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.

Spatial memory requires hypocretins to elevate medial entorhinal gamma oscillations.

The hypocretin (Hcrt) (also known as orexin) neuropeptidic wakefulness-promoting system is implicated in the regulation of spatial memory, but its specific role and mechanisms remain poorly understood. In this study, we revealed the innervation of the medial entorhinal cortex (MEC) by Hcrt neurons in mice. Using the genetically encoded G-protein-coupled receptor activation-based Hcrt sensor, we observed a significant increase in Hcrt levels in the MEC during novel object-place exploration. We identified the function of Hcrt at presynaptic glutamatergic terminals, where it recruits fast-spiking parvalbumin-positive neurons and promotes gamma oscillations. Bidirectional manipulations of Hcrt neurons' projections from the lateral hypothalamus (LHHcrt) to MEC revealed the essential role of this pathway in regulating object-place memory encoding, but not recall, through the modulation of gamma oscillations. Our findings highlight the significance of the LHHcrt-MEC circuitry in supporting spatial memory and reveal a unique neural basis for the hypothalamic regulation of spatial memory.

The signs of computer tomography combined with artificial intelligence can indicate the correlation between status of consciousness and primary brainstem hemorrhage of patients.

Background: For patients of primary brainstem hemorrhage (PBH), it is crucial to find a method that can quickly and accurately predict the correlation between status of consciousness and PBH. Objective: To analyze the value of computer tomography (CT) signs in combination with artificial intelligence (AI) technique in predicting the correlation between status of consciousness and PBH. Methods: A total of 120 patients with PBH were enrolled from August 2011 to March 2021 according to the criteria. Patients were divided into three groups [consciousness, minimally conscious state (MCS) and coma] based on the status of consciousness. Then, first, Mann-Whitney U test and Spearman rank correlation test were used on the factors: gender, age, stages of intracerebral hemorrhage, CT signs with AI or radiology physicians, hemorrhage involving the midbrain or ventricular system. We collected hemorrhage volumes and mean CT values with AI. Second, those significant factors were screened out by the Mann-Whitney U test and those highly or moderately correlated by Spearman's rank correlation test, and a further ordinal multinomial logistic regression analysis was performed to find independent predictors of the status of consciousness. At last, receiver operating characteristic (ROC) curves were drawn to calculate the hemorrhage volume for predictively assessing the status of consciousness. Results: Preliminary meaningful variables include hemorrhage involving the midbrain or ventricular system, hemorrhage volume, grade of hematoma shape and density, and CT value from Mann-Whitney U test and Spearman rank correlation test. It is further shown by ordinal multinomial logistic regression analysis that hemorrhage volume and hemorrhage involving the ventricular system are two major predictors of the status of consciousness. It showed from ROC that the hemorrhage volumes of <3.040 mL, 3.040 ~ 6.225 mL and >6.225 mL correspond to consciousness, MCS or coma, respectively. If the hemorrhage volume is the same, hemorrhage involving the ventricular system should be correlated with more severe disorders of consciousness (DOC). Conclusion: CT signs combined with AI can predict the correlation between status of consciousness and PBH. Hemorrhage volume and hemorrhage involving the ventricular system are two independent factors, with hemorrhage volume in particular reaching quantitative predictions.

A Sleep-Specific Midbrain Target for Sevoflurane Anesthesia.

Sevoflurane has been the most widely used inhaled anesthetics with a favorable recovery profile; however, the precise mechanisms underlying its anesthetic action are still not completely understood. Here the authors show that sevoflurane activates a cluster of urocortin 1 (UCN1+ )/cocaine- and amphetamine-regulated transcript (CART+ ) neurons in the midbrain involved in its anesthesia. Furthermore, growth hormone secretagogue receptor (GHSR) is highly enriched in sevoflurane-activated UCN1+ /CART+ cells and is necessary for sleep induction. Blockade of GHSR abolishes the excitatory effect of sevoflurane on UCN1+ /CART+ neurons and attenuates its anesthetic effect. Collectively, their data suggest that anesthetic action of sevoflurane necessitates the GHSR activation in midbrain UCN1+ /CART+ neurons, which provides a novel target including the nucleus and receptor in the field of anesthesia.

Comparative expression analysis of TEADs and their splice variants in mouse embryonic stem cells.

Transcriptional enhanced associate domain (TEAD) transcription factors play important roles in embryonic stem cell (ESC) renewal and differentiation. Four TEAD transcription factors (Tead1, Tead2, Tead3 and Tead4) and their various splice variants have been discovered in mice, but the expression pattern of them during pluripotency state transition is unclear. Here, we investigated the expression of TEADs and their splice variants in mouse ESCs at different pluripotent/differentiating states and adult mouse tissues. Our results preliminarily revealed the diversity and heterogeneity of TEAD family, which is helpful for understanding their overlapping and distinctive functions. Furthermore, a novel splice variant of Tead1 was identified and named Tead1 isoform 4.

Researches on cognitive sequelae of burn injury: Current status and advances.

Burn injury is a devastating disease with high incidence of disability and mortality. The cognitive dysfunctions, such as memory defect, are the main neurological sequelae influencing the life quality of burn-injured patients. The post-burn cognitive dysfunctions are related to the primary peripheral factors and the secondary cerebral inflammation, resulting in the destruction of blood-brain barrier (BBB), as is shown on Computed Tomography (CT) and magnetic resonance imaging examinations. As part of the neurovascular unit, BBB is vital to the nutrition and homeostasis of the central nervous system (CNS) and undergoes myriad alterations after burn injury, causing post-burn cognitive defects. The diagnosis and treatment of cognitive dysfunctions as burn injury sequelae are of great importance. In this review, we address the major manifestations and interventions of post-burn cognitive defects, as well as the mechanisms involved in memory defect, including neuroinflammation, destruction of BBB, and hormone imbalance.

Sustained Activity of Hippocampal Parvalbumin-Expressing Interneurons Supports Trace Eyeblink Conditioning in Mice.

Although recent studies have revealed an involvement of hippocampal interneurons in learning the association among time-separated events, its underlying cellular mechanisms remained not fully clarified. Here, we combined multichannel recording and optogenetics to elucidate how the hippocampal parvalbumin-expressing interneurons (PV-INs) support associative learning. To address this issue, we trained the mice (both sexes) to learn hippocampus-dependent trace eyeblink conditioning (tEBC) in which they associated a light flash conditioned stimulus (CS) with a corneal air puff unconditioned stimuli (US) separated by a 250 ms time interval. We found that the hippocampal PV-INs exhibited learning-associated sustained activity at the early stage of tEBC acquisition. Moreover, the PV-IN sustained activity was positively correlated with the occurrence of conditioned eyeblink responses at the early learning stage. Suppression of the PV-IN sustained activity impaired the acquisition of tEBC, whereas the PV-IN activity suppression had no effect on the acquisition of delay eyeblink conditioning, a hippocampus-independent learning task. Learning-associated augmentation in the excitatory pyramidal cell-to-PVIN drive may contribute to the formation of PV-IN sustained activity. Suppression of the PV-IN sustained activity disrupted hippocampal gamma but not theta band oscillation during the CS-US interval period. Gamma frequency (40 Hz) activation of the PV-INs during the CS-US interval period facilitated the acquisition of tEBC. Our current findings highlight the involvement of hippocampal PV-INs in tEBC acquisition and reveal insights into the PV-IN activity kinetics which are of key importance for the hippocampal involvement in associative learning.SIGNIFICANCE STATEMENT The cellular mechanisms underlying associative learning have not been fully clarified. Previous studies focused on the involvement of hippocampal pyramidal cells in associative learning, whereas the activity and function of hippocampal interneurons were largely neglected. We herein demonstrated the hippocampal PV-INs exhibited learning-associated sustained activity, which was required for the acquisition of tEBC. Furthermore, we showed evidence that the PV-IN sustained activity might have arisen from the learning-associated augmentation in excitatory pyramidal cell-to-PVIN drive and contributed to learning-associated augmentation in gamma band oscillation during tEBC acquisition. Our findings provide more mechanistic understanding of the cellular mechanisms underlying the hippocampal involvement in associative learning.

Prognosticators and Prognostic Nomograms for Leiomyosarcoma Patients With Metastasis.

Individual survival prediction and risk stratification are of vital importance to optimize the individualized treatment of metastatic leiomyosarcoma (LMS) patients. This study aimed to identify the prognostic factors for metastatic LMS patients and establish prognostic models for overall survival (OS) and cancer-specific survival (CSS). The data of LMS patients with metastasis between 2010 and 2015 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. The entire cohort was randomly divided into a training cohort and a validation cohort. The influences of primary tumor site, localized and distant metastases, and sites and number of metastases on the prognosis of metastatic LMS patients were firstly explored by Kaplan-Meier curves and log-rank tests. Furthermore, the effective therapeutic regimens and prognosticators for metastatic LMS patients were also analyzed by Cox analysis. In addition, two prognostic nomograms for OS and CSS were established, and their predictive performances were evaluated by the methods of receiver operating characteristic (ROC) curves, time-dependent ROC curves, calibration curves, and decision curve analysis (DCA). A total of 498 patients were finally collected from the SEER database and were randomly assigned to the training set (N = 332) and validation set (N = 166). No significant differences in OS were observed in patients with distant organ metastasis and localized metastasis. For patients who have already developed distant organ metastasis, the sites and number of metastases seemed to be not closely associated with survival. Patients who received chemotherapy got significantly longer survival than that of their counterparts. In univariate and multivariate Cox analyses, variables of surgery, chemotherapy, age, and tumor size were identified as independent predictors for OS and CSS, and distant metastasis was also independently associated with CSS. The areas under the curve (AUCs) of ROC curves of the nomogram for predicting 1-, 3-, and 5-year OS were 0.770, 0.800, and 0.843, respectively, and those for CSS were 0.777, 0.758, and 0.761, respectively. The AUCs of time-dependent AUCs were all over 0.750. The calibration curves and DCA curves also showed excellent performance of the prognostic nomograms. Metastasis is associated with reduced survival, while the sites and the number of metastases are not significantly associated with survival. The established nomogram is a useful tool that can help to perform survival stratification and to optimize prognosis-based decision-making in clinical practice.

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.

The roles of neuron-NG2 glia synapses in promoting oligodendrocyte development and remyelination.

NG2 immunopositive progenitor cells, also simply termed as NG2 glia and thought mainly to be oligodendrocyte precursor cells (OPCs), form synaptic connections with neurons in gray and white matters of brain. One of the most classical features of oligodendrocyte lineage cells is myelination, which will favor neuronal signaling transmission. Thus, is there a causal link between the specific synapses of neuron-NG2 glia and myelination? Building on this, here, we will discuss several relevant issues. First, in order to understand the synapses, it is necessary to integrate the definite inputs onto NG2 glia. We show that the synaptic activities and myelination are not synchronized, so the synapses are more likely to regulate early development of NG2 glia and prepare for myelination. Furthermore, several studies have suggested that the synapses also play a role in recovery of pathological conditions, such as multiple sclerosis (MS). Therefore, elucidating the activities of neuron-NG2 glia synapses will be beneficial for both physiological and pathological conditions. Graphical abstract The existence of neuron-NG2 glia synapses reveals that the neuronal activities projecting to NG2 glia is an elaborate regulation, and the signaling from neurons to NG2 glia is frequent in early stage. The neuron-NG2 glia synapses indirectly provide a basic condition to support myelination by extrasynaptic communication. The neuron-NG2 glia synapses also promote remyelination, and it occurs similar to physiological conditions.

Prognostic value of pre-treatment Naples prognostic score (NPS) in patients with osteosarcoma.

BACKGROUND: This study aimed to evaluate the clinical significance of pre-treatment Naples prognostic score (NPS) in patients with osteosarcoma. METHODS: The clinical data of 133 osteosarcoma patients between January 2011 and February 2018 in our hospital was retrospectively collected and analyzed. NPS was calculated from four parameters, including serum albumin level, serum total cholesterol (TC), lymphocyte-to-monocyte ratio (LMR), and neutrophil-to-lymphocyte ratio (NLR). Patients were divided into three groups (group 1-3) based on NPS. The relationships between NPS and clinical features, overall survival (OS), and progression-free survival (PFS) were analyzed. Two prediction models based on NPS and clinical parameters were developed: clinical parameters model (model A), and the combined model of NPS and clinical parameters (model B). Their predictive performances were further evaluated and compared. RESULTS: The median follow-up time of this cohort was 46.0 (range, 5-75) months, while the median OS and PFS was 40 (range, 5-75) months and 36 (range, 5-71) months, respectively. NPS was significantly correlated with gender, tumor location, Enneking stage, pathological fracture, local recurrence, and metastasis (all P < 0.05). Variables of NPS, Enneking stage, local recurrence, metastasis, and NLR were confirmed as independent prognostic factors for OS and PFS by univariate and multivariate Cox analysis. Prediction model B obtained larger AUCs for OS and PFS and showed better consistency between nomogram-predicted and actual survival than that of model A at the follow-up time of 1-, 3-, and 5-year. CONCLUSIONS: NPS was a novel, reliable, and multidimensional prognostic scoring system with favorable predictive performance for patients with osteosarcoma.

Nitric oxide might be an inducing factor in cognitive impairment in Alzheimer's disease via downregulating the monocarboxylate transporter 1.

Alzheimer's disease (AD) is a typical neurodegenerative disease in central nervous system (CNS). Generally speaking, patients with severe AD are often accompanied with cognitive impairment. Oligodendrocytes (OLs) are myelin-forming cells in CNS, and myelin injury potentially has something to do with the cognitive impairment in AD. Based on the previous experimental studies, it has been recognized that nitric oxide (NO), as a signaling molecule, might have an influence on the axon and myelin by affecting the energy transport mechanism of OLs through monocarboxylate transporter 1 (MCT1). Interestingly, a novel model of cell signaling----axo-myelinic synapse (AMS) has been put forward. In the context of this model, chances are that a new way is established in which NO can influence the pathogenesis of AD by down-regulating the expression of MCT1. As a consequence, it may provide attractive prospective and underlying drug targeting effects for the treatment of AD.

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.