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Based on single cell RNA-sequencing of 622 adult mouse sensory neurons, Usoskin et al . performed unbiased classification to identify the cellular and molecular complexity underlying somatic sensation. Eleven different subtypes were identified, including some previously unknown populations such as a new class of neuron which may be sensitive to inflammatory itch. The primary sensory system requires the integrated function of multiple cell types, although its full complexity remains unclear. We used comprehensive transcriptome analysis of 622 single mouse neurons to classify them in an unbiased manner, independent of any a priori knowledge of sensory subtypes. Our results reveal eleven types: three distinct low-threshold mechanoreceptive neurons, two proprioceptive, and six principal types of thermosensitive, itch sensitive, type C low-threshold mechanosensitive and nociceptive neurons with markedly different molecular and operational properties. Confirming previously anticipated major neuronal types, our results also classify and provide markers for new, functionally distinct subtypes. For example, our results suggest that itching during inflammatory skin diseases such as atopic dermatitis is linked to a distinct itch-generating type. We demonstrate single-cell RNA-seq as an effective strategy for dissecting sensory responsive cells into distinct neuronal types. The resulting catalog illustrates the diversity of sensory types and the cellular complexity underlying somatic sensation.

The adrenal glands affect a variety of processes such as stress responses and metabolism. The mature adrenal gland is formed from multiple tissue sources, including cells of neural origin. Furlan et al. traced the origins of these cells. The cells first become Schwann cell precursors and follow along nerves to travel from the dorsal root ganglia of the spine to the adrenal gland. Once there, the cells differentiate into chromaffin cells. The authors used singlecell transcriptomics to reveal the shifts in functional programs during migration, development, and differentiation. Science , this issue p. eaal3753 The adrenal gland is built from cells that travel along highways of nerves. Adrenaline is a fundamental circulating hormone for bodily responses to internal and external stressors. Chromaffin cells of the adrenal medulla (AM) represent the main neuroendocrine adrenergic component and are believed to differentiate from neural crest cells. We demonstrate that large numbers of chromaffin cells arise from peripheral glial stem cells, termed Schwann cell precursors (SCPs). SCPs migrate along the visceral motor nerve to the vicinity of the forming adrenal gland, where they detach from the nerve and form postsynaptic neuroendocrine chromaffin cells. An intricate molecular logic drives two sequential phases of gene expression, one unique for a distinct transient cellular state and another for cell type specification. Subsequently, these programs down-regulate SCP-gene and up-regulate chromaffin cell–gene networks. The AM forms through limited cell expansion and requires the recruitment of numerous SCPs. Thus, peripheral nerves serve as a stem cell niche for neuroendocrine system development.

The basolateral amygdala (BLA) plays essential roles in behaviors motivated by stimuli with either positive or negative valence, but how it processes motivationally opposing information and participates in establishing valence-specific behaviors remains unclear. Here, by targeting Fezf2 -expressing neurons in the BLA, we identify and characterize two functionally distinct classes in behaving mice, the negative-valence neurons and positive-valence neurons, which innately represent aversive and rewarding stimuli, respectively, and through learning acquire predictive responses that are essential for punishment avoidance or reward seeking. Notably, these two classes of neurons receive inputs from separate sets of sensory and limbic areas, and convey punishment and reward information through projections to the nucleus accumbens and olfactory tubercle, respectively, to drive negative and positive reinforcement. Thus, valence-specific BLA neurons are wired with distinctive input–output structures, forming a circuit framework that supports the roles of the BLA in encoding, learning and executing valence-specific motivated behaviors. Zhang et al. report that the BLA contains ‘hardwired’ positive-valence and negative-valence neurons, which each express Fezf2 but have distinct connectivity. These neurons separately drive learning and expression of avoidance or approach behavior.

In the mouse, nerve-associated peripheral glial cells give rise to mesenchymal stem cells that contribute to the development and growth of adult teeth. Glial cells as a source of multipotency This study of tooth organogenesis in the continuously growing mouse incisor system shows that nerve-associated peripheral glial cells can give rise to mesenchymal stem cells that contribute to the development and growth of adult teeth. Mesenchymal stem cells are being used as a source of adult stem cells in numerous clinical trials, and the existence of a glia-to-mesenchymal cell transition raises interesting questions about what other cell types may share a glial origin. Mesenchymal stem cells occupy niches in stromal tissues where they provide sources of cells for specialized mesenchymal derivatives during growth and repair 1 . The origins of mesenchymal stem cells have been the subject of considerable discussion, and current consensus holds that perivascular cells form mesenchymal stem cells in most tissues. The continuously growing mouse incisor tooth offers an excellent model to address the origin of mesenchymal stem cells. These stem cells dwell in a niche at the tooth apex where they produce a variety of differentiated derivatives. Cells constituting the tooth are mostly derived from two embryonic sources: neural crest ectomesenchyme and ectodermal epithelium 2 . It has been thought for decades that the dental mesenchymal stem cells 3 giving rise to pulp cells and odontoblasts derive from neural crest cells after their migration in the early head and formation of ectomesenchymal tissue 4 , 5 . Here we show that a significant population of mesenchymal stem cells during development, self-renewal and repair of a tooth are derived from peripheral nerve-associated glia. Glial cells generate multipotent mesenchymal stem cells that produce pulp cells and odontoblasts. By combining a clonal colour-coding technique 6 with tracing of peripheral glia, we provide new insights into the dynamics of tooth organogenesis and growth.

Objectives To assess the accuracy of MRI-derived liver surface nodularity (LSN) score for staging of hepatic fibrosis in patients with non-alcoholic fatty liver disease (NAFLD). Methods Forty-seven patients with clinicopathological diagnosis of NAFLD who underwent 1.5-T liver MRI within 12 months of liver biopsy were included. Axial non-contrast T1-weighted 3D GRE was used for image analysis. LSN of the left lobe was measured using a custom semiautomated software. Histopathologic analysis (F0–F4) served as the reference standard for staging of fibrosis. Mann-Whitney test and Spearman’s correlation coefficient were used to compare LSN scores between different stages of fibrosis and to assess the correlation. Diagnostic performance of LSN score for detection of significant (F2–F4) and advanced (F3–F4) fibrosis was assessed by receiver operating characteristics (ROC) curve. p value of less than 0.05 was considered statistically significant different. Results Twenty-one subjects had advanced fibrosis. The LSN scores among different stages of fibrosis were significantly different ( p  < 0.001). The correlation between LSN score and stage of fibrosis was also strong ( ρ  = 0.71; p  < 0.001). The areas under ROC curves for detection of significant and advanced fibrosis were 0.80 (95% CI 0.66–0.95) and 0.86 (95% CI 0.75–0.97), using a threshold of 2.23 and 2.44, respectively. This method showed 81% sensitivity and 88% specificity for detection of advanced fibrosis. Conclusion MR-based LSN score is a promising non-invasive objective tool for detection of advanced fibrosis in patients with NAFLD. Key Points • Liver surface nodularity (LSN) score is a fast retrospective method for precise quantification of nodularity of liver surface. • MR-based LSN score is a promising non-invasive objective tool to accurately detect different stages of fibrosis in patients with non-alcoholic fatty liver disease (NAFLD).

Objectives To evaluate targetoid appearance on T2-weighted imaging and signs of tumor vascular involvement as potential new LI-RADS features for differentiating hepatocellular carcinoma (HCC) from other non-HCC primary liver carcinomas (PLCs). Methods This IRB-approved, retrospective study was performed at two liver transplant centers. The final population included 375 patients with pathologically proven lesions imaged between 2007 and 2017 with contrast-enhanced CT or MRI. The cohort consisted of 165 intrahepatic cholangiocarcinomas and 74 combined hepatocellular-cholangiocarcinomas, with the addition of 136 HCCs for control. Two abdominal radiologists (R1; R2) independently reviewed the imaging studies (112 CT; 263 MRI) and recorded the presence of targetoid appearance on T2-weighted images and features of tumor vascular involvement including encasement, narrowing, tethering, occlusion, and obliteration. The sensitivity and specificity of each feature were calculated for the diagnosis of non-HCC PLCs. Cohen’s kappa ( k ) test was used to assess inter-reader agreement. Results The sensitivity of targetoid appearance on T2-weighted images for the diagnosis of non-HCC PLCs was 27.5% and 32.6% (R1 and R2) and the specificity was 98.2% and 97.3% (R1 and R2). Among the features of tumor vascular involvement, those providing the highest sensitivity for non-HCC PLCs were vascular encasement (R1: 34.3%; R2: 37.2%) and obliteration (R1: 25.5%; R2: 29.7%). The highest specificity for non-HCC PLCs was provided by tethering (R1: 100%; R2: 97.1%) and occlusion (R1: 99.3%; R2: 99.3%). The inter-reader agreement was moderate to substantial ( k = 0.48–0.77). Conclusions Targetoid appearance on T2-weighted images and features of tumor vascular involvement demonstrated high specificity for non-HCC malignancy. Key Points • Targetoid appearance on T2-weighted imaging and signs of tumor vascular involvement have high specificity (92–100%) for the diagnosis of non-HCC PLCs, regardless of the presence of liver risk factors. • In the subset of patients with risk factors for HCC, the sensitivity of signs of tumor vascular involvement decreases for both readers (1.7–20.3%), while the specificity increases reaching values higher than 94.2%. • The inter-reader agreement is substantial for targetoid appearance on T2-weighted images (k = 0.74) and moderate to substantial for signs of tumor vascular involvement (k = 0.48–0.77).

Nociception is protective and prevents tissue damage but can also facilitate chronic pain. Whether a general principle governs these two types of pain is unknown. Here, we show that both basal mechanical and neuropathic pain are controlled by the microRNA-183 (miR-183) cluster in mice. This single cluster controls more than 80% of neuropathic pain–regulated genes and scales basal mechanical sensitivity and mechanical allodynia by regulating auxiliary voltage-gated calcium channel subunits α2δ-1 and α2δ-2. Basal sensitivity is controlled in nociceptors, and allodynia involves TrkB⁺ light-touch mechanoreceptors. These light-touch–sensitive neurons, which normally do not elicit pain, produce pain during neuropathy that is reversed by gabapentin. Thus, a single microRNA cluster continuously scales acute noxious mechanical sensitivity in nociceptive neurons and suppresses neuropathic pain transduction in a specific, light-touch–sensitive neuronal type recruited during mechanical allodynia.

The peripheral autonomic nervous system reaches far throughout the body and includes neurons of diverse functions, such as sympathetic and parasympathetic. We show that the parasympathetic system in mice–including trunk ganglia and the cranial ciliary, pterygopalatine, lingual, submandibular, and otic ganglia–arise from glial cells in nerves, not neural crest cells. The parasympathetic fate is induced in nerve-associated Schwann cell precursors at distal peripheral sites. We used multicolor Cre-reporter lineage tracing to show that most of these neurons arise from bi-potent progenitors that generate both glia and neurons. This nerve origin places cellular elements for generating parasympathetic neurons in diverse tissues and organs, which may enable wiring of the developing parasympathetic nervous system.

ObjectiveThis study was conducted in order to assess the diagnostic accuracy of LI-RADS v2018 ancillary features (AFs) favoring malignancy applied to LR-3 and LR-4 observations on gadoxetate-enhanced MRI.MethodsIn this retrospective dual-institution study, we included consecutive patients at high risk for hepatocellular carcinoma (HCC) imaged with gadoxetate disodium-enhanced MRI between 2009 and 2014 fulfilling the following criteria: (i) at least one LR-3 or LR-4 observation ≥ 10 mm; (ii) nonrim arterial phase hyperenhancement; and (iii) confirmation of benignity or malignancy by pathology or imaging follow-up. We compared the distribution of AFs between HCCs and benign observations and the diagnostic performance for the diagnosis of HCC using univariate and multivariate analyses. Significance was set at p value < 0.05.ResultsTwo hundred five observations were selected in 155 patients (108 M, 47 F) including 167 (81.5%) LR-3 and 38 (18.5%) LR-4. There were 126 (61.5%) HCCs and 79 (28.5%) benign lesions. A significantly larger number of AFs favoring malignancy were found in LR-3 and LR-4 lesions that progressed to HCC compared to benign lesions (p < 0.001 and p = 0.003, respectively). The most common AFs favoring malignancy in HCCs were hepatobiliary phase (HBP) hypointensity (p < 0.001), transitional phase hypointensity (p < 0.001), and mild–moderate T2 hyperintensity (p < 0.001). Sensitivity and specificity of AFs for the diagnosis of HCC ranged 0.8–76.2% and 86.1–100%, respectively. HBP hypointensity yielded the highest sensitivity but also the lowest specificity and was the only AF remaining independently associated with the diagnosis of HCC at multivariate logistic regression analysis (OR 14.83, 95% CI 5.81–42.76, p < 0.001).ConclusionsAmong all AFs, HBP hypointensity yields the highest sensitivity for the diagnosis of HCC.Key Points• LR-3 and LR-4 observations diagnosed as HCC have a significantly higher number of ancillary features favoring malignancy compared to observations proven to be benign.• The presence of three or more ancillary features favoring malignancy has a high specificity (96.2%) for the diagnosis of HCC.• Among all ancillary features favoring malignancy, hepatobiliary phase hypointensity yields the highest sensitivity, but also the lowest specificity for the diagnosis of HCC.