Probes for INS

IEIP and DOMS are two types of muscle pain induced by exercise. IEIP occurs during whereas DOMS appears days after exercise. Acid sensing ion channels (ASICs) expressed in muscle afferents, play a role in different pain conditions. ASICs are regulated via chemicals released during intense muscle contraction and microinjuries. Recently, we showed that ASICs are required for IEIP. Here, we tested if ASICs are also required for DOMS. Wild type (WT) and ASIC3-/- mice were divided into control and exercise groups. Exercise group underwent an exhaustive exercise; control group were placed on a non-moving treadmill. Locomotor movement was measured via Open field test to examine fatigue and/or soreness immediately and 24h after exercise. Next, exercise-induced muscle pain was assessed by muscle withdrawal threshold (MWT) at baseline, immediately and 24h after exercise. Our results showed; ASIC3-/- had similar baseline locomotor activity, muscle pain responses and exercise performance as WT. However, ASIC3-/- showed different responses after exercise compared to WT. WT had a lower MWT immediately and 24h after exercise compared to baseline. On the other hand, ASIC3-/- showed a lower MWT only 24h after exercise, but not immediately after. In addition, ASIC3-/- had significant lower locomotor activity than WT immediately after exercise. Also, ASIC3-/- had significant lower movement 24h after exercise compared to control ASIC3-/-, however this difference was not significant for WT mice. In summary, while WT and ASIC3-/- had a same exercise performance, they had different pain perception and fatigue immediately, but not 24h after exercise. Unlike WT, ASIC3-/- did not develop IEIP, even though ASIC3-/- had a higher fatigue level than WT as measured by diminished locomotion after exercise. On the other hand, ASIC3-/- developed DOMS a day after exercise like WT. These results show ASICs are required for immediate exercise-induced pain, but not exercise-induced fatigue and DOMS. Supported by the Department of Veterans Affairs Merit Award (5I01BX000776).

Memory retrieval refers to the fundamental ability of organisms to make use of acquired, sometimes inconsistent, information about the world. Although memory acquisition has been studied extensively, the neurobiological mechanisms underlying memory retrieval remain largely unknown. Conditioned taste aversion (CTA) is a robust associative paradigm, through which animals can be trained to express aversion toward innately appetitive tastants. The anterior insula (aIC) is indispensable in the ability of mammals to retrieve associative information regarding tastants that have been previously linked with gastric malaise. Here, we show that CTA memory retrieval promotes cell-type-specific activation in the aIC. Using chemogenetic tools in the aIC, we found that CTA memory acquisition requires activation of excitatory neurons and inhibition of inhibitory neurons, whereas retrieval necessitates activation of both excitatory and inhibitory aIC circuits. CTA memory retrieval at the aIC activates parvalbumin (PV) interneurons and increases synaptic inhibition onto activated pyramidal neurons projecting to the basolateral amygdala (aIC-BLA). Unlike innately appetitive taste memory retrieval, CTA retrieval increases synaptic inhibition onto aIC-BLA-projecting neurons that is dependent on activity in aIC PV interneurons. PV aIC interneurons coordinate CTA memory retrieval and are necessary for its dominance when conflicting internal representations are encountered over time. The reinstatement of CTA memories following extinction is also dependent on activation of aIC PV interneurons, which increase the frequency of inhibition onto aIC-BLA-projecting neurons. This newly described interaction of PV and a subset of excitatory neurons can explain the coherency of aversive memory retrieval, an evolutionary pre-requisite for animal survival.

METHODS : Gene expression of ABCA1 and ApoA1 on human donor tissue and iPSC-RPE were examined by qPCR (n=3). Bulk RNAseq examined transcript changes in key RCT genes on donor retinas across different stages of disease progression. RNAscope probes (ACDBio) were designed against abca1 transcripts with appropriate mismatch controls. Neutral lipid stain with oil-red O on 10um cryo-sections of abca1 KO and wild type (WT) eyes (N= 5). Two siRNAs knocked down abca1 in iPSC-RPE cells to assess abca1 contribution to cholesterol efflux (n=3). Samples were analyzed with the cholesterol efflux kit (ab196985) and compared to non-targeting control siRNAs. Histological analysis of ABCA1 protein using anti-ABCA1 (Invitrogen-MA516026) on human donor retinas (AMD1 vs AMD3).

Background: Adrenocortical carcinoma (ACC) is a very rare and aggressive, endocrine malignancy with still limited treatment options. Approximately 60% of patients with ACC show endogenous glucocorticoid excess which could be one potential cause, why first clinical trials with immunotherapies, like immune checkpoint inhibitors, showed only modest results. Due to the lack of an ACC-specific antigen structure, other immunotherapeutic approaches, like specialized cancer treatments using chimeric antigen receptor (CAR) therapy in ACC, have not been tested so far. In this study, we evaluated the expression of a new enticing tumor antigen (TA*) structure and investigated the effect of TA-specific CAR-T cells _in vitro_.

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The most abundant circulating CD3- population in patients with cHL was a newly identified monocyte subset with increased expression of multiple immunosuppressive and tumorigenic cytokines and chemokines, PD-L1 and SIRPa. This newly identified monocytic population was virtually absent from the blood of healthy donors. RNAscope analysis of the intact tumor microenvironment localized these tumor-infiltrating monocytes/macrophages to the immediate proximity of HRS cells. Monocytes from patients whose disease progressed following PD-1 blockade expressed significantly higher levels of immunosuppressive cytokine/chemokine signature which led to the development of a predictive transcriptional assay. We identified a comparable circulating monocyte population and transcriptional signature associated with unresponsiveness to PD-1 blockade in an additional solid tumor underscoring the broad-based significance of these findings.

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel type b coronavirus responsible for the COVID-19 pandemic. With over 224 million confirmed infections with this virus and more than 4.6 million people dead because of it, it is critically important to define the immunological processes occurring in the human response to this virus and pathogenetic mechanisms of its deadly manifestation. This perspective focuses on the contribution of the recently discovered interaction of SARS-CoV-2 Spike protein with neuropilin 1 (NRP1) receptor, NRP1 as a virus entry receptor for SARS-CoV-2, its role in different physiologic and pathologic conditions, and the potential to target the Spike-NRP1 interaction to combat virus infectivity and severe disease manifestations.

We use cookies to make sure that our website works properly, as well as some ‘optional’ cookies to personalise content and advertising, provide social media features and analyse how people use our site. By accepting some or all optional cookies you give consent to the processing of your personal data, including transfer to third parties, some in countries outside of the European Economic Area that do not offer the same data protection standards as the country where you live. You can decide which optional cookies to accept by clicking on ‘Manage Settings’, where you can also find more information about how your personal data is processed. Further information can be found in our privacy policy [https://link.springer.com/privacystatement].

Disruption of homeostatic microRNA (miRNA) expression levels is known to cause human neuropathology. However, the gene regulatory and phenotypic effects of altering a miRNA's in vivo abundance (rather than its binary gain or loss) are not well understood. By genetic combination, we generated an allelic series of mice expressing varying levels of miR-218, a motor neuron-selective gene regulator associated with motor neuron disease. Titration of miR-218 cellular dose unexpectedly revealed complex, non-ratiometric target mRNA dose responses and distinct gene network outputs. A non-linearly responsive regulon exhibited a steep miR-218 dose-dependent threshold in repression that, when crossed, resulted in severe motor neuron synaptic failure and death. This work demonstrates that a miRNA can govern distinct gene network outputs at different expression levels and that miRNA-dependent phenotypes emerge at particular dose ranges because of hidden regulatory inflection points of their underlying gene networks.

The mesenchymal subtype of glioblastoma is thought to be determined by both cancer cell-intrinsic alterations and extrinsic cellular interactions, but remains poorly understood. Here, we dissect glioblastoma-to-microenvironment interactions by single-cell RNA sequencing analysis of human tumors and model systems, combined with functional experiments. We demonstrate that macrophages induce a transition of glioblastoma cells into mesenchymal-like (MES-like) states. This effect is mediated, both in vitro and in vivo, by macrophage-derived oncostatin M (OSM) that interacts with its receptors (OSMR or LIFR) in complex with GP130 on glioblastoma cells and activates STAT3. We show that MES-like glioblastoma states are also associated with increased expression of a mesenchymal program in macrophages and with increased cytotoxicity of T cells, highlighting extensive alterations of the immune microenvironment with potential therapeutic implications.

Biological organization crosses multiple spatial scales: from molecular, cellular, to tissues and organs. The proliferation of molecular profiling technologies enables increasingly detailed cataloging of the components at each scale. However, the scarcity of spatial profiling has made it challenging to bridge across these scales. Emerging technologies based on highly multiplexed in situ profiling are paving the way to study the spatial organization of cells and tissues in greater detail. These new technologies provide the data needed to cross the scale from cell biology to physiology and identify the fundamental principles that govern tissue organization. Here, we provide an overview of these key technologies and discuss the current and future insights these powerful techniques enable.