A connectome-wide association study of altered functional connectivity in schizophrenia based on resting-state fMRI.

BACKGROUND: Aberrant resting-state functional connectivity is a neuropathological feature of schizophrenia (SCZ). Prior investigations into functional connectivity abnormalities have primarily employed seed-based connectivity analysis, necessitating predefined seed locations. To address this limitation, a data-driven multivariate method known as connectome-wide association study (CWAS) has been proposed for exploring whole-brain functional connectivity. METHODS: We conducted a CWAS analysis involving 46 patients with SCZ and 40 age- and sex-matched healthy controls. Multivariate distance matrix regression (MDMR) was utilized to identify key nodes in the brain. Subsequently, we conducted a follow-up seed-based connectivity analysis to elucidate specific connectivity patterns between regions of interest (ROIs). Additionally, we explored the spatial correlation between changes in functional connectivity and underlying molecular architectures by examining correlations between neurotransmitter/transporter distribution densities and functional connectivity. RESULTS: MDMR revealed the right medial frontal gyrus and the left calcarine sulcus as two key nodes. Follow-up analysis unveiled hypoconnectivity between the right medial frontal superior gyrus and the right fusiform gyrus, as well as hypoconnectivity between the left calcarine sulcus and the right lingual gyrus in SCZ. Notably, a significant association between functional connectivity strength and positive symptom severity was identified. Furthermore, altered functional connectivity patterns suggested potential dysfunctions in the dopamine, serotonin, and gamma-aminobutyric acid systems. CONCLUSIONS: This study elucidated reduced functional connectivity both within and between the medial frontal regions and the occipital cortex in patients with SCZ. Moreover, it indicated potential alterations in molecular architecture, thereby expanding current knowledge regarding neurobiological changes associated with SCZ.

Acute stress impairs intentional memory suppression through aberrant prefrontal cortex activation in high trait ruminators.

Objective: Research shows that the effect of acute stress on intentional memory suppression could be modulated by individual differences in psychological traits. However, whether acute stress distinctly affects intentional memory suppression in high trait ruminators, a high at-risk group of stress-related disorders, and the neural correlations, remains unclear. Method: 55 healthy college students were divided into high and low trait ruminators (HTR and LTR), Following stress manipulation, a Think/No Think task assessed the memory suppression performance. Functional near-infrared spectroscopy was applied to explore the neural correlates. Psychophysiological interaction analyses were used to assess how the functional connectivity between a seed region and another brain region was modulated by tasks during memory suppression, further mediating memory suppression performance and state rumination. Results: The HTR exhibited poorer memory suppression performance than the LTR under the stress condition. Aberrant activation patterns and task-modulated functional connectivity in the dorsal prefrontal cortex (DLPFC) and superior temporal gyrus (STG) were observed only in the HTR during memory suppression under the stress condition. The effect of memory suppression performance on the state rumination of individuals was significantly mediated by the task-modulated functional connectivity between the DLPFC and STG. Conclusions: The findings could provide insights for prevention or early intervention in the development of stress-related disorders in HTR.

Aberrant positive affect dynamics in individuals with subthreshold depression: Evidence from laboratory and real-world assessments / Dinámica aberrante del afecto positivo en individuos con depresión subumbral: evidencia de evaluaciones de laboratorio y del mundo real

Background/Objective: Reduced positive affect (PA) is a core feature of major depressive disorder (MDD). However, the precursor of MDD, subthreshold depression (StD), has received less attention in this regard. Therefore, we examined PA dynamics in StD, integrating laboratory-based and ecological momentary assessment (EMA) approaches. Method: Participants were college students recruited from Chinese universities (31 with StD, and 39 healthy controls (HC)). Positive mood was induced in the laboratory by an eight-minute comedy clip used to assess PA reactivity and maintenance. To extend findings to the real world and explore mechanisms of PA maintenance, 53 participants with StD and 64 HC reported their emotional states 14 times daily for one week via EMA. Multilevel models were used to test for predictors of PA inertia. Results: In the laboratory, participants with StD achieved the same PA reactivity as HC when facing positive stimuli, yet the curve-fitting revealed difficulties for the StD group in maintaining PA over time. Such reduced capacity was further observed in real-world settings, manifesting in significantly greater PA inertia. Conclusions: High PA inertia in daily life may reflect resistance to mood change in StD, explaining anhedonia and difficulties with emotional maintenance, and highlighting the need for early identification.(AU)

Age-related positive emotional reactivity decline associated with the anterior insula based resting-state functional connectivity.

Recent studies have suggested that emotional reactivity changes with age, but the neural basis is still unclear. The insula may be critical for the emotional reactivity. The current study examined how ageing affects emotional reactivity using the emotional reactivity task data from a human sample (Cambridge Center for Age and Neuroscience, N = 243, age 18-88 years). The resting-state magnetic resonance measurements from the same sample were used to investigate the potential mechanisms of the insula. In the initial analysis, we conducted partial correlation assessments to examine the associations between emotional reactivity and age, as well as between the gray matter volume (GMV) of the insula and age. Our results revealed that emotional reactivity, especially positive emotional reactivity, decreased with age and that the GMV of the insula was negatively correlated with age. Subsequently, the bilateral insula was divided into six subregions to calculate the whole brain resting-state functional connectivity (rsFC). The mediating effect of the rsFC on age and emotional reactivity was then calculated. The results showed that the rsFC of the left anterior insula (AI) with the right hippocampus, and the rsFCs of the right AI with the striatum and the thalamus were mediated the relationship between positive emotional reactivity and age. Our findings suggest that attenuating emotional reactivity with age may be a strategic adaptation fostering emotional stability and diminishing emotional vulnerability. Meanwhile, the findings implicate a key role for the AI in the changes in positive emotional reactivity with age.

Aberrant positive affect dynamics in individuals with subthreshold depression: Evidence from laboratory and real-world assessments.

Background/Objective: Reduced positive affect (PA) is a core feature of major depressive disorder (MDD). However, the precursor of MDD, subthreshold depression (StD), has received less attention in this regard. Therefore, we examined PA dynamics in StD, integrating laboratory-based and ecological momentary assessment (EMA) approaches. Method: Participants were college students recruited from Chinese universities (31 with StD, and 39 healthy controls (HC)). Positive mood was induced in the laboratory by an eight-minute comedy clip used to assess PA reactivity and maintenance. To extend findings to the real world and explore mechanisms of PA maintenance, 53 participants with StD and 64 HC reported their emotional states 14 times daily for one week via EMA. Multilevel models were used to test for predictors of PA inertia. Results: In the laboratory, participants with StD achieved the same PA reactivity as HC when facing positive stimuli, yet the curve-fitting revealed difficulties for the StD group in maintaining PA over time. Such reduced capacity was further observed in real-world settings, manifesting in significantly greater PA inertia. Conclusions: High PA inertia in daily life may reflect resistance to mood change in StD, explaining anhedonia and difficulties with emotional maintenance, and highlighting the need for early identification.

Global-brain functional connectivity related with trait anxiety and its association with neurotransmitters and gene expression profiles.

BACKGROUND: Numerous studies have explored the neural correlates of trait anxiety, a predisposing factor for several stress-related disorders. However, the findings from previous studies are inconsistent, which might be due to the limited regions of interest (ROI). A recent approach, named global-brain functional connectivity (GBC), has been demonstrated to address the shortcomings of ROI-based analysis. Furthermore, research on the transcriptome-connectome association has provided an approach to link the microlevel transcriptome profile with the macroscale brain network. In this paper, we aim to explore the neurobiology of trait anxiety with an imaging transcriptomic approach using GBC, biological neurotransmitters, and transcriptome profiles. METHODS: Using a sample of resting-state fMRI data, we investigated trait anxiety-related alteration in GBC. We further used behavioral analysis, spatial correlation analysis, and postmortem gene expression to separately assess the cognitive functions, neurotransmitters, and transcriptional profiles related to alteration in GBC in individuals with trait anxiety. RESULTS: GBC values in the ventromedial prefrontal cortex and the precuneus were negatively correlated with levels of trait anxiety. This alteration was correlated with behavioral terms including social cognition, emotion, and memory. A strong association was revealed between trait anxiety-related alteration in GBC and neurotransmitters, including dopaminergic, serotonergic, GABAergic, and glutamatergic systems in the ventromedial prefrontal cortex and the precuneus. The transcriptional profiles explained the functional connectivity, with correlated genes enriched in transmembrane signaling. LIMITATIONS: Several limitations should be taken into account in this research. For example, future research should consider using some different approaches based on dynamic or task-based functional connectivity analysis, include more neurotransmitter receptors, additional gene expression data from different samples or more genes related to other stress-related disorders. Meanwhile, it is of great significance to include a larger sample size of individuals with a diagnosis of major depression disorder or other disorders for analysis and comparison and apply stricter multiple-comparison correction and threshold settings in future research. CONCLUSIONS: Our research employed multimodal data to investigate GBC in the context of trait anxiety and to establish its associations with neurotransmitters and transcriptome profiles. This approach may improve understanding of the neural mechanism, together with the biological and molecular genetic foundations of GBC in trait anxiety.

Natural Sunlight Photocatalytic Synthesis of Benzoxazole-Bridged Covalent Organic Framework for Photocatalysis.

Although natural sunlight-mediated photocatalysis is a clean, efficient, and green approach to access organic products, its application in the synthesis of covalent organic frameworks (COFs), however, is still unprecedented. Herein, we first report the sunlight photocatalytic synthesis of COF under ambient conditions. Furthermore, this "window ledge" reaction generated benzoxazole-linked COF is stable and can be applied as a reusable photocatalyst to highly promote visible-light-driven aerobic oxidation of sulfides to sulfoxides. These results not only enrich the COF synthetic methodology but also open a new route to access COFs in a green and sustainable way.

Ceruloplasmin Deficiency Impaired Brain Iron Metabolism and Behavior in Mice.

Iron accumulation is an important cause of various brain diseases. As a ferroxidase, ceruloplasmin (Cp) plays a key role in iron homeostasis and its abnormal activity leads to iron accumulation. However, the detailed biological function of Cp in brain iron homeostasis needs to be investigated. In this study, Cp knockout mice were prepared and the changes in iron content and protein expression related to iron metabolism were detected. The results showed that iron accumulation occurred in multiple tissues and organs of Cp knockout mice, but there was no obvious change in brain tissues. However, Cp deficiency affected the expression of many iron metabolism-related proteins in midbrain, such as DMT1+IRE, heavy chain ferritin (H-ferritin) and light chain ferritin (L-ferritin). Cp deficiency also impaired the behavioral ability of mice, including weakened exercise ability and reduced motor coordination. In vitro cell experiment indicated that the sensitivity of Cp knockout neuron and astrocyte to hypoxia was higher than that of wild type, which means Cp deficiency leads to the damage of cell self-protection. All these results confirm that Cp exerts a protective effect on the brain by regulating iron metabolism.

Anti-Adhesive, Platelet Gathering Effects of c-RGD Modified Poly(p-dioxanone-co-l-Phe) Electrospun Membrane and Its Comprehensive Application in Intestinal Anastomosis.

Intestinal resection and anastomosis are performed in over a million people with various bowel diseases annually. Excessive fibrosis and anastomotic site leakage are the main complications of anastomosis surgery, despite great improvements in operative technique and equipment in recent years. In this study, cRGD modified poly(p-dioxanone-co-l-Phe) (PDPA) membranes are designed and applied in intestinal anastomosis to simultaneously solve the two aforementioned complications. cRGD is modified onto PDPA membranes through both physical absorption and π-π accumulation between d-Phe of cRGD and l-Phe of PDPA. Although cRGD modification enhanced the biocompatibility of PDPA membranes, cRGD modified PDPA membrane suppresses fibroblast proliferation both in vitro and in vivo as a result of degradation and subsequent release of fibroblast suppressive l-Phe from PDPA. Meanwhile, platelets are entrapped by cRGD modified PDPA membranes through the specific binding of cRGD and platelet GPIIbIIIa . cRGD modified PDPA membranes are applied in rat intestinal anastomosis, and both adhesion and stenosis are successfully prevented at anastomotic sites. At the same time, bursting pressure, which represents healing intensity at anastomotic sites, is promoted. The gathering and activation of platelets on PDPA membranes induce secretion of autologous PDGF and VEGF to facilitate angiogenesis and subsequent healing of anastomotic sites.

PLGA/PLCA casting and PLGA/PDPA electrospinning bilayer film for prevention of postoperative adhesion.

Postoperative adhesion is a common complication and preventing adhesions during or immediately after operation is particularly important. The application of solid barrier materials represents the most successful clinical strategy to prevent postoperative adhesion. However, a simple physical barrier effect might be insufficient in preventing adhesion satisfactorily. Multilayered structures can be designed with an outer layer as the barrier and an inner layer to respond to relative drug release. In this article, bilayer film composed of a PLGA/PLCA casting layer as barrier and PLGA/PDPA electrospinning layer to respond to the release of anti-fibrosis drug l-Phe was designed and synthesized. The adhesion prevention effect of the above PLGA/PLCA/PDPA bilayer film was examined and compared with single PLGA/PLCA casting film and single PLGA/PDPA electrospinning film by applying rabbit sidewall defect-cecum abrasion model. As demonstrated by histological observation and immunohistochemical analysis, the bilayer film was the most effective of the three films in postoperative adhesion prevention in terms of both physical barrier effect and anti-fibrosis effect of the PDPA macromolecular prodrug. Besides anti-fibrosis effect, PDPA could also suppress excess proliferation of vascular endothelial cells and microvessel caused by long-term stimulation of implantation materials to the surrounding tissues. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B: 2030-2039, 2019.

The in vivo anti-fibrotic function of calcium sensitive receptor (CaSR) modulating poly(p-dioxanone-co-l-phenylalanine) prodrug.

In present study, the apoptosis induction and proliferation suppression effects of l-phenylalanine (l-Phe) on fibroblasts were confirmed. The action sites of l-Phe on fibroblasts suppression were deduced to be calcium sensitive receptor (CaSR) which could cause the release of endoplasmic reticulum (ER) Ca2+ stores; disruption of intracellular Ca2+ homeostasis triggers cell apoptosis via the ER or mitochondrial pathways. The down-regulation of CaSR were observed after the application of l-Phe, and the results those l-Phe triggered the increasing of intracellular Ca2+ concentration and calcineurin expression, and then the apoptosis and increasing G1 fraction of fibroblasts have verified our deduction. Hence, l-Phe could be seen as a kind of anti-fibrotic drugs for the crucial participation of fibroblast in the occurrence of fibrosis. And then, poly(p-dioxanone-co-l-phenylalanine) (PDPA) which could prolong the in-vivo anti-fibrotic effect of l-Phe for the sustained release of l-Phe during its degradation could be treated as anti-fibrotic polymer prodrugs. Based on the above, the in vivo anti-fibrotic function of PDPA was evaluated in rabbit ear scarring, rat peritoneum lipopolysaccharide, and rat sidewall defect/cecum abrasion models. PDPA reduced skin scarring and suppressed peritoneal fibrosis and post operation adhesion as well as secretion of transforming growth factor-ß1 in injured tissue. These results indicate that PDPA is an effective agent for preventing fibrosis following tissue injury. STATEMENT OF SIGNIFICANCE: We have previously demonstrated that poly(p-dioxanone-co-l-phenylalanine) (PDPA) could induce apoptosis to fibroblast and deduced that the inhibitory effect comes from l-phenylalanine. In present study, the inhibition mechanism of l-phenylalanine on fibroblast proliferation was demonstrated. The calcium sensitive receptor (CaSR) was found to be the action site. The CaSR was downregulated after the application of l-phenylalanine, and then the ER Ca2+ stores were released. The released Ca2+ can simultaneously activate Ca2+/calcineurin and then trigger apoptosis and G1 arrest of fibroblast. Hence, l-phenylalanine could be seen as anti-fibrosis drug and PDPA which conjugate l-phenylalanine by hydrolytic covalent bonds could be seen as l-phenylalanine polymer prodrug. Based above, the in vivo anti-fibrotic function of PDPA were verified in three different animal models.

pH and Glucose Dual-Responsive Injectable Hydrogels with Insulin and Fibroblasts as Bioactive Dressings for Diabetic Wound Healing.

pH and glucose dual-responsive injectable hydrogels were prepared through the cross-linking of Schiff's base and phenylboronate ester using phenylboronic-modified chitosan, poly(vinyl alcohol) and benzaldehyde-capped poly(ethylene glycol). Protein drugs and live cells could be incorporated into the hydrogels during the in situ cross-linking, displaying sustained and pH/glucose-triggered drug release from the hydrogels and cell viability and proliferation in the three-dimensional hydrogel matrix as well. Hence, the hydrogels with insulin and fibroblasts were considered as bioactive dressings for diabetic wound healing. A streptozotocin-induced diabetic rat model was used to evaluate the efficacy of hydrogel dressings in wound repair. The results revealed that the incorporation of insulin and L929 in the hydrogels could promote neovascularization and collagen deposition and enhance the wound-healing process of diabetic wounds. Thus, the drug- and cell-loaded hydrogels have promising potential in wound healing as a medicated system for various therapeutic proteins and live cells.

In vitro and in vivo degradation of potential anti-adhesion materials: Electrospun membranes of poly(ester-amide) based on l-phenylalanine and p-(dioxanone).

Electrospun membranes of poly(p-dioxanone-co-l-phenylalanine) (PDPA) hold potential as an anti-adhesion material. Since adjustable degradation properties are important for anti-adhesion materials, in this study, the in vitro and in vivo degradation processes of PDPA electrospun membranes were investigated in detail. The morphological analysis of these membranes revealed the main degradation conditions of PDPA membranes. The weight remaining and molecular weight variation showed that the overall degradation rate of the membranes could be adjusted by modulating the molecular structure of the PDPAs. Especially, α-chymotrypsin could catalyze the degradation process of PDPAs. Based on these results, the in vitro degradation mechanism was demonstrated, and confirmed by 1 H NMR of the hydrolysis products. Finally, the in vivo degradation and biocompatibility of different PDPAs were investigated. The kinetic study showed that the in vitro and in vivo molecular weight loss of PDPAs have the first-order characteristics. The in vivo degradation rate of the most Phe-containing PDPA-3 is the slowest, and this result relates to the biocompatibilities of PDPAs. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 1369-1378, 2017.

[Effect of 3-n-butylphthalide pretreatment on expression of the HSP70 after brain ischemia/reperfusion].

OBJECTIVE: To explore the effect of 3-n-butylphthalide pretreatment on the delayed neuronal death(DND) and the expreesion of heat shock protein70 (HSP70) in rat hippocampus after ischemia/ reperfusion. METHODS: All rats were randomly divided into sham group (n = 36), total cerebral ischemia (TCI) group (n = 36), butylphthalide (NBP) group (n = 6), NBP + TCI group( n = 36), quercetin + NBP + TCI group (n = 6), dimethyl sulfoxide (DMSO) + NBP + TCI group (n = 6). The model of total cerebral ischemia/reperfusion was established by blocking vertebral arteries and carotid arteries. In sham group, TCI group and NBP group, the animals were further divided into instantly, 6 h, 12 h, 1 d, 3 d, 5 d groups according to the time interval after sham operation or TCI. Histological changes of the hippocampus were evaluated using thionin staining under light microscope by determining the delayed neuronal death (DND) and the expression of HSP70 was assayed using immunohistochemistry. RESULTS: NBP pretreatment could reduce delayed neuronal death in CA1 of hippocampus induced by TCI-reperfusion injury in rats, and up-regulated the expression of HSP70 in CA1 hippocampus of brain ischemic/reperfusion for 5 days. Quercetin blocked the acquirement of the brain ischemic tolerance induced by NBP preconditioning. CONCLUSION: 3-n-butylphthalide (NBP) prevents the neurons from ischemia/reperfusion injury through upregulating the expression of HSP70.

Alteration of transcriptional profile in human bronchial epithelial cells induced by cigarette smoke condensate.

Despite the significance of cigarette smoke for carcinogenesis, the molecular mechanisms that lead to increased susceptibility of human cancers are not well-understood. In our present study, the oncogenic transforming effects of cigarette smoke condensate (CSC) were examined using papillomavirus-immortalized human bronchial epithelial cells (BEP2D). Growth kinetics, saturation density, resistance to serum-induced terminal differentiation, anchorage-independent growth and tumorigenicity in nude mice were used to investigate the various stages of transformation in BEP2D cells. Illumina microarray platforms were used to explore the CSC-induced alteration of global mRNA expression profiles of the earlier period and the advanced stage of CSC-treated BEP2D cells. We showed here that a series of sequential steps arose among CSC-treated immortalized human bronchial epithelial cells, including altered growth kinetics, resistance to serum-induced terminal differentiation, and anchorage-independence growth. In the earlier period of CSC treatment, 265 genes were down-regulated and 63 genes were up-regulated, respectively, and in the advanced stage of CSC treatment, 313 genes were down-regulated and 145 genes were up-regulated, respectively. Notably, among those genes, the expression of some of imprinted genes such as IGF2, NDN, H19 and MEG3 were all silenced or down-regulated in CSC-treated cells. These genes reactivated after 5 microM 5-aza-2-deoxycytidine (5-aza-dC) treatment. These results demonstrated that long-term treatment of human bronchial epithelial cells with CSC may adversely affect their genetic and epigenetic integrity and lead to further transformation.