TCF7L2 acts as a molecular switch in midbrain to control mammal vocalization through its DNA binding domain but not transcription activation domain.

Vocalization is an essential medium for social signaling in birds and mammals. Periaqueductal gray (PAG) a conserved midbrain structure is believed to be responsible for innate vocalizations, but its molecular regulation remains largely unknown. Here, through a mouse forward genetic screening we identified one of the key Wnt/ß-catenin effectors TCF7L2/TCF4 controls ultrasonic vocalization (USV) production and syllable complexity during maternal deprivation and sexual encounter. Early developmental expression of TCF7L2 in PAG excitatory neurons is necessary for the complex trait, while TCF7L2 loss reduces neuronal gene expressions and synaptic transmission in PAG. TCF7L2-mediated vocal control is independent of its ß-catenin-binding domain but dependent of its DNA binding ability. Patient mutations associated with developmental disorders, including autism spectrum disorders, disrupt the transcriptional repression effect of TCF7L2, while mice carrying those mutations display severe USV impairments. Therefore, we conclude that TCF7L2 orchestrates gene expression in midbrain to control vocal production through its DNA binding but not transcription activation domain.

Brain structural alterations detected by an automatic quantified tool as an indicator for MCI diagnosing in type 2 diabetes mellitus patients: A magnetic resonance imaging study.

Background and objectives: Type 2 diabetes mellitus (T2DM) is an important risk factors for mild cognitive impairment (MCI). Structural magnetic resonance imaging (sMRI) is an effective and widely used method to investigate brain pathomorphological injury in neural diseases. In present study, we aimed to determine the brain regional alterations that correlated to the incidence of MCI in T2DM patients. Materials and methods: Eighteen T2DM patients with and without MCI (DMCI/T2DM) respectively, and eighteen age/gender-matched healthy controls (HC) were recruited. Brain MRI imagines of all the individuals were subjected to automatic quantified brain sub-structure volume segmentation and measurement by Dr. brain ™ software. The relative volume of total gray matter (TGM), total white matter (TWM), and 68 pairs (left and right) of brain sub-structures were compared between the three groups. Cognitive function correlation analysis and receiver operating characteristic (ROC) curve analysis were conducted in the MCI-related brain regions in T2DM patients, and we utilized a machine learning method to classify the three group of subjects. Results: 10 and 27 brain sub-structures with significant relative volumetric alterations were observed in T2DM patients without MCI and T2DM patients with MCI, respectively (p < 0.05). Compared with T2DM patients without MCI, eight critical regions include right anterior orbital gyrus, right calcarine and cerebrum, left cuneus, left entorhinal area, left frontal operculum, right medial orbital gyrus, right occipital pole, left temporal pole had significant lower volumetric ratio in T2DM patients with MCI (p < 0.05). Among them, the decrease of volumetric ratio in several regions had a positive correlation with Montreal Cognitive Assessment (MoCA) scores and Mini-Mental State Examination (MMSE) scores. The classification results conducted based on these regions as features by random forest algorithm yielded good accuracies of T2DM/HC 69.4%, DMCI/HC 72.2% and T2DM/DMCI 69.4%. Conclusions: Certain brain regional structural lesions occurred in patients with T2DM, and this condition was more serious in T2DM patients combined with MCI. A systematic way of segmenting and measuring the whole brain has a potential clinical value for predicting the presence of MCI for T2DM patients.

ZIF/Co-C3N4 with enhanced electrocatalytic reduction of carbon dioxide activity by the photoactivation process.

Introducing the effect of light into an electrocatalytic system is an effective method to improve electrocatalytic carbon dioxide reduction (CO2RR). Here, the composite catalyst (ZIF/Co-C3N4) was prepared for the electrocatalytic reduction of carbon dioxide. The Faraday efficiency of the catalytic reduction of CO2 to CO under light could reach 90.34% at -0.67 V vs. the RHE (reversible hydrogen electrode), which was 30% higher than that obtained under darkness, and the overpotential was reduced by 200 mV. Chemical kinetics experiments and in-situ transient photovoltage (TPV) tests show that the reason for highly efficient CO2RR is intermediate CO2- formed by activated CO2 in the electrocatalytic system under light. This work offers a deep insight into the photo-activated electrocatalytic reduction of carbon dioxide, and also opens a new way to devise efficient catalysts for CO2RR.

Carbon-Dot-Based White-Light-Emitting Diodes with Adjustable Correlated Color Temperature Guided by Machine Learning.

Here, we show the fabrication of the carbon dots (CDs) with green and orange emissions from PTCDA (perylene-3,4,9,10-tetracarboxylic dianhydride). Using these CDs as emitters, the orange (or green) CDs LEDs were fabricated, which show electroluminescence (EL) spectra centered at 560 nm (or 498 nm) with an external quantum efficiency (EQE) of 1.98 % (1.76 %) adhering a luminescence of 626 cd m-2 (or 519 cd m-2 ). The machine learning was successfully used to predict PL CCT value. With the model, the white photoluminescence (PL) emission with adjustable correlated color temperature (CCT) from 3093 to 11018 K via combining blue, green, and orange CDs was achieved. Then, we obtained the warm white CDs LEDs with CCT of 3107, 4071 and 4548 K, and cold white CDs LEDs with CCT of 5632 (CIE coordinates of (0.33, 0.33), EQE: 1.18 %, luminescence: 598 cd m-2 ) and 6034 K accurately.

Primarily Disrupted Default Subsystems Cause Impairments in Inter-system Interactions and a Higher Regulatory Burden in Alzheimer's Disease.

Background: Intrinsically organized large-scale brain networks and their interactions support complex cognitive function. Investigations suggest that the default network (DN) is the earliest disrupted network and that the frontoparietal control network (FPCN) and dorsal attention network (DAN) are subsequently impaired in Alzheimer's disease (AD). These large-scale networks comprise different subsystems (DN: medial temporal lobe (MTL), dorsomedial prefrontal cortex (DM) subsystems and a Core; FPCN: FPCNA and FPCNB). Our previous research has indicated that different DN subsystems are not equally damaged in AD. However, changes in the patterns of interactions among these large-scale network subsystems and the underlying cause of the alterations in AD remain unclear. We hypothesized that disrupted DN subsystems cause specific impairments in inter-system interactions and a higher regulatory burden for the FPCNA. Method: To test this hypothesis, Granger causality analysis (GCA) was performed to explore effective functional connectivity (FC) pattern of these networks. The regional information flow strength (IFS) was calculated and compared across groups to explore changes in the subsystems and their inter-system interactions and the relationship between them. To investigate specific inter-system changes, we summed the inter-system IFS and performed correlation analyses of the bidirectional inter-system IFS, which was compared across groups. Additionally, correlation analyses of dynamic effective FC patterns were performed to reveal alterations in the temporal co-evolution of sets of inter-subsystem interactions. Furthermore, we used partial correlation analysis to quantify the FPCN's regulatory effects. Finally, we applied a support vector machine (SVM) linear classifier to probe which network most effectively discriminated patients from controls. Results: Compared with controls, AD patients showed a decreased intra-DN regional IFS, which was significantly related to the inter-network's IFS. The IFS between the DN subsystems and FPCN subsystems/DAN decreased. Critically, the correlation values of the decreased bidirectional IFS between the DN subsystems and FPCNA diminished. Additionally, the Core and DM play pivotal roles in disordered temporal co-evolution. Furthermore, the FPCNA showed enhanced regulation of the Core. Finally, the MTL subsystem and Core were effective at discriminating patients from controls. Conclusion: The predominantly disrupted DN subsystems caused impaired inter-system interactions and created a higher regulatory burden for the FPCNA.

A Brain Network Constructed on an L1-Norm Regression Model Is More Sensitive in Detecting Small World Network Changes in Early AD.

Most previous imaging studies have used traditional Pearson correlation analysis to construct brain networks. This approach fails to adequately and completely account for the interaction between adjacent brain regions. In this study, we used the L1-norm linear regression model to test the small-world attributes of the brain networks of three groups of patients, namely, those with mild cognitive impairment (MCI), Alzheimer's disease (AD), and healthy controls (HCs); we attempted to identify the method that may detect minor differences in MCI and AD patients. Twenty-four AD patients, 33 MCI patients, and 27 HC elderly subjects were subjected to functional MRI (fMRI). We applied traditional Pearson correlation and the L1-norm to construct the brain networks and then tested the small-world attributes by calculating the following parameters: clustering coefficient (Cp), path length (Lp), global efficiency (Eg), and local efficiency (Eloc). As expected, L1 could detect slight changes, mainly in MCI patients expressing higher Cp and Eloc; however, no statistical differences were found between MCI patients and HCs in terms of Cp, Lp, Eg, and Eloc, using Pearson correlation. Compared with HCs, AD patients expressed a lower Cp, Eloc, and Lp and an increased Eg using both connectivity metrics. The statistical differences between the groups indicated the brain networks constructed by the L1-norm were more sensitive to detect slight small-world network changes in early stages of AD.

Boronic acid derivatized lanthanide-polyoxometalates with novel B-OH-Ln and B-O-Nb bridges.

Three new boronic acid derivatized lanthanide-polyoxometalates (BA-Ln-POMs) were synthesized, in which boronic acids served as bi- or tri-dentate ligands and exhibited interesting coordination ability towards POMs and LnIII. The pH was found to be crucial in controlling the coordination modes of boronic acid and the formation of B-O-Ln and B-O-Nb bridges. Compared with the boronic acid-free Ln-POM, a longer lifetime was observed for compound 2Eu due to the coordination of boronic acids to the EuIII center.

Lithium and its isotopes as tracers of groundwater salinization: A study in the southern coastal plain of Laizhou Bay, China.

In the southern coastal plain of Laizhou Bay, due to intensive exploitation of groundwater since the early 1970s, the shallow aquifer has been severely influenced by saltwater intrusion, which causes the extraction to shift from shallow to deeper aquifer changing the hydrogeological condition greatly. This study was conducted to investigate the groundwater salinization using hydrochemistry and H, O and Li isotope data. Dissolved Li shows a linear correlation with Cl and Br in seawater, brine and saline groundwater indicating the marine Li source, whereas the enrichment of Li in surface water, brackish and fresh groundwater is impacted by dissolution of silicate minerals. The analyses of hydrochemistry and isotopes (H, O and Li) indicate that brine originated from seawater evaporation, followed by mixing processes and some water-rock interactions; shallow saline groundwater originated from brine diluted with seawater and fresh groundwater; deep saline groundwater originated from seawater intrusion. The negative correlation of δ7Li and Li/Na in surface water, brackish and fresh groundwater is contrary to the general conclusion, indicating the slow weathering of silicate minerals and hydraulic interaction between surface water and shallow groundwater in this area. The analyses of hydrochemistry and isotopes (Li, H and O) can well identify the salinity sources and isotope fractionation in groundwater flow and mixing, especially groundwater with high TDS. As both mixing with saltwater and isotope fractionation can explain the combination of high δ7Li and low TDS in brackish groundwater, isotope fractionation may limit their use in recognizing salinity sources of groundwater with low TDS.

Primary Disruption of the Memory-Related Subsystems of the Default Mode Network in Alzheimer's Disease: Resting-State Functional Connectivity MRI Study.

Background: Recent studies have indicated that the default mode network (DMN) comprises at least three subsystems: The medial temporal lobe (MTL) and dorsal medial prefrontal cortex (DMPFC) subsystems and a core comprising the anterior MPFC (aMPFC) and posterior cingulate cortex (PCC). Additionally, the disruption of the DMN is related to Alzheimer's disease (AD). However, little is known regarding the changes in these subsystems in AD, a progressive disease characterized by memory impairment. Here, we performed a resting-state functional connectivity (FC) analysis to test our hypothesis that the memory-related MTL subsystem was predominantly disrupted in AD. Method: To reveal specific subsystem changes, we calculated the strength and number of FCS in the DMN intra- and inter-subsystems across individuals and compared the FC of the two groups. To further examine which pairs of brain regional functional connections contributed to the subsystem alterations, correlation coefficients between any two brain regions in the DMN were compared across groups. Additionally, to identify which regions made the strongest contributions to the subsystem changes, we calculated the regional FC strength (FCS), which was compared across groups. Results: For the intra-subsystem, decreased FC number and strength occurred in the MTL subsystem of AD patients but not in the DMPFC subsystem or core. For the inter-subsystems, the AD group showed decreased FCS and number between the MTL subsystem and PCC and a decreased number between the PCC and DMPFC subsystem. Decreased inter-regional FCS were found within the MTL subsystem in AD patients relative to controls: The posterior inferior parietal lobule (pIPL) showed decreased FC with the hippocampal formation (HF), parahippocampal cortex (PHC) and ventral MPFC (vMPFC). Decreased inter-regional FCS of the inter-subsystems were also found in AD patients: The HF and/or PHC showed decreased FC with dMPFC and TPJ, located in the DMPFC subsystem, and with PCC. AD patients also showed decreased FC between the PCC and TLC of the dMPFC subsystem. Furthermore, the HF and PHC in the MTL subsystem showed decreased regional FCS. Conclusion: Decreased intrinsic FC was mainly associated with the MTL subsystem of the AD group, suggesting that the MTL subsystem is predominantly disrupted.

Groundwater vulnerability assessment using the GALDIT model and the improved DRASTIC model: a case in Weibei Plain, China.

This study employed a modified DRASTIC model (AHP-DRASTIC model) and GALDIT model to evaluate the inherent vulnerability of shallow groundwater in Weibei Plain in Shandong Province of China and its vulnerability to seawater intrusion. The AHP-DRASTIC model uses the analytic hierarchy process (AHP) to determine the weight of each parameter and reduces the subjectivity of evaluation. The vulnerability map generated by the AHP-DRASTIC model shows four types of vulnerability: high (25.0%), higher (28.0%), moderate (29.7%), and low (17.3%), and the high-vulnerability areas are mainly distributed in the area north of Qingxiang Town and south of Changyi County. The distribution of high-vulnerability areas mainly related to the depth of groundwater table is 4-8 m, and the recharge of rainfall is 100-175 mm/year. The vulnerability map generated by the GALDIT model shows four types of vulnerability: high (33.5%), higher (23.4%), moderate (22.1%), and low (21.0%), and the high-vulnerability areas are mainly distributed in the coastal areas of Hanting District-Zhuli Town, the areas north of Linqu County, and the areas south of Shouguang County. The distribution of high-vulnerability areas mainly related to the distance between these areas and the coast is < 2.5 km, with aquifer thickness > 15 m. Total dissolved solid, NO3-, Cl-, and SO42- are used to verify the accuracy of the DRASTIC model, the AHP-DRASTIC model, and the GALDIT model. The results show that the AHP-DRASTIC model is more suitable for the assessment of inherent vulnerability of shallow groundwater in the study area than the DRASTIC model, and human activities have a major impact on the verification of vulnerability and should be considered when conducting groundwater vulnerability verification. The results of this study can provide grounds for groundwater management and protection and land use planning in the study area and provide new ideas for groundwater vulnerability assessment in coastal areas.

Author Correction: CRISPR interference-based specific and efficient gene inactivation in the brain.

In the version of this article initially published, the affiliation for Jian Zhang and Shuangli Mi was incomplete. In addition to the Key Laboratory of Genomics and Precision Medicine, they are also affiliated with the University of Chinese Academy of Sciences, Beijing, China. In Supplementary Fig. 1h,l, the molecular mass marker accompanying Snap25 was labeled 58 kDa; the correct value is 25 kDa. In Supplementary Fig. 9b,c, the top panel was labeled Syt1, with molecular mass markers ranging from 46 to 100 kDa; it is actually Snap25, with molecular mass markers ranging from 17 to 46 kDa. The errors have been corrected in the HTML and PDF versions of the article.

CRISPR interference-based specific and efficient gene inactivation in the brain.

CRISPR-Cas9 has been demonstrated to delete genes in postmitotic neurons. Compared to the establishment of proliferative cell lines or animal strains, it is more challenging to acquire a highly homogeneous consequence of gene editing in a stable neural network. Here we show that dCas9-based CRISPR interference (CRISPRi) can efficiently silence genes in neurons. Using a pseudotarget fishing strategy, we demonstrate that CRISPRi shows superior targeting specificity without detectable off-target activity. Furthermore, CRISPRi can achieve multiplex inactivation of genes fundamental for neurotransmitter release with high efficiency. By developing conditional CRISPRi tools targeting synaptotagmin I (Syt1), we modified the excitatory to inhibitory balance in the dentate gyrus of the mouse hippocampus and found that the dentate gyrus has distinct regulatory roles in learning and affective processes in mice. We therefore recommend CRISPRi as a useful tool for more rapid investigation of gene function in the mammalian brain.

Rapid non-genomic effects of glucocorticoids on oxidative stress in a guinea pig model of asthma.

BACKGROUND AND OBJECTIVE: Glucocorticoids (GC) may exert therapeutic effects in asthma by a rapid non-genomic mechanism. The lungs of asthmatic patients are exposed to oxidative stress, which is believed to be critical in the pathogenesis of asthma. The aim of this study was to investigate whether GC exert a rapid non-genomic effect on oxidative stress in asthmatic guinea pigs. METHODS: The guinea pig asthma model was used to assess inhibitory effects of budesonide (BUD) on oxidative stress. BAL fluid (BALF), trolox equivalent antioxidant capacity and lung manganese superoxide dismutase (MnSOD) activity were measured by spectrophotometry. Superoxide anion production was measured by cytochrome c reduction assay. RESULTS: Oxidative stress occurred within minutes following antigen challenge and BUD reduced the severity of oxidative stress in asthmatic guinea pigs within 15 min. BUD significantly decreased BALF trolox equivalent antioxidant capacity and lung MnSOD activity, as compared with those of vehicle-treated asthmatic guinea pigs (P < 0.05). Additionally, BUD rapidly inhibited in vitro superoxide anion production by BALF cells and bronchi harvested from sensitized animals. These rapid effects were not blocked by the GC receptor antagonist RU486 and/or the protein synthesis inhibitor cycloheximide. CONCLUSIONS: BUD reduced oxidative stress in a guinea pig model of asthma by a rapid non-genomic mechanism. These data suggest new mechanisms whereby GC treatments may benefit asthma.