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The outbreak of Zika virus (ZIKV) in 2016 created worldwide health emergency which demand urgent research efforts on understanding the virus biology and developing therapeutic strategies. Here, we present a time-resolved chemical proteomic strategy to track the early-stage entry of ZIKV into host cells. ZIKV was labeled on its surface with a chemical probe, which carries a photocrosslinker to covalently link virus-interacting proteins in living cells on UV exposure at different time points, and a biotin tag for subsequent enrichment and mass spectrometric identification of the receptor or other host proteins critical for virus internalization. We identified Neural Cell Adhesion Molecule (NCAM1) as a potential ZIKV receptor and further validated it through overexpression, knockout, and inhibition of NCAM1 in Vero cells and human glioblastoma cells U-251 MG. Collectively, the strategy can serve as a universal tool to map virus entry pathways and uncover key interacting proteins. The mechanism underlying the cellular entry of Zika virus is not fully understood. Here, the authors use a chemically modified virus and time-resolved proteomics to capture interacting host proteins during virus entry and identify NCAM1 as a ZIKV receptor.

Bipolar disorder (BD) is associated with a high risk of suicidality, and it is challenging to predict suicide attempts in clinical practice to date. Although structural and functional connectivity alterations from neuroimaging studies have been previously reported in BD with suicide attempts, little is known about how abnormal structural and functional connectivity relates to each other. Here, we hypothesize that structure connectivity constrains functional connectivity, and structural–functional coupling is a more sensitive biomarker to detect subtle brain abnormalities than any single modality in BD patients with a current major depressive episode who had attempted suicide. By investigating structural and resting-state fMRI connectivity, as well as their coupling among 191 BD depression patients with or without a history of suicide attempts and 113 healthy controls, we found that suicide attempters in BD depression patients showed significantly decreased central-temporal structural connectivity, increased frontal–temporal functional connectivity, along with decreased structural–functional coupling compared with non-suicide attempters. Crucially, the altered structural connectivity network predicted the abnormal functional connectivity network profile, and the structural–functional coupling was significantly correlated with suicide risk but not with depression or anxiety severity. Our findings suggest that the structural connectome is the key determinant of brain dysfunction, and structural–functional coupling could serve as a valuable trait-like biomarker for BD suicidal predication over and above the intramodality network connectivity. Such a measure can have clinical implications for early identification of suicide attempters with BD depression and inform strategies for prevention.

Background This study aimed to evaluate the working memory (WM) updating ability of patients with major depressive disorder (MDD) and investigate the potential underlying neuroelectric oscillatory mechanisms. The overall goal was to identify potential biological markers of impaired WM updating function in MDD. Methods 56 patients with MDD and 43 age- and gender-matched healthy controls (HCs) were recruited. All participants underwent clinical evaluations and electroencephalography (EEG) was used to record their brain activity in real time while performing the n-back task (0- and 2-back). Two-way analysis of variance was used to compare the WM behavioral performance and theta (4–8 Hz), alpha (8–13 Hz), and gamma (30–45 Hz) band powers between the two groups. Further, Spearman correlation analysis was performed to examine the relationships between the significant differential oscillation patterns and (1) emotional symptoms and (2) WM performance in the MDD group. Results Compared to the control group, the MDD group showed poorer accuracy and reaction time in the 2-back task. During the WM encoding phase of the 2-back task, the patient group exhibited decreased parietal theta oscillation activity, which was significantly correlated with lower accuracy and longer reaction times. Additionally, the control group exhibited stronger frontal-midline theta and occipital alpha oscillations during the 2-back task. This distinct pattern of activity as a function of task difficulty was not observed in the MDD group. Conclusions MDD patients demonstrated impaired WM updating ability, primarily due to abnormalities in the memory encoding phase. The weakened parietal theta oscillation activity and the abnormal patterns of frontal-midline theta and occipital alpha oscillations might constitute the neurophysiological basis of these functional differences.

Background Bipolar disorder (BD) and major depressive disorder (MDD) are classified as distinct diagnostic categories. However, early identification of BD from MDD is challenging due to their high overlap in clinical features, particularly in late adolescence and early adulthood. This study aimed to explore biomarkers for the early identification of BD from MDD. Methods The study consists of 139 BD, 148 unipolar depression (UD), and 128 healthy controls (HC) participants ranging from late adolescence to early adulthood. In addition, an independent group of 62 patients initially diagnosed with MDD at baseline and transitioned to BD during follow-up was identified as initial depressive episode BD (IDE-BD). Cortical thickness and surface area were measured for all participants, along with the associations with clinical symptoms. Results IDE-BD shares similar cortical thickness patterns with BD and UD. Compared to HC, cortical thinning in the left inferior temporal cortex was observed across all depressive episode groups. Cortical thickness alterations in the right caudal anterior cingulate cortex (cACC.R) were observed specifically in the BD and IDE-BD but were absent in the UD. Compared to UD, IDE-BD exhibited significantly increased cortical thickness in the cACC.R. Moreover, the increase in cACC.R thickness in the IDE-BD was associated with hypomania and suicide risk scores. Conclusions In this cross-diagnostic study focusing on late adolescence and early adulthood, we found evidence suggesting shared and disease-specific cortical thickness patterns of depressive episodes. Our study offers potential insights into the neuropathological mechanisms of mood disorders and may contribute to the early identification of BD from MDD.

Background Major depressive disorder (MDD) often presents alongside physical illnesses, such as a high incidence of subclinical hypothyroidism (SHypo) in patients, highlighting the common occurrence of these comorbidities. Recent research has indicated that the presence of comorbid SHypo in individuals diagnosed with MDD may result in notable alterations in both brain structure and function. This study aimed was to investigate the neurological mechanisms underlying this co-occurrence using a data-driven approach to analyze brain activity patterns. Methods Twenty-nine patients diagnosed with MDD without any comorbid conditions (nSHypo-MDD) were included in the study, along with 29 MDD patients who also had SHypo (SHypo-MDD), 26 patients with SHypo only, and 29 healthy individuals as controls (HCs). Each participant received resting-state functional magnetic resonance imaging scans and underwent neuropsychological evaluations. Results We found significantly altered functional connectivity (FC) within the resting-state networks (RSNs) of the ventral and dorsal sensorimotor network (VSMN and DSMN) and occipital pole visual network (PVN) ( p  < 0.05, FDR corrected). A vital interaction effect between SHypo and MDD was detected in the PVN, showing that SHypo-MDD patients had higher FC values in the left cuneus than nSHypo-MDD patients. Serum-free triiodothyronine (FT3) levels in SHypo-MDD patients demonstrated an inverse relationship with FC values of the right supplementary motor area (SMA.R) ( r  = − 0.563, p  = 0.003). Furthermore, the FC values in the left cuneus are positively associated with the Digit Symbol Substitution Test (DSST) scores ( r  = 0.507, p  = 0.008). Conclusions Our study reveals significant FC changes in SHypo-MDD patients, particularly in the PVN, VSMN, and DSMN, suggesting compensatory mechanisms that mitigate cognitive deficits and highlighting the need for integrated management of SHypo and MDD to improve cognitive outcomes.

The spatial distribution characteristics and influencing factors of tourist attractions in China are analyzed by GIS and SPSS. The spatial distribution characteristics and main influencing factors of urban landscape tourism resources in China are deeply explored in order to provide a reference for the construction of a national park system and for the optimal allocation of tourism resources in the future. The results show the following: (1) the spatial pattern of tourism resources in China is strong in the southeast and weak in the northwest. It shows the spatial structure of a global concentrated contiguous distribution, A-level zonal distribution, and national point distribution. The distribution pattern of concentrated contiguous areas is consistent with the spatial distribution of major urban agglomerations in China. (2) There is a serious imbalance in the allocation of A-level tourist attractions in Central, Southwest, Northwest, and Northeast China. The allocation of A-level tourist attractions in East China is in an absolute dominant position, whereas that in South China and North China is at a medium level. National tourism resources show obvious characteristics of being strong in the east and weak in the west. We mainly take the provincial capital city as the core point of agglomeration, showing the obvious “administrative district” distribution characteristics. (3) The level of urban management, the scale of urban construction, the development of the real estate industry, the employment population of tertiary industry, and the level of urban economic development are all factors that have a significant correlation with the spatial distribution of urban tourism resources.

Bipolar disorder (BD) and unipolar depression (UD) are defined as distinct diagnostic categories. However, due to some common clinical and pathophysiological features, it is a clinical challenge to distinguish them, especially in the early stages of BD. This study aimed to explore the common and disease-specific connectivity patterns in BD and UD. This study was constructed over 181 BD, 265 UD and 204 healthy controls. In addition, an independent group of 90 patients initially diagnosed with major depressive disorder at the baseline and then transferred to BD with the episodes of mania/hypomania during follow-up, was identified as initial depressive episode BD (IDE-BD). All participants completed resting-state functional magnetic resonance imaging (R-fMRI) at recruitment. Both network-based analysis and graph theory analysis were applied. Both BD and UD showed decreased functional connectivity (FC) in the whole brain network. The shared aberrant network across groups of patients with depressive episode (BD, IDE-BD and UD) mainly involves the visual network (VN), somatomotor networks (SMN) and default mode network (DMN). Analysis of the topological properties over the three networks showed that decreased clustering coefficient was found in BD, IDE-BD and UD, however, decreased shortest path length and increased global efficiency were only found in BD and IDE-BD but not in UD. The study indicate that VN, SMN, and DMN, which involve stimuli reception and abstraction, emotion processing, and guiding external movements, are common abnormalities in affective disorders. The network separation dysfunction in these networks is shared by BD and UD, however, the network integration dysfunction is specific to BD. The aberrant network integration functions in BD and IDE-BD might be valuable diagnostic biomarkers.

Microglia, the immune competent cells of the central nervous system (CNS), normally exist in a resting state characterized by a ramified morphology with many processes, and become activated to amoeboid morphology in response to brain injury, infection, and a variety of neuroinflammatory stimuli. Many studies focused on how neurotransmitters affect microglia activation in pathophysiological circumstances. In this study, we tried to gain mechanistic insights on how dopamine (DA) released from neurons modulates cellular functions of resting and activated microglia. DA induced the reduction of the number of cellular processes, the increase of cell adhesion/spreading, and the increase of vimentin filaments in resting primary and BV microglia. In contrast to resting cells, DA downregulated the cell spreading and phagocytosis of microglia activated by LPS. DA also significantly downregulated ERK1/2 phosphorylation in activated microglia, but not in resting microglia. Downregulation of ERK1/2 by DA in activated microglia required receptor signaling. In contrast, we found a significant increase of p38MAPK activity by DA treatment in resting, but not in activated microglia. These latter effects required the uptake of DA through the high-affinity transporter but did not require receptor signaling. Activation of p38MAPK resulted in the increase of focal adhesion number via phosphorylation of paxillin at Ser . These results indicate that DA might have a differential, depending upon the activation stage of microglia, impact on cellular functions such as adhesion and phagocytosis.

ZIKV is a recently emerged mosquito-borne flavivirus that can cause devastating congenital Zika syndrome in pregnant women and Guillain-Barré syndrome in adults, but how ZIKV specifically targets the placenta is not well understood. Here, we identified an alkaline phosphatase (ALPP) that is expressed primarily in placental tissue and promotes ZIKV infection by colocalizing with ZIKV proteins and preventing their proteasome-mediated degradation. The phosphatase activity of ALPP could be required for optimal ZIKV infection, and ALPP is stabilized by BIP via its chaperone activity. This report provides novel insights into host factors required for ZIKV infection, which potentially has implications for ZIKV infection of the placenta. Zika virus (ZIKV) infection during pregnancy causes intrauterine growth defects and microcephaly, but knowledge of the mechanism through which ZIKV infects and replicates in the placenta remains elusive. Here, we found that ALPP, an alkaline phosphatase expressed primarily in placental tissue, promoted ZIKV infection in both human placental trophoblasts and astrocytoma cells. ALPP bound to ZIKV structural and nonstructural proteins and thereby prevented their proteasome-mediated degradation and enhanced viral RNA replication and virion biogenesis. In addition, the function of ALPP in ZIKV infection depends on its phosphatase activity. Furthermore, we demonstrated that ALPP was stabilized through interactions with BIP, which is the endoplasmic reticulum (ER)-resident heat shock protein 70 chaperone. The chaperone activity of BIP promoted ZIKV infection and mediated the interaction between ALPP and ZIKV proteins. Collectively, our findings reveal a previously unrecognized mechanism through which ALPP facilitates ZIKV replication by coordinating with the BIP protein. IMPORTANCE ZIKV is a recently emerged mosquito-borne flavivirus that can cause devastating congenital Zika syndrome in pregnant women and Guillain-Barré syndrome in adults, but how ZIKV specifically targets the placenta is not well understood. Here, we identified an alkaline phosphatase (ALPP) that is expressed primarily in placental tissue and promotes ZIKV infection by colocalizing with ZIKV proteins and preventing their proteasome-mediated degradation. The phosphatase activity of ALPP could be required for optimal ZIKV infection, and ALPP is stabilized by BIP via its chaperone activity. This report provides novel insights into host factors required for ZIKV infection, which potentially has implications for ZIKV infection of the placenta.

Bipolar disorder type II (BD-II) is linked to an increased suicidal risk. Since a prior suicide attempt (SA) is the single most important risk factor for sequent suicide, the elucidation of involved neural substrates is critical for its prevention. Therefore, we examined the spontaneous brain activity and its temporal variabilities in suicide attempters with bipolar II during a major depressive episode. In this cross-sectional study, 101 patients with BD-II, including 44 suicidal attempters and 57 non-attempters, and 60 non-psychiatric controls underwent a resting-state functional magnetic resonance imaging (fMRI). Participants were assessed with Hamilton Rating Scale for Depression (HAMD) and Nurses , Global Assessment of Suicide Risk (NGASR). The dynamics of low-frequency fluctuation (dALFF) was measured using sliding-window analysis and its correlation with suicidal risk was conducted using Pearson correlation. Compared to non-attempters, suicidal attempters showed an increase in brain activity and temporal dynamics in the anterior cingulate cortex (ACC). In addition, the temporal variabilities of ACC activity positively correlated with suicidal risk (R = 0.45, p  = 0.004), while static ACC activity failed to (R = 0.08, p  > 0.05). Our findings showed that an aberrant static ALFF and temporal variability could affect suicidal behavior in BD-II patients. However, temporal variability of neuronal activity was more sensitive than static amplitude in reflecting diathesis for suicide in BD-II. Dynamics of brain activity could be considered in developing neuromarkers for suicide prevention.