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A holistic understanding of tissue and organ structure and function requires the detection of molecular constituents in their original three-dimensional (3D) context. Imaging mass cytometry (IMC) enables simultaneous detection of up to 40 antigens and transcripts using metal-tagged antibodies but has so far been restricted to two-dimensional imaging. Here we report the development of 3D IMC for multiplexed 3D tissue analysis at single-cell resolution and demonstrate the utility of the technology by analysis of human breast cancer samples. The resulting 3D models reveal cellular and microenvironmental heterogeneity and cell-level tissue organization not detectable in two dimensions. 3D IMC will prove powerful in the study of phenomena occurring in 3D space such as tumor cell invasion and is expected to provide invaluable insights into cellular microenvironments and tissue architecture.

Funder: Cancer Research UK (CRUK); doi: https://doi.org/10.13039/501100000289, Funder: AstraZeneca; doi: https://doi.org/10.13039/100004325, The heterogeneity of breast cancer plays a major role in drug response and resistance and has been extensively characterized at the genomic level. Here, a single-cell breast cancer mass cytometry (BCMC) panel is optimized to identify cell phenotypes and their oncogenic signalling states in a biobank of patient-derived tumour xenograft (PDTX) models representing the diversity of human breast cancer. The BCMC panel identifies 13 cellular phenotypes (11 human and 2 murine), associated with both breast cancer subtypes and specific genomic features. Pre-treatment cellular phenotypic composition is a determinant of response to anticancer therapies. Single-cell profiling also reveals drug-induced cellular phenotypic dynamics, unravelling previously unnoticed intra-tumour response diversity. The comprehensive view of the landscapes of cellular phenotypic heterogeneity in PDTXs uncovered by the BCMC panel, which is mirrored in primary human tumours, has profound implications for understanding and predicting therapy response and resistance.

Identifying transcript location in cells Identifying where specific RNAs occur within a cell or tissue has been limited by technology and imaging capabilities. Expansion microscopy has allowed for better visualization of small structures by expanding the tissues with a polymer- and hydrogel-based system. Alon et al. combined expansion microscopy with long-read in situ RNA sequencing, resulting in a more precise visualization of the location of specific transcripts. This method, termed “ExSeq” for expansion sequencing, was used to detect RNAs, both new transcripts and those previously demonstrated to localize to neuronal dendrites. Unlike other in situ sequencing methods, ExSeq does not target sets of genes. This technology thus unites spatial resolution, multiplexing, and an unbiased approach to reveal insights into RNA localization and its physiological roles in developing and active tissue. Science , this issue p. eaax2656

Aberrant neural oscillations hallmark numerous brain disorders. Here, we first report a method to track the phase of neural oscillations in real-time via endpoint-corrected Hilbert transform (ecHT) that mitigates the characteristic Gibbs distortion. We then used ecHT to show that the aberrant neural oscillation that hallmarks essential tremor (ET) syndrome, the most common adult movement disorder, can be noninvasively suppressed via electrical stimulation of the cerebellum phase-locked to the tremor. The tremor suppression is sustained after the end of the stimulation and can be phenomenologically predicted. Finally, using feature-based statistical-learning and neurophysiological-modelling we show that the suppression of ET is mechanistically attributed to a disruption of the temporal coherence of the oscillation via perturbation of the tremor generating a cascade of synchronous activity in the olivocerebellar loop. The suppression of aberrant neural oscillation via phase-locked driven disruption of temporal coherence may represent a powerful neuromodulatory strategy to treat brain disorders.

Pathological over-activity of the CA1 subfield of the human anterior hippocampus has been identified as a potential predictive marker for transition from a prodromal state to overt schizophrenia. Psychosis, in turn, is associated with elevated activity in the anterior subiculum, the hippocampal output stage directly activated by CA1. Over-activity in these subfields may represent a useful endophenotype to guide translationally predictive preclinical models. To recreate this endophenotype and study its causal relation to deficits in the positive and cognitive symptom domains, we optogenetically activated excitatory neurons of the ventral hippocampus (vHPC; analogous to the human anterior hippocampus), targeting the ventral subiculum. Consistent with previous studies, we found that vHPC over-activity evokes hyperlocomotion, a rodent correlate of positive symptoms. vHPC activation also impaired performance on the spatial novelty preference (SNP) test of short-term memory, regardless of whether stimulation was applied during the encoding or retrieval stage of the task. Increasing dopamine transmission with amphetamine produced hyperlocomotion, but was not associated with SNP impairments. This suggests that short-term memory impairments resulting from hippocampal over-activity likely arise independently of a hyperdopaminergic state, a finding that is consistent with the pharmaco-resistance of cognitive symptoms in patients.

An interesting discussion of the Eurocurrency market is now regularly found in most leading textbooks on money and banking and financial markets and institutions. The reader is usually introduced to something of the history and evolution of the market, its operational mechanics, and its usefulness as a medium for interest rate arbitrage, hedging, and speculating. Typically missing from these otherwise excellent treatments, however, is a generalized discussion of the demand for Eurocurrency deposits. Such an omission is not only puzzling, given the attention paid to the demand for domestic bank balances, it is also confusing to faculty and students who often find it difficult to understand why the theoretical and institutional framework that is used to explain the demand for domestic deposits cannot be applied, with appropriate modifications, to the demand for Eurocurrency deposits. After all, a bank is a bank and a deposit is a deposit. The problem seems to arise from the reluctance of most authors to associate the demand for Eurocurrency deposits with the same motives that are widely assumed to underlie the demand for domestic deposits, namely, transactions. precautionary, and speculative motives. In discussing these issues, I will present a compelling argument in support of the proposition that the demand for Eurocurrency deposits stems, in part, from the holder's demand for transactions balances. and by inference, for precautionary balances. A speculative demand for Eurocurrency deposits could also be demonstrated; however, such a discussion is beyond the scope of this article. It should be understood that the Eurocurrency deposits contemplated here refer to net as opposed to gross Eurocurrency deposits. The latter definition includes a large volume of interbank deposits, which are not relevant to this discussion.

Since the organization of the International Bank for Reconstruction and Development (The World Bank) in 1944, a large number of development oriented financial institutions have emerged throughout the world. By applying their unique form of intermediation to development problems, these Development Banks (DBs), as they have come to be known, have become a major catalyst in the process of economic development. Over the years, numerous proposals for funding borderlands development have surfaced but few of them have directly addressed the possibility of establishing a Borderland Development Bank (BDB). A related proposal was outlined at a conference of U.S.-Mexico border state governors by Carols G. Velez-Ibanez (1983). The proposal called for the establishment of a "Borderlands Development Foundation" which would assist area development in a number of ways; including, stabilizing the region's infrastructure, environment, and population movements. It was also suggested that such a foundation might develop a data base for use in planning and in monitoring demographic, economic, political and social trends in the region. Unfortunately, this rather promising proposal has yet to be realized. This study examines the contributions to development that could be made by a BDB, and the potential public support for such an institution. If a BDB could be organized in such a way as to minimize the Mexican fear of U.S. domination of the bank's activities, it could play a major role in the economic development of the region and strengthen what Hansen (1986b) describes as "the many interdependencies that exist between the Mexican and U.S. borderlands." Most of the development proposals, including government sponsored commissions, have been unilateral, focusing on the needs of only one side of the border, which may explain why they have thus far not been very successful. Perhaps a BDB which enjoyed bilateral public and private sponsorship, and whose mandate was to foster economic development on both sides of the border would stand a better chance of success. The first section of this article discusses the nature of a development bank, the second section discusses the possible impediments to growth along the border, the third section discusses the BDB as a possible solution to these impediments, and the last section provides a summary and concluding remarks.

THE VOLUME of literature on the credit-creating powers of the Euro-dollar market, although small, is growing. This paper contends that the stock of net Euro-dollar deposits (En) can be expressed as the product of a Euro-dollar base (B) and a Euro-dollar multiplier (k). As in domestic models, the terms of the multiplier reflect asset choices of the sectors reflected by them. A parallel between the flow of funds within the Euro-dollar market and most domestic banking systems exists. Except that no single institution serves as a Euro-dollar central bank, the two systems are highly comparable.

Optogenetics has become an important research tool and is being considered as the basis for several neural prostheses. However, few studies have applied optogenetics to the auditory brainstem. This study explored whether optical activation of the cochlear nucleus (CN) elicited responses in neurons in higher centers of the auditory pathway and whether it elicited an evoked response. Viral-mediated gene transfer was used to express channelrhodopsin-2 (ChR2) in the mouse CN. Blue light was delivered via an optical fiber placed near the surface of the infected CN and recordings were made in higher-level centers. Optical stimulation evoked excitatory multiunit spiking activity throughout the tonotopic axis of the central nucleus of the inferior colliculus (IC) and the auditory cortex (Actx). The pattern and magnitude of IC activity elicited by optical stimulation was comparable to that obtained with a 50 dB SPL acoustic click. This broad pattern of activity was consistent with histological confirmation of green fluorescent protein (GFP) label of cell bodies and axons throughout the CN. Increasing pulse rates up to 320 Hz did not significantly affect threshold or bandwidth of the IC responses, but rates higher than 50 Hz resulted in desynchronized activity. Optical stimulation also evoked an auditory brainstem response, which had a simpler waveform than the response to acoustic stimulation. Control cases showed no responses to optical stimulation. These data suggest that optogenetic control of central auditory neurons is feasible, but opsins with faster channel kinetics may be necessary to convey information at rates typical of many auditory signals.