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The development of Gonadotropin releasing hormone-1 (GnRH) neurons is important for a functional reproduction system in vertebrates. Disruption of GnRH results in hypogonadism and if accompanied by anosmia is termed Kallmann Syndrome (KS). From their origin in the nasal placode, GnRH neurons migrate along the olfactory-derived vomeronasal axons to the nasal forebrain junction and then turn caudally into the developing forebrain. Although research on the origin of GnRH neurons, their migration and genes associated with KS has identified multiple factors that influence development of this system, several aspects still remain unclear. This review discusses development of the olfactory system, factors that regulate GnRH neuron formation and development of the olfactory system, migration of the GnRH neurons from the nose into the brain, and mutations in humans with KS that result from disruption of normal GnRH/olfactory systems development.

Gonadotropin releasing hormone (GnRH) neurons, part of the hypothalamic-pituitary-gonadal axis, regulate reproduction. Prenatally, GnRH neurons migrate into the brain from the nasal placode along terminal nerve fibers, intermixed with olfactory sensory axons and olfactory ensheathing cells (OECs). An expression analysis from embryonic GnRH neurons identified the G protein-coupled receptor 37 (GPR37 or PAEL-r). GPR37 has been linked to (1) juvenile Parkinson's disease in humans, (2) oligodendrocyte differentiation, and (3) Wnt/β-catenin signaling during neurogenesis. In this study, the role of GPR37 was investigated in the developing GnRH/olfactory system. PCR and immunocytochemistry confirmed expression of GPR37 in migrating GnRH neurons as well as in OECs. Inhibition of GPR37 signaling in nasal explants attenuated GnRH neuronal migration and OEC movement. Examination of GPR37 deficient mice revealed a decrease in the olfactory bulb nerve layer and attenuated/delayed maturation and migration of GnRH neurons into the brain. These data demonstrate a developmental role for GPR37 signaling in neural migration. Reproduction is controlled by gonadotrophin releasing hormone (GnRH) neurons located in the central nervous system. Embryonically, GnRH neurons originate in the nasal/olfactory placode and migrate into the brain on axonal tracks from cells in the vomeronasal organ, intermixed with olfactory sensory axons and olfactory ensheathing cells (OECs). An expression analysis from embryonic GnRH neurons identified the G protein-coupled receptor 37. Here we show that inhibition of GPR37 signaling in nasal explants and mutant mice attenuated GnRH neuronal migration. Signaling via GPR37 also perturbed OEC movement, resulting in a decrease in the olfactory bulb nerve layer . Together, these results identify a new role for GPR37 signaling during development - modulating cell migration.

Stromal cell-derived factor-1 (SDF-1) and chemokine receptor type 4 (CXCR4) are regulators of neuronal migration (e.g., GnRH neurons, cortical neurons, and hippocampal granule cells). However, how SDF-1/CXCR4 alters cytoskeletal components remains unclear. Developmentally regulated brain protein (drebrin) stabilizes actin polymerization, interacts with microtubule plus ends, and has been proposed to directly interact with CXCR4 in T cells. The current study examined, in mice, whether CXCR4 under SDF-1 stimulation interacts with drebrin to facilitate neuronal migration. Bioinformatic prediction of protein–protein interaction highlighted binding sites between drebrin and crystallized CXCR4. In migrating GnRH neurons, drebrin, CXCR4, and the microtubule plus-end binding protein EB1 were localized close to the cell membrane. Coimmunoprecipitation (co-IP) confirmed a direct interaction between drebrin and CXCR4 using wild-type E14.5 whole head and a GnRH cell line. Analysis of drebrin knockout (DBN1 KO) mice showed delayed migration of GnRH cells into the brain. A decrease in hippocampal granule cells was also detected, and co-IP confirmed a direct interaction between drebrin and CXCR4 in PN4 hippocampi. Migration assays on primary neurons established that inhibiting drebrin (either pharmacologically or using cells from DBN1 KO mice) prevented the effects of SDF-1 on neuronal movement. Bioinformatic prediction then identified binding sites between drebrin and the microtubule plus end protein, EB1, and super-resolution microscopy revealed decreased EB1 and drebrin coexpression after drebrin inhibition. Together, these data show a mechanism by which a chemokine, via a membrane receptor, communicates with the intracellular cytoskeleton in migrating neurons during central nervous system development.

Fructose-1,6-bisphosphatase, a key enzyme in gluconeogenesis, is subject to metabolic regulation. The human muscle isozyme is significantly more sensitive towards the allosteric inhibitor, AMP, than the liver isoform. Here we report crystal structures and kinetic studies for wild-type human muscle Fru-1,6-Pase, the AMP-bound (1.6 Å), and product-bound complexes of the Q32R mutant, which was firstly introduced by an error in the cloning. Our high-resolution structure reveals for the first time that the higher sensitivity of the muscle isozyme towards AMP originates from an additional water-mediated, H-bonded network established between AMP and the binding pocket. Also present in our structures are a metaphosphate molecule, alternate conformations of Glu97 coordinating Mg(2+), and possible metal migration during catalysis. Although the individual subunit is similar to previously reported Fru-1,6-Pase structures, the tetrameric assembly of all these structures deviates from the canonical R- or T-states, representing novel tetrameric assemblies. Intriguingly, the concentration of AMP required for 50% inhibition of the Q32R mutant is increased 19-fold, and the cooperativity of both AMP and Mg(2+) is abolished or decreased. These structures demonstrate the Q32R mutation affects the conformations of both N-terminal residues and the dynamic loop 52-72. Also importantly, structural comparison indicates that this mutation in helix α2 is detrimental to the R-to-T conversion as evidenced by the absence of quaternary structural changes upon AMP binding, providing direct evidence for the critical role of helix α2 in the allosteric signal transduction.

In vertebrates, Gonadotropin releasing hormone-1 (GnRH) neuroendocrine cells originate in the olfactory placode and migrate into the forebrain where they regulate reproduction. However, the embryonic lineage of their progenitors remains controversial. Most GnRH neurons are derived from placodal ectodermal progenitor cells, but data from lineage tracing in zebrafish (Whitlock et al., 2003) and mouse (Forni and Wray, 2012) indicate that some GnRH progenitor cells have a neural crest (NC) origin. In contrast, a recent study in zebrafish (Aguillon et al., 2018), using Islet-1/2 expression, identified this LIM-homeodomain protein in all developing GnRH neuroendocrine cells, and the authors concluded a homogenous origin from progenitors within the preplacodal ectoderm. Evidence in different animal models and systems suggests that expression of Islet-1 plays a pivotal role in cell fate specification and differentiation. Thus, expression of Islet-1/2 in all GnRH cells in the nasal placode may not be lineage dependent but rather initiated locally in the placode as part of the program for GnRH cell specification and/or differentiation. This study addresses this issue and shows two populations of olfactory derived GnRH neurons in embryonic mouse: Islet-1/2(+) and Islet-1/2(-). Notably, triple-label immunofluorescence using the NC lineage tracer Wnt1, showed that GnRH neurons derived from Wnt1 progenitors are Islet-1/2(-). These results are consistent with two separate origins of GnRH neuroendocrine cells and suggest that either (1) NC-derived GnRH cells differentiate earlier than PE-derived GnRH cells or (2) different programs are used for cell specification in NC- vs. PE-derived GnRH cells.

[This corrects the article on p. e71242 in vol. 8.].

Chimeric antigen receptor (CAR) T cells are highly effective in treating haematological malignancies, but associated toxicities and the need for lymphodepletion limit their use in people with autoimmune disease. To explore the use of CAR T cells for the treatment of people with autoimmune disease, and to improve their safety, we engineered them with RNA (rCAR-T)—rather than the conventional DNA approach—to target B-cell maturation antigen (BCMA) expressed on plasma cells. To test the suitability of our approach, we used rCAR-T to treat individuals with myasthenia gravis, a prototypical autoantibody disease mediated partly by pathogenic plasma cells. MG-001 was a prospective, multicentre, open-label, phase 1b/2a study of Descartes-08, an autologous anti-BCMA rCAR-T therapy, in adults (ie, aged ≥18 years) with generalised myasthenia gravis and a Myasthenia Gravis Activities of Daily Living (MG-ADL) score of 6 or higher. The study was done at eight sites (ie, academic medical centres or community neurology clinics) in the USA. Lymphodepletion chemotherapy was not used. In part 1 (phase 1b), participants with Myasthenia Gravis Foundation of America (MGFA) disease class III–IV generalised myasthenia gravis received three ascending doses of Descartes-08 to determine a maximum tolerated dose. In part 2 (phase 2a), participants with generalised myasthenia gravis with MGFA disease class II–IV received six doses at the maximum tolerated dose in an outpatient setting. The primary objective was to establish safety and tolerability of Descartes-08; secondary objectives were to assess myasthenia gravis disease severity and biomarkers in participants who received Descartes-08. This trial is registered with clinicaltrials.gov, NCT04146051. We recruited 16 individuals for screening between Jan 7, 2020 and Aug 3, 2022. 14 participants were enrolled (n=3 in part 1, n=11 in part 2). Ten participants were women and four were men. Two individuals did not qualify due to low baseline MG-ADL score (n=1) or lack of generalised disease (n=1). Median follow-up in part 2 was 5 months (range 3–9 months). There was no dose-limiting toxicity, cytokine release syndrome, or neurotoxicity. Common adverse events were headache (six of 14 participants), nausea (five of 14), vomiting (three of 14), and fever (four of 14), which resolved within 24 h of infusion. Fevers were not associated with increased markers of cytokine release syndrome (IL-6, IL-2, and TNF). Mean improvements from baseline to week 12 were –6 (95% CI –9 to –3) for MG-ADL score, –7 (–11 to –3) for Quantitative Myasthenia Gravis score, –14 (–19 to –9) for Myasthenia Gravis Composite score, and –9 (–15 to –3) for Myasthenia Gravis Quality of Life 15-revised score. In this first study of an rCAR-T therapy in individuals with an autoimmune disease, Descartes-08 appeared to be safe and was well tolerated. Descartes-08 infusions were followed by clinically meaningful decreases on myasthenia gravis severity scales at up to 9 months of follow-up. rCAR-T therapy warrants further investigation as a potential new treatment approach for individuals with myasthenia gravis and other autoimmune diseases. Cartesian Therapeutics and National Institute of Neurological Disorders and Stroke of the National Institutes of Health.

This thesis presents a comprehensive investigation into the properties of asymptotically hyperbolic manifolds and provides an exact definition for asymptotically symmetric manifolds.Chapter 1 begins with a thorough classification of symmetric spaces of non-compact type, as detailed in Section 1.1. Utilizing parabolic geometry, we then explore the boundary geometry of symmetric spaces of non-compact type, aiming to precisely define asymptotically symmetric manifolds in Section 1.2.Chapter 2 focuses on the perturbation existence of asymptotically hyperbolic Einstein manifolds. Following the methodology proposed by O. Biquard, we present the conceptual proof of perturbation existence for general asymptotically symmetric manifolds, as outlined in their work.In Chapter 3, we examine the stability of asymptotically hyperbolic Einstein manifolds under normalized Ricci flow. Drawing on R. Bamler’s research, we establish a reduction of the stability problem to estimating the heat kernel for the Lichnerowicz operator (refer to Lemma 3.2.2). Furthermore, we discuss the underlying ideas behind proving these heat kernel estimates.Finally, in the last chapter, we introduce our improved result on long-time existence, building upon the work presented in. This enhancement in long-time existence demonstrates the significant contributions made by this thesis.

Interproximal caries detection is critical for effective dental treatment. We report an ultrathin lensed fiber-based manual scanning optical coherence tomography (OCT) needle probe to enables the direct imaging of the interproximal caries between two adjacent teeth. We aim to design and fabricate the ultrathin lensed fiber-based manual scanning OCT needle probe, and validate the performance of the proposed probe by applying it to the imaging of the phantom sample, the human skin tissue and the interproximal caries between two adjacent teeth. A homemade lensed fiber is packaged into a 21-gauge hypodermic needle to create a high-flexibility, ultrathin probe. A decorrelation algorithm is employed for image reconstruction based on manual scanning. The performances of the developed needle probe are experimentally measured. The probe is incorporated in a swept-source OCT system to image the phantom sample, the human skin tissue, and the interproximal caries between two adjacent teeth. The working distance and focused spot diameter of the developed probe are measured to be 1.22 mm and , respectively. The correctly reconstructed OCT images of the phantom, skin tissue, and the tooth tissue demonstrate the performance of the developed ultrathin lensed fiber-based manual scanning OCT needle probe. The distinct structural difference between the healthy and abnormal teeth tissue validates the efficacy of the proposed method. We propose an ultrathin lensed fiber-based manual scanning OCT needle probe potentially useful for the interproximal caries detection. The design, fabrication, and performances of the developed needle probe are demonstrated. We address a critical issue in the caries diagnostics and offer a promising tool for the future clinical applications.