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Attention deficit hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders in childhood. Numerous resting-state functional magnetic resonance imaging (rs-fMRI) studies in ADHD have been performed using traditional low-frequency bands (0.01–0.08 Hz). However, the neural activity patterns of frequency subbands in ADHD still require further investigation. The purpose of this study is to explore the frequency-dependent characteristics and neural activity patterns of ADHD subtypes. We selected the ADHD combined type (ADHD-C, N = 25), ADHD inattentive type (ADHD-I, N = 26) and typically developing (TD, N = 28) children from the ADHD-200 Consortium. Based on the slow-5 band (0.01–0.027 Hz) and slow-4 band (0.027–0.073 Hz), we generated static and dynamic fractional amplitude of low-frequency fluctuation (fALFF) and regional homogeneity (ReHo) maps for each participant. A flexible-factorial analysis of variance model was performed on static and temporal dynamic rs-fMRI measurements within two subbands. Results revealed that the orbital-frontal gyrus, precuneus, superior temporal gyrus and angular gyrus were found to have obvious frequency band and group interaction effects. The intrinsic neural activity differences among three groups were more prominent in the slow-5 frequency band compared to the slow-4 band. In addition, the indices of significant interaction regions showed correlations with the progression of the disease and the features in slow-5 showed an advantageous diagnostic performance compared with those in slow-4. The results suggested the intrinsic neural activities of ADHD subtypes were frequency-dependent. The frequency-specific analysis of static and dynamic brain activity may provide a deeper understanding of neurophysiological dysfunction patterns in ADHD subtypes and provide supplementary information for assessing ADHD subtypes.

Abstract Background It is well established that traumatic brain injury (TBI) causes acute and chronic alterations in systemic immune function and that systemic immune changes contribute to posttraumatic neuroinflammation and neurodegeneration. However, how TBI affects bone marrow (BM) hematopoietic stem/progenitor cells chronically and to what extent such changes may negatively impact innate immunity and neurological function has not been examined. Methods To further understand the role of BM cell derivatives on TBI outcome, we generated BM chimeric mice by transplanting BM from chronically injured or sham (i.e., 90 days post-surgery) congenic donor mice into otherwise healthy, age-matched, irradiated CD45.2 C57BL/6 (WT) hosts. Immune changes were evaluated by flow cytometry, multiplex ELISA, and NanoString technology. Moderate-to-severe TBI was induced by controlled cortical impact injury and neurological function was measured using a battery of behavioral tests. Results TBI induced chronic alterations in the transcriptome of BM lineage−c-Kit+Sca1+ (LSK+) cells in C57BL/6 mice, including modified epigenetic and senescence pathways. After 8 weeks of reconstitution, peripheral myeloid cells from TBI→WT mice showed significantly higher oxidative stress levels and reduced phagocytic activity. At eight months after reconstitution, TBI→WT chimeric mice were leukopenic, with continued alterations in phagocytosis and oxidative stress responses, as well as persistent neurological deficits. Gene expression analysis revealed BM-driven changes in neuroinflammation and neuropathology after 8 weeks and 8 months of reconstitution, respectively. Chimeric mice subjected to TBI at 8 weeks and 8 months post-reconstitution showed that longer reconstitution periods (i.e., time post-injury) were associated with increased microgliosis and leukocyte infiltration. Pre-treatment with a senolytic agent, ABT-263, significantly improved behavioral performance of aged C57BL/6 mice at baseline, although it did not attenuate neuroinflammation in the acutely injured brain. Conclusions TBI causes chronic activation and progressive dysfunction of the BM stem/progenitor cell pool, which drives long-term deficits in hematopoiesis, innate immunity, and neurological function, as well as altered sensitivity to subsequent brain injury.

Ethylene is an essential indicator of fruit ripening and climacteric or non-climacteric nature. This study investigated the postharvest behavior of five Chinese bayberry cultivars ‘Biqi’, ‘Dongkui’, ‘Fenhong’, ‘Xiazhihong’, and ‘Shuijing’. The fruits were harvested mature and stored at room temperature (25 °C) and under cold storage conditions (4 °C) to investigate the dynamics of ethylene production, firmness, anthocyanin content, and cell wall polysaccharide composition, as well as basic fruit physicochemical characteristics. The results show that Chinese bayberry is a climacteric fruit with ethylene production peaking shortly after harvest, especially at room temperature. Fruit color intensified over time due to anthocyanin accumulation, particularly in the flesh core. Darker cultivars produced more ethylene, which correlated with higher anthocyanin levels. At room temperature, ‘Biqi’ (black) had the highest ethylene production (4.03 µL·kg−1·h−1) and anthocyanin content (0.91 mg/g FW), while ‘Shuijing’, the white cultivar, had the lowest ethylene levels (1.9 µL·kg−1·h−1) and anthocyanin content (0.03 mg/g FW). Firmness significantly decreased at room temperature due to the degradation of hemicellulose and insoluble pectin, whereas cold storage mitigates this effect. After 3 days at room temperature, the average of firmness decreased by 23.7% in the five cultivars, compared to 12.7% under cold storage. Total soluble solids increase during storage, enhancing sweetness, especially at room temperature, with ‘Biqi’ increasing from 9.2 to 10.9% at 4 °C. Titratable acidity slightly decreased over time: the value for ‘Biqi’ decreased from 1.2% to 0.95% at room temperature and 1.1% at 4 °C. Citric, malic, and tartaric acid generally declined at room temperature but stabilized under cold storage. Sucrose, fructose, and glucose increased or remained stable, with significant varietal differences. Our results indicate that storing Chinese bayberry at 4 °C effectively preserves its quality and extends postharvest life. These findings underscore ethylene’s key role in regulating ripening, postharvest quality, and shelf life by influencing fruit color, firmness, and overall consumer appeal.

Numerous voxel-based resting-state functional magnetic resonance imaging (rs-fMRI) measurements have been used to characterize spontaneous brain activity in attention deficit hyperactivity disorder (ADHD). However, the practical distinctions and commonalities among these intrinsic brain activity measures remain to be fully explored, and whether the functional concordance is related to frequency is still unknown. The study included 25 ADHD, combined type (ADHD-C); 26 ADHD, inattentive type (ADHD-I); and 28 typically developing (TD) children. We calculated the voxel-wise (temporal) and volume-wise (spatial) concordance among dynamic rs-fMRI indices in the slow-5 (0.01–0.027 Hz) and slow-4 (0.027–0.073 Hz) frequency bands, respectively. The spatiotemporal concordance within the slow-4 and slow-5 bands among the ADHD-C, ADHD-I, and TD groups was compared. Although the ADHD-C and ADHD-I groups showed similar volume-wise concordance, comparison analysis revealed that compared with ADHD-C patients, ADHD-I patients exhibited decreased voxel-wise concordance in the right median cingulate and paracingulate gyrus (MCC) and right supplementary motor area (SMA) in the slow-5 band. In addition, the voxel-wise concordance was negatively correlated with the diagnostic scores of ADHD subtypes. Our results suggest that functional concordance is frequency dependent, and dynamic concordance analysis based on specific frequency bands may provide a novel approach for investigating the pathophysiological differences among ADHD subtypes.

Abstract The pecan is a salt-alkali-tolerant plant, and its fruit and wood have high economic value. This study aimed to explore the molecular mechanisms responsible for salt stress tolerance in the pecan grown under hydroponic conditions to simulate salt stress. The results showed that the photosynthetic rate (Pn) was reduced in response to salt stress, while the intercellular carbon dioxide concentrations (Ci) increased. The response of the pecan to salt stress was measured using iTRAQ (isobaric tags for relative or absolute quantitation) and LC/MS (liquid chromatography and mass spectrometry) non-targeted metabolomics technology. A total of 198 differentially expressed proteins (65 down-regulated and 133 up-regulated) and 538 differentially expressed metabolites (283 down-regulated and 255 up-regulated) were identified after exposure to salt stress for 48 h. These genes were associated with 21 core pathways, shown by Kyoto Encyclopedia of Genes and Genomes annotation and enrichment, including the metabolic pathways involved in nucleotide sugar and amino sugar metabolism, amino acid biosynthesis, starch and sucrose metabolism, and phenylpropane biosynthesis. In addition, analysis of interactions between the differentially expressed proteins and metabolites showed that two key nodes of the salt stress regulatory network, L-fucose and succinate, were up-regulated and down-regulated, respectively, suggesting that these metabolites may be significant for adaptations to salt stress. Finally, several key proteins were further verified by parallel reaction monitoring. In conclusion, this study used physiological, proteomic, and metabolomic methods to provide an important preliminary foundation for improving the salt tolerance of pecans.

Abstract Background The liver plays an important role in production and metabolism of homocysteine (Hcy), which has been reported to be involved in liver injury. In our previous work, we confirm that Hcy can induce liver injury by activating endoplasmic reticulum (ER) stress. However, the underlying mechanisms remain largely unknown. Results In present study, we established the Hcy-induced liver injury model by feeding cbs +/− mice with high methionine diet, and found that a considerable mass of disordered arrangement of hepatocytes and enlarged space between hepatocytes were frequently occurred in the liver of cbs +/− mice, accompanied with elevated expression levels of apoptosis-related proteins. In addition, Hcy could activate ER stress both in cbs +/− mice and hepatocytes. Mechanistically, Hcy promoted the expression levels of proteasome 26S subunit non-ATPase 10 (PSMD10) in hepatocytes; and the expression of ER stress indicators and apoptosis-associated proteins were significantly suppressed when PSMD10 was silenced in hepatocytes under Hcy treatment. Moreover, bioinformatics analysis and luciferase reporter assay demonstrated that PSMD10 was a target gene of miR-212-5p. Consistently, miR-212-5p overexpression could inhibit ER stress-mediated apoptosis of hepatocytes under Hcy treatment. With the help of co-immunoprecipitation assay, we identified that the interaction between PSMD10 and GRP78 accelerated ER stress-mediated hepatic apoptosis induced by Hcy. Conclusions Our findings indicate that miR-212-5p directly targets PSMD10 and subsequently activates ER stress to promote Hcy-induced apoptosis of hepatocytes. We propose that endogenous PSMD10 physically interacts with GRP78 to regulate ER stress. Our study may provide the therapeutic target for the liver injury induced by Hcy.

Abstract Background Based on amyloid cascade and tau hypotheses, protein biomarkers of different Aβ and tau species in cerebrospinal fluid (CSF) and blood/plasma/serum have been examined to correlate with brain pathology. Recently, unbiased proteomic profiling of these human samples has been initiated to identify a large number of novel AD biomarker candidates, but it is challenging to define reliable candidates for subsequent large-scale validation. Methods We present a comprehensive strategy to identify biomarker candidates of high confidence by integrating multiple proteomes in AD, including cortex, CSF and serum. The proteomes were analyzed by the multiplexed tandem-mass-tag (TMT) method, extensive liquid chromatography (LC) fractionation and high-resolution tandem mass spectrometry (MS/MS) for ultra-deep coverage. A systems biology approach was used to prioritize the most promising AD signature proteins from all proteomic datasets. Finally, candidate biomarkers identified by the MS discovery were validated by the enzyme-linked immunosorbent (ELISA) and TOMAHAQ targeted MS assays. Results We quantified 13,833, 5941, and 4826 proteins from human cortex, CSF and serum, respectively. Compared to other studies, we analyzed a total of 10 proteomic datasets, covering 17,541 proteins (13,216 genes) in 365 AD, mild cognitive impairment (MCI) and control cases. Our ultra-deep CSF profiling of 20 cases uncovered the majority of previously reported AD biomarker candidates, most of which, however, displayed no statistical significance except SMOC1 and TGFB2. Interestingly, the AD CSF showed evident decrease of a large number of mitochondria proteins that were only detectable in our ultra-deep analysis. Further integration of 4 cortex and 4 CSF cohort proteomes highlighted 6 CSF biomarkers (SMOC1, C1QTNF5, OLFML3, SLIT2, SPON1, and GPNMB) that were consistently identified in at least 2 independent datasets. We also profiled CSF in the 5xFAD mouse model to validate amyloidosis-induced changes, and found consistent mitochondrial decreases (SOD2, PRDX3, ALDH6A1, ETFB, HADHA, and CYB5R3) in both human and mouse samples. In addition, comparison of cortex and serum led to an AD-correlated protein panel of CTHRC1, GFAP and OLFM3. In summary, 37 proteins emerged as potential AD signatures across cortex, CSF and serum, and strikingly, 59% of these were mitochondria proteins, emphasizing mitochondrial dysfunction in AD. Selected biomarker candidates were further validated by ELISA and TOMAHAQ assays. Finally, we prioritized the most promising AD signature proteins including SMOC1, TAU, GFAP, SUCLG2, PRDX3, and NTN1 by integrating all proteomic datasets. Conclusions Our results demonstrate that novel AD biomarker candidates are identified and confirmed by proteomic studies of brain tissue and biofluids, providing a rich resource for large-scale biomarker validation for the AD community.

Red bayberry is a sweet, tart fruit native to China and grown widely in the south. The key organic compounds forming the distinctive aroma in red bayberry, are terpenoids, mainly β-caryophyllene and α-pinene. However, the key genes responsible for different terpenoids are still unknown. Here, transcriptome analysis on samples from four cultivars, during fruit development, with different terpenoid production, provided candidate genes for volatile organic compound (VOC) production. Terpene synthases (TPS) are key enzymes regulating terpenoid biosynthesis, and 34 TPS family members were identified in the red bayberry genome. MrTPS3 in chromosome 2 and MrTPS20 in chromosome 7 were identified as key genes regulating β-caryophyllene and α-pinene synthesis, respectively, by qRT-PCR. Subcellular localization and enzyme activity assay showed that MrTPS3 was responsible for β-caryophyllene (sesquiterpenes) production and MrTPS20 for α-pinene (monoterpenes). Notably, one amino acid substitution between dark color cultivars and light color cultivars resulted in the loss of function of MrTPS3, causing the different β-caryophyllene production. Our results lay the foundation to study volatile organic compounds (VOCs) in red bayberry and provide potential genes for molecular breeding.

Background and Purpose: Hearing loss is associated with rising risks of emotional impairments, suggesting emotional processing networks might be involved in the neural plasticity after hearing loss. This study was conducted to explore how functional connectivity of the amygdala reconfigures in the auditory deprived brain and better understand the neural mechanisms underlying hearing loss-related emotional disturbances.Methods: In total, 38 chronic sensorineural hearing loss (SNHL) patients and 37 healthy controls were recruited for multimodal magnetic resonance imaging scanning and neuropsychological assessments. Voxel-wise functional connectivity (FC) maps of both the left and right amygdala were conducted and compared between the SNHL patients and healthy controls. The uncinate fasciculus (UF), an association fiber pathway, was reconstructed in both groups. The track number, mean track length, fractional anisotropy (FA) and mean diffusion values of the left and right UF were further quantified, respectively. Besides, Pearson's correlation analyses were conducted to investigate the relationship between the functional/structural abnormalities and the negative emotional states in SNHL patients.Results: The SNHL patients presented higher depressive and anxious levels compared to the healthy controls. Decreased FCs were detected between the amygdala and the auditory cortex, striatum, multimodal processing areas, and frontoparietal control areas in the SNHL patients. The amygdala was found to be structurally connected with several FC decreased regions through the UF. Moreover, the hypo-synchronization and the white matter impairment were both found to be associated with patients' elevated anxious status.Conclusions: These functional and structural findings depicted the reconfiguration of the amygdala in SNHL, which provided a new perspective toward the functional circuit mechanisms targeting the emotional impairments related to hearing loss.

Alkali stress, a type of abiotic stress, severely inhibits plant growth. Only a few studies have investigated the mechanism underlying the transcriptional-level response of Morella cerifera to saline-alkali stress. Based on RNA-seq technology, gene expression differences in the fibrous roots of M. cerifera seedlings exposed to low- and high-concentration alkali stress (LAS and HAS, respectively) were investigated, and the corresponding 1312 and 1532 alkali stress-responsive genes were identified, respectively. According to gene set enrichment analysis, 65 gene sets were significantly enriched. Of these, 24 gene sets were shared by both treatment groups. LAS and HAS treatment groups exhibited 9 (all downregulated) and 32 (23 downregulated) unique gene sets, respectively. The differential gene sets mainly included those involved in trehalose biosynthesis and metabolism, phospholipid translocation, and lignin catabolism. Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed that M. cerifera seedlings were specifically enriched in stilbenoid, diarylheptanoid, and gingerol biosynthesis; phenylalanine, tyrosine, and tryptophan biosynthesis; and sesquiterpenoid and triterpenoid biosynthesis. Moreover, the related genes involved in hormone signaling pathways and transcription factors were determined through a localization analysis of core abiotic stress pathways. These genes and their molecular mechanisms will be the focus of future research.

The molecular mechanism of sex development and differentiation in the economically important dioecious fruit tree, red bayberry (Morella rubra), was revealed using next-generation transcriptome sequencing (NGS), and comparative analyses were used to identify differentially expressed genes (DEGs) in female and male flower buds. A total of 7029 of these DEGs were identified at two early development stages. KEGG pathway enrichment analysis revealed that plant hormone signal transduction was significantly overrepresented, and 91 genes related to hormones were identified. An analysis of 7029 DEGs revealed 161 hormone-related genes, with the 42 related to auxin and 26 related to ethylene being the most highly represented. A total of 62 genes were significantly up-regulated in females and 29 were in males, with 18 of them specifically expressed in females and 10 in males. A total of 415 transcription factors were identified, with 129 genes up-regulated in females and 53 in males. Moreover, 38 had female-specific expression and 18 had male-specific expression. Using weighted gene co-expression network analysis (WGCNA), two modules were found to be associated with sexual type. In the module coded light-green, there were five genes related to hormones, one to flower development and ten transcription factors with four genes specifically expressed in the males and four in females. The hub gene in the light-green module is MR0TCONS_00017483.1 (ACO), which is involved in ethylene biosynthesis and had male-specific expression. Among the transcription factors, three of the four male-specific expressed genes involved in flavonoid biosynthesis, including the MYB gene MR1TCONS_00020658.1 and two BHLH genes, MR6G001563.1 and MR8G020751.1, played important roles in male floral differentiation. In the dark-cyan module, six hormone-related genes, five transcription factors and three flower development genes were identified with the hub gene MR1G019545.1 (ETR1), which participates in the ethylene signaling pathway, and MR4G023618.1, which encodes the C3H zinc finger transcription factor. These results indicate that ethylene is the key hormone that interacts with other hormones and transcription factors to regulate sex differentiation in the red bayberry, which also provides new insights into the mechanism of sex determination and differentiation in the red bayberry.

Potassium (K) nutrition plays a key role in alleviating a variety of peel disorders in tree fruit, but the effect of this nutrient on the physiological and metabolic profiles involved in the fruit splitting of citrus remains unclear. Three levels of K were used to treat citrus ‘Ehime Kashi 34’ (Citrus Nishinoka × C. Shiranui), a hybrid cultivar with fruit that easily split. The results showed that the roots of the treatment with K fertilizer increased the contents of calcium (Ca2+), nitrogen (N), and K in the skin and flesh, the fruit firmness ratio of the peel to the flesh, photosynthetic rate, stomatal conductance, and concentration of intercellular CO2. In contrast, it decreases the relative chlorophyll index and content of Ca2+ in the leaves. Simultaneously, 59 and 13 differentially expressed metabolites (DEMs) were detected in the peel and flesh, respectively, after treatment with K. Of them, five compounds were upregulated, including the synthesis of various amino acids in the peel and the accumulation of various glycoside metabolites in the flesh which were upregulated. The accumulation of levels of gibberellin and glycoside were downregulated. That could be the main reason why potassium alleviates fruit splitting.

The use of thrombolysis in acute ischemic stroke is restricted to a small proportion of patients because of the rigid 4·5-h window. With advanced imaging-based patient selection strategy, rescuing penumbra is critical to improving clinical outcomes. In this study, we included 155 acute ischemic stroke patients (84 patients in training dataset, age from 43 to 80, 59 males; 71 patients in validation dataset, age from 36 to 80, 45 males) who underwent MR scan within the first 9-h after onset, from 7 independent centers. Based on the mismatch concept, penumbra and core area were identified and quantitatively analyzed. Moreover, predictive models were developed and validated to provide an approach for identifying patients who may benefit from thrombolytic therapy. Predictive models were constructed, and corresponding areas under the curve (AUC) were calculated to explore their performances in predicting clinical outcomes. Additionally, the models were validated using an independent dataset both on Day-7 and Day-90. Significant correlations were detected between the mismatch ratio and clinical assessments in both the training and validation datasets. Treatment option, baseline systolic blood pressure, National Institutes of Health Stroke Scale score, mismatch ratio, and three regional radiological parameters were selected as biomarkers in the combined model to predict clinical outcomes of acute ischemic stroke patients. With the external validation, this predictive model reached AUCs of 0·863 as short-term validation and 0·778 as long-term validation. This model has the potential to provide quantitative biomarkers that aid patient selection for thrombolysis either within or beyond the current time window. Keywords: Penumbra, Predictive model, Clinical outcome, Acute ischemic stroke, Thrombolysis

Abstract Attention deficit hyperactivity disorder (ADHD) is a common disorder that emerges in school-age children. The diagnostic model based on neuroimaging features could be beneficial for ADHD in twofold: identifying individuals with ADHD and discovering the discriminative patterns for patients. The dynamic functional connectivity of ADHD remains unclear. Towards this end, 100 children with ADHD and 140 normal controls were obtained from the ADHD-200 Consortium. The raw features were derived from the temporal variability between intrinsic connectivity networks (ICNs) as well as the demographic and covariate variables. The diagnostic model was based on the support vector machines (SVMs). The performance of diagnostic model was analyzed using leave-one-out cross-validation (LOOCV) and 10-folds cross-validations (CVs). The diagnostic model based on inter-ICN variability outperformed that based on inter-ICN functional connectivity and inter-ICN phase synchrony. The LOOCV achieved total accuracy of 78.75%, the sensitivity of 76%, and the specificity of 80.71%. The 10-folds CVs achieved average prediction accuracy of 75.54% ± 1.34%, average sensitivity of 70.5% ± 2.34%, and average specificity of 77.44% ± 1.47%. In addition, the discriminative patterns for ADHD were discovered using SVMs. The discriminative patterns confirmed with previous findings. In summary, individuals with ADHD could be identified through inter-ICN variability, which could be potential biomarkers for diagnostic model of ADHD.

Abstract Background Recent literatures indicate that maternal hormone exposure is a risk factor for autism spectrum disorder (ASD). We hypothesize that prenatal progestin exposure may counteract the neuroprotective effect of estrogen and contribute to ASD development, and we aim to develop a method to ameliorate prenatal progestin exposure-induced autism-like behavior. Methods Experiment 1: Prenatal progestin exposure-induced offspring are treated with resveratrol (RSV) through either prenatal or postnatal exposure and then used for autism-like behavior testing and other biomedical analyses. Experiment 2: Prenatal norethindrone (NET) exposure-induced offspring are treated with ERβ knockdown lentivirus together with RSV for further testing. Experiment 3: Pregnant dams are treated with prenatal NET exposure together with RSV, and the offspring are used for further testing. Results Eight kinds of clinically relevant progestins were used for prenatal exposure in pregnant dams, and the offspring showed decreased ERβ expression in the amygdala with autism-like behavior. Oral administration of either postnatal or prenatal RSV treatment significantly reversed this effect with ERβ activation and ameliorated autism-like behavior. Further investigation showed that RSV activates ERβ and its target genes by demethylation of DNA and histone on the ERβ promoter, and then minimizes progestin-induced oxidative stress as well as the dysfunction of mitochondria and lipid metabolism in the brain, subsequently ameliorating autism-like behavior. Conclusions We conclude that resveratrol ameliorates prenatal progestin exposure-induced autism-like behavior through ERβ activation. Our data suggest that prenatal progestin exposure is a strong risk factor for autism-like behavior. Many potential clinical progestin applications, including oral contraceptive pills, preterm birth drugs, and progestin-contaminated drinking water or seafood, may be risk factors for ASD. In addition, RSV may be a good candidate for clinically rescuing or preventing ASD symptoms in humans, while high doses of resveratrol used in the animals may be a potential limitation for human application.

Aberrant brain structural change in cirrhotic patients with or without hepatic encephalopathy is one of the most typical cases in voxel-based morphometry (VBM) studies. However, there exist inconsistent results regarding to the volume change of the thalamus. Furthermore, the relationship between thalamus structural change and cirrhotic symptoms has not yet been fully elucidated. To address these two issues, we repeated two VBM analyses in SPM and FreeSurfer and compared the two measurements with manually measured thalamic volumes. We also correlated the VBM results with clinical indexes related to cirrhosis to further investigate the relationship between thalamic structural change and liver cirrhosis. The inconsistent result of thalamic structural change was successfully reproduced in regard to the volume measurements of SPM and FreeSurfer. The manually measured results demonstrate an increase in the volume of the thalamus in cirrhotic patients compared to healthy controls, which differs from the results of FreeSurfer. The structural change of thalamus closely correlated with the blood biochemical indexes, including albumin levels, blood coagulation time, and AST/ALT ratio. All of these biochemical indexes are closely related to the severity of liver cirrhosis. Beyond all the results, this study also provides a good demonstration of the difference between multiple VBM measurements for clinicians. Keywords: VBM, Hepatic Encephalopathy, Grey Matter volume, Thalamus

Engineering cell factories for producing biofuels and pharmaceuticals has spurred great interests to develop rapid and efficient synthetic biology tools customized for modular pathway engineering. Along the way, combinatorial gene expression control through modification of regulatory element offered tremendous opportunity for fine-tuning gene expression and generating digital-like genetic circuits. In this report, we present an efficient evolutionary approach to build a range of regulatory control elements. The reported method allows for rapid construction of promoter, 5′UTR, terminator and trans-activating RNA libraries. Synthetic overlapping oligos with high portion of degenerate nucleotides flanking the regulatory element could be efficiently assembled to a vector expressing fluorescence reporter. This approach combines high mutation rate of the synthetic DNA with the high assembly efficiency of Gibson Mix. Our constructed library demonstrates broad range of transcriptional or translational gene expression dynamics. Specifically, both the promoter library and 5′UTR library exhibits gene expression dynamics spanning across three order of magnitude. The terminator library and trans-activating RNA library displays relatively narrowed gene expression pattern. The reported study provides a versatile toolbox for rapidly constructing a large family of prokaryotic regulatory elements. These libraries also facilitate the implementation of combinatorial pathway engineering principles and the engineering of more efficient microbial cell factory for various biomanufacturing applications.

Sensorineural hearing loss (SNHL), sometimes accompanied with tinnitus, is associated with dysfunctions within and outside the classical auditory pathway. The salience network, which is anchored in bilateral anterior insula and dorsal anterior cingulate cortex, has been implicated in sensory integration. Partial auditory deprivation could alter the characteristics of the salience network and other related brain areas, thereby contributing to hearing impairments-induced neuropsychiatric symptoms. To test this hypothesis, we performed fMRI scanning and neuropsychological tests on 32 subjects with long-term bilateral hearing impairment and 30 well-matched Controls. Non-directional functional connectivity and directional Granger causality analysis were used to identify aberrant spatial and temporal patterns of connections targeting bilateral anterior insula and dorsal anterior cingulate cortex. We found that the left anterior insula showed decreased connectivity with right precentral gyrus and superior frontal gyrus. The connections between the dorsal anterior cingulate cortex and middle frontal gyrus, superior parietal gyrus and supplementary motor area (SMA) were also reduced. Relative to Controls, SNHL patients showed abnormal effective connectivity of the salience network, including inferior temporal gyrus, cerebellum lobule VI, lobule VIII, precentral gyrus, middle frontal gyrus and SMA. Furthermore, correlation analysis demonstrated that some of these atypical connectivity measures were correlated with performance of neuropsychiatric tests. These findings suggest that the inefficient modulation of the salience network might contribute to the neural basis of SNHL and tinnitus, as well as associated cognition and emotion deficits.

Objective: Hearing loss, one main risk factor of tinnitus and hyperacusis, is believed to involve significant central functional abnormalities. The recruitment of the auditory cortex in non-auditory sensory and higher-order cognitive processing has been demonstrated in the hearing-deprived brain. The dorsolateral prefrontal cortex (dlPFC), which has dense anatomical connections with the auditory pathway, is known to play a crucial role in multi-sensory integration, auditory regulation, and cognitive processing. This study aimed to verify the role of the dlPFC in the cross-modal reorganization and cognitive participation of the auditory cortex in long-term sensorineural hearing loss (SNHL) by combining functional and structural measurements.Methods: Thirty five patients with long-term bilateral SNHL and 35 matched healthy controls underwent structural imaging, resting-state functional magnetic resonance imaging (rs-fMRI), diffusion tensor imaging (DTI), and neuropsychological assessments. Ten SNHL patients were with subjective tinnitus.Results: No differences in gray matter volume, spontaneous neural activity, or diffusion characteristics in the dlPFC were found between the SNHL and control groups. The functional connectivity (FC) between the dlPFC and the auditory cortex and visual areas, such as the cuneus, fusiform, lingual cortex, and calcarine sulcus was increased in patients with SNHL. ANOVA and post hoc tests revealed similar FC alterations in the SNHL patients with and without tinnitus when compared with the normal hearing controls, and SNHL patients with and without tinnitus showed no difference in the dlPFC FC. The FC in the auditory cortex was associated with the symbol digit modality test (SDMT) scores in the SNHL patients, which reflect attentional function, processing speed, and visual working memory. Hearing-related FC with the dlPFC was found in the lingual cortex. A tract-based spatial statistics (TBSS) analysis revealed decreased fractional anisotropy (FA) values, mainly in the temporal inferior fronto-occipital fasciculus (IFOF), which showed remarkable negative correlations with the mean hearing thresholds in SNHL.Conclusion: Higher functional coupling between the dlPFC and auditory and visual areas, accompanied by decreased FA along the IFOF connecting the frontal cortex and the occipito-temporal area, might mediate cross-modal plasticity via top-down regulation and facilitate the involvement of the auditory cortex in higher-order cognitive processing following long-term SNHL.

Objects: Sensorineural hearing loss (SNHL) involves wide-ranging functional reorganization, and is associated with accumulating risk of cognitive and emotional dysfunction. The coordination of multiple functional networks supports normal brain functions. Here, we aimed to evaluate the functional connectivity (FC) patterns involving multiple resting-state networks (RSNs), and the correlations between the functional remodeling of RSNs and the potential cognitive or emotional impairments in SNHL.Methods: Thirty long-term bilateral SNHL patients and 39 well-matched healthy controls were recruited for assessment of resting-state functional magnetic resonance imaging and neuropsychological tests.Results: Using independent component analysis, 11 RSNs were identified. Relative to the healthy controls, patients with SNHL presented apparent abnormalities of intra-network FC involving right frontoparietal network, posterior temporal network, and sensory motor network. Disrupted between-network FC was also revealed in the SNHL patients across both higher-order cognitive control networks and multiple sensory networks. Eight of the eleven RSNs showed altered functional synchronization using a seed network to whole brain FC method, particularly in the ventromedial prefrontal cortex. In addition, these functional abnormalities were correlated with cognition- and emotion-related performances.Interpretations: These findings supported our hypotheses that long-term SNHL involves notable dysconnectivity of multiple RSNs. Our study provides important insights into the pathophysiological mechanisms of SNHL, and sheds lights on the neural substrates underlying the possible cognitive and emotional dysfunctions following SNHL.

The insular cortex plays an important role in multimodal sensory processing, audio-visual integration and emotion; however, little is known about how the insula is affected by auditory deprivation due to sensorineural hearing loss (SNHL). To address this issue, we used structural and functional magnetic resonance imaging to determine if the neural activity within the insula and its interregional functional connectivity (FC) was disrupted by SNHL and if these alterations were correlated clinical measures of emotion and cognition. Thirty-five SNHL subjects and 54 Controls enrolled in our study underwent auditory evaluation, neuropsychological assessments, functional and structure MRI, respectively. Twenty five patients and 20 Controls underwent arterial spin labeling scanning. FC of six insula subdivisions were assessed and the FC results were compared to the neuropsychological tests. Interregional connections were also compared among insula-associated networks, including salience network (SN), default mode network (DMN), and central executive network (CEN). Compared to Controls, SNHL subjects demonstrated hyperperfusion in the insula and significantly decreased FC between some insula subdivisions and other brain regions, including thalamus, putamen, precentral gyrus, postcentral gyrus, mid-cingulate cortex, dorsolateral prefrontal cortex, rolandic operculum. Anxiety, depression and cognitive impairments were correlated with FC values. Abnormal interactions among SN, DMN, and CEN were observed in SNHL group. Our result provides support for the “inefficient high-order control” theory of the insula in which the auditory deprivation caused by SNHL contributes to impaired sensory integration and central deficits in emotional and cognitive processing.

Extranodal nasal-type natural killer/T-cell lymphoma (NKTCL) is an Epstein-Barr virus (EBV)-associated lymphoma with a strong tendency relapse or be refractory in response to chemotherapy. Development of a new strategy for NKTCL treatment is still quite necessary. In this study, we found that aspirin treatment suppresses VEGF expression in NKTCL SNK-6 cells. Further investigation showed that aspirin treatment increases histone methylation in the range of −100~0 that is proximal to the transcription start site on the VEGF promoter, subsequently decreasing the binding ability of Sp1 to the VEGF promoter with VEGF suppression. Furthermore, aspirin treatment modulates mitochondrial function with increased ROS formation and apoptosis in NKTCL cells. Aspirin treatment alone slightly inhibits NKTCL SNK-6 tumor growth and EBV replication; while in the presence of histone deacetylase inhibitor (HDACi) chidamide (CDM), aspirin significantly suppresses the VEGF signaling pathway with increased ROS overgeneration and EBV inhibition. We also showed that with the addition of chidamide, aspirin significantly suppresses NKTCL tumor growth in both in vitro cell culture and in vivo mouse model with prolonged mouse survival. This is the first time that the potential mechanism for aspirin-mediated VEGF suppression and anti-tumor effect has been discovered, and this study provides a new strategy for anti-tumor drug development for NKTCL treatment based on aspirin-mediated targeting of the VEGF signaling pathway and ROS formation.

Abnormal neural activity in the cerebellum has been implicated in hearing impairments, but the effects of long-term hearing loss on cerebellar function are poorly understood. To further explore the role of long-term bilateral sensorineural hearing loss on cerebellar function, we investigated hearing loss-induced changes among neural networks within cerebellar subregions and the changes in cerebellar-cerebral connectivity patterns using resting-state functional MRI. Twenty-one subjects with long-term bilateral moderate-to-severe sensorineural hearing loss and 21 matched controls with clinically normal hearing underwent MRI scanning and a series of neuropsychological tests targeting cognition and emotion. Voxel-wise functional connectivity (FC) analysis demonstrated decreased couplings between the cerebellum and other cerebral areas, including the temporal pole (TP), insula, supramarginal gyrus, inferior frontal gyrus (IFG), medial frontal gyrus, and thalamus, in long-term bilateral sensorineural hearing loss patients. An ROI-wise FC analysis found weakened interregional connections within cerebellar subdivisions. Moreover, there was a negative correlation between anxiety and FC between the left cerebellar lobe VI and left insula. Hearing ability and anxiety scores were also correlated with FC between the left cerebellar lobe VI and left TP, as well as the right cerebellar lobule VI and left IFG. Our results suggest that sensorineural hearing loss disrupts cerebellar-cerebral circuits, some potentially linked to anxiety, and interregional cerebellar connectivity. The findings contribute to a growing body showing that auditory deprivation caused by cochlear hearing loss disrupts not only activity with the classical auditory pathway but also portions of the cerebellum that communicates with other cortical networks.

Mapping individual brain networks has drawn significant research interest in recent years. Most individual brain networks developed to date have been based on fMRI or diffusion MRI. Given recent concerns regarding confounding artifacts, various preprocessing steps are generally included in functional or structural brain networks. Notably, voxel-based morphometry (VBM) derived from anatomical MRI exhibits high signal-to-noise ratios and has been applied to individual interregional morphological networks. To the best of our knowledge, individual voxel-wise morphological networks remain unexplored. The goal of this research is twofold: to build novel metrics for individual voxel-wise morphological networks and to test the reliability of the proposed morphological connectivity. To this end, anatomical scans of a cohort of healthy subjects were obtained from a public database. The anatomical datasets were preprocessed and normalized to the standard brain space. For each individual, wavelet-transform was applied on the VBM measures to obtain voxel-wise hierarchical features. The voxel-wise morphological connectivity was computed based on the wavelet features. Reliable brain hubs were detected by the z-scores of degree centrality. High reliability was discovered by test-retest analysis. No effects of wavelet scale, network threshold or network type were found on hubs of group-level degree centrality. However, significant effects of wavelet scale, network threshold and network type were found on individual-level degree centrality. Significant effects of network threshold and network type were found on reliability of degree centrality. The results suggested that the voxel-wise morphological connectivity was reliable and exhibited a hub structure. Moreover, the voxel-wise morphological connectivity could reflect individual differences. In summary, individual voxel-wise wavelet-based features can probe morphological connectivity and may be beneficial for investigating the brain morphological connectomes.

The flow field in a hypersonic inlet model at a design point of M = 6 has been studied experimentally. The focus of the current study is to present the time-resolved flow characteristics of separation shock around the cowl and the correlation between the separation shock oscillation induced by the unstart flow and the wall pressure fluctuation when the inlet is in a state of unstart. High-speed Schlieren flow visualization is used to capture the transient shock structure. High-frequency pressure transducers are installed on the wall around both the cowl and isolator areas to detect the dynamic pressure distribution. A schlieren image quantization method based on gray level detection and calculation is developed to analyze the time-resolved spatial structure of separation shock. Results indicate that the induced separation shock oscillation and the wall pressure fluctuation are closely connected, and they show the same frequency variation characteristics. The unsteady flow pattern of the “little buzz” and “big buzz” modes are clarified based on time-resolved Schlieren images of separation shock. Furthermore, the appropriate location of the pressure transducers is determined on the basis of the combined analysis of fluctuating wall-pressure and oscillating separation shock data.

AIMS:To precisely characterize the penumbra by MRI based on a modified photothrombotic stroke mouse model. METHODS:The proximal middle cerebral artery was occluded by a convenient laser system in conjunction with an intravenous injection of Rose Bengal in mice. And the suture MCAO model was performed in seven mice as a comparison of the reproducibility. One hour after occlusion, the penumbra was defined in six random photothrombotic stroke mice by mismatch between perfusion-weighted imaging and the apparent diffusion coefficient map on a home-made workstation. After imaging, three random mice of them were chosen to perform the reperfusion surgery. And the other three mice were sacrificed to stain for several potential penumbra markers, such as c-fos and heart shock protein 90. In the remaining mice, the evolution of the lesions was detected on the apparent diffusion coefficient map, diffusion-weighted imaging and T2-weighted imaging at 1, 3, 6, 12 and 24 hours. After evaluating the neurological deficit scores, the brains were sectioned and stained by triphenyltetrazolium chloride and Nissl. RESULTS:The mice subjected to photothrombosis showed significant behavioral deficits. One hour after occlusion, the low perfusion areas on the perfusion-weighted imaging interlaced with the hypointense areas on the apparent diffusion coefficient map, demonstrating that the penumbra was located both surrounding and inside the lesions. This phenomenon was subsequently confirmed by the c-fos and heart shock protein 90 staining. The final T2-weighted images of the mice subjected to the reperfusion surgery were also consistent with the penumbra images at one hour. At early stages, the lesions were clearly identified on the apparent diffusion coefficient map; the volumes of the lesions on the diffusion-weighted imaging and T2-weighted imaging did not reach a maximum until 12 hours. The coefficient of variation (CV) of the final lesions in the photothrombotic stroke mice was 21.7% (0.08 of 0.37) on T2-weighted imaging and 27.8% (0.10 of 0.35) on triphenyltetrazolium chloride, representing a high reproducibility (n = 7). While the CV of the lesions in the MCAO stroke mice was only 70% (0.24 of 0.34, n = 4). CONCLUSIONS:This study has provided a precise imaging definition of the penumbra based on a reproducible photothrombotic stroke mouse model.

The neurotoxicity of paraquat dichloride (PQ) was assessed in two inbred strains of 9- or 16-week old male C57BL/6 mice housed in two different laboratories and compared to the effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). PQ was administered by intraperitoneal injections; either once (20 mg/kg) or twice (10 mg/kg) weekly for 3 weeks, while MPTP-HCl was injected 4 times on a single day (20 mg/kg/dose). Brains were collected 8, 16, 24, 48, 96 or 168 hours after the last PQ treatment, and 48 or 168 hours after MPTP treatment. Dopamine neurons in the substantia nigra pars compacta (SNpc) were identified by antibodies to tyrosine hydroxylase (TH+) and microglia were identified using Iba-1 immunoreactivity. The total number of TH+ neurons and the number of resting and activated microglia in the SNpc at 168 hours after the last dose were estimated using model- or design-based stereology, with investigators blinded to treatment. In a further analysis, a pathologist, also blinded to treatment, evaluated the SNpc and/or striatum for loss of TH+ neurons (SNpc) or terminals (striatum), cell death (as indicated by amino cupric silver uptake, TUNEL and/or caspase 3 staining) and neuroinflammation (as indicated by Iba-1 and/or GFAP staining). PQ, administered either once or twice weekly to 9- or 16-week old mice from two suppliers, had no effect on the number of TH+ neurons or microglia in the SNpc, as assessed by two groups, each blinded to treatment, using different stereological methods. PQ did not induce neuronal cell loss or degeneration in the SNpc or striatum. Additionally, there was no evidence of apoptosis, microgliosis or astrogliosis. In MPTP-treated mice, the number of TH+ neurons in the SNpc was significantly decreased and the number of activated microglia increased. Histopathological assessment found degenerating neurons/terminals in the SNpc and striatum but no evidence of apoptotic cell death. MPTP activated microglia in the SNpc and increased the number of astrocytes in the SNpc and striatum.

Post-stroke cognitive dysfunction greatly influences patients' quality of life after stroke. However, its neurophysiological basis remains unknown. This study utilized resting-state functional magnetic resonance imaging (fMRI) to investigate the alterations in regional coherence in patients after subcortical stroke.Resting-state fMRI measurements were acquired from 16 post-stroke patients with poor cognitive function (PSPC), 16 post-stroke patients with good cognitive function (PSGC) and 30 well-matched healthy controls (HC). Regional homogeneity (ReHo) was used to detect alterations in regional coherence. Abnormalities in regional coherence correlated with scores on neuropsychological scales.Compared to the HC and the PSGC, the PSPC showed remarkably decreased ReHo in the bilateral anterior cingulate cortex and the left posterior cingulate cortex/precuneus. ReHo in the bilateral anterior cingulate cortex positively correlated with the scores on the Symbol Digit Modalities Test (r = 0.399, P = 0.036) and the Complex Figure Test-delayed recall subtest (r = 0.397, P = 0.036) in all post-stroke patients. Moreover, ReHo in the left posterior cingulate cortex/precuneus positively correlated with the scores on the Forward Digit Span Test (r = 0.485, P = 0.009) in all post-stroke patients.Aberrant regional coherence was observed in the anterior and posterior cingulate cortices in post-stroke patients with cognitive dysfunction. ReHo could represent a promising indicator of neurobiological deficiencies in post-stroke patients.

Hearing loss often triggers an inescapable buzz (tinnitus) and causes everyday sounds to become intolerably loud (hyperacusis), but exactly where and how this occurs in the brain is unknown. To identify the neural substrate for these debilitating disorders, we induced both tinnitus and hyperacusis with an ototoxic drug (salicylate) and used behavioral, electrophysiological, and functional magnetic resonance imaging (fMRI) techniques to identify the tinnitus–hyperacusis network. Salicylate depressed the neural output of the cochlea, but vigorously amplified sound-evoked neural responses in the amygdala, medial geniculate, and auditory cortex. Resting-state fMRI revealed hyperactivity in an auditory network composed of inferior colliculus, medial geniculate, and auditory cortex with side branches to cerebellum, amygdala, and reticular formation. Functional connectivity revealed enhanced coupling within the auditory network and segments of the auditory network and cerebellum, reticular formation, amygdala, and hippocampus. A testable model accounting for distress, arousal, and gating of tinnitus and hyperacusis is proposed.

Normal aging is associated with cognitive decline. Evidence indicates that large-scale brain networks are affected by aging; however, it has not been established whether aging has equivalent effects on specific large-scale networks. In the present study, 40 healthy subjects including 22 older (aged 60-80 years) and 18 younger (aged 22-33 years) adults underwent resting-state functional MRI scanning. Four canonical resting-state networks, including the default mode network (DMN), executive control network (ECN), dorsal attention network (DAN) and salience network, were extracted, and the functional connectivities in these canonical networks were compared between the younger and older groups. We found distinct, disruptive alterations present in the large-scale aging-related resting brain networks: the ECN was affected the most, followed by the DAN. However, the DMN and salience networks showed limited functional connectivity disruption. The visual network served as a control and was similarly preserved in both groups. Our findings suggest that the aged brain is characterized by selective vulnerability in large-scale brain networks. These results could help improve our understanding of the mechanism of degeneration in the aging brain. Additional work is warranted to determine whether selective alterations in the intrinsic networks are related to impairments in behavioral performance.

Adenosine (ADO), a non-classical neurotransmitter and neuromodulator, and its metabolites adenosine triphosphate (ATP), adenosine diphosphate (ADP) and adenosine monophosphate (AMP), have been shown to play an important role in a number of biochemical processes. Although their signaling is well described, it has been difficult to directly, accurately and simultaneously quantitate these purines in tissue or fluids. Here, we describe a novel method for measuring adenosine (ADO) and its metabolites using high performance liquid chromatography with electrochemical detection (HPLC-ECD). Using this chromatographic technique, we examined baseline levels of ADO and ATP, ADP and AMP in 6 different brain regions of the C57BL/6J mouse: stratum, cortex, hippocampus, olfactory bulb, substantia nigra and cerebellum and compared ADO levels in 5 different strains of mice (C57BL/6J, Swiss-Webster, FVB/NJ, 129P/J, and BALB/c). These studies demonstrate that baseline levels of purines vary significantly among the brain regions as well as between different mouse strains. These dissimilarities in purine concentrations may explain the variable phenotypes among background strains described in neurological disease models.

Restorative/protective therapies to restore dopamine neurons in the substantia nigra pars compacta (SNpc) are greatly needed to effectively change the debilitating course of Parkinson's disease. In this study, we tested the therapeutic potential of a neurogenic neurosteroid, allopregnanolone, in the restoration of the components of the nigrostriatal pathway in MPTP-lesioned mice by measuring striatal dopamine levels, total and tyrosine hydroxylase immunoreactive neuron numbers and BrdU-positive cells in the SNpc. An acute treatment (once/week for two weeks) with allopregnanolone restored the number of tyrosine hydroxylase-positive and total cell numbers in the SNpc of MPTP-lesioned mice, even though this did not increase striatal dopamine. It was also noted that MPTP treated mice to which allopregnanolone was administered had an increase in BrdU-positive cells in the SNpc. The effects of allopregnanolone in MPTP-lesioned mice were more apparent in mice that underwent behavioral tests. Interestingly, mice treated with allopregnanolone after MPTP lesion were able to perform at levels similar to that of non-lesioned control mice in a rotarod test. These data demonstrate that allopregnanolone promotes the restoration of tyrosine hydroxylase immunoreactive neurons and total cells in the nigrostriatal tract, improves the motor performance in MPTP-treated mice, and may serve as a therapeutic strategy for Parkinson's disease.

BACKGROUND: Methylphenidate (MPH) is a psychostimulant that exerts its pharmacological effects via preferential blockade of the dopamine transporter (DAT) and the norepinephrine transporter (NET), resulting in increased monoamine levels in the synapse. Clinically, methylphenidate is prescribed for the symptomatic treatment of ADHD and narcolepsy; although lately, there has been an increased incidence of its use in individuals not meeting the criteria for these disorders. MPH has also been misused as a "cognitive enhancer" and as an alternative to other psychostimulants. Here, we investigate whether chronic or acute administration of MPH in mice at either 1 mg/kg or 10 mg/kg, affects cell number and gene expression in the basal ganglia. METHODOLOGY/PRINCIPAL FINDINGS: Through the use of stereological counting methods, we observed a significant reduction (∼20%) in dopamine neuron numbers in the substantia nigra pars compacta (SNpc) following chronic administration of 10 mg/kg MPH. This dosage of MPH also induced a significant increase in the number of activated microglia in the SNpc. Additionally, exposure to either 1 mg/kg or 10 mg/kg MPH increased the sensitivity of SNpc dopaminergic neurons to the parkinsonian agent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Unbiased gene screening employing Affymetrix GeneChip® HT MG-430 PM revealed changes in 115 and 54 genes in the substantia nigra (SN) of mice exposed to 1 mg/kg and 10 mg/kg MPH doses, respectively. Decreases in the mRNA levels of gdnf, dat1, vmat2, and th in the substantia nigra (SN) were observed with both acute and chronic dosing of 10 mg/kg MPH. We also found an increase in mRNA levels of the pro-inflammatory genes il-6 and tnf-α in the striatum, although these were seen only at an acute dose of 10 mg/kg and not following chronic dosing. CONCLUSION: Collectively, our results suggest that chronic MPH usage in mice at doses spanning the therapeutic range in humans, especially at prolonged higher doses, has long-term neurodegenerative consequences.

Exercise has been demonstrated to potently protect substantia nigra pars compacta (SN) dopaminergic neurons from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity. One mechanism proposed to account for this neuroprotection is the upregulation of neurotrophic factors. Several neurotrophic factors, including Brain Derived Neurotrophic Factor (BDNF), have been shown to upregulate in response to exercise. In order to determine if exercise-induced neuroprotection is dependent upon BDNF, we compared the neuroprotective effects of voluntary exercise in mice heterozygous for the BDNF gene (BDNF+/-) with strain-matched wild-type (WT) mice. Stereological estimates of SNpc DA neurons from WT mice allowed 90 days exercise via unrestricted running demonstrated complete protection against the MPTP-induced neurotoxicity. However, BDNF+/- mice allowed 90 days of unrestricted exercise were not protected from MPTP-induced SNpc DA neuron loss. Proteomic analysis comparing SN and striatum from 90 day exercised WT and BDNF+/- mice showed differential expression of proteins related to energy regulation, intracellular signaling and trafficking. These results suggest that a full genetic complement of BDNF is critical for the exercise-induced neuroprotection of SNpc DA neurons.

The etiology of the vast majority of Parkinson's disease (PD) cases is unknown. It is generally accepted that there is an interaction between exposures to environmental agents with underlying genetic sensitivity. Recent epidemiological studies have shown that people living in agricultural communities have an increased risk of PD. Within these communities, paraquat (PQ) is one of the most utilized herbicides. PQ acts as a direct redox cycling agent to induce formation of free radicals and when administered to mice induces the cardinal symptoms of parkinsonism, including loss of TH+-positive dopaminergic (DA) neurons in the ventral midbrain's substantia nigra pars compacta (SNpc). Here we show that PQ-induced SNpc neuron loss is highly dependent on genetic background: C57BL/6J mice rapidly lose ∼50% of their SNpc DA neurons, whereas inbred Swiss-Webster (SWR/J) mice do not show any significant loss. We intercrossed these two strains to map quantitative trait loci (QTLs) that underlie PQ-induced SNpc neuron loss. Using genome-wide linkage analysis we detected two significant QTLs. The first is located on chromosome 5 (Chr 5) centered near D5Mit338, whereas the second is on Chr 14 centered near D14Mit206. These two QTLs map to different loci than a previously identified QTL (Mptp1) that controls a significant portion of strain sensitivity to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), suggesting that the mechanism of action of these two parkinsonian neurotoxins are different.

Objective: The aim of the study was to investigate the therapeutic effects of modified electroconvulsive therapy (MECT) in combination with risperidone tablets and psychotherapy in the treatment of patients with treatment-resistant schizophrenia (TRS). Methods: Patients with TRS admitted to the psychiatric department of our hospital between January 2018 and December 2019 were selected as study participants. They were randomly divided into a control group and a study group, with the control group receiving risperidone tablets and psychotherapy, and the study group undergoing MECT as well as the control group treatment. The mood scores, efficacy, and side effects of the 2 groups were compared. Results: After treatment, the Hamilton Anxiety Rating Scale (t = 2.316, P = .021) and Hamilton Depression Rating Scale (t = 2.919, P = .013) scores of the study group were significantly lower than those of the control group. The overall remission rate in the study group was 96.3%, which was higher than that of the control group (2 = 9.319, P = .007). The Positive and Negative Syndrome Scale (t = 8.126, P = .003), Traumatic Exposure Severity Scale (t = 13.210, P = .002), and Brief Psychiatric Rating Scale (t = 6.412, P = .001) scores were significantly lower in the study group than in the control group. The Wechsler Memory Scale score was higher in the study group than in the control group (t = 3.971, P = .002). Conclusion: The use of MECT in combination with risperidone tablets and psychotherapy can effectively improve patient mood, increase efficacy, reduce adverse effects, promote memory recovery, and shorten recovery time in patients with TRS. [ABSTRACT FROM AUTHOR]