Disease Activity Score 10 (sJADAS10) that distinguish the states of inactive disease (ID), minimal disease activity (MDA), moderate disease activity (MoDA), and high disease activity (HDA) in children with systemic juvenile idiopathic arthritis, based on subjective disease state assessment by the treating pediatric rheumatologist.
Cold-induced expression of a truncated adenylyl cyclase 3 acts as rheostat to brown fat function
Authors: Sajjad Khani, Hande Topel, Ronja Kardinal, Ana Rita Tavanez, Ajeetha Josephrajan, Bjørk Ditlev Marcher Larsen, Michael James Gaudry, Philipp Leyendecker, Nadia Meincke Egedal, Aylin Seren Güller, Natasa Stanic, Phillip M. M. Ruppert, Isabella Gaziano, Nils Rouven Hansmeier, Elena Schmidt, Paul Klemm, Lara-Marie Vagliano, Rainer Stahl, Fraser Duthie, Jens-Henning Krause, Ana Bici, Christoph Andreas Engelhard, Sabrina Gohlke, Peter Frommolt, Thorsten Gnad, Alvaro Rada-Iglesias, Marta Pradas-Juni, Tim Julius Schulz, Frank Thomas Wunderlich, Alexander Pfeifer, Alexander Bartelt, Martin Jastroch, Dagmar Wachten, Jan-Wilhelm Kornfeld
Journal: Nature Metabolism (2024)

Promoting brown adipose tissue (BAT) activity innovatively targets obesity and metabolic disease. While thermogenic activation of BAT is well understood, the rheostatic regulation of BAT to avoid excessive energy dissipation remains ill-defined. Here, we demonstrate that adenylyl cyclase 3 (AC3) is key for BAT function. We identified a cold-inducible promoter that generates a 5′ truncated AC3 mRNA isoform (Adcy3-at), whose expression is driven by a cold-induced, truncated isoform of PPARGC1A (PPARGC1A-AT). Male mice lacking Adcy3-at display increased energy expenditure and are resistant to obesity and ensuing metabolic imbalances. Mouse and human AC3-AT are retained in the endoplasmic reticulum, unable to translocate to the plasma membrane and lack enzymatic activity. AC3-AT interacts with AC3 and sequesters it in the endoplasmic reticulum, reducing the pool of adenylyl cyclases available for G-protein-mediated cAMP synthesis. Thus, AC3-AT acts as a cold-induced rheostat in BAT, limiting adverse consequences of cAMP activity during chronic BAT activation. Truncated version of adenylyl cyclase 3 acts as a cold-induced rheostat during long-term brown adipose tissue activation.
The role of the human hippocampus in decision-making under uncertainty
Authors: Bahaaeddin Attaallah, Pierre Petitet, Rhea Zambellas, Sofia Toniolo, Maria Raquel Maio, Akke Ganse-Dumrath, Sarosh R. Irani, Sanjay G. Manohar, Masud Husain
Journal: Nature Human Behaviour (2024)

The role of the hippocampus in decision-making is beginning to be more understood. Because of its prospective and inferential functions, we hypothesized that it might be required specifically when decisions involve the evaluation of uncertain values. A group of individuals with autoimmune limbic encephalitis-a condition known to focally affect the hippocampus-were tested on how they evaluate reward against uncertainty compared to reward against another key attribute: physical effort. Across four experiments requiring participants to make trade-offs between reward, uncertainty and effort, patients with acute limbic encephalitis demonstrated blunted sensitivity to reward and effort whenever uncertainty was considered, despite demonstrating intact uncertainty sensitivity. By contrast, the valuation of these two attributes (reward and effort) was intact on uncertainty-free tasks. Reduced sensitivity to changes in reward under uncertainty correlated with the severity of hippocampal damage. Together, these findings provide evidence for a context-sensitive role of the hippocampus in value-based decision-making, apparent specifically under conditions of uncertainty.
Utilization of colorectal cancer screening tests across European countries: a cross-sectional analysis of the European health interview survey 2018–2020
Authors: Idris Ola, Rafael Cardoso, Michael Hoffmeister, Hermann Brenner
Journal: The Lancet Regional Health - Europe (2024)

SummaryBackgroundColorectal cancer (CRC) screening has been shown to reduce CRC incidence and mortality, and most European countries have started to implement CRC screening programs in the past 20 years. Consequently, this study aimed to estimate the utilization of fecal tests and colonoscopy, as well as investigate factors associated with their utilization based on specific screening program characteristics in European countries.MethodsWe analyzed data from the European Health Interview Survey 2018–2020 to determine the utilization of fecal tests [guaiac-based fecal occult blood test (gFOBT) or fecal immunochemical test (FIT)] within the preceding 2 years or colonoscopy within the preceding 10 years among people aged 50–74 years, based on the type of screening offered in each country. Using multivariable logistic regression and sub-group meta-analysis, factors associated with screening use were determined.FindingsThe analyses included data from 129,750 respondents across 29 European countries, with participant counts ranging from 1511 individuals in Iceland to 11,755 individuals in Germany. Unit response rates ranged from 22% to 88%. The use of either test was highest among countries with fully rolled-out programs with fecal tests [from 37.7% (867/2379) in Croatia to 74.9% (2321/3085) in Denmark] and in countries offering colonoscopy as an alternative screening method [from 26.2% (854/3329) in Greece to 75.4% (1192/1760) in Luxembourg]. We observed the lowest utilization of either test in countries with no program or small-scale programs [6.3% (195/3179) in Bulgaria to 34.2% (722/2144) in Latvia]. Across all types of screening offers, younger age, being without a partner, low education, rural residence, and living in large households were associated with lower utilization, as were poor lifestyle scores and prolonged periods without physician consultation.InterpretationOur findings point to large disparities and much room for improvement in CRC screening offers and utilization across Europe.FundingThere was no funding source for this study.
Senescent CAFs mediate immunosuppression and drive breast cancer progression
Authors: Jiayu Ye, John M. Baer, Douglas V. Faget, Vasilios A. Morikis, Qihao Ren, Anupama Melam, Ana Paula Delgado, Xianmin Luo, Satarupa Mullick Bagchi, Jad I. Belle, Edward Campos, Michael Friedman, Deborah J. Veis, Erik S. Knudsen, Agnieszka K. Witkiewicz, Scott Powers, Gregory D. Longmore, David G. DeNardo, Sheila A. Stewart
Journal: Cancer Discovery (2024)

Abstract The tumor microenvironment (TME) profoundly influences tumorigenesis, with gene expression in the breast TME capable of predicting clinical outcomes. The TME is complex and includes distinct cancer-associated fibroblast (CAF) subtypes whose contribution to tumorigenesis remains unclear. Here, we identify a subset of myofibroblast CAFs (myCAF) that are senescent (senCAF) in mouse and human breast tumors. Utilizing the MMTV-PyMT;INK-ATTAC (INK) mouse model, we found that senCAF-secreted extracellular matrix specifically limits natural killer (NK) cell cytotoxicity to promote tumor growth. Genetic or pharmacologic senCAF elimination unleashes NK cell killing, restricting tumor growth. Finally, we show that senCAFs are present in HER2+, ER+, and triple-negative breast cancer and in ductal carcinoma in situ (DCIS) where they predict tumor recurrence. Together, these findings demonstrate that senCAFs are potently tumor promoting and raise the possibility that targeting them by senolytic therapy could restrain breast cancer development. Significance: senCAFs limit NK cell-mediated killing, thereby contributing to breast cancer progression. Thus, targeting senCAFs could be a clinically viable approach to limit tumor progression. See related article by Belle et al., p. 1324.
Transient, Image‐Guided Gel‐Dissection for Percutaneous Thermal Ablation
Authors: Kathy Liu, Mario Russo, Joshua S. Ellis, John Di Capua, Dufan Wu, Sara Smolinski‐Zhao, Sanjeeva Kalva, Ronald S. Arellano, Zubin Irani, Raul Uppot, Stephen W. Linderman, Rajiv Gupta, Joanna Aizenberg, Shriya Srinivasan, Avik Som
Journal: Advanced Healthcare Materials (2024)

Abstract Image‐guided tumor ablative therapies are mainstay cancer treatment options but often require intra‐procedural protective tissue displacement to reduce the risk of collateral damage to neighboring organs. Standard of care strategies, such as hydrodissection (fluidic injection), are limited by rapid diffusion of fluid and poor retention time, risking injury to adjacent organs, increasing cancer recurrence rates from incomplete tumor ablations, and limiting patient qualification. Herein, a “gel‐dissection” technique is developed, leveraging injectable hydrogels for longer‐lasting, shapeable, and transient tissue separation to empower clinicans with improved ablation operation windows and greater control. A rheological model is designed to understand and tune gel‐dissection parameters. In swine models, gel‐dissection achieves 24 times longer‐lasting tissue separation dynamics compared to saline, with 40% less injected volume. Gel‐dissection achieves anti‐dependent dissection between free‐floating organs in the peritoneal cavity and clinically significant thermal protection, with the potential to expand minimally invasive therapeutic techniques, especially across locoregional therapies including radiation, cryoablation, endoscopy, and surgery.
Phase II Safety and Clinical Comparison With Single-Photon Emission Computed Tomography Myocardial Perfusion Imaging for Detection of Coronary Artery Disease
Authors: Daniel S. Berman, Jamshid Maddahi, B.K. Tamarappoo, Johannes Czernin, Raymond Taillefer, James E. Udelson, C. Michael Gibson, Marybeth Devine, Joel Lazewatsky, Gajanan Bhat, Dana Washburn
Journal: Journal of the American College of Cardiology (2012)
Grid Cells in Cognition: Mechanisms and Function
Authors: Ling L. Dong, Ila R. Fiete
Journal: Annual Review of Neuroscience (2024)

The activity patterns of grid cells form distinctively regular triangular lattices over the explored spatial environment and are largely invariant to visual stimuli, animal movement, and environment geometry. These neurons present numerous fascinating challenges to the curious (neuro)scientist: What are the circuit mechanisms responsible for creating spatially periodic activity patterns from the monotonic input-output responses of single neurons? How and why does the brain encode a local, nonperiodic variable-the allocentric position of the animal-with a periodic, nonlocal code? And, are grid cells truly specialized for spatial computations? Otherwise, what is their role in general cognition more broadly? We review efforts in uncovering the mechanisms and functional properties of grid cells, highlighting recent progress in the experimental validation of mechanistic grid cell models, and discuss the coding properties and functional advantages of the grid code as suggested by continuous attractor network models of grid cells.