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Transsexualism and sex-related differences in hemispheric asymmetry.

Sex differences in human brain lateralization are documented by studies on normal subjects, patients with the unilateral brain damage, and individuals with atypical level of hormones. However, there is no agreement as to the specific role of gender in the development of hemispheric asymmetry. This experiment was designed to examine whether gender identity plays an important role in the formation of brain lateralization, as some recent data seem to suggest. A group of subjects showing gender dysphoria (transsexuals) and two groups of control male and female subjects were presented with verbal and visual-spatial tasks. Results show that neither biological sex nor gender identity are sufficient factors to determine the pattern of hemispheric asymmetry.

Adolescent↗

Neurones associated with saccade metrics in the monkey central mesencephalic reticular formation.

Neurones in the central mesencephalic reticular formation (cMRF) begin to discharge prior to saccades. These long lead burst neurones interact with major oculomotor centres including the superior colliculus (SC) and the paramedian pontine reticular formation (PPRF). Three different functions have been proposed for neurones in the cMRF: (1) to carry eye velocity signals that provide efference copy information to the SC (feedback), (2) to provide duration signals from the omnipause neurones to the SC (feedback), or (3) to participate in the transformation from the spatial encoding of a target selection signal in the SC into the temporal pattern of discharge used to drive the excitatory burst neurones in the pons (feed-forward). According to each respective proposal, specific predictions about cMRF neuronal discharge have been formulated. Individual neurones should: (1) encode instantaneous eye velocity, (2) burst specifically in relation to saccade duration but not to other saccade metrics, or (3) have a spectrum of weak to strong correlations to saccade dynamics. To determine if cMRF neurones could subserve these multiple oculomotor roles, we examined neuronal activity in relation to a variety of saccade metrics including amplitude, velocity and duration. We found separate groups of cMRF neurones that have the characteristics predicted by each of the proposed models. We also identified a number of subgroups for which no specific model prediction had previously been established. We found that we could accurately predict the neuronal firing pattern during one type of saccade behaviour (visually guided) using the activity during an alternative behaviour with different saccade metrics (memory guided saccades). We suggest that this evidence of a close relationship of cMRF neuronal discharge to individual saccade metrics supports the hypothesis that the cMRF participates in multiple saccade control pathways carrying saccade amplitude, velocity and duration information within the brainstem.

Action Potentials↗

Spatial and temporal regulation of 3-phosphoinositides by PI 3-kinase and PTEN mediates chemotaxis.

We have investigated the mechanisms of leading edge formation in chemotaxing Dictyostelium cells. We demonstrate that while phosphatidylinositol 3-kinase (PI3K) transiently translocates to the plasma membrane in response to chemoattractant stimulation and to the leading edge in chemotaxing cells, PTEN, a negative regulator of PI3K pathways, exhibits a reciprocal pattern of localization. By uniformly localizing PI3K along the plasma membrane, we show that chemotaxis pathways are activated along the lateral sides of cells and PI3K can initiate pseudopod formation, providing evidence for a direct instructional role of PI3K in leading edge formation. These findings provide evidence that differential subcellular localization and activation of PI3K and PTEN is required for proper chemotaxis.

Animals↗

Development of surface pattern during division in Paramecium. II. Defective spatial control in the mutant kin241.

kin241 is a monogenic nuclear recessive mutation producing highly pleiotropic effects on cell size and shape, generation time, thermosensitivity, nuclear reorganization and cortical organization. We have analyzed the nature of the cortical disorders and their development during division, using various specific antibodies labelling either one of the cortical cytoskeleton components, as was previously done for analysis of cortical pattern formation in the wild type. Several abnormalities in basal body properties were consistently observed, although with a variable frequency: extra microtubules in either the triplets or in the lumen; nucleation of a second kinetodesmal fiber; abnormal orientation of the newly formed basal body with respect to the mother one. The latter effect seems to account for the major observed cortical disorders (reversal, intercalation of supplementary ciliary rows). The second major effect of the mutation concerns the spatiotemporal map of cortical reorganization during division. Excess basal body proliferation occurs and is correlated with modified boundaries of some of the cortical domains identified in the wild type on the basis of their basal body duplication pattern. This is the first mutant described in a ciliate in which both the structure and duplication of basal bodies and the body plan are affected. The data support the conclusion that the mutation does not alter the nature of the morphogenetic signal(s) which pervade the dividing cell, nor the competence of cytoskeletal structures to respond to signalling, but affects the local interpretation of the signals.

Animals↗

Distribution of neuronal intermediate filament proteins in the developing mouse olfactory system.

The distribution of neuronal intermediate filament proteins in the developing mouse olfactory bulb and olfactory epithelium was characterized by immunocytochemical approach. Antibodies against alpha-internexin, neurofilament triplet proteins (NFTPs; NF-L, NF-M, and NF-H) and peripherin were used to determine their expression at different developmental stages. Alpha-internexin and peripherin were first found to be co-localized in the olfactory neuroepithelium during early development. At the perinatal stage, expression patterns of alpha-internexin and peripherin are distinguishable by spatial and temporal manner: peripherin is predominantly expressed in the olfactory nerves; whereas alpha-internexin is expressed in both olfactory nerves and olfactory bulb. Our observation suggests that peripherin as well as alpha-internexin may play some roles in the process formation of olfactory nerves during development. In the developing olfactory periglomerulus, alpha-internexin was found around postnatal Day 3, whereas NFTPs were not observed until postnatal Day 7. Our data showed that the expression of alpha-internexin preceded those of the NFTPs in most neurons of the developing olfactory bulb. Some small neurons in the adult olfactory bulb were uniquely labeled with antibody to alpha-internexin. Our results suggest that alpha-internexin may play a functional role in the neuronal cytoarchitecture of developing olfactory system, and can be a neuronal marker for detecting postmitotic migrating neurons in the adult olfactory bulb.

Animals↗

The control of chondrogenesis.

Chondrogenesis is the earliest phase of skeletal development, involving mesenchymal cell recruitment and migration, condensation of progenitors, and chondrocyte differentiation, and maturation and resulting in the formation of cartilage and bone during endochondral ossification. This process is controlled exquisitely by cellular interactions with the surrounding matrix, growth and differentiation factors, and other environmental factors that initiate or suppress cellular signaling pathways and transcription of specific genes in a temporal-spatial manner. Vertebrate limb development is controlled by interacting patterning systems involving prominently the fibroblast growth factor (FGF), bone morphogenetic protein (BMP), and hedgehog pathways. Both positive and negative signaling kinases and transcription factors, such as Sox9 and Runx2, and interactions among them determine whether the differentiated chondrocytes remain within cartilage elements in articular joints or undergo hypertrophic maturation prior to ossification. The latter process requires extracellular matrix remodeling and vascularization controlled by mechanisms that are not understood completely. Recent work has revealed novel roles for mediators such as GADD45beta, transcription factors of the Dlx, bHLH, leucine zipper, and AP-1 families, and the Wnt/beta-catenin pathway that interact at different stages during chondrogenesis.

Animals↗

Contributions of cell adhesion molecules to altered synaptic weightings during memory consolidation.

The fundamental concept that synapse growth and change are associated with learning is considered a "replay" of early neurodevelopmental principles that instruct neural connectivity pattern. Common mechanisms suggested to link the process of memory formation through synaptic elaboration are exemplified by the activity of cell adhesion molecules following learning and that center on waves of glycoprotein synthesis occurring in the 6- to 8-h and 10- to 12-h posttraining periods of consolidation. These are associated with spatially clustered granule cells in the adult rat hippocampus that show a transient time-dependent increase in ribosome production and greater microtubular complexity and dendritic spine number 6 to 8 h following training. The elimination and/or selection of the synapses to be retained in the memory trace is proposed to be dependent on cell adhesion molecule glycosylation events in the 10- to 12-h posttraining period. The existence of similar cell adhesion molecule glycosylation mechanisms within a corticohippocampal pathway is used to contribute to a model of memory in which sensory representations are eventually consolidated through relative change in synaptic weightings.

Animals↗

Spatial and temporal variability of ground-level ozone in Castilla-León (Spain).

Ozone is a secondary air pollutant that has received extensive attention in the literature, mainly because of the adverse effects that exposure to it can cause, particularly in vegetation during the growing season. Because meteorological conditions strongly influence the efficiency of photochemical processes leading to ozone formation and destruction, ground-level ozone air pollution is currently being considered as a regional-scale phenomenon rather than a local one. This role of O3 as a regional-scale pollutant often implies the handling of large data sets in order to obtain information about its spatial and temporal variability patterns over a given broad region. Rotated principal component analysis (RPCA) is known to be one of the most powerful mathematical tools that can be used to achieve this aim. RPCA was applied in this paper to the summer and winter hourly time series of ground-level O3, concentrations recorded during 2 consecutive years (1996-1997) at 26 urban and suburban sites in Castilla-León (Spain). This procedure permitted the identification of different subregions where O3 concentrations show different spatio-temporal variability patterns. These variability patterns are mainly associated with the interaction of regional-level meteorological and anthropogenic factors. Some differences between winter and summer patterns were also found.

Air Pollutants↗

Hepatocyte growth factor-induced calcium waves in hepatocytes as revealed with rapid scanning confocal microscopy.

Cytosolic Ca2+ transients induced by hepatocyte growth factor (HGF) were imaged in primary cultured rat hepatocytes using newly developed rapid scanning confocal microscopes and indo-1. HGF (40 ng/ml) increased cytosolic free Ca2+ concentration ([Ca2+]i) in about 60% of hepatocytes, in 45% of which the increases were oscillatory. In each of the oscillatory hepatocytes, the repetitive increases in [Ca2+]i originated from a specific same region adjacent to the cell membrane and propagated across the cell like waves. Phenylephrine (10 microM) also induced Ca2+ waves. The locus where HGF-induced Ca2+ waves and phenylephrine-induced Ca2+ waves were originated was the same, and there was a correlation in the peak height between HGF-induced Ca2+ waves and phenylephrine-induced Ca2+ waves in each cell, although the mechanisms of inositol 1,4,5-trisphosphate (ins(1,4,5)P3) formation induced by HGF should be different from those by phenylephrine. On the other hand, there was no correlation between sensitivity of each cell to HGF and that to phenylephrine which were measured as latent periods prior to Ca2+ rises after an addition of the agonists. These results suggested the following: the spatial patterns of Ca2+ waves were decided by a common mechanism, probably not the propagation of ins(1,4,5)P3 but the distribution of ins(1,4,5)P3-sensitive Ca2+ pools; sensitivities of each cell to the agonists did not mainly depend on the common mechanism.

Adrenergic alpha-Agonists↗

Memory processing and apamin induce immediate early gene expression in mouse brain.

The present study analyses the effects of learning on the spatial pattern and the time-course of changes of immediate early gene messenger RNA's (c-fos and c-jun) in mouse brain produced by training in an appetitive bar-pressing task. Activation of c-fos and c-jun after training is strictly located in the hippocampal formation and is learning-dependent. Levels of both proto-oncogene mRNAs in the trained group were 4 to 5 times higher than in the sham-conditioned group. Injections of apamin, a bee venom neurotoxin that selectively blocks a class of Ca(2+)-activated K+ channels and improves learning and memory retention, produced as compared to untrained animals a 3- to 5-fold increase of expression of c-fos and c-jun with the same pattern as that observed in the trained animals. Post-training injection of 0.2 mg/kg apamin enhanced 1.4-fold the expression of both immediate early genes in CA1, CA3 and dentate gyrus as compared to trained saline-injected mice. All these results suggest that apamin-induced increase of immediate early gene expression might be related to the apamin-induced facilitation of learning.

Animals↗

Reactivation of Hox gene expression during bone regeneration.

Previous studies have explored the link between bone regeneration and skeletogenesis. Although a great deal is known regarding tissue and cell based events, especially those involving ossification and chondrogenesis, much remains unknown about the molecular similarity of repair and development. Since the functional significance of Homeobox (Hox) genes in embryonic skeletogenesis has been well documented through knockout and deficiency studies, we chose to investigate whether members of this family are reactivated during fracture repair. Specifically, we examined the temporal and spatial expression of Msx-1, Msx-2, rHox, Hoxa-2 and Hoxd-9, because of their involvement in limb development. Utilizing quantitative reverse transcriptase RT-PCR (qPCR), mRNA levels from all five genes were shown to be upregulated during fracture repair at all times tested (post-fracture day 3-21), as compared to intact bone. Further, using in situ hybridization and immunohistochemistry, spatial expression of these genes was localized to osteoblasts, chondrocytes and periosteal osteoprogenitor cells found within the fracture callus, the foremost cells responsible for the reparative phase of the healing process. Given the contribution of Hox genes in skeletal development, our results suggest that these genes are involved in either the patterning or formation of the fracture callus, further supporting the notion that bone regeneration recapitulates skeletal development.

Animals↗

The involvement of cAMP signaling pathway in axis specification in Xenopus embryos.

The cAMP signaling system has been postulated to be involved in embryogenesis of many animal species, however, little is known about its role in embryonic axis formation in vertebrates. In this study, the role of the cAMP signaling pathway in patterning the body plan of the Xenopus embryo was investigated by expressing and activating the exogenous human 5-hydroxytryptamine type 1a receptor (5-HT(1a)R) which inhibits adenylyl cyclase through inhibitory G-protein in embryos in a spatially- and temporally-controlled manner. In embryos, ventral, but not dorsal expression and stimulation of this receptor during blastula and gastrula stages induced secondary axes but were lacking anterior structures. At the molecular level, 5-HT(1a)R stimulation induced expression of the dorsal mesoderm marker genes, and downregulated expression of the ventral markers but had no effect on expression of the pan mesodermal marker gene in ventral marginal zone explants. In addition, ventral expression and stimulation of the receptor partially restored dorsal axis of UV-irradiated axis deficient embryo. Finally, the total mass of cAMP differs between dorsal and ventral regions of blastula and gastrula embryos and this is regulated in a temporally-specific manner. These results suggest that the cAMP signaling system may be involved in the transduction of ventral signals in patterning early embryos.

Animals↗

Cognitive representation of negative numbers.

To understand negative numbers, must we refer to positive number representations (the phylogenetic hypothesis), or do we acquire a negative mental number line (the ontogenetic hypothesis)? In the experiment reported here, participants made lateralized button responses to indicate the larger of two digits from the range -9 to 9. Digit pairs were displayed spatially congruent or incongruent with either a phylogenetic or an ontogenetic mental number line. The pattern of decision latencies suggests that negative numbers become associated with left space, thus supporting the ontogenetic view.

Adult↗

CCDC137 knockdown suppresses bladder cancer progression by downregulating SCD.

BACKGROUND: The Coiled-coil domain-containing (CCDC) family, due to its unique protein structural domain and broad involvement in diverse biological processes, has emerged as a focus in oncology research. Nevertheless, its clinical significance and function in bladder cancer (BLCA) remain poorly defined. METHODS: Machine learning algorithms were employed to identify pivotal CCDC genes in the cancer genome atlas (TCGA), and a prognostic model was subsequently constructed. Multi-omics data encompassing pan-cancer cohorts, single-cell sequencing, and spatial transcriptomics were integrated to characterize the expression patterns and prognostic significance of Coiled-coil domain-containing 137 (CCDC137), a previously uncharacterized CCDC family member in BLCA. Tissue microarray confirmed CCDC137 abnormal expression in bladder carcinoma specimens. The effect of CCDC137 knockdown on BLCA progression was evaluated through CCK8 assay, clonogenic formation, wound healing, Transwell, and subcutaneous xenograft models. RNA sequencing, quantitative RT-PCR, and western blot were utilized to delineate its regulatory network. RESULTS: A prognostic model incorporating 10 CCDC genes was successfully established in the TCGA-BLCA cohort. Then, we found that CCDC137 exhibited pan-cancer overexpression and usually correlation with poor clinical outcomes. Immunohistochemistry further substantiated its dysregulation in bladder carcinoma. Integrated multi-omics analyses suggested associations between CCDC137 expression and a tumor immunosuppressive microenvironment. CCDC137 knockdown significantly suppressed bladder cancer cell proliferation and migratory capacity in vitro. Correspondingly, subcutaneous xenograft tumor growth was inhibited in vivo. Moreover, decreased expression of stearoyl-CoA desaturase (SCD), a key lipid metabolic enzyme, accompanied CCDC137 depletion. These findings collectively suggest a cancer-promoting role for CCDC137 in bladder carcinoma. CONCLUSIONS: This systematic investigation combining multi-omics bioinformatics analyses and experimental validation demonstrates the role of CCDC137 in bladder carcinoma progression, providing novel mechanistic insights into the pathogenesis of BLCA and offering a theoretical foundation for therapeutic targeting of CCDC137 in urothelial malignancies.

Urinary Bladder Neoplasms↗

Overlapping effects of different members of the FGF family on lens fiber differentiation in transgenic mice.

Fibroblast growth factors (FGFs), such as FGF-1, have been shown to induce differentiation of lens epithelial cells both in tissue culture and in transgenic mice. In the present study, using the alpha A-crystallin promoter, we generated transgenic mice that express different FGFs (FGF-4, FGF-7, FGF-8, FGF-9) specifically in the lens. All four FGFs induced changes in ocular development. Microphthalmic eyes were evident in transgenic mice expressing FGF-8, FGF-9 and some lines expressing FGF-4. A developmental study of the microphthalmic eyes revealed that, by embryonic day 15, expression of these FGFs induced lens epithelial cells to undergo premature fiber differentiation. In less severely affected lines expressing FGF-4 or FGF-7, the lens epithelial cells exhibited a premature exit from the cell cycle and underwent a fiber differentiation response later in development, leading to cataract formation. The responsiveness of lens cells to different FGFs indicates that these proteins stimulate the same or overlapping downstream signalling pathway(s). These overlapping effects of different FGFs on a common cell type indicate that the normal developmental roles for these genes are determined by the temporal and spatial regulation of their expression patterns. The fact that any of these FGFs can induce ocular defects and loss of lens transparency implies that it is essential for the normal eye to maintain very specific spatial control over FGF expression in order to prevent cataract induction.

Animals↗

Multiple Eph receptors and B-class ephrins regulate midline crossing of corpus callosum fibers in the developing mouse forebrain.

Agenesis of the corpus callosum (CC) is a rare birth defect that occurs in isolated conditions and in combination with other developmental cerebral abnormalities. Recent identification of families of growth and guidance molecules has generated interest in the mechanisms that regulate callosal growth. One family, ephrins and Eph receptors, has been implicated in mediating midline pathfinding decisions; however, the complexity of these interactions has yet to be unraveled. Our studies shed light on which B-class ephrins and Eph receptors function to regulate CC midline growth and how these molecules interact with important guideposts during development. We show that multiple Eph receptors (B1, B2, B3, and A4) and B-class ephrins (B1, B2, and B3) are present and function in developing forebrain callosal fibers based on both spatial and temporal expression patterns and analysis of gene-targeted knock-out mice. Defects are most pronounced in the combination double knock-out mice, suggesting that compensatory mechanisms exist for several of these family members. Furthermore, these CC defects range from mild hypoplasia to complete agenesis and Probst's bundle formation. Further analysis revealed that Probst's bundle formation may reflect aberrant glial formations and/or altered sensitivity of CC axons to other guidance cues. Our results support a significant role for ephrins and Eph receptors in CC development and may provide insight to possible mechanisms involved in axon midline crossing and human disorder.

Animals↗

The effects of Janus Green B on the temporal and spatial pattern of feather germ morphogenesis.

The normal timing and appearance of feather germs was perturbed by injecting the dye Janus Green B into the amniotic fluid of chick embryos at late stage 28, prior to the first appearance of feather germs. This treatment prevented feather germ morphogenesis in some regions while elsewhere it delayed normal morphological development. The Janus Green B effect lasted for approximately 98 hours. Feather regions, which normally form epidermal placodes during the period of treatment, showed the longest delays in subsequent feather germ formation and were the most likely to remain featherless. These results suggest that the epidermal placode stage is critical for feather germ formation. Janus Green B appears to prevent feather germ morphogenesis by interfering with development prior to this critical stage. Since severely affected regions fail to recover their capacity to form feather germs, even after the period of sensitivity to the dye, a limited period of competence is suggested for feather germ formation.

Animals↗

Multi-omics analyses reveal DjTcf4 critical for proper timing of differentiation in planarian regeneration.

The blastema is key to forming complete tissues in regenerating Dugesia japonica (D. japonica). However, the dynamic changes in cellular compositions and transcription landscapes in blastema during regeneration are understudied. Here, through genome reannotation, 3D spatial transcriptome construction, single-cell RNA sequencing (scRNA-seq), and single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq) analyses of changes in gene expression and chromatin structures, we delineate key transcription factors regulating the developmental trajectories of major cell clusters in the regenerating head. Importantly, we find that the T cell factor 4 (DjTcf4)-positive cells highly accumulate at wound areas, and its gene network is critical for the proper timing of development during regeneration in multiple progenitor cells. Depletion of DjTcf4 and its target genes leads to singular eye and/or dull tail phenotypes and delays regeneration. Taken together, we build multi-omics atlases in D. japonica and reveal the noncanonical function of the DjTcf4 network in developmental pattern formation, laying a foundation for studies of regeneration in D. japonica.

Animals↗