Focused ultrasound (FUS) with microbubbles opens the blood-brain barrier (BBB) for targeted drug delivery into the brain. How brain endothelial cells (BECs) respond to either low acoustic pressures known to open the BBB transiently, or high pressures that cause brain damage, is incompletely characterized. Here, we apply FUS at low (450 kPa) and high (750 kPa) pressures in mice where BBB tight junctions are labelled with eGFP and find that arteriole and capillary BECs respond to low pressure by a transient reorganization of tight junctions associated with BBB opening. Moreover, this process does not depend on caveolae. In contrast, BBB opening at high pressure is associated with tight junction obliteration even after 72 hours, allowing persistent fibrinogen passage and microglial activation. Single-cell RNA-sequencing of BECs from FUS-BBBO mice shows that the transcriptomic responses of BECs exposed to high pressure are dominated by the stress response and cell junction disassembly, whereas lower pressure induces primarily genes responsible for intracellular repair. Therefore, transient reorganization of tight junctions and repair responses mediate safe BBB opening for therapeutic delivery.

Understanding the impact of long-term opioid exposure on the embryonic brain is critical due to the surging number of pregnant mothers with opioid dependency. However, this has been limited by human brain inaccessibility and cross-species differences in animal models. Here, a human midbrain model is established that uses hiPSC-derived midbrain organoids to assess cell-type-specific responses to acute and chronic fentanyl treatment and fentanyl withdrawal. Single-cell mRNA sequencing of 25,510 cells from organoids in different treatment groups reveals that chronic fentanyl treatment arrests neuronal subtype specification during early midbrain development and alters synaptic activity and neuron projection. In contrast, acute fentanyl treatment increases dopamine release but does not significantly alter gene expression related to cell lineage development. These results provide the first examination of the effects of opioid exposure on human midbrain development at the single-cell level.

We propose an ex vivo T cell expansion system that mimics natural antigen-presenting cells (APCs) for adoptive cell therapy (ACT). Microfiber scaffolds coated with dendritic cell (DC) membrane replicate physicochemical properties of dendritic cells specific for T cell activation such as rapid recognition by T cells, long duration of T cell tethering, and DC-specific co-stimulatory cues. The DC membrane-coated scaffold is first surface-immobilized with T cell stimulatory ligands, anti-CD3 (αCD3) and anti-CD28 (αCD28) antibodies, followed by adsorption of releasable interleukin-2 (IL-2). The scaffolds present both surface and soluble cues to T cells ex vivo in the same way that these cues are presented by natural APCs in vivo. We demonstrate that the DC-mimicking scaffold promotes greater polyclonal expansion of primary human T cells as compared to αCD3/αCD28-functionalized Dynabead. More importantly, major histocompatibility complex molecules derived from the DC membrane of the scaffold allow antigen-specific T cell expansion with target cell-specific killing ability. In addition, most of the expanded T cells (∼97%) can be harvested from the scaffold by density gradient centrifugation. Overall, the DC-mimicking scaffold offers a scalable, modular, and customizable platform for rapid expansion of highly functional T cells for ACT.

Neuroimmunomodulation is a promising form of drug-free treatment for neurological diseases ranging from Alzheimer’s disease to depression. The evidence supporting the efficacy of focused ultrasound (FUS) neuroimmunomodulation is encouraging; however, the method has yet to be standardized, and its mechanism remains poorly understood. Methods of FUS neuroimmunomodulation can be categorized into three paradigms based on the parameters used. In the first paradigm, focused ultrasound blood–brain barrier opening (FUS-BBBO) combines FUS with microbubbles (MB) to transiently and safely induce BBB opening. In the second paradigm, focused ultrasound neuromodulation (FUS-N) harnesses the acoustic effects of FUS alone (without MB). In the third paradigm, focused ultrasound with microbubbles without BBBO (FUS + MB) combines MB with FUS below the BBBO pressure threshold—harnessing the mechanical effects of FUS without opening the barrier. Due to the recent evidence of brain macrophage modulation in response to FUS-BBBO, we provide the first direct comparison of brain macrophage modulation between all three paradigms both in the presence and absence of Alzheimer’s disease (AD) pathology. Flow cytometry and single-cell sequencing are employed to identify FUS-BBBO as the FUS paradigm, which maximizes brain macrophage modulation, including an increase in the population of neuroprotective, disease-associated microglia and direct correlation between treatment cavitation dose and brain macrophage phagocytosis. Next, we combine spatial and single-cell transcriptomics with immunohistochemical validation to provide the first characterization of brain macrophage distribution in response to FUS-BBBO. Given their relevance within neurodegeneration and perturbation response, we emphasize the analysis of three brain macrophage populations—disease- and interferon-associated microglia and central-nervous-system-associated macrophages. We find and validate the redistribution of each population with an overall trend toward increased interaction with the brain–cerebrospinal fluid barrier (BCSFB) after FUS-BBBO, an effect that is found to be more pronounced in the presence of disease pathology. This study addresses the prior lack of FUS neuroimmunomodulation paradigm optimization and mechanism characterization, identifying that FUS-BBBO best modulates brain macrophage response via complex redistribution.

The COVID-19 pandemic has aggravated a preexisting epidemic: the opioid crisis. Much literature has shown that the circumstances imposed by COVID-19, such as social distancing regulations, medical and financial instability, and increased mental health issues, have been detrimental to those with opioid use disorder (OUD). In addition, unexpected neurological sequelae in COVID-19 patients suggest that COVID-19 compromises neuroimmunity, induces hypoxia, and causes respiratory depression, provoking similar effects as those caused by opioid exposure. Combined conditions of COVID-19 and OUD could lead to exacerbated complications. With limited human in vivo options to study these complications, we suggest that iPSC-derived brain organoid models may serve as a useful platform to investigate the physiological connection between COVID-19 and OUD. This mini-review highlights the advances of brain organoids in other neuropsychiatric and infectious diseases and suggests their potential utility for investigating OUD and COVID-19, respectively.

DiGeorge Syndrome, or 22q11.2 deletion syndrome (22q11.2 DS), is a genetic disorder caused by microdeletions in chromosome 22, impairing the function of endothelial cells (EC) and/or mural cells and leading to deficits in blood vessel development such as abnormal aortic arch morphology, tortuous retinal vessels, and tetralogy of Fallot. The mechanism by which dysfunctional endothelial cells and pericytes contribute to the vasculopathy, however, remains unknown. In this study, we used human blood vessel organoids (VOs) generated from iPSC of 22q11.2 DS patients to model the vascular malformations and genetic dysfunctions. We combined high-resolution lightsheet imaging and single-cell transcriptome analysis to link the genetic profile and vascular phenotype at the single-cell level. We developed a comprehensive analytical methodology by integrating deep learning-mediated blood vessel segmentation, network graph construction, and tessellation analysis for automated morphology characterization. We report that 22q11.2DS VOs demonstrate a smaller size with increased angiogenesis/sprouting, suggesting a less stable vascular network. Overall, clinical presentations of smaller vascular diameter, less connected vasculature, and increased branch points were recapitulated in 22q11.2DS VOs. Single-cell transcriptome profiling showed heterogeneity in both 22q11.2DS and control VOs, but the former demonstrated alterations in endothelial characteristics that are organ-specific and suggest a perturbation in the vascular developmental process. Intercellular communication analysis indicated that the vascular dysfunctions in 22q11.2 deletion were due to a lower cell-cell contact and upregulated extracellular matrix organization involving collagen and fibronectin. Voronoi diagram-based tessellation analysis also indicated that the colocalization of endothelial tubes and mural cells was different between control and 22q11.2 VOs, indicating that alterations in EC and mural interactions might contribute to the deficits in vascular network formation. This study illustrates the utility of VO in revealing the pathogenesis of 22q11.2DS vasculopathy.

Journal of Palliative MedicineVol. 23, No. 1 Letters to the EditorHome-Based Primary Care as a Teaching Site for Palliative CareJennifer M. Reckrey, Moshe J. Willner, Linda V. DeCherrie, and Elizabeth T. McCormickJennifer M. ReckreyAddress correspondence to: Jennifer M. Reckrey, MD, Division of General Internal Medicine, Department of Geriatrics and Palliative Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1216, New York, NY 10029 E-mail Address: jennifer.reckrey@mountsinai.orgDepartment of Geriatrics and Palliative Medicine, Division of General Internal Medicine, Icahn School of Medicine at Mount Sinai, New York, New York.Search for more papers by this author, Moshe J. WillnerColumbia University, New York, New York.Search for more papers by this author, Linda V. DeCherrieDepartment of Geriatrics and Palliative Medicine, Division of General Internal Medicine, Icahn School of Medicine at Mount Sinai, New York, New York.Search for more papers by this author, and Elizabeth T. McCormickDepartment of Geriatrics and Palliative Medicine, Division of General Internal Medicine, Icahn School of Medicine at Mount Sinai, New York, New York.Search for more papers by this authorPublished Online:23 Dec 2019https://doi.org/10.1089/jpm.2019.0388AboutSectionsView articleView Full TextPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail View article"Home-Based Primary Care as a Teaching Site for Palliative Care." Journal of Palliative Medicine, 23(1), p. 7FiguresReferencesRelatedDetails Volume 23Issue 1Jan 2020 InformationCopyright 2020, Mary Ann Liebert, Inc., publishersTo cite this article:Jennifer M. Reckrey, Moshe J. Willner, Linda V. DeCherrie, and Elizabeth T. McCormick.Home-Based Primary Care as a Teaching Site for Palliative Care.Journal of Palliative Medicine.Jan 2020.7-7.http://doi.org/10.1089/jpm.2019.0388Published in Volume: 23 Issue 1: December 23, 2019PDF download

Orbital angular momentum (OAM) has gained interest due to its potential to increase capacity in optical communication systems as well as an additional domain for reconfigurable networks. This is due to the following: (i) coaxially propagated OAM beams with different charges are mutually orthogonal, (ii) OAM beams can be efficiently multiplexed and demultiplexed, and (iii) OAM charges can be efficiently manipulated. Therefore, multiple data-carrying OAM beams could have the potential capability for reconfigurable optical switching and routing. In this paper, we discuss work involving reconfigurable OAM-based optical add/drop multiplexing, space switching, polarization switching, channel hopping, and multicasting.

We experimentally studied the performance of a delay-line interferometer-based optical signal-to-noise ratio (OSNR) monitor that is pre-calibrated in optimal conditions for 25-Gbaud pol-muxed quadrature-amplitude-modulation (QAM) signals, when unpredicted changes outside the monitor occurred either in the transmitter or the link.

A stochastic-parallel-gradient-descent algorithm (SPGD) based on Zernike polynomials is proposed to generate the phase correction pattern for a distorted orbital angular momentum (OAM) beam. The Zernike-polynomial coefficients for the correction pattern are obtained by monitoring the intensity profile of the distorted OAM beam through an iteration-based feedback loop. We implement this scheme and experimentally show that the proposed approach improves the quality of the turbulence-distorted OAM beam. Moreover, we apply phase correction patterns derived from a probe OAM beam through emulated turbulence to correct other OAM beams transmitted through the same turbulence. Our experimental results show that the patterns derived this way simultaneously correct multiple OAM beams propagating through the same turbulence, and the crosstalk among these modes is reduced by more than 5 dB.

We propose and demonstrate an all optical phase noise mitigation scheme by mixing differentially delayed nonlinear products. For 40-Gbits/s signals, phase squeezing results in phase noise range reduction of around 50% and 1.5 dB OSNR gain at BER 10-5.

An intensity-based algorithm is employed to derive the correction phase pattern for a distorted probe orbital-angular-momentum (OAM) beam. This correction pattern is used to compensate the distortions of three multiplexed OAM beams, each carrying a 50-Gbaud QPSK signal. The crosstalk between channels is reduced by >5 dB with this approach.

A mode (de)multiplexer in a basis of OAM modes for MIMO-based and non-MIMO-based multimode fiber systems is experimentally demonstrated which via a single optical element can (de)multiplex and generate individual modes with potential scalability.

We investigate the orthogonality of orbital angular momentum (OAM) with other multiplexing domains and present a free-space data link that uniquely combines OAM-, polarization-, and wavelength-division multiplexing. Specifically, we demonstrate the multiplexing/demultiplexing of 1008 data channels carried on 12 OAM beams, 2 polarizations, and 42 wavelengths. Each channel is encoded with 100 Gbit/s quadrature phase-shift keying data, providing an aggregate capacity of 100.8 Tbit/s (12×2×42×100 Gbit/s).

We demonstrate optical Nyquist channel generation based on a comb-based optical tapped-delay-line. The frequency lines of an optical frequency comb are used as the taps of the optical tapped-delay-line to perform a finite-impulse response (FIR) filter function. A single optical nonlinear element is utilized to multiplex the taps and form the Nyquist signal. The tunablity of the approach over the baud rate and modulation format is shown. Optical signal-to-noise ratio penalty of 2.8 dB is measured for the 11-tap Nyquist filtering of 32-Gbaud QPSK signal.

We experimentally demonstrate tunable optical Nyquist generation of 32Gbaud QPSK signals using optical tapped-delay line. Optical Nyquist spectra for different number of taps are shown, and 20% EVM and 2.8 dB OSNR penalty at BER of 1e-3 are measured.

We discuss data switching techniques in communication networks using orbital-angular-momentum (OAM) multiplexing. Reconfigurable functions such as optical add/drop multiplexing, data switching between OAM beams from different input ports, and polarization switching are described.

We demonstrate reconfigurable orbital angular momentum (OAM) and polarization manipulation of OAM- and polarization-multiplexed 100 Gbit/s quadrature phase shift keying (QPSK) data channels. Each data channel's OAM value and its polarization state can be arbitrarily changed by taking advantage of the unique wavefront profile of OAM beams using liquid crystal on silicon-based spatial light modulators. The manipulation operation introduces a power penalty of <1 dB for 100 Gbit/s QPSK signals.

In this paper, we present a free-space link utilizing orbital angular momentum (OAM) multiplexing, where only a proportion of the beam is received. Partially receiving an OAM mode could lead to crosstalk between neighboring modes. Here, we analyzed the effect of the aperture size on the system crosstalk both numerically and experimentally. We also demonstrated an optical data link with a total capacity of 200 Gbit/s using receiver with partial aperture. Bit error rate (BER) performance of the partial receiver is measured for different receiver aperture sizes.

United States. Defense Advanced Research Projects Agency. Information in a Photon (InPho) Program