Fusobacterium nucleatum Promotes Chemoresistance to Colorectal Cancer by Modulating Autophagy.

Gut microbiota are linked to chronic inflammation and carcinogenesis. Chemotherapy failure is the major cause of recurrence and poor prognosis in colorectal cancer patients. Here, we investigated the contribution of gut microbiota to chemoresistance in patients with colorectal cancer. We found that Fusobacterium (F.) nucleatum was abundant in colorectal cancer tissues in patients with recurrence post chemotherapy, and was associated with patient clinicopathological characterisitcs. Furthermore, our bioinformatic and functional studies demonstrated that F. nucleatum promoted colorectal cancer resistance to chemotherapy. Mechanistically, F. nucleatum targeted TLR4 and MYD88 innate immune signaling and specific microRNAs to activate the autophagy pathway and alter colorectal cancer chemotherapeutic response. Thus, F. nucleatum orchestrates a molecular network of the Toll-like receptor, microRNAs, and autophagy to clinically, biologically, and mechanistically control colorectal cancer chemoresistance. Measuring and targeting F. nucleatum and its associated pathway will yield valuable insight into clinical management and may ameliorate colorectal cancer patient outcomes.

Small peptide signaling via OsCIF1/2 mediates Casparian strip formation at the root endodermal and nonendodermal cell layers in rice.

The Casparian strip (CS) is a ring-like lignin structure deposited between endodermal cells that forms an apoplastic barrier to control the selective uptake of nutrients in vascular plants. However, the molecular mechanism of CS formation in rice (Oryza sativa), which possesses one CS each in the endodermis and exodermis, is relatively unknown. Here, we functionally characterized CS INTEGRITY FACTOR1 (OsCIF1a, OsCIF1b), OsCIF2, and SCHENGEN3 (OsSGN3a, OsSGN3b) in rice. OsCIF1s and OsCIF2 were mainly expressed in the stele, while OsSGN3s localized around the CS at the endodermis. Knockout of all three OsCIFs or both OsSGN3s resulted in a discontinuous CS and a dramatic reduction in compensatory (less localized) lignification and suberization at the endodermis. By contrast, ectopic overexpression of OsCIF1 or OsCIF2 induced CS formation as well as overlignification and oversuberization at single or double cortical cell layers adjacent to the endodermis. Ectopic co-overexpression of OsCIF1 and SHORTROOT1 (OsSHR1) induced the formation of more CS-like structures at multiple cortical cell layers. Transcriptome analysis identified 112 downstream genes modulated by the OsCIF1/2-OsSGN3 signaling pathway, which is involved in CS formation and activation of the compensatory machinery in native endodermis and nonnative endodermis-like cell layers. Our results provide important insights into the molecular mechanism of CIF-mediated CS formation at the root endodermal and nonendodermal cell layers.

Computational design of transmembrane pores.

Transmembrane channels and pores have key roles in fundamental biological processes1 and in biotechnological applications such as DNA nanopore sequencing2-4, resulting in considerable interest in the design of pore-containing proteins. Synthetic amphiphilic peptides have been found to form ion channels5,6, and there have been recent advances in de novo membrane protein design7,8 and in redesigning naturally occurring channel-containing proteins9,10. However, the de novo design of stable, well-defined transmembrane protein pores that are capable of conducting ions selectively or are large enough to enable the passage of small-molecule fluorophores remains an outstanding challenge11,12. Here we report the computational design of protein pores formed by two concentric rings of α-helices that are stable and monodisperse in both their water-soluble and their transmembrane forms. Crystal structures of the water-soluble forms of a 12-helical pore and a 16-helical pore closely match the computational design models. Patch-clamp electrophysiology experiments show that, when expressed in insect cells, the transmembrane form of the 12-helix pore enables the passage of ions across the membrane with high selectivity for potassium over sodium; ion passage is blocked by specific chemical modification at the pore entrance. When incorporated into liposomes using in vitro protein synthesis, the transmembrane form of the 16-helix pore-but not the 12-helix pore-enables the passage of biotinylated Alexa Fluor 488. A cryo-electron microscopy structure of the 16-helix transmembrane pore closely matches the design model. The ability to produce structurally and functionally well-defined transmembrane pores opens the door to the creation of designer channels and pores for a wide variety of applications.

Multiparametric Characterization of Focal Cortical Dysplasia Using 3D MR Fingerprinting.

OBJECTIVES: To develop a multiparametric machine-learning (ML) framework using high-resolution 3 dimensional (3D) magnetic resonance (MR) fingerprinting (MRF) data for quantitative characterization of focal cortical dysplasia (FCD). MATERIALS: We included 119 subjects, 33 patients with focal epilepsy and histopathologically confirmed FCD, 60 age- and gender-matched healthy controls (HCs), and 26 disease controls (DCs). Subjects underwent whole-brain 3 Tesla MRF acquisition, the reconstruction of which generated T1 and T2 relaxometry maps. A 3D region of interest was manually created for each lesion, and z-score normalization using HC data was performed. We conducted 2D classification with ensemble models using MRF T1 and T2 mean and standard deviation from gray matter and white matter for FCD versus controls. Subtype classification additionally incorporated entropy and uniformity of MRF metrics, as well as morphometric features from the morphometric analysis program (MAP). We translated 2D results to individual probabilities using the percentage of slices above an adaptive threshold. These probabilities and clinical variables were input into a support vector machine for individual-level classification. Fivefold cross-validation was performed and performance metrics were reported using receiver-operating-characteristic-curve analyses. RESULTS: FCD versus HC classification yielded mean sensitivity, specificity, and accuracy of 0.945, 0.980, and 0.962, respectively; FCD versus DC classification achieved 0.918, 0.965, and 0.939. In comparison, visual review of the clinical magnetic resonance imaging (MRI) detected 48% (16/33) of the lesions by official radiology report. In the subgroup where both clinical MRI and MAP were negative, the MRF-ML models correctly distinguished FCD patients from HCs and DCs in 98.3% of cross-validation trials for the magnetic resonance imaging negative group and MAP negative group. Type II versus non-type-II classification exhibited mean sensitivity, specificity, and accuracy of 0.835, 0.823, and 0.83, respectively; type IIa versus IIb classification showed 0.85, 0.9, and 0.87. In comparison, the transmantle sign was present in 58% (7/12) of the IIb cases. INTERPRETATION: The MRF-ML framework presented in this study demonstrated strong efficacy in noninvasively classifying FCD from normal cortex and distinguishing FCD subtypes. ANN NEUROL 2024.

Portable Hadamard-Transform Raman Spectrometer: A Powerful Analytical Tool for Point-of-Care Testing.

A portable Hadamard-transform Raman spectrometer with excellent performance was fabricated consisting of a 785 nm laser, an optical filter, an optical system, a control system, and a signal processing system. As the core of the spectrometer, the optical system was composed of a slit, collimator, optical grating, reflector, digital micromirror devices (DMD), lens system, and InGaAs photodetector. Compared with a conventional dispersive Raman spectrometer, the proposed Raman spectrometer adopted the DMD and corresponding controlling device (DLPC350 control chip) to collect the Raman spectrum. Thus, in our design, the gratings are fixed, while the full Raman spectrum was collected by the deflection of the micromirror. This design can greatly improve the vibration resistance ability of the spectrometer since the gratings are not rotating during the spectrum collecting. More importantly, Hadamard-transform was used as signal processing technology, which has the ability of faster calculation, the merits of high energy input, single detector multichannel simultaneous detection (imaging) ability, and high signal-to-noise ratio (SNR). Hence, the Hadamard-transform portable Raman spectrometer has the potential to be applied in the field of point-of-care testing (POCT).

Roles of TRP and PIEZO receptors in autoimmune diseases.

Autoimmune diseases are pathological autoimmune reactions in the body caused by various factors, which can lead to tissue damage and organ dysfunction. They can be divided into organ-specific and systemic autoimmune diseases. These diseases usually involve various body systems, including the blood, muscles, bones, joints and soft tissues. The transient receptor potential (TRP) and PIEZO receptors, which resulted in David Julius and Ardem Patapoutian winning the Nobel Prize in Physiology or Medicine in 2021, attracted people's attention. Most current studies on TRP and PIEZO receptors in autoimmune diseases have been carried out on animal model, only few clinical studies have been conducted. Therefore, this study aimed to review existing studies on TRP and PIEZO to understand the roles of these receptors in autoimmune diseases, which may help elucidate novel treatment strategies.

Efficient pulse sequence design framework for high-dimensional MR fingerprinting scans using systematic error index.

PURPOSE: For effective optimization of MR fingerprinting (MRF) pulse sequences, estimating and minimizing errors from actual scan conditions are crucial. Although virtual-scan simulations offer an approximation to these errors, their computational demands become expensive for high-dimensional MRF frameworks, where interactions between more than two tissue properties are considered. This complexity makes sequence optimization impractical. We introduce a new mathematical model, the systematic error index (SEI), to address the scalability challenges for high-dimensional MRF sequence design. METHODS: By eliminating the need to perform dictionary matching, the SEI model approximates quantification errors with low computational costs. The SEI model was validated in comparison with virtual-scan simulations. The SEI model was further applied to optimize three high-dimensional MRF sequences that quantify two to four tissue properties. The optimized scans were examined in simulations and healthy subjects. RESULTS: The proposed SEI model closely approximated the virtual-scan simulation outcomes while achieving hundred- to thousand-times acceleration in the computational speed. In both simulation and in vivo experiments, the optimized MRF sequences yield higher measurement accuracy with fewer undersampling artifacts at shorter scan times than the heuristically designed sequences. CONCLUSION: We developed an efficient method for estimating real-world errors in MRF scans with high computational efficiency. Our results illustrate that the SEI model could approximate errors both qualitatively and quantitatively. We also proved the practicality of the SEI model of optimizing sequences for high-dimensional MRF frameworks with manageable computational power. The optimized high-dimensional MRF scans exhibited enhanced robustness against undersampling and system imperfections with faster scan times.

Self-calibrated subspace reconstruction for multidimensional MR fingerprinting for simultaneous relaxation and diffusion quantification.

PURPOSE: To propose a new reconstruction method for multidimensional MR fingerprinting (mdMRF) to address shading artifacts caused by physiological motion-induced measurement errors without navigating or gating. METHODS: The proposed method comprises two procedures: self-calibration and subspace reconstruction. The first procedure (self-calibration) applies temporally local matrix completion to reconstruct low-resolution images from a subset of under-sampled data extracted from the k-space center. The second procedure (subspace reconstruction) utilizes temporally global subspace reconstruction with pre-estimated temporal subspace from low-resolution images to reconstruct aliasing-free, high-resolution, and time-resolved images. After reconstruction, a customized outlier detection algorithm was employed to automatically detect and remove images corrupted by measurement errors. Feasibility, robustness, and scan efficiency were evaluated through in vivo human brain imaging experiments. RESULTS: The proposed method successfully reconstructed aliasing-free, high-resolution, and time-resolved images, where the measurement errors were accurately represented. The corrupted images were automatically and robustly detected and removed. Artifact-free T1, T2, and ADC maps were generated simultaneously. The proposed reconstruction method demonstrated robustness across different scanners, parameter settings, and subjects. A high scan efficiency of less than 20 s per slice has been achieved. CONCLUSION: The proposed reconstruction method can effectively alleviate shading artifacts caused by physiological motion-induced measurement errors. It enables simultaneous and artifact-free quantification of T1, T2, and ADC using mdMRF scans without prospective gating, with robustness and high scan efficiency.

Quantifying 3D MR fingerprinting (3D-MRF) reproducibility across subjects, sessions, and scanners automatically using MNI atlases.

PURPOSE: Quantitative MRI techniques such as MR fingerprinting (MRF) promise more objective and comparable measurements of tissue properties at the point-of-care than weighted imaging. However, few direct cross-modal comparisons of MRF's repeatability and reproducibility versus weighted acquisitions have been performed. This work proposes a novel fully automated pipeline for quantitatively comparing cross-modal imaging performance in vivo via atlas-based sampling. METHODS: We acquire whole-brain 3D-MRF, turbo spin echo, and MPRAGE sequences three times each on two scanners across 10 subjects, for a total of 60 multimodal datasets. The proposed automated registration and analysis pipeline uses linear and nonlinear registration to align all qualitative and quantitative DICOM stacks to Montreal Neurological Institute (MNI) 152 space, then samples each dataset's native space through transformation inversion to compare performance within atlas regions across subjects, scanners, and repetitions. RESULTS: Voxel values within MRF-derived maps were found to be more repeatable (σT1 = 1.90, σT2 = 3.20) across sessions than vendor-reconstructed MPRAGE (σT1w = 6.04) or turbo spin echo (σT2w = 5.66) images. Additionally, MRF was found to be more reproducible across scanners (σT1 = 2.21, σT2 = 3.89) than either qualitative modality (σT1w = 7.84, σT2w = 7.76). Notably, differences between repeatability and reproducibility of in vivo MRF were insignificant, unlike the weighted images. CONCLUSION: MRF data from many sessions and scanners can potentially be treated as a single dataset for harmonized analysis or longitudinal comparisons without the additional regularization steps needed for qualitative modalities.

3D MR fingerprinting for dynamic contrast-enhanced imaging of whole mouse brain.

PURPOSE: Quantitative MRI enables direct quantification of contrast agent concentrations in contrast-enhanced scans. However, the lengthy scan times required by conventional methods are inadequate for tracking contrast agent transport dynamically in mouse brain. We developed a 3D MR fingerprinting (MRF) method for simultaneous T1 and T2 mapping across the whole mouse brain with 4.3-min temporal resolution. METHOD: We designed a 3D MRF sequence with variable acquisition segment lengths and magnetization preparations on a 9.4T preclinical MRI scanner. Model-based reconstruction approaches were employed to improve the accuracy and speed of MRF acquisition. The method's accuracy for T1 and T2 measurements was validated in vitro, while its repeatability of T1 and T2 measurements was evaluated in vivo (n = 3). The utility of the 3D MRF sequence for dynamic tracking of intracisternally infused gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) in the whole mouse brain was demonstrated (n = 5). RESULTS: Phantom studies confirmed accurate T1 and T2 measurements by 3D MRF with an undersampling factor of up to 48. Dynamic contrast-enhanced MRF scans achieved a spatial resolution of 192 × 192 × 500 µm3 and a temporal resolution of 4.3 min, allowing for the analysis and comparison of dynamic changes in concentration and transport kinetics of intracisternally infused Gd-DTPA across brain regions. The sequence also enabled highly repeatable, high-resolution T1 and T2 mapping of the whole mouse brain (192 × 192 × 250 µm3) in 30 min. CONCLUSION: We present the first dynamic and multi-parametric approach for quantitatively tracking contrast agent transport in the mouse brain using 3D MRF.

Repeat it without me: Crowdsourcing the T1 mapping common ground via the ISMRM reproducibility challenge.

PURPOSE: T1 mapping is a widely used quantitative MRI technique, but its tissue-specific values remain inconsistent across protocols, sites, and vendors. The ISMRM Reproducible Research and Quantitative MR study groups jointly launched a challenge to assess the reproducibility of a well-established inversion-recovery T1 mapping technique, using acquisition details from a seminal T1 mapping paper on a standardized phantom and in human brains. METHODS: The challenge used the acquisition protocol from Barral et al. (2010). Researchers collected T1 mapping data on the ISMRM/NIST phantom and/or in human brains. Data submission, pipeline development, and analysis were conducted using open-source platforms. Intersubmission and intrasubmission comparisons were performed. RESULTS: Eighteen submissions (39 phantom and 56 human datasets) on scanners by three MRI vendors were collected at 3 T (except one, at 0.35 T). The mean coefficient of variation was 6.1% for intersubmission phantom measurements, and 2.9% for intrasubmission measurements. For humans, the intersubmission/intrasubmission coefficient of variation was 5.9/3.2% in the genu and 16/6.9% in the cortex. An interactive dashboard for data visualization was also developed: https://rrsg2020.dashboards.neurolibre.org. CONCLUSION: The T1 intersubmission variability was twice as high as the intrasubmission variability in both phantoms and human brains, indicating that the acquisition details in the original paper were insufficient to reproduce a quantitative MRI protocol. This study reports the inherent uncertainty in T1 measures across independent research groups, bringing us one step closer to a practical clinical baseline of T1 variations in vivo.

Motion Robust MR Fingerprinting Scan to Image Neonates With Prenatal Opioid Exposure.

PURPOSE: To explore whether MR fingerprinting (MRF) scans provide motion-robust and quantitative brain tissue measurements for non-sedated infants with prenatal opioid exposure (POE). STUDY TYPE: Prospective. POPULATION: 13 infants with POE (3 male; 12 newborns (age 7-65 days) and 1 infant aged 9-months). FIELD STRENGTH/SEQUENCE: 3T, 3D T1-weighted MPRAGE, 3D T2-weighted TSE and MRF sequences. ASSESSMENT: The image quality of MRF and MRI was assessed in a fully crossed, multiple-reader, multiple-case study. Sixteen image quality features in three types-image artifacts, structure and myelination visualization-were ranked by four neuroradiologists (8, 7, 5, and 8 years of experience respectively), using a 3-point scale. MRF T1 and T2 values in 8 white matter brain regions were compared between babies younger than 1 month and babies between 1 and 2 months. STATISTICAL TESTS: Generalized estimating equations model to test the significance of differences of regional T1 and T2 values of babies under 1 month and those older. MRI and MRF image quality was assessed using Gwet's second order auto-correlation coefficient (AC2) with confidence levels. The Cochran-Mantel-Haenszel test was used to assess the difference in proportions between MRF and MRI for all features and stratified by the type of features. A P value <0.05 was considered statistically significant. RESULTS: The MRF of two infants were excluded in T1 and T2 value analysis due to severe motion artifact but were included in the image quality assessment. In infants under 1 month of age (N = 6), the T1 and T2 values were significantly higher compared to those between 1 and 2 months of age (N = 4). MRF images showed significantly higher image quality ratings in all three feature types compared to MRI images. CONCLUSIONS: MR Fingerprinting scans have potential to be a motion-robust and efficient method for nonsedated infants. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 1.

Combining magnetic resonance fingerprinting with voxel-based morphometric analysis to reduce false positives for focal cortical dysplasia detection.

OBJECTIVE: We aim to improve focal cortical dysplasia (FCD) detection by combining high-resolution, three-dimensional (3D) magnetic resonance fingerprinting (MRF) with voxel-based morphometric magnetic resonance imaging (MRI) analysis. METHODS: We included 37 patients with pharmacoresistant focal epilepsy and FCD (10 IIa, 15 IIb, 10 mild Malformation of Cortical Development [mMCD], and 2 mMCD with oligodendroglial hyperplasia and epilepsy [MOGHE]). Fifty-nine healthy controls (HCs) were also included. 3D lesion labels were manually created. Whole-brain MRF scans were obtained with 1 mm3 isotropic resolution, from which quantitative T1 and T2 maps were reconstructed. Voxel-based MRI postprocessing, implemented with the morphometric analysis program (MAP18), was performed for FCD detection using clinical T1w images, outputting clusters with voxel-wise lesion probabilities. Average MRF T1 and T2 were calculated in each cluster from MAP18 output for gray matter (GM) and white matter (WM) separately. Normalized MRF T1 and T2 were calculated by z-scores using HCs. Clusters that overlapped with the lesion labels were considered true positives (TPs); clusters with no overlap were considered false positives (FPs). Two-sample t-tests were performed to compare MRF measures between TP/FP clusters. A neural network model was trained using MRF values and cluster volume to distinguish TP/FP clusters. Ten-fold cross-validation was used to evaluate model performance at the cluster level. Leave-one-patient-out cross-validation was used to evaluate performance at the patient level. RESULTS: MRF metrics were significantly higher in TP than FP clusters, including GM T1, normalized WM T1, and normalized WM T2. The neural network model with normalized MRF measures and cluster volume as input achieved mean area under the curve (AUC) of .83, sensitivity of 82.1%, and specificity of 71.7%. This model showed superior performance over direct thresholding of MAP18 FCD probability map at both the cluster and patient levels, eliminating ≥75% FP clusters in 30% of patients and ≥50% of FP clusters in 91% of patients. SIGNIFICANCE: This pilot study suggests the efficacy of MRF for reducing FPs in FCD detection, due to its quantitative values reflecting in vivo pathological changes. © 2024 International League Against Epilepsy.

Abnormal cerebral blood flow in children with developmental stuttering.

BACKGROUND: Stuttering affects approximately 5% of children; however, its neurological basis remains unclear. Identifying imaging biomarkers could aid in early detection. Accordingly, we investigated resting-state cerebral blood flow (CBF) in children with developmental stuttering. METHODS: Pulsed arterial spin labelling magnetic resonance imaging was utilised to quantify CBF in 35 children with developmental stuttering and 27 healthy controls. We compared normalised CBF between the two groups and evaluated the correlation between abnormal CBF and clinical indicators. RESULTS: Compared with healthy controls, the stuttering group exhibited decreased normalised CBF in the cerebellum lobule VI bilaterally, right cuneus, and left superior occipital gyrus and increased CBF in the right medial superior frontal gyrus, left rectus, and left dorsolateral superior frontal gyrus. Additionally, normalised CBF in the left cerebellum lobule VI and left superior occipital gyrus was positively correlated with stuttering severity. CONCLUSIONS: Children who stutter display decreased normalised CBF primarily in the cerebellum and occipital gyrus, with increased normalised CBF in the frontal gyrus. Additionally, the abnormal CBF in the left cerebellum lobule VI and left superior occipital gyrus was associated with more severe symptoms, suggesting that decreased CBF in these areas may serve as a novel neuroimaging clue for stuttering. IMPACT: Stuttering occurs in 5% of children and often extends into adulthood, which may negatively affect quality of life. Early detection and treatment are essential. We used pulsed arterial spin labelling magnetic resonance imaging to visualise the resting-state cerebral blood flow (CBF) in children who stutter and healthy children. Normalised CBF was decreased in stutterers in the cerebellum and occipital gyrus and increased in the frontal gyrus. Stuttering severity was linked to abnormal normalised CBF in the left cerebellum lobule VI and left superior occipital gyrus, suggesting that CBF may serve as a novel neuroimaging clue for stuttering.

CircOGDH Is a Penumbra Biomarker and Therapeutic Target in Acute Ischemic Stroke.

BACKGROUND: Acute ischemic stroke (AIS) is a leading cause of disability and mortality worldwide. Prediction of penumbra existence after AIS is crucial for making decision on reperfusion therapy. Yet a fast, inexpensive, simple, and noninvasive predictive biomarker for the poststroke penumbra with clinical translational potential is still lacking. We aim to investigate whether the CircOGDH (circular RNA derived from oxoglutarate dehydrogenase) is a potential biomarker for penumbra in patients with AIS and its role in ischemic neuronal damage. METHODS: CircOGDH was screened from penumbra of middle cerebral artery occlusion mice and was assessed in plasma of patients with AIS by quantitative polymerase chain reaction. Magnetic resonance imaging was used to examine the penumbra volumes. CircOGDH interacted with miR-5112 (microRNA-5112) in primary cortical neurons was detected by fluorescence in situ hybridization, RNA immunoprecipitation, and luciferase reporter assay. Adenovirus-mediated CircOGDH knockdown ameliorated neuronal apoptosis induced by COL4A4 (Gallus collagen, type IV, alpha IV) overexpression. Transmission electron microscope, nanoparticle tracking analysis, and Western blot were performed to confirm exosomes. RESULTS: CircOGDH expression was dramatically and selectively upregulated in the penumbra tissue of middle cerebral artery occlusion mice and in the plasma of 45 patients with AIS showing a 54-fold enhancement versus noncerebrovascular disease controls. Partial regression analysis revealed that CircOGDH expression was positively correlated with the size of penumbra in patients with AIS. Sequestering of miR-5112 by CircOGDH enhanced COL4A4 expression to elevate neuron damage. Additionally, knockdown of CircOGDH significantly enhanced neuronal cell viability under ischemic conditions. Furthermore, the expression of CircOGDH in brain tissue was closely related to that in the serum of middle cerebral artery occlusion mice. Finally, we found that CircOGDH was highly expressed in plasma exosomes of patients with AIS compared with those in noncerebrovascular disease individuals. CONCLUSIONS: These results demonstrate that CircOGDH is a potential therapeutic target for regulating ischemia neuronal viability, and is enriched in neuron-derived exosomes in the peripheral blood, exhibiting a predictive biomarker of penumbra in patients with AIS.

Crystal structure of a membrane-bound O-acyltransferase.

Membrane-bound O-acyltransferases (MBOATs) are a superfamily of integral transmembrane enzymes that are found in all kingdoms of life1. In bacteria, MBOATs modify protective cell-surface polymers. In vertebrates, some MBOAT enzymes-such as acyl-coenzyme A:cholesterol acyltransferase and diacylglycerol acyltransferase 1-are responsible for lipid biosynthesis or phospholipid remodelling2,3. Other MBOATs, including porcupine, hedgehog acyltransferase and ghrelin acyltransferase, catalyse essential lipid modifications of secreted proteins such as Wnt, hedgehog and ghrelin, respectively4-10. Although many MBOAT proteins are important drug targets, little is known about their molecular architecture and functional mechanisms. Here we present crystal structures of DltB, an MBOAT responsible for the D-alanylation of cell-wall teichoic acid in Gram-positive bacteria11-16, both alone and in complex with the D-alanyl donor protein DltC. DltB contains a ring of 11 peripheral transmembrane helices, which shield a highly conserved extracellular structural funnel extending into the middle of the lipid bilayer. The conserved catalytic histidine residue is located at the bottom of this funnel and is connected to the intracellular DltC through a narrow tunnel. Mutation of either the catalytic histidine or the DltC-binding site of DltB abolishes the D-alanylation of lipoteichoic acid and sensitizes the Gram-positive bacterium Bacillus subtilis to cell-wall stress, which suggests cross-membrane catalysis involving the tunnel. Structure-guided sequence comparison among DltB and vertebrate MBOATs reveals a conserved structural core and suggests that MBOATs from different organisms have similar catalytic mechanisms. Our structures provide a template for understanding structure-function relationships in MBOATs and for developing therapeutic MBOAT inhibitors.

Normative quantitative relaxation atlases for characterization of cortical regions using magnetic resonance fingerprinting.

Quantitative magnetic resonance (MR) has been used to study cyto- and myelo-architecture of the human brain non-invasively. However, analyzing brain cortex using high-resolution quantitative MR acquisition can be challenging to perform using 3T clinical scanners. MR fingerprinting (MRF) is a highly efficient and clinically feasible quantitative MR technique that simultaneously provides T1 and T2 relaxation maps. Using 3D MRF from 40 healthy subjects (mean age = 25.6 ± 4.3 years) scanned on 3T magnetic resonance imaging, we generated whole-brain gyral-based normative MR relaxation atlases and investigated cortical-region-based T1 and T2 variations. Gender and age dependency of T1 and T2 variations were additionally analyzed. The coefficient of variation of T1 and T2 for each cortical-region was 3.5% and 7.3%, respectively, supporting low variability of MRF measurements across subjects. Significant differences in T1 and T2 were identified among 34 brain regions (P < 0.001), lower in the precentral, postcentral, paracentral lobule, transverse temporal, lateral occipital, and cingulate areas, which contain sensorimotor, auditory, visual, and limbic functions. Significant correlations were identified between age and T1 and T2 values. This study established whole-brain MRF T1 and T2 atlases of healthy subjects using a clinical 3T scanner, which can provide a quantitative and region-specific baseline for future brain studies and pathology detection.

The quest for nanoparticle-powered vaccines in cancer immunotherapy.

Despite recent advancements in cancer treatment, this disease still poses a serious threat to public health. Vaccines play an important role in preventing illness by preparing the body's adaptive and innate immune responses to combat diseases. As our understanding of malignancies and their connection to the immune system improves, there has been a growing interest in priming the immune system to fight malignancies more effectively and comprehensively. One promising approach involves utilizing nanoparticle systems for antigen delivery, which has been shown to potentiate immune responses as vaccines and/or adjuvants. In this review, we comprehensively summarized the immunological mechanisms of cancer vaccines while focusing specifically on the recent applications of various types of nanoparticles in the field of cancer immunotherapy. By exploring these recent breakthroughs, we hope to identify significant challenges and obstacles in making nanoparticle-based vaccines and adjuvants feasible for clinical application. This review serves to assess recent breakthroughs in nanoparticle-based cancer vaccinations and shed light on their prospects and potential barriers. By doing so, we aim to inspire future immunotherapies for cancer that harness the potential of nanotechnology to deliver more effective and targeted treatments.

Automated design of pulse sequences for magnetic resonance fingerprinting using physics-inspired optimization.

Magnetic resonance fingerprinting (MRF) is a method to extract quantitative tissue properties such as [Formula: see text] and [Formula: see text] relaxation rates from arbitrary pulse sequences using conventional MRI hardware. MRF pulse sequences have thousands of tunable parameters, which can be chosen to maximize precision and minimize scan time. Here, we perform de novo automated design of MRF pulse sequences by applying physics-inspired optimization heuristics. Our experimental data suggest that systematic errors dominate over random errors in MRF scans under clinically relevant conditions of high undersampling. Thus, in contrast to prior optimization efforts, which focused on statistical error models, we use a cost function based on explicit first-principles simulation of systematic errors arising from Fourier undersampling and phase variation. The resulting pulse sequences display features qualitatively different from previously used MRF pulse sequences and achieve fourfold shorter scan time than prior human-designed sequences of equivalent precision in [Formula: see text] and [Formula: see text] Furthermore, the optimization algorithm has discovered the existence of MRF pulse sequences with intrinsic robustness against shading artifacts due to phase variation.

Information Seeking and Receiving of Older Adults with Diabetes in the Online Health Community: An Information Need Contextualization Perspective.

Online health communities (OHCs) are important online health communication channels for older adults with diabetes to access health information. When seeking health information, they often disclose a variety of contextual information (e.g., socio-economic situations) in their questions. Selective contextual information disclosure is a type of communication strategy for users in OHCs to elicit replies from others. In this study, we adopted text analysis to investigate what contextual information older adults with diabetes disclose to articulate their information needs and used the fixed-effect Poisson model to examine the relationships between different types of contextual information disclosure and informational support receipt. Our analyses were based on a dataset of 4,505 questions and corresponding replies from an online diabetes community. The results showed that cognitive information is the most frequently disclosed contextual information, while older adults tend to disclose demographic information in their questions less. Providing demographic and situational details in questions can enhance informational support receiving, resulting in an increased number of informational supports. However, disclosing cognitive, affective, informational channels, or support information does not significantly affect the informational support receiving. These findings can contribute to extending our existing understanding of information seekers' communication strategies in OHCs.