Synergistic detoxification efficiency and mechanism of triclocarban degradation by a bacterial consortium in the liver-gut-microbiota axis of zebrafish (Danio rerio).

Triclocarban (TCC), an emerging organic contaminant, poses a potential threat to human health with long-term exposure. Here, Rhodococcus rhodochrous BX2 and Pseudomonas sp. LY-1 were utilized to degrade TCC at environmental related concentrations for enhancing TCC biodegradation and investigating whether the toxicity of intermediate metabolites is lower than that of the parent compound. The results demonstrated that the bacterial consortium could degrade TCC by 82.0% within 7 days. The calculated 96 h LC50 for TCC, as well as its main degradation product 3,4-Dichloroaniline (DCA) were 0.134 mg/L and 1.318 mg/L respectively. Biodegradation also alleviated histopathological lesions induced by TCC in zebrafish liver and gut tissues. Liver transcriptome analysis revealed that biodegradation weakened differential expression of genes involved in disrupted immune regulation and lipid metabolism caused by TCC, verified through RT-qPCR analysis and measurement of related enzyme activities and protein contents. 16 S rRNA sequencing indicated that exposure to TCC led to gut microbial dysbiosis, which was efficiently improved through TCC biodegradation, resulting in decreased relative abundances of major pathogens. Overall, this study evaluated potential environmental risks associated with biodegradation of TCC and explored possible biodetoxification mechanisms, providing a theoretical foundation for efficient and harmless bioremediation of environmental pollutants.

Improved fluorescence-based assay for rapid screening and evaluation of SARS-CoV-2 main protease inhibitors.

The outbreak of coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a global threat to human health. In parallel with vaccines, efficacious antivirals are urgently needed. SARS-CoV-2 main protease (Mpro) is an attractive drug target for antiviral development owing to its key roles in virus replication and host immune evasion. Due to the limitations of currently available methods, the development of novel high-throughput screening assays is of the highest importance for the discovery of Mpro inhibitors. In this study, we first developed an improved fluorescence-based assay for rapid screening of Mpro inhibitors from an anti-infection compound library using a versatile dimerization-dependent red fluorescent protein (ddRFP) biosensor. Utilizing this assay, we identified MG-101 as a competitive Mpro inhibitor in vitro. Moreover, our results revealed that ensitrelvir is a potent Mpro inhibitor, but baicalein, chloroquine, ebselen, echinatin, and silibinin are not. Therefore, this robust ddRFP assay provides a faithful avenue for rapid screening and evaluation of Mpro inhibitors to fight against COVID-19.

[Preparation and characterization of a fluorogenic ddRFP-M biosensor as a specific SARS-CoV-2 main protease substrate].

The conventional peptide substrates of SARS-CoV-2 main protease (Mpro) are frequently associated with high cost, unstable kinetics, and multistep synthesis. Hence, there is an urgent need to design affordable and stable Mpro substrates for pharmacological research. Herein, we designed a functional Mpro substrate based on a dimerization-dependent red fluorescent protein (ddRFP) for the evaluation of Mpro inhibitors in vitro. The codon-optimized DNA fragment encoding RFP-A1 domain, a polypeptide linker containing Mpro cleavage sequence (AVLQS), and the RFP-B1 domain was subcloned into the pET-28a vector. After transformation into Escherichia coli Rosetta(DE3) cells, the kanamycin resistant transformants were selected. Using a low temperature induction strategy, most of the target proteins (ddRFP-M) presented in the supernatant fractions were collected and purified by a HisTrapTM chelating column. Subsequently, the inhibition of Mpro by ensitrelvir and baicalein was assessed using ddRFP-M assay, and the biochemical properties of ddRFP-M substrate were analyzed. Our results showed that the fluorogenic substrate ddRFP-M was successfully prepared from E. coli cells, and this biosensor exhibited the expected specificity, sensitivity, and reliability. In conclusion, the production of the fluorogenic substrate ddRFP-M provides an expedient avenue for the assessment of Mpro inhibitors in vitro.

Evaluation of natural products from virtual screenings as SARS-CoV-2 main protease inhibitors using combinational experiments.

Recently, andrographolide, kaempferol, maslinic acid, rutin, and schaftoside have been identified as potent SARS-CoV-2 main protease (Mpro) inhibitors via molecular docking studies. However, no comprehensive in vitro testing of these compounds against Mpro has been conducted. In this study, we rigorously evaluated the in vitro inhibition of Mpro by these compounds using combinational experiments, including fluorescence resonance energy transfer (FRET), fluorescence polarization (FP), and dimerization-dependent red fluorescent protein (ddRFP) assays. Our data revealed that these compounds are not Mpro inhibitors based on the results from a set of in vitro assays. These results suggest that an efficient combination of a molecular docking approach and an experimental assay is essential for the discovery of Mpro inhibitors in the future.

Altered interhemispheric functional connectivity in patients with obsessive-compulsive disorder and its potential in therapeutic response prediction.

The trajectory of voxel-mirrored homotopic connectivity (VMHC) after medical treatment in obsessive-compulsive disorder (OCD) and its value in prediction of treatment response remains unclear. This study aimed to investigate the pathophysiological mechanism of OCD, as well as biomarkers for prediction of pharmacological efficacy. Medication-free patients with OCD and healthy controls (HCs) underwent magnetic resonance imaging. The patients were scanned again after a 4-week treatment with paroxetine. The acquired data were subjected to VMHC, support vector regression (SVR), and correlation analyses. Compared with HCs (36 subjects), patients with OCD (34 subjects after excluding two subjects with excessive head movement) exhibited significantly lower VMHC in the bilateral superior parietal lobule (SPL), postcentral gyrus, and calcarine cortex, and VMHC in the postcentral gyrus was positively correlated with cognitive function. After treatment, the patients showed increased VMHC in the bilateral posterior cingulate cortex/precuneus (PCC/PCu) with the improvement of symptoms. SVR results showed that VMHC in the postcentral gyrus at baseline could aid to predict a change in the scores of OCD scales. This study revealed that SPL, postcentral gyrus, and calcarine cortex participate in the pathophysiological mechanism of OCD while PCC/PCu participate in the pharmacological mechanism. VMHC in the postcentral gyrus is a potential predictive biomarker of the treatment effects in OCD.

Shared and distinctive neural substrates of generalized anxiety disorder with or without depressive symptoms and their roles in prognostic prediction.

BACKGROUND: The neurophysiological mechanisms underlying generalized anxiety disorder (GAD) with or without depressive symptoms are obscure. This study aimed to uncover them and assess their predictive value for treatment response. METHODS: We enrolled 98 GAD patients [58 (age: 33.22 ± 10.23 years old, males/females: 25/33) with and 40 (age: 33.65 ± 10.49 years old, males/females: 14/26) without depressive symptoms] and 54 healthy controls (HCs, age: 32.28 ± 10.56 years old, males/females: 21/33). Patients underwent clinical assessments and resting-state functional MRI (rs-fMRI) at baseline and after 4-week treatment with paroxetine, while HCs underwent rs-fMRI at baseline only. Regional homogeneity (ReHo) was employed to measure intrinsic brain activity. We compared ReHo in patients to HCs and examined changes in ReHo within the patient groups after treatment. Support vector regression (SVR) analyses were conducted separately for each patient group to predict the patients' treatment response. RESULTS: Both patient groups exhibited higher ReHo in the middle/superior frontal gyrus decreased ReHo in different brain regions compared to HCs. Furthermore, differences in ReHo were detected between the two patient groups. After treatment, the patient groups displayed distinct ReHo change patterns. By utilizing SVR based on baseline abnormal ReHo, we effectively predicted treatment response of patients (p-value for correlation < 0.05). LIMITATIONS: The dropout rate was relatively high. CONCLUSIONS: This study identified shared and unique neural substrates in GAD patients with or without depressive symptoms, potentially serving as biomarkers for treatment response prediction. Comorbid depressive symptoms were associated with differences in disease manifestation and treatment response compared to pure GAD cases.

Shared and distinctive dysconnectivity patterns underlying pure generalized anxiety disorder (GAD) and comorbid GAD and depressive symptoms.

The resting-state connectivity features underlying pure generalized anxiety disorder (GAD, G1) and comorbid GAD and depressive symptoms (G2) have not been directly compared. Furthermore, it is unclear whether these features might serve as potential prognostic biomarkers and change with treatment. Degree centrality (DC) in G1 (40 subjects), G2 (58 subjects), and healthy controls (HCs, 54 subjects) was compared before treatment, and the DC of G1 or G2 at baseline was compared with that after 4 weeks of paroxetine treatment. Using support vector regression (SVR), voxel-wise DC across the entire brain and abnormal DC at baseline were employed to predict treatment response. At baseline, G1 and G2 exhibited lower DC in the left mid-cingulate cortex and vermis IV/V compared to HCs. Additionally, compared to HCs, G1 had lower DC in the left middle temporal gyrus, while G2 showed higher DC in the right inferior temporal/fusiform gyrus. However, there was no significant difference in DC between G1 and G2. The SVR based on abnormal DC at baseline could successfully predict treatment response in responders in G2 or in G1 and G2. Notably, the predictive performance based on abnormal DC at baseline surpassed that based on DC across the entire brain. After treatment, G2 responders showed lower DC in the right medial orbital frontal gyrus, while no change in DC was identified in G1 responders. The G1 and G2 showed common and distinct dysconnectivity patterns and they could potentially serve as prognostic biomarkers. Furthermore, DC in patients with GAD could change with treatment.

Reduced lysosomal density in neuronal dendrites mediates deficits in synaptic plasticity in Huntington's disease.

Huntington's disease (HD) usually causes cognitive disorders, including learning difficulties, that emerge before motor symptoms. Mutations related to lysosomal trafficking are linked to the pathogenesis of neurological diseases, whereas the cellular mechanisms remain elusive. Here, we discover a reduction in the dendritic density of lysosomes in the hippocampus that correlates with deficits in synaptic plasticity and spatial learning in early CAG-140 HD model mice. We directly manipulate intraneuronal lysosomal positioning with light-induced CRY2:CIB1 dimerization and demonstrate that lysosomal abundance in dendrites positively modulates long-term potentiation of glutamatergic synapses onto the neuron. This modulation depends on lysosomal Ca2+ release, which further promotes endoplasmic reticulum (ER) entry into spines. Importantly, optogenetically restoring lysosomal density in dendrites rescues the synaptic plasticity deficit in hippocampal slices of CAG-140 mice. Our data reveal dendritic lysosomal density as a modulator of synaptic plasticity and suggest a role of lysosomal mispositioning in cognitive decline in HD.

Uncovering the Neural Correlates of Anhedonia Subtypes in Major Depressive Disorder: Implications for Intervention Strategies.

Major depressive disorder (MDD) represents a serious public health concern, negatively affecting individuals' quality of life and making a substantial contribution to the global burden of disease. Anhedonia is a core symptom of MDD and is associated with poor treatment outcomes. Variability in anhedonia components within MDD has been observed, suggesting heterogeneity in psychopathology across subgroups. However, little is known about anhedonia subgroups in MDD and their underlying neural correlates across subgroups. To address this question, we employed a hierarchical cluster analysis based on Temporal Experience of Pleasure Scale subscales in 60 first-episode, drug-naive MDD patients and 32 healthy controls. Then we conducted a connectome-wide association study and whole-brain voxel-wise functional analyses for identified subgroups. There were three main findings: (1) three subgroups with different anhedonia profiles were identified using a data mining approach; (2) several parts of the reward network (especially pallidum and dorsal striatum) were associated with anticipatory and consummatory pleasure; (3) different patterns of within- and between-network connectivity contributed to the disparities of anhedonia profiles across three MDD subgroups. Here, we show that anhedonia in MDD is not uniform and can be categorized into distinct subgroups, and our research contributes to the understanding of neural underpinnings, offering potential treatment directions. This work emphasizes the need for tailored approaches in the complex landscape of MDD. The identification of homogeneous, stable, and neurobiologically valid MDD subtypes could significantly enhance our comprehension and management of this multifaceted condition.

Abnormal regional activity in the prefrontal-limbic circuit at rest: Potential imaging markers and treatment predictors in drug-naive anxiety disorders.

BACKGROUND: Previous research has identified functional impairments within the prefrontal-limbic circuit in individuals with anxiety disorders. However, the link between these deficiencies, clinical symptoms, and responses to antipsychotic treatment is still not fully understood. This study aimed to investigate abnormal regional activity within the prefrontal-limbic circuit among drug-naive individuals diagnosed with generalized anxiety disorder (GAD) and panic disorder (PD) and to analyze changes following treatment. METHODS: Resting-state magnetic resonance imaging was performed on a cohort of 118 anxiety disorder patients (64 GAD, 54 PD) and 61 healthy controls (HCs) at baseline. Among them, 52 patients with GAD and 44 patients with PD underwent a 4-week treatment regimen of paroxetine. Fractional amplitude of low-frequency fluctuation (fALFF) measurements and pattern classification techniques were employed to analyze the data in accordance with the human Brainnetome atlas. RESULTS: Both patients with GAD and PD demonstrated decreased fALFF in the right cHipp subregion of the hippocampus and increased fALFF in specified subregions of the cingulate and orbitofrontal lobe. Notably, patients with PD exhibited significantly higher fALFF in the left A24cd subregion compared to patients with GAD, while other ROI subregions showed no significant variations between the two patient groups. Whole-brain analysis revealed abnormal fALFF in both patient groups, primarily in specific areas of the cingulate and parasingulate gyrus, as well as the inferior and medial orbitofrontal gyrus (OFG). Following a 4-week treatment period, specific subregions in the GAD and PD groups showed a significant decrease in fALFF. Further analysis using support vector regression indicated that fALFF measurements in the right A13 and right A24cd subregions may be predictive of treatment response among anxiety disorder patients. CONCLUSIONS: Aberrant functional activity in certain subregions of the prefrontal-limbic circuit appears to be linked to the manifestation of anxiety disorders. These findings suggest potential imaging indicators for individual responses to antipsychotic treatment.

First Report of Postharvest Fruit Rot Caused by Botrytis cinerea on Blue Honeysuckle (Lonicera caerulea L.) Fruit in China.

Blue honeysuckle (Lonicera caerulea L.) fruit is growing in popularity as a natural, functional 'super fruit', but its storage is challenged by pathogen infection. In June 2022, approximately 30% of 100 kg of blue honeysuckle fruits (cv. Lanjingling) obtained in Harbin, China (128.70°E, 44.87°N) showed postharvest fruit rot symptoms after 15 d of storage at 4°C, leading to whole fruit rotting with gray fungal growth (Fig.1 A). Small (1-2 mm) segments of infected tissue were obtained from 20 randomly selected fruits which were surface sterilized with 75% ethanol for 30 s and 5% sodium hypochlorite (NaOCl) for 3 min, rinsed three times with sterile distilled water, dried in paper towel, and plated in 9 cm Petri dishes containing potato dextrose agar (PDA). Five purified cultures were obtained and their front colonies were dark brown (Fig.1 C) on the PDA plates after 5 d at 25°C (Alam et al. 2019; Riquelme-Toledo et al. 2020). The conidia (n = 50) were single-celled, hyaline, either ellipsoid or ovoid, and measured 7.5-15.0 µm (11.7 µm average) × 6.0-11.4 µm (8.3 µm average). The conidiophores (Fig.1 E) were branched at the apex bearing bunches of conidia resembling grape clusters (Ellis 1971). For molecular confirmation, genomic DNA was extracted from a representative isolate LDGS-3 using the Ezup Column Fungi Genomic DNA Purification kit (Sangon Biotech, Shanghai, China). The internal transcribed spacer region (ITS, GenBank ON952502), heat shock protein (HSP60, GenBank OP039103), the second-largest subunit of RNA polymerase II (RPB2, GenBank OP186114) and glyceraldehyde 3-phosphate dehydrogenase (G3PDH, GenBank OQ658508) genes were partially amplified with the respective primers ITS1/ITS4, HSP60f/HSP60r, RPB2f/RPB2r, and G3PDH-F/G3PDH-R (Staats et al. 2005; White et al. 1990). BLAST analysis revealed that the sequences of the four genes showed 100% homology with the MH782039, MH796663, MN448501 and MH796662 sequences for isolates of Botrytis cinerea. Based on morphology and molecular characteristics, the isolate LDGS-3 was identified as B. cinerea. For pathogenicity, twenty healthy blue honeysuckle fruits (cv. Lanjingling) were superficially sterilized with 75% ethanol and washed with distilled water. Ten inoculated blue honeysuckle fruits, which were injected with 10 µL conidial suspension of isolate LDGS-3 (106 spores/mL) displayed fruit rot symptoms (Fig.1 B) inside 9 cm Petri dishes after 10 d at 4°C, while no symptoms were detected on ten fruits inoculated with sterile distilled water (Alam et al. 2019). The same isolate that was reisolated from infected fruits with the same morphological and molecular traits was also identified as B. cinerea, confirming Koch's postulates. B. cinerea was previously reported in Henan Province, China in hawthorn (Zhang et al. 2018). To our knowledge, this is the first report of postharvest fruit rot caused by B. cinerea on blue honeysuckle fruit in China, which will aid future management of this emerging postharvest disease.

Disrupted functional connectivity associated with cognitive impairment in generalized anxiety disorder (GAD) and comorbid GAD and depression: a follow-up fMRI study.

BACKGROUND: Impaired functional connectivity between the bilateral hemispheres may serve as the neural substrate for anxiety and depressive disorders, yet its role in comorbid generalized anxiety disorder (GAD) and depression, as well as the effect of treatment on this connectivity, remains unclear. We sought to examine functional connectivity between homotopic regions of the 2 hemispheres (voxel-mirrored homotopic connectivity [VMHC]) among people with GAD with and without comorbid depression at baseline and after a 4-week paroxetine treatment. METHODS: Drug-naïve patients with GAD, with or without comorbid depression and healthy controls underwent functional magnetic resonance imaging and clinical assessments at baseline and after treatment. We compared VMHC and seed-based functional connectivity across the 3 groups. We performed correlation analysis and support vector regression (SVR) to examine the intrinsic relationships between VMHC and symptoms. RESULTS: Both patient groups (n = 40 with GAD only, n = 58 with GAD and depression) showed decreased VMHC in the precuneus, posterior cingulate cortex and lingual gyrus compared with healthy controls (n = 54). Moreover, they showed decreased VMHC in different brain regions compared with healthy controls. However, we did not observe any significant differences between the 2 patient groups. Seeds from abnormal VMHC clusters in patient groups had decreased functional connectivity. Voxel-mirrored homotopic connectivity in the precuneus, posterior cingulate cortex and lingual gyrus was negatively correlated with cognitive impairment among patients with GAD only and among all patients. The SVR analysis based on abnormal VMHC showed significant positive correlations (p < 0.0001) between predicted and actual treatment responses. However, we did not observe significant differences in VMHC or functional connectivity after treatment. LIMITATIONS: A notable dropout rate and intergroup somatic symptom variations may have biased the results. CONCLUSION: Patients with GAD with or without comorbid depression exhibited shared and distinct abnormal VMHC patterns, which might be linked to their cognitive deficits. These patterns have the potential to serve as prognostic biomarkers for GAD.Clinical trial registration: ClinicalTrials.gov NCT03894085.

An Activatable Near-Infrared Fluorescent Probe for Precise Detection of the Pulmonary Metastatic Tumors: A Traditional Molecule Having a Stunning Turn.

An accurate detection of lung metastasis is of great significance for making better treatment choices and improving cancer prognosis, but remains a big challenge in clinical practice. In this study, we propose a reinventing strategy to develop a pH-activatable near-infrared (NIR) fluorescent nanoprobe, pulmonary metastasis tracer (denoted as PMT), based on assembly of NIR dye IR780 and calcium phosphate (CaP). By delicately tuning the intermolecular interactions during the assembly process and dye doping content, as well as the synthetic condition of probe, the fluorescence of PMT could be finely adjusted via the tumor acidity-triggered disassembly. Notably, the selected PMT9 could sharply convert subtle pH variations into a distinct fluorescence signal to generate high fluorescence ON/OFF contrast, dramatically reducing the background signals. Benefiting from such preferable features, PMT9 is able to precisely identify not only the tumor sites in orthotopic lung cancer models but also the pulmonary metastases in mice with remarkable signal-to-background ratio (SBR). This study provides a unique strategy to turn shortcomings of traditional dye IR780 during in vivo imaging into advantages and further expand the application of fluorescent probe to image lung associated tumor lesions.

Deviant spontaneous neural activity as a potential early-response predictor for therapeutic interventions in patients with schizophrenia.

Objective: Previous studies have established significant differences in the neuroimaging characteristics between healthy controls (HCs) and patients with schizophrenia (SCZ). However, the relationship between homotopic connectivity and clinical features in patients with SCZ is not yet fully understood. Furthermore, there are currently no established neuroimaging biomarkers available for the diagnosis of SCZ or for predicting early treatment response. The aim of this study is to investigate the association between regional homogeneity and specific clinical features in SCZ patients. Methods: We conducted a longitudinal investigation involving 56 patients with SCZ and 51 HCs. The SCZ patients underwent a 3-month antipsychotic treatment. Resting-state functional magnetic resonance imaging (fMRI), regional homogeneity (ReHo), support vector machine (SVM), and support vector regression (SVR) were used for data acquisition and analysis. Results: In comparison to HCs, individuals with SCZ demonstrated reduced ReHo values in the right postcentral/precentral gyrus, left postcentral/inferior parietal gyrus, left middle/inferior occipital gyrus, and right middle temporal/inferior occipital gyrus, and increased ReHo values in the right putamen. It is noteworthy that there was decreased ReHo values in the right inferior parietal gyrus after treatment compared to baseline data. Conclusion: The observed decrease in ReHo values in the sensorimotor network and increase in ReHo values in the right putamen may represent distinctive neurobiological characteristics of patients with SCZ, as well as a potential neuroimaging biomarker for distinguishing between patients with SCZ and HCs. Furthermore, ReHo values in the sensorimotor network and right putamen may serve as predictive indicators for early treatment response in patients with SCZ.

Breaking the Fear Barrier: Aberrant Activity of Fear Networks as a Prognostic Biomarker in Patients with Panic Disorder Normalized by Pharmacotherapy.

Panic disorder (PD) is a prevalent type of anxiety disorder. Previous studies have reported abnormal brain activity in the fear network of patients with PD. Nonetheless, it remains uncertain whether pharmacotherapy can effectively normalize these abnormalities. This longitudinal resting-state functional magnetic resonance imaging study aimed to investigate the spontaneous neural activity in patients with PD and its changes after pharmacotherapy, with a focus on determining whether it could predict treatment response. The study included 54 drug-naive patients with PD and 54 healthy controls (HCs). Spontaneous neural activity was measured using regional homogeneity (ReHo). Additionally, support vector regression (SVR) was employed to predict treatment response from ReHo. At baseline, PD patients had aberrant ReHo in the fear network compared to HCs. After 4 weeks of paroxetine treatment (20 mg/day), a significant increase in ReHo was observed in the left fusiform gyrus, which had shown reduced ReHo before treatment. The SVR analysis showed significantly positive correlations (p < 0.0001) between the predicted and actual reduction rates of the severity of anxiety and depressive symptoms. Here, we show patients with PD had abnormal spontaneous neural activities in the fear networks. Furthermore, these abnormal spontaneous neural activities can be partially normalized by pharmacotherapy and serve as candidate predictors of treatment response. Gaining insight into the trajectories of brain activity normalization following treatment holds the potential to provide vital insights for managing PD.

Altered resting-state cerebellar-cerebral functional connectivity in patients with panic disorder before and after treatment.

The study aimed to investigate the functional connectivity (FC) between the cerebellum and intrinsic cerebral networks in patients with panic disorder (PD), and to observe changes in the cerebellar-cerebral FC following pharmacotherapy. Fifty-four patients with PD and 54 healthy controls (HCs) underwent clinical assessments and functional magnetic resonance imaging scans before and after a 5-week paroxetine treatment. Seed-based cerebellar-cerebral FC was compared between the PD and HC groups, as well as between patients with PD before and after treatment. Additionally, the correlations between FC and clinical features of PD were analyzed. Compared to HCs, patients with PD had altered cerebellar-cerebral FC in the default mode, affective-limbic, and sensorimotor networks. Moreover, a negative correlation between cerebellar-insula disconnection and the severity of depressive symptoms in patients with PD (Pearson correlation, r = -0.424, p = 0.001, Bonferroni corrected) was found. After treatment, most of the enhanced FCs observed in patients with PD at baseline returned to levels similar to those observed in HCs. However, the reduced FC at baseline did not significantly change after treatment. The findings suggest that patients with PD have specific deficits in resting-state cerebellar-cerebral FC and that paroxetine may improve PD by restoring the balance of cerebellar-cerebral FC. These findings emphasize the crucial involvement of cerebellar-cerebral FC in the neuropsychological mechanisms underlying PD and in the potential pharmacological mechanisms of paroxetine for treating PD.