A two-step method of cyclolinopeptide (linusorb) preparation from flaxseed cake via dry-screening.

Linusorbs (LO), cyclolinopeptides, are a group of cyclic hydrophobic peptides and considered a valuable by-product of flaxseed oil due to numerous health benefits. Currently applied acetone or methanol extraction could contaminate the feedstocks for further food-grade application. Using flaxseed cake as feedstock, this study established a practical method for preparing LO from pressed cake. Firstly, LO composition of 15 flaxseed cultivars was analyzed. Next, cold-pressed cake was milled and screened mechanically. The kernel and hull fractions were separated based on the disparity of their mechanical strength. Monitored by hyperspectral fluorescence, the LO-enriched kernel fraction separated from cold-pressed flaxseed cake was further used as feedstock for LO production. After ethanol extraction, partition, and precipitation, LOs were extracted from cold-pressed flaxseed cake with a purity of 91.4%. The proposed method could serve as feasible flaxseed cake valorization strategy and enable the preparation of other polar compounds such as flax lignan and mucilage.

Stability of tryptophan-containing LOs in flaxseed oil and their response towards γ-tocopherol.

Linusorbs (LOs), significantly influence oil quality and sensory properties of flaxseed oil. Trp-containing LOs exhibit distinct oxidative behavior when γ-tocopherol (γ-T) is present. Polar fractions of crude flaxseed oil were stripped via silica absorption, and reintroduced (LO and γ-T) separately into the oil matrix to investigate their interaction during storage. Compared with crude oil, LOs account for 18.49% reduction of p-anisidine value, while LOs with γ-T contributed to most of the endogenous antioxidant effect in crude oil. γ-T was found to suppress oxidation of Trp-containing LO at early stage (Met form), while facilitate oxidation while at their mid-stage (MetO form, Methionine sulfoxide). In vitro oxidation shows that CLD more likely cleaved into peptide fragments, while few products retain intact ring structures. LC-MS/MS analysis and silicon simulation revealed proximity between MetO and Trp residues, facilitating inter- or intra-molecular reactions and ring structure rupture. Remarkably, the presence of γ-T facilitate these phenomena.

Novel histone post-translational modifications in Alzheimer's disease: current advances and implications.

Alzheimer's disease (AD) has a complex pathogenesis, and multiple studies have indicated that histone post-translational modifications, especially acetylation, play a significant role in it. With the development of mass spectrometry and proteomics, an increasing number of novel HPTMs, including lactoylation, crotonylation, ß-hydroxybutyrylation, 2-hydroxyisobutyrylation, succinylation, and malonylation, have been identified. These novel HPTMs closely link substance metabolism to gene regulation, and an increasing number of relevant studies on the relationship between novel HPTMs and AD have become available. This review summarizes the current advances and implications of novel HPTMs in AD, providing insight into the deeper pathogenesis of AD and the development of novel drugs.

Pickering emulsions stabilized by chitosan-flaxseed gum-hyaluronic acid nanoparticles for controlled topical release of ferulic acid.

Chitosan (CS) based nanoparticles (NPs) were fabricated via an ionic gelation reaction modified by flaxseed gum (FG) or sodium tripolyphosphate (STPP). The average particle size, morphology, interfacial tension, and wettability of NPs were characterized. The particle size of CS-STPP-HA (hyaluronic acid)-FA (ferulic acid) NPs and CS-FG-HA-FA NPs was 400.8 nm and 262.4 nm, respectively under the optimized conditions of CS/STPP = 5:1 (w/w) or CS/FG = 1:1 (v/v) with HA concentration of 0.25 mg/mL and FA dosage of 25 µM. FG acted as a good alternative for STPP to form particles with CS in stabilizing Pickering emulsion with an internal diacylglycerol (DAG) phase of 50-80 % (v/v). The complex nanoparticles had high surface activity and contact angle close to 90 °C, being able to tightly packed at the droplet surface. The emulsions had high thermal, ionic and oxidative stability. With the aid of moisturizing polysaccharides and DAG oil, the emulsions had a good sustained-release ability for FA with deeper penetration and retention into the dermis of the skin. Thus, FG and HA-based NPs serve as green vehicles for the fabrication of novel Pickering emulsions and possess great potential to be applied as a delivery system for lipophilic active agents in functional food and cosmetic products.

Single-subject cortical morphological brain networks: Phenotypic associations and neurobiological substrates.

Although single-subject morphological brain networks provide an important way for human connectome studies, their roles and origins are poorly understood. Combining cross-sectional and repeated structural magnetic resonance imaging scans from adults, children and twins with behavioral and cognitive measures and brain-wide transcriptomic, cytoarchitectonic and chemoarchitectonic data, this study examined phenotypic associations and neurobiological substrates of single-subject morphological brain networks. We found that single-subject morphological brain networks explained inter-individual variance and predicted individual outcomes in Motor and Cognition domains, and distinguished individuals from each other. The performance can be further improved by integrating different morphological indices for network construction. Low-moderate heritability was observed for single-subject morphological brain networks with the highest heritability for sulcal depth-derived networks and higher heritability for inter-module connections. Furthermore, differential roles of genetic, cytoarchitectonic and chemoarchitectonic factors were observed for single-subject morphological brain networks. Cortical thickness-derived networks were related to the three factors with contributions from genes enriched in membrane and transport related functions, genes preferentially located in supragranular and granular layers, overall thickness in the molecular layer and thickness of wall in the infragranular layers, and metabotropic glutamate receptor 5 and dopamine transporter; fractal dimension-, gyrification index- and sulcal depth-derived networks were only associated with the chemoarchitectonic factor with contributions from different sets of neurotransmitter receptors. Most results were reproducible across different parcellation schemes and datasets. Altogether, this study demonstrates phenotypic associations and neurobiological substrates of single-subject morphological brain networks, which provide intermediate endophenotypes to link molecular and cellular architecture and behavior and cognition.

Single-subject cortical morphological brain networks across the adult lifespan.

Age-related changes in focal cortical morphology have been well documented in previous literature; however, how interregional coordination patterns of the focal cortical morphology reorganize with advancing age is not well established. In this study, we performed a comprehensive analysis of the topological changes in single-subject morphological brain networks across the adult lifespan. Specifically, we constructed four types of single-subject morphological brain networks for 650 participants (aged from 18 to 88 years old), and characterized their topological organization using graph-based network measures. Age-related changes in the network measures were examined via linear, quadratic, and cubic models. We found profound age-related changes in global small-world attributes and efficiency, local nodal centralities, and interregional similarities of the single-subject morphological brain networks. The age-related changes were mainly embodied in cortical thickness networks, involved in frontal regions and highly connected hubs, concentrated on short-range connections, characterized by linear changes, and susceptible to connections between limbic, frontoparietal, and ventral attention networks. Intriguingly, nonlinear (i.e., quadratic or cubic) age-related changes were frequently found in the insula and limbic regions, and age-related cubic changes preferred long-range morphological connections. Finally, we demonstrated that the morphological similarity in cortical thickness between two frontal regions mediated the relationship between age and cognition measured by Cattell scores. Taken together, these findings deepen our understanding of adaptive changes of the human brain with advancing age, which may account for interindividual variations in behaviors and cognition.

Multimodal and multiscale evidence for network-based cortical thinning in major depressive disorder.

BACKGROUND: Major depressive disorder (MDD) is associated with widespread, irregular cortical thickness (CT) reductions across the brain. However, little is known regarding mechanisms that govern spatial distribution of the reductions. METHODS: We combined multimodal MRI and genetic, cytoarchitectonic and chemoarchitectonic data to examine structural covariance, functional synchronization, gene co-expression, cytoarchitectonic similarity and chemoarchitectonic covariance between regions atrophied in MDD. RESULTS: Regions atrophied in MDD were associated with significantly higher structural covariance, functional synchronization, gene co-expression and chemoarchitectonic covariance. These results were robust against methodological variations in brain parcellation and null model, reproducible in patients and controls, and independent of age at onset of MDD. Despite no significant differences in the cytoarchitectonic similarity, MDD-related CT reductions were susceptible to specific cytoarchitectonic class of association cortex. Further, we found that nodal shortest path lengths to disease epicenters derived from structural (right supramarginal gyrus) and chemoarchitectonic covariance (right sulcus intermedius primus) networks of healthy brains were correlated with the extent to which a region was atrophied in MDD, supporting the transneuronal spread hypothesis that regions closer to the epicenters are more susceptible to MDD. Finally, we showed that structural covariance and functional synchronization among regions atrophied in MDD were mainly related to genes enriched in metabolic and membrane-related processes, driven by genes in excitatory neurons, and associated with specific neurotransmitter transporters and receptors. CONCLUSIONS: Altogether, our findings provide empirical evidence for and genetic and molecular insights into connectivity-constrained CT thinning in MDD.

Cerebellar connectome alterations and associated genetic signatures in multiple sclerosis and neuromyelitis optica spectrum disorder.

BACKGROUND: The cerebellum plays key roles in the pathology of multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD), but the way in which these conditions affect how the cerebellum communicates with the rest of the brain (its connectome) and associated genetic correlates remains largely unknown. METHODS: Combining multimodal MRI data from 208 MS patients, 200 NMOSD patients and 228 healthy controls and brain-wide transcriptional data, this study characterized convergent and divergent alterations in within-cerebellar and cerebello-cerebral morphological and functional connectivity in MS and NMOSD, and further explored the association between the connectivity alterations and gene expression profiles. RESULTS: Despite numerous common alterations in the two conditions, diagnosis-specific increases in cerebellar morphological connectivity were found in MS within the cerebellar secondary motor module, and in NMOSD between cerebellar primary motor module and cerebral motor- and sensory-related areas. Both diseases also exhibited decreased functional connectivity between cerebellar motor modules and cerebral association cortices with MS-specific decreases within cerebellar secondary motor module and NMOSD-specific decreases between cerebellar motor modules and cerebral limbic and default-mode regions. Transcriptional data explained > 37.5% variance of the cerebellar functional alterations in MS with the most correlated genes enriched in signaling and ion transport-related processes and preferentially located in excitatory and inhibitory neurons. For NMOSD, similar results were found but with the most correlated genes also preferentially located in astrocytes and microglia. Finally, we showed that cerebellar connectivity can help distinguish the three groups from each other with morphological connectivity as predominant features for differentiating the patients from controls while functional connectivity for discriminating the two diseases. CONCLUSIONS: We demonstrate convergent and divergent cerebellar connectome alterations and associated transcriptomic signatures between MS and NMOSD, providing insight into shared and unique neurobiological mechanisms underlying these two diseases.

A comprehensive evaluation of multicentric reliability of single-subject cortical morphological networks on traveling subjects.

Despite the prevalence of research on single-subject cerebral morphological networks in recent years, whether they can offer a reliable way for multicentric studies remains largely unknown. Using two multicentric datasets of traveling subjects, this work systematically examined the inter-site test-retest (TRT) reliabilities of single-subject cerebral morphological networks, and further evaluated the effects of several key factors. We found that most graph-based network measures exhibited fair to excellent reliabilities regardless of different analytical pipelines. Nevertheless, the reliabilities were affected by choices of morphological index (fractal dimension > sulcal depth > gyrification index > cortical thickness), brain parcellation (high-resolution > low-resolution), thresholding method (proportional > absolute), and network type (binarized > weighted). For the factor of similarity measure, its effects depended on the thresholding method used (absolute: Kullback-Leibler divergence > Jensen-Shannon divergence; proportional: Jensen-Shannon divergence > Kullback-Leibler divergence). Furthermore, longer data acquisition intervals and different scanner software versions significantly reduced the reliabilities. Finally, we showed that inter-site reliabilities were significantly lower than intra-site reliabilities for single-subject cerebral morphological networks. Altogether, our findings propose single-subject cerebral morphological networks as a promising approach for multicentric human connectome studies, and offer recommendations on how to determine analytical pipelines and scanning protocols for obtaining reliable results.

Aberrant single-subject morphological brain networks in first-episode, treatment-naive adolescents with major depressive disorder.

Background: Neuroimaging-based connectome studies have indicated that major depressive disorder (MDD) is associated with disrupted topological organization of large-scale brain networks. However, the disruptions and their clinical and cognitive relevance are not well established for morphological brain networks in adolescent MDD. Objective: To investigate the topological alterations of single-subject morphological brain networks in adolescent MDD. Methods: Twenty-five first-episode, treatment-naive adolescents with MDD and 19 healthy controls (HCs) underwent T1-weighted magnetic resonance imaging and a battery of neuropsychological tests. Single-subject morphological brain networks were constructed separately based on cortical thickness, fractal dimension, gyrification index, and sulcus depth, and topologically characterized by graph-based approaches. Between-group differences were inferred by permutation testing. For significant alterations, partial correlations were used to examine their associations with clinical and neuropsychological variables in the patients. Finally, a support vector machine was used to classify the patients from controls. Results: Compared with the HCs, the patients exhibited topological alterations only in cortical thickness-based networks characterized by higher nodal centralities in parietal (left primary sensory cortex) but lower nodal centralities in temporal (left parabelt complex, right perirhinal ectorhinal cortex, right area PHT and right ventral visual complex) regions. Moreover, decreased nodal centralities of some temporal regions were correlated with cognitive dysfunction and clinical characteristics of the patients. These results were largely reproducible for binary and weighted network analyses. Finally, topological properties of the cortical thickness-based networks were able to distinguish the MDD adolescents from HCs with 87.6% accuracy. Conclusion: Adolescent MDD is associated with disrupted topological organization of morphological brain networks, and the disruptions provide potential biomarkers for diagnosing and monitoring the disease.

Effects of Long-Term Exposure to 2260 m Altitude on Working Memory and Resting-State Activity in the Prefrontal Cortex: A Large-Sample Cross-Sectional Study.

It has been well established that very-high-altitude (>4000 m) environments can affect human cognitive function and brain activity. However, the effects of long-term exposure to moderate altitudes (2000−3000 m) on cognitive function and brain activity are not well understood. In the present cross-sectional study, we utilized an N-back working memory task and resting-state functional near-infrared spectroscopy to examine the effects of two years of exposure to 2260 m altitude on working memory and resting-state brain activity in 208 college students, compared with a control group at the sea level. The results showed that there was no significant change in spatial working memory performance after two years of exposure to 2260 m altitude. In contrast, the analysis of resting-state brain activity revealed changes in functional connectivity patterns in the prefrontal cortex (PFC), with the global efficiency increased and the local efficiency decreased after two years of exposure to 2260 m altitude. These results suggest that long-term exposure to moderate altitudes has no observable effect on spatial working memory performance, while significant changes in functional connectivity and brain network properties could possibly occur to compensate for the effects of mild hypoxic environments. To our knowledge, this study is the first to examine the resting state activity in the PFC associated with working memory in people exposed to moderate altitudes.

Subregion-specific, modality-dependent and timescale-sensitive hippocampal connectivity alterations in patients with first-episode, drug-naïve major depression disorder.

BACKGROUND: Despite accumulating evidence for the hippocampus as a key dysfunctional node in major depressive disorder (MDD), previous findings are controversial possibly due to heterogeneous and small clinical samples, complicated hippocampal structure, and different imaging modalities and analytical methods. METHODS: We collected structural and resting-state functional MRI data from 100 first-episode, drug-naïve MDD patients and 99 healthy controls. A subset of the participants (34 patients and 33 controls) also completed a battery of neuropsychological tests and childhood trauma questionnaires. Seed-based morphological and functional (static and dynamic) connectivity were calculated for ten hippocampal subregions, followed by analyses of dynamic functional connectivity states (k-means clustering), connectivity cross-modality relationships (cosine similarity), and connectivity associations with clinical and neuropsychological variables (Spearman correlation). RESULTS: Between-group comparisons revealed abnormal hippocampal connectivity in the patients that depended on 1) hippocampal subdivisions: the cornu ammonis (CA) was the most seriously affected subregion, in particular the right CA1 for functional connectivity alterations; 2) imaging modality: morphological connectivity revealed seldom and sporadic alterations with different lobes, while functional connectivity identified numerous and convergent alterations with prefrontal regions; and 3) time scale: dynamic functional connectivity was more sensitive than static functional connectivity, in particular in revealing alterations between the right CA1 and contralateral prefrontal cortex. Among the 34 patients, functional connectivity alterations of the CA1 were related to the history of childhood trauma in the patients. LIMITATIONS: Only a subset of the patients completed the neuropsychological tests, which may cause underestimation of cognitive relevance of hippocampal connectivity alterations. CONCLUSIONS: Disrupted hippocampal CA1 functional connectivity plays key roles in the pathophysiology of MDD and may act as a potential diagnostic biomarker for the disease.

Aberrant Development of Cross-Frequency Multiplex Functional Connectome in First-Episode, Drug-Naive Major Depressive Disorder and Schizophrenia.

Introduction: Both major depressive disorder (MDD) and schizophrenia (SCH) are characterized by neurodevelopmental abnormalities; however, transdiagnostic and diagnosis-specific patterns of such abnormalities have rarely been examined, particularly in large-scale functional brain networks via advanced multilayer network models. Methods: Here, we collected resting-state functional magnetic resonance imaging data from 45 MDD patients, 64 SCH patients, and 48 healthy controls (HCs; 13-45 years old), and we constructed functional networks in different frequency intervals. The frequency-dependent networks were then fused by multiplex network models, followed by graph-based topological analyses. Results: We found that functional networks of the patients showed common neurodevelopmental abnormalities in the right ventromedial parietooccipital sulcus (opposite correlations with age to HCs), whereas functional networks of the MDD patients exhibited specific alterations in the left superior parietal lobule and right precentral gyrus with respect to cross-frequency interactions. These findings were quite different from those from brain networks within each frequency interval, which revealed SCH-specific neurodevelopmental abnormalities in the right superior temporal gyrus (opposite correlations with age to the other two groups) in 0.027-0.073 Hz, and SCH-specific alterations in the left superior temporal gyrus and bilateral insula in 0.073-0.198 Hz. Finally, multivariate analysis of age prediction revealed that the subcortical network lost prediction ability in both patient groups, whereas the visual network exhibited additional prediction ability in the MDD patients. Discussion and Conclusion: Altogether, these findings demonstrate transdiagnostic and diagnosis-specific neurodevelopmental abnormalities and alterations in large-scale functional brain networks between MDD and SCH, which have important implications for understanding shared and unique neural mechanisms underlying the diseases.

Taxonomic status of Chinese blue sheep (Pseudois nayaur): new evidence of a distinct subspecies.

The blue sheep is an endemic species to the Qinghai-Tibet Plateau and surrounding regions. It has been regarded as having 2 subspecies: Pseudois nayaur nayaur and P. n. szechuanensis. However, such a classification remains controversial. Herein, we analyze 10 microsatellite loci and part of the mitochondrial control region for clarification in such taxonomic debates. We use samples from 168 individuals from 6 geographic populations covering almost all the distribution areas of the species in China to carry out comparisons. Phylogenetic trees derived from both the microsatellite and mitochondrial markers combined with the discriminant analysis of principal components (DAPC) and the STRUCTURE analysis reveal that the individuals in the Helan Mountains are well grouped with a distinct evolutionary lineage and are significantly different from the other populations of P. n. szechuanensis according to Fst values, implying that this isolated population should be categorized as a valid subspecies; namely, Pseudois nayaur alashanicus. The isolation-by-distance (IBD) analysis shows a significant positive relationship between genetic and geographical distances among the populations.