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Thymidine nucleotide metabolism controls human telomere length (vol 55, pg 568, 2023)

NATURE GENETICS 2023年第7期55卷 1251-1251页

作者： Mannherz, William 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 Harvard Initiat RNA Med Biol & Biomed Sci Program Boston MA 02115 USA Harvard Med Sch Harvard MIT MD PhD Program Dept Pediat Boston MA 02115 USA

Telomere length in humans is associated with lifespan and severe diseases, yet the genetic determinants of telomere length remain incompletely defined. Here we performed genome-wide CRISPR–Cas9 functional telomere length screening and identified thymidine (dT) nucleotide metabolism as a limiting factor in human telomere maintenance. Targeted genetic disruption using CRISPR–Cas9 revealed multiple telomere length control points across the thymidine nucleotide metabolism pathway: decreasing dT nucleotide salvage via deletion of the gene encoding nuclear thymidine kinase (TK1) or de novo production by knockout of the thymidylate synthase gene (TYMS) decreased telomere length, whereas inactivation of the deoxynucleoside triphosphohydrolase-encoding gene SAMHD1 lengthened telomeres. Remarkably, supplementation with dT alone drove robust telomere elongation by telomerase in cells, and thymidine triphosphate stimulated telomerase activity in a substrate-independent manner in vitro. In induced pluripotent stem cells derived from patients with genetic telomere biology disorders, dT supplementation or inhibition of SAMHD1 promoted telomere restoration. Our results demonstrate a critical role of thymidine metabolism in controlling human telomerase and telomere length, which may be therapeutically actionable in patients with fatal degenerative diseases.

关键词： Genetic engineering Haematological diseases High-throughput screening Stem-cell research

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Alterations in facial expressions in individuals at risk for psychosis: a facial electromyography approach using emotionally evocative film clips

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PSYCHOLOGICAL MEDICINE 2023年第12期53卷 5829-5838页

作者： Gupta, Tina Osborne, K. Juston Nadig, Ajay Haase, Claudia M. mittal, Vijay A. Univ Pittsburgh Dept Psychiat Pittsburgh PA 15213 USA Northwestern Univ Dept Psychol Evanston IL USA Harvard Med Sch Harvard MIT MD PhD Program Boston MA 02115 USA Northwestern Univ Sch Educ & Social Policy Evanston IL USA

Background Negative symptoms such as blunted facial expressivity are characteristic of schizophrenia. However, it is not well-understood if and what abnormalities are present in individuals at clinical high-risk (CHR) for psychosis. Methods This experimental study employed facial electromyography (left zygomaticus major and left corrugator supercilia) in a sample of CHR individuals (N = 34) and healthy controls (N = 32) to detect alterations in facial expressions in response to emotionally evocative film clips and to determine links with symptoms. Results Findings revealed that the CHR group showed facial blunting manifested in reduced zygomatic activity in response to an excitement (but not amusement, fear, or sadness) film clip compared to controls. Reductions in zygomatic activity in the CHR group emerged in response to the emotionally evocative peak period of the excitement film clip. Lower zygomaticus activity during the excitement clip was related to anxiety while lower rates of change in zygomatic activity during the excitement video clip were related to higher psychosis risk conversion scores. Conclusions Together, these findings inform vulnerability/disease driving mechanisms and biomarker and treatment development.

关键词： Clinical high-risk electromyography evocative film clips facial expressions negative symptoms schizophrenia

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Neurosurgery elucidates somatic mutations

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SCIENCE 2023年第6677期382卷 1360-1362页

作者： Maury, Eduardo A. Walsh, Christopher A. Kahle, Kristopher T. Boston Childrens Hosp Manton Ctr Orphan Dis Div Genet & Genom Boston MA 02115 USA Harvard Med Sch Harvard MIT MD PhD Program Boston MA 02115 USA Broad Inst MIT & Harvard Program Med & Populat Genet Cambridge MA 02142 USA Boston Childrens Hosp Howard Hughes Med Inst Boston MA 02115 USA Broad Inst MIT & Harvard Program Neurosci Cambridge MA USA Boston Childrens Hosp Dept Neurosurg Boston MA USA Massachusetts Gen Hosp Dept Neurosurg Boston MA USA

Surgical innovation is helping to identify roles for somatic mutations in brain disorders Somatic variants are genomic alterations present in some cells of the body but not in others. In contrast to inherited germline variants, somatic variants are typically acquired during postzygotic cell divisions or from environmental factors. Somatic variants in a given tissue can also be highly dynamic, such as in the brain, where the number of clonal variants can change during aging and disease (1). Neuro-oncology has greatly benefited from the analyses of somatic mutations in tissue obtained from surgical biopsies or resections. Increased understanding of somatic mutations in brain tumors brought a revolution in prognostication and individualized treatments. Somatic mutations are now increasingly being implicated in neurological disorders beyond cancer, particularly in children with congenital brain and cerebrovascular diseases. Teams of neurosurgeons and scientists are performing gene sequencing on surgical brain samples from these patients- paving the way to expand understanding of nononcologic brain disease through the study of somatic mutations.

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Insights into Neurodegeneration in Parkinson's Disease from Single-Cell and Spatial Genomics

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MOVEMENT DISORDERS 2023年第4期38卷 518-525页

作者： Kamath, Tushar Macosko, Evan Z. Broad Inst Stanley Ctr Psychiat Res Cambridge MA USA Harvard Med Sch Cambridge MA USA Harvard Univ Harvard MIT MD PhD Program Cambridge MA USA Massachusetts Gen Hosp Dept Psychiat Boston MA USA Broad Inst Stanley Ctr Psychiat Res 75 Ames St Cambridge MA 02139 USA

Parkinson's disease (PD) is pathologically defined by the death of dopaminergic (DA) neurons within the pars compacta of the substantia nigra. To date, the cause of this multifaceted disease remains largely unclear, which may contribute in part to a current lack of disease-modifying therapies. Recent advances in single-cell and spatial genomic profiling tools have provided powerful new ways to measure cellular state changes in brain diseases. Here, we describe how these tools have offered insight into these complex disorders and highlight a recently performed comprehensive study of DA neuron susceptibility in PD. The data generated by this recent work provide evidence for the role of specific pathways and common genetic variants resulting in the loss of a critical DA subtype in PD. We conclude by outlining a set of basic and translational opportunities that arise from those data and insights gathered from this work. (c) 2023 International Parkinson and Movement Disorder Society.

关键词： Parkinson's disease dopaminergic substantia nigra

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Addressing the longitudinal components of surgical treatments

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EUROPEAN JOURNAL OF EPIDEMIOLOGY 2023年第10期38卷 1019-1023页

作者： Messinger, Chelsea J. Madenci, Arin L. Wanis, Kerollos Nashat Harvard TH Chan Sch Publ Hlth Dept Epidemiol 677 Huntington Ave Boston MA 02115 USA Harvard Med Sch Harvard MIT MD PhD Program Boston MA 02115 USA Boston Childrens Hosp Dept Surg Boston MA USA Western Univ Dept Surg London ON Canada

Despite their pre- and postoperative components, surgical treatment strategies have typically been cast as point interventions in causal inference research. When longitudinal perioperative components affect outcomes of interest, leaving them unspecified or failing to measure adherence to them complicates the interpretation of effect estimates. Inspired by two recent landmark trials that assessed the risk of stroke or death after transcatheter aortic valve replacement (TAVR) compared with surgical aortic valve replacement (SAVR), the PARTNER 3 trial and the Evolut Low Risk trial, we discuss possible ways that different postoperative therapies in treatment arms and incomplete adherence to those therapies can impact the interpretation of intention-to-treat effect estimates in surgical trials. We argue that surgical treatments are not necessarily point interventions, and make recommendations for improving the design and analysis of trials involving surgical interventions. Central to these recommendations is the need for investigators to specify and report adherence to longitudinal perioperative treatment components.

关键词： Causal inference Randomized control trial Surgery Transportability Time-varying exposure Adherence

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A good step toward low-cost prognostication of liver-related outcome awaits more validation

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JOURNAL OF HEPATOLOGY 2022年第3期77卷 887-889页

作者： Song, Jiunn Jiang, Z. Gordon Harvard Med Sch Harvard MIT MD PhD Program Boston MA 02115 USA Harvard Med Sch Beth Israel Deaconess Med Ctr Dept Med Div Gastroenterol & Hepatol Boston MA 02115 USA

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Model-directed generation of artificial CRISPR-Cas13a guide RNA sequences improves nucleic acid detection

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NATURE BIOTECHNOLOGY 2024年 1-8页

作者： Mantena, Sreekar Pillai, Priya P. Petros, Brittany A. Welch, Nicole L. Myhrvold, Cameron Sabeti, Pardis C. Metsky, Hayden C. Broad Inst MIT & Harvard Cambridge MA 02142 USA Harvard Univ Dept Stat Cambridge MA USA Harvard Univ Dept Mol & Cellular Biol Cambridge MA USA Harvard Med Sch Div Hlth Sci & Technol Cambridge MA USA MIT Cambridge MA USA Harvard Massachusetts Inst Technol MD PhD Program Boston MA USA Harvard Med Sch Dept Syst Biol Boston MA USA Princeton Univ Dept Mol Biol Princeton NJ USA Princeton Univ Dept Chem & Biol Engn Princeton NJ USA Princeton Univ Omenn Darling Bioengn Inst Princeton NJ USA Princeton Univ Dept Chem Princeton NJ USA Howard Hughes Med Inst Chevy Chase MD 20815 USA Harvard Univ Dept Organism & Evolutionary Biol Cambridge MA 02138 USA Harvard TH Chan Sch Publ Hlth Dept Immunol & Infect Dis Boston MA 02115 USA

CRISPR guide RNA sequences deriving exactly from natural sequences may not perform optimally in every application. Here we implement and evaluate algorithms for designing maximally fit, artificial CRISPR-Cas13a guides with multiple mismatches to natural sequences that are tailored for diagnostic applications. These guides offer more sensitive detection of diverse pathogens and discrimination of pathogen variants compared with guides derived directly from natural sequences and illuminate design principles that broaden Cas13a targeting. Model-directed generative design is applied to CRISPR-Cas13a guide RNAs, outperforming natural sequences.

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Impulsivity and risk-seeking as Bayesian inference under dopaminergic control

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NEUROPSYCHOPHARMACOLOGY 2022年第2期47卷 465-476页

作者： Mikhael, John G. Gershman, Samuel J. Harvard Med Sch Program Neurosci Boston MA 02115 USA Harvard Med Sch MD PhD Program Boston MA 02115 USA Harvard Univ Dept Psychol 33 Kirkland St Cambridge MA 02138 USA Harvard Univ Ctr Brain Sci Cambridge MA 02138 USA MIT Ctr Brains Minds & Machines 77 Massachusetts Ave Cambridge MA 02139 USA

Bayesian models successfully account for several of dopamine (DA)'s effects on contextual calibration in interval timing and reward estimation. In these models, tonic levels of DA control the precision of stimulus encoding, which is weighed against contextual information when making decisions. When DA levels are high, the animal relies more heavily on the (highly precise) stimulus encoding, whereas when DA levels are low, the context affects decisions more strongly. Here, we extend this idea to intertemporal choice and probability discounting tasks. In intertemporal choice tasks, agents must choose between a small reward delivered soon and a large reward delivered later, whereas in probability discounting tasks, agents must choose between a small reward that is always delivered and a large reward that may be omitted with some probability. Beginning with the principle that animals will seek to maximize their reward rates, we show that the Bayesian model predicts a number of curious empirical findings in both tasks. First, the model predicts that higher DA levels should normally promote selection of the larger/later option, which is often taken to imply that DA decreases 'impulsivity,' and promote selection of the large/risky option, often taken to imply that DA increases 'risk-seeking.' However, if the temporal precision is sufficiently decreased, higher DA levels should have the opposite effect-promoting selection of the smaller/sooner option (higher impulsivity) and the small/safe option (lower risk-seeking). Second, high enough levels of DA can result in preference reversals. Third, selectively decreasing the temporal precision, without manipulating DA, should promote selection of the larger/later and large/risky options. Fourth, when a different post-reward delay is associated with each option, animals will not learn the option-delay contingencies, but this learning can be salvaged when the post-reward delays are made more salient. Finally, the Bayesian model pre

关键词： Cognitive neuroscience Reward Medicine/Public Health general Psychiatry Neurosciences Behavioral Sciences Pharmacotherapy Biological Psychology

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Rare germline structural variants increase risk for pediatric solid tumors

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SCIENCE 2025年第6729期387卷 eadq0071页

作者： Gillani, Riaz Collins, Ryan L. Crowdis, Jett Garza, Amanda Jones, Jill K. Walker, Mark Sanchis-Juan, Alba Whelan, Christopher W. Pierce-Hoffman, Emma Talkowski, Michael E. Brand, Harrison Haigis, Kevin LoPiccolo, Jaclyn AlDubayan, Saud H. Gusev, Alexander Crompton, Brian D. Janeway, Katherine A. Van Allen, Eliezer M. Dana Farber Canc Inst Dept Pediat Oncol Boston MA 02115 USA Broad Inst MIT & Harvard Canc Program Cambridge MA 02142 USA Harvard Med Sch Boston MA 02115 USA Boston Childrens Hosp Boston MA 02115 USA Dana Farber Canc Inst Dept Med Oncol Boston MA 02115 USA Harvard Med Sch Harvard MIT MD PhD Program Boston MA 02115 USA Broad Inst MIT & Harvard Data Sci Platform Cambridge MA 02142 USA Massachusetts Gen Hosp Ctr Genom Med Boston MA 02114 USA Broad Inst MIT & Harvard Program Med & Populat Genet Cambridge MA 02142 USA Broad Inst MIT & Harvard Stanley Ctr Psychiat Res Cambridge MA 02142 USA Massachusetts Gen Hosp Dept Neurol Boston MA 02114 USA Dana Farber Canc Inst Dept Canc Biol Boston MA 02115 USA Brigham & Womens Hosp Dept Med 75 Francis St Boston MA 02115 USA Brigham & Womens Hosp Div Genet 75 Francis St Boston MA 02115 USA King Saudi bin Abdulaziz Univ Hlth Sci Coll Med Riyadh Saudi Arabia Harvard TH Chan Sch Publ Hlth Dept Epidemiol Boston MA USA Dana Farber Canc Inst Ctr Canc Genom Boston MA 02115 USA

Pediatric solid tumors are a leading cause of childhood disease mortality. In this work, we examined germline structural variants (SVs) as risk factors for pediatric extracranial solid tumors using germline genome sequencing of 1765 affected children, their 943 unaffected parents, and 6665 adult controls. We discovered a sex-biased association between very large (>1 megabase) germline chromosomal abnormalities and increased risk of solid tumors in male children. The overall impact of germline SVs was greatest in neuroblastoma, where we uncovered burdens of ultrarare SVs that cause loss of function of highly expressed, mutationally constrained genes, as well as noncoding SVs predicted to disrupt chromatin domain boundaries. Collectively, we estimate that rare germline SVs explain 1.1 to 5.6% of pediatric cancer liability, establishing them as an important component of disease predisposition.

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SLC25A38 is required for mitochondrial pyridoxal 5'-phosphate (PLP) accumulation

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NATURE COMMUNICATIONS 2025年第1期16卷 1-19页

作者： Pena, Izabella A. Shi, Jeffrey S. Chang, Sarah M. Yang, Jason Block, Samuel Adelmann, Charles H. Keys, Heather R. Ge, Preston Bathla, Shveta Witham, Isabella H. Sienski, Grzegorz Nairn, Angus C. Sabatini, David M. Lewis, Caroline A. Kory, Nora Vander Heiden, Matthew G. Heiman, Myriam MIT Picower Inst Learning & Memory Cambridge MA 02139 USA MIT Dept Brain & Cognit Sci Cambridge MA 02139 USA MIT Dept Biol Cambridge MA USA MIT David H Koch Inst Integrat Canc Res Cambridge MA USA Harvard MIT MD PhD Program Boston MA USA Whitehead Inst Biomed Res Cambridge MA USA Massachusetts Gen Hosp Ctr Canc Res Boston MA USA Harvard Med Sch Massachusetts Gen Hosp Cutaneous Biol Res Ctr Dept Dermatol Boston MA USA Yale Sch Med Dept Psychiat New Haven CT USA MIT Dept Biol Engn Cambridge MA USA Inst Organ Chem & Biochem IOCB Prague Czech Republic UMass Chan Med Sch Program Mol Med Worcester MA USA Harvard TH Chan Sch Publ Hlth Boston MA USA Dana Farber Canc Inst Boston MA USA Childrens Hosp Eastern Ontario CHEO Res Inst Ottawa ON Canada

Many essential proteins require pyridoxal 5'-phosphate, the active form of vitamin B6, as a cofactor for their activity. These include enzymes important for amino acid metabolism, one-carbon metabolism, polyamine synthesis, erythropoiesis, and neurotransmitter metabolism. A third of all mammalian pyridoxal 5'-phosphate-dependent enzymes are localized in the mitochondria;however, the molecular machinery involved in the regulation of mitochondrial pyridoxal 5'-phosphate levels in mammals remains unknown. In this study, we used a genome-wide CRISPR interference screen in erythroleukemia cells and organellar metabolomics to identify the mitochondrial inner membrane protein SLC25A38 as a regulator of mitochondrial pyridoxal 5'-phosphate. Loss of SLC25A38 causes depletion of mitochondrial, but not cellular, pyridoxal 5'-phosphate, and impairs cellular proliferation under both physiological and low vitamin B6 conditions. Metabolic changes associated with SLC25A38 loss suggest impaired mitochondrial pyridoxal 5'-phosphate-dependent enzymatic reactions, including serine to glycine conversion catalyzed by serine hydroxymethyltransferase-2 as well as ornithine aminotransferase. The proliferation defect of SLC25A38-null K562 cells in physiological and low vitamin B6 media can be explained by the loss of serine hydroxymethyltransferase-2-dependent production of one-carbon units and downstream de novo nucleotide synthesis. Our work points to a role for SLC25A38 in mitochondrial pyridoxal 5'-phosphate accumulation and provides insights into the pathology of congenital sideroblastic anemia.

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