Sun, J;Yuan, Y;Wu, X;Liu, A;Wang, J;Yang, S;Liu, B;Kong, Y;Wang, L;Li, Q;Zhang, S;Yuan, T;Xu, T;Huang, J;
| DOI: 10.2139/ssrn.4013919
The use of body-focused repetitive behaviors (BFRBs) is conceptualized as a means for emotion regulation upon stress exposure. However, it is unclear about the neurological mechanism on how repetitive behaviors affect emotion regulation to cope with stress. Here, we identify that excitatory somatostatin-positive neurons in the medial paralemniscal nucleus (MPLSST neurons) control self-grooming and encode reward. MPLSST neuronal activity is responsible for self-grooming initiation and maintenance. Loss-of-function of MPLSST neurons attenuates both self-grooming motor actions and anxiety alleviation upon stress exposure. Activating MPLSST neurons generate reward and drive reinforcement through eliciting dopamine release in the downstream target of the ventral tegmental area (VTA), and neuropeptide SST facilitates the rewarding impact of MPLSST neurons. MPLSST neuron-mediated self-grooming is triggered by inputs from the central amygdala (CeA). Our study validates a CeA-MPLSST-VTADA circuit mediating the impact of self-grooming on emotion regulation to cope with stress through generating reward and pleasurable feelings.
Hoffman, E;Dang, U;Clemens, P;
| DOI: Genotypes were determined by PCR using commercial vendors (Transnetyx, Cordova, TN, USA).
Vamorolone is a first-in-class steroidal anti-inflammatory drug with novel structure/activity relationships with glucocorticoid and mineralocorticoid receptor targets compared to deflazacort or prednisone. Published open-label dose-finding studies (0.25-6.0 mg/kg/day) in DMD showed significant motor function improvement over 24 weeks for 2.0 and 6.0 mg/kg/day dose groups (n=48; age 4 to 6-month delay and maintained a higher dose through the remaining study period. Analyses of disease trajectories showed a strong effect of age at initiation of treatment. Subjects initiating treatment at 4-5 years showed highest clinical outcome performance levels as well as a delayed decline of motor function compared to subjects initially treated with low doses (0.25 or 0.75 mg/kg/day). Stratification of participants by treatment period at high doses (2.5 years; or delayed start 2.0 years), and/or by age showed data consistent with a disease modifying effect for many outcome measures. Vamorolone treatment was not associated with typical safety concerns of corticosteroid treatment (slowing of linear growth, insulin resistance, decreases in osteocalcin).
Open Forum Infectious Diseases
Ward, R;Aghaeepour, N;Bhattacharyya, R;Clish, C;Gaudillière, B;Hacohen, N;Mansour, M;Mudd, P;Pasupneti, S;Presti, R;Rhee, E;Sen, P;Spec, A;Tam, J;Villani, A;Woolley, A;Hsu, J;Vyas, J;
| DOI: 10.1093/ofid/ofab483
The field of infectious diseases currently takes a reactive approach, treating infections as they present in patients. Although certain populations are known to be at greater risk of developing infection (e.g., immunocompromised), we lack a systems approach to define the true risk of future infection for a patient. Guided by impressive gains in -omics technologies, future strategies to infectious diseases should take a precision approach to infection through identification of patients at intermediate and high-risk of infection and deploy targeted preventative measures (i.e., prophylaxis). The advances of high-throughput immune profiling by multiomics approaches (i.e., transcriptomics, epigenomics, metabolomics, proteomics) holds the promise to identify patients at increased risk of infection and enable risk-stratifying approaches to be applied in the clinic. Integration of patient-specific data using machine learning improves the effectiveness of prediction, providing the necessary technologies needed to propel the field of infectious diseases medicine into the era of personalized medicine.
Immunological mechanisms of vaccine-induced protection against COVID-19 in humans
Nature reviews. Immunology
Sadarangani, M;Marchant, A;Kollmann, TR;
PMID: 34211186 | DOI: 10.1038/s41577-021-00578-z
Most COVID-19 vaccines are designed to elicit immune responses, ideally neutralizing antibodies (NAbs), against the SARS-CoV-2 spike protein. Several vaccines, including mRNA, adenoviral-vectored, protein subunit and whole-cell inactivated virus vaccines, have now reported efficacy in phase III trials and have received emergency approval in many countries. The two mRNA vaccines approved to date show efficacy even after only one dose, when non-NAbs and moderate T helper 1 cell responses are detectable, but almost no NAbs. After a single dose, the adenovirus vaccines elicit polyfunctional antibodies that are capable of mediating virus neutralization and of driving other antibody-dependent effector functions, as well as potent T cell responses. These data suggest that protection may require low levels of NAbs and might involve other immune effector mechanisms including non-NAbs, T cells and innate immune mechanisms. Identifying the mechanisms of protection as well as correlates of protection is crucially important to inform further vaccine development and guide the use of licensed COVID-19 vaccines worldwide.
Alpha oscillations and event-related potentials reflect distinct dynamics of attribute construction and evidence accumulation in dietary decision making
HajiHosseini, A;Hutcherson, CA;
PMID: 34263723 | DOI: 10.7554/eLife.60874
How does regulatory focus alter attribute value construction (AVC) and evidence accumulation (EA)? We recorded electroencephalogram during food choices while participants responded naturally or regulated their choices by attending to health attributes or decreasing attention to taste attributes. Using a drift diffusion model, we predicted the time course of neural signals associated with AVC and EA. Results suggested that event-related potentials (ERPs) correlated with the time course of model-predicted taste-attribute signals, with no modulation by regulation. By contrast, suppression of frontal and occipital alpha power correlated with the time course of EA, tracked tastiness according to its goal relevance, and predicted individual variation in successful down-regulation of tastiness. Additionally, an earlier rise in frontal and occipital theta power represented food tastiness more strongly during regulation and predicted a weaker influence of food tastiness on behaviour. Our findings illuminate how regulation modifies the representation of attributes during the process of EA.
mRNA distribution in skeletal muscle is associated with mRNA size
Pinheiro, H;Pimentel, MR;Sequeira, C;Oliveira, LM;Pezzarossa, A;Roman, W;Gomes, ER;
PMID: 34164679 | DOI: 10.1242/jcs.256388
Skeletal muscle myofibers are large and elongated cells with multiple and evenly distributed nuclei. Nuclear distribution suggests that each nucleus influences a specific compartment within the myofiber and implies a functional role for nuclear positioning. Compartmentalization of specific mRNAs and proteins has been reported at the neuromuscular and myotendinous junctions, but mRNA distribution in non-specialized regions of the myofibers remains largely unexplored. We report that the bulk of mRNAs is enriched around the nucleus of origin and that this perinuclear accumulation depends on recently transcribed mRNAs. Surprisingly, mRNAs encoding large proteins - giant mRNAs - are spread throughout the cell and do not exhibit perinuclear accumulation. Furthermore, by expressing exogenous transcripts with different sizes we found that size contributes to mRNA spreading independently of mRNA sequence. Both these mRNA distribution patterns depend on microtubules and are independent of nuclear dispersion, mRNA expression level and stability, and the characteristics of the encoded protein. Thus, we propose that mRNA distribution in non-specialized regions of skeletal muscle is size selective to ensure cellular compartmentalization and simultaneous long-range distribution of giant mRNAs.
Functionally distinct POMC-expressing neuron subpopulations in hypothalamus revealed by intersectional targeting
Biglari, N;Gaziano, I;Schumacher, J;Radermacher, J;Paeger, L;Klemm, P;Chen, W;Corneliussen, S;Wunderlich, CM;Sue, M;Vollmar, S;Klöckener, T;Sotelo-Hitschfeld, T;Abbasloo, A;Edenhofer, F;Reimann, F;Gribble, FM;Fenselau, H;Kloppenburg, P;Wunderlich, FT;Brüning, JC;
PMID: 34002087 | DOI: 10.1038/s41593-021-00854-0
Pro-opiomelanocortin (POMC)-expressing neurons in the arcuate nucleus of the hypothalamus represent key regulators of metabolic homeostasis. Electrophysiological and single-cell sequencing experiments have revealed a remarkable degree of heterogeneity of these neurons. However, the exact molecular basis and functional consequences of this heterogeneity have not yet been addressed. Here, we have developed new mouse models in which intersectional Cre/Dre-dependent recombination allowed for successful labeling, translational profiling and functional characterization of distinct POMC neurons expressing the leptin receptor (Lepr) and glucagon like peptide 1 receptor (Glp1r). Our experiments reveal that POMCLepr+ and POMCGlp1r+ neurons represent largely nonoverlapping subpopulations with distinct basic electrophysiological properties. They exhibit a specific anatomical distribution within the arcuate nucleus and differentially express receptors for energy-state communicating hormones and neurotransmitters. Finally, we identify a differential ability of these subpopulations to suppress feeding. Collectively, we reveal a notably distinct functional microarchitecture of critical metabolism-regulatory neurons.
IL-1R1-dependent signaling coordinates epithelial regeneration in response to intestinal damage
Cox, CB;Storm, EE;Kapoor, VN;Chavarria-Smith, J;Lin, DL;Wang, L;Li, Y;Kljavin, N;Ota, N;Bainbridge, TW;Anderson, K;Roose-Girma, M;Warming, S;Arron, JR;Turley, SJ;de Sauvage, FJ;van Lookeren Campagne, M;
PMID: 33963061 | DOI: 10.1126/sciimmunol.abe8856
Repair of the intestinal epithelium is tightly regulated to maintain homeostasis. The response after epithelial damage needs to be local and proportional to the insult. How different types of damage are coupled to repair remains incompletely understood. We report that after distinct types of intestinal epithelial damage, IL-1R1 signaling in GREM1+ mesenchymal cells increases production of R-spondin 3 (RSPO3), a Wnt agonist required for intestinal stem cell self-renewal. In parallel, IL-1R1 signaling regulates IL-22 production by innate lymphoid cells and promotes epithelial hyperplasia and regeneration. Although the regulation of both RSPO3 and IL-22 is critical for epithelial recovery from Citrobacter rodentium infection, IL-1R1-dependent RSPO3 production by GREM1+ mesenchymal cells alone is sufficient and required for recovery after dextran sulfate sodium-induced colitis. These data demonstrate how IL-1R1-dependent signaling orchestrates distinct repair programs tailored to the type of injury sustained that are required to restore intestinal epithelial barrier function.
Single-cell dissection of cellular components and interactions shaping the tumor immune phenotypes in ovarian cancer
Hornburg, M;Desbois, M;Lu, S;Guan, Y;Lo, AA;Kaufman, S;Elrod, A;Lotstein, A;DesRochers, TM;Munoz-Rodriguez, JL;Wang, X;Giltnane, J;Mayba, O;Turley, SJ;Bourgon, R;Daemen, A;Wang, Y;
PMID: 33961783 | DOI: 10.1016/j.ccell.2021.04.004
Distinct T cell infiltration patterns, i.e., immune infiltrated, excluded, and desert, result in different responses to cancer immunotherapies. However, the key determinants and biology underpinning these tumor immune phenotypes remain elusive. Here, we provide a high-resolution dissection of the entire tumor ecosystem through single-cell RNA-sequencing analysis of 15 ovarian tumors. Immune-desert tumors are characterized by unique tumor cell-intrinsic features, including metabolic pathways and low antigen presentation, and an enrichment of monocytes and immature macrophages. Immune-infiltrated and -excluded tumors differ markedly in their T cell composition and fibroblast subsets. Furthermore, our study reveals chemokine receptor-ligand interactions within and across compartments as potential mechanisms mediating immune cell infiltration, exemplified by the tumor cell-T cell cross talk via CXCL16-CXCR6 and stromal-immune cell cross talk via CXCL12/14-CXCR4. Our data highlight potential molecular mechanisms that shape the tumor immune phenotypes and may inform therapeutic strategies to improve clinical benefit from cancer immunotherapies.
The role of EBV in hematolymphoid proliferations: Emerging concepts relevant to diagnosis and treatment
Ababneh, E;Saad, AM;Crane, GM;
PMID: 33829526 | DOI: 10.1111/his.14379
Epstein-Barr virus (EBV) is a ubiquitous gammaherpesvirus with >90% of the adult population worldwide harboring latent infection. A small subset of those infected develop EBV-associated neoplasms including a range of lymphoproliferative disorders (LPD). The diagnostic distinction of these entities appears increasingly relevant as our understanding of EBV-host interactions and mechanisms of EBV-driven lymphomagenesis improves. EBV may lower the mutational threshold for malignant transformation, create potential vulnerabilities related to viral alteration of cell metabolism and allow for improved immune targeting. However, these tumors may escape immune surveillance by affecting their immune microenvironment, limiting viral gene expression or potential loss of the viral episome. Methods to manipulate the latency state of the virus to enhance immunogenicity are emerging as well as the potential to detect so-called "hit and run" cases where EBV has been lost. Finally, measurement of EBV DNA remains an important biomarker for screening and monitoring of LPD. Methods to distinguish EBV DNA derived from virions during lytic activation from latent, methylated EBV DNA present in EBV-associated neoplasms may broaden the utility of this testing, particularly in patients with compromised immune function. We will highlight some of these emerging areas relevant to the diagnosis and treatment of EBV-associated LPD with potential applicability to other EBV-associated neoplasms. This article is protected by
Top-Down Control of Sweet and Bitter Taste in the Mammalian Brain
Jin, H;Fishman, ZH;Ye, M;Wang, L;Zuker, CS;
PMID: 33417862 | DOI: 10.1016/j.cell.2020.12.014
Hardwired circuits encoding innate responses have emerged as an essential feature of the mammalian brain. Sweet and bitter evoke opposing predetermined behaviors. Sweet drives appetitive responses and consumption of energy-rich food sources, whereas bitter prevents ingestion of toxic chemicals. Here we identified and characterized the neurons in the brainstem that transmit sweet and bitter signals from the tongue to the cortex. Next we examined how the brain modulates this hardwired circuit to control taste behaviors. We dissect the basis for bitter-evoked suppression of sweet taste and show that the taste cortex and amygdala exert strong positive and negative feedback onto incoming bitter and sweet signals in the brainstem. Finally we demonstrate that blocking the feedback markedly alters responses to ethologically relevant taste stimuli. These results illustrate how hardwired circuits can be finely regulated by top-down control and reveal the neural basis of an indispensable behavioral response for all animals.
McHenry JA, Otis JM, Rossi MA, Robinson JE, Kosyk O, Miller NW, McElligott ZA, Budygin EA, Rubinow DR, Stuber GD.
PMID: 28135243 | DOI: 10.1038/nn.4487
Neural networks that control reproduction must integrate social and hormonal signals, tune motivation, and coordinate social interactions. However, the neural circuit mechanisms for these processes remain unresolved. The medial preoptic area (mPOA), an essential node for social behaviors, comprises molecularly diverse neurons with widespread projections. Here we identify a steroid-responsive subset of neurotensin (Nts)-expressing mPOA neurons that interface with the ventral tegmental area (VTA) to form a socially engaged reward circuit. Using in vivo two-photon imaging in female mice, we show that mPOANts neurons preferentially encode attractive male cues compared to nonsocial appetitive stimuli. Ovarian hormone signals regulate both the physiological and cue-encoding properties of these cells. Furthermore, optogenetic stimulation of mPOANts-VTA circuitry promotes rewarding phenotypes, social approach and striatal dopamine release. Collectively, these data demonstrate that steroid-sensitive mPOA neurons encode ethologically relevant stimuli and co-opt midbrain reward circuits to promote prosocial behaviors critical for species survival.
