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Metabolic constraint of human telomere length by nucleotide salvage efficiency

NATURE COMMUNICATIONS 2025年第1期16卷 1-14页

作者： Mannherz, William Crompton, Andrew Lampl, Noah Agarwal, Suneet Boston Childrens Hosp Oncol & Stem Cell Program Div Hematol Boston MA 02115 USA Dana Farber Canc Inst Pediat Oncol Boston MA 02215 USA Harvard Med Sch Harvard Stem Cell Inst Dept Pediat Harvard Initiat RNA Med Boston MA 02215 USA Harvard Med Sch Biol & Biomed Sci PhD Program Biol & Biomed Sci PhD Program Boston MA 02215 USA Harvard Med Sch Harvard MIT MD PhD Program Boston MA 02215 USA

Human telomere length is tightly regulated and associated with diseases at either extreme, but how these bounds are established remains incompletely understood. Here, we developed a rapid cell-based telomere synthesis assay and found that nucleoside salvage bidirectionally constrains human telomere length. Metabolism of deoxyguanosine (dG) or guanosine via purine nucleoside phosphorylase (PNP) and hypoxanthine-guanine phosphoribosyltransferase to form guanine ribonucleotides strongly inhibited telomerase and shortened telomeres. Conversely, salvage of dG to its nucleotide forms via deoxycytidine kinase drove potent telomerase activation, the extent of which was controlled by the dNTPase SAMHD1. Circumventing limits on salvage by expressing Drosophila melanogaster deoxynucleoside kinase or augmenting dG metabolism using the PNP inhibitor ulodesine robustly lengthened telomeres in human cells, including those from patients with lethal telomere diseases. Our results provide an updated paradigm for telomere length control, wherein telomerase reverse transcriptase activity is actively and bidirectionally constrained by the availability of its dNTP substrates, in a manner that may be therapeutically actionable.

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Accounting for future populations in health research

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BIOETHICS 2024年第5期38卷 401-409页

作者： Pierson, Leah Harvard Med Sch Harvard MIT MD PhD Program Boston MA 02115 USA Harvard TH Chan Sch Publ Hlth Dept Global Hlth & Populat Boston MA USA

The research we fund today will improve the health of people who will live tomorrow. But future people will not all benefit equally: decisions we make about what research to prioritize will predictably affect when and how much different people benefit from research. Organizations that fund health research should thus fairly account for the health needs of future populations when setting priorities. To this end, some research funders aim to allocate research resources in accordance with disease burden, prioritizing illnesses that cause more morbidity and mortality. In this article, I defend research funders' practice of aligning research funding with disease burden but argue that funders should aim to align research funding with future-rather than present-disease burden. I suggest that research funders should allocate research funding in proportion to aggregated estimates of disease burden over the period when research could plausibly start to yield benefits until indefinitely into the future.

关键词： disease burden health policy longtermism priority setting resource allocation

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ATR blocks telomerase from converting DNA breaks into telomeres

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SCIENCE 2024年第6684期383卷 763-770页

作者： Kinzig, Charles G. Zakusilo, George Takai, Kaori K. Myler, Logan R. de Lange, Titia Rockefeller Univ Lab Cell Biol & Genet New York NY 10065 USA Weill Cornell Rockefeller Sloan Kettering Triinst MD PhD Program New York NY 10065 USA

Telomerase, the enzyme that maintains telomeres at natural chromosome ends, should be repressed at double-strand breaks (DSBs), where neotelomere formation can cause terminal truncations. We developed an assay to detect neotelomere formation at Cas9- or I-SceI-induced DSBs in human cells. Telomerase added telomeric repeats to DSBs, leading to interstitial telomeric repeat insertions or the formation of functional neotelomeres accompanied by terminal deletions. The threat that telomerase poses to genome integrity was minimized by ataxia telangiectasia and Rad3-related (ATR) kinase signaling, which inhibited telomerase at resected DSBs. In addition to acting at resected DSBs, telomerase used the extruded strand in the Cas9 enzyme-product complex as a primer for neotelomere formation. We propose that although neotelomere formation is detrimental in normal human cells, it may allow cancer cells to escape from breakage-fusion-bridge cycles.

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The elevated stroke and death rates among asymptomatic patients undergoing carotid stenting in the Pacific Northwest are associated with high-risk patient selection

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JOURNAL OF VASCULAR SURGERY 2025年第4期81卷 929-937.e12页

作者： Ghosh, Rahul Elizaga, Norma Murphy, Blake Cornett, Carrie Tran, Nam Zettervall, Sara L. Dansey, Kirsten D. Univ Washington Div Vasc Surg 1959 NE Pacific StBox 358811 Seattle WA 98195 USA Texas A&M Coll Med MD PhD Program College Stn TX USA

Objective: Current guidelines recommend treatment of patients with asymptomatic carotid stenosis when stroke/death rates less than 3% can be achieved. However, in the Pacific Northwest region of the Vascular Quality Initiative, elevated stroke/death rates have been reported. This study aims to characterize regional and center-specific outcomes for transcarotid artery revascularization (TCAR) and transfemoral carotid artery stenting (TF-CAS) and investigate potential underlying drivers. Methods: A retrospective review of asymptomatic patients undergoing TCAR and TF-CAS in the Vascular Quality Initiative for the Pacific Northwest region from 2016 to 2022 was performed. The primary outcome was the composite of stroke or death within 30 days of index hospitalization. Overall regional outcomes and center-specific outcomes were assessed. A high stroke/death rate was defined as greater than 3%. Demographics, comorbidities, and operative risk factors were then compared between centers with high and low stroke/death rates. Results: A total of 1154 asymptomatic patients across 27 centers underwent carotid stenting in the Pacific Northwest from 2016 to 2022, of which 886(76.8%) underwent TCAR and 268(23.2%) underwent TF-CAS. The overall stroke/death rates were 2.5% and 3.0% for TCAR and TF-CAS, respectively. Among centers with stroke/death rates above 3%, for both TCAR and TF-CAS, all were in the top one-half of centers by volume. When patients undergoing TCAR were assessed, those treated at centers with high stroke/ death rate underwent revascularization at higher volume centers (12 vs 7 cases per year;P = .03), which treated fewer patients with >80% stenosis (42.1% vs 52.2%;P < .01) and more patients with high-risk anatomy (42.3% vs 35.3%;P = .01), and high-risk physiology as defined by an American Society of Anesthesiologists (ASA) class of 4 or 5 (25.5% vs 17.5%;P < .01). Among patients undergoing TF-CAS, those treated at centers with a high stroke/death rate were more lik

关键词： Asymptomatic Carotid artery stenting Patient selection Perioperative outcomes Transcarotid artery revascularization Transfemoral carotid artery stenting

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Telehealth virtual reality intervention reduces chronic pain in a randomized crossover study

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NPJ DIGITAL MEDICINE 2025年第1期8卷 1-8页

作者： Colloca, Luana Han, Anna Massalee, Rachel Raghuraman, Nandini Cundiff-O'Sullivan, Rachel L. Colloca, Giancarlo Wang, Yang Univ Maryland Sch Nursing Dept Pain & Translat Symptom Sci Baltimore MD 21201 USA Univ Maryland Ctr Adv Chron Pain Res Baltimore MD 21201 USA Univ Maryland Sch Med Dept Anesthesiol & Psychiat Baltimore MD 21201 USA Univ Maryland Sch Nursing Placebo Opin Ctr Baltimore MD 21201 USA Towson Univ Dept Comp & Informat Sci Informat Technol PhD Program Towson MD USA

The efficacy of telehealth Virtual Reality (VR) for chronic pain, a promising digital intervention, remains underexplored due to methodological challenges. In a 5-week crossover trial, we compared VR to matched audio content control in individuals with chronic pain. VR significantly reduced pain intensity, anxiety, and pain interference while improving mood and sleep quality. Findings highlight the potential of telehealth-based VR for addressing real-world challenges in managing chronic pain. ISRCTN12473220 (07/18/2023).

关键词： eHealth

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DNA methylation and the opposing NmdAR dysfunction in schizophrenia and major depression disorders: a converging model for the therapeutic effects of psychedelic compounds in the treatment of psychiatric illness

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MOLECULAR PSYCHIATRY 2023年第11期28卷 4553-4567页

作者： Flynn, L. Taylor Gao, Wen-Jun Drexel Univ Coll Med Dept Neurobiol & Anat Philadelphia PA 19104 USA Drexel Univ Coll Med MD PhD Program Philadelphia PA 19104 USA

Psychedelic compounds are being increasingly explored as a potential therapeutic option for treating several psychiatric conditions, despite relatively little being known about their mechanism of action. One such possible mechanism, DNA methylation, is a process of epigenetic regulation that changes gene expression via chemical modification of nitrogenous bases. DNA methylation has been implicated in the pathophysiology of several psychiatric conditions, including schizophrenia (SZ) and major depressive disorder (mdD). In this review, we propose alterations to DNA methylation as a converging model for the therapeutic effects of psychedelic compounds, highlighting the N-methyl D-aspartate receptor (NmdAR), a crucial mediator of synaptic plasticity with known dysfunction in both diseases, as an example and anchoring point. We review the established evidence relating aberrant DNA methylation to NmdAR dysfunction in SZ and mdD and provide a model asserting that psychedelic substances may act through an epigenetic mechanism to provide therapeutic effects in the context of these disorders.

关键词： Neuroscience Schizophrenia

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PulsePoint dispatch associated patient characteristics and prehospital outcomes in a mid-sized metropolitan area

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RESUSCITATION 2022年第0期170卷 36-43页

作者： Smida, Tanner Salerno, Jessica Weiss, Leonard Martin-Gill, Christian Salcido, David D. Univ Pittsburgh Sch Med Pittsburgh PA USA West Virginia Univ MD PhD Program Morgantown WV 26506 USA

Background: Mobile phone-based dispatch of volunteers to out-of-hospital cardiac arrests (OHCA) has been shown to increase the likelihood of early CPR and AED application. In the United States, limited characterization of patients encountered as a result of such systems exists. Aims: Examine prehospital case characteristics and outcomes from a multi-year deployment of PulsePoint Respond in Pittsburgh, Pennsylvania. Methods: PulsePoint event timing, location, and associated prehospital electronic health records (ePCRs) were obtained for EMS-encountered OHCA cases that did and did not generate PulsePoint alerts within the service area of Pittsburgh EMS from July 2016 to October 2020. ePCRs were reviewed and OHCA case characteristics were extracted according to the Utstein template. PulsePoint-associated OHCA and nonPulsePoint-associated OHCA were compared. Results: Of 840 total PulsePoint dispatches, 64 (7.6%) were for OHCA associated with a resuscitation attempt. Forty-one (64.1%) were witnessed, 38 (59.4%) received bystander CPR, and 13 (20.0%) of these patients had an AED applied prior to EMS arrival. Twenty-seven (39.7%) had an initial shockable rhythm, and 31 (48.4%) patients achieved ROSC in the field. In the city of Pittsburgh, there were 1229 total OHCA during the study period, with an estimated 29.6% occurring in public. When PulsePoint-associated and publicly occurring non-PulsePoint-associated OHCA were compared, baseline characteristics (age, sex, witnessed status) were similar, but PulsePoint-associated OHCA received more bystander CPR (p = 0.008). Conclusions: A minority of PulsePoint dispatches in Pittsburgh were triggered by true OHCA. The majority of OHCA during the study period occurred within private residences where PulsePoint responders are not currently dispatched. PulsePoint dispatches were associated with prognostically favorable OHCA characteristics and increased bystander CPR performance.

关键词： PulsePoint PulsePoint Respond CPR Bystander CPR Bystander defibrillation AED Automated external defibrillator Public access AED Out-of-hospital cardiac arrest Cardiac arrest OHCA Bystander CPR recruitment Bystander Crowdsourcing Crowdsourcing CPR BLS Bystander intervention Smartphone Smartphone app Smartphone application

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Delay discounting and nucleus accumbens functional connectivity are related to weight status in adolescents from the ABCD study

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PEDIATRIC OBESITY 2025年第4期20卷 e13173页

作者： Overholtzer, L. Nate Ahmadi, Hedyeh Bottenhorn, Katherine Hsu, Eustace Herting, Megan M. Univ Southern Calif Dept Populat & Publ Hlth Sci Los Angeles CA 90007 USA Univ Southern Calif Neurosci Grad Program Los Angeles CA USA USC Caltech MD PhD Program Los Angeles CA USA Univ Southern Calif Dept Psychol Los Angeles CA USA

Background: Despite the growing epidemic of paediatric obesity, questions remain regarding potential neural mechanisms for individual risk. Delay discounting is a cognitive process of comparison of valuation between immediate and delayed reward, which has been inconsistently linked to weight status. Moreover, central to the brain's reward system is the nucleus accumbens, a region structurally and functionally altered in obesity. Objectives/Methods: This study aimed to examine the relationships between two continuous metrics of weight status, performance on a monetary delay-discounting task and nucleus accumbens functional connectivity in 10-12-year-olds from the Adolescent Brain and Cognitive Development (ABCD) Study. Results: Using multilevel longitudinal linear modelling, we found greater discounting was associated with higher BMI Z-scores (BMIz) and waist-to-height ratio Z-scores (WHtRz) (N = 3819). Moreover, we observed functional connectivity of the nucleus accumbens to the cingulo-opercular, dorsal attention, fronto-parietal, salience and ventral attention networks were predictive of BMIz (N = 1817). Nucleus accumbens functional connectivity was not found to mediate the association between delay- discounting behaviour and BMIz. Conclusions: Delay discounting and nucleus accumbens functional connectivity are independently related to weight status in a large sample of early adolescents. A better understanding of the relationship between reward and overeating behaviours may better inform obesity interventions.

关键词： childhood obesity nucleus accumbens resting state reward sensitivity

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Large-scale genomic survey with deep learning-based method reveals strain-level phage specificity determinants

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GIGASCIENCE 2024年第13期13卷 giae017页

作者： Yang, Yiyan Dufault-Thompson, Keith Yan, Wei Cai, Tian Xie, Lei Jiang, Xiaofang NIH Natl Lib Med Bethesda MD 20894 USA CUNY Grad Ctr PhD Program Biochem New York NY 10016 USA CUNY Hunter Coll Dept Comp Sci New York NY 10065 USA

Background Phage therapy, reemerging as a promising approach to counter antimicrobial-resistant infections, relies on a comprehensive understanding of the specificity of individual phages. Yet the significant diversity within phage populations presents a considerable challenge. Currently, there is a notable lack of tools designed for large-scale characterization of phage receptor-binding proteins, which are crucial in determining the phage host *** In this study, we present SpikeHunter, a deep learning method based on the ESM-2 protein language model. With SpikeHunter, we identified 231,965 diverse phage-encoded tailspike proteins, a crucial determinant of phage specificity that targets bacterial polysaccharide receptors, across 787,566 bacterial genomes from 5 virulent, antibiotic-resistant pathogens. Notably, 86.60% (143,200) of these proteins exhibited strong associations with specific bacterial polysaccharides. We discovered that phages with identical tailspike proteins can infect different bacterial species with similar polysaccharide receptors, underscoring the pivotal role of tailspike proteins in determining host range. The specificity is mainly attributed to the protein's C-terminal domain, which strictly correlates with host specificity during domain swapping in tailspike proteins. Importantly, our dataset-driven predictions of phage-host specificity closely match the phage-host pairs observed in real-world phage therapy cases we *** Our research provides a rich resource, including both the method and a database derived from a large-scale genomics survey. This substantially enhances understanding of phage specificity determinants at the strain level and offers a valuable framework for guiding phage selection in therapeutic applications.

关键词： phage-host specificity phage receptor-binding protein bacterial polysaccharide serotype phage therapy

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Postoperative Pathway Allows Elective Craniotomy Patients to Bypass Intensive Care Unit Safely: Commentary on Recent Article in Journal of Neurosurgery

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WORLD NEUROSURGERY 2023年 173卷 276-277页

作者： Hoffman, Samantha E. Gupta, Saksham Arnaout, Omar Brigham & Womens Hosp Dept Neurosurg Boston MA 02115 USA Harvard Med Sch Harvard MIT MD PhD Program Boston MA 02115 USA

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