Value-related learning in the olfactory bulb occurs through pathway-dependent perisomatic inhibition of mitral cells.

Associating values to environmental cues is a critical aspect of learning from experiences, allowing animals to predict and maximise future rewards. Value-related signals in the brain were once considered a property of higher sensory regions, but their wide distribution across many brain regions is increasingly recognised. Here, we investigate how reward-related signals begin to be incorporated, mechanistically, at the earliest stage of olfactory processing, namely, in the olfactory bulb. In head-fixed mice performing Go/No-Go discrimination of closely related olfactory mixtures, rewarded odours evoke widespread inhibition in one class of output neurons, that is, in mitral cells but not tufted cells. The temporal characteristics of this reward-related inhibition suggest it is odour-driven, but it is also context-dependent since it is absent during pseudo-conditioning and pharmacological silencing of the piriform cortex. Further, the reward-related modulation is present in the somata but not in the apical dendritic tuft of mitral cells, suggesting an involvement of circuit components located deep in the olfactory bulb. Depth-resolved imaging from granule cell dendritic gemmules suggests that granule cells that target mitral cells receive a reward-related extrinsic drive. Thus, our study supports the notion that value-related modulation of olfactory signals is a characteristic of olfactory processing in the primary olfactory area and narrows down the possible underlying mechanisms to deeper circuit components that contact mitral cells perisomatically.

Development and validation of a nomogram for predicting in-hospital mortality of patients with cervical spine fractures without spinal cord injury.

BACKGROUND: The incidence of cervical spine fractures is increasing every day, causing a huge burden on society. This study aimed to develop and verify a nomogram to predict the in-hospital mortality of patients with cervical spine fractures without spinal cord injury. This could help clinicians understand the clinical outcome of such patients at an early stage and make appropriate decisions to improve their prognosis. METHODS: This study included 394 patients with cervical spine fractures from the Medical Information Mart for Intensive Care III database, and 40 clinical indicators of each patient on the first day of admission to the intensive care unit were collected. The independent risk factors were screened using the Least Absolute Shrinkage and Selection Operator regression analysis method, a multi-factor logistic regression model was established, nomograms were developed, and internal validation was performed. A receiver operating characteristic (ROC) curve was drawn, and the area under the ROC curve (AUC), net reclassification improvement (NRI), and integrated discrimination improvement (IDI) were calculated to evaluate the discrimination of the model. Moreover, the consistency between the actual probability and predicted probability was reflected using the calibration curve and Hosmer-Lemeshow (HL) test. A decision curve analysis (DCA) was performed, and the nomogram was compared with the scoring system commonly used in clinical practice to evaluate the clinical net benefit. RESULTS: The nomogram indicators included the systolic blood pressure, oxygen saturation, respiratory rate, bicarbonate, and simplified acute physiology score (SAPS) II. The results showed that our model had satisfactory predictive ability, with an AUC of 0.907 (95% confidence interval [CI] = 0.853-0.961) and 0.856 (95% CI = 0.746-0.967) in the training set and validation set, respectively. Compared with the SAPS-II system, the NRI values of the training and validation sets of our model were 0.543 (95% CI = 0.147-0.940) and 0.784 (95% CI = 0.282-1.286), respectively. The IDI values of the training and validation sets were 0.064 (95% CI = 0.004-0.123; P = 0.037) and 0.103 (95% CI = 0.002-0.203; P = 0.046), respectively. The calibration plot and HL test results confirmed that our model prediction results showed good agreement with the actual results, where the HL test values of the training and validation sets were P = 0.8 and P = 0.95, respectively. The DCA curve revealed that our model had better clinical net benefit than the SAPS-II system. CONCLUSION: We explored the in-hospital mortality of patients with cervical spine fractures without spinal cord injury and constructed a nomogram to predict their prognosis. This could help doctors assess the patient's status and implement interventions to improve prognosis accordingly.

Development and validation of a nomogram for predicting in-hospital mortality in patients with nonhip femoral fractures.

BACKGROUND: The incidence of nonhip femoral fractures is gradually increasing, but few studies have explored the risk factors for in-hospital death in patients with nonhip femoral fractures in the ICU or developed mortality prediction models. Therefore, we chose to study this specific patient group, hoping to help clinicians improve the prognosis of patients. METHODS: This is a retrospective study based on the data from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database. Least absolute shrinkage and selection operator (LASSO) regression was used to screen risk factors. The receiver operating characteristic (ROC) curve was drawn, and the areas under the curve (AUC), net reclassification index (NRI) and integrated discrimination improvement (IDI) were calculated to evaluate the discrimination of the model. The consistency between the actual probability and the predicted probability was assessed by the calibration curve and Hosmer-Lemeshow goodness of fit test (HL test). Decision curve analysis (DCA) was performed, and the nomogram was compared with the scoring system commonly used in clinical practice to evaluate the clinical net benefit. RESULTS: The LASSO regression analysis showed that heart rate, temperature, red blood cell distribution width, blood urea nitrogen, Glasgow Coma Scale (GCS), Simplified Acute Physiology Score II (SAPSII), Charlson comorbidity index and cerebrovascular disease were independent risk factors for in-hospital death in patients with nonhip femoral fractures. The AUC, IDI and NRI of our model in the training set and validation set were better than those of the GCS and SAPSII scoring systems. The calibration curve and HL test results showed that our model prediction results were in good agreement with the actual results (P = 0.833 for the HL test of the training set and P = 0.767 for the HL test of the validation set). DCA showed that our model had a better clinical net benefit than the GCS and SAPSII scoring systems. CONCLUSION: In this study, the independent risk factors for in-hospital death in patients with nonhip femoral fractures were determined, and a prediction model was constructed. The results of this study may help to improve the clinical prognosis of patients with nonhip femoral fractures.

Dense and Sparse Labelling of Mitral Cells by Oral and Intraperitoneal Routes of Tamoxifen Administration.

Cell type-specific labelling and manipulation using Cre-driver lines have become integral to analyses of neuronal circuits in the brain. To study how mitral cells of the olfactory bulb process olfactory information and how they contribute to behavior, an inducible Cre-driver line, Lbhd2-CreERT2, can be used. In this chapter, we describe two methods for administering tamoxifen. The first method achieves a dense recombination pattern using tamoxifen-containing food, while the second method involving an intraperitoneal injection is suited for sparse labelling.

A bibliometric analysis of global publication trends on rTMS and aphasia.

BACKGROUND: Aphasia is one of the most devastating cognitive disorders caused by brain injury and seriously hinders patients' rehabilitation and quality of life. Repetitive transcranial magnetic stimulation involves the repeated application of extracranial pulsed magnetic fields to the local central nervous system to alter the membrane potential of cortical nerve cells, generating induced currents that affect brain metabolism and electrical activity. As one of the most popular noninvasive brain stimulation techniques, it has been used to treat aphasia. However, only a few bibliometric studies have examined the research direction and main findings in the field. METHODS: To obtain an in-depth understanding of the research status and trend in this area, a bibliometric analysis based on the Web of Science database was conducted. VOSviewer (Leiden University, Leiden, Netherlands) and Microsoft Excel (Microsoft, Redmond, USA) were used to extract bibliometric information. Analysis of global distribution was conducted using the webpage mapping implement GunnMap2 (http://lert.co.nz/map/). RESULTS: Publications in this field were retrieved from the Web of Science Core Collection database, and 189 articles met the final inclusion criteria. The most influential authors, institutions, journals, and countries were Ralph MA from the University of Manchester, Harvard University, Neuropsychologia, and the USA, respectively. CONCLUSION: This study revealed publication patterns and emerging trends in the literature, providing a detailed and objective overview of the current state of research on repetitive transcranial magnetic stimulation for the treatment of aphasia. This information will be of great benefit to anyone seeking information about this field and can serve as a reference guide for researchers aiming to conduct further research.

Virtual reality-based real-time imaging reveals abnormal cortical dynamics during behavioral transitions in a mouse model of autism.

Functional connectivity (FC) can provide insight into cortical circuit dysfunction in neuropsychiatric disorders. However, dynamic changes in FC related to locomotion with sensory feedback remain to be elucidated. To investigate FC dynamics in locomoting mice, we develop mesoscopic Ca2+ imaging with a virtual reality (VR) environment. We find rapid reorganization of cortical FC in response to changing behavioral states. By using machine learning classification, behavioral states are accurately decoded. We then use our VR-based imaging system to study cortical FC in a mouse model of autism and find that locomotion states are associated with altered FC dynamics. Furthermore, we identify FC patterns involving the motor area as the most distinguishing features of the autism mice from wild-type mice during behavioral transitions, which might correlate with motor clumsiness in individuals with autism. Our VR-based real-time imaging system provides crucial information to understand FC dynamics linked to behavioral abnormality of neuropsychiatric disorders.

Effects of Stimulus Timing on the Acquisition of an Olfactory Working Memory Task in Head-Fixed Mice.

Acquisition of a behavioral task is influenced by many factors. The relative timing of stimuli is such a factor and is especially relevant for tasks relying on short-term memory, like working memory paradigms, because of the constant evolution and decay of neuronal activity evoked by stimuli. Here, we assess two aspects of stimulus timing on the acquisition of an olfactory delayed nonmatch-to-sample (DNMS) task. We demonstrate that head-fixed male mice learn to perform the task more quickly when the initial training uses a shorter sample-test odor delay without detectable loss of generalizability. Unexpectedly, we observed a slower task acquisition when the odor-reward interval was shorter. The effect of early reward timing was accompanied by a shortening of reaction times and more frequent sporadic licking. Analysis of this result using a drift-diffusion model indicated that a primary consequence of early reward delivery is a lowered threshold to act, or a lower decision bound. Because an accurate performance with a lower decision bound requires greater discriminability in the sensory representations, this may underlie the slower learning rate with early reward arrival. Together, our results reflect the possible effects of stimulus timing on stimulus encoding and its consequence on the acquisition of a complex task.SIGNIFICANCE STATEMENT This study describes how head-fixed mice acquire a working memory task (olfactory delayed nonmatch-to-sample task). We simplified and optimized the stimulus timing, allowing robust and efficient training of head-fixed mice. Unexpectedly, we found that early reward timing leads to slower learning. Analysis of this data using a computational model (drift-diffusion model) revealed that the reward timing affects the behavioral threshold, or how quickly animals respond to a stimulus. But, to still be accurate with early reaction times, the sensory representation needs to become even more refined. This may explain the slower learning rate with early reward timing.

Identification of a potential diagnostic signature for postmenopausal osteoporosis via transcriptome analysis.

Purpose: We aimed to establish the transcriptome diagnostic signature of postmenopausal osteoporosis (PMOP) to identify diagnostic biomarkers and score patient risk to prevent and treat PMOP. Methods: Peripheral blood mononuclear cell (PBMC) expression data from PMOP patients were retrieved from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were screened using the "limma" package. The "WGCNA" package was used for a weighted gene co-expression network analysis to identify the gene modules associated with bone mineral density (BMD). Least absolute shrinkage and selection operator (LASSO) regression was used to construct a diagnostic signature, and its predictive ability was verified in the discovery cohort. The diagnostic values of potential biomarkers were evaluated by receiver operating characteristic curve (ROC) and coefficient analysis. Network pharmacology was used to predict the candidate therapeutic molecules. PBMCs from 14 postmenopausal women with normal BMD and 14 with low BMD were collected, and RNA was extracted for RT-qPCR validation. Results: We screened 2420 differentially expressed genes (DEGs) from the pilot cohort, and WGCNA showed that the blue module was most closely related to BMD. Based on the genes in the blue module, we constructed a diagnostic signature with 15 genes, and its ability to predict the risk of osteoporosis was verified in the discovery cohort. RT-qPCR verified the expression of potential biomarkers and showed a strong correlation with BMD. The functional annotation results of the DEGs showed that the diagnostic signature might affect the occurrence and development of PMOP through multiple biological pathways. In addition, 5 candidate molecules related to diagnostic signatures were screened out. Conclusion: Our diagnostic signature can effectively predict the risk of PMOP, with potential application for clinical decisions and drug candidate selection.

Deubiquitinase USP29 correlates RORγt expression and its association with thymoma myasthenia gravis.

OBJECTIVE: The objective of this study was to examine the expression of deubiquitylases USP29 in thymomas with myasthenia gravis (MG) and research associated immunological processes. METHODS: 69 MG patients with thymomas, 21 thymoma patients without MG, and 31 healthy controls were classified into three groups (categories): group with MG-associated thymoma (MG-T), group with non-MG-associated thymoma (NMG-T), and group with healthy controls (HC). In thymomas, the mRNA and protein levels of RORγt and USP29 were examined by real-time reverse transcription polymerase chain reaction (real-time RT-PCR) and western blotting. Th17 cell counts in MG patients with thymomas were investigated by flow cytometry. RESULTS: In MG-related thymomas, the mRNA and protein levels of deubiquitylases USP29 were substantially elevated. USP29 post-transcriptionally regulated RORγt. In MG patients with thymomas, the expression of USP29 was positively linked to the RORγt expression and Th17 cell frequency. CONCLUSION: This work exhibited that the elevated USP29 enhanced RORγt expression, which in turn affected the Th17 cell growth in thymomatous MG. Our data suggest that USP29 might take part in the regulation of RORγt expression and Th17 cell generation and constitute an innovative regulatory function for USP29 in autoimmune disease.

A competitive immunoassay based on engineered magnetic/fluorescent nanoparticles and biolayer interferometry-based assay for T-2 toxin determination.

For the first time a competitive immunoassay was developed by employing T-2 antibody-functionalized magnetite nanoparticles and T-2 toxin-conjugated fluorescent quantum dots (QDs). Free T-2 and the T-2-modified QDs compete for binding to antibody-modified magnetic beads; the magnetic beads collected by magnetic separation were subjected to fluorescence intensity analysis (with excitation/emission wavelengths at 460/616 nm). This competitive immunoassay for T-2 toxin determination was applied both in a microcentrifuge tube and on a 96-well plate. The dynamic range of the immunoassay is 1-100 ng mL-1, the limit of detection (LOD) is 0.1 ng mL-1, and determination was completed in about 40 min and 30 min in the microcentrifuge tube and 96-well plate, respectively. Moreover, the biolayer interferometry (BLI) technique was employed for T-2 determination for the first time, in which the conjugate of T-2 toxin and bovine serum albumin (BSA) was immobilized on the sensors before detection. Its average recovery of T-2 toxin from barley sample ranged from 82.00 to 123.33%, and the relative standard deviation (RSD) was between 9.42 and 15.73%. The LOD of the BLI-based assay is 5 ng mL-1, and it only takes 10 min to finish the determination. Graphical abstract.

Structure-Based Virtual Screening and Biological Evaluation of Peptide Inhibitors for Polo-Box Domain.

The polo-box domain of polo-like kinase 1 (PLK1-PBD) is proved to have crucial roles in cell proliferation. Designing PLK1-PBD inhibitors is challenging due to their poor cellular penetration. In this study, we applied a virtual screening workflow based on a combination of structure-based pharmacophore modeling with molecular docking screening techniques, so as to discover potent PLK1-PBD peptide inhibitors. The resulting 9 virtual screening peptides showed affinities for PLK1-PBD in a competitive binding assay. In particular, peptide 5 exhibited an approximately 100-fold increase in inhibitory activity (IC50 = 70 nM), as compared with the control poloboxtide. Moreover, cell cycle experiments indicated that peptide 5 effectively inhibited the expression of p-Cdc25C and cell cycle regulatory proteins by affecting the function of PLK1-PBD, thereby inducing mitotic arrest at the G2/M phase. Overall, peptide 5 can serve as a potent lead for further investigation as PLK1-PBD inhibitors.

Clinical and angiographic outcomes following endovascular treatment of very small (3 mm or smaller) intracranial aneurysm: A single-center experience.

Treatments for very small (3 mm or smaller) intracranial aneurysms (VSAs) remain controversial. The aim of this study was to evaluate the efficacy of endovascular treatment for VSAs and to evaluate clinical risk factors associated with complications.This retrospective study enrolled 82 VSA patients who underwent coil embolization in our institution. Angiographic outcomes were assessed according to the Meyers classification. The clinical results were evaluated using the modified Rankin scale (mRS) immediately after coiling, at discharge, and during follow-up. A Mann-Whitney U test was performed for non-normally distributed continuous variables. A Pearson χ test or Fisher's exact test was performed for categorical variables.Among 82 aneurysms, 54 were treated with stent-assisted coiling (SAC) embolization. Thromboembolic complications were seen in 2 patients (2.4%). Intraoperative rupture occurred in 4 patients (4.9%). Other adverse events occurred in 2 patients (2.4%). Two patients (2.4%) had permanent disabling neurologic deficit (mRS 3-6) because of complications. The overall mortality rate was 1.2%. Adverse events were correlated with the location of aneurysms (P = .02), Fisher grade (P = .01), and treatment experience (P = .03). Patients with middle cerebral artery (MCA) bifurcation and anterior communicating artery (ACoA) aneurysms were more likely to experience a higher incidence of complication. Thirty-five patients underwent angiographic follow-up. The complete occlusion rate improved from an immediate 37.8% to 80.0% at follow-up.In the short term, coiling is a safe and effective approach for the treatment of VSAs. SAC may be associated with a high rate of further occlusion during short-term follow-up. Endovascular treatment of VSAs at middle cerebral artery bifurcation or anterior communicating artery is associated with a higher incidence of complications.

Gold Nanoparticles dotted Reduction Graphene Oxide Nanocomposite Based Electrochemical Aptasensor for Selective, Rapid, Sensitive and Congener-Specific PCB77 Detection.

Gold nanoparticles (AuNP) dotted reduction graphene oxide (RGO-AuNP) is used as a platform for an aptamer biosensor to selectively detect 3,3'4,4'-polychlorinated biphenyls (PCB77). By anchoring aptamers onto the binding sites of RGO-AuNP and making use of the synergy effect of RGO and AuNP, the RGO-AuNP based biosensor exhibits superior analytical performances to AuNP based biosensor in terms of sensitivity and repeatability. The sensitivity of RGO-AuNP based aptamers (RGO-AuNP-Ap) biosensor (226.8 µA cm-2) is nearly two times higher than that of Au based biosensors (AuNP-Ap/Au electrode, 147.2 µA cm-2). The RGO-AuNP-Ap/Au biosensor demonstrated a linear response for PCB77 concentrations between 1 pg L-1 and 10 µg L-1, with a low limit of detection (LOD) of 0.1 pg L-1. The superb LOD satisfies the exposure thresholds (uncontaminated water < 0.1 ng L-1) set out by International Agency for Research on Cancer (IARC) and the Environmental Protection Agency (EPA). The proposed biosensor can be a powerful tool for rapid, sensitive and selective detection of PCBs on site.

Comparative study of graphene nanosheet- and multiwall carbon nanotube-based electrochemical sensor for the sensitive detection of cadmium.

A novel nanocomposite was obtained through the controlled surface modification of graphene nanosheets (nanographene) with Nafion by ultrasonic oscillation. The composite was used as an ultrasensitive platform for the detection of cadmium ions (Cd(2+)) by differential pulse anodic stripping voltammetry (DPASV) analysis. The performance of the nanographene-based sensor was systematically compared with that of a multiwall carbon nanotube (MWCNT)-modified sensor. The results indicate that the nanographene-based sensor exhibits significant advantages over the MWCNT-based sensor in terms of repeatability, sensitivity and limit of detection (LOD). The nanographene-based sensor displayed superior analytical performance over a linear range of Cd(2+) concentrations from 0.25µgL(-1) to 5µgL(-1), with a LOD of 3.5ngL(-1). This sensor was also used to systematically screen for 6 types of chemicals, including sodium salts, magnesium salts and zinc salts. It was observed that the sensor could successfully differentiate cadmium ions from interferents (magnesium salts, zinc salts, etc.). The nanographene-based sensor was also demonstrated to be a promising and reliable tool for the rapid detection of cadmium existing in tap water and for the rapid on-site analysis of critical pollution levels of cadmium.

[Determination of phenol in water by electrochemical tyrosinase biosensor based on ordered graphitized mesoporous carbon and evaluated by high performance liquid chromatography].

A novel electrochemical tyrosinase biosensor based on ordered graphitized mesoporous carbon (GMC) was obtained, which was used as a platform for phenol detection. The accuracy of tyrosinase biosensor method was comparatively evaluated by high performance liquid chromatography (HPLC). By entrapping tyrosinase molecules (6.5 nm x 9.8 nm x 5.5 nm) into the mesopores of GMC (diameter 10 nm, GMC10), the "interspace confinement effect" of GMC10 may improve the stability of tyrosinase in vitro. After 21-day storage, the GMC10-based tyrosinase biosensor retained more than 85% of its initial response. It is indicated that GMC10 with "interspace confinement effect" can significantly prolong the life of tyrosinase molecules in vitro. Furthermore, the GMC-based tyrosinase biosensor displayed excellent analytical performances for phenol detection, such as stability, repeatability, selectivity, sensitivity and limit of detection. The GMC-based tyrosinase biosensor demonstrated a linear response for phenol from 0. 1 to 10 µmol/L with a low detection limit of 20 nmol/L. The comparative study between HPLC and GMC-based tyrosinase biosensor showed that the detection of phenol in water sample by the GMC-based tyrosinase biosensor method is reliable, accurate and effective. The proposed GMC-based tyrosinase biosensor proved to be a very promising "pre-alarm" tool for rapid detecting phenol pollution in emergency accidents.