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Wanted: An endothelial cell targeting atlas for nanotherapeutic delivery in allograft organs

AMERICAN JOURNAL OF TRANSPLANTATION 2022年第7期22卷 1754-1759页

作者： Liburd, Samuel T., Jr. Shi, Audrey A. Pober, Jordan S. Tietjen, Gregory T. Yale Sch Med MD PhD Program New Haven CT USA Yale Univ Dept Biomed Engn New Haven CT 06520 USA Yale Sch Med Dept Surg New Haven CT USA Yale Univ Dept Immunobiol New Haven CT USA

Despite the profound shortage of organs available for transplant in the U.S., over 5,000 donated organs were declined for use in 2020. Many of these organs were declined due to donor comorbidities or preservation injuries that predispose grafts to rejection and loss. The risks of these poor outcomes can potentially be reduced by pre-transplant application of normothermic machine perfusion (NMP). To date, the clinical use of NMP has focused on extending preservation and improving organ assessment, but the opportunity for ex situ therapeutic delivery may be the most transformative aspect of this technology. In this Personal Viewpoint, we argue that the endothelial cells (ECs) that line the graft vasculature are an accessible, under-exploited, and attractive target for transplant therapeutics delivered during NMP. We further contend that molecularly targeted nanoparticles (NPs) represent a promising therapeutic vehicle particularly well-suited to NMP. However, to achieve this potential, we need to answer the following three key questions: (1) What EC sub-populations exist within an organ? (2) How can these cells be accessed? (3) And most important, how can preferential retention of NPs by the cells of interest be maximized? Here we argue for creating an EC-targeting atlas as a body of knowledge that answers these questions.

关键词： artificial organs/support devices drug interaction editorial/personal viewpoint organ perfusion and preservation solid organ transplantation vascular biology

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The Emergence of Network Activity Patterns in the Somatosensory Cortex-An Early Window to Autism Spectrum Disorders

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NEUROSCIENCE 2021年第0期466卷 298-309页

作者： Iannone, Andrew F. Garcia, Natalia V. De Marco Weill Cornell Med Ctr Neurogenet Brain & Mind Res Inst New York NY 10021 USA Sloan Kettering TriInst MD PhD Program New York NY 10021 USA

Across mammalian species, patterned activity in neural populations is a prominent feature of developing sensory cortices. Numerous studies have long appreciated the diversity of these patterns, characterizing their differences in spatial and temporal dynamics. In the murine somatosensory cortex, neuronal co-activation is thought to guide the formation of sensory maps and prepare the cortex for sensory processing after birth. While pioneering studies deftly utilized slice electrophysiology and unit recordings to characterize correlated activity, a detailed understanding of the underlying circuits remains poorly understood. More recently, advances in in vivo calcium imaging in awake mouse pups and increasing genetic tractability of neuronal types have allowed unprecedented manipulation of circuit components at select developmental timepoints. These novel approaches have proven fundamental in uncovering the identity of neurons engaged in correlated activity during development. In particular, recent studies have highlighted interneurons as key in refining the spatial extent and temporal progression of patterned activity. Here, we discuss how emergent synchronous activity across the first postnatal weeks is shaped by underlying gamma aminobutyric acid (GABA)ergic contributors in the somatosensory cortex. Further, the importance of participation in specific activity patterns per se for neuronal maturation and perdurance will be of particular highlight in this survey of recent literature. Finally, we underscore how aberrant neuronal synchrony and disrupted inhibitory interneuron activity underlie sensory perturbations in neurodevelopmental disorders, particularly Autism Spectrum Disorders (ASDs), emphasizing the importance of future investigative approaches that incorporate the spatiotemporal features of patterned activity alongside the cellular components to probe disordered circuit assembly. (c) 2021 IBRO. Published by Elsevier Ltd. All rights reserved.

关键词： development interneurons GABA network activity calcium imaging barrel cortex

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Combinatorial development of nebulized mRNA delivery formulations for the lungs

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NATURE NANOTECHNOLOGY 2024年第3期19卷 364-375页

作者： Jiang, Allen Y. Witten, Jacob Raji, Idris O. Eweje, Feyisayo Macisaac, Corina Meng, Sabrina Oladimeji, Favour A. Hu, Yizong Manan, Rajith S. Langer, Robert Anderson, Daniel G. MIT Dept Chem Engn Cambridge MA 02139 USA MIT David H Koch Inst Integrat Canc Res Cambridge MA 02139 USA MIT Dept Biol Engn Cambridge MA 02139 USA Boston Childrens Hosp Dept Anesthesiol Boston MA 02115 USA MIT Harvard & MIT Div Hlth Sci & Technol Cambridge MA 02139 USA Harvard MIT MD PhD Program Boston MA USA MIT Inst Med Engn & Sci Cambridge MA 02139 USA

Inhaled delivery of mRNA has the potential to treat a wide variety of diseases. However, nebulized mRNA lipid nanoparticles (LNPs) face several unique challenges including stability during nebulization and penetration through both cellular and extracellular barriers. Here we develop a combinatorial approach addressing these barriers. First, we observe that LNP formulations can be stabilized to resist nebulization-induced aggregation by altering the nebulization buffer to increase the LNP charge during nebulization, and by the addition of a branched polymeric excipient. Next, we synthesize a combinatorial library of ionizable, degradable lipids using reductive amination, and evaluate their delivery potential using fully differentiated air-liquid interface cultured primary lung epithelial cells. The final combination of ionizable lipid, charge-stabilized formulation and stability-enhancing excipient yields a significant improvement in lung mRNA delivery over current state-of-the-art LNPs and polymeric nanoparticles. Nebulized mRNA delivery has broad therapeutic potential but has proven challenging. Here, the authors report on a modified lipid nanoparticle with improved conditions to allow nebulization and demonstrate its application for delivering mRNA to the lungs.

关键词： Biomedical engineering Drug delivery Nanomedicine Nanoparticles

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Image-based 3D genomics through chromatin tracing

NATURE REVIEWS METHODS PRIMERS

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NATURE REVIEWS METHODS PRIMERS 2024年第1期4卷 1页

作者： Yang, Tianqi Wang, Siyuan Yale Univ Dept Genet New Haven CT 06519 USA Yale Univ Dept Cell Biol New Haven CT 06520 USA Yale Univ Yale Combined Program Biol & Biomed Sci New Haven CT 06510 USA Yale Univ Mol Cell Biol Genet & Dev Program New Haven CT 06520 USA Yale Univ Biochem Quantitat Biol Biophys & Struct Biol Progr New Haven CT 06510 USA Yale Univ MD PhD Program New Haven CT 06520 USA Yale Univ Sch Med Yale Ctr RNA Sci & Med New Haven CT 06520 USA Yale Univ Sch Med Yale Liver Ctr New Haven CT 06520 USA

Correct organization of higher-order genome folding is essential for the regulation of gene expression, DNA replication and other genomic functions. Technological advances in high-throughput sequencing-based methods have allowed for systematic profiling of the fundamental architectural features of chromatin organization at the genome level. However, how chromatin is folded in 3D space at single-cell and single-chromosome-copy resolution in intact cells and tissues has been a long-standing question owing to a lack of appropriate methodology. Recent advances in chromatin labelling, imaging and automated fluidics technologies have led to the development of chromatin tracing, enabling direct mapping of the 3D chromatin folding trajectory in situ at the single-cell and single-molecule level. Within nearly a decade of its development, chromatin tracing has been applied at different genomic scales and to a spectrum of cell types and model organisms, improving our understanding of the structures, mechanisms and functions of chromatin organization in various biological and medical areas. In this Primer, we introduce the experimental principles, data analysis procedures and current applications of chromatin tracing. We describe how chromatin tracing can be combined with multimodal imaging and genetic screening technologies and provide a perspective on the limitations of current chromatin tracing approaches and the direction of technological developments for filling major gaps in discoveries.

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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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Massively parallel knock-in engineering of human T cells

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NATURE BIOTECHNOLOGY 2023年第9期41卷 1239-+页

作者： Dai, Xiaoyun Park, Jonathan J. Du, Yaying Na, Zhenkun Lam, Stanley Z. Chow, Ryan D. Renauer, Paul A. Gu, Jianlei Xin, Shan Chu, Zhiyuan Liao, Cun Clark, Paul Zhao, Hongyu Slavoff, Sarah Chen, Sidi Yale Univ Sch Med Dept Genet New Haven CT 06520 USA Yale Univ Syst Biol Inst West Haven CT 06520 USA Yale Univ Ctr Canc Syst Biol West Haven CT 06520 USA Yale Univ MD PhD Program West Haven CT 06520 USA Yale Univ Mol Cell Biol Genet & Dev Program New Haven CT 06520 USA Yale Univ Dept Chem New Haven CT USA Yale Univ Inst Biomol Design & Discovery West Haven CT USA Yale Univ Sch Publ Hlth Dept Biostat New Haven CT USA Yale Univ Immunobiol Program New Haven CT 06520 USA Yale Univ Computat Biol & Bioinformat Program New Haven CT USA

The efficiency of targeted knock-in for cell therapeutic applications is generally low, and the scale is limited. In this study, we developed CLASH, a system that enables high-efficiency, high-throughput knock-in engineering. In CLASH, Cas12a/Cpf1 mRNA combined with pooled adeno-associated viruses mediate simultaneous gene editing and precise transgene knock-in using massively parallel homology-directed repair, thereby producing a pool of stably integrated mutant variants each with targeted gene editing. We applied this technology in primary human T cells and performed time-coursed CLASH experiments in blood cancer and solid tumor models using CD3, CD8 and CD4 T cells, enabling pooled generation and unbiased selection of favorable CAR-T variants. Emerging from CLASH experiments, a unique CRISPR RNA (crRNA) generates an exon3 skip mutant of PRDM1 in CAR-Ts, which leads to increased proliferation, stem-like properties, central memory and longevity in these cells, resulting in higher efficacy in vivo across multiple cancer models, including a solid tumor model. The versatility of CLASH makes it broadly applicable to diverse cellular and therapeutic engineering applications. Unbiased selection of CAR-T cells is achieved by massively parallel knock-in engineering.

关键词： Cancer therapy Genomic engineering Genomics High-throughput screening

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Trajectories of physical frailty and cognitive impairment in older adults in United States nursing homes

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BMC GERIATRICS 2022年第1期22卷 1-13页

作者： Yuan, Yiyang Lapane, Kate L. Tjia, Jennifer Baek, Jonggyu Liu, Shao-Hsien Ulbricht, Christine M. Univ Massachusetts Grad Sch Biomed Sci Clin & Populat Hlth Res PhD Program Chan Med Sch Worcester MA 01605 USA Univ Massachusetts Dept Populat & Quantitat Hlth Sci Chan Med Sch Worcester MA 01605 USA NIMH NIH Bethesda MD 20892 USA

Background U.S. nursing homes provide long-term care to over 1.2 million older adults, 60% of whom were physically frail and 68% had moderate or severe cognitive impairment. Limited research has examined the longitudinal experience of these two conditions in older nursing home residents. Methods This national longitudinal study included newly-admitted non-skilled nursing care older residents who had Minimum Data Set (mdS) 3.0 (2014-16) assessments at admission, 3 months, and 6 months (n = 266,001). Physical frailty was measured by FRAIL-NH and cognitive impairment by the Brief Interview for Mental Status. Separate sets of group-based trajectory models were fitted to identify the trajectories of physical frailty and trajectories of cognitive impairment, and to estimate the association between older residents' characteristics at admission with each set of trajectories. A dual trajectory model was used to quantify the association between the physical frailty trajectories and cognitive impairment trajectories. Results Over the course of the first six months post-admission, five physical frailty trajectories ["Consistently Frail" (prevalence: 53.0%), "Consistently Pre-frail" (29.0%), "Worsening Frailty" (7.6%), "Improving Frailty" (5.5%), and "Consistently Robust" (4.8%)] and three cognitive impairment trajectories ["Consistently Severe Cognitive Impairment" (35.5%), "Consistently Moderate Cognitive Impairment" (31.8%), "Consistently Intact/Mild Cognitive Impairment" (32.7%)] were identified. One in five older residents simultaneously followed the trajectories of "Consistently Frail" and "Consistently Severe Cognitive Impairment". Characteristics associated with higher odds of the "Improving Frailty", "Worsening Frailty", "Consistently Pre-frail" and "Consistently Frail" trajectories included greater at-admission cognitive impairment, age >= 85 years, admitted from acute hospitals, cardiovascular/metabolic diagnoses, neurological diagnoses, hip or other fractures, and pr

关键词： Physical frailty Cognitive impairment Nursing home Trajectory Group-based trajectory model

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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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Evaluating the effectiveness and quality of mobile applications for perinatal depression and anxiety: A systematic review and meta-analysis

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JOURNAL OF AFFECTIVE DISORDERS 2022年第0期296卷 443-453页

作者： Tsai, Zoe Kiss, Adam Nadeem, Shaheer Sidhom, Karen Owais, Sawayra Faltyn, Mateusz Van Lieshout, Ryan J. McMaster Univ Fac Hlth Sci Hamilton ON Canada McMaster Univ Dept Kinesiol Hamilton ON Canada McMaster Univ Fac Hlth Sci MD PhD Program Hamilton ON Canada Univ British Columbia Dept Math Vancouver BC Canada McMaster Univ Dept Psychiat & Behav Neurosci Hamilton ON Canada

Background: Our objectives were to assess: (1) the effectiveness of existing mHealth apps for reducing symptoms of maternal depression and/or anxiety during the prenatal period and/or the first year postpartum, and (2) the app quality of commercially available apps targeting perinatal depression and/or anxiety. Methods: To address Objective 1, we searched five electronic databases (MEDLINE, CINAHL, PsycINFO, Web of Science, and Embase) from their inception until May 3rd, 2021. For the second objective, we searched Google Play and Apple App Stores in the United States, United Kingdom, Canada, and Australia until May 3rd, 2021. Results: Our search identified 3,897 articles, seven of which were meta-analyzed. mHealth apps did not improve perinatal depression (Smd,-0.39;95% CI,-0.80 to 0.03) or anxiety (Smd, 0.01;95% CI,-0.13 to 0.16) within the first 3 months post-intervention or at 6 months post-intervention. Our search of app stores identified 74 commercially available apps, 37 of which were evaluated via MARS tool. Current apps for perinatal anxiety and/ or depression were rated to be of moderate quality on the MARS (mean, 3.6/5). Limitations: There is a small number of overall studies in this field and the individual studies have methodological limitations. Furthermore, few apps identified in our app store search have been clinically tested. Conclusion: Despite their widespread availability, mHealth apps do not appear to effectively reduce perinatal depression or anxiety, and few were subjectively rated to be of high quality. There is a need to develop higher quality mHealth apps and assess their potential to improve perinatal maternal mental health.

关键词： mHealth Apps Mobile health Postpartum depression

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Review of electrospun microtube array membrane (MTAM)-a novel new class of hollow fiber for encapsulated cell therapy (ECT) in clinical applications

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JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART B-APPLIED BIOMATERIALS 2024年第1期112卷 e35348-e35348页

作者： Chew, Chee Ho Lee, Hsin-Lun Chen, Amanda Lin Huang, Wan-Ting Chen, Shu-Mei Liu, Yen-Lin Chen, Chien-Chung Taipei Med Univ Grad Inst Biomed Mat & Tissue Engn Coll Biomed Engn Taipei Taiwan MTAMTech Corp Res & Mkt Dept Taipei Taiwan Taipei Med Univ Hosp Dept Radiat Oncol Taipei Taiwan NCI Immune Deficiency Cellular Therapy Program Bethesda MD USA Taipei Med Univ Div Neurosurg Taipei Taiwan Taipei Med Univ Hosp Dept Pediat Taipei Taiwan Taipei Med Univ Coll Med Int PhD Program Cell Therapy & Regenerat Med Taipei Taiwan Taipei Med Univ PhD Program Translat Med Taipei Taiwan Taipei Med Univ Coll Biomed Engn Int PhD Program Biomed Engn Taipei Taiwan Taipei Med Univ Coll Pharm PhD Program Biotechnol Res & Dev Taipei Taiwan Taipei Med Univ Coll Biomed Engn Grad Inst Biomed Mat & Tissue Engn Taipei 11052 Taiwan

Encapsulated cell therapy (ECT) shows significant potential for treating neurodegenerative disorders including Alzheimer's and Parkinson's, which currently lack curative medicines and must be managed symptomatically. This novel technique encapsulates functional cells with a semi-permeable membrane, providing protection while enabling critical nutrients and therapeutic substances to pass through. Traditional ECT procedures, on the other hand, pose difficulties in terms of cell survival and retrieval. We introduce the Microtube Array Membrane (MTAM), a revolutionary technology that solves these constraints, in this comprehensive overview. Microtube Array Membrane has distinct microstructures that improve encapsulated cells' long-term viability by combining the advantages of macro and micron scales. Importantly, the MTAM platform improves biosafety by allowing the entire encapsulated unit to be retrieved in the event of an adverse reaction. Our findings show that MTAM-based ECT has a great potential in a variety of illness situations. For cancer treatment, hybridoma cells secreting anti-CEACAM 6 antibodies inhibit triple-negative breast cancer cell lines for an extended period of time. In animal brain models of Alzheimer's disease, hybridoma cells secreting anti-pTau antibodies successfully reduce pTau buildup, accompanied by improvements in memory performance. In mouse models, MTAM-encapsulated primary cardiac mesenchymal stem cells dramatically improve overall survival and heart function. These findings illustrate the efficacy and adaptability of MTAM-based ECT in addressing major issues such as immunological isolation, cell viability, and patient safety. We provide new possibilities for the treatment of neurodegenerative illnesses and other conditions by combining the potential of ECT with MTAM. Continued research and development in this subject has a lot of promise for developing cell therapy and giving hope to people suffering from chronic diseases.

关键词： Alzhimer's disease breast cancer cardiac disease encapsulated cell therapy (ECT) microtube Array membrane (MTAM)

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