Site-specific tethering nanobodies on recombinant adeno-associated virus vectors for retargeted gene therapy.

Recombinant adeno-associated viruses (rAAVs) have been extensively studied for decades as carriers for delivering therapeutic genes. However, designing rAAV vectors with selective tropism for specific cell types and tissues has remained challenging. Here, we introduce a strategy for redirecting rAAV by attaching nanobodies with desired tropism at specific sites, effectively replacing the original tropism. To demonstrate this concept, we initially modified the genetic code of rAAV2 to introduce an azido-containing unnatural amino acid at a precise site within the capsid protein. Following a screening process, we identified a critical site (N587+1) where the introduction of unnatural amino acid eliminated the natural tropism of rAAV2. Subsequently, we successfully redirected rAAV2 by conjugating various nanobodies at the N587+1 site, using click and SpyTag-Spycatcher chemistries to form nanobody-AAV conjugates (NACs). By investigating the relationship between NACs quantity and effect and optimizing the linker between rAAV2 and the nanobody using a cathepsin B-susceptible valine-citrulline (VC) dipeptide, we significantly improved gene delivery efficiency both in vitro and in vivo. This enhancement can be attributed to the facilitated endosomal escape of rAAV2. Our method offers an exciting avenue for the rational modification of rAAV2 as a retargeting vehicle, providing a convenient platform for precisely engineering various rAAV2 vectors for both basic research and therapeutic applications. STATEMENT OF SIGNIFICANCE: AAVs hold great promise in the treatment of genetic diseases, but their clinical use has been limited by off-target transduction and efficiency. Here, we report a strategy to construct NACs by conjugating a nanobody or scFv to an rAAV capsid site, specifically via biorthogonal click chemistry and a spy-spycatcher reaction. We explored the structure-effect and quantity-effect relationships of NACs and then optimized the transduction efficiency by introducing a valine-citrulline peptide linker. This approach provides a biocompatible method for rational modification of rAAV as a retargeting platform without structural disruption of the virus or alteration of the binding capacity of the nanobody, with potential utility across a broad spectrum of applications in targeted imaging and gene delivery.

Consequences of eye movements for spatial selectivity.

What determines spatial tuning in the visual system? Standard views rely on the assumption that spatial information is directly inherited from the relative position of photoreceptors and shaped by neuronal connectivity.1,2 However, human eyes are always in motion during fixation,3,4,5,6 so retinal neurons receive temporal modulations that depend on the interaction of the spatial structure of the stimulus with eye movements. It has long been hypothesized that these modulations might contribute to spatial encoding,7,8,9,10,11,12 a proposal supported by several recent observations.13,14,15,16 A fundamental, yet untested, consequence of this encoding strategy is that spatial tuning is not hard-wired in the visual system but critically depends on how the fixational motion of the eye shapes the temporal structure of the signals impinging onto the retina. Here we used high-resolution techniques for eye-tracking17 and gaze-contingent display control18 to quantitatively test this distinctive prediction. We examined how contrast sensitivity, a hallmark of spatial vision, is influenced by fixational motion, both during normal active fixation and when the spatiotemporal stimulus on the retina is altered to mimic changes in fixational control. We showed that visual sensitivity closely follows the strength of the luminance modulations delivered within a narrow temporal bandwidth, so changes in fixational motion have opposite visual effects at low and high spatial frequencies. By identifying a key role for oculomotor activity in spatial selectivity, these findings have important implications for the perceptual consequences of abnormal eye movements, the sources of perceptual variability, and the function of oculomotor control.

The functional and structural alterations in brain regions related to the fear network model in panic disorder: A resting-state fMRI and T1-weighted imaging study.

Abnormal functional connectivity (FC) within the fear network model (FNM) has been identified in panic disorder (PD) patients, but the specific local structural and functional properties, as well as effective connectivity (EC), remain poorly understood in PD. The purpose of this study was to investigate the structural and functional patterns of the FNM in PD. Magnetic resonance imaging data were collected from 33 PD patients and 35 healthy controls (HCs). Gray matter volume (GMV), degree centrality (DC), regional homogeneity (ReHo), and amplitude of low-frequency fluctuation (ALFF) were used to identify the structural and functional characteristics of brain regions within the FNM in PD. Subsequently, FC and EC of abnormal regions, based on local structural and functional features, and their correlation with clinical features were further examined. PD patients exhibited preserved GMV, ReHo, and ALFF in the brain regions of the FNM compared with HCs. However, increased DC in the bilateral amygdala was observed in PD patients. The amygdala and its subnuclei exhibited altered EC with rolandic operculum, insula, medial superior frontal gyrus, supramarginal gyrus, opercular part of inferior frontal gyrus, and superior temporal gyrus. Additionally, Hamilton Anxiety Scale score was positively correlated with EC from left lateral nuclei (dorsal portion) of amygdala to right rolandic operculum and left superior temporal gyrus. Our findings revealed a reorganized functional network in PD involving brain regions regulating exteroceptive-interoceptive signals, mood, and somatic symptoms. These results enhance our understanding of the neurobiological underpinnings of PD, suggesting potential biomarkers for diagnosis and targets for therapeutic intervention.

Genome-wide identification of nitrate transporter 1/peptide transporter family (NPF) induced by arbuscular mycorrhiza in the maize genome.

The Transporter 1/Peptide Transporter Family (NPF) is essential for the uptake and transport of nitrate nitrogen. Significant increases in nitrogen have been increasingly reported for many mycorrhizal plants, but there are few reports on maize. Here, we have identified the maize NPF family and screened for arbuscular mycorrhiza fungi (AMF) induced NPFs. In this study, a systematic analysis of the maize NPF gene family was performed. A total of 82 NPF genes were identified in maize. ZmNPF4.5 was strongly induced by AMF in both low and high nitrogen. Lotus japonicus hairy root-induced transformation experiments showed that ZmNPF4.5 promoter-driven GUS activity was restricted to cells containing tufts. Yeast backfill experiments indicate that ZmNPF4.5 functions in nitrate uptake. Therefore, we speculate that ZmNPF4.5 is a key gene for nitrate-nitrogen uptake in maize through the mycorrhizal pathway. This is a reference value for further exploring the acquisition of nitrate-nitrogen by maize through AMF pathway. Supplementary Information: The online version contains supplementary material available at 10.1007/s12298-024-01464-3.

Multi-pool chemical exchange saturation transfer MRI in glioma grading, molecular subtyping and evaluating tumor proliferation.

PURPOSE: To evaluate the performance of multi-pool Chemical exchange saturation transfer (CEST) MRI in prediction of glioma grade, isocitrate dehydrogenase (IDH) mutation, alpha-thalassemia/mental retardation syndrome X-linked (ATRX) loss and Ki-67 labeling index (LI), based on the fifth edition of the World Health Organization classification of central nervous system tumors (WHO CNS5). METHODS: 95 patients with adult-type diffuse gliomas were analyzed. The amide, direct water saturation (DS), nuclear Overhauser enhancement (NOE), semi-solid magnetization transfer (MT) and amine signals were derived using Lorentzian fitting, and asymmetry-based amide proton transfer-weighted (APTwasym) signal was calculated. The mean value of tumor region was measured and intergroup differences were estimated using student-t test. The receiver operating curve (ROC) and area under the curve (AUC) analysis were used to evaluate the diagnostic performance of signals and their combinations. Spearman correlation analysis was performed to evaluate tumor proliferation. RESULTS: The amide and DS signals were significantly higher in high-grade gliomas compared to low-grade gliomas, as well as in IDH-wildtype gliomas compared to IDH-mutant gliomas (all p < 0.001). The DS, MT and amine signals showed significantly differences between ATRX loss and retention in grade 2/3 IDH-mutant gliomas (all p < 0.05). The combination of signals showed the highest AUC in prediction of grade (0.857), IDH mutation (0.814) and ATRX loss (0.769). Additionally, the amide and DS signals were positively correlated with Ki-67 LI (both p < 0.001). CONCLUSION: Multi-pool CEST MRI demonstrated good potential to predict glioma grade, IDH mutation, ATRX loss and Ki-67 LI.

Quantitative susceptibility mapping of multiple system atrophy and Parkinson's disease correlates with neurotransmitter reference maps.

BACKGROUND: Multiple system atrophy (MSA) and Parkinson's disease (PD) are neurodegenerative disorders characterized by α-synuclein pathology, disrupted iron homeostasis and impaired neurochemical transmission. Considering the critical role of iron in neurotransmitter synthesis and transport, our study aims to identify distinct patterns of whole-brain iron accumulation in MSA and PD, and to elucidate the corresponding neurochemical substrates. METHODS: A total of 122 PD patients, 58 MSA patients and 78 age-, sex-matched health controls underwent multi-echo gradient echo sequences and neurological evaluations. We conducted voxel-wise and regional analyses using quantitative susceptibility mapping to explore MSA or PD-specific alterations in cortical and subcortical iron concentrations. Spatial correlation approaches were employed to examine the topographical alignment of cortical iron accumulation patterns with normative atlases of neurotransmitter receptor and transporter densities. Furthermore, we assessed the associations between the colocalization strength of neurochemical systems and disease severity. RESULTS: MSA patients exhibited increased susceptibility in the striatal, midbrain, cerebellar nuclei, as well as the frontal, temporal, occipital lobes, and anterior cingulate gyrus. In contrast, PD patients displayed elevated iron levels in the left inferior occipital gyrus, precentral gyrus, and substantia nigra. The excessive iron accumulation in MSA or PD correlated with the spatial distribution of cholinergic, noradrenaline, glutamate, serotonin, cannabinoids, and opioid neurotransmitters, and the degree of this alignment was related to motor deficits. CONCLUSIONS: Our findings provide evidence of the interaction between iron accumulation and non-dopamine neurotransmitters in the pathogenesis of MSA and PD, which inspires research on potential targets for pharmacotherapy.

Long-term effects of childhood single-parent family structure on brain connectivity and psychological well-being.

The high and increasing proportion of single-parent families is considered a risk factor associated with various childhood trauma experiences. Consequently, concerns have been raised regarding the potential long-term effects of the childhood single-parent family structure. In this study, we employed advanced magnetic resonance imaging technology, including morphometric similarity mapping, functional connectivity density, and network-based analysis, to investigate brain connectivity and behavioral differences among young adults who were raised in single-parent families. Our study also aimed to explore the relationship between these differences and childhood trauma experiences. The results showed that individuals who grew up in single-parent families exhibited higher levels of anxiety, depression, and harm-avoidant personality. The multimodal MRI analysis further showed differences in regional and network-based connectivity properties in the single-parent family group, including increased functional connectivity density in the left inferior parietal lobule, enhanced cortical structural connectivity between the left isthmus cingulate cortex and peri-calcarine cortex, and an increase in temporal functional connectivity. Moreover, elevated levels of anxiety and depression, along with heightened functional connectivity density in the left inferior parietal lobule and increased temporal functional connectivity, were found to be correlated with a greater number of childhood trauma experiences. Through analyzing multiple data patterns, our study provides objective neuropsychobiological evidence for the enduring impact of childhood single-parent family structure on psychiatric vulnerability in adulthood.

The influence of accelerated brain aging on coactivation pattern dynamics in Parkinson's disease.

Aging is widely acknowledged as the primary risk factor for brain degeneration, with Parkinson's disease (PD) tending to follow accelerated aging trajectories. We aim to investigate the impact of structural brain aging on the temporal dynamics of a large-scale functional network in PD. We enrolled 62 PD patients and 32 healthy controls (HCs). The level of brain aging was determined by calculating global and local brain age gap estimates (G-brainAGE and L-brainAGE) from structural images. The neural network activity of the whole brain was captured by identifying coactivation patterns (CAPs) from resting-state functional images. Intergroup differences were assessed using the general linear model. Subsequently, a spatial correlation analysis between the L-brainAGE difference map and CAPs was conducted to uncover the anatomical underpinnings of functional alterations. Compared to HCs (-3.73 years), G-brainAGE was significantly higher in PD patients (+1.93 years), who also exhibited widespread elevation in L-brainAGE. G-brainAGE was correlated with disease severity and duration. PD patients spent less time in CAPs involving activated default mode and the fronto-parietal network (DMN-FPN), as well as the sensorimotor and salience network (SMN-SN), and had a reduced transition frequency from other CAPs to the DMN-FPN and SMN-SN CAPs. Furthermore, the pattern of localized brain age acceleration showed spatial similarities with the SMN-SN CAP. Accelerated structural brain aging in PD adversely affects brain function, manifesting as dysregulated brain network dynamics. These findings provide insights into the neuropathological mechanisms underlying neurodegenerative diseases and imply the possibility of interventions for modifying PD progression by slowing the brain aging process.

Aquaporin ZmTIP2;3 Promotes Drought Resistance of Maize through Symbiosis with Arbuscular Mycorrhizal Fungi.

Arbuscular mycorrhizal fungi symbiosis plays important roles in enhancing plant tolerance to biotic and abiotic stresses. Aquaporins have also been linked to improved drought tolerance in plants and the regulation of water transport. However, the mechanisms that underlie this association remain to be further explored. In this study, we found that arbuscular mycorrhiza fungi symbiosis could induce the gene expression of the aquaporin ZmTIP2;3 in maize roots. Moreover, compared with the wild-type plants, the maize zmtip2;3 mutant also showed a lower total biomass, colonization rate, relative water content, and POD and SOD activities after arbuscular mycorrhiza fungi symbiosis under drought stress. qRT-PCR assays revealed reduced expression levels of stress genes including LEA3, P5CS4, and NECD1 in the maize zmtip2;3 mutant. Taken together, these data suggest that ZmTIP2;3 plays an important role in promoting maize tolerance to drought stress during arbuscular mycorrhiza fungi symbiosis.

Uncovering the GacS-mediated role in evolutionary progression through trajectory reconstruction in Pseudomonas aeruginosa.

The genetic diversities of subpopulations drive the evolution of pathogens and affect their ability to infect hosts and cause diseases. However, most studies to date have focused on the identification and characterization of adaptive mutations in single colonies, which do not accurately reflect the phenotypes of an entire population. Here, to identify the composition of variant subpopulations within a pathogen population, we developed a streamlined approach that combines high-throughput sequencing of the entire population cells with genotyping of single colonies. Using this method, we reconstructed a detailed quorum-sensing (QS) evolutionary trajectory in Pseudomonas aeruginosa. Our results revealed a new adaptive mutation in the gacS gene, which codes for a histidine kinase sensor of a two-component system (TCS), during QS evolution. This mutation reduced QS activity, allowing the variant to sweep throughout the whole population, while still being vulnerable to invasion by the emerging QS master regulator LasR-null mutants. By tracking the evolutionary trajectory, we found that mutations in gacS facilitated QS-rewiring in the LasR-null mutant. This rapid QS revertant caused by inactive GacS was found to be associated with the promotion of ribosome biogenesis and accompanied by a trade-off of reduced bacterial virulence on host cells. In conclusion, our findings highlight the crucial role of the global regulator GacS in modulating the progression of QS evolution and the virulence of the pathogen population.

The impact of paramagnetic rim lesions on cortical thickness and gray to white matter contrast in relapsing-remitting multiple sclerosis.

Background: Paramagnetic rim lesions (PRLs) on susceptibility magnetic resonance sequences have been suggested as an imaging marker of disease progression in multiple sclerosis. This retrospective cross-sectional study aimed to investigate the impact of PRLs on cortical thickness and gray matter (GM) to white matter (WM) contrast in relapsing-remitting multiple sclerosis (RRMS). Methods: A total of 82 RRMS patients (40 patients with at least 1 PRL and 42 patients without PRL) and 43 healthy controls (HC) were included in this study. The T1-weighted images (T1WI) were processed with the FreeSurfer pipeline. GM to WM signal intensity ratio (GWR) was obtained from T1WI by dividing the GM signal intensity by the WM signal intensity for each vertex. Group differences in cortical thickness and GWR were tested on reconstructed cortical surface. Results: Compared to HC, patients with PRL had thinner mean cortical thickness (P<0.001), higher mean GWR (P=0.001), and lower brain structure volumes (cortex volume, P=0.001; WM volume, P<0.001; deep GM volume, P<0.001). Vertex-based analysis found significant cortical thinning in several regions and increased GWR in a wider range of regions in patients with PRL. The two types of clusters had both overlapping regions and independent regions. However, in patients without PRL, only a few regions showed significant cortical thickness changes. Correlation analysis found that in patients with PRL, only PRL volume showed a significant negative correlation with mean cortical thickness (P=0.048), and PRL volume and count, non-PRL count, and total lesion volume were significantly and positively correlated with mean GWR (P<0.05). Conclusions: There were significant changes in cortical thickness, GWR, and brain structure volume in RRMS patients with PRL that may contribute to further understanding of the pathological mechanisms underlying neurological tissue damage.

Uncovering a hidden functional role of the XRE-cupin protein PsdR as a novel quorum-sensing regulator in Pseudomonas aeruginosa.

XRE-cupin family proteins containing an DNA-binding domain and a cupin signal-sensing domain are widely distributed in bacteria. In Pseudomonas aeruginosa, XRE-cupin transcription factors have long been recognized as regulators exclusively controlling cellular metabolism pathways. However, their potential functional roles beyond metabolism regulation remain unknown. PsdR, a typical XRE-cupin transcriptional regulator, was previously characterized as a local repressor involved solely in dipeptide metabolism. Here, by measuring quorum-sensing (QS) activities and QS-controlled metabolites, we uncover that PsdR is a new QS regulator in P. aeruginosa. Our RNA-seq analysis showed that rather than a local regulator, PsdR controls a large regulon, including genes associated with both the QS circuit and non-QS pathways. To unveil the underlying mechanism of PsdR in modulating QS, we developed a comparative transcriptome approach named "transcriptome profile similarity analysis" (TPSA). Using this TPSA method, we revealed that PsdR expression causes a QS-null-like transcriptome profile, resulting in QS-inactive phenotypes. Based on the results of TPSA, we further demonstrate that PsdR directly binds to the promoter for the gene encoding the QS master transcription factor LasR, thereby negatively regulating its expression and influencing QS activation. Moreover, our results showed that PsdR functions as a negative virulence regulator, as inactivation of PsdR enhanced bacterial cytotoxicity on host cells. In conclusion, we report on a new QS regulation role for PsdR, providing insights into its role in manipulating QS-controlled virulence. Most importantly, our findings open the door for a further discovery of untapped functions for other XRE-Cupin family proteins.

Large-scale functional network connectivity mediates the association between nigral neuromelanin hypopigmentation and motor impairment in Parkinson's disease.

Neuromelanin hypopigmentation within substantia nigra pars compacta (SNc) reflects the loss of pigmented neurons, which in turn contributes to the dysfunction of the nigrostriatal and striato-cortical pathways in Parkinson's disease (PD). Our study aims to investigate the relationships between SN degeneration manifested by neuromelanin reduction, functional connectivity (FC) among large-scale brain networks, and motor impairment in PD. This study included 68 idiopathic PD patients and 32 age-, sex- and education level-matched healthy controls who underwent neuromelanin-sensitive magnetic resonance imaging (MRI), functional MRI, and motor assessments. SN integrity was measured using the subregional contrast-to-noise ratio calculated from neuromelanin-sensitive MRI. Resting-state FC maps were obtained based on the independent component analysis. Subsequently, we performed partial correlation and mediation analyses in SN degeneration, network disruption, and motor impairment for PD patients. We found significantly decreased neuromelanin within SN and widely altered inter-network FCs, mainly involved in the basal ganglia (BG), sensorimotor and frontoparietal networks in PD. In addition, decreased neuromelanin content was negatively correlated with the dorsal sensorimotor network (dSMN)-medial visual network connection (P = 0.012) and dSMN-BG connection (P = 0.004). Importantly, the effect of SN neuromelanin hypopigmentation on motor symptom severity in PD is partially mediated by the increased connectivity strength between BG and dSMN (indirect effect = - 1.358, 95% CI: - 2.997, - 0.147). Our results advanced our understanding of the interactions between neuromelanin hypopigmentation in SN and altered FCs of functional networks in PD and suggested the potential of multimodal metrics for early diagnosis and monitoring the response to therapies.

A normative modeling approach to quantify white matter changes and predict functional outcomes in stroke patients.

Objectives: The diverse nature of stroke necessitates individualized assessment, presenting challenges to case-control neuroimaging studies. The normative model, measuring deviations from a normal distribution, provides a solution. We aim to evaluate stroke-induced white matter microstructural abnormalities at group and individual levels and identify potential prognostic biomarkers. Methods: Forty-six basal ganglia stroke patients and 46 healthy controls were recruited. Diffusion-weighted imaging and clinical assessment were performed within 7 days after stroke. We used automated fiber quantification to characterize intergroup alterations of segmental diffusion properties along 20 fiber tracts. Then each patient was compared to normative reference (46 healthy participants) by Mahalanobis distance tractometry for 7 significant fiber tracts. Mahalanobis distance-based deviation loads (MaDDLs) and fused MaDDLmulti were extracted to quantify individual deviations. We also conducted correlation and logistic regression analyses to explore relationships between MaDDL metrics and functional outcomes. Results: Disrupted microstructural integrity was observed across the left corticospinal tract, bilateral inferior fronto-occipital fasciculus, left inferior longitudinal fasciculus, bilateral thalamic radiation, and right uncinate fasciculus. The correlation coefficients between MaDDL metrics and initial functional impairment ranged from 0.364 to 0.618 (p < 0.05), with the highest being MaDDLmulti. Furthermore, MaDDLmulti demonstrated a significant enhancement in predictive efficacy compared to MaDDL (integrated discrimination improvement [IDI] = 9.62%, p = 0.005) and FA (IDI = 34.04%, p < 0.001) of the left corticospinal tract. Conclusion: MaDDLmulti allows for assessing behavioral disorders and predicting prognosis, offering significant implications for personalized clinical decision-making and stroke recovery. Importantly, our method demonstrates prospects for widespread application in heterogeneous neurological diseases.

An engineered influenza virus to deliver antigens for lung cancer vaccination.

The development of cancer neoantigen vaccines that prime the anti-tumor immune responses has been hindered in part by challenges in delivery of neoantigens to the tumor. Here, using the model antigen ovalbumin (OVA) in a melanoma model, we demonstrate a chimeric antigenic peptide influenza virus (CAP-Flu) system for delivery of antigenic peptides bound to influenza A virus (IAV) to the lung. We conjugated attenuated IAVs with the innate immunostimulatory agent CpG and, after intranasal administration to the mouse lung, observed increased immune cell infiltration to the tumor. OVA was then covalently displayed on IAV-CPG using click chemistry. Vaccination with this construct yielded robust antigen uptake by dendritic cells, a specific immune cell response and a significant increase in tumor-infiltrating lymphocytes compared to peptides alone. Lastly, we engineered the IAV to express anti-PD1-L1 nanobodies that further enhanced regression of lung metastases and prolonged mouse survival after rechallenge. Engineered IAVs can be equipped with any tumor neoantigen of interest to generate lung cancer vaccines.

A new magnetic state selection method in high-performance optically detected compact cesium beam clocks.

We perform a new scheme of magnetic state selection in optically detected compact cesium beam clocks. Unlike the conventional method, we select atoms in the ground state |F = 4, mF ≠ -4⟩ by pointing the atomic collimator to the convex pole of the magnet realizing the two-wire magnetic field and detect atoms in |F = 3⟩ after interacting with the microwave field using a distributed feedback laser. The fluorescence background is greatly reduced as the inherent residual atoms |F = 4, mF = -4⟩ are avoided in this reversed scheme. The velocity distribution is narrowed, and the most probable velocity is decreased, since atomic trajectories are close to the weak-field region. We also investigate the relationship between the position of the atomic collimator and the distributions of the atomic beam, which is consistent with the Monte Carlo-based simulation model. By applying the reversed scheme and setting the deviated position of the collimator to 1.3 mm, the signal contrast is improved from 0.7 to 3, and the short-term frequency stability reaches 3.0 × 10-12 τ-1/2, nearly three times better than that of the high-performance version of Microsemi 5071A.

Diffusion along the perivascular space as a potential biomarker for glioma grading and isocitrate dehydrogenase 1 mutation status prediction.

Background: The diffusion tensor image analysis along the perivascular space (DTI-ALPS) may have the potential to reflect glymphatic dysfunction in patients with glioma. The study aimed to determine the correlation of DTI-ALPS with glioma grade and isocitrate dehydrogenase 1 (IDH1) genotype and to then compare the ALPS index with other diffusion metrics. Methods: In this study, 81 patients with glioma and 31 healthy controls underwent magnetic resonance imaging (MRI) examination. The ALPS-index, fractional anisotropy (FA), mean diffusivity (MD), and mean kurtosis (MK) were calculated. Comparisons were made between the left and right hemispheres and between patients and controls. IDH1 status was compared after age adjustment. The diagnostic performance of each metric was assessed via receiver operating characteristic (ROC) analysis. Results: In patients with glioma, the ALPS-index of the hemisphere ipsilateral to glioma was significantly lower than that of the hemisphere contralateral to glioma (1.417±0.177 vs. 1.478±0.165; P=0.002), and the bilateral ALPS-index values in patients were significantly decreased compared with those in healthy controls. The ALPS-index was significantly higher in lower-grade gliomas (LrGGs) than that in glioblastomas (GBMs) (1.495±0.151 vs. 1.320±0.159; P<0.001) and was significantly lower in IDH1-wild-type LrGGs than in IDH1-mutant LrGGs (1.400±0.185 vs. 1.530±0.123; P=0.036). FA, MD, and MK also showed significant differences between LrGGs and GBMs and between IDH1-mutant and IDH1-wild-type LrGGs (P<0.05). Furthermore, the combination of the ALPS-index with FA, MD, or MK, exhibited superior discrimination ability compared to each metric used alone. The ALPS-index combined with MD had the highest area under the curve (AUC) of 0.854 as compared to that of 0.614-0.807 for a single metric in glioma grading, while for IDH1 mutation prediction, this combination had the highest AUC of 0.861 as compared to that of 0.707-0.778 for a single metric. Conclusions: The reduced ALPS-index may reflect tumor-induced glymphatic system impairment, and the ALPS-index may be able to complement conventional diffusion metrics in glioma grading and IDH1 genotyping.

Enhanced Resonance for Facilitated Modulation of Large-Area Perovskite Films with Stable Photovoltaics.

Upscaling efficient and stable perovskite films is a challenging task in the industrialization of perovskite solar cells partly due to the lack of high-performance hole transport materials (HTMs), which can simultaneously promote hole transport and regulate the quality of perovskite films especially in inverted solar cells. Here, a novel HTM based on N-C = O resonance structure is designed for facilitating the modulation of the crystallization and bottom-surface defects of perovskite films. Benefiting from the resonance interconversion (N-C = O and N+ = C-O- ) in donor-resonance-donor (D-r-D) architecture and interactions with uncoordinated Pb2+ in perovskite, the resulting D-r-D HTM with two donor units exhibits not only excellent hole extraction and transport capacities, but also efficient crystallization modulation of perovskite for high-quality photovoltaic films in large area. The D-r-D HTM-based large-area (1.02 cm2 ) devices exhibit high power conversion efficiencies (PCEs) up to 21.0%. Moreover, the large-area devices have excellent photo-thermal stability, showing only a 2.6% reduction in PCE under continuous AM 1.5G light illumination at elevated temperature (≈65 °C) for over 1320 h without encapsulation.