Ig Superfamily Ligand and Receptor Pairs Expressed in Synaptic Partners in Drosophila.

Information processing relies on precise patterns of synapses between neurons. The cellular recognition mechanisms regulating this specificity are poorly understood. In the medulla of the Drosophila visual system, different neurons form synaptic connections in different layers. Here, we sought to identify candidate cell recognition molecules underlying this specificity. Using RNA sequencing (RNA-seq), we show that neurons with different synaptic specificities express unique combinations of mRNAs encoding hundreds of cell surface and secreted proteins. Using RNA-seq and protein tagging, we demonstrate that 21 paralogs of the Dpr family, a subclass of immunoglobulin (Ig)-domain containing proteins, are expressed in unique combinations in homologous neurons with different layer-specific synaptic connections. Dpr interacting proteins (DIPs), comprising nine paralogs of another subclass of Ig-containing proteins, are expressed in a complementary layer-specific fashion in a subset of synaptic partners. We propose that pairs of Dpr/DIP paralogs contribute to layer-specific patterns of synaptic connectivity.

Integration of temporal and spatial patterning generates neural diversity.

In the Drosophila optic lobes, 800 retinotopically organized columns in the medulla act as functional units for processing visual information. The medulla contains over 80 types of neuron, which belong to two classes: uni-columnar neurons have a stoichiometry of one per column, while multi-columnar neurons contact multiple columns. Here we show that combinatorial inputs from temporal and spatial axes generate this neuronal diversity: all neuroblasts switch fates over time to produce different neurons; the neuroepithelium that generates neuroblasts is also subdivided into six compartments by the expression of specific factors. Uni-columnar neurons are produced in all spatial compartments independently of spatial input; they innervate the neuropil where they are generated. Multi-columnar neurons are generated in smaller numbers in restricted compartments and require spatial input; the majority of their cell bodies subsequently move to cover the entire medulla. The selective integration of spatial inputs by a fixed temporal neuroblast cascade thus acts as a powerful mechanism for generating neural diversity, regulating stoichiometry and the formation of retinotopy.

Neurodevelopmental and transcriptomic effects of CRISPR/Cas9-induced somatic orco mutation in honey bees.

In insects, odorant receptors facilitate olfactory communication and require the functionality of the highly conserved co-receptor gene orco. Genome editing studies in a few species of ants and moths have revealed that orco can also have a neurodevelopmental function, in addition to its canonical role in adult olfaction, discovered first in Drosophila melanogaster. To extend this analysis, we determined whether orco mutations also affect the development of the adult brain of the honey bee Apis mellifera, an important model system for social behavior and chemical communication. We used CRISPR/Cas9 to knock out orco and examined anatomical and molecular consequences. To increase efficiency, we coupled embryo microinjection with a laboratory egg collection and in vitro rearing system. This new workflow advances genomic engineering technologies in honey bees by overcoming restrictions associated with field studies. We used Sanger sequencing to quickly select individuals with complete orco knockout for neuroanatomical analyses and later validated and described the mutations with amplicon sequencing. Mutant bees had significantly fewer glomeruli, smaller total volume of all the glomeruli, and higher mean individual glomerulus volume in the antennal lobe compared to wild-type controls. RNA-Sequencing revealed that orco knockout also caused differential expression of hundreds of genes in the antenna, including genes related to neural development and genes encoding odorant receptors. The expression of other types of chemoreceptor genes was generally unaffected, reflecting specificity of CRISPR activity in this study. These results suggest that neurodevelopmental effects of orco are related to specific insect life histories.

Valence of social information is encoded in different subpopulations of mushroom body Kenyon cells in the honeybee brain.

Over 600 Myr of evolutionary divergence between vertebrates and invertebrates is associated with considerable neuroanatomical variation both across and within these lineages. By contrast, valence encoding is an important behavioural trait that is evolutionarily conserved across vertebrates and invertebrates, and enables individuals to distinguish between positive (potentially beneficial) and negative (potentially harmful) situations. We tested the hypothesis that social interactions of positive and negative valence are modularly encoded in the honeybee brain (i.e. encoded in different cellular subpopulations) as in vertebrate brains. In vertebrates, neural activation patterns are distributed across distinct parts of the brain, suggesting that discrete circuits encode positive or negative stimuli. Evidence for this hypothesis would suggest a deep homology of neural organization between insects and vertebrates for valence encoding, despite vastly different brain sizes. Alternatively, overlapping localization of valenced social information in the brain would imply a 're-use' of circuitry in response to positive and negative social contexts, potentially to overcome the energetic constraints of a tiny brain. We used immediate early gene expression to map positively and negatively valenced social interactions in the brain of the western honeybee Apis mellifera. We found that the valence of a social signal is represented by distinct anatomical subregions of the mushroom bodies, an invertebrate sensory neuropil associated with social behaviour, multimodal sensory integration, learning and memory. Our results suggest that the modularization of valenced social information in the brain is a fundamental property of neuroanatomical organization.

Temporal patterning of Drosophila medulla neuroblasts controls neural fates.

In the Drosophila optic lobes, the medulla processes visual information coming from inner photoreceptors R7 and R8 and from lamina neurons. It contains approximately 40,000 neurons belonging to more than 70 different types. Here we describe how precise temporal patterning of neural progenitors generates these different neural types. Five transcription factors-Homothorax, Eyeless, Sloppy paired, Dichaete and Tailless-are sequentially expressed in a temporal cascade in each of the medulla neuroblasts as they age. Loss of Eyeless, Sloppy paired or Dichaete blocks further progression of the temporal sequence. We provide evidence that this temporal sequence in neuroblasts, together with Notch-dependent binary fate choice, controls the diversification of the neuronal progeny. Although a temporal sequence of transcription factors had been identified in Drosophila embryonic neuroblasts, our work illustrates the generality of this strategy, with different sequences of transcription factors being used in different contexts.

Gut microbiota contribute to variations in honey bee foraging intensity.

Gut microbiomes are increasingly recognized for mediating diverse biological aspects of their hosts, including complex behavioral phenotypes. Although many studies have reported that experimental disruptions to the gut microbial community result in atypical host behavior, studies that address how gut microbes contribute to adaptive behavioral trait variation are rare. Eusocial insects represent a powerful model to test this, because of their simple gut microbiota and complex division of labor characterized by colony-level variation in behavioral phenotypes. Although previous studies report correlational differences in gut microbial community associated with division of labor, here, we provide evidence that gut microbes play a causal role in defining differences in foraging behavior between European honey bees (Apis mellifera). We found that gut microbial community structure differed between hive-based nurse bees and bees that leave the hive to forage for floral resources. These differences were associated with variation in the abundance of individual microbes, including Bifidobacterium asteroides, Bombilactobacillus mellis, and Lactobacillus melliventris. Manipulations of colony demography and individual foraging experience suggested that differences in gut microbial community composition were associated with task experience. Moreover, single-microbe inoculations with B. asteroides, B. mellis, and L. melliventris caused effects on foraging intensity. These results demonstrate that gut microbes contribute to division of labor in a social insect, and support a role of gut microbes in modulating host behavioral trait variation.

China county-based prostate specific antigen screening for prostate cancer and a cost-effective analysis.

BACKGROUND: Prostate cancer is one of the most common malignant tumors worldwide, and is the third-leading cause of cancer death in men. Nearly 70% of new prostate cancer patients in China are locally advanced or widely metastatic with poor prognosis. Providing active treatment to early stage prostate cancer patients can improve the prognosis of prostate cancer patients. Thus, this study sought to evaluate the economy of early prostate specific antigen (PSA) screening for high-risk prostate cancer. METHODS: Based on the data collected from the PSA screening activities of 11 county hospitals from October 2019 to April 2021, this study evaluated a high-risk prostate cancer population who received PSA screening and their quality of life and economy. The screening population comprised males aged over 50 years. All screening patients were tested for PSA. If the PSA value is unnormal, a further diagnosis based on magnetic resonance imagining (MRI) or a transrectal ultrasound-guided prostate biopsy were performed. The decision-tree and Markov model was used to simulate the process of disease development of high-risk prostate cancer patients who underwent screenings and those who did not, and the incremental cost-effectiveness ratio was also evaluated. RESULTS: A total of 13,726 men received a PSA screening. Of these, 1,062 men had abnormal PSA values, and 73 of these were diagnosed with prostate cancer. Of these 73 patients, 40, 21, and 12 had early stage, mid-stage, and late-stage prostate cancer, respectively. Compared to the patients unscreened, the 1,000 patients who received an early PSA screening increased their quality-adjusted life year (QALY) by 15.69 years; however, each QALY had an additional cost of 38,550 yuan, which was lower than the willingness to pay threshold of 72,447 yuan (per capita gross domestic product in 2020). CONCLUSIONS: For high-risk prostate cancer patients, early screenings have a cost-effective advantage over no screenings. Thus, early screening should be vigorously promoted for high-risk prostate cancer patients.

Glia relay differentiation cues to coordinate neuronal development in Drosophila.

Neuronal birth and specification must be coordinated across the developing brain to generate the neurons that constitute neural circuits. We used the Drosophila visual system to investigate how development is coordinated to establish retinotopy, a feature of all visual systems. Photoreceptors achieve retinotopy by inducing their target field in the optic lobe, the lamina neurons, with a secreted differentiation cue, epidermal growth factor (EGF). We find that communication between photoreceptors and lamina cells requires a signaling relay through glia. In response to photoreceptor-EGF, glia produce insulin-like peptides, which induce lamina neuronal differentiation. Our study identifies a role for glia in coordinating neuronal development across distinct brain regions, thus reconciling the timing of column assembly with that of delayed differentiation, as well as the spatiotemporal pattern of lamina neuron differentiation.

A Unique Class of Neural Progenitors in the Drosophila Optic Lobe Generates Both Migrating Neurons and Glia.

How neuronal and glial fates are specified from neural precursor cells is an important question for developmental neurobiologists. We address this question in the Drosophila optic lobe, composed of the lamina, medulla, and lobula complex. We show that two gliogenic regions posterior to the prospective lamina also produce lamina wide-field (Lawf) neurons, which share common progenitors with lamina glia. These progenitors express neither canonical neuroblast nor lamina precursor cell markers. They bifurcate into two sub-lineages in response to Notch signaling, generating lamina glia or Lawf neurons, respectively. The newly born glia and Lawfs then migrate tangentially over substantial distances to reach their target tissue. Thus, Lawf neurogenesis, which includes a common origin with glia, as well as neuronal migration, resembles several aspects of vertebrate neurogenesis.

Immunosuppressive activity of the Chinese medicinal plant Tripterygium wilfordii. III. Suppression of graft-versus-host disease in murine allogeneic bone marrow transplantation by the PG27 extract.

BACKGROUND: PG27 is an active fraction purified from an extract of a Chinese medicinal plant, Tripterygium wilfordii Hook f. We tested PG27 in murine allogeneic bone marrow transplantation (BMT) and investigated the mechanism of graft-versus-host disease (GVHD) suppression. METHODS: Recipients in the C57BL/6 --> BDF1 murine BMT model received oral or intraperitoneal PG27. RESULTS: Fourteen days of PG27 given orally or intraperitoneally prevented GVHD development and produced extended disease-free survival (more than 300 days) for many animals. PG490-88, a semisynthetic derivative of PG490 (triptolide, present in PG27), was also efficacious. PG27 reduced day 7 splenic allospecific cytotoxic T lymphocyte levels by more than 99% compared with vehicle-treated mice. Compared with normals, spleens from control allogeneic BMT mice displayed significantly reduced mononuclear cell content, an increased percentage of CD8+ cells, fewer CD4+ cells, and more activated ([interleukin-2 receptor+], IL-2R+) CD8+ T cells. PG27 increased mononuclear cell recovery, and significantly reduced the day-14 percentages of CD3+ and IL-2R+ cells in allogeneic BMT mice, producing results similar to those for syngeneic BMT mice. PG27 significantly increased concanavalin A-stimulated in vitro IL-4 production by day-14 splenocytes, with a 7- to 8-fold higher level than that produced by control cells. CONCLUSIONS: PG27 treatment for only 14 days prevented GVHD induction and development and produced long-term survival. PG27 largely normalized splenic T lymphocyte subsets, reduced allospecific cytotoxic T lymphocyte activity, and increased IL-4 production capability. PG27 may suppress GVHD by the induction of anergy and a deviation away from a proinflammatory phenotype, which could be reflected in the increased potential for IL-4 production.

Sequential axon-derived signals couple target survival and layer specificity in the Drosophila visual system.

Neural circuit formation relies on interactions between axons and cells within the target field. While it is well established that target-derived signals act on axons to regulate circuit assembly, the extent to which axon-derived signals control circuit formation is not known. In the Drosophila visual system, anterograde signals numerically match R1-R6 photoreceptors with their targets by controlling target proliferation and neuronal differentiation. Here we demonstrate that additional axon-derived signals selectively couple target survival with layer specificity. We show that Jelly belly (Jeb) produced by R1-R6 axons interacts with its receptor, anaplastic lymphoma kinase (Alk), on budding dendrites to control survival of L3 neurons, one of three postsynaptic targets. L3 axons then produce Netrin, which regulates the layer-specific targeting of another neuron within the same circuit. We propose that a cascade of axon-derived signals, regulating diverse cellular processes, provides a strategy for coordinating circuit assembly across different regions of the nervous system.

Temporal patterning of neural progenitors in Drosophila.

Drosophila has recently become a powerful model system to understand the mechanisms of temporal patterning of neural progenitors called neuroblasts (NBs). Two different temporal sequences of transcription factors (TFs) have been found to be sequentially expressed in NBs of two different systems: the Hunchback, Krüppel, Pdm1/Pdm2, Castor, and Grainyhead sequence in the Drosophila ventral nerve cord; and the Homothorax, Klumpfuss, Eyeless, Sloppy-paired, Dichaete, and Tailless sequence that patterns medulla NBs. In addition, the intermediate neural progenitors of type II NB lineages are patterned by a different sequence: Dichaete, Grainyhead, and Eyeless. These three examples suggest that temporal patterning of neural precursors by sequences of TFs is a common theme to generate neural diversity. Cross-regulations, including negative feedback regulation and positive feedforward regulation among the temporal factors, can facilitate the progression of the sequence. However, there are many remaining questions to understand the mechanism of temporal transitions. The temporal sequence progression is intimately linked to the progressive restriction of NB competence, and eventually determines the end of neurogenesis. Temporal identity has to be integrated with spatial identity information, as well as with the Notch-dependent binary fate choices, in order to generate specific neuron fates.

Deterministic or stochastic choices in retinal neuron specification.

There are two views on vertebrate retinogenesis: a deterministic model dependent on fixed lineages and a stochastic model in which choices of division modes and cell fates cannot be predicted. In this issue of Neuron, He et al. (2012) address this question in zebrafish using live imaging and mathematical modeling.

[Expression and clinical significance of galectin-3 in well-differentiated thyroid carcinoma].

BACKGROUND & OBJECTIVE: The most challenging problem in diagnosing thyroid nodules is to distinguish benign disease from malignant disease. Although fine-needle aspiration cytology (FNAC) is an important diagnostic procedure, its inherent limitations affect the diagnostic accuracy. Therefore, this study was designed to search for biological markers which can distinguish benign lesion from malignant lesion of thyroid. METHODS: The expression of galectin-3 in 30 specimens of thyroid cancer, 10 specimens of thyroid adenoma, and 10 specimens of nodular thyroid goiter were detected by LSAB immunocytochemistry. The results of routine pathologic examination of gland species were set as golden standard. RESULTS: The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy rate of impression immunocytochemistry in detecting galectin-3 were 96.66%, 100.00%, 100.00%, 95.23%, and 98.00%, respectively; those of routine impression cytology were 86.66%, 100.00%, 100.00%, 83.33%, and 92.00%, respectively; those of fine-needle aspiration biopsy (FNAB) were 86.66%, 100.00%, 100.00%, 83.33%, and 92.00%, respectively; those of FNAC were 76.66%, 100.00%, 100.00%, 74.07%, and 86.00%, respectively. Galectin-3 was commonly expressed in well-differentiated thyroid carcinoma, but didn't express in thyroid adenoma and nodular thyroid goiter. CONCLUSIONS: Galectin-3 is commonly expressed in thyroid malignant lesions, but not in benign lesions. Immunocytochemistry assay can distinguish well-differentiated thyroid carcinoma from thyroid adnoma and nodular thyroid goiter.