tbuckley/cabot-search huggingface dataset:
Lipo-Xenopeptide Polyplexes for CRISPR/Cas9 based Gene editing at ultra-low dose
Authors: Janin Germer, Anna-Lina Lessl, Jana Pöhmerer, Melina Grau, Eric Weidinger, Miriam Höhn, Mina Yazdi, Martino Alfredo Cappelluti, Angelo Lombardo, Ulrich Lächelt, Ernst Wagner
Journal: Journal of Controlled Release (2024)

Double pH-responsive xenopeptide carriers containing succinoyl tetraethylene pentamine (Stp) and lipo amino fatty acids (LAFs) were evaluated for CRISPR/Cas9 based genome editing. Different carrier topologies, variation of LAF/Stp ratios and LAF types as Cas9 mRNA/sgRNA polyplexes were screened in three different reporter cell lines using three different genomic targets (Pcsk9, eGFP, mdx exon 23). One U-shaped and three bundle (B2)-shaped lipo-xenopeptides exhibiting remarkable efficiencies were identified. Genome editing potency of top carriers were observed at sub-nanomolar EC
Type 2 cannabinoid receptor expression on microglial cells regulates neuroinflammation during graft-versus-host disease
Authors: Alison Moe, Aditya Rayasam, Garrett Sauber, Ravi K. Shah, Ashley Doherty, Cheng-Yin Yuan, Aniko Szabo, Bob M. Moore, Marco Colonna, Weiguo Cui, Julian Romero, Anthony E. Zamora, Cecilia J. Hillard, William R. Drobyski
Journal: Journal of Clinical Investigation (2024)

Neuroinflammation is a recognized complication of immunotherapeutic approaches such as immune checkpoint inhibitor treatment, chimeric antigen receptor therapy, and graft versus host disease (GVHD) occurring after allogeneic hematopoietic stem cell transplantation. While T cells and inflammatory cytokines play a role in this process, the precise interplay between the adaptive and innate arms of the immune system that propagates inflammation in the central nervous system remains incompletely understood. Using a murine model of GVHD, we demonstrate that type 2 cannabinoid receptor (CB2R) signaling plays a critical role in the pathophysiology of neuroinflammation. In these studies, we identify that CB2R expression on microglial cells induces an activated inflammatory phenotype which potentiates the accumulation of donor-derived proinflammatory T cells, regulates chemokine gene regulatory networks, and promotes neuronal cell death. Pharmacological targeting of this receptor with a brain penetrant CB2R inverse agonist/antagonist selectively reduces neuroinflammation without deleteriously affecting systemic GVHD severity. Thus, these findings delineate a therapeutically targetable neuroinflammatory pathway and has implications for the attenuation of neurotoxicity after GVHD and potentially other T cell-based immunotherapeutic approaches.
High intratumoral 5-hydroxymethylcytosine levels protect against disease relapse in patients with atypical fibroxanthoma and pleomorphic dermal sarcoma
Authors: Thilo Gambichler, Fahimeh Razeghpour, Emilia Sorescu, Markus Stücker, Nessr Abu Rached, Jürgen C Becker, Laura Susok
Journal: British Journal of Dermatology (2024)

Hydroxymethylation plays a significant role in cancer development and progression. We hypothesized that hydroxymethylation markers may have prognostic potential in AFX/PDS (atypical fibroxanthoma/pleomorphic dermal sarcoma) as also observed in other tumours. Moreover, we wanted to find out whether hydroxymethylation markers might aid differentiation between AFX and PDS.
Bioprinting of Stable Bionic Interfaces Using Piezoresistive Hydrogel Organoelectronics
Authors: Antonia Georgopoulou, Miriam Filippi, Lisa Stefani, Felix Drescher, Aiste Balciunaite, Arnaud Scherberich, Robert Katzschmann, Frank Clemens
Journal: Advanced Healthcare Materials (2024)

Abstract Bionic tissues offer an exciting frontier in biomedical research by integrating biological cells with artificial electronics, such as sensors. One critical hurdle is the development of artificial electronics that can mechanically harmonize with biological tissues, ensuring a robust interface for effective strain transfer and local deformation sensing. In this study, a highly tissue‐integrative, soft mechanical sensor fabricated from a composite piezoresistive hydrogel. The composite not only exhibits exceptional mechanical properties, with elongation at the point of fracture reaching up to 680%, but also maintains excellent biocompatibility across multiple cell types. Furthermore, the material exhibits bioadhesive qualities, facilitating stable cell adhesion to its surface. A unique advantage of the formulation is the compatibility with 3D bioprinting, an essential technique for fabricating stable interfaces. A multimaterial sensorized 3D bionic construct is successfully bioprinted, and it is compared to structures produced via hydrogel casting. In contrast to cast constructs, the bioprinted ones display a high (87%) cell viability, preserve differentiation ability, and structural integrity of the sensor–tissue interface throughout the tissue development duration of 10 d. With easy fabrication and effective soft tissue integration, this composite holds significant promise for various biomedical applications, including implantable electronics and organ‐on‐a‐chip technologies.
Small extracellular vesicles of organoid-derived human retinal stem cells remodel Müller cell fate via miRNA: A novel remedy for retinal degeneration
Authors: Shudong Huang, Yuxiao Zeng, Qiang Guo, Ting Zou, Zheng Qin Yin
Journal: Journal of Controlled Release (2024)

Remodeling retinal Müller glial fate, including gliosis inhibition and pro-reprogramming, represents a crucial avenue for treating degenerative retinal diseases. Stem cell transplantation exerts effects on modulating retinal Müller glial fate. However, the optimized stem cell products and the underlying therapeutic mechanisms need to be investigated. In the present study, we found that retinal progenitor cells from human embryonic stem cell-derived retinal organoids (hERO-RPCs) transferred extracellular vesicles (EVs) into Müller cells following subretinal transplantation into RCS rats. Small EVs from hERO-RPCs (hERO-RPC-sEVs) were collected and were found to delay photoreceptor degeneration and protect retinal function in RCS rats. hERO-RPC-sEVs were taken up by Müller cells both in vivo and in vitro, and inhibited gliosis while promoting early dedifferentiation of Müller cells. We further explored the miRNA profiles of hERO-RPC-sEVs, which suggested a functional signature associated with neuroprotection and development, as well as the regulation of stem cell and glial fate. Mechanistically, hERO-RPC-sEVs might regulate the fate of Müller cells by miRNA-mediated nuclear factor I transcription factors B (NFIB) downregulation. Collectively, our findings offer novel mechanistic insights into stem cell therapy and promote the development of EV-centered therapeutic strategies.
Single-cell Atlas of Penile Cancer Reveals TP53 Mutations as a Driver of an Aggressive Phenotype, Irrespective of Human Papillomavirus Status, and Provides Clues for Treatment Personalization
Authors: Laura Elst, Gino Philips, Kaat Vandermaesen, Ayse Bassez, Francesca Lodi, Manon T.A. Vreeburg, Oscar R. Brouwer, Rogier Schepers, Thomas Van Brussel, Sambit K. Mohanty, Anil V. Parwani, Lien Spans, Isabelle Vanden Bempt, Gerd Jacomen, Marcella Baldewijns, Diether Lambrechts, Maarten Albersen
Journal: European Urology (2024)
Ligand‐Selective Targeting of Macrophage Hydrogel Elicits Bone Immune‐Stem Cell Endogenous Self‐Healing Program to Promote Bone Regeneration (Adv. Healthcare Mater. 11/2024)
Authors: Jiahao Wang, Liang Zhang, Lingjun Wang, Jincheng Tang, Wei Wang, Yichang Xu, Ziang Li, Zhouye Ding, Xinzhao Jiang, Kun Xi, Liang Chen, Yong Gu
Journal: Advanced Healthcare Materials (2024)
Characterization of NMCR-3, NMCR-4 and NMCR-5, three novel non-mobile colistin resistance determinants: Implications for MCR-3, MCR-7, and MCR-5 progenitors, respectively
Authors: Yating Guo, Geng Zou, Anusak Kerdsin, Constance Schultsz, Can Hu, Weicheng Bei, Huanchun Chen, Jinquan Li, Yang Zhou
Journal: Drug Resistance Updates (2024)
Impact of Viscosity on Human Hepatoma Spheroids in Soft Core–Shell Microcapsules (Adv. Healthcare Mater. 11/2024)
Authors: Xuan Peng, Željko Janićijević, Sandy Lemm, Sandra Hauser, Michael Knobel, Jens Pietzsch, Michael Bachmann, Larysa Baraban
Journal: Advanced Healthcare Materials (2024)
Ancestry, ethnicity, and race: explaining inequalities in cardiometabolic disease
Authors: Sophie V. Eastwood, Gibran Hemani, Sarah H. Watkins, Aylwyn Scally, George Davey Smith, Nishi Chaturvedi
Journal: Trends in Molecular Medicine (2024)

Population differences in cardiometabolic disease remain unexplained. Misleading assumptions over genetic explanations are partly due to terminology used to distinguish populations, specifically ancestry, race, and ethnicity. These terms differentially implicate environmental and biological causal pathways, which should inform their use. Genetic variation alone accounts for a limited fraction of population differences in cardiometabolic disease. Research effort should focus on societally driven, lifelong environmental determinants of population differences in disease. Rather than pursuing population stratifiers to personalize medicine, we advocate removing socioeconomic barriers to receipt of and adherence to healthcare interventions, which will have markedly greater impact on improving cardiometabolic outcomes. This requires multidisciplinary collaboration and public and policymaker engagement to address inequalities driven by society rather than biology per se.
CD80 on skin stem cells promotes local expansion of regulatory T cells upon injury to orchestrate repair within an inflammatory environment
Authors: Jingyun Luan, Cynthia Truong, Aleksandra Vuchkovska, Weijie Guo, Jennifer Good, Bijun Liu, Audrey Gang, Nicole Infarinato, Katherine Stewart, Lisa Polak, Hilda Amalia Pasolli, Emma Andretta, Alexander Y. Rudensky, Elaine Fuchs, Yuxuan Miao
Journal: Immunity (2024)

Following tissue damage, epithelial stem cells (SCs) are mobilized to enter the wound, where they confront harsh inflammatory environments that can impede their ability to repair the injury. Here, we investigated the mechanisms that protect skin SCs within this inflammatory environment. Characterization of gene expression profiles of hair follicle SCs (HFSCs) that migrated into the wound site revealed activation of an immune-modulatory program, including expression of CD80, major histocompatibility complex class II (MHCII), and CXC motif chemokine ligand 5 (CXCL5). Deletion of CD80 in HFSCs impaired re-epithelialization, reduced accumulation of peripherally generated Treg (pTreg) cells, and increased infiltration of neutrophils in wounded skin. Importantly, similar wound healing defects were also observed in mice lacking pTreg cells. Our findings suggest that upon skin injury, HFSCs establish a temporary protective network by promoting local expansion of Treg cells, thereby enabling re-epithelialization while still kindling inflammation outside this niche until the barrier is restored.
Exogenous non-coding dsDNA-dependent trans-activation of phagocytes augments anti-tumor immunity
Authors: Tiphaine Delaunay, Sehee Son, Seongji Park, Balveen Kaur, Jeonghyun Ahn, Glen N. Barber
Journal: Cell Reports Medicine (2024)

Stimulator of interferon genes (STING)-dependent signaling is requisite for effective anti-microbial and anti-tumor activity. STING signaling is commonly defective in cancer cells, which enables tumor cells to evade the immunosurveillance system. We evaluate here whether intrinsic STING signaling in such tumor cells could be reconstituted by creating recombinant herpes simplex viruses (rHSVs) that express components of the STING signaling pathway. We observe that rHSVs expressing STING and/or cGAS replicate inefficiently yet retain in vivo anti-tumor activity, independent of oncolytic activityrequisite on the trans-activation of extrinsic STING signaling in phagocytes by engulfed microbial dsDNA species. Accordingly, the in vivo effects of virotherapy could be simulated by nanoparticles incorporating non-coding dsDNA species, which comparably elicit the trans-activation of phagocytes and augment the efficacy of established cancer treatments including checkpoint inhibition and radiation therapy. Our results help elucidate mechanisms of virotherapeutic anti-tumor activity as well as provide alternate strategies to treat cancer.
The Thermodynamics of Mind
Authors: Morten L. Kringelbach, Yonatan Sanz Perl, Gustavo Deco
Journal: Trends in Cognitive Sciences (2024)

To not only survive, but also thrive, the brain must efficiently orchestrate distributed computation across space and time. This requires hierarchical organisation facilitating fast information transfer and processing at the lowest possible metabolic cost. Quantifying brain hierarchy is difficult but can be estimated from the asymmetry of information flow. Thermodynamics has successfully characterised hierarchy in many other complex systems. Here, we propose the 'Thermodynamics of Mind' framework as a natural way to quantify hierarchical brain orchestration and its underlying mechanisms. This has already provided novel insights into the orchestration of hierarchy in brain states including movie watching, where the hierarchy of the brain is flatter than during rest. Overall, this framework holds great promise for revealing the orchestration of cognition.
Trends in cause-specific mortality among people with type 2 and type 1 diabetes from 2002 to 2019: a Danish population-based study
Authors: Tinne Laurberg, Susanne B. Graversen, Annelli Sandbæk, Sarah H. Wild, Rimke C. Vos, Henrik Støvring
Journal: The Lancet Regional Health - Europe (2024)

BackgroundDespite advances in primary and secondary prevention of cardiovascular disease, excess mortality persists within the diabetes population. This study explores the components of this excess mortality and their interaction with sex.MethodsUsing Danish registries (2002–2019), we identified residents aged 18–99 years, their diabetes status, and recorded causes of death. Applying Lexis-based methods, we computed age-standardized mortality rates (asMRs), mortality relative risks (asMRRs), and log-linear trends for cause-specific mortality.FindingsFrom 2002 to 2019, 958,278 individuals died in Denmark (T2D: 148,620; T1D: 7830) during 84.4 M person-years. During the study period, overall asMRs declined, driven by reducing cardiovascular mortality, notably in men with T2D. Conversely, cancer mortality remained high, making cancer the leading cause of death in individuals with T2D. Individuals with T2D faced an elevated mortality risk from nearly all cancer types, ranging from 9% to 257% compared to their non-diabetic counterparts. Notably, obesity-related cancers exhibited the highest relative risks: liver cancer (Men: asMRR 3.58 (3.28; 3.91); Women: asMRR 2.49 (2.14; 2.89)), pancreatic cancer (Men: asMRR 3.50 (3.25; 3.77); Women: asMRR 3.57 (3.31; 3.85)), and kidney cancer (Men: asMRR 2.10 (1.84; 2.40); Women: asMRR 2.31 (1.92; 2.79)). In men with type 2 diabetes, excess mortality remained stable, except for dementia. In women, diabetes-related excess mortality increased by 6–17% per decade across all causes of death, except cardiovascular disease.InterpretationIn the last decade, cancer has emerged as the leading cause of death among individuals with T2D in Denmark, emphasizing the need for diabetes management strategies incorporating cancer prevention. A sex-specific approach is crucial to address persistently higher relative mortality in women with diabetes.FundingSupported by Steno Diabetes Center Aarhus, which is partially funded by an unrestricted donation from the Novo Nordisk Foundation, and by The Danish Diabetes Academy.
Genetic predisposition and antipsychotic treatment effect on metabolic syndrome in schizophrenia: a ten-year follow-up study using the Estonian Biobank
Authors: Maris Alver, Silva Kasela, Liina Haring, Laura Birgit Luitva, Krista Fischer, Märt Möls, Lili Milani
Journal: The Lancet Regional Health - Europe (2024)

BackgroundSchizophrenia (SCZ) patients exhibit 30% higher prevalence of metabolic syndrome (MetS) compared to the general population with its suboptimal management contributing to increased mortality. Large-scale studies providing real-world evidence of the underlying causes remain limited.MethodsTo address this gap, we used real-world health data from the Estonian Biobank, spanning a median follow-up of ten years, to investigate the impact of genetic predisposition and antipsychotic treatment on the development of MetS in SCZ patients. Specifically, we set out to characterize antipsychotic treatment patterns, genetic predisposition of MetS traits, MetS prognosis, and body mass index (BMI) trajectories, comparing SCZ cases (n = 677) to age- and sex-matched controls (n = 2708).FindingsSCZ cases exhibited higher genetic predisposition to SCZ (OR = 1.75, 95% CI 1.58–1.94), but lower polygenic burden for increased BMI (OR = 0.88, 95% CI 0.88–0.96) and C-reactive protein (OR = 0.88, 95% CI 0.81–0.97) compared to controls. While SCZ cases showed worse prognosis of MetS (HR 1.95, 95% CI 1.54–2.46), higher antipsychotic adherence within the first treatment year was associated with reduced long-term MetS incidence. Linear mixed modelling, incorporating multiple BMI timepoints, underscored the significant contribution of both, antipsychotic medication, and genetic predisposition to higher BMI, driving the substantially upward trajectory of BMI in SCZ cases.InterpretationThese findings contribute to refining clinical risk prediction and prevention strategies for MetS among SCZ patients and emphasize the significance of incorporating genetic information, long-term patient tracking, and employing diverse perspectives when analyzing real-world health data.FundingEU Horizon 2020, Swedish Research Council, Estonian Research Council, Estonian Ministry of Education and Research, University of Tartu.
Development and validation of a preoperative radiomics-based nomogram to identify patients who can benefit from splenic hilar lymphadenectomy: a pooled analysis of three prospective trials
Authors: Bin-bin Xu, Hua-Long Zheng, Chun-sen Chen, Liang-liang Xu, Zhen Xue, Ling-hua Wei, Hong-hong Zheng, Li-li Shen, Chao-Hui Zheng, Ping Li, Jian-Wei Xie, Jian-xian Lin, Yu-hui Zheng, Chang-Ming Huang
Journal: International Journal of Surgery (2024)
Clustering of predicted loss-of-function variants in genes linked with monogenic disease can explain incomplete penetrance
Authors: Robin N Beaumont, Gareth Hawkes, Adam C Gunning, Caroline F Wright
Journal: Genome Medicine (2024)

Abstract Background Genetic variants that severely alter protein products (e.g. nonsense, frameshift) are often associated with disease. For some genes, these predicted loss-of-function variants (pLoFs) are observed throughout the gene, whilst in others, they occur only at specific locations. We hypothesised that, for genes linked with monogenic diseases that display incomplete penetrance, pLoF variants present in apparently unaffected individuals may be limited to regions where pLoFs are tolerated. To test this, we investigated whether pLoF location could explain instances of incomplete penetrance of variants expected to be pathogenic for Mendelian conditions. Methods We used exome sequence data in 454,773 individuals in the UK Biobank (UKB) to investigate the locations of pLoFs in a population cohort. We counted numbers of unique pLoF, missense, and synonymous variants in UKB in each quintile of the coding sequence (CDS) of all protein-coding genes and clustered the variants using Gaussian mixture models. We limited the analyses to genes with ≥ 5 variants of each type (16,473 genes). We compared the locations of pLoFs in UKB with all theoretically possible pLoFs in a transcript, and pathogenic pLoFs from ClinVar, and performed simulations to estimate the false-positive rate of non-uniformly distributed variants. Results For most genes, all variant classes fell into clusters representing broadly uniform variant distributions, but genes in which haploinsufficiency causes developmental disorders were less likely to have uniform pLoF distribution than other genes ( P &lt; 2.2 × 10 −6 ). We identified a number of genes, including ARID1B and GATA6 , where pLoF variants in the first quarter of the CDS were rescued by the presence of an alternative translation start site and should not be reported as pathogenic. For other genes, such as ODC1 , pLoFs were located approximately uniformly across the gene, but pathogenic pLoFs were clustered only at the end, consistent with a gain-of-function disease mechanism. Conclusions Our results suggest the potential benefits of localised constraint metrics and that the location of pLoF variants should be considered when interpreting variants.
Transcription factor Tox2 is required for metabolic adaptation and tissue residency of ILC3 in the gut
Authors: Arundhoti Das, Gustavo Ulises Martinez-Ruiz, Nicolas Bouladoux, Apollo Stacy, Josquin Moraly, Maria Vega-Sendino, Yongge Zhao, Marieke Lavaert, Yi Ding, Abigail Morales-Sanchez, Christelle Harly, Mina O Seedhom, Raj Chari, Parirokh Awasthi, Tomoko Ikeuchi, Yueqiang Wang, Jinfang Zhu, Niki M Moutsopoulos, WanJun Chen, Jonathan W Yewdell, Virginia Smith Shapiro, Sergio Ruiz, Naomi Taylor, Yasmine Belkaid, Avinash Bhandoola
Journal: Immunity (2024)
Reply to Peter Ka-Fung Chiu, Xiaobo Wu, Giorgio Gandaglia, European Association of Urology Young Academic Urologists Prostate Cancer Working Party. Beyond Statistical Significance: Unveiling the Advantages of Transperineal Versus Transrectal Prostate Biopsies. Eur Urol. In press
Authors: Jim C Hu, Andrew J Vickers, Edward M Schaeffer
Journal: European Urology (2024)
Impact of one night of sleep restriction on sleepiness and cognitive function: A systematic review and meta-analysis
Authors: Larissa N Wüst, Noëmi C Capdevila, Lina T Lane, Carolin F Reichert, Ruta Lasauskaite
Journal: Sleep Medicine Reviews (2024)

Detrimental consequences of chronic sleep restriction on cognitive function are well established in the literature. However, effects of a single night of sleep restriction remain equivocal. Therefore, we synthesized data from 44 studies to investigate effects of sleep restriction to 2-6 h sleep opportunity on sleepiness and cognition in this meta-analysis. We investigated subjective sleepiness, sustained attention, choice reaction time, cognitive throughput, working memory, and inhibitory control. Results revealed a significant increase in subjective sleepiness following one night of sleep restriction (Standardized Mean Difference (SMD) = 0.986, p < 0.001), while subjective sleepiness was not associated with sleep duration during sleep restriction (β = -0.214, p = 0.039, significance level 0.01). Sustained attention, assessed via common 10-min tasks, was impaired, as demonstrated through increased reaction times (SMD = 0.512, p < 0.001) and attentional lapses (SMD = 0.489, p < 0.001). However, the degree of impaired attention was not associated with sleep duration (ps > 0.090). We did not find significant effects on choice reaction time, cognitive throughput, working memory, or inhibitory control. Overall, results suggest that a single night of restricted sleep can increase subjective sleepiness and impair sustained attention, a cognitive function crucial for everyday tasks such as driving.
Development of a Phthalate Environmental Reproductive Health Literacy (PERHL) Scale
Authors: Kathryn S. Tomsho, Marlee R. Quinn, Gary Adamkiewicz, Tamarra James-Todd
Journal: Environmental Health Perspectives (2024)

Substantial evidence exists linking phthalate exposure to adverse reproductive health outcomes. Current US federal regulations of consumer product chemicals place the onus on individuals to mitigate their exposure to phthalates, with assumptions of sufficient environmental health literacy (EHL). Few validated scales for people of reproductive age exist to evaluate phthalate-specific EHL.