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An otherwise healthy two-month-old female C57BL/6J mouse presented with a left-sided head tilt. Differential diagnoses included idiopathic necrotizing arteritis, bacterial otitis media/interna (Pasteurella pneumotropica,Pseudomonas aeruginosa,Streptococcus sp.,Mycoplasma pulmonisandBurkholderia gladioli), encephalitis, an abscess, neoplasia, a congenital malformation and an accidental or iatrogenic head trauma. Magnetic resonance imaging (MRI) revealed a large space-occupying right olfactory lobe intra-axial lesion with severe secondary left-sided subfalcine herniation. Following imaging, the animal was euthanized due to poor prognosis. Histopathologic examination revealed a unilateral, full-thickness bone defect at the base of the cribriform plate and nasal conchae dysplasia, resulting in the herniation of the olfactory bulb into the nasal cavity. There was also a left midline-shift of the frontal cortex and moderate catarrhal sinusitis in the left mandibular sinus. The MRI and histopathologic changes are consistent with a congenital malformation of the nasal cavity and frontal aspect of the skull known as an ethmoidal meningoencephalocele. Encephaloceles are rare abnormalities caused by herniation of contents of the brain through a defect in the skull which occur due to disruption of the neural tube closure at the level anterior neuropore or secondary to trauma, surgical complications, cleft palate or increased intracranial pressure. The etiology is incompletely understood but hypotheses include genetics, vitamin deficiency, teratogens, infectious agents and environmental factors. Ethmoidal encephaloceles have been reported in multiple species including humans but have not been reported previously in mice. There are multiple models for spontaneous and induced craniofacial malformation in mice, but none described for ethmoidal encephaloceles.

Active co-delivery of tumor antigens (Ag) and alpha-galactosylceramide (alpha-GalCer), a potent agonist for invariant Natural Killer T (iNKT) cells, to cross-priming CD8 alpha(+) dendritic cells (DCs) was previously shown to promote strong anti-tumor responses in mice. Here, we designed a nanoparticle-based vaccine able to target human CD141(+) (BDCA3(+)) DCs - the equivalent of murine CD8 alpha(+) DCs - and deliver both tumor Ag (Melan A) and alpha-GalCer. This nanovaccine was inoculated into humanized mice that mimic the human immune system (HIS) and possess functionaliNKT cells and CD8(+) T cells, called HIS-CD8/NKT mice. We found that multiple immunizations of HIS-CD8/NKT mice with the nanovaccine resulted in the activation and/or expansion of human CD141(+) DCs andiNKT cells and ultimately elicited a potent Melan-A-specific CD8(+) T cell response, as determined by tetramer staining and ELISpot assay. Single-cell proteomics further detailed the highly polyfunctional CD8(+) T cells induced by the nanovaccine and revealed their predictive potential for vaccine potency. This finding demonstrates for the first time the unique ability of humaniNKT cells to license cross-priming DCsin vivoand adds a new dimension to the current strategy of cancer vaccine development.

Humoral immunity in mammals relies on the function of two developmentally and functionally distinct B-cell subsets-B1 and B2 cells. While B2 cells are responsible for the adaptive response to environmental antigens, B1 cells regulate the production of polyreactive and low-affinity antibodies for innate humoral immunity. The molecular mechanism of B-cell specification into different subsets is understudied. In this study, we identified lysine methyltransferase NSD2 (MMSET/WHSC1) as a critical regulator of B1 cell development. In contrast to its minor impact on B2 cells, deletion of the catalytic domain of NSD2 in primary B cells impairs the generation of B1 lineage. Thus, NSD2, a histone H3 K36 dimethylase, is the first-in-class epigenetic regulator of a B-cell lineage in mice.

Piloerection (goosebumps) requires concerted actions of the hair follicle, the arrector pili muscle (APM), and the sympathetic nerve, providing a model to study interactions across epithelium, mesenchyme, and nerves. Here, we show that APMs and sympathetic nerves form a dual-component niche to modulate hair follicle stem cell (HFSC) activity. Sympathetic nerves form synapse-like structures with HFSCs and regulate HFSCs through norepinephrine, whereas APMs maintain sympathetic innervation to HFSCs. Without norepinephrine signaling, HFSCs enter deep quiescence by down-regulating the cell cycle and metabolism while up-regulating quiescence regulators Foxp1 and Fgf18. During development, HFSC progeny secretes Sonic Hedgehog (SHH) to direct the formation of this APM-sympathetic nerve niche, which in turn controls hair follicle regeneration in adults. Our results reveal a reciprocal interdependence between a regenerative tissue and its niche at different stages and demonstrate sympathetic nerves can modulate stem cells through synapse-like connections and neurotransmitters to couple tissue production with demands.

Microglial cells play a key role in brain homeostasis from development to adulthood. Here we show the involvement of a site-specific phosphorylation of Presenilin 1 (PS1) in microglial development. Profiles of microglia-specific transcripts in different temporal stages of development, combined with multiple systematic transcriptomic analysis and quantitative determination of microglia progenitors, indicate that the phosphorylation of PS1 at serine 367 is involved in the temporal dynamics of microglial development, specifically in the developing brain rudiment during embryonic microgliogenesis. We constructed a developing brain-specific microglial network to identify transcription factors linked to PS1 during development. Our data showed that PS1 functional connections appear through interaction hubs atPu.1,Irf8andRela-p65transcription factors. Finally, we showed that the total number of microglia progenitors was markedly reduced in the developing brain rudiment of embryos lacking PS1 phosphorylation compared to WT. Our work identifies a novel role for PS1 in microglial development.

Mdn1 is an essential mechanoenzyme that uses the energy from ATP hydrolysis to physically reshape and remodel, and thus mature, the 605 subunit of the ribosome. This massive (>500 kDa) protein has an N-terminal AAA (ATPase associated with diverse cellular activities) ring, which, like dynein, has six ATPase sites. The AAA ring is followed by large (>2,000 aa) linking domains that include an similar to 500-aa disordered (D/E-rich) region, and a C-terminal substratebinding MIDAS domain. Recent models suggest that intramolecular docking of the MIDAS domain onto the AAA ring is required for Mdn1 to transmit force to its ribosomal substrates, but it is not currently understood what role the linking domains play, or why tethering the MIDAS domain to the AAA ring is required for protein function. Here, we use chemical probes, single-particle electron microscopy, and native mass spectrometry to study the AAA and MIDAS domains separately or in combination. We find that Mdn1 lacking the D/E-rich and MIDAS domains retains ATP and chemical probe binding activities. Free MIDAS domain can bind to the AAA ring of this construct in a stereo-specific bimolecular interaction, and, interestingly, this binding reduces ATPase activity. Whereas intramolecular MIDAS docking appears to require a treatment with a chemical inhibitor or preribosome binding, bimolecular MIDAS docking does not. Hence, tethering the MIDAS domain to the AAA ring serves to prevent, rather than promote, MIDAS docking in the absence of inducing signals.

Detection methods for Demodex musculi were historically unreliable, and testing was rarely performed because its prevalence in laboratory mice was underestimated. Although infestations are unapparent in most mouse strains, D. musculi burdens are higher and clinical signs detected in various immunodeficient strains. The parasite's influence on the immune system of immunocompetent mice is unknown. We characterized mite burden (immunocompetent and immunodeficient strains) and immunologic changes (immunocompetent strains only) in naive Swiss Webster (SW; outbred), C57BL/6NCrl (B6; Th1 responder), BALB/cAnNCrl (BALB/c; Th2 responder) and NOD.Cg-Prkdc(scid) Il2rg(tm1Wjl)/SzJ (NSG; immunodeficient) mice after exposure to Demodex-infested NSG mice. Infested and uninfested age-matched mice of each strain (n = 5) were euthanized 14, 28, 56, and 112 d after exposure. Mite burden was determined through PCR analysis and skin histopathology; B-cell and CD4(+) and CD8(+) T-cell counts and activation states (CD25 and CD69) were evaluated by using flow cytometry; CBC counts were performed; and serum IgE levels were measured by ELISA. Mite burden and PCR copy number correlated in NSG mice, which had the highest mite burden, but not in immunocompetent strains. Infested immunocompetent animals developed diffuse alopecia by day 112, and both BALB/c and C57BL/6 mice had significantly increased IgE levels. These findings aligned with the skewed Th1 or Th2 immunophenotype of each strain. BALB/c mice mounted the most effective host response, resulting in the lowest mite burden of all immunocompetent strains at 112 d after infestation without treatment. Clinically significant hematologic abnormalities were absent and immunophenotype was unaltered in immunocompetent animals. Topical treatment with imidacloprid-moxidectin (weekly for 8 wk) was effective at eradicating mites by early as 7 d after treatment. IgE levels decreased substantially in infested BALB/c mice after treatment. These findings demonstrate a need for D. musculi surveillance in mouse colonies, because the infestation may influence the use of infested mice in select studies.

This year is a plague year. The COVID-19 pandemic, caused by the coronavirus SARS-CoV-2, is burning across the globe as we anxiously await an effective vaccine or drug to control it. Another plague, of a much older kind — one that is not curable with vaccines or medicine — is currently raging in Africa (Fig. 1) and the Middle East. Seasons of unusually heavy rains, driven by climate change (see go.nature.com/3fchnrm), have created population explosions of swarming desert locusts (Schistocerca gregaria). Swarms can contain billions of insects and cover hundreds of square kilometres. These insects strip vegetation and crops, threatening the precarious existence of subsistence farmers and contributing to food insecurity in vulnerable regions. The only effective weapon for fighting such locust plagues is the aerial spraying of pesticides, but the swarms are fast-moving and unpredictable, and spraying devastates beneficial insects.