Age-associated cortical similarity networks correlate with cell type-specific transcriptional signatures.

Human brain structure shows heterogeneous patterns of change across adults aging and is associated with cognition. However, the relationship between cortical structural changes during aging and gene transcription signatures remains unclear. Here, using structural magnetic resonance imaging data of two separate cohorts of healthy participants from the Cambridge Centre for Aging and Neuroscience (n = 454, 18-87 years) and Dallas Lifespan Brain Study (n = 304, 20-89 years) and a transcriptome dataset, we investigated the link between cortical morphometric similarity network and brain-wide gene transcription. In two cohorts, we found reproducible morphometric similarity network change patterns of decreased morphological similarity with age in cognitive related areas (mainly located in superior frontal and temporal cortices), and increased morphological similarity in sensorimotor related areas (postcentral and lateral occipital cortices). Changes in morphometric similarity network showed significant spatial correlation with the expression of age-related genes that enriched to synaptic-related biological processes, synaptic abnormalities likely accounting for cognitive decline. Transcription changes in astrocytes, microglia, and neuronal cells interpreted most of the age-related morphometric similarity network changes, which suggest potential intervention and therapeutic targets for cognitive decline. Taken together, by linking gene transcription signatures to cortical morphometric similarity network, our findings might provide molecular and cellular substrates for cortical structural changes related to cognitive decline across adults aging.

The co-activation pattern between the DMN and other brain networks affects the cognition of older adults: evidence from naturalistic stimulation fMRI data.

Brain function changes affect cognitive functions in older adults, yet the relationship between cognition and the dynamic changes of brain networks during naturalistic stimulation is not clear. Here, we recruited the young, middle-aged and older groups from the Cambridge Center for Aging and Neuroscience to investigate the relationship between dynamic metrics of brain networks and cognition using functional magnetic resonance imaging data during movie-watching. We found six reliable co-activation pattern (CAP) states of brain networks grouped into three pairs with opposite activation patterns in three age groups. Compared with young and middle-aged adults, older adults dwelled shorter time in CAP state 4 with deactivated default mode network (DMN) and activated salience, frontoparietal and dorsal-attention networks (DAN), and longer time in state 6 with deactivated DMN and activated DAN and visual network, suggesting altered dynamic interaction between DMN and other brain networks might contribute to cognitive decline in older adults. Meanwhile, older adults showed easier transfer from state 6 to state 3 (activated DMN and deactivated sensorimotor network), suggesting that the fragile antagonism between DMN and other cognitive networks might contribute to cognitive decline in older adults. Our findings provided novel insights into aberrant brain network dynamics associated with cognitive decline.

A neural network with a human learning paradigm for breast fibroadenoma segmentation in sonography.

BACKGROUND: Breast fibroadenoma poses a significant health concern, particularly for young women. Computer-aided diagnosis has emerged as an effective and efficient method for the early and accurate detection of various solid tumors. Automatic segmentation of the breast fibroadenoma is important and potentially reduces unnecessary biopsies, but challenging due to the low image quality and presence of various artifacts in sonography. METHODS: Human learning involves modularizing complete information and then integrating it through dense contextual connections in an intuitive and efficient way. Here, a human learning paradigm was introduced to guide the neural network by using two consecutive phases: the feature fragmentation stage and the information aggregation stage. To optimize this paradigm, three fragmentation attention mechanisms and information aggregation mechanisms were adapted according to the characteristics of sonography. The evaluation was conducted using a local dataset comprising 600 breast ultrasound images from 30 patients at Suining Central Hospital in China. Additionally, a public dataset consisting of 246 breast ultrasound images from Dataset_BUSI and DatasetB was used to further validate the robustness of the proposed network. Segmentation performance and inference speed were assessed by Dice similarity coefficient (DSC), Hausdorff distance (HD), and training time and then compared with those of the baseline model (TransUNet) and other state-of-the-art methods. RESULTS: Most models guided by the human learning paradigm demonstrated improved segmentation on the local dataset with the best one (incorporating C3ECA and LogSparse Attention modules) outperforming the baseline model by 0.76% in DSC and 3.14 mm in HD and reducing the training time by 31.25%. Its robustness and efficiency on the public dataset are also confirmed, surpassing TransUNet by 0.42% in DSC and 5.13 mm in HD. CONCLUSIONS: Our proposed human learning paradigm has demonstrated the superiority and efficiency of ultrasound breast fibroadenoma segmentation across both public and local datasets. This intuitive and efficient learning paradigm as the core of neural networks holds immense potential in medical image processing.

Cortical thickness alterations are associated with astrocytes and excitatory neuron-specific transcriptome signatures in pediatric bipolar disorder.

Bipolar disorder (BD) is a heritable psychiatric disorder with a complex etiology that is often associated with cortical alterations. Morphometric studies in adults with BD are well established; however, few have examined cortical changes in pediatric BD (PBD). Additionally, the correlation between cortical thickness (CT) changes in PBD and gene expression remains elusive. Here, we performed an integrative analysis using neuroimaging data from 58 PBD individuals and the Allen human brain transcriptomic dataset. We applied partial least squares (PLS) regression analysis on structural MRI data and cortical gene expression, enrichment and specific cell type analysis to investigate the genetic correlates of CT alterations in PBD. We found the expression levels of PBD-related genes showed significant spatial correlations with CT differences. Further enrichment and specific cell type analysis revealed that transcriptome signatures associated with cortical thinning were enriched in synaptic signaling, ion channels, astrocytes, and excitatory neurons. Neurodevelopmental patterns of these genes showed significantly increased expression in the cerebellum, cortex, and subcortical regions during the adolescence period. These results highlight neurodevelopmental transcriptional changes could account for most of the observed correlations with CT differences in PBD, which offers a novel perspective to understand biological conceptualization mechanisms for the genetic correlates of CT alterations.

Preoperative Frailty Assessment Predicts Postoperative Mortality, Delirium and Pneumonia in Elderly Lung Cancer Patients: A Retrospective Cohort Study.

BACKGROUND: The purpose of this study was to investigate the predictive value of the 5-factor modified frailty index (mFI-5) for postoperative mortality, delirium and pneumonia in patients over 65 years of age undergoing elective lung cancer surgery. METHODS: Data were collected from a single-center retrospective cohort study conducted in a general tertiary hospital from January 2017 to August 2019. In total, the study included 1372 elderly patients aged over 65 who underwent elective lung cancer surgery. They were divided into frail group (mFI-5, 2-5), prefrail group (mFI-5, 1) and robust group (mFI-5, 0) on the basis of mFI-5 classification. The primary outcome was postoperative 1-year all-cause mortality. Secondary outcomes were postoperative pneumonia and postoperative delirium. RESULTS: Frailty group had the highest incidence of postoperative delirium (frailty 31.2% versus prefrailty 1.6% versus robust 1.5%, p < 0.001), postoperative pneumonia (frailty 23.5% versus prefrailty 7.2% versus robust 7.7%, p < 0.001), and postoperative 1-year mortality (frailty 7.0% versus prefrailty 2.2% versus robust 1.9%. p < 0.001). Frail patients have significantly longer length of hospitalization than those in the robust group and prefrail patients (p < 0.001). Multivariate analysis showed a clear link between frailty and increased risk of postoperative delirium (aOR 2.775, 95% CI 1.776-5.417, p < 0.001), postoperative pneumonia (aOR 3.291, 95% CI 2.169-4.993, p < 0.001) and postoperative 1-year mortality (aOR 3.364, 95% CI, 1.516-7.464, p = 0.003). CONCLUSIONS: mFI-5 has potential clinical utility in predicting postoperative death, delirium and pneumonia incidence in elderly patients undergoing radical lung cancer surgery. Frailty screening of patients (mFI-5) may provide benefits in risk stratification, targeted intervention efforts, and assist physicians in clinical decision-making.

Immediate visual reproduction negatively correlates with brain entropy of parahippocampal gyrus and inferior occipital gyrus in bipolar II disorder adolescents.

BACKGROUND: Brain entropy reveals complexity and irregularity of brain, and it has been proven to reflect brain complexity alteration in disease states. Previous studies found that bipolar disorder adolescents showed cognitive impairment. The relationship between complexity of brain neural activity and cognition of bipolar II disorder (BD-II) adolescents remains unclear. METHODS: Nineteen BD-II patients (14.63 ±1.57 years old) and seventeen age-gender matched healthy controls (HCs) (14.18 ± 1.51 years old) were enlisted. Entropy values of all voxels of the brain in resting-state functional MRI data were calculated and differences of them between BD-II and HC groups were evaluated. After that, correlation analyses were performed between entropy values of brain regions showing significant entropy differences and clinical indices in BD-II adolescents. RESULTS: Significant differences were found in scores of immediate visual reproduction subtest (VR-I, p = 0.003) and Stroop color-word test (SCWT-1, p = 0.015; SCWT-2, p = 0.004; SCWT-3, p = 0.003) between the two groups. Compared with HCs, BD-II adolescents showed significant increased brain entropy in right parahippocampal gyrus and right inferior occipital gyrus. Besides, significant negative correlations between brain entropy values of right parahippocampal gyrus, right inferior occipital gyrus and immediate visual reproduction subtest scores were observed in BD-II adolescents. CONCLUSIONS: The findings of the present study suggested that the disrupted function of corticolimbic system is related with cognitive abnormality of BD-II adolescents. And from the perspective temporal dynamics of brain system, the current study, brain entropy may provide available evidences for understanding the underlying neural mechanism in BD-II adolescents.

Oral administration of human FGF21 expressed by mycelium of Cordyceps militaris improves blood glucose and lipid in type II diabetes mellitus.

The purpose of this study was to express human FGF21 (hFGF21) using Cordyceps militaris (C. militaris) as a bioreactor and to observe its hypoglycemic and lipid-lowering effects on type II diabetes. The recombinant plasmid pCB130-hFGF21 was transformed into C. militaris to form recombinant recombinant C. militaris (RhFGF21), the stability of RhFGF21 in vitro and in vivo was analyzed. RhFGF21 significantly promoted glucose uptake in a dose-dependent manner in adipocytes and increased the levels of p-PLCγ, p-FRS2 and p-ERK, which was consistent with the commercial hFGF21. In animal experiments, oral RhFGF21 obviously reduced the levels of glucose, insulin, TG, T-CHO, NEFA, and LDL-C in the blood, the contents of ALT, AST, TNF-α, MCP-1, F4/80, CD68 and CD11b in the fatty liver, and the apoptosis of pancreatic cells. C. militaris is an excellent carrier that can stabilize the expression of hFGF21 and protect the biological activity of hFGF21 during oral administration, which provides a theoretical basis for the development of hFGF21 oral preparations for type II diabetes.

Beneficial Effects of Oleosomes Fused with Human Fibroblast Growth Factor 1 on Wound Healing via the Promotion of Angiogenesis.

In our previous study, human fibroblast growth factor 1 was successfully fused with oleosomes, energy-storing organelles of seeds, which are considered to be excellent "expression carriers" for substances with a convenient purification process. The present work aimed to explore the beneficial effects of oleosomes fused with human fibroblast growth factor 1 (OLAF) on wound healing. The data showed marked improvements in terms of the angiogenesis, vascular integrity, collagen and inflammation on the wound sites of rats with a full-thickness skin defect. Moreover, the positive role of OLAF in promoting angiogenesis and its possible pathways were clarified in vivo and in vitro. The results showed that the number, length and branches of the blood vessels of the chick embryo chorioallantoic membrane were markedly increased after OLAF treatment. Meanwhile, the in vitro results also revealed that 100 ng/mL OLAF exhibited a promoting effect on the proliferation, migration and tube formation of human umbilical vein endothelial cells. In addition, the potential of OLAF to improve wound angiogenesis was demonstrated to be associated with an up-regulated PI3K/Akt pathway by transcriptome sequencing analysis and the introduction of a PI3K/Akt pathway inhibitor (LY294002). These findings suggest that OLAF has many prospects in the development of drugs for wound healing.

Selective optogenetic activation of orexinergic terminals in the basal forebrain and locus coeruleus promotes emergence from isoflurane anaesthesia in rats.

BACKGROUND: The neuropeptide orexin promotes arousal from general anaesthesia, however the neuronal circuits that mediate this effect have not been defined. We investigated whether orexinergic neurones modulate the basal forebrain (BF) and locus coeruleus (LC) in emergence from anaesthesia. METHODS: Hcrtcre rats were generated using a CRISPR/Cas9-based approach. Viruses encoding optogenetic probes were injected into the perifornical lateral hypothalamic (PeFLH) area, optogenetic fibres were embedded in the PeFLH, BF, or LC, and changes in anaesthesia state under 1.4 vol% or 0.8 vol% isoflurane were determined. RESULTS: In the PeFLH, 98.8% (0.4%) of orexin-A-positive cells expressed tdTomato, and 91.9% (2.2%) of tdTomato cells were orexin-A-positive. Under 1.4 vol% isoflurane anaesthesia, compared with control groups, burst suppression ratio was less, and emergence time was shorter in groups with optogenetic activation of orexinergic cell bodies in the PeFLH (923 [162] vs 493 [68] s, P=0.0003) or orexinergic terminals in the BF (937 (122) vs 674 (108) s, P=0.0049) or LC (913 [128] vs 742 [76] s, P=0.022). Optical stimulation of orexinergic terminals in the BF and LC also improved the movement scores of rats under 0.8 vol% isoflurane anaesthesia. CONCLUSIONS: Activation of orexinergic terminals in the FB or LC mediates facilitation of emergence from anaesthesia by orexinergic neurones during isoflurane anaesthesia.

Optimization of the extraction conditions and dermal toxicity of oil body fused with acidic fibroblast growth factor (OLAF).

INTRODUCTION: Oil body (OB), a subcellular organelle that stores oil in plant seeds, is considered a new transdermal drug delivery system. With the increasing understanding of the OB and its main protein (oleosin), numerous studies have been conducted on OB as "carrier" for the expression of exogenous proteins. In our previous study, oil body fused with aFGF (OLAF) was obtained using a plant oil body expression system that had been preliminarily proven to be effective in accelerating the healing of skin wounds. However, no dermal toxicological information on OLAF is available. OBJECTIVE: To ensure the dermal safety of OLAF, a series of tests (the acute dermal toxicity test, 21-day repeat dermal toxicity test, dermal irritation test and skin sensitisation test) were conducted after optimising the extraction protocol of OLAF. MATERIALS AND METHODS: To improve the extraction rate of OLAF, response surface methodology (RSM) was first employed to optimise the extraction conditions. Then, Wistar rats were exposed to OLAF (400 mg·kg-1 body weight) in two different ways (6 hours/time for 24 hours and 1 time/day for 21 days) to evaluate the acute dermal toxicity and 21-day repeated dermal toxicity of OLAF. In the acute dermal toxicity test, clinical observations were conducted to evaluate the toxicity, behaviour, and health of the animals for 14 consecutive days. Similarly, the clinical signs, body weight, haematological and biochemical parameters, histopathological changes and other indicators were also detected during the 21 days administration. For the dermal irritation test, single and multiple doses of OLAF (125 mg·kg-1 body weight) were administered to albino rabbits for 14 days (1 time/day). The irritation reaction on the skin of each albino rabbit was recorded and scored. Meanwhile, skin sensitisation to OLAF was conducted using guinea pigs for a period of 28 days. RESULTS: Suitable extraction conditions for OLAF (PBS concentration 0.01, pH of PBS 8.6, solid-liquid ratio 1:385 g·mL-1) were obtained using RSM. Under these conditions, the extraction rate and particle size of OLAF were 7.29% and 1290 nm, respectively. In the tests of acute dermal toxicity and 21-day repeated dermal toxicity, no mortality or significant differences were observed in terms of clinical signs, body weight, haematological parameters, biochemical parameters and anatomopathological analysis. With respect to the dermal irritation test and skin sensitisation test, no differences in erythema, oedema or other abnormalities were observed between treatment and control groups on gross and histopathological examinations. CONCLUSIONS: The results of this study suggest that OLAF does not cause obvious toxicity, skin sensitisation or irritation in animals.