In the developing brain, transcription factors (TFs) direct the formation of a diverse array of neurons and glia. We identifed 1445 putative TFs in the mouse genome. We used in situ hybridization to map the expression of over 1000 of these TFs and TF-coregulator genes in the brains of developing mice. We found that 349 of these genes showed restricted expression patterns that were adequate to describe the anatomical organization of the brain. We provide a comprehensive inventory of murine TFs and their expression patterns in a searchable brain atlas database.

Identification of common mechanisms underlying organ development and primary tumor formation should yield new insights into tumor biology and facilitate the generation of relevant cancer models. We have developed a novel method to project the gene expression profiles of medulloblastomas (MBs)-human cerebellar tumors-onto a mouse cerebellar development sequence: postnatal days 1-60 (P1-P60). Genomically, human medulloblastomas were closest to mouse P1-P10 cerebella, and normal human cerebella were closest to mouse P30-P60 cerebella. Furthermore, metastatic MBs were highly associated with mouse P5 cerebella, suggesting that a clinically distinct subset of tumors is identifiable by molecular similarity to a precise developmental stage. Genewise, down-and up-regulated MB genes segregate to late and early stages of development, respectively. Comparable results for human lung cancer vis-a-vis the developing mouse lung suggest the generalizability of this multiscalar developmental perspective on tumor biology. Our findings indicate both a recapitulation of tissue-specific developmental programs in diverse solid tumors and the utility of tumor characterization on the developmental time axis for identifying novel aspects of clinical and biological behavior.[Keywords: cerebellar development; medulloblastoma; comparative genomics; multiscale models; metastasis; principle component analysis] Supplemental material is available at http://www.genesdev.org. Received December 30, 2003; revised version accepted February 25, 2004. In the 19th century, Lobstein and Cohnheim were among the first to theorize similarities between human embryogenesis and the biology of cancer cells (Rather 1978). The brain tumor classification system of Bailey and Cushing (1926), from which modern taxonomies derive, emphasizes the histologic resemblance to cells of the developing central nervous system (CNS; Bailey and Cushing 1926). Nevertheless, the putative relationship between underlying mechanisms in normal development and tumorigenesis remains controversial for most types of cancer, particularly the solid tumors such as medulloblastomas (MBs) and carcinomas.Here, we focused on the relationship between genes regulated during oncogenesis in the human cerebellar tumor, MB, and the developing wild-type mouse cerebellum during postnatal days 1-60 (P1-P60). The cerebellum is the brain structure largely responsible for coordinating motor activities. Granule neurons, the most abundant cell type in the cerebellum during development, are derived from precursors of the embryonic hindbrain (Hallonet et al. 1990). In mice, the major phase of granule cell proliferation commences at birth and peaks by P8-P10 (Altman and Bayer 1987). Differentiation is complete by P60 in mice, and at ∼18 mo of age in humans. Granule neuron progenitors are thought to be the predominant dysregulated cell type from which the majority of MB cases arise (Kadin et al. 1970;Reddy and Packer 1999). MBs are the most common pediatric CNS malignancy and comprise two primary histological...

SummaryHost-microbiota mutualism has been established during long-term coevolution. A diverse and rich gut microbiota plays an essential role in the development and maturation of the host immune system. Education of the adaptive immune compartment by gut microbiota antigens is important in establishing immune balance. In particular, a critical time frame immediately after birth provides a 'window of opportunity' for the development of lymphoid structures, differentiation and maturation of T and B cells and, most importantly, establishment of immune tolerance to gut commensals. Depending on the colonization niche, antigen type and metabolic property of different gut microbes, CD4 T-cell responses vary greatly, which results in differentiation into distinct subsets. As a consequence, certain bacteria elicit effector-like immune responses by promoting the production of pro-inflammatory cytokines such as interferon-c and interleukin-17A, whereas other bacteria favour the generation of regulatory CD4 T cells and provide help with gut homeostasis. The microbiota have profound effects on B cells also. Gut microbial exposure leads to a continuous diversification of B-cell repertoire and the production of Tdependent and -independent antibodies, especially IgA. These combined effects of the gut microbes provide an elegant educational process to the adaptive immune network. Contrariwise, failure of this process results in a reduced homeostasis with the gut microbiota, and an increased susceptibility to various immune disorders, both inside and outside the gut. With more definitive microbial-immune relations waiting to be discovered, modulation of the host gut microbiota has a promising future for disease intervention.

Target-derived neurotrophic factors are of basic importance for survival of neurons. In the normal state, such neurotrophic factors, synthesized by the target tissues, are taken up by nerve terminals and transported by retrograde axonal transport in axons to the nerve-cell bodies to maintain their viability. After nerve injury, neurotrophic factors are synthesized by non-neuronal cells (Schwann cells and fibroblasts) in the nerve trunk, thereby supporting the outgrowth of axons. Neurite-outgrowth-promoting factors on cell surfaces (cell adhesion molecules, "recognition molecules") or in the extracellular matrix promote extension of the axons by providing an appropriate "adhesiveness" in the substrate. Both neurotrophic and neurite-outgrowth-promoting factors are essential for axonal growth after injury. Specificity in end-organ reinnervation is a complex phenomenon which may be based on physical factors at the zone of injury, as well as on molecular interaction between axons and substrate cells along the pathways and at the target level. Such processes may include molecular recognition of appropriate axons and maintenance of such axons by trophic mechanisms, as well as the pruning of inappropriate axons. The ultimate errors in target reinnervation are reflected in a cortical re-organization in the somatosensory cortex. The capacity of the brain to "reprogram" itself and adapt to this functional re-organization is critical for the ultimate recovery of functional sensory/motor function after nerve injuries.

No abstract

The systematic separation strategy has long and widely been applied in the research and development of herbal medicines. However, the pharmacological effects of many bioactive constituents are much weaker than those of the corresponding herbal extracts. Thus, there is a consensus that purer herbal extracts are sometimes less effective. Pharmacological loss of purified constituents is closely associated with their significantly reduced intestinal absorption after oral administration. In this review, pharmacokinetic synergies among constituents in herbal extracts during intestinal absorption were systematically summarized to broaden the general understanding of the pharmaceutical nature of herbal medicines. Briefly, some coexisting constituents including plant-produced primary and secondary metabolites, promote the intestinal absorption of active constituents by improving solubility, inhibiting first-pass elimination mediated by drug-metabolizing enzymes or drug transporters, increasing the membrane permeability of enterocytes, and reversibly opening the paracellular tight junction between enterocytes. Moreover, some coexisting constituents change the forms of bioactive constituents via mechanisms including the formation of natural nanoparticles. This review will focus on explaining this new synergistic mechanism. Thus, herbal extracts can be considered mixtures of bioactive compounds and pharmacokinetic synergists. This review may provide ideas and strategies for further research and development of herbal medicines.

B cells, which are critical for intestinal homeostasis, remain understudied in ulcerative colitis (UC). In this study, we recruited three cohorts of patients with UC (primary cohort, n = 145; validation cohort 1, n = 664; and validation cohort 2, n = 143) to comprehensively define the landscape of B cells during UC-associated intestinal inflammation. Using single-cell RNA sequencing, single-cell IgH gene sequencing and protein-level validation, we mapped the compositional, transcriptional and clonotypic landscape of mucosal and circulating B cells. We found major perturbations within the mucosal B cell compartment, including an expansion of naive B cells and IgG + plasma cells with curtailed diversity and maturation. Furthermore, we isolated an auto-reactive plasma cell clone targeting integrin αvβ6 from inflamed UC intestines. We also identified a subset of intestinal CXCL13-expressing TFH-like T peripheral helper cells that were associated with the pathogenic B cell response. Finally, across all three cohorts, we confirmed that changes in intestinal humoral immunity are reflected in circulation by the expansion of gut-homing plasmablasts that correlates with disease activity and predicts disease complications. Our data demonstrate a highly dysregulated B cell response in UC and highlight a potential role of B cells in disease pathogenesis.UC is a chronic inflammatory bowel disease (IBD) characterized by relapsing episodes of inflammation of the colonic mucosa 1 . In healthy individuals, intestinal B cell responses are dominated by the homeostatic generation of IgA-producing plasma cells (PCs) that promote under exclusive licence to Springer Nature America, Inc. 2022Reprints and permissions information is available at www.nature.com/reprints.

The forkhead transcription factor FoxM1 has been reported to regulate, variously, proliferation and/or spindle formation during the G 2 /M transition of the cell cycle. Here we define specific functions of