The Brassinosteroid Receptor StBRI1 Promotes Tuber Development by Enhancing Plasma Membrane H+-ATPase Activity in Potato.

The brassinosteroid (BR) receptor BRASSINOSTEROID-INSENSITIVE 1 (BRI1) plays a critical role in plant growth and development. Although much is known about how BR signaling regulates growth and development in many crop species, the role of StBRI1 in regulating potato (Solanum tuberosum) tuber development is not well understood. To address this question, a series of comprehensive genetic and biochemical methods were applied in this investigation. It was determined that StBRI1 and Solanum tuberosum PLASMA MEMBRANE (PM) PROTON ATPASE2 (PHA2), a PM-localized proton ATPase, play important roles in potato tuber development. The individual overexpression of StBRI1 and PHA2 led to a 22% and 25% increase in tuber yield per plant, respectively. Consistent with the genetic evidence, in vivo interaction analysis using double transgenic lines and PM H+-ATPase activity assays indicated that StBRI1 interacts with the C-terminus of PHA2, which restrains the intramolecular interaction of the PHA2 C-terminus with the PHA2 central loop to attenuate autoinhibition of PM H+-ATPase activity, resulting in increased PHA2 activity. Furthermore, the extent of PM H+-ATPase autoinhibition involving phosphorylation-dependent mechanisms corresponds to phosphorylation of the penultimate Thr residue (Thr-951) in PHA2. These results suggest that StBRI1 phosphorylates PHA2 and enhances its activity, which subsequently promotes tuber development. Altogether, our results uncover a BR-StBRI1-PHA2 module that regulates tuber development and suggest a prospective strategy for improving tuberous crop growth and increasing yield via the cell surface-based BR signaling pathway.

Hippo cooperates with p53 to maintain foregut homeostasis and suppress the malignant transformation of foregut basal progenitor cells.

Basal progenitor cells serve as a stem cell pool to maintain the homeostasis of the epithelium of the foregut, including the esophagus and the forestomach. Aberrant genetic regulation in these cells can lead to carcinogenesis, such as squamous cell carcinoma (SCC). However, the underlying molecular mechanisms regulating the function of basal progenitor cells remain largely unknown. Here, we use mouse models to reveal that Hippo signaling is required for maintaining the homeostasis of the foregut epithelium and cooperates with p53 to repress the initiation of foregut SCC. Deletion of Mst1/2 in mice leads to epithelial overgrowth in both the esophagus and forestomach. Further molecular studies find that Mst1/2-deficiency promotes epithelial growth by enhancing basal cell proliferation in a Yes-associated protein (Yap)-dependent manner. Moreover, Mst1/2 deficiency accelerates the onset of foregut SCC in a carcinogen-induced foregut SCC mouse model, depending on Yap. Significantly, a combined deletion of Mst1/2 and p53 in basal progenitor cells sufficiently drives the initiation of foregut SCC. Therefore, our studies shed light on the collaborative role of Hippo signaling and p53 in maintaining squamous epithelial homeostasis while suppressing malignant transformation of basal stem cells within the foregut.

Uncoordinated chemistry enables highly conductive and stable electrolyte/filler interfaces for solid-state lithium-sulfur batteries.

Composite-polymer-electrolytes (CPEs) embedded with advanced filler materials offer great promise for fast and preferential Li+ conduction. The filler surface chemistry determines the interaction with electrolyte molecules and thus critically regulates the Li+ behaviors at the interfaces. Herein, we probe into the role of electrolyte/filler interfaces (EFI) in CPEs and promote Li+ conduction by introducing an unsaturated coordination Prussian blue analog (UCPBA) filler. Combining scanning transmission X-ray microscope stack imaging studies and first-principle calculations, fast Li+ conduction is revealed only achievable at a chemically stable EFI, which can be established by the unsaturated Co-O coordination in UCPBA to circumvent the side reactions. Moreover, the as-exposed Lewis-acid metal centers in UCPBA efficiently attract the Lewis-base anions of Li salts, which facilitates the Li+ disassociation and enhances its transference number (tLi+). Attributed to these superiorities, the obtained CPEs realize high room-temperature ionic conductivity up to 0.36 mS cm-1 and tLi+ of 0.6, enabling an excellent cyclability of lithium metal electrodes over 4,000 h as well as remarkable capacity retention of 97.6% over 180 cycles at 0.5 C for solid-state lithium-sulfur batteries. This work highlights the crucial role of EFI chemistry in developing highly conductive CPEs and high-performance solid-state batteries.

Proximal tubular MBD2 promotes autophagy to drive the progression of AKI caused by vancomycin via regulation of miR-597-5p/S1PR1 axis.

Our recent investigation has indicated that the global deletion of MBD2 can mitigate the progression of AKI induced by VAN. Nevertheless, the role and regulatory mechanisms of proximal tubular MBD2 in this pathophysiological process have yet to be elucidated. Our preceding investigation revealed that autophagy played a crucial role in advancing AKI induced by VAN. Consequently, we postulated that MBD2 present in the proximal tubule could upregulate the autophagic process to expedite the onset of AKI. In the present study, we found for the first time that MBD2 mediated the autophagy production induced by VAN. Through the utilization of miRNA chip analysis, we have mechanistically demonstrated that MBD2 initiates the activation of miR-597-5p through promoter demethylation. This process leads to the suppression of S1PR1, which results in the induction of autophagy and apoptosis in renal tubular cells. Besides, PT-MBD2-KO reduced autophagy to attenuate VAN-induced AKI via regulation of the miR-597-5p/S1PR1 axis, which was reversed by rapamycin. Finally, the overexpression of MBD2 aggravated the diminished VAN-induced AKI in autophagy-deficient mice (PT-Atg7-KO). These data demonstrate that proximal tubular MBD2 facilitated the process of autophagy via the miR-597-5p/S1PR1 axis and subsequently instigated VAN-induced AKI through the induction of apoptosis. The potentiality of MBD2 being a target for AKI was established.

FANCD2 deficiency sensitizes SHH medulloblastoma to radiotherapy via ferroptosis.

Radiotherapy is one of the standard therapeutic regimens for medulloblastoma (MB). Tumor cells utilize DNA damage repair (DDR) mechanisms to survive and develop resistance during radiotherapy. It has been found that targeting DDR sensitizes tumor cells to radiotherapy in several types of cancer, but whether and how DDR pathways are involved in the MB radiotherapy response remain to be determined. Single-cell RNA sequencing was carried out on 38 MB tissues, followed by expression enrichment assays. Fanconi anemia group D2 gene (FANCD2) expression was evaluated in MB samples and public MB databases. The function of FANCD2 in MB cells was examined using cell counting assays (CCK-8), clone formation, lactate dehydrogenase activity, and in mouse orthotopic models. The FANCD2-related signaling pathway was investigated using assays of peroxidation, a malondialdehyde assay, a reduced glutathione assay, and using FerroOrange to assess intracellular iron ions (Fe2+ ). Here, we report that FANCD2 was highly expressed in the malignant sonic hedgehog (SHH) MB subtype (SHH-MB). FANCD2 played an oncogenic role and predicted worse prognosis in SHH-MB patients. Moreover, FANCD2 knockdown markedly suppressed viability, mobility, and growth of SHH-MB cells and sensitized SHH-MB cells to irradiation. Mechanistically, FANCD2 deficiency led to an accumulation of Fe2+ due to increased divalent metal transporter 1 expression and impaired glutathione peroxidase 4 activity, which further activated ferroptosis and reduced proliferation of SHH-MB cells. Using an orthotopic mouse model, we observed that radiotherapy combined with silencing FANCD2 significantly inhibited the growth of SHH-MB cell-derived tumors in vivo. Our study revealed FANCD2 as a potential therapeutic target in SHH-MB and silencing FANCD2 could sensitize SHH-MB cells to radiotherapy via inducing ferroptosis. © 2024 The Pathological Society of Great Britain and Ireland.

The mediating role of trait impulsivity in the relation between cue-induced craving and functional connectivity within the salience network among abstinent patients with methamphetamine use disorder.

Given the widespread use and relapse of methamphetamine (METH), it has caused serious public health burdens globally. However, the neurobiological basis of METH addiction remains poorly understood. Therefore, this study aimed to use magnetic resonance imaging (MRI) to investigate changes in brain networks and their connection to impulsivity and drug craving in abstinent individuals with METH use disorder (MUDs). A total of 110 MUDs and 55 age- and gender-matched healthy controls (HCs) underwent resting-state functional MRI and T1-weighted imaging scans, and completed impulsivity and cue-induced craving measurements. We applied independent component analysis to construct functional brain networks and multivariate analysis of covariance to investigate group differences in network connectivity. Mediation analyses were conducted to explore the relationships among brain-network functional connectivity (FC), impulsivity, and drug craving in the patients. MUDs showed increased connectivity in the salience network (SN) and decreased connectivity in the default mode network compared to HCs. Impulsivity was positively correlated with FC within the SN and played a completely mediating role between METH craving and FC within the SN in MUDs. These findings suggest alterations in functional brain networks underlying METH dependence, with SN potentially acting as a core neural substrate for impulse control disorders.

Alterations in the brain functional network of abstinent male individuals with methamphetamine use disorder.

Methamphetamine is a highly addictive psychostimulant drug that is abused globally and is a serious threat to health worldwide. Unfortunately, the specific mechanism underlying addiction remains unclear. Thus, this study aimed to investigate the characteristics of functional connectivity in the brain network and the factors influencing methamphetamine use disorder in patients using magnetic resonance imaging. We included 96 abstinent male participants with methamphetamine use disorder and 46 age- and sex-matched healthy controls for magnetic resonance imaging. Compared with healthy controls, participants with methamphetamine use disorder had greater impulsivity, fewer small-world attributes of the resting-state network, more nodal topological attributes in the cerebellum, greater functional connectivity strength within the cerebellum and between the cerebellum and brain, and decreased frontoparietal functional connectivity strength. In addition, after controlling for covariates, the partial correlation analysis showed that small-world properties were significantly associated with methamphetamine use frequency, psychological craving, and impulsivity. Furthermore, we revealed that the small-word attribute significantly mediated the effect of methamphetamine use frequency on motor impulsivity in the methamphetamine use disorder group. These findings may further improve our understanding of the neural mechanism of impulse control dysfunction underlying methamphetamine addiction and assist in exploring the neuropathological mechanism underlying methamphetamine use disorder-related dysfunction and rehabilitation.

Outdoor Light at Night, Air Pollution, and Risk of Cerebrovascular Disease: A Cohort Study in China.

BACKGROUND: We sought to explore the associations of outdoor light at night (LAN) and air pollution with the risk of cerebrovascular disease (CeVD). METHODS: We included a total of 28 302 participants enrolled in Ningbo, China from 2015 to 2018. Outdoor LAN and air pollution were assessed by Satellite-derived images and land-use regression models. CeVD cases were confirmed by medical records and death certificates and further subdivided into ischemic and hemorrhagic stroke. Cox proportional hazard models were used to estimate hazard ratios and 95% CIs. RESULTS: A total of 1278 CeVD cases (including 777 ischemic and 133 hemorrhagic stroke cases) were identified during 127 877 person-years of follow-up. In the single-exposure models, the hazard ratios for CeVD were 1.17 (95% CI, 1.06-1.29) for outdoor LAN, 1.25 (1.12-1.39) for particulate matter with an aerodynamic diameter ≤2.5 µm, 1.14 (1.06-1.22) for particulate matter with aerodynamic diameter ≤10 µm, and 1.21 (1.06-1.38) for NO2 in every interquartile range increase. The results were similar for ischemic stroke, whereas no association was observed for hemorrhagic stroke. In the multiple-exposure models, the associations of outdoor LAN and PM with CeVD persisted but not for ischemic stroke. Furthermore, no interaction was observed between outdoor LAN and air pollution. CONCLUSIONS: Levels of exposure to outdoor LAN and air pollution were positively associated with the risk of CeVD. Furthermore, the detrimental effects of outdoor LAN and air pollution might be mutually independent.

Exosomal circSIPA1L3-mediated intercellular communication contributes to glucose metabolic reprogramming and progression of triple negative breast cancer.

BACKGROUND: Breast cancer is the most common malignant tumor, and metastasis remains the major cause of poor prognosis. Glucose metabolic reprogramming is one of the prominent hallmarks in cancer, providing nutrients and energy to support dramatically elevated tumor growth and metastasis. Nevertheless, the potential mechanistic links between glycolysis and breast cancer progression have not been thoroughly elucidated. METHODS: RNA-seq analysis was used to identify glucose metabolism-related circRNAs. The expression of circSIPA1L3 in breast cancer tissues and serum was examined by qRT-PCR, and further assessed its diagnostic value. We also evaluated the prognostic potential of circSIPA1L3 by analyzing a cohort of 238 breast cancer patients. Gain- and loss-of-function experiments, transcriptomic analysis, and molecular biology experiments were conducted to explore the biological function and regulatory mechanism of circSIPA1L3. RESULTS: Using RNA-seq analysis, circSIPA1L3 was identified as the critical mediator responsible for metabolic adaption upon energy stress. Gain- and loss-of-function experiments revealed that circSIPA1L3 exerted a stimulative effect on breast cancer progression and glycolysis, which could also be transported by exosomes and facilitated malignant behaviors among breast cancer cells. Significantly, the elevated lactate secretion caused by circSIPA1L3-mediated glycolysis enhancement promoted the recruitment of tumor associated macrophage and their tumor-promoting roles. Mechanistically, EIF4A3 induced the cyclization and cytoplasmic export of circSIPA1L3, which inhibited ubiquitin-mediated IGF2BP3 degradation through enhancing the UPS7-IGF2BP3 interaction. Furthermore, circSIPA1L3 increased mRNA stability of the lactate export carrier SLC16A1 and the glucose intake enhancer RAB11A through either strengthening their interaction with IGF2BP3 or sponging miR-665, leading to enhanced glycolytic metabolism. Clinically, elevated circSIPA1L3 expression indicated unfavorable prognosis base on the cohort of 238 breast cancer patients. Moreover, circSIPA1L3 was highly expressed in the serum of breast cancer patients and exhibited high diagnostic value for breast cancer patients. CONCLUSIONS: Our study highlights the oncogenic role of circSIPA1L3 through mediating glucose metabolism, which might serve as a promising diagnostic and prognostic biomarker and potential therapeutic target for breast cancer.

The glycolytic enzyme PFKFB3 drives kidney fibrosis through promoting histone lactylation-mediated NF-κB family activation.

Persistently elevated glycolysis in kidney has been demonstrated to promote chronic kidney disease (CKD). However, the underlying mechanism remains largely unclear. Here, we observed that 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), a key glycolytic enzyme, was remarkably induced in kidney proximal tubular cells (PTCs) following ischemia-reperfusion injury (IRI) in mice, as well as in multiple etiologies of patients with CKD. PFKFB3 expression was positively correlated with the severity of kidney fibrosis. Moreover, patients with CKD and mice exhibited increased urinary lactate/creatine levels and kidney lactate, respectively. PTC-specific deletion of PFKFB3 significantly reduced kidney lactate levels, mitigated inflammation and fibrosis, and preserved kidney function in the IRI mouse model. Similar protective effects were observed in mice with heterozygous deficiency of PFKFB3 or those treated with a PFKFB3 inhibitor. Mechanistically, lactate derived from PFKFB3-mediated tubular glycolytic reprogramming markedly enhanced histone lactylation, particularly H4K12la, which was enriched at the promoter of NF-κB signaling genes like Ikbkb, Rela, and Relb, activating their transcription and facilitating the inflammatory response. Further, PTC-specific deletion of PFKFB3 inhibited the activation of IKKß, I κ B α, and p65 in the IRI kidneys. Moreover, increased H4K12la levels were positively correlated with kidney inflammation and fibrosis in patients with CKD. These findings suggest that tubular PFKFB3 may play a dual role in enhancing NF-κB signaling by promoting both H4K12la-mediated gene transcription and its activation. Thus, targeting the PFKFB3-mediated NF-κB signaling pathway in kidney tubular cells could be a novel strategy for CKD therapy.

Profiling of long non-coding RNAs in hippocampal-entorhinal system subfields: impact of RN7SL1 on neuroimmune response modulation in Alzheimer's disease.

Alzheimer's disease (AD) is recognized as the predominant cause of dementia, and neuroimmune processes play a pivotal role in its pathological progression. The involvement of long non-coding RNAs (lncRNAs) in AD has attracted widespread attention. Herein, transcriptomic analysis of 262 unique samples extracted from five hippocampal-entorhinal system subfields of individuals with AD pathology and without AD pathology revealed distinctive lncRNA expression profiles. Through differential expression and coexpression analyses, we identified 16 pivotal lncRNAs. Notably, RN7SL1 knockdown significantly modulated microglial responses upon oligomeric amyloid-ß stimulation, resulting in a considerable decrease in proinflammatory cytokine production and subsequent neuronal damage. These findings highlight RN7SL1 as an essential neuroimmune-related lncRNA that could serve as a prospective target for AD diagnosis and treatment.

High-Energy-Density Solid-State Metal-Air Batteries: Progress, Challenges, and Perspectives.

Next-generation batteries have long been considered a transition to more sustainable storage technologies. Among them, metal-air batteries (MABs) with low cost, high safety, and environmental friendliness have shown great potential for future large-scale applications. Motivated by the desirable characteristics, significant progress is made in suppressing serious parasitic reactions, improving electrochemical performance, and increasing the energy density in MABs. Compared to the widely reported liquid electrolyte strategy, solid-state electrolytes (SSEs) can thoroughly solve the volatilization challenges of liquid electrolytes and protect the oxygen electrodes without the formation of diffusion-blocking oxide phases. Notably, SSEs for MABs are still in their infancy, and many thorny challenges still need to be solved. In this review, the main electrochemical mechanism, key challenges, and some important progress are sorted out for solid-state MABs, such as lithium-air, zinc-air, aluminum-air, and magnesium-air batteries. Besides their fundamental significance, these configurations are further compared in terms of energy density, cost, carbon footprint, energy consumption, rate performance, cycle performance, safety, and air stability of prevailing electrolytes.

A Zinc Oxide Nanowire-Modified Mineralized Collagen Scaffold Promotes Infectious Bone Regeneration.

Bone infection poses a major clinical challenge that can hinder patient recovery and exacerbate postoperative complications. This study has developed a bioactive composite scaffold through the co-assembly and intrafibrillar mineralization of collagen fibrils and zinc oxide (ZnO) nanowires (IMC/ZnO). The IMC/ZnO exhibits bone-like hierarchical structures and enhances capabilities for osteogenesis, antibacterial activity, and bacteria-infected bone healing. During co-cultivation with human bone marrow mesenchymal stem cells (BMMSCs), the IMC/ZnO improves BMMSC adhesion, proliferation, and osteogenic differentiation even under inflammatory conditions. Moreover, it suppresses the activity of Gram-negative Porphyromonas gingivalis and Gram-positive Streptococcus mutans by releasing zinc ions within the acidic infectious microenvironment. In vivo, the IMC/ZnO enables near-complete healing of infected bone defects within the intricate oral bacterial milieu, which is attributed to IMC/ZnO orchestrating M2 macrophage polarization, and fostering an osteogenic and anti-inflammatory microenvironment. Overall, these findings demonstrate the promise of the bioactive scaffold IMC/ZnO for treating bacteria-infected bone defects.

Avian Reovirus σA Protein Inhibits Type I Interferon Production by Abrogating Interferon Regulatory Factor 7 Activation.

Type I interferon (IFN) response is the first line of host-based innate immune defense against viral infections. However, viruses have developed multiple strategies to counter host IFN responses, so they may continue infecting hosts via effective replication. Avian reovirus (ARV), an RNA virus, causes viral arthritis or tenosynovitis in chickens. Previous studies have shown that ARV is highly resistant to the antiviral effects of IFN. However, the underlying mechanisms that enable ARV to block the IFN pathway remain unclear. In this study, we found that ectopic expression of ARV protein, σA, significantly inhibited the production of IFN-ß induced by melanoma-differentiation-associated gene 5 (MDA5) and poly(I·C). Knockdown of σA during ARV infection enhances the IFN-ß response and suppresses viral replication. ARV σA inhibited the MDA5-mediated IFN-ß activation by targeting interferon regulatory factor 7 (IRF7). Further studies demonstrated that σA interacts with IRF7, thereby blocking IRF7 dimerization and nuclear translocation, finally leading to the inhibition of IFN-ß production. These findings reveal a novel mechanism that allows ARV to evade host antiviral immunity. IMPORTANCE ARV, the causative agent of viral arthritis or tenosynovitis in chickens, has a significant economic impact as it results in poor weight gain and increased feed conversion ratios. The MDA5-mediated IFN-ß signal pathway plays an important role in host antiviral defense. Therefore, RNA viruses have developed mechanisms to counter this signaling pathway and successfully establish infection. However, the strategies adopted by ARV to block MDA5-IRF7 signaling remain unclear. In the current study, we demonstrated that ARV σA inhibits this pathway by binding to IRF7, which blocked IRF7 dimerization and nuclear translocation. Our findings may provide insights into how avian reovirus counteracts the innate antiviral immunity of the host to ensure viral replication.

Colorful multi-plane augmented reality display with dynamically tunable reflective Pancharatnam-Berry phase lens.

Reflective cholesteric liquid crystal (CLC) Pancharatnam-Berry phase lens (PBL) devices have attracted significant attention in augmented reality (AR) display due to their wide spectral and angular response bandwidths, high diffraction efficiency, and polarization selectivity. However, currently reported CLC reflective PBLs are either limited by monochrome display or suffers from complicated design for colorful display. Herein, we demonstrate a colorful multi-plane AR display system with dynamically tunable reflective PBL. The reflective PBL is fabricated by polymer-stabilized cholesteric liquid crystal (PSCLC) that provides dynamical and continuous tunability of color and focal length by direct current (DC) voltage. A proof-of-concept colorful multi-plane AR device is demonstrated, where over 90% diffraction efficiency at desired wavelength has been obtained. The proposed simple, compact, and light AR display system capable of color-imaging with multi-depth shows great application potential in the vehicle-mounted head-up display (HUD).

Interaction effects of MTHFR C677T and A1298C polymorphisms with maternal glycated haemoglobin levels on adverse birth outcomes.

AIMS: The role of maternal genetic factors in the association between high glycated haemoglobin (HbA1c) levels and adverse birth outcomes remains unclear. MATERIALS AND METHODS: In this study, the maternal HbA1c levels of 5108 normoglycemic pregnant women in China were measured, and A1298C and C677T polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene were genotyped. RESULTS: Elevated HbA1c levels during the second trimester were associated with increased risks of macrosomia, large-for-gestational age (LGA), preterm birth (PTB), and reduced gestational age (p < 0.05). Pregnant women with MTHFR A1298C AA or C677T CT + TT genotypes were susceptible to adverse pregnancy outcomes related to HbA1c levels. Among pregnant women with the A1298C AA genotype, each standard deviation (SD) increase in HbA1c levels increased the risk of PTB by 1.32-times and reduced the gestational age by 0.11 weeks (p < 0.05). For MTHFR C677T CC + TT genotype carriers, higher HbA1c levels were associated with 1.49-, 1.24-, and 1.23-times increased risks of macrosomia, LGA, and PTB, respectively (p < 0.05). A U-shaped curve for PTB risk in relation to HbA1c levels was observed among the C677T CC + TT participants, with a cut-off value of 4.58%. Among subjects with the A1298C AA genotype combined with the C677T CT + TT genotype, each SD increase in HbA1c levels was associated with 1.40 and 1.37-times increased risks of LGA and PTB, respectively. CONCLUSIONS: Our findings highlight the importance of glycaemic control during pregnancy and the potential impact of genetic factors on birth outcomes. However, further large-scale studies are required to confirm these findings.

Mediation of White Matter Alterations in the Association Between Ventricular Dilation and Cognitive Decline in Hydrocephalus Patients: An MRI Study.

BACKGROUND: Cognitive impairment is commonly observed in hydrocephalus patients. Ventricular enlargement compresses brain parenchyma, especially the white matter (WM). PURPOSE: To investigate whether the relationship between ventricular dilation and cognitive decline in hydrocephalus patients is mediated by WM alterations. STUDY TYPE: Retrospective. POPULATION: 51 communicating hydrocephalus patients (median age, 54 years), 50 obstructive hydrocephalus patients (median age, 49 years), and 53 control subjects (median age, 50 years). FIELD STRENGTH/SEQUENCE: Diffusion tensors imaging, 3D T1 BRAVO, 3D FIESTA, CUBE T2, and FLAIR sequences at 3T. ASSESSMENT: DTI parameters (skeletonized fractional anisotropy (FA), skeletonized mean diffusivity (MD), and peak width of skeletonized mean diffusivity p(PSMD)) were extracted using FSL software. Global, periventricular, and deep white matter hyperintensity (WMH) volumes, degree of ventricular enlargement (Evans index), and other conventional imaging markers (number of lacunes and perivascular spaces, intracranial and brain volume) were extracted using united imaging intelligence. Cognitive tests included Montreal cognitive assessment (MoCA), clock drawing test (CDT), and vocabulary fluency test (VFT). STATISTICAL TESTS: Multivariable linear regression analysis, mediation analyses, and dominance analysis. P-value <0.05 was considered significant. RESULTS: The degree of ventricular dilation, DTI parameters, and cognitive function scores were interrelated. The skeletonized FA values (ß = -0.0917, 95% confidence interval (CI): -0.205, -0.024) and normalized global WMH volume (ß = -0.0635, 95% CI: -0.13, -0.0005) together mediated 37.2% of the association between Evans index and MoCA. A comparable causal pathway was found for periventricular WMHs but not for deep WMHs. Dominance analysis indicated skeletonized FA values had a greater impact on cognition than WMH volume. The skeletonized FA values also mediated the association between Evans index and CDT (ß = -0.0897, 95% CI: -0.165, -0.026) and VFT (ß = -0.1589, 95% CI: -0.27, -0.083). CONCLUSION: WM alterations were causal mediators between ventricular dilation and cognitive decline in hydrocephalus patients. EVIDENCE LEVEL: 3. TECHNICAL EFFICACY: Stage 3.

Irisin ameliorates diabetic kidney disease by restoring autophagy in podocytes.

Many studies have highlighted the importance of moderate exercise. While it can attenuate diabetic kidney disease, its mechanism has remained unclear. The level of myokine irisin in plasma increases during exercise. We found that irisin was decreased in diabetic patients and was closely related to renal function, proteinuria, and podocyte autophagy injury. Muscle-specific overexpression of PGC-1α (mPGC-1α) in a mouse model is known to increase plasma irisin levels. The mPGC-1α mice were crossed with db/m mice to obtain db/db mPGC-1α+ mice in the present study. Compared to db/db mice without mPGC-1α, plasma irisin was increased, and albuminuria and glomerular pathological damage were both alleviated in db/db mPGC-1α+ mice. Impaired autophagy in podocytes was restored as well. Irisin inhibited the activation of the PI3K/AKT/mTOR signaling pathway in cultured human podocytes and improved damaged autophagy induced by high glucose levels. Then, db/db mice were treated with recombinant irisin, which had similar beneficial effects on the kidney as those in db/db mPGC-1α+ mice, with alleviated glomerular injury and albuminuria. Moreover, the autophagy in podocytes was also significantly restored. These results suggest that irisin secreted by skeletal muscles protects the kidney from diabetes mellitus damage. It also restores autophagy in podocytes by inhibiting the abnormal activation of the PI3K/AKT/mTOR signaling pathway. Thus, irisin may become a new drug for the prevention and treatment of diabetic nephropathy.

U-fiber diffusion kurtosis and susceptibility characteristics in relapsing-remitting multiple sclerosis may be related to cognitive deficits and neurodegeneration.

OBJECTIVES: To evaluate the diffusion kurtosis and susceptibility change in the U-fiber region of patients with relapsing-remitting multiple sclerosis (pwRRMS) and their correlations with cognitive status and degeneration. MATERIALS AND METHODS: Mean kurtosis (MK), axial kurtosis (AK), radial kurtosis (RK), kurtosis fractional anisotropy (KFA), and the mean relative quantitative susceptibility mapping (mrQSM) values in the U-fiber region were compared between 49 pwRRMS and 48 healthy controls (HCs). The U-fiber were divided into upper and deeper groups based on the location. The whole brain volume, gray and white matter volume, and cortical thickness were obtained. The correlations between the mrQSM values, DKI-derived metrics in the U-fiber region and clinical scale scores, brain morphologic parameters were further investigated. RESULTS: The decreased MK, AK, RK, KFA, and increased mrQSM values in U-fiber lesions (p < 0.001, FDR corrected), decreased RK, KFA, and increased mrQSM values in U-fiber non-lesions (p = 0.034, p < 0.001, p < 0.001, FDR corrected) were found in pwRRMS. There were differences in DKI-derived metrics and susceptibility values between the upper U-fiber region and the deeper one for U-fiber non-lesion areas of pwRRMS and HCs (p < 0.05), but not for U-fiber lesions in DKI-derived metrics. The DKI-derived metrics and susceptibility values were widely related with cognitive tests and brain atrophy. CONCLUSION: RRMS patients show abnormal diffusion kurtosis and susceptibility characteristics in the U-fiber region, and these underlying tissue abnormalities are correlated with cognitive deficits and degeneration. CLINICAL RELEVANCE STATEMENT: The macroscopic and microscopic tissue damages of U-fiber help to identify cognitive impairment and brain atrophy in multiple sclerosis and provide underlying pathophysiological mechanism. KEY POINTS: • Diffusion kurtosis and susceptibility changes are present in the U-fiber region of multiple sclerosis. • There are gradients in diffusion kurtosis and susceptibility characteristics in the U-fiber region. • Tissue damages in the U-fiber region are correlated with cognitive impairment and brain atrophy.

Dual glucagon-like peptide-1 and glucagon receptor agonism reduces energy intake in type 2 diabetes with obesity.

AIMS: To establish which components of energy balance mediate the clinically significant weight loss demonstrated with use of cotadutide, a glucagon-like peptide-1 (GLP-1)/glucagon receptor dual agonist, in early-phase studies. MATERIALS AND METHODS: We conducted a phase 2a, single-centre, randomized, placebo-controlled trial in overweight and obese adults with type 2 diabetes. Following a 16-day single-blind placebo run-in, participants were randomized 2:1 to double-blind 42-day subcutaneous treatment with cotadutide (100-300 µg daily) or placebo. The primary outcome was percentage weight change. Secondary outcomes included change in energy intake (EI) and energy expenditure (EE). RESULTS: A total of 12 participants (63%) in the cotadutide group and seven (78%) in the placebo group completed the study. The mean (90% confidence interval [CI]) weight change was -4.0% (-4.9%, -3.1%) and -1.4% (-2.7%, -0.1%) for the cotadutide and placebo groups, respectively (p = 0.011). EI was lower with cotadutide versus placebo (-41.3% [-66.7, -15.9]; p = 0.011). Difference in EE (per kJ/kg lean body mass) for cotadutide versus placebo was 1.0% (90% CI -8.4, 10.4; p = 0.784), assessed by doubly labelled water, and -6.5% (90% CI -9.3, -3.7; p < 0.001), assessed by indirect calorimetry. CONCLUSION: Weight loss with cotadutide is primarily driven by reduced EI, with relatively small compensatory changes in EE.