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Synthetic chest X-ray images from text prompts 根据文字提示合成胸部 X 光图像
IF 28.1 1区 医学 Q1 ENGINEERING, BIOMEDICAL Pub Date : 2024-10-07 DOI: 10.1038/s41551-024-01261-z
Daniel Truhn, Jakob Nikolas Kather
A latent diffusion model pre-trained on pairs of natural images and text descriptors can be adapted to generate realistic chest radiographs that are controlled by free-form medical text prompts.
在自然图像和文本描述符对上预先训练的潜在扩散模型可用于生成由自由格式医学文本提示控制的逼真胸片。
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引用次数: 0
Immunometabolic cues recompose and reprogram the microenvironment around implanted biomaterials 免疫代谢线索对植入生物材料周围的微环境进行重组和重编程
IF 26.8 1区 医学 Q1 ENGINEERING, BIOMEDICAL Pub Date : 2024-10-04 DOI: 10.1038/s41551-024-01260-0
Chima V. Maduka, Axel D. Schmitter-Sánchez, Ashley V. Makela, Evran Ural, Katlin B. Stivers, Hunter Pope, Maxwell M. Kuhnert, Oluwatosin M. Habeeb, Anthony Tundo, Mohammed Alhaj, Artem Kiselev, Shoue Chen, Alexis Donneys, Wade P. Winton, Jenelle Stauff, Peter J. H. Scott, Andrew J. Olive, Kurt D. Hankenson, Ramani Narayan, Sangbum Park, Jennifer H. Elisseeff, Christopher H. Contag
Circulating monocytes infiltrate and coordinate immune responses in tissues surrounding implanted biomaterials and in other inflamed tissues. Here we show that immunometabolic cues in the biomaterial microenvironment govern the trafficking of immune cells, including neutrophils and monocytes, in a manner dependent on the chemokine receptor 2 (CCR2) and the C-X3-C motif chemokine receptor 1 (CX3CR1). This affects the composition and activation states of macrophage and dendritic cell populations, ultimately orchestrating the relative composition of pro-inflammatory, transitory and anti-inflammatory CCR2+, CX3CR1+ and CCR2+ CX3CR1+ immune cell populations. In amorphous polylactide implants, modifying immunometabolism by glycolytic inhibition drives a pro-regenerative microenvironment principally by myeloid cells. In crystalline polylactide implants, together with arginase-1-expressing myeloid cells, T helper 2 cells and γδ+ T cells producing interleukin-4 substantially contribute to shaping the metabolically reprogrammed pro-regenerative microenvironment. Our findings inform the premise that local metabolic states regulate inflammatory processes in the biomaterial microenvironment. Immunometabolic cues surrounding implanted biomaterials govern the trafficking of subsets of neutrophils, monocytes and other immune cells, and determine the relative composition of pro-inflammatory and anti-inflammatory immune cell populations.
循环中的单核细胞在植入的生物材料周围组织和其他发炎组织中浸润并协调免疫反应。在这里,我们展示了生物材料微环境中的免疫代谢线索以一种依赖于趋化因子受体 2(CCR2)和 C-X3-C motif 趋化因子受体 1(CX3CR1)的方式控制着包括中性粒细胞和单核细胞在内的免疫细胞的迁移。这会影响巨噬细胞和树突状细胞群的组成和活化状态,最终协调促炎性、暂时性和抗炎性 CCR2+、CX3CR1+ 和 CCR2+ CX3CR1+ 免疫细胞群的相对组成。在无定形聚乳酸植入物中,通过抑制糖酵解来改变免疫代谢,从而主要通过髓系细胞来推动有利于再生的微环境。在结晶聚乳酸植入物中,T辅助2细胞和产生白细胞介素-4的γδ+ T细胞与表达精氨酸酶-1的髓系细胞一起,为塑造代谢重编程的促再生微环境做出了重大贡献。我们的研究结果证明了一个前提,即局部代谢状态可调节生物材料微环境中的炎症过程。
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引用次数: 0
Amine headgroups in ionizable lipids drive immune responses to lipid nanoparticles by binding to the receptors TLR4 and CD1d 可离子化脂质中的胺头基通过与 TLR4 和 CD1d 受体结合驱动对纳米脂质颗粒的免疫反应
IF 26.8 1区 医学 Q1 ENGINEERING, BIOMEDICAL Pub Date : 2024-10-03 DOI: 10.1038/s41551-024-01256-w
Namit Chaudhary, Lisa N. Kasiewicz, Alexandra N. Newby, Mariah L. Arral, Saigopalakrishna S. Yerneni, Jilian R. Melamed, Samuel T. LoPresti, Katherine C. Fein, Daria M. Strelkova Petersen, Sushant Kumar, Rahul Purwar, Kathryn A. Whitehead
Lipid nanoparticles (LNPs) are the most clinically advanced delivery vehicle for RNA therapeutics, partly because of established lipid structure–activity relationships focused on formulation potency. Yet such knowledge has not extended to LNP immunogenicity. Here we show that the innate and adaptive immune responses elicited by LNPs are linked to their ionizable lipid chemistry. Specifically, we show that the amine headgroups in ionizable lipids drive LNP immunogenicity by binding to Toll-like receptor 4 and CD1d and by promoting lipid-raft formation. Immunogenic LNPs favour a type-1 T-helper-cell-biased immune response marked by increases in the immunoglobulins IgG2c and IgG1 and in the pro-inflammatory cytokines tumour necrosis factor, interferon γ and the interleukins IL-6 and IL-2. Notably, the inflammatory signals originating from these receptors inhibit the production of anti-poly(ethylene glycol) IgM antibodies, preventing the often-observed loss of efficacy in the LNP-mediated delivery of siRNA and mRNA. Moreover, we identified computational methods for the prediction of the structure-dependent innate and adaptive responses of LNPs. Our findings may help accelerate the discovery of well-tolerated ionizable lipids suitable for repeated dosing. Amine headgroups in ionizable lipids drive the immunogenicity of lipid nanoparticles by binding to Toll-like receptor 4 and CD1d and by promoting lipid-raft formation.
脂质纳米颗粒(LNPs)是临床上最先进的 RNA 治疗药物递送载体,部分原因是脂质结构与活性的关系已经确立,重点在于配方的有效性。然而,这些知识尚未扩展到 LNP 的免疫原性。在这里,我们证明了 LNPs 引起的先天性和适应性免疫反应与其可电离的脂质化学性质有关。具体来说,我们发现可离子化脂质中的胺头基通过与 Toll 样受体 4 和 CD1d 结合以及促进脂质移植物的形成来驱动 LNP 的免疫原性。免疫原性 LNP 有利于 1 型 T 辅助细胞为主的免疫反应,其特征是免疫球蛋白 IgG2c 和 IgG1 以及促炎细胞因子肿瘤坏死因子、干扰素 γ 和白细胞介素 IL-6 和 IL-2 的增加。值得注意的是,来自这些受体的炎症信号抑制了抗聚乙二醇 IgM 抗体的产生,从而避免了在 LNP 介导的 siRNA 和 mRNA 传输过程中经常出现的功效损失。此外,我们还找到了预测 LNPs 结构依赖性先天反应和适应性反应的计算方法。我们的发现可能有助于加快发现耐受性良好、适合重复给药的可电离脂质。
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引用次数: 0
Accurate prediction of disease-risk factors from volumetric medical scans by a deep vision model pre-trained with 2D scans 用二维扫描预训练的深度视觉模型从体积医学扫描中准确预测疾病风险因素
IF 28.1 1区 医学 Q1 ENGINEERING, BIOMEDICAL Pub Date : 2024-10-01 DOI: 10.1038/s41551-024-01257-9
Oren Avram, Berkin Durmus, Nadav Rakocz, Giulia Corradetti, Ulzee An, Muneeswar G. Nittala, Prerit Terway, Akos Rudas, Zeyuan Johnson Chen, Yu Wakatsuki, Kazutaka Hirabayashi, Swetha Velaga, Liran Tiosano, Federico Corvi, Aditya Verma, Ayesha Karamat, Sophiana Lindenberg, Deniz Oncel, Louay Almidani, Victoria Hull, Sohaib Fasih-Ahmad, Houri Esmaeilkhanian, Maxime Cannesson, Charles C. Wykoff, Elior Rahmani, Corey W. Arnold, Bolei Zhou, Noah Zaitlen, Ilan Gronau, Sriram Sankararaman, Jeffrey N. Chiang, Srinivas R. Sadda, Eran Halperin

The application of machine learning to tasks involving volumetric biomedical imaging is constrained by the limited availability of annotated datasets of three-dimensional (3D) scans for model training. Here we report a deep-learning model pre-trained on 2D scans (for which annotated data are relatively abundant) that accurately predicts disease-risk factors from 3D medical-scan modalities. The model, which we named SLIViT (for ‘slice integration by vision transformer’), preprocesses a given volumetric scan into 2D images, extracts their feature map and integrates it into a single prediction. We evaluated the model in eight different learning tasks, including classification and regression for six datasets involving four volumetric imaging modalities (computed tomography, magnetic resonance imaging, optical coherence tomography and ultrasound). SLIViT consistently outperformed domain-specific state-of-the-art models and was typically as accurate as clinical specialists who had spent considerable time manually annotating the analysed scans. Automating diagnosis tasks involving volumetric scans may save valuable clinician hours, reduce data acquisition costs and duration, and help expedite medical research and clinical applications.

由于用于模型训练的三维(3D)扫描注释数据集有限,机器学习在涉及容积生物医学成像任务中的应用受到限制。在此,我们报告了一种在二维扫描(注释数据相对丰富)上预先训练的深度学习模型,该模型能从三维医学扫描模式中准确预测疾病风险因素。我们将该模型命名为 SLIViT(意为 "通过视觉转换器进行切片整合"),它将给定的容积扫描预处理为二维图像,提取其特征图,并将其整合为一个预测结果。我们在八个不同的学习任务中对该模型进行了评估,包括涉及四种容积成像模式(计算机断层扫描、磁共振成像、光学相干断层扫描和超声波)的六个数据集的分类和回归。SLIViT 的表现始终优于特定领域的最先进模型,其准确性通常不亚于花费大量时间手动标注分析扫描结果的临床专家。将涉及容积扫描的诊断任务自动化,可以节省临床医生的宝贵时间,降低数据采集成本,缩短数据采集时间,并有助于加快医学研究和临床应用。
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引用次数: 0
A fast all-optical 3D photoacoustic scanner for clinical vascular imaging 用于临床血管成像的快速全光三维光声扫描仪
IF 28.1 1区 医学 Q1 ENGINEERING, BIOMEDICAL Pub Date : 2024-09-30 DOI: 10.1038/s41551-024-01247-x
N. T. Huynh, E. Zhang, O. Francies, F. Kuklis, T. Allen, J. Zhu, O. Abeyakoon, F. Lucka, M. Betcke, J. Jaros, S. Arridge, B. Cox, A. A. Plumb, P. Beard

The clinical assessment of microvascular pathologies (in diabetes and in inflammatory skin diseases, for example) requires the visualization of superficial vascular anatomy. Photoacoustic tomography (PAT) scanners based on an all-optical Fabry–Perot ultrasound sensor can provide highly detailed 3D microvascular images, but minutes-long acquisition times have precluded their clinical use. Here we show that scan times can be reduced to a few seconds and even hundreds of milliseconds by parallelizing the optical architecture of the sensor readout, by using excitation lasers with high pulse-repetition frequencies and by exploiting compressed sensing. A PAT scanner with such fast acquisition minimizes motion-related artefacts and allows for the volumetric visualization of individual arterioles, venules, venous valves and millimetre-scale arteries and veins to depths approaching 15 mm, as well as for dynamic 3D images of time-varying tissue perfusion and other haemodynamic events. In exploratory case studies, we used the scanner to visualize and quantify microvascular changes associated with peripheral vascular disease, skin inflammation and rheumatoid arthritis. Fast all-optical PAT may prove useful in cardiovascular medicine, oncology, dermatology and rheumatology.

微血管病变(例如糖尿病和炎症性皮肤病)的临床评估需要表层血管解剖的可视化。基于全光学法布里-珀罗超声传感器的光声层析(PAT)扫描仪可以提供非常详细的三维微血管图像,但长达几分钟的采集时间使其无法用于临床。在这里,我们展示了通过并行化传感器读出的光学结构、使用高脉冲重复频率的激发激光器以及利用压缩传感技术,扫描时间可以缩短到几秒甚至几百毫秒。具有这种快速采集功能的 PAT 扫描仪能最大限度地减少与运动相关的伪影,并能对单个动脉血管、静脉、静脉瓣膜和毫米级的动脉和静脉(深度接近 15 毫米)进行容积可视化,以及对随时间变化的组织灌注和其他血流动力学事件进行动态三维成像。在探索性案例研究中,我们使用该扫描仪对与外周血管疾病、皮肤炎症和类风湿性关节炎相关的微血管变化进行了可视化和量化。快速全光 PAT 可能会在心血管医学、肿瘤学、皮肤病学和风湿病学领域大有用武之地。
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引用次数: 0
Engineered allogeneic T cells decoupling T-cell-receptor and CD3 signalling enhance the antitumour activity of bispecific antibodies 脱钩 T 细胞受体和 CD3 信号的工程异体 T 细胞可增强双特异性抗体的抗肿瘤活性
IF 26.8 1区 医学 Q1 ENGINEERING, BIOMEDICAL Pub Date : 2024-09-25 DOI: 10.1038/s41551-024-01255-x
Edo Kapetanovic, Cédric R. Weber, Marine Bruand, Daniel Pöschl, Jakub Kucharczyk, Elisabeth Hirth, Claudius Dietsche, Riyaz Khan, Bastian Wagner, Olivier Belli, Rodrigo Vazquez-Lombardi, Rocío Castellanos- Rueda, Raphael B. Di Roberto, Kevin Kalinka, Luca Raess, Kevin Ly, Shivam Rai, Petra S. Dittrich, Randall J. Platt, Elisa Oricchio, Sai T. Reddy
Bispecific antibodies (biAbs) used in cancer immunotherapies rely on functional autologous T cells, which are often damaged and depleted in patients with haematological malignancies and in other immunocompromised patients. The adoptive transfer of allogeneic T cells from healthy donors can enhance the efficacy of biAbs, but donor T cells binding to host-cell antigens cause an unwanted alloreactive response. Here we show that allogeneic T cells engineered with a T-cell receptor that does not convert antigen binding into cluster of differentiation 3 (CD3) signalling decouples antigen-mediated T-cell activation from T-cell cytotoxicity while preserving the surface expression of the T-cell-receptor–CD3 signalling complex as well as biAb-mediated CD3 signalling and T-cell activation. In mice with CD19+ tumour xenografts, treatment with the engineered human cells in combination with blinatumomab (a clinically approved biAb) led to the recognition and clearance of tumour cells in the absence of detectable alloreactivity. Our findings support the development of immunotherapies combining biAbs and ‘off-the-shelf’ allogeneic T cells. The antitumour activity of bispecific antibodies in immunocompromised hosts can be potentiated via allogeneic T cells engineered with a T-cell receptor that decouples antigen-mediated T-cell activation from T-cell cytotoxicity.
癌症免疫疗法中使用的双特异性抗体(biAbs)依赖于功能性自体 T 细胞,而血液恶性肿瘤患者和其他免疫功能低下的患者的自体 T 细胞往往会受损和耗竭。采用健康供体的异体 T 细胞可以提高生物抗体的疗效,但供体 T 细胞与宿主细胞抗原结合会引起不必要的异体反应。在这里,我们展示了用T细胞受体设计的异体T细胞,这种T细胞受体不会将抗原结合转化为分化3簇(CD3)信号,从而使抗原介导的T细胞活化与T细胞细胞毒性脱钩,同时保留了T细胞受体-CD3信号复合物的表面表达以及生物抗体介导的CD3信号和T细胞活化。在患有 CD19+ 肿瘤异种移植的小鼠身上,用工程化人体细胞与 blinatumomab(一种临床批准的生物抗原)联合治疗,可以在检测不到异体反应的情况下识别和清除肿瘤细胞。我们的研究结果支持将生物抗体与 "现成的 "异体T细胞结合起来开发免疫疗法。
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引用次数: 0
Meta-analysis of the make-up and properties of in vitro models of the healthy and diseased blood-brain barrier. 健康和患病血脑屏障体外模型的组成和特性的元分析。
IF 28.1 1区 医学 Q1 ENGINEERING, BIOMEDICAL Pub Date : 2024-09-20 DOI: 10.1038/s41551-024-01250-2
James G Shamul,Zhiyuan Wang,Hyeyeon Gong,Wenquan Ou,Alisa M White,Diogo P Moniz-Garcia,Shuo Gu,Alisa Morss Clyne,Alfredo Quiñones-Hinojosa,Xiaoming He
In vitro models of the human blood-brain barrier (BBB) are increasingly used to develop therapeutics that can cross the BBB for treating diseases of the central nervous system. Here we report a meta-analysis of the make-up and properties of transwell and microfluidic models of the healthy BBB and of BBBs in glioblastoma, Alzheimer's disease, Parkinson's disease and inflammatory diseases. We found that the type of model, the culture method (static or dynamic), the cell types and cell ratios, and the biomaterials employed as extracellular matrix are all crucial to recapitulate the low permeability and high expression of tight-junction proteins of the BBB, and to obtain high trans-endothelial electrical resistance. Specifically, for models of the healthy BBB, the inclusion of endothelial cells and pericytes as well as physiological shear stresses (~10-20 dyne cm-2) are necessary, and when astrocytes are added, astrocytes or pericytes should outnumber endothelial cells. We expect this meta-analysis to facilitate the design of increasingly physiological models of the BBB.
人体血脑屏障(BBB)的体外模型越来越多地被用于开发能穿过BBB治疗中枢神经系统疾病的疗法。在此,我们报告了对健康血脑屏障以及胶质母细胞瘤、阿尔茨海默病、帕金森病和炎症性疾病中的血脑屏障的transwell和微流控模型的组成和特性进行的荟萃分析。我们发现,模型的类型、培养方法(静态或动态)、细胞类型和细胞比例以及用作细胞外基质的生物材料对再现 BBB 的低通透性和高表达紧密连接蛋白以及获得高跨内皮电阻都至关重要。具体来说,对于健康的 BBB 模型,内皮细胞和周细胞的加入以及生理剪切应力(约 10-20 达因厘米-2)是必要的,当加入星形胶质细胞时,星形胶质细胞或周细胞的数量应多于内皮细胞。我们希望这项荟萃分析能促进设计越来越多的 BBB 生理模型。
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引用次数: 0
Non-viral targeted insertion of large payloads into T cells 以非病毒为靶向将大型有效载荷植入 T 细胞
IF 26.8 1区 医学 Q1 ENGINEERING, BIOMEDICAL Pub Date : 2024-09-16 DOI: 10.1038/s41551-024-01252-0
Zsuzsanna Izsvák
The nuclease Cas9 and DNA-repair pathway homology-mediated end joining can be leveraged to efficiently and non-virally integrate large DNA payloads into genomic target sites in primary T cells.
利用核酸酶 Cas9 和 DNA 修复途径同源物介导的末端连接,可以高效、非病毒性地将大 DNA 有效载荷整合到原代 T 细胞的基因组靶位点。
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引用次数: 0
In situ formation of biomolecular condensates as intracellular drug reservoirs for augmenting chemotherapy 原位形成生物分子凝聚物,作为细胞内药物库,用于增强化疗效果
IF 26.8 1区 医学 Q1 ENGINEERING, BIOMEDICAL Pub Date : 2024-09-13 DOI: 10.1038/s41551-024-01254-y
Tingxizi Liang, Yuxiang Dong, Irina Cheng, Ping Wen, Fengqin Li, Feng Liu, Qing Wu, En Ren, Peifeng Liu, Hongjun Li, Zhen Gu
Biomolecular condensates, which arise from liquid–liquid phase separation within cells, may provide a means of enriching and prolonging the retention of small-molecule drugs within cells. Here we report a method for the controlled in situ formation of biomolecular condensates as reservoirs for the enrichment and retention of chemotherapeutics in cancer cells, and show that the approach can be leveraged to enhance antitumour efficacies in mice with drug-resistant tumours. The method involves histones as positively charged proteins and doxorubicin-intercalated DNA strands bioorthogonally linked via a click-to-release reaction between trans-cyclooctene and tetrazine groups. The reaction temporarily impaired the phase separation of histones in vitro, favoured the initiation of liquid–liquid phase separation within cells and led to the formation of biomolecular condensates that were sufficiently large to be retained within tumour cells. The controlled formation of biomolecular condensates as drug reservoirs within cells may offer new options for boosting the efficacies of cancer therapies. The controlled in situ formation of biomolecular condensates as intracellular reservoirs for the enrichment and retention of a chemotherapeutic in cancer cells enhanced antitumour activities in mice with drug-resistant tumours.
由细胞内液-液相分离产生的生物分子凝聚物可为富集和延长小分子药物在细胞内的保留时间提供一种方法。在这里,我们报告了一种原位受控形成生物分子凝聚体的方法,这种凝聚体是富集和保留癌细胞中化疗药物的贮库,并表明这种方法可用于提高抗药性肿瘤小鼠的抗肿瘤疗效。该方法通过反式环辛烯和四嗪基团之间的点击释放反应,将组蛋白作为带正电荷的蛋白质与多柔比星插入的 DNA 链生物正交连接起来。这种反应暂时阻碍了组蛋白在体外的相分离,有利于启动细胞内的液-液相分离,并导致生物分子凝聚物的形成,这种凝聚物足够大,可以保留在肿瘤细胞内。在细胞内可控地形成生物分子凝聚物作为药物储存库,可为提高癌症疗法的疗效提供新的选择。
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引用次数: 0
Learning what keeps nanomedicines in tumours 了解让纳米药物留在肿瘤中的原因
IF 26.8 1区 医学 Q1 ENGINEERING, BIOMEDICAL Pub Date : 2024-09-13 DOI: 10.1038/s41551-024-01251-1
Yifan Wang, Benjamin R. Schrank, Wen Jiang, Betty Y. S. Kim
An analysis of histopathological data from mouse and human tumours via machine learning reveals that the densities of blood vessels and tumour-associated macrophages are predictive features of the degree of tumoural accumulation of polymeric and liposomal nanomedicines.
通过机器学习分析小鼠和人类肿瘤的组织病理学数据发现,血管和肿瘤相关巨噬细胞的密度是聚合物和脂质体纳米药物在肿瘤中积累程度的预测特征。
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引用次数: 0
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Nature Biomedical Engineering
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