Length-Dependent Transition from Extended to Folded Shapes in Short Oligomers of an Azetidine-Based α-Amino Acid: The Critical Role of NH···N H-Bonds.

Hydrogen bonds (H-bonds) are ubiquitous in peptides and proteins and are central to the stabilization of their structures. Inter-residue H-bonds between non-adjacent backbone amide NH and C=O motifs lead to the well-known secondary structures of helices, turns and sheets, but it is recognized that other H-bonding modes may be significant, including the weak intra-residue H-bond (called a C5 H-bond) that implicates the NH and C=O motifs of the same amino acid residue. Peptide model compounds that adopt stable C5 H-bonds are not readily available and the so-called 2.05-helix, formed by successive C5 H-bonds, is an elusive secondary structure. Using a combination of theoretical chemistry and spectroscopic studies in both the gas phase and solution phase, we have demonstrated that derivatives of 3-amino-1-methylazetidine-3-carboxylic acid, Aatc(Me) can form sidechain-backbone N-H···N C6γ H-bonds that accompany-and thereby stabilize-C5 H-bonds. In the capped trimer of Aatc(Me), extended C5/C6γ motifs are sufficiently robust to challenge classical 310-helix formation in solution and the fully-extended 2.05-helix conformer has been characterized in the gas phase. Concurrent H-bonding support for successive C5 motifs is a new axiom for stabilizing the extended backbone secondary structure in short peptides.

Modafinil attenuates inflammation via inhibiting Akt/NF-κB pathway in apoE-deficient mouse model of atherosclerosis.

Modafinil, an FDA approved wakefulness drug prescribed to narcolepsy patients, has recently been shown to have anti-inflammatory effects and provides protection against neuroinflammation. It is unknown if modafinil can also protect against atherosclerosis, pathogenesis of which implicates inflammation. Using an apoE-deficient mouse model, we tried to elucidate the effects of modafinil treatment on the development of atherosclerosis. We tested serum levels of cytokines. We isolated mouse bone marrow-derived macrophages (BMDMs), detected effect of modafinil on the viability and proliferation of BMDMs, and on oxidized low-density lipoprotein-induced IL-6 and TNF-α, and supernatant level of IFN-γ as well as NF-κB activity in BMDMs. Modafinil inhibited the development of atherosclerosis in apoE-/- mice. Modafinil suppressed the secretion of pro-inflammatory cytokines IL-6, TNF and IFN-γ, and promoted secretion of anti-inflammatory cytokines IL-4 and IL-10. Modafinil inhibited viability and proliferation of macrophages by negatively regulating levels of pro-inflammatory cytokines, p-Akt, p-IKBα and NF-κB activity in macrophages. Modafinil mitigates inflammation in apoE-/- atherosclerosis mice via inhibiting NF-κB activity in macrophages, and could potentially serve as a therapeutic agent for atherosclerosis.

[Effect of hydrogen-rich saline on cardiomyocyte autophagy during myocardial ischemia-reperfusion in aged rats].

OBJECTIVE: To investigate the effects of hydrogen-rich saline on cardiomyocyte autophagy during myocardial ischemia-reperfusion in aged rats. METHODS: One hundred and fifty healthy male Sprague Dawley rats, 18 months old, weighing 400-540 g were selected. The rats were then randomly divided into 5 groups (n = 30): Normal control group (group I); Sham operation group (group II); Myocardial ischemia-reperfusion group (group III); Hydrogen-rich saline group (group IV); Normal saline group (group V). No any processing in group I. In group II, the anterior descending branch was only exposed but not ligated. Myocardial I/R was induced by occlusion of anterior descending branch of left coronary artery for 30 min followed by 12 h and 24 h of reperfusion with Bimbaum. Hydrogen-rich saline 1 ml/100 g were injected intraperitoneally 5 min before reperfusion in group IV. Normal saline 1 ml/100 g were injected intraperitoneally 5 min before reperfusion in group V. The rats were sacrificed at 12 h and 24 h of reperfusion and hearts were removed. The pathological changes of myocardial tissue were detected by HE staining. The rate of cardiomyocyte autophagy were detected by the MDC fluorescent dye and flow cytometry instrument. The expression of AMPK, mTOR, Beclin1, LC3 in myocardial tissue was investigated by Western blot. RESULT: Compared with groups I and II, the rate of cardiomyocyte autophagy, the expression of AMPK, mTOR, Beclin1, LC3 in myocardial tissue were significantly increased at 12 h, 24 h in groups III, IV and V (F = 23.45, 26.65, 25.58; F = 23.16, 25.15, 27.85; F = 21.04, 24.83, 27.43; F = 22.15, 25.79, 29.05; F = 22.58, 27.25, 28.46), P < 0.05. Compared with group III and V, the rate of cardiomyocyte autophagy, the expression of AMPK, mTOR, Beclin1, LC3 were significantly decreased at 12 h, 24 h in group IV (F = 21.29, 24.71; F = 22.37, 25.84; F = 20.48, 22.38; F = 21.76, 28.43; F = 22.54, 27.21), P < 0.05. CONCLUSION: Hydrogen-rich saline can attenuate myocardial reperfusion injury through inhibiting cardiomyocyte autophagy. The mechanism may be associated with decreasing the expression of AMPK, mTOR, Beclin1, LC3 in myocardial tissue.

[Effects of hydrogen-rich saline on endoplasmic reticulum stress during myocardial ischemia-reperfusion in rats].

OBJECTIVE: To explore the effects of hydrogen-rich saline on endoplasmic reticulum stress during myocardial ischemia-reperfusion (I/R) in rats. METHODS: A total of 150 healthy male Sprague-Dawley rats were selected and then randomly divided into 5 groups of normal control (I), sham operation (II), myocardial ischemia-reperfusion (III), hydrogen-rich saline (IV) and normal saline (V) (n = 30 each). Group I had no treatment. In group II, anterior descending branch was merely exposed but not ligated. Myocardial I/R was induced by an occlusion of anterior descending branch of left coronary artery for 30 min followed by 12 h and 24 h of reperfusion with bimbaum. Hydrogen-rich saline 1 ml/100 g was injected intraperitoneally 5 min before reperfusion in group IV. Normal saline 1 ml/100 g was injected intraperitoneally 5 min before reperfusion in group V. The rats were sacrificed at 12 h and 24 h of reperfusion and heart tissues harvested. The pathological changes of myocardial tissue were detected by hematoxylin & eosin staining. The apoptotic cardiomyocytes of myocardial tissue were tested by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL). And the expressions of GRP78, Caspase-12, Bcl-2 and Bax in myocardial tissue were detected by Western blot. RESULTS: Compared with groups I and II, the numbers of apoptotic cardiomyocytes, the expression of GRP78, Caspase-12 and Bax in myocardial tissue significantly increased and the expression of Bcl-2 in myocardial tissue significantly decreased in groups III, IV and V. Compared with group III and V, the numbers of apoptotic cardiomyocytes, the expression of GRP78, Caspase-12 and Bax in myocardial tissue significantly decreased while the expression of Bcl-2 in myocardial tissue significantly increased in group IV. CONCLUSIONS: Hydrogen-rich saline may decrease cell apoptosis and attenuate myocardial reperfusion injury through inhibiting endoplasmic reticulum stress. The mechanism may be associated with decreasing the expression of GRP78, Caspase-12 and Bax and increasing the expression of Bcl-2 in myocardial tissue.

Influence of TMX2-CTNND1 polymorphism on cortical thickness in schizophrenia patients and unaffected siblings: an exploratory study based on target region sequencing.

OBJECTIVE: The advancement of neuroimaging and genetic research has revealed the presence of morphological abnormalities and numerous risk genes, along with their associations. We aimed to estimate magnetic resonance imaging-derived cortical thickness across multiple brain regions. METHODS: The cortical thickness of 129 schizophrenia patients, 42 of their unaffected siblings, and 112 healthy controls was measured and the candidate genes were sequenced. Comparisons were made of cortical thickness (including 68 regions of the Desikan-Killiany Atlas) and genetic variants (in 108 risk genes for schizophrenia) among the three groups, and correlation analyses were performed regarding cortical thickness, clinical symptoms, cognitive tests (such as the N-back task and the logical memory test), and genetic variants. RESULTS: Schizophrenia patients had significantly thinner bilateral frontal, temporal, and parietal gyri than healthy controls and unaffected siblings. Association analyses in target genes showed that four single nucleotide variants (SNVs) were significantly associated with schizophrenia, including thioredoxin-related transmembrane protein 2-catenin, cadherin-associated protein, delta 1 (SNV20673) (positive false discovery rate [PFDR] = 0.008) and centromere protein M (rs35542507, rs41277477, rs73165153) (PFDR = 0.030). Additionally, cortical thickness in the right pars triangularis was lower in carriers of the SNV20673 variant than in non-carriers (PFDR = 0.048). Finally, a positive correlation was found between right pars triangularis cortical thickness and logical memory in schizophrenia patients (r = 0.199, p = 0.032). CONCLUSIONS: This study identified regional morphological abnormalities in schizophrenia, including the right homologue of Broca's area, which was associated with a risk variant that affected delta-1 catenin and logical memory. These findings suggest a potential association between candidate gene loci, cortical thickness, and schizophrenia.

Effects of sulfoxide and sulfone sidechain-backbone hydrogen bonding on local conformations in peptide models.

We examine peptide model systems designed to probe short-range N-H⋯OS sidechain-backbone hydrogen bonding involving amino acid residues with sidechain sulfoxide or sulfone functional groups and its effects on local conformations. A strong 7-membered ring hydrogen bond of this type accompanies an intra-residue N-H⋯OC interaction and stabilizes an extended backbone conformation in preference to classical folded structures.

Polygenic risk for schizophrenia and the language network: Putative compensatory reorganization in unaffected siblings.

Language-related symptoms, such as disorganized, impoverished speech and communicative behaviors, are one of the core features of schizophrenia. These features most strongly correlate with cognitive deficits and polygenic risk among various symptom dimensions of schizophrenia. Nevertheless, unaffected siblings with genetic high-risk fail to show consistent deficits in language network (LN), indicating that either (1) polygenic risk has no notable effect on LN and/or (2) siblings show compensatory changes in opposing direction to patients. To answer this question, we related polygenic risk scores (PRS) to the region-level, tract-level, and systems-level structure (cortical thickness and fiber connectivity) of LN in 182 patients, 48 unaffected siblings and 135 healthy controls. We also studied the relationships between symptoms, language-related cognition, social functioning and LN structure. We observed a significantly lower thickness in LN (especially the Broca's, Wernicke's area and their right homologues) in patients. Siblings had a distinctly higher thickness in parts of the LN and a more pronounced small-world-like structural integration within the LN. Patients with reduced LN thickness had higher PRS, more disorganization and impoverished speech with lower language-related cognition and social functioning. We conclude that the genetic susceptibility and putative compensatory changes for schizophrenia operate, in part, via key regions in the Language Network.

Temporal Stability of Dynamic Default Mode Network Connectivity Negatively Correlates with Suicidality in Major Depressive Disorder.

Previous studies have demonstrated that the suicidality in patients with major depressive disorder (MDD) is related to abnormal brain functional connectivity (FC) patterns. However, little is known about its relationship with dynamic functional connectivity (dFC) based on the assumption that brain FCs fluctuate over time. Temporal stabilities of dFCs within the whole brain and nine key networks were compared between 52 MDD patients and 21 age, sex-matched healthy controls (HCs) using resting-state functional magnetic resonance imaging and temporal correlation coefficients. The alterations in MDD were further correlated with the scores of suicidality item in the Hamilton Rating Scale for Depression (HAMD). Compared with HCs, the MDD patients showed a decreased temporal stability of dFC as indicated by a significantly decreased temporal correlation coefficient at the global level, as well as within the default mode network (DMN) and subcortical network. In addition, temporal correlation coefficients of the DMN were found to be significantly negatively correlated with the HAMD suicidality item scores in MDD patients. These results suggest that MDD may be characterized by excessive temporal fluctuations of dFCs within the DMN and subcortical network, and that decreased stability of DMN connectivity may be particularly associated with the suicidality in MDD.

Problematic smartphone use is associated with differences in static and dynamic brain functional connectivity in young adults.

Introduction: This study aimed to investigate the possible associations between problematic smartphone use and brain functions in terms of both static and dynamic functional connectivity patterns. Materials and methods: Resting-state functional magnetic resonance imaging data were scanned from 53 young healthy adults, all of whom completed the Short Version of the Smartphone Addiction Scale (SAS-SV) to assess their problematic smartphone use severity. Both static and dynamic functional brain network measures were evaluated for each participant. The brain network measures were correlated the SAS-SV scores, and compared between participants with and without a problematic smartphone use after adjusting for sex, age, education, and head motion. Results: Two participants were excluded because of excessive head motion, and 56.9% (29/51) of the final analyzed participants were found to have a problematic smartphone use (SAS-SV scores ≥ 31 for males and ≥ 33 for females, as proposed in prior research). At the global network level, the SAS-SV score was found to be significantly positively correlated with the global efficiency and local efficiency of static brain networks, and negatively correlated with the temporal variability using the dynamic brain network model. Large-scale subnetwork analyses indicated that a higher SAS-SV score was significantly associated with higher strengths of static functional connectivity within the frontoparietal and cinguloopercular subnetworks, as well as a lower temporal variability of dynamic functional connectivity patterns within the attention subnetwork. However, no significant differences were found when directly comparing between the groups of participants with and without a problematic smartphone use. Conclusion: Our results suggested that problematic smartphone use is associated with differences in both the static and dynamic brain network organizations in young adults. These findings may help to identify at-risk population for smartphone addiction and guide targeted interventions for further research. Nevertheless, it might be necessary to confirm our findings in a larger sample, and to investigate if a more applicable SAS-SV cutoff point is required for defining problematic smartphone use in young Chinese adults nowadays.

Changes in brain network properties in major depressive disorder following electroconvulsive therapy: a combined static and dynamic functional magnetic resonance imaging study.

BACKGROUND: Major depressive disorder (MDD) is a common and intractable mood disorder. Electroconvulsive therapy (ECT) is a common means of brain electrical stimulation for the treatment of MDD, but the neurobiological mechanism of its clinical symptom relief effect is still to be explored. This study aims to explore how ECT plays a role in depression remissions by investigating the changes of static and dynamic brain network characteristics in MDD patients before and after ECT. METHODS: Resting-state functional magnetic resonance imaging (fMRI) scans were obtained from nine MDD patients twice before and after a full course of ECT, all of whom responded to ECT as defined by at least a 50% reduction from baseline Hamilton Depression Scale (HAMD) scores. Both static and dynamic characteristics of the functional brain network were compared between the pre- and post-ECT scans for all participants, and the correlations between changes in clinical symptoms and altered network metrics were also investigated. RESULTS: The clustering coefficient and local efficiency in static brain networks were increased significantly, while the global flexibility of dynamic brain networks was decreased significantly after ECT. Several regions of interest (ROIs) that changed significantly at the local level were also identified, which involved regions of the cerebellum, hippocampus as well as frontal and temporal cortices. Although not significant, the decrease of HAMD scores were associated with trends of changed network metrics after ECT. CONCLUSIONS: Our results suggest that ECT may alleviate the depressive symptoms of MDD by decreasing the randomness of the brain network as reflected by changes in both static and dynamic network properties and that the temporal gyrus, frontal gyrus, hippocampus, and cerebellar regions may play key roles in such mechanisms. These findings have important implications for our understandings of ECT and depression. However, this study is limited by a relatively small sample size and the results should be confirmed in larger samples.

Role of Strain-Induced Microscale Compositional Pulling on Optical Properties of High Al Content AlGaN Quantum Wells for Deep-Ultraviolet LED.

A systematic study was carried out for strain-induced microscale compositional pulling effect on the structural and optical properties of high Al content AlGaN multiple quantum wells (MQWs). Investigations reveal that a large tensile strain is introduced during the epitaxial growth of AlGaN MQWs, due to the grain boundary formation, coalescence and growth. The presence of this tensile strain results in the microscale inhomogeneous compositional pulling and Ga segregation, which is further confirmed by the lower formation enthalpy of Ga atom than Al atom on AlGaN slab using first principle simulations. The strain-induced microscale compositional pulling leads to an asymmetrical feature of emission spectra and local variation in emission energy of AlGaN MQWs. Because of a stronger three-dimensional carrier localization, the area of Ga segregation shows a higher emission efficiency compared with the intrinsic area of MQWs, which is benefit for fabricating efficient AlGaN-based deep-ultraviolet light-emitting diode.

Sex difference in the prevalence of psychotic-like experiences in adolescents: results from a pooled study of 21,248 Chinese participants.

Psychotic-like experiences (PLEs) are subclinical psychotic symptoms in the general population which are linked to increased risks for later psychiatric disorders. Male and female adolescents were reported to experience PLEs differently, but the results were mixed in previous studies. This study aimed to investigate possible sex differences in the prevalence of adolescent PLEs using a large pooled sample. A total of 21,248 Chinese adolescents aged 11 to 19 years were included, which were drawn from five separate cross-sectional surveys undertaken between 2015 to 2021 in China. PLEs were measured by the 8-item Community Assessment of Psychic Experiences. Using binary logistic regression analyses, no significant sex differences were found in the overall prevalence of PLEs after controlling for age and dataset effects. As for specific PLE subtypes, however, being female was associated with a higher prevalence of delusion of reference and a lower prevalence of visual hallucinations. Furthermore, post-hoc subgroup analyses showed that the sex differences in visual hallucinations persist across both early (<= 14 years old) and late (> 14 years old) adolescence, while differences in the delusion of reference were significant in only early adolescence. These findings may help us to further understand the biological basis of PLEs.

Acute Effect of Betel Quid Chewing on Brain Network Dynamics: A Resting-State Functional Magnetic Resonance Imaging Study.

Betel quid (BQ) is one of the most popular addictive substances in the world. However, the neurophysiological mechanism underlying BQ addiction remains unclear. This study aimed to investigate whether and how BQ chewing would affect brain function in the framework of a dynamic brain network model. Resting-state functional magnetic resonance imaging scans were collected from 24 male BQ-dependent individuals and 26 male non-addictive healthy individuals before and promptly after chewing BQ. Switching rate, a measure of temporal stability of functional brain networks, was calculated at both global and local levels for each scan. The results showed that BQ-dependent and healthy groups did not significantly differ on switching rate before BQ chewing (F = 0.784, p = 0.381, analysis of covariance controlling for age, education, and head motion). After chewing BQ, both BQ-dependent (t = 2.674, p = 0.014, paired t-test) and healthy (t = 2.313, p = 0.029, paired t-test) individuals showed a significantly increased global switching rate compared to those before chewing BQ. Significant corresponding local-level effects were observed within the occipital areas for both groups, and within the cingulo-opercular, fronto-parietal, and cerebellum regions for BQ-dependent individuals. Moreover, in BQ-dependent individuals, switching rate was significantly correlated with the severity of BQ addiction assessed by the Betel Quid Dependence Scale scores (Spearman's rho = 0.471, p = 0.020) before BQ chewing. Our study provides preliminary evidence for the acute effects of BQ chewing on brain functional dynamism. These findings may provide insights into the neural mechanisms of substance addictions.

Age-Related Decrease in Default-Mode Network Functional Connectivity Is Accelerated in Patients With Major Depressive Disorder.

Major depressive disorder (MDD) is a common psychiatric disorder which is associated with an accelerated biological aging. However, little is known whether such process would be reflected by a more rapid aging of the brain function. In this study, we tested the hypothesis that MDD would be characterized by accelerated aging of the brain's default-mode network (DMN) functions. Resting-state functional magnetic resonance imaging data of 971 MDD patients and 902 healthy controls (HCs) was analyzed, which was drawn from a publicly accessible, multicenter dataset in China. Strength of functional connectivity (FC) and temporal variability of dynamic functional connectivity (dFC) within the DMN were calculated. Age-related effects on FC/dFC were estimated by linear regression models with age, diagnosis, and diagnosis-by-age interaction as variables of interest, controlling for sex, education, site, and head motion effects. The regression models revealed (1) a significant main effect of age in the predictions of both FC strength and dFC variability; and (2) a significant main effect of diagnosis and a significant diagnosis-by-age interaction in the prediction of FC strength, which was driven by stronger negative correlation between age and FC strength in MDD patients. Our results suggest that (1) both healthy participants and MDD patients experience decrease in DMN FC strength and increase in DMN dFC variability along age; and (2) age-related decrease in DMN FC strength may occur at a faster rate in MDD patients than in HCs. However, further longitudinal studies are still needed to understand the causation between MDD and accelerated aging of brain.

Influence of TMX2-CTNND1 polymorphism on cortical thickness in schizophrenia patients and unaffected siblings: an exploratory study based on target region sequencing

Objective: The advancement of neuroimaging and genetic research has revealed the presence of morphological abnormalities and numerous risk genes, along with their associations. We aimed to estimate magnetic resonance imaging-derived cortical thickness across multiple brain regions. Methods: The cortical thickness of 129 schizophrenia patients, 42 of their unaffected siblings, and 112 healthy controls was measured and the candidate genes were sequenced. Comparisons were made of cortical thickness (including 68 regions of the Desikan-Killiany Atlas) and genetic variants (in 108 risk genes for schizophrenia) among the three groups, and correlation analyses were performed regarding cortical thickness, clinical symptoms, cognitive tests (such as the N-back task and the logical memory test), and genetic variants. Results: Schizophrenia patients had significantly thinner bilateral frontal, temporal, and parietal gyri than healthy controls and unaffected siblings. Association analyses in target genes showed that four single nucleotide variants (SNVs) were significantly associated with schizophrenia, including thioredoxin-related transmembrane protein 2-catenin, cadherin-associated protein, delta 1 (SNV20673) (positive false discovery rate [PFDR] = 0.008) and centromere protein M (rs35542507, rs41277477, rs73165153) (PFDR = 0.030). Additionally, cortical thickness in the right pars triangularis was lower in carriers of the SNV20673 variant than in non-carriers (PFDR = 0.048). Finally, a positive correlation was found between right pars triangularis cortical thickness and logical memory in schizophrenia patients (r = 0.199, p = 0.032). Conclusions: This study identified regional morphological abnormalities in schizophrenia, including the right homologue of Broca's area, which was associated with a risk variant that affected delta-1 catenin and logical memory. These findings suggest a potential association between candidate gene loci, cortical thickness, and schizophrenia.

TNFα-induced downregulation of microRNA-186 contributes to apoptosis in rat primary cardiomyocytes.

Progressive loss of cardiac cardiomyocytes is involved in pathogenesis of heart failure. Inflammation is considered as a major risk factor that triggers cardiomyocytes apoptosis or induces cellular damage. Proinflammatory cytokines such as TNFα can directly activate cell apoptosis or promote oxidant production that damages cellular structure eventually. We investigated TNFα mediated apoptosis in cultured rat primary cardiomyocytes. Annexin V/PI staining and apoptosis biomarker expression were used to examine cardiomyocytes cell apoptosis response. We also identified key microRNA that plays a regulatory role in this pathway with genetic and biochemical approaches. Apoptosis Inducing Factor (AIF) expression was found to be upregulated with 10µg/ml or 50µg/ml TNFα stimulation for 24h, which was associated with apoptotic index. Subsequently, miR-186 was identified as direct regulator of AIF in TNFα mediated cardiomyocytes apoptosis from microRNA expression profiling. miR-186 level was downregulated with TNFα treatment that was correlated with AIF induction. Last, in the rescue experiment, miR-186 mimic protected cardiomyocytes against TNFα mediated apoptosis. Collectively, the results suggest TNFα-induced AIF upregulation contributes to apoptosis in rat primary cardiomyocytes through regulating miR-186 expression, which implies miR-186 could be a potential therapeutic target for preventing inflammation associated cardiac damage.

High density GaN/AlN quantum dots for deep UV LED with high quantum efficiency and temperature stability.

High internal efficiency and high temperature stability ultraviolet (UV) light-emitting diodes (LEDs) at 308 nm were achieved using high density (2.5 × 10(9) cm(-2)) GaN/AlN quantum dots (QDs) grown by MOVPE. Photoluminescence shows the characteristic behaviors of QDs: nearly constant linewidth and emission energy, and linear dependence of the intensity with varying excitation power. More significantly, the radiative recombination was found to dominant from 15 to 300 K, with a high internal quantum efficiency of 62% even at room temperature.