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The Seventh Annual Deep Brain Stimulation (DBS) Think Tank held on September 8th of 2019 addressed the most current: (1) use and utility of complex neurophysiological signals for development of adaptive neurostimulation to improve clinical outcomes; (2) Advancements in recent neuromodulation techniques to treat neuropsychiatric disorders; (3) New developments in optogenetics and DBS; (4) The use of augmented Virtual reality (VR) and neuromodulation; (5) commercially available technologies; and (6) ethical issues arising in and from research and use of DBS. These advances serve as both "markers of progress" and challenges and opportunities for ongoing address, engagement, and deliberation as we move to improve the functional capabilities and translational value of DBS. It is in this light that these proceedings are presented to inform the field and initiate ongoing discourse. As consistent with the intent, and spirit of this, and prior DBS Think Tanks, the overarching goal is to continue to develop multidisciplinary collaborations to rapidly advance the field and ultimately improve patient outcomes.

The habenula, an ancient small brain area in the epithalamus, densely expresses nicotinic acetylcholine receptors and is critical for nicotine intake and aversion. As such, identification of strategies to manipulate habenular activity may yield approaches to treat nicotine addiction. Here we show that GPR151, an orphan G-protein-coupled receptor (GPCR) highly enriched in the habenula of humans and rodents, is expressed at presynaptic membranes and synaptic vesicles and associates with synaptic components controlling vesicle release and ion transport. Deletion of Gpr151 inhibits evoked neurotransmission but enhances spontaneous miniature synaptic currents and eliminates short-term plasticity induced by nicotine. We find that GPR151 couples to the G-alpha inhibitory protein G alpha(o1) to reduce cyclic adenosine monophosphate (cAMP) levels in mice and in GPR151-expressing cell lines that are amenable to ligand screens. Gpr151- knockout (KO) mice show diminished behavioral responses to nicotine and self-administer greater quantities of the drug, phenotypes rescued by viral reexpression of Gpr151 in the habenula. These data identify GPR151 as a critical modulator of habenular function that controls nicotine addiction vulnerability.

Background: The aim is to compare the machine learning-based coronary-computed tomography fractional flow reserve (CT-FFRML) and coronary-computed tomographic morphological plaque characteristics with the resting full-cycle ratio (RFRTM) as a novel invasive resting pressure-wire index for detecting hemodynamically significant coronary artery stenosis. Methods: In our single center study, patients with coronary artery disease (CAD) who had a clinically indicated coronary computed tomography angiography (cCTA) and subsequent invasive coronary angiography (ICA) with pressure wire-measurement were included. On-site prototype CT-FFRML software and on-site CT-plaque software were used to calculate the hemodynamic relevance of coronary stenosis. Results: We enrolled 33 patients (70% male, mean age 68 +/- 12 years). On a per-lesion basis, the area under the receiver operating characteristic curve (AUC) of CT-FFRML (0.90) was higher than the AUCs of the morphological plaque characteristics length/minimal luminal diameter(4) (LL/MLD4; 0.80), minimal luminal diameter (MLD; 0.77), remodeling index (RI; 0.76), degree of luminal diameter stenosis (0.75), and minimal luminal area (MLA; 0.75). Conclusion: CT-FFRML and morphological plaque characteristics show a significant correlation to detected hemodynamically significant coronary stenosis. Whole CT-FFRML had the best discriminatory power, using RFRTM as the reference standard.

Antiretroviral therapy (ART) prevented premature mortality and improved the quality of life among people living with the human immunodeficiency virus (PLWH), such that now more than half of PLWH in the United States are 50 years of age and older. Increased longevity among PLWH has resulted in a significant rise in chronic, comorbid diseases. However, the implementation of guideline-based interventions for preventing, treating, and managing such age-related, chronic conditions among the HIV population is lacking. The PRECluDE consortium supported by the Center for Translation Research and Implementation Science at the National Heart, Lung, and Blood Institute catalyzes implementation research on proven-effective interventions for co-occurring heart, lung, blood, and sleep diseases and conditions among PLWH. These collaborative research studies use novel implementation frameworks with HIV, mental health, cardiovascular, and pulmonary care to advance comprehensive HIV and chronic disease healthcare in a variety of settings and among diverse populations. Published by Elsevier Inc.

Antibody cloning from single B cells is an essential tool for characterizing humoral immune responses and obtaining valuable therapeutic and analytical reagents. Antibody cloning from individuals with high serologic titers to HIV-1, Influenza, Malaria and ZIKV has led to new insights that inform vaccine design efforts. In contrast to humans and mice, less is known about antibody cloning from single B cells in macaques. Here, we describe a protocol to identify and purify single antigen-specific macaque B cells, and subsequently clone and produce macaque monoclonal antibodies. The sorting strategy requires the use of a combination of fluorochrome labeled antigens and omission of anti-IgG antibodies that can interfere with antigen binding and vice versa. Optimized methods for macaque antibody gene amplification, DNA preparation for antibody production and antibody screening by ELISA are also presented.

Vision not only detects and recognizes objects, but performs rich inferences about the underlying scene structure that causes the patterns of light we see. Inverting generative models, or "analysis-by-synthesis", presents a possible solution, but its mechanistic implementations have typically been too slow for online perception, and their mapping to neural circuits remains unclear. Here we present a neurally plausible efficient inverse graphics model and test it in the domain of face recognition. The model is based on a deep neural network that learns to invert a three-dimensional face graphics program in a single fast feedforward pass. It explains human behavior qualitatively and quantitatively, including the classic "hollow face" illusion, and it maps directly onto a specialized face-processing circuit in the primate brain. The model fits both behavioral and neural data better than state-of-the-art computer vision models, and suggests an interpretable reverse-engineering account of how the brain transforms images into percepts.

Bacterial and archaeal CRISPR-Cas systems provide RNA-guided immunity against genetic invaders such as bacteriophages and plasmids. Upon target RNA recognition, type III CRISPR-Cas systems produce cyclic-oligoadenylate second messengers that activate downstream effectors, including Csm6 ribonucleases, via their CARF domains. Here, we show that Enteroccocus italicus Csm6 (EiCsm6) degrades its cognate cyclic hexa-AMP (cA6) activator, and report the crystal structure of EiCsm6 bound to a cA6 mimic. Our structural, biochemical, and in vivo functional assays reveal how cA6 recognition by the CARF domain activates the Csm6 HEPN domains for collateral RNA degradation, and how CARF domain-mediated cA6 cleavage provides an intrinsic off-switch to limit Csm6 activity in the absence of ring nucleases. These mechanisms facilitate rapid invader clearance and ensure termination of CRISPR interference to limit self-toxicity.

Lactate is an end product of glucose metabolism, which serves metabolic and nonmetabolic functions. A new study by Zhang et al. establishes a novel function for lactate whereby it is utilized in a new histone modification, histone lysine lactylation, to regulate gene expression in macrophages.

How do early embryos allocate the resources stored in the sperm and egg? Recently, we established isothermal calorimetry to measure heat dissipation by living zebra-fish embryos and to estimate the energetics of specific developmental events. During the reductive cleavage divisions, the rate of heat dissipation increases from similar to 60 nJ.s(-1) at the two-cell stage to similar to 90 nJ.s(-1) at the 1024-cell stage. Here we ask which cellular process(es) drive this increasing energetic cost. We present evidence that the cost is due to the increase in the total surface area of all the cells of the embryo. First, embryo volume stays constant during the cleavage stage, indicating that the increase is not due to growth. Second, the heat increase is blocked by nocodazole, which inhibits DNA replication, mitosis, and cell division; this suggests some aspect of cell proliferation contributes to these costs. Third, the heat increases in proportion to the total cell surface area rather than total cell number. Fourth, the heat increase falls within the range of the estimated costs of maintaining and assembling plasma membranes and associated proteins. Thus, the increase in total plasma membrane associated with cell proliferation is likely to contribute appreciably to the total energy budget of the embryo.

The mammalian gastrointestinal tract harbors a large reservoir of tissue macrophages, which, in concert with other immune cells, help to maintain a delicate balance between tolerance to commensal microbes and food antigens, and resistance to potentially harmful microbes or toxins. Beyond their roles in resistance and tolerance, recent studies have uncovered novel roles played by tissue-resident, including intestinal-resident macrophages in organ physiology. Here, we will discuss recent advances in the understanding of the origin, phenotype and function of macrophages residing in the different layers of the intestine during homeostasis and under pathological conditions.