Dominant mechanism in spinal cord injury-induced immunodeficiency syndrome (SCI-IDS): sympathetic hyperreflexia.

Clinical studies have shown that individuals with spinal cord injury (SCI) are particularly susceptible to infectious diseases, resulting in a syndrome called SCI-induced immunodeficiency syndrome (SCI-IDS), which is the leading cause of death after SCI. It is believed that SCI-IDS is associated with exaggerated activation of sympathetic preganglionic neurons (SPNs). After SCI, disruption of bulbospinal projections from the medulla oblongata C1 neurons to the SPNs results in the loss of sympathetic inhibitory modulation from the brain and brainstem and the occurrence of abnormally high levels of spinal sympathetic reflexes (SSR), named sympathetic hyperreflexia. As the post-injury survival time lengthens, mass recruitment and anomalous sprouting of excitatory interneurons within the spinal cord result in increased SSR excitability, resulting in an excess sympathetic output that disrupts the immune response. Therefore, we first analyze the structural underpinnings of the spinal cord-sympathetic nervous system-immune system after SCI, then demonstrate the progress in highlighting mechanisms of SCI-IDS focusing on norepinephrine (NE)/Beta 2-adrenergic receptor (ß2-AR) signal pathways, and summarize recent preclinical studies examining potential means such as regulating SSR and inhibiting ß2-AR signal pathways to improve immune function after SCI. Finally, we present research perspectives such as to promote the effective regeneration of C1 neurons to rebuild the connection of C1 neurons with SPNs, to regulate excitable or inhibitory interneurons, and specifically to target ß2-AR signal pathways to re-establish neuroimmune balance. These will help us design effective strategies to reverse post-SCI sympathetic hyperreflexia and improve the overall quality of life for individuals with SCI.

Ventromedial Thalamus-Projecting DCN Neurons Modulate Associative Sensorimotor Responses in Mice.

The deep cerebellar nuclei (DCN) integrate various inputs to the cerebellum and form the final cerebellar outputs critical for associative sensorimotor learning. However, the functional relevance of distinct neuronal subpopulations within the DCN remains poorly understood. Here, we examined a subpopulation of mouse DCN neurons whose axons specifically project to the ventromedial (Vm) thalamus (DCNVm neurons), and found that these neurons represent a specific subset of DCN units whose activity varies with trace eyeblink conditioning (tEBC), a classical associative sensorimotor learning task. Upon conditioning, the activity of DCNVm neurons signaled the performance of conditioned eyeblink responses (CRs). Optogenetic activation and inhibition of the DCNVm neurons in well-trained mice amplified and diminished the CRs, respectively. Chemogenetic manipulation of the DCNVm neurons had no effects on non-associative motor coordination. Furthermore, optogenetic activation of the DCNVm neurons caused rapid elevated firing activity in the cingulate cortex, a brain area critical for bridging the time gap between sensory stimuli and motor execution during tEBC. Together, our data highlights DCNVm neurons' function and delineates their kinematic parameters that modulate the strength of associative sensorimotor responses.

Sleep Deprivation Impairs Learning-Induced Increase in Hippocampal Sharp Wave Ripples and Associated Spike Dynamics during Recovery Sleep.

Sleep deprivation (SD) causes deficits in off-line memory consolidation, but the underlying network oscillation mechanisms remain unclear. Hippocampal sharp wave ripple (SWR) oscillations play a critical role in off-line memory consolidation. Therefore, we trained mice to learn a hippocampus-dependent trace eyeblink conditioning (tEBC) task and explored the influence of 1.5-h postlearning SD on hippocampal SWRs and related spike dynamics during recovery sleep. We found an increase in hippocampal SWRs during postlearning sleep, which predicted the consolidation of tEBC in conditioned mice. In contrast, sleep-deprived mice showed a loss of tEBC learning-induced increase in hippocampal SWRs during recovery sleep. Moreover, the sleep-deprived mice exhibited weaker reactivation of tEBC learning-associated pyramidal cells in hippocampal SWRs during recovery sleep. In line with these findings, tEBC consolidation was impaired in sleep-deprived mice. Furthermore, sleep-deprived mice showed augmented fast excitation from pyramidal cells to interneurons and enhanced participation of interneurons in hippocampal SWRs during recovery sleep. Among various interneurons, parvalbumin-expressing interneurons specifically exhibited overexcitation during hippocampal SWRs. Our findings suggest that altered hippocampal SWRs and associated spike dynamics during recovery sleep may be candidate network oscillation mechanisms underlying SD-induced memory deficits.

Hippocampal Interneurons are Required for Trace Eyeblink Conditioning in Mice.

While the hippocampus has been implicated in supporting the association among time-separated events, the underlying cellular mechanisms have not been fully clarified. Here, we combined in vivo multi-channel recording and optogenetics to investigate the activity of hippocampal interneurons in freely-moving mice performing a trace eyeblink conditioning (tEBC) task. We found that the hippocampal interneurons exhibited conditioned stimulus (CS)-evoked sustained activity, which predicted the performance of conditioned eyeblink responses (CRs) in the early acquisition of the tEBC. Consistent with this, greater proportions of hippocampal pyramidal cells showed CS-evoked decreased activity in the early acquisition of the tEBC. Moreover, optogenetic suppression of the sustained activity in hippocampal interneurons severely impaired acquisition of the tEBC. In contrast, suppression of the sustained activity of hippocampal interneurons had no effect on the performance of well-learned CRs. Our findings highlight the role of hippocampal interneurons in the tEBC, and point to a potential cellular mechanism subserving associative learning.

Establishment and validation of prognostic nomograms to predict overall survival and cancer-specific survival for patients with osteosarcoma.

This study aimed to develop and validate nomograms predicting the survival of osteosarcoma patients from the SEER database and our hospital. Data of 1,066 osteosarcoma patients from the SEER database were randomly divided into a development cohort (n=800) and validation cohort one (n=266). Another cohort of 126 patients from our hospital was utilized as validation cohort two. Univariate and multivariate Cox analyses were performed to identify the independent prognostic factors for overall survival (OS) and cancer-specific survival (CSS). Nomograms predicting the 3- and 5-year OS and CSS probability were constructed and validated. The predictive performances of the established nomograms were evaluated by the concordance index (C-index) and the calibration plot. Variables of age, surgical stage, surgery, grade, tumor site, and tumor size were identified as independent prognosticators for OS and CSS in Cox analyses. The C-indexes for OS and CSS in the development cohort were 0.818 and 0.829. Comparatively, the C-indexes for OS and CSS were 0.843 and 0.834, 0.736 and 0.782 for validation cohort one and two, respectively. Calibration plots showed excellent consistency between nomogram prediction and actual survival. Nomograms based on the SEER database are of high accuracy and can serve as a reliable tool for individualized consultation and survival prediction in osteosarcoma patients.

CONUT Score or/and Peripheral Blood CD4+/CD8+ Ratio-Based Web Dynamic Nomograms to Predict the Individualized Survival of Patients with Advanced Osteosarcoma.

BACKGROUND: Nutritional and immune status is paramount for the overall survival (OS) of patients with advanced osteosarcoma. Comprehensive prognostic predictors based on the two indices are scarce. This study aimed to construct and validate individualized web dynamic nomograms based on CONUT score or/and peripheral blood CD4+/CD8+ ratio for OS in patients with advanced osteosarcoma. MATERIALS AND METHODS: The clinical data of 376 advanced osteosarcoma patients from January 2000 to December 2019 were retrospectively collected. Data from the 301 patients (diagnosed in the first 15 years) were used as the development set and data from the remaining 75 patients were assigned as the validation set. Multivariate Cox regression analyses were conducted and three prediction models were constructed, namely, CD4+/CD8+ ratio univariate model (model 1), CONUT score univariate model (model 2), and CD4+/CD8+ ratio plus CONUT score (model 3). These models were visualized by conventional nomograms and individualized web dynamic nomograms, and their performances were further evaluated by C-index, calibration curve, receiver operating characteristic (ROC) curve, and decision curve analysis (DCA), respectively. RESULTS: In multivariate Cox analysis, age, metastasis, ALP, CD4+/CD8+ ratio, chemotherapy, and CONUT score were identified as independent prognostic factors for OS. The calibration curves of the three models all showed good agreement between the actual observation and nomogram prediction for 1-year overall survival. In the development set, the C-index and area under the curve (AUC) of model 3 (0.837, 0.848) were higher than that of model 1 (0.765, 0.773) and model 2 (0.712, 0.749). Similar trends were observed in the validation set. The net benefits of model 3 were better than the other two models within the threshold probability of 36-80% in DCA. CONCLUSION: CONUT score and peripheral CD4+/CD8+ ratio are easily available, reliable, and economical prognostic predictors for survival prediction and stratification in patients with advanced osteosarcoma, but the two predictors combined can establish a better prognosis prediction model.

Neuronal Activity in the Cerebellum During the Sleep-Wakefulness Transition in Mice.

Cerebellar malfunction can lead to sleep disturbance such as excessive daytime sleepiness, suggesting that the cerebellum may be involved in regulating sleep and/or wakefulness. However, understanding the features of cerebellar regulation in sleep and wakefulness states requires a detailed characterization of neuronal activity within this area. By performing multiple-unit recordings in mice, we showed that Purkinje cells (PCs) in the cerebellar cortex exhibited increased firing activity prior to the transition from sleep to wakefulness. Notably, the increased PC activity resulted from the inputs of low-frequency non-PC units in the cerebellar cortex. Moreover, the increased PC activity was accompanied by decreased activity in neurons of the deep cerebellar nuclei at the non-rapid eye-movement sleep-wakefulness transition. Our results provide in vivo electrophysiological evidence that the cerebellum has the potential to actively regulate the sleep-wakefulness transition.

Apatinib as targeted therapy for advanced bone and soft tissue sarcoma: a dilemma of reversing multidrug resistance while suffering drug resistance itself.

Bone and soft tissue sarcomas are rare malignant tumors originated from mesenchymal tissues. They harbor more than 50 distinct subtypes and differ in pathological features and clinical courses. Despite the significant improvements in modern multi-modality treatment, the outcomes and overall survival rates remain poor for patients with advanced, refractory, metastatic, or relapsed diseases. The growth and metastasis of bone and soft tissue sarcoma largely depend on angiogenesis, and VEGF/VEGFR pathway is considered as the most prominent player in angiogenesis. Therefore, blockade of VEGF/VEGFR pathways is a promising therapeutic strategy to retard neovascularization. Several VEGFR inhibitors have been developed and revealed their favorable anti-neoplastic effects in various cancers, but such desirable anti-tumor effects are not obtained in advanced sarcomas because of multiple reasons, such as drug tolerance, short duration of response, and severe adverse effects. Fortunately, preclinical and clinical studies have indicated that apatinib is a novel promising VEGFR2 inhibitor showing potent anti-angiogenic and anti-neoplastic activities in advanced sarcomas. Especially, apatinib has showed notable characteristics in multidrug resistance reversal, tumor regression, vascular normalization, immunosuppression alleviation, and enhancement of chemotherapeutic and radiotherapeutic effects. However, apatinib also gets struck in dilemma of reversing multidrug resistance of chemotherapeutic agents while suffering drug resistance itself, and several difficulties should be tackled before full use of apatinib. In this review, we discuss the outstanding characteristics and main predicaments of apatinib as targeted therapy in advanced sarcomas. Bone and soft tissue sarcomas are rare but malignant tumors originated from mesenchymal tissues. They harbor more than 100 distinct subtypes and differ in features of pathologies and clinical courses. Despite the significant improvements in modern multi-modality treatment, the outcomes and overall survival rates remain poor for patients with advanced, refractory, metastatic, or relapsed lesions. The growth and metastasis of bone and soft tissue sarcoma largely depend on angiogenesis and VEGF/VEGFR pathways play a pivotal role in angiogenesis. Therefore, blockade of VEGF/VEGFR pathways is a promising therapeutic strategy. Several VEGFR inhibitors have been developed and verified in clinical trials but with unfavorable outcomes. Fortunately, preclinical studies and clinical trials have indicated that apatinib is a novel promising VEGFR2 inhibitor showing potent anti-angiogenic and anti-neoplastic activities in advanced sarcomas. Actually, apatinib has showed notable characteristics in multidrug resistance reversal, tumor regression, vascular normalization, immunosuppression alleviation, enhancement of chemotherapeutic and radiotherapeutic effects. However, apatinib also gets struck in dilemma of reversing multidrug resistance of chemotherapeutic agents while suffering drug resistance itself, and several difficulties should be tackled before full use of apatinib. In this review, we discuss the outstanding characteristics and main predicaments of apatinib as targeted therapy in advanced sarcomas.

A method for combining multiple-units readout of optogenetic control with natural stimulation-evoked eyeblink conditioning in freely-moving mice.

A growing pool of transgenic mice expressing Cre-recombinases, together with Cre-dependent opsin viruses, provide good tools to manipulate specific neural circuits related to eyeblink conditioning (EBC). However, currently available methods do not enable to get fast and precise readout of optogenetic control when the freely-moving mice are receiving EBC training. In the current study, we describe a laser diode (LD)-optical fiber (OF)-Tetrode assembly that allows for simultaneous multiple units recording and optical stimulation. Since the numbers of various cables that require to be connected are minimized, the LD-OF-Tetrode assembly can be combined with CS-US delivery apparatus for revealing the effects of optical stimulation on EBC in freely- moving mice. Moreover, this combination of techniques can be utilized to optogenetically intervene in hippocampal neuronal activities during the post-conditioning sleep in a closed-loop manner. This novel device thus enhances our ability to explore how specific neuronal assembly contributes to associative motor memory in vivo.

Neuron-NG2 cell synapses: novel functions for regulating NG2 cell proliferation and differentiation.

NG2 cells are a population of CNS cells that are distinct from neurons, mature oligodendrocytes, astrocytes, and microglia. These cells can be identified by their NG2 proteoglycan expression. NG2 cells have a highly branched morphology, with abundant processes radiating from the cell body, and express a complex set of voltage-gated channels, AMPA/kainate, and GABA receptors. Neurons notably form classical and nonclassical synapses with NG2 cells, which have varied characteristics and functions. Neuron-NG2 cell synapses could fine-tune NG2 cell activities, including the NG2 cell cycle, differentiation, migration, and myelination, and may be a novel potential therapeutic target for NG2 cell-related diseases, such as hypoxia-ischemia injury and periventricular leukomalacia. Furthermore, neuron-NG2 cell synapses may be correlated with the plasticity of CNS in adulthood with the synaptic contacts passing onto their progenies during proliferation, and synaptic contacts decrease rapidly upon NG2 cell differentiation. In this review, we highlight the characteristics of classical and nonclassical neuron-NG2 cell synapses, the potential functions, and the fate of synaptic contacts during proliferation and differentiation, with the emphasis on the regulation of the NG2 cell cycle by neuron-NG2 cell synapses and their potential underlying mechanisms.

Progesterone alleviates neural behavioral deficits and demyelination with reduced degeneration of oligodendroglial cells in cuprizone-induced mice.

Demyelination occurs widely in neurodegenerative diseases. Progesterone has neuroprotective effects, is known to reduce the clinical scores and the inflammatory response. Progesterone also promotes remyelination in experimental autoimmune encephalomyelitis and cuprizone-induced demyelinating brain. However, it still remains unclear whether progesterone can alleviate neural behavioral deficits and demyelination with degeneration of oligodendroglial cells in cuprizone-induced mice. In this study, mice were fed with 0.2% cuprizone to induce demyelination, and treated with progesterone to test its potential protective effect on neural behavioral deficits, demyelination and degeneration of oligodendroglial cells. Our results showed noticeable alleviation of neural behavioral deficits following progesterone treatment as assessed by changes in average body weight, and activity during the open field and Rota-rod tests when compared with the vehicle treated cuprizone group. Progesterone treatment alleviated demyelination as shown by Luxol fast blue staining, MBP immunohistochemical staining, and electron microscopy. There was an obvious decrease in TUNEL and Caspase-3-positive apoptotic cells, and an increase in the number of oligodendroglial cells staining positive for PDGFRα, Olig2, Sox10 and CC-1 antibody in the brains of cuprizone-induced mice after progesterone administration. These results indicate that progesterone can alleviate neural behavioral deficits and demyelination against oligodendroglial cell degeneration in cuprizone-induced mice.

Oligodendrocyte N-methyl-D-aspartate receptor signaling: insights into its functions.

Myelination by oligodendrocytes facilitates rapid nerve conduction. Loss of oligodendrocytes and failure of myelination lead to nerve degeneration and numerous demyelinating white matter diseases. N-methyl-D-aspartate (NMDA) receptors, which are key regulators on neuron survival and functions, have been recently identified to express in oligodendrocytes, especially in the myelin sheath. NMDA receptor signaling in oligodendrocytes plays crucial roles in energy metabolism and myelination. In the present review, we highlight the subcellular location-specific impairment of excessive NMDA receptor signaling on oligodendrocyte energy metabolism in soma and myelin, and the mechanisms including Ca(2+) overload, acidotoxicity, mitochondria dysfunction, and impairment of respiratory chains. Conversely, physiological NMDA receptor signaling regulates differentiation and migration of oligodendrocytes. How can we use above knowledge to treat excitotoxic oligodendrocyte loss, congenital myelination deficiency, or postnatal demyelination? A thorough understanding of NMDA receptor signaling-mediated cellular events in oligodendrocytes at the pathophysiological level will no doubt aid in exploring effective therapeutic strategies for demyelinating white matter diseases.

Modulation of FGF receptor signaling as an intervention and potential therapy for myelin breakdown in Alzheimer's disease.

Alzheimer's disease (AD) is the most common neurodegenerative disease and oligodendrocyte degeneration and white matter damage play a critical role in the pathogenesis of AD. FGF/FGF receptor signaling have been implicated in diverse cellular processes including cell apoptosis, survival, adhesion, migration, differentiation, and proliferation, as well as key regulators of the development of the central nervous system (including in axon guidance and synaptogenesis) via multiple signal pathways. It has been demonstrated that FGF infusion or gene transfer restores neurogenesis in subventricular zone and hippocampal functions in aged mice and mouse models of AD and has therapeutic implications for neurocognitive disorders. Besides, FGF receptor signaling in oligodendrocytes regulates myelin sheath thickness via Erk1/2 MAPK and PI3K/Akt/mTOR signaling, which sequentially regulates progression through distinct stages of oligodendrocyte differentiation. The effect could be effectively antagonized by the potent, selective tyrosine kinase inhibitor of FGF receptor activity. We therefore propose that modulation of FGF receptor signaling will suppress the development of oligodendrocyte degeneration and myelin breakdown or white matter damage in mouse models or patients of AD and improve or restore the pathological and clinical symptoms of cognitive decline, and FGF receptor signaling with its inhibitors and/or gene transfer would serve as an intervention and potential therapy for myelin breakdown and cognitive decline in AD.

MicroRNA patents in demyelinating diseases: a new diagnostic and therapeutic perspective.

MicroRNAs (miRNAs, miRs) are a class of non-coding single-stranded RNAs, which can negatively regulate gene expression at posttranscriptional levels by miRNA-mRNA interaction. It has been demonstrated that miRNAs play important roles in a variety of biological process, including cell proliferation, differentiation, apoptosis, and tumorigenesis. Recent studies have shown crucial roles of specific miRNAs in controlling oligodendrocyte (OL) differentiation and myelination. Dysregulation of miRNAs is a vital event in the pathogenesis of demyelinating diseases. Furthermore, new patents of miRNAs also provide new strategies for gene therapy and miR-drug development for demyelinating diseases, especially multiple sclerosis. In this review, we briefly introduce the roles of miRNAs in OL differentiation and in the pathogenesis of demyelinating diseases, with emphasis on the implication of miRNAs patents in disease diagnostic and therapeutic perspective and its related technologies and challenges in clinical application.

MicroRNAs: novel regulators of oligodendrocyte differentiation and potential therapeutic targets in demyelination-related diseases.

MicroRNAs (miRNAs or miRs) are a class of endogenous small non-coding RNAs that consist of about 22 nucleotides and play critical roles in various biological processes, including cell proliferation, differentiation, apoptosis, and tumorigenesis. In recent years, some specific miRNA, such as miR-219, miR-138, miR-9, miR-23, and miR-19b were found to participate in the regulation of oligodendrocyte (OL) differentiation and myelin maintenance, as well as in the pathogenesis of demyelination-related diseases (e.g., multiple sclerosis, ischemic stroke, and leukodystrophy). These miRNAs control their target mRNA or regulate the protein levels of some signaling pathways, and participate in OL differentiation and the pathogenesis of demyelination-related diseases. During pathologic processes, the expression levels of specific miRNAs are dynamically altered. Therefore, miRNAs act as diagnostic and prognostic indicators of defects in OL differentiation and demyelination-related diseases, and they can provide potential targets for therapeutic drug development.

ID2: A negative transcription factor regulating oligodendroglia differentiation.

Remyelination of the central nervous system in multiple sclerosis patients is often incomplete. Remyelination depends on normal oligodendrogenesis and the differentiation of oligodendrocyte precursor cells (OPC) into mature oligodendrocytes (OL). Inhibitor of DNA binding (ID), a transcription factor, is thought to inhibit oligodendrogenesis and the differentiation of OPC. This Mini-Review aims to reveal the roles of and mechanisms used by IDs (mainly ID2) in this process. An interaction between ID2 and retinoblastoma tumor suppressor is responsible for the cell cycle transition from G1 to S. The translocation of ID2 between the nucleus and cytoplasm is regulated by E47 and OLIG. An interaction between ID2 and OLIG mediates the inhibitory effects of bone morphogenic proteins and G protein-coupled receptor 17 on oligodendroglia differentiation. ID2 expression is regulated by Wnt and histone deacetylases during the differentiation of OPC. ID4, another member of the ID family, functions similarly to ID2 in regulating the differentiation of OPC. The main difference is that ID4 is essential for oligodendrogenesis, whereas ID2 is nonessential. This could have important implications for demyelinating diseases, and interfering with these pathways might represent a viable therapeutic approach for these diseases.

Developmental changes and subcellular location in inhibitor of DNA binding 2 (Id2) immunoreactivity in the rat Corpus callosum.

The mechanisms underlying oligodendrocyte differentiation and myelination are still unclear, but understanding them will be critical for the development of therapies for multiple sclerosis. Inhibitor of DNA binding 2 (Id2) is a transcription factor thought to inhibit oligodendrocyte differentiation, however, it is not known whether the developmental changes and subcellular localization of Id2 are related to myelination. Therefore, we investigated the developmental changes in and the subcellular localization of Id2 immunoreactivity in the rat Corpus callosum, at post-natal developmental stages P0, P7, P14, P21, P42 and P90, by immunohistochemistry. Id2 expression increased from P0 to a peak at P42, the late stage of myelination in the Corpus callosum. Id2 immunostaining decreased slightly, but still remained high at P90. Subcellular localization of Id2 changed from presence in cytoplasm at P14 to the nuclei at P42. Moreover, Id2 was mainly co-localized with CC-1-immunopositive mature oligodendrocytes at P42. These results may be consistent with Id2 inhibitory function in oligodendrocyte differentiation, at the end of myelination or in compaction of myelin in the Corpus callosum of postnatal rat brain.

Protective effects of catalpol on oligodendrocyte death and myelin breakdown in a rat model of chronic cerebral hypoperfusion.

Chronic cerebral hypoperfusion is thought to induce white matter lesions (WMLs) with oligodendrocyte (OLG) death and myelin breakdown. Although apoptosis is believed to be involved in the pathologic process of WMLs, effective therapies for such remain lacking. In the present study, we investigated whether catalpol, an iridoid glycoside, could act on oligodendrocytes (OLGs) and myelin sheaths in a rat chronic hypoperfusion model, and whether transcription factor cAMP-responsive element binding protein (CREB) phosphorylation is involved in the resulting neuroprotection. A rat model of chronic cerebral hypoperfusion was prepared by bilateral common carotid artery ligation. On the 30th day after hypoperfusion, OLG loss and myelin disruption in the ischemic white matter were more severe and evident than in the sham control. Spatial memory was also more seriously impaired in rats after hypoperfusion. Treatment with catalpol significantly suppressed diminished OLGs and myelin breakdown, and promoted the recovery of cognitive decline. The expression of Bcl-2 and phosphorylated CREB (p-CREB) was also significantly increased by catalpol treatment. In conclusion, catalpol could protect against hypoperfusion-induced WMLs and cognitive impairment through the p-CREB signaling pathway leading to downstream upregulation of Bcl-2. Our results suggest that catalpol may be a useful approach for treating cerebrovascular WMLs.

The hemangioblast: from concept to authentication.

The hemangioblast hypothesis has been hotly debated for over a century. Hemangioblasts are defined as multipotent cells that can give rise to both hematopoietic cells and endothelial cells. The existence of hemangioblasts has now been confirmed and many important molecules and several signaling pathways are involved in their generation and differentiation. Fibroblast growth factor, renin-angiotensin system and runt-related transcription factor 1 (Runx1) direct the formation of hemangioblasts through highly selective gene expression patterns. On the other hand, the hemogenic endothelium theory and a newly discovered pattern of hematopoietic/endothelial differentiation make the genesis of hemangioblasts more complicated. But how hemangioblasts are formed and how hematopoietic cells or endothelial cells are derived from remains largely unknown. Here we summarize the current knowledge of the signaling pathways and molecules involved in hemangioblast development and suggest some future clinical applications.

Progesterone attenuates neurological behavioral deficits of experimental autoimmune encephalomyelitis through remyelination with nucleus-sublocalized Olig1 protein.

Multiple sclerosis (MS) is the most common demyelination disease of central nervous system (CNS). The deterioration of the disease is characterized by the axonal loss with defective remyelination. Progesterone can promote the remyelination, but whether it exerts beneficial effect on treatment of MS still remains unclear. Olig1 protein is a key regulator in the remyelination, when the intracellular sublocalization plays an import role too. We observed the effect of progesterone on experimental autoimmune encephalomyelitis (EAE) in rats by injecting the progesterone after the neurological behavioral deficits were shown up. The results showed no continuous increase of the nervous function score from day 10 after injection (p<0.05). Electron microscopy and LFB staining found prominent increase of OD value of normal myelin in the brain from day 6 after injection (p<0.05). Olig1 protein was localized almost completely in the cytoplasm of Olig1-positive cells from normal rats' brain. In EAE rats, the Olig1 protein has been translocated to the nucleus of 32.17% of Olig1-positive cells, which was increased to 68.52% after injection with progesterone at day 6 after injection (p<0.01). The results indicate that the progesterone is beneficial to attenuating neurological behavioral deficits, for it can promote more successful remyelination of EAE with aid of the nucleus-sublocalized Olig1 protein.