Probes for INS

Malignant salivary gland tumours characterized by mucoepidermal differentiation with sclerotic stroma rich in lymphocytes and eosinophils have been designated the name sclerosing mucoepidermoid carcinoma with eosinophilia1-4 (SMECE). However, it has not been listed as an entity in the chapter on salivary gland, 2022 WHO Classification of Head and Neck Tumours5 . Some reports highlighted the lack of MAML2 translocation in these tumours, as distinct from classical mucoepidermoid carcinoma (MEC) of the salivary glands. Some argued against grouping them under MEC based on their variable morphological features and the lack of MAML2 translocation. This counterargument is supported by the prominence of keratinization in the squamoid component and relatively reduced glandular or intermediate cell component noted in SMECE, such that other entities e.g. adenosquamous carcinoma should be considered in the differential diagnosis. The lack of a well-documented molecular marker also makes categorizing SMECE as a distinct entity difficult. A same-named tumour has been described in the thyroid6 . The thyroid SMECE lacks common thyroid cancer mutations nor MAML2 translocation according to studies by Shah et al7 . Whether SMECE of the head and neck region share similar histogenetic origin or molecular derangement requires further studies on larger tumour series. The underlying mechanism for the sclerotic stroma and eosinophilia has received little attention as these features could be seen in other tumours. We report a similar case in the parotid gland that was initially diagnosed as Langerhans cell histiocytosis due to the prominent Langerhans cell and eosinophilic reaction. It recurred 2 years later as a frank carcinoma fitting into the SMECE category by morphology. Molecular studies provided possible new understanding concerning the Langerhans cell and eosinophilic reaction.

Plexiform fibrohistiocytic tumor (PFHT) is a mesenchymal tumor of intermediate malignancy, typically occurring in the superficial soft tissues of young patients and displaying a biphasic pattern, with nodules of histiocytoid cells surrounded by fascicles of myofibroblastic spindled cells. The pathogenesis of PHFT is unknown. We comprehensively studied 39 PFHT, occurring in 25 females (66%) and 13 males (34%), ranging from 2 to 55 years of age (median 21 years). The tumors most often occurred in the upper extremity (n = 16, 41%) and ranged from 0.4 to 6.1 cm in size (median 1.5 cm). One patient with known neurofibromatosis type 1 presented with metachronous tumors of the finger and back. Clinical follow-up (29 patients; range 5-168 months; median 60 months) showed 3 tumors to have recurred locally; none was metastasized. One patient died of an unrelated cause; all others were alive without disease at the time of last follow-up. Immunohistochemistry showed the histiocytoid nodules of all cases to contain CD163/CD11c-positive histiocytes and cells negative for both markers ("null cells"). CSF1 expression was present in "null cells" in 7/10 cases (RNAscope chromogenic in situ hybridization). The Ki-67 labeling index was very low (< 5%); Ki-67-positive cells within histiocytoid nodules appeared to represent "null cells." All tested cases were negative for significant mutations or fusion events (TruSight Mutation Panel, TruSight Fusion Panel, Mayo Clinic Melanoma Targeted Gene Panel). We conclude that PHFT may be even more indolent than has been appreciated, although classification as an "intermediate" tumor is correct. We hypothesize that the CSF1-producing "null cells" of PHFT may represent the neoplastic element, with the bulk of the tumor masses comprising recruited and reactive cell populations.

Exposure to irregular lighting schedules leads to deficits in affective behaviors. The retino-recipient perihabenular nucleus (PHb) of the dorsal thalamus has been shown to mediate these effects in mice. However, the mechanisms of how light information is processed within the PHb remains unknown. Here, we show that the PHb contains a distinct cluster of GABAergic neurons that receive direct retinal input. These neurons are part of a larger inhibitory network composed of the thalamic reticular nucleus and zona incerta, known to modulate thalamocortical communication. In addition, PHbGABA neurons locally modulate excitatory-relay neurons, which project to limbic centers. Chronic exposure to irregular light-dark cycles alters photo-responsiveness and synaptic output of PHbGABA neurons, disrupting daily oscillations of genes associated with inhibitory and excitatory PHb signaling. Consequently, selective and chronic PHbGABA manipulation results in mood alterations that mimic those caused by irregular light exposure. Together, light-mediated disruption of PHb inhibitory networks underlies mood deficits.

Mechanical allodynia (MA) represents one prevalent symptom of chronic pain. Previously we and others have identified spinal and brain circuits that transmit or modulate the initial establishment of MA. However, brain-derived descending pathways that control the laterality and duration of MA are still poorly understood. Here we report that the contralateral brain-to-spinal circuits, from Oprm1 neurons in the lateral parabrachial nucleus (lPBNOprm1), via Pdyn neurons in the dorsal medial regions of hypothalamus (dmHPdyn), to the spinal dorsal horn (SDH), act to prevent nerve injury from inducing contralateral MA and reduce the duration of bilateral MA induced by capsaicin. Ablating/silencing dmH-projecting lPBNOprm1 neurons or SDH-projecting dmHPdyn neurons, deleting Dyn peptide from dmH, or blocking spinal κ-opioid receptors all led to long-lasting bilateral MA. Conversely, activation of dmHPdyn neurons or their axonal terminals in SDH can suppress sustained bilateral MA induced by lPBN lesion.

The genetic causes of primary antibody deficiencies and autism spectrum disorder (ASD) are largely unknown. Here, we report a patient with hypogammaglobulinemia and ASD who carries biallelic mutations in the transcription factor PAX5. A patient-specific Pax5 mutant mouse revealed an early B cell developmental block and impaired immune responses as the cause of hypogammaglobulinemia. Pax5 mutant mice displayed behavioral deficits in all ASD domains. The patient and the mouse model showed aberrant cerebellar foliation and severely impaired sensorimotor learning. PAX5 deficiency also caused profound hypoplasia of the substantia nigra and ventral tegmental area due to loss of GABAergic neurons, thus affecting two midbrain hubs, controlling motor function and reward processing, respectively. Heterozygous Pax5 mutant mice exhibited similar anatomic and behavioral abnormalities. Lineage tracing identified Pax5 as a crucial regulator of cerebellar morphogenesis and midbrain GABAergic neurogenesis. These findings reveal new roles of Pax5 in brain development and unravel the underlying mechanism of a novel immunological and neurodevelopmental syndrome.

Obesity is a global pandemic that is causally linked to many life-threatening diseases. Apart from some rare genetic conditions, the biological drivers of overeating and reduced activity are unclear. Here, we show that neurotensin-expressing neurons in the mouse interstitial nucleus of the posterior limb of the anterior commissure (IPAC), a nucleus of the central extended amygdala, encode dietary preference for unhealthy energy-dense foods. Optogenetic activation of IPACNts neurons promotes obesogenic behaviors, such as hedonic eating, and modulates food preference. Conversely, acute inhibition of IPACNts neurons reduces feeding and decreases hedonic eating. Chronic inactivation of IPACNts neurons recapitulates these effects, reduces preference for sweet, non-caloric tastants and, furthermore, enhances locomotion and energy expenditure; as a result, mice display long-term weight loss and improved metabolic health and are protected from obesity. Thus, the activity of a single neuronal population bidirectionally regulates energy homeostasis. Our findings could lead to new therapeutic strategies to prevent and treat obesity.