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Although dysregulation of mitochondrial dynamics has been linked to cellular senescence, which contributes to advanced age-related disorders, it is unclear how Krüppel-like factor 5 (Klf5), an essential transcriptional factor of cardiovascular remodeling, mediates the link between mitochondrial dynamics and vascular smooth muscle cell (VSMC) senescence. Here, we show that Klf5 down-regulation in VSMCs is correlated with rupture of abdominal aortic aneurysm (AAA), an age-related vascular disease. Mice lacking Klf5 in VSMCs exacerbate vascular senescence and progression of angiotensin II (Ang II)-induced AAA by facilitating reactive oxygen species (ROS) formation. Klf5 knockdown enhances, while Klf5 overexpression suppresses mitochondrial fission. Mechanistically, Klf5 activates eukaryotic translation initiation factor 5a (eIF5a) transcription through binding to the promoter of eIF5a, which in turn preserves mitochondrial integrity by interacting with mitofusin 1 (Mfn1). Accordingly, decreased expression of eIF5a elicited by Klf5 down-regulation leads to mitochondrial fission and excessive ROS production. Inhibition of mitochondrial fission decreases ROS production and VSMC senescence. Our studies provide a potential therapeutic target for age-related vascular disorders.

Migraine is a type of headache with multiple neurological symptoms. Prior neuroimaging studies in patients with migraine based on functional magnetic resonance imaging have found regional as well as network‐level alterations in brain function. Here, we expand on prior studies by establishing whole‐brain functional connectivity patterns in patients with migraine using dimensionality reduction techniques. We studied functional brain connectivity in 50 patients with episodic migraine and sex‐ and age‐matched healthy controls. Using dimensionality reduction techniques that project high‐dimensional functional connectivity onto low‐dimensional representations (i.e., eigenvectors), we found significant between‐group differences in the eigenvectors between patients with migraine and healthy controls, particularly in the sensory/motor and limbic cortices. Furthermore, we assessed between‐group differences in subcortical connectivity with subcortical weighted manifolds defined by subcortico‐cortical connectivity multiplied by cortical eigenvectors and revealed significant alterations in the amygdala. Finally, leveraging supervised machine learning, we moderately predicted headache frequency using cortical and subcortical functional connectivity features, again indicating that sensory and limbic regions play a particularly important role in predicting migraine frequency. Our study confirmed that migraine is a hierarchical disease of the brain that shows alterations along the sensory‐limbic axis, and therefore, the functional connectivity in these areas could be a useful marker to investigate migraine symptomatology. We investigated functional connectome alterations in patients with migraine using dimensionality reduction techniques. We found significant between‐group differences in low‐dimensional representations of functional connectivity between patients with migraine and healthy controls, particularly in the sensory/motor and limbic cortices. Supervised machine learning indicated that imaging features of sensory/motor regions play an important role in predicting migraine frequency.

Background Obesity (waist circumference, body mass index (BMI)) and lifestyle factors (dietary habits, smoking, alcohol drinking, Sedentary behavior) have been associated with risk of benign prostatic hyperplasia (BPH) in observational studies, but whether these associations are causal is unclear. Methods We performed a univariable and multivariable Mendelian randomization study to evaluate these associations. Genetic instruments associated with exposures at the genome-wide significance level ( P  < 5 × 10 –8 ) were selected from corresponding genome-wide associations studies (n = 216,590 to 1,232,091 individuals). Summary-level data for BPH were obtained from the UK Biobank (14,126 cases and 169,762 non-cases) and FinnGen consortium (13,118 cases and 72,799 non-cases). Results from UK Biobank and FinnGen consortium were combined using fixed-effect meta-analysis. Results The combined odds ratios (ORs) of BPH were 1.24 (95% confidence interval (CI), 1.07–1.43, P  = 0.0045), 1.08 (95% CI 1.01–1.17, P  = 0.0175), 0.94 (95% CI 0.67–1.30, P  = 0.6891), 1.29 (95% CI 0.88–1.89, P  = 0.1922), 1.23 (95% CI 0.85–1.78, P  = 0.2623), and 1.04 (95% CI 0.76–1.42, P  = 0.8165) for one standard deviation (SD) increase in waist circumference, BMI, and relative carbohydrate, fat, protein and sugar intake, 1.05 (95% CI 0.92–1.20, P  = 0.4581) for one SD increase in prevalence of smoking initiation, 1.10 (95% CI 0.96–1.26, P  = 0.1725) and 0.84 (95% CI 0.69–1.02, P  = 0.0741) for one SD increase of log-transformed smoking per day and drinks per week, and 1.31 (95% CI 1.08–1.58, P  = 0.0051) for one SD increase in sedentary behavior. Genetically predicted waist circumference (OR = 1.26, 95% CI 1.11–1.43, P  = 0.0004) and sedentary behavior (OR = 1.14, 95% CI 1.05–1.23, P  = 0.0021) were associated with BPH after the adjustment of BMI. Conclusion This study supports independent causal roles of high waist circumference, BMI and sedentary behavior in BPH.

Many chronic diseases such as Alzheimer’s disease, diabetes, and cardiovascular diseases are closely related to in vivo oxidative stress caused by excessive reactive oxygen species (ROS). Natural polysaccharides, as a kind of biomacromolecule with good biocompatibility, have been widely used in biomedical and medicinal applications due to their superior antioxidant properties. In this review, scientometric analysis of the highly cited papers in the Web of Science (WOS) database finds that antioxidant activity is the most widely studied and popular among pharmacological effects of natural polysaccharides. The antioxidant mechanisms of natural polysaccharides mainly contain the regulation of signal transduction pathways, the activation of enzymes, and the scavenging of free radicals. We continuously discuss the antioxidant activities of natural polysaccharides and their derivatives. At the same time, we summarize their applications in the field of pharmaceutics/drug delivery, tissue engineering, and antimicrobial food additives/packaging materials. Overall, this review provides up-to-date information for the further development and application of natural polysaccharides with antioxidant activities.

Sustained pain is a major characteristic of clinical pain disorders, but it is difficult to assess in isolation from co-occurring cognitive and emotional features in patients. In this study, we developed a functional magnetic resonance imaging signature based on whole-brain functional connectivity that tracks experimentally induced tonic pain intensity and tested its sensitivity, specificity and generalizability to clinical pain across six studies (total n = 334). The signature displayed high sensitivity and specificity to tonic pain across three independent studies of orofacial tonic pain and aversive taste. It also predicted clinical pain severity and classified patients versus controls in two independent studies of clinical low back pain. Tonic and clinical pain showed similar network-level representations, particularly in somatomotor, frontoparietal and dorsal attention networks. These patterns were distinct from representations of experimental phasic pain. This study identified a brain biomarker for sustained pain with high potential for clinical translation. The functional magnetic resonance imaging connectivity pattern of tonic experimental orofacial pain can be used as a quantitative and unbiased biomarker of clinical pain.

•Micapipe is a comprehensive pipeline to process multimodal MRI data.•Micapipe generates matrices describing cortico-cortical microstructural similarity, functional connectivity, structural connectivity, and spatial proximity.•The pipeline provides easy-to-verify outputs and visualizations for quality control.•Outputs are hierarchically organized with BIDS-conform naming.•Our evaluations show reproducible processing across several 3T and 7T datasets. Multimodal magnetic resonance imaging (MRI) has accelerated human neuroscience by fostering the analysis of brain microstructure, geometry, function, and connectivity across multiple scales and in living brains. The richness and complexity of multimodal neuroimaging, however, demands processing methods to integrate information across modalities and to consolidate findings across different spatial scales. Here, we present micapipe, an open processing pipeline for multimodal MRI datasets. Based on BIDS-conform input data, micapipe can generate i) structural connectomes derived from diffusion tractography, ii) functional connectomes derived from resting-state signal correlations, iii) geodesic distance matrices that quantify cortico-cortical proximity, and iv) microstructural profile covariance matrices that assess inter-regional similarity in cortical myelin proxies. The above matrices can be automatically generated across established 18 cortical parcellations (100–1000 parcels), in addition to subcortical and cerebellar parcellations, allowing researchers to replicate findings easily across different spatial scales. Results are represented on three different surface spaces (native, conte69, fsaverage5), and outputs are BIDS-conform. Processed outputs can be quality controlled at the individual and group level. micapipe was tested on several datasets and is available at https://github.com/MICA-MNI/micapipe, documented at https://micapipe.readthedocs.io/, and containerized as a BIDS App http://bids-apps.neuroimaging.io/apps/. We hope that micapipe will foster robust and integrative studies of human brain microstructure, morphology, function, cand connectivity.

•Investigated interaction effects between sex and autism condition.•Sex ratio was matched using the Gaussian mixture model-based oversampling.•Low-dimensional principal functional gradients were generated.•Sex-related effects were linked to gene enrichment in cortex, thalamus, and striatum.•Gradients showed varying associations with symptom severity across sexes. Autism spectrum disorder (ASD) is an atypical neurodevelopmental condition with a diagnostic ratio largely differing between male and female participants. Due to the sex imbalance in participants with ASD, we lack an understanding of the differences in connectome organization of the brain between male and female participants with ASD. In this study, we matched the sex ratio using a Gaussian mixture model-based oversampling technique and investigated the differences in functional connectivity between male and female participants with ASD using low-dimensional principal gradients. Between-group comparisons of the gradient values revealed significant interaction effects of sex in the sensorimotor, attention, and default mode networks. The sex-related differences in the gradients were highly associated with higher-order cognitive control processes. Transcriptomic association analysis provided potential biological underpinnings, specifying gene enrichment in the cortex, thalamus, and striatum during development. Finally, the principal gradients were differentially associated with symptom severity of ASD between sexes, highlighting significant effects in female participants with ASD. Our work proposed an oversampling method to mitigate sex imbalance in ASD and observed significant sex-related differences in functional connectome organization. The findings may advance our knowledge about the sex heterogeneity in large-scale brain networks in ASD.

The endosomal-lysosomal system is made up of a set of intracellular membranous compartments that dynamically interconvert, which is comprised of early endosomes, recycling endosomes, late endosomes, and the lysosome. In addition, autophagosomes execute autophagy, which delivers intracellular contents to the lysosome. Maturation of endosomes and/or autophagosomes into a lysosome creates an unique acidic environment within the cell for proteolysis and recycling of unneeded cellular components into usable amino acids and other biomolecular building blocks. In the endocytic pathway, gradual maturation of endosomes into a lysosome and acidification of the late endosome are accompanied by vesicle trafficking, protein sorting and targeted degradation of some sorted cargo. Two opposing sorting systems are operating in these processes: the endosomal sorting complex required for transport (ESCRT) supports targeted degradation and the retromer supports retrograde retrieval of certain cargo. The endosomal-lysosomal system is emerging as a central player in a host of neurodegenerative diseases, demonstrating potential roles which are likely to be revealed in pathogenesis and for viable therapeutic strategies. Here we focus on the physiological process of endosomal-lysosomal maturation, acidification and sorting systems along the endocytic pathway, and further discuss relationships between abnormalities in the endosomal-lysosomal system and neurodegenerative diseases, especially Alzheimer’s disease (AD).

Brain structure scaffolds intrinsic function, supporting cognition and ultimately behavioral flexibility. However, it remains unclear how a static, genetically controlled architecture supports flexible cognition and behavior. Here, we synthesize genetic, phylogenetic and cognitive analyses to understand how the macroscale organization of structure-function coupling across the cortex can inform its role in cognition. In humans, structure-function coupling was highest in regions of unimodal cortex and lowest in transmodal cortex, a pattern that was mirrored by a reduced alignment with heritable connectivity profiles. Structure-function uncoupling in macaques had a similar spatial distribution, but we observed an increased coupling between structure and function in association cortices relative to humans. Meta-analysis suggested regions with the least genetic control (low heritable correspondence and different across primates) are linked to social-cognition and autobiographical memory. Our findings suggest that genetic and evolutionary uncoupling of structure and function in different transmodal systems may support the emergence of complex forms of cognition. Brain structure scaffolds intrinsic function, supporting cognition and behavioral flexibility. Here, the authors show how macroscale organization of cortical microstructure and resting-state function uncouple in transmodal cortex of humans and macaques.