Immune checkpoint therapy-elicited sialylation of IgG antibodies impairs antitumorigenic type I interferon responses in hepatocellular carcinoma.

The reinvigoration of anti-tumor T cells in response to immune checkpoint blockade (ICB) therapy is well established. Whether and how ICB therapy manipulates antibody-mediated immune response in cancer environments, however, remains elusive. Using tandem mass spectrometric analysis of modification of immunoglobulin G (IgG) from hepatoma tissues, we identified a role of ICB therapy in catalyzing IgG sialylation in the Fc region. Effector T cells triggered sialylation of IgG via an interferon (IFN)-γ-ST6Gal-I-dependent pathway. DC-SIGN+ macrophages represented the main target cells of sialylated IgG. Upon interacting with sialylated IgG, DC-SIGN stimulated Raf-1-elicited elevation of ATF3, which inactivated cGAS-STING pathway and eliminated subsequent type-I-IFN-triggered antitumorigenic immunity. Although enhanced IgG sialylation in tumors predicted improved therapeutic outcomes for patients receiving ICB therapy, impeding IgG sialylation augmented antitumorigenic T cell immunity after ICB therapy. Thus, targeting antibody-based negative feedback action of ICB therapy has potential for improving efficacy of cancer immunotherapies.

Spatial functional reorganizations can serve as potential biomarkers of post facial palsy synkinesis.

Facial palsy can result in a serious complication known as facial synkinesis, causing both physical and psychological harm to the patients. There is growing evidence that patients with facial synkinesis have brain abnormalities, but the brain mechanisms and underlying imaging biomarkers remain unclear. Here, we employed functional magnetic resonance imaging (fMRI) to investigate brain function in 31 unilateral post facial palsy synkinesis patients and 25 healthy controls during different facial expression movements and at rest. Combining surface-based mass-univariate analysis and multivariate pattern analysis, we identified diffused activation and intrinsic connection patterns in the primary motor cortex and the somatosensory cortex on the patient's affected side. Further, we classified post facial palsy synkinesis patients from healthy subjects with favorable accuracy using the support vector machine based on both task-related and resting-state functional magnetic resonance imaging data. Together, these findings indicate the potential of the identified functional reorganizations to serve as neuroimaging biomarkers for facial synkinesis diagnosis.

fMRI, LFP, and anatomical evidence for hierarchical nociceptive routing pathway between somatosensory and insular cortices.

The directional organization of multiple nociceptive regions, particularly within obscure operculoinsular areas, underlying multidimensional pain processing remains elusive. This study aims to establish the fundamental organization between somatosensory and insular cortices in routing nociceptive information. By employing an integrated multimodal approach of high-field fMRI, intracranial electrophysiology, and transsynaptic viral tracing in rats, we observed a hierarchically organized connection of S1/S2 → posterior insula → anterior insula in routing nociceptive information. The directional nociceptive pathway determined by early fMRI responses was consistent with that examined by early evoked LFP, intrinsic effective connectivity, and anatomical projection, suggesting fMRI could provide a valuable facility to discern directional neural circuits in animals and humans non-invasively. Moreover, our knowledge of the nociceptive hierarchical organization of somatosensory and insular cortices and the interface role of the posterior insula may have implications for the development of targeted pain therapies.

Hydrogenated V2O5 with Improved Optical and Electrochemical Activities for Photo-Accelerated Lithium-Ion Batteries.

Solar power represents an abundant and readily available source of renewable energy. However, its intermittent nature necessitates external energy storage solutions, which can often be expensive, bulky, and associated with energy conversion losses. This study introduces the concept of a photo-accelerated battery that seamlessly integrates energy harvesting and storage functions within a single device. In this research, a novel approach for crafting photocathodes is presented using hydrogenated vanadium pentoxide (H:V2O5) nanofibers. This method enhances optical activity, electronic conductivity, and ion diffusion rates within photo-accelerated Li-ion batteries. This study findings reveal that H:V2O5 exhibits notable improvements in specific capacity under both dark and illuminated conditions. Furthermore, it demonstrates enhanced diffusion kinetics and charge storage performance when exposed to light, as compared to pristine counterparts. This strategy of defect engineering holds great promise for the development of high-performance photocathodes in future energy storage applications.

Single-cell profiling reveals kidney CD163+ dendritic cell participation in human lupus nephritis.

OBJECTIVES: The current work aimed to provide a comprehensive single-cell landscape of lupus nephritis (LN) kidneys, including immune and non-immune cells, identify disease-associated cell populations and unravel their participation within the kidney microenvironment. METHODS: Single-cell RNA and T cell receptor sequencing were performed on renal biopsy tissues from 40 patients with LN and 6 healthy donors as controls. Matched peripheral blood samples from seven LN patients were also sequenced. Multiplex immunohistochemical analysis was performed on an independent cohort of 60 patients and validated using flow cytometric characterisation of human kidney tissues and in vitro assays. RESULTS: We uncovered a notable enrichment of CD163+ dendritic cells (DC3s) in LN kidneys, which exhibited a positive correlation with the severity of LN. In contrast to their counterparts in blood, DC3s in LN kidney displayed activated and highly proinflammatory phenotype. DC3s showed strong interactions with CD4+ T cells, contributing to intrarenal T cell clonal expansion, activation of CD4+ effector T cell and polarisation towards Th1/Th17. Injured proximal tubular epithelial cells (iPTECs) may orchestrate DC3 activation, adhesion and recruitment within the LN kidneys. In cultures, blood DC3s treated with iPTECs acquired distinct capabilities to polarise Th1/Th17 cells. Remarkably, the enumeration of kidney DC3s might be a potential biomarker for induction treatment response in LN patients. CONCLUSION: The intricate interplay involving DC3s, T cells and tubular epithelial cells within kidneys may substantially contribute to LN pathogenesis. The enumeration of renal DC3 holds potential as a valuable stratification feature for guiding LN patient treatment decisions in clinical practice.

Differential Recovery of Submodality Touch Neurons and Interareal Communication in Sensory Input-Deprived Area 3b and S2 Cortices.

Cortical reactivation and regain of interareal functional connections have been linked to the recovery of hand grasping behavior after loss of sensory inputs in primates. We investigated contributions of neurons in two hierarchically organized somatosensory areas, 3b and S2, by characterizing local field potential (LFP) and multiunit spiking activity in five states (rest, stimulus-on, sustained, stimulus-off, and induced) and interareal communication after grasping behavior of dorsal column lesioned male squirrel monkeys had mostly recovered. Compared with normal cortex, fMRI, LFP, and spiking response magnitudes to step indentations were significantly weaker. The sustained component of the spiking recovered much better than the stimulus-off response. Correlation between overall spiking and γ LFP remained strong within each recovered areas 3b and S2. The interareal correlations of γ LFP were severely disrupted, except in the resting and stimulus-on periods. Interareal correlation of spiking was disrupted in the stimulus-off period only. In summary, submodality of low threshold mechanoreceptive neurons recovered differentially in input-deprived area 3b and S2 when impaired global hand grasping behavior returned. Slow-adapting-like neurons recovered, whereas rapid-adapting-like neurons did not. Interareal communications were also severely compromised. We propose that slow-adapting-like neurons and afferents in recovered area 3b and S2 mediate recovery of impaired grasping behavior after dorsal column tract lesion.SIGNIFICANCE STATEMENT Sensory feedback is essential for execution of hand grasping behavior in primates. Reactivations of somatosensory cortices have been attributed to recovery of such behavior after loss of sensory inputs via largely unknown mechanisms. In input-deprived area 3b and S2 cortex, after hand grasping behavior mostly recovered, we found slow-adapting-like neurons were greatly recovered, whereas rapid-adapting-like neurons did not. Communications between area 3b and S2 neurons were severely compromised. We suggest that recovery of slow-adapting-like neurons in input-deprived area 3b and S2 may mediate the recovery of hand grasping behavior.

Dendrite-Free Zinc Anodes Enabled by Exploring Polar-Face-Rich 2D ZnO Interfacial Layers for Rechargeable Zn-Ion Batteries.

Zinc metal is a promising candidate for anodes in zinc-ion batteries (ZIBs), but its widespread implementation is hindered by dendrite growth in aqueous electrolytes. Dendrites lead to undesirable side reactions, such as hydrogen evolution, passivation, and corrosion, causing reduced capacity during prolonged cycling. In this study, an approach is explored to address this challenge by directly growing 1D zinc oxide (ZnO) nanorods (NRs) and 2D ZnO nanoflakes (NFs) on Zn anodes, forming artificial layers to enhance ZIB performance. The incorporation of ZnO on the anode offers both chemical and thermal stability and leverages its n-type semiconductor nature to facilitate the formation of ohmic contacts. This results in efficient electron transport during Zn ion plating and stripping processes. Consequently, the ZnO NFs-coated Zn anodes demonstrate significantly improved charge storage performance, achieving 348 mAh g-1 , as compared to ZnO NRs (250 mAh g-1 ) and pristine Zn (160 mAh g-1 ) anodes when evaluated in full cells with V2 O5 cathodes. One significant advantage of ZnO NFs lies in their highly polar surfaces, promoting strong interactions with water molecules and rendering them exceptionally hydrophilic. This characteristic enhances the ability of ZnO NFs to desolvate Zn2+ ions, leading to improved charge storage performance.

Predicting meningioma grades and pathologic marker expression via deep learning.

OBJECTIVES: To establish a deep learning (DL) model for predicting tumor grades and expression of pathologic markers of meningioma. METHODS: A total of 1192 meningioma patients from two centers who underwent surgical resection between September 2018 and December 2021 were retrospectively included. The pathological data and post-contrast T1-weight images for each patient were collected. The patients from institute I were subdivided into training, validation, and testing sets, while the patients from institute II served as the external testing cohort. The fine-tuned ResNet50 model based on transfer learning was adopted to classify WHO grade in the whole cohort and predict Ki-67 index, H3K27me3, and progesterone receptor (PR) status of grade 1 meningiomas. The predictive performance was evaluated by the accuracy and loss curve, confusion matrix, receiver operating characteristic curve (ROC), and area under curve (AUC). RESULTS: The DL prediction model for each label achieved high predictive performance in two cohorts. For WHO grade prediction, the area under the curve (AUC) was 0.966 (95%CI 0.957-0.975) in the internal testing set and 0.669 (95%CI 0.643-0.695) in the external validation cohort. The AUC in predicting Ki-67 index, H3K27me3, and PR status were 0.905 (95%CI 0.895-0.915), 0.773 (95%CI 0.760-0.786), and 0.771 (95%CI 0.750-0.792) in the internal testing set and 0.591 (95%CI 0.562-0.620), 0.658 (95%CI 0.648-0.668), and 0.703 (95%CI 0.674-0.732) in the external validation cohort, respectively. CONCLUSION: DL models can preoperatively predict meningioma grades and pathologic marker expression with favorable predictive performance. CLINICAL RELEVANCE STATEMENT: Our DL model could predict meningioma grades and expression of pathologic markers and identify high-risk patients with WHO grade 1 meningioma, which would suggest a more aggressive operative intervention preoperatively and a more frequent follow-up schedule postoperatively. KEY POINTS: WHO grades and some pathologic markers of meningioma were associated with therapeutic strategies and clinical outcomes. A deep learning-based approach was employed to develop a model for predicting meningioma grades and the expression of pathologic markers. Preoperative prediction of meningioma grades and the expression of pathologic markers was beneficial for clinical decision-making.

Changes in Hip Labral Size Two Years After Arthroscopic Repair Are Correlated With Preoperative Measurements on Magnetic Resonance Imaging.

PURPOSE: The purposes of our study were 1) to investigate the potential change of labral size after arthroscopic repair and 2) to analyze the relationship between acetabular labral size and functional outcomes. METHODS: In this retrospective study, patients diagnosed with labral tear and undergoing hip arthroscopic repair in our institution between September 2016 and December 2018 were included. Magnetic resonance imaging was obtained preoperatively and postoperatively, and the labral length and labral height were measured in three anatomic sites: 11:30, 1:30, and 3:00 positions. All patients completed at least 2-year follow-up. Patients whose preoperative labral size in any position wider than 2 standard deviation away from the mean were identified as the hypertrophic labrum group and were compared with the control in radiographic variables and patient-reported outcomes (PROs), including the visual analog scale (VAS), modified Harris Hip Score (mHHS), the International Hip Outcome Tool-12 (iHOT-12) and the Hip Outcome Score-Activities of Daily Living (HOS-ADL). RESULTS: A total of 82 patients (82 hips) were included, and the mean follow-up period was 39.54 ± 8.48 months. Significant improvement in PROs was determined before and after surgeries. Twelve patients were identified with labral hypertrophy and had higher postoperative mHHS scores, higher postoperative iHOT-12 scores, and greater improvement in HOS-ADL compared with the control group. Patients with larger preoperative anterosuperior labral height exhibited more favorable clinical outcomes. Meanwhile, no significantly morphologic change in labral size was determined. CONCLUSION: There is no significantly morphologic change in labral size of superior, anterosuperior, and anterior labrum after arthroscopic repair. Patients with hypertrophic labrum achieved more favorable clinical outcomes compared with those with normal-sized labrum. LEVEL OF EVIDENCE: Level III, retrospective comparative prognostic trial.

Graph theory analysis identified two hubs that connect sensorimotor and cognitive and cortical and subcortical nociceptive networks in the non-human primate.

Pain perception involves multiple brain regions and networks. Understanding how these brain networks work together is fundamental for appreciating network-wise changes reported in patients with chronic pain disorders. Parcellating pain related networks and understanding their causal relationships is the first step to understand how painful information is processed, integrated, and modulated, and it requires direct manipulation of specific brain regions. Nonhuman primates (NHP) offer an ideal model system to achieve these goals because cortical and subcortical regions in the NHP brain are established based on a variety of different types of data collected in a way that is not feasible or, at least, extremely difficult in humans (i.e., histology data, tract-tracing, intracerebral recordings). In addition, different methodological techniques can also help characterize and further understand these brain cortical and subcortical regions over the course of development. Here we used a heat nociceptive stimulation that is proven to elicit activity of nociceptive neurons in the cortex to refine and parcellate the whole brain nociceptive functional networks, to identify key network hubs, and to characterize network-wise temporal dynamic signatures using high-resolution fMRI. We first functionally localized 24 cortical and subcortical regions that responded to heat nociceptive stimuli (somatosensory area 1/2, area 3a/3b, S2, posterior insula (pIns), anterior insula, area 7b, posterior parietal cortex, anterior cingulate cortex (ACC), prefrontal cortex, caudate, and mediodorsal (MD) and ventral posterior lateral (VPL) thalamic nuclei) and used them as seeds in resting state fMRI (rsfMRI) data analysis. We applied both hierarchical clustering and graph-theory analyses of the pairwise rsfMRI correlation metrics and identified five cortical and one subcortical sub-networks: strong resting state functional connectivity (rsFC) between ACC and prefrontal regions, parietal cortex and area 7b, S2 and posterior insula, areas 3a/3b and 1/2 within the S1 cortex, and thalamic MD and caudate nuclei. The rsFC strengths between cortical areas within each subnetwork were significantly stronger than those between subcortical regions. Regions within each sub-network also exhibited highly correlated temporal dynamics at rest, but the overall dynamic patterns varied drastically across sub-networks. Graph-theory analysis identified the MD nucleus as a hub that connects subcortical and cortical nociceptive sub-networks. The S2-pIns connection joins the sensory and affective/cognitive sub-networks.

3D-printed regenerative polycaprolactone/silk fibroin osteogenic and chondrogenic implant for treatment of hip dysplasia.

Hip dysplasia is a developmental disorder that resulted in insufficient acetabular coverage. Current surgical treatments are technically demanding, complex, invasive, and often lead to associated complications. Therefore, the development of regenerative implants that fit to the bone and induce osteogenesis and chondrogenesis is in high demand. In this study, an implant was developed in which the osteogenic part was 3D printed using polycaprolactone (PCL), crosslinked with dopamine, and subjected to surface mineralization; while the chondrogenic part was prepared using silk fibroin (SF) and bone morphogenetic protein 2. Physical and chemical characterization of the implant was conducted using energy dispersive spectrometry (EDS) and scanning electron microscopy (SEM). The viability of rabbit adipose-derived mesenchymal stem cell (ADSCs) was evaluated by LIVE/DEAD staining and alamarBlue. SEM showed crosslinked polydopamine and crystals produced by mineralization on the surface of the implant, while EDS revealed the deposition of calcium and phosphorus on its surface. LIVE/DEAD staining and alamarBlue assay demonstrated that both the PCL and SF parts exhibit good biocompatibility. An in vivo hip dysplasia model was established in rabbits using a bone rongeur to make acetabular defects. Macroscopic observation, histological analysis, postoperative imaging, and biomechanical analysis of this model demonstrated the osteogenic and chondrogenic effects of the implant, and revealed that it provided good coverage of the femoral head, restoring the anatomical morphology of the acetabulum. Thus, this novel regenerative and cytocompatible implant provides a potentially viable strategy for the treatment of hip dysplasia.

Activation of peroxymonosulfate by α-MnO2 for Orange â removal in water.

Developing high-efficiency catalysts for peroxymonosulfate (PMS)-based advanced oxidation processes is important for eliminating pollutants in water. Herein, α-MnO2 with major exposed {110} and {100} facets prepared via a hydrothermal method were used as catalysts to activate PMS for the degradation of Orange Ⅰ (OⅠ). α-MnO2-100, with more abundant surface hydroxyl groups and greater reductive ability, performed remarkably better than α-MnO2-110 for degrading OⅠ. OⅠ removal of 86.20% was obtained in the α-MnO2-100/PMS system. The apparent rate constant of OⅠ removal over α-MnO2-100 was 2.11 times higher than that of α-MnO2-110. The effects of PMS concentration, catalyst dosage, OⅠ concentration, initial pH, anions and humic acid (HA) on OⅠ degradation in the α-MnO2-100/PMS system were systematically investigated. Quenching experiments and electron paramagnetic resonance (EPR) demonstrated that SO4•-, •OH, O2•- and 1O2 were the reactive oxygen species (ROS) in the α-MnO2-100/PMS system. Moreover, the possible degradation pathway of OⅠ in the α-MnO2-100/PMS system was proposed. This work provides an ideal metal oxide catalyst for sewage remediation.

Ultrafast Dynamics and Catalytic Mechanism of Fatty Acid Photodecarboxylase.

Fatty acid photodecarboxylase is a newly discovered flavin photoenzyme that converts a carboxylic acid into a hydrocarbon and a carbon dioxide molecule through decarboxylation. The enzymatic reactions are poorly understood. In this study, we carefully characterized its dynamic evolution with femtosecond spectroscopy. We observed initial electron transfer from the substrate to the flavin cofactor in 347 ps with a stretched dynamic behavior and subsequently captured the critical carbonyloxy radical. The dominant process following this step was decarboxylation in 5.8 ns to form an alkyl radical and a carbon dioxide molecule. We further identified the absorption bands of two carbonyloxy and alkyl radical intermediates. The overall enzymatic quantum efficiency determined by our obtained timescales is 0.81, consistent with the steady-state value. The results are essential to the elucidation of the enzyme mechanism and catalytic photocycle, providing a molecular basis for potential design of flavin-based artificial photoenzymes.

Hip arthroscopy has good clinical outcomes in the treatment of osteoid osteoma of the acetabulum.

BACKGROUND: Osteoid osteoma (OO) of the acetabulum is a relatively rare disease. However, the the clinical outcomes of hip arthroscopy for treatment of OO of the acetabulum are still uncertain. METHODS: We evaluated consecutive patients who were diagnosed with OO of the acetabulum and who underwent hip arthroscopy at our hospital between January 2013 and March 2020. All patients underwent a preoperative physical examination. Preoperative supine anteroposterior hip radiography, cross-table lateral radiographs, computed tomography (CT), and magnetic resonance imaging were performed in all patients. The alpha angle and lateral center-edge angle were measured before surgery. Supine anteroposterior hip radiography and CT were performed in all patients postoperatively. Preoperative patient-reported outcomes (PROs), including Visual Analog Scale (VAS), the International Hip Outcome Tool-12 (iHOT-12) and modified Harris Hip Score (mHHS), and PROs at final follow-up were evaluated. RESULTS: A total of 6 patients (mean age, 18.7 years; age range, 6-31 years; 5 males and 1 females) were included in this study. The average follow-up period after surgery was 28.3 months (range, 6-90 months). Before surgery, the mean mHHS was 45.2 ± 10.5 (range, 33-56), the mean iHOT-12 was 33.3 ± 14.5 (range, 13-49), and mean VAS was 8.2 ± 1.0 (range, 7-9). At one month after surgery, mean mHHS was 78.7 ± 1.9 (range, 77-81), iHOT-12 was 71.0 ± 4.5 (range, 68-80), and mean VAS was 0. At the final post-operative follow-up, mean mHHS was 89.2 ± 2.1 (range, 86-91), iHOT-12 was 93.5 ± 5.0 (range, 88-98), and mean VAS was 0. All results, except VAS between one month after surgery and at final follow-up, demonstrated statistically significant improvement (P < 0.05). One patient underwent revision surgery. CONCLUSIONS: Hip arthroscopy has good clinical outcomes in the treatment of OO of the acetabulum. Further study on the mechanism of secondary femoroacetabular impingement (FAI) caused by OO of the acetabulum is needed. More cases of arthroscopic excision and longer follow-up are also needed to better prove the clinical outcomes of hip arthroscopy for OO of the acetabulum.

Ultrasound and Ultrasound-Guided Hip Injection Have High Accuracy in the Diagnosis of Femoroacetabular Impingement With Atypical Symptoms.

PURPOSE: To evaluate the diagnostic value of ultrasound and ultrasound-guided hip injection in the diagnosis of femoroacetabular impingement (FAI) with atypical symptoms. METHODS: We evaluated consecutive patients diagnosed with FAI and with atypical symptoms who underwent ultrasound-guided hip injection between January 2017 and February 2019. All patients underwent systematic physical examination, ultrasound examination, magnetic resonance imaging (MRI) examination, and ultrasound-guided injection before surgery. Patients with positive response to ultrasound-guided hip injection were recommended to undergo arthroscopic surgery to treat intra-articular pathology. Sensitivity, specificity, accuracy, and positive predictive value (PPV) of ultrasound and MRI were calculated by using arthroscopic surgery as the gold standard. The accuracy of ultrasound-guided hip injection was recorded. Preoperative and postoperative patient-reported outcomes included visual analog scale for pain and modified Harris Hip Score. RESULTS: A total of 78 patients with atypical symptoms were diagnosed with FAI. Among these 78 patients, 50 patients had positive responses to injection and 28 patients had negative responses to injection. A total of 36 patients finally underwent arthroscopic surgery. Response to the ultrasound-guided intra-articular injection was 91.7% accurate for detecting the presence of intra-articular abnormality. There were no complications of injection in any of the patients. The sensitivity, PPV, and accuracy by ultrasound diagnosis of cam impingement were 82.9%, 96.7%, and 80.6%, respectively. The sensitivity and accuracy by ultrasound diagnosis of anterosuperior labral tear were both 72.2%. For MRI diagnosis of cam impingement, the sensitivity, PPV and accuracy were 72.2%, 96.3%, and 74.3%, respectively. For MRI diagnosis of labral tear, the sensitivity and accuracy were both 88.9%. Thirty-four patients (94.4%) surpassed the minimal clinically important difference, and 33 patients (91.7%) achieved the patient acceptable symptomatic state. CONCLUSIONS: Ultrasound and ultrasound-guided hip injection have high accuracy in the diagnosis of femoroacetabular impingement with atypical symptoms. LEVEL OF EVIDENCE: IV, case series.

Plasma Cell Polarization to the Immunoglobulin G Phenotype in Hepatocellular Carcinomas Involves Epigenetic Alterations and Promotes Hepatoma Progression in Mice.

BACKGROUND & AIMS: Little is known about the composition and generation of plasma cell subsets in patients with hepatocellular carcinoma (HCC) and how these associate with outcomes. We investigated whether, or how, plasma cells differentiate and function in patients with HCC and mice with liver tumors. METHODS: We analyzed subset composition and distribution of plasma cells in HCC samples from 342 patients who underwent curative resection at the Cancer Center of Sun Yat-sen University in China; samples of non-tumor liver tissue were used as controls. We associated plasma cell profiles with patient outcomes. Tissue-derived leukocytes were analyzed by flow cytometry and real-time polymerase chain reaction. The ability of macrophages to regulate plasma cell differentiation was determined in ex vivo cultures of cells from human HCC tissues. C57BL/6 and BALB/c mice were given injections of Hepa1-6 cells, which formed hepatomas, or H22 cells, which formed ascitic hepatomas. Gene expression patterns were analyzed in human HCC, mouse hepatoma, and non-tumor tissues by real-time polymerase chain reaction. Mice with hepatomas were given injections of GSK126 (an inhibitor of histone H3 lysine 27 methyltransferase [EZH2]) and 5-AZA-dC (an inhibitor of DNA methyltransferases); tumor tissues were analyzed by immunofluorescence and immunohistochemistry for the presence of immune cells and cytokines. RESULTS: B cells isolated from HCCs had somatic hypermutations and class-switch recombinations to the IgG phenotype that were not observed in non-tumor tissues. Increased level of plasma cells correlated with poor outcomes of patients. Activated CD4+ T cells from HCCs stimulated C-X-C motif chemokine 10 (CXCL10) production by macrophages. CXCL10 bound CXC chemokine receptor 3 on B cells and signaled via extracellular signal-regulated kinase to cause them to become IgG-producing plasma cells. IgG activated Fc receptors on macrophages and induced them to produce interleukin 6, interleukin 10, and C-C motif chemokine ligand 20 (CCL20). In mice with hepatomas, depletion of B cells prevented generation of these macrophage, increased the anti-tumor T cell response, and reduced growth of hepatomas. However, these effects were lost after injection of CXC chemokine receptor 3-positive plasma cells. Human HCC and mouse hepatoma tissues had increased expression of DNA methyltransferase 1 and EZH2 compared with non-tumor tissues. Injection of mice with GSK126 and 5-AZA-dC induced expression of CXCL10 by tumor cells and caused plasma cell polarization, suppression of the anti-tumor T cell response, and hepatoma growth. CONCLUSIONS: Human HCC tissues contain B cells with class-switch recombinations to the IgG phenotype. Activated CD4+ T cells from HCCs stimulate CXCL10 production by macrophages; CXCL10 binds CXC chemokine receptor 3 on B cells and causes them to become IgG-producing plasma cells. IgG activates Fc receptor in macrophages to produce cytokines that reduce the anti-tumor immune response. In mice with hepatomas, depletion of B cells prevented generation of these macrophages, increased the anti-tumor T cell response, and reduced growth of hepatomas. This pathway involves increased expression of DNA methyltransferase 1 and EZH2 by HCC and hepatoma cells.

Structural insights into DNA degradation by human mitochondrial nuclease MGME1.

Mitochondrial nucleases play important roles in accurate maintenance and correct metabolism of mtDNA, the own genetic materials of mitochondria that are passed exclusively from mother to child. MGME1 is a highly conserved DNase that was discovered recently. Mutations in MGME1-coding gene lead to severe mitochondrial syndromes characterized by external ophthalmoplegia, emaciation, and respiratory failure in humans. Unlike many other nucleases that are distributed in multiple cellular organelles, human MGME1 is a mitochondria-specific nuclease; therefore, it can serve as an ideal target for treating related syndromes. Here, we report one HsMGME1-Mn2+ complex and three different HsMGME1-DNA complex structures. In combination with in vitro cleavage assays, our structures reveal the detailed molecular basis for substrate DNA binding and/or unwinding by HsMGME1. Besides the conserved two-cation-assisted catalytic mechanism, structural analysis of HsMGME1 and comparison with homologous proteins also clarified substrate binding and cleavage directionalities of the DNA double-strand break repair complexes RecBCD and AddAB.

High spatial correspondence at a columnar level between activation and resting state fMRI signals and local field potentials.

Although blood oxygenation level-dependent (BOLD) fMRI has been widely used to map brain responses to external stimuli and to delineate functional circuits at rest, the extent to which BOLD signals correlate spatially with underlying neuronal activity, the spatial relationships between stimulus-evoked BOLD activations and local correlations of BOLD signals in a resting state, and whether these spatial relationships vary across functionally distinct cortical areas are not known. To address these critical questions, we directly compared the spatial extents of stimulated activations and the local profiles of intervoxel resting state correlations for both high-resolution BOLD at 9.4 T and local field potentials (LFPs), using 98-channel microelectrode arrays, in functionally distinct primary somatosensory areas 3b and 1 in nonhuman primates. Anatomic images of LFP and BOLD were coregistered within 0.10 mm accuracy. We found that the point spread functions (PSFs) of BOLD and LFP responses were comparable in the stimulus condition, and both estimates of activations were slightly more spatially constrained than local correlations at rest. The magnitudes of stimulus responses in area 3b were stronger than those in area 1 and extended in a medial to lateral direction. In addition, the reproducibility and stability of stimulus-evoked activation locations within and across both modalities were robust. Our work suggests that the intrinsic resolution of BOLD is not a limiting feature in practice and approaches the intrinsic precision achievable by multielectrode electrophysiology.

Discrete Modules and Mesoscale Functional Circuits for Thermal Nociception within Primate S1 Cortex.

This study addresses one long-standing question of whether functional separations are preserved for somatosensory modalities of touch, heat, and cold nociception within primate primary somatosensory (S1) cortex. This information is critical for understanding how the nature of pain is represented in the primate brain. Using a combination of submillimeter-resolution fMRI and microelectrode local field potential (LFP) and spike recordings, we identified spatially segregated cortical zones for processing touch and nociceptive heat and cold stimuli in somatotopically appropriate areas 3a, 3b, 1, and 2 of S1 in male monkeys. The distances between zones were comparable (∼3.4 mm) across stimulus modalities (heat, cold, and tactile), indicating the existence of uniform, modality-specific modules. Stimulus-evoked LFP maps validated the fMRI maps in areas 3b and 1. Isolation of heat and cold nociceptive neurons from the fMRI zones confirmed the validity of using fMRI to probe nociceptive regions and circuits. Resting-state fMRI analysis revealed distinct intrinsic functional circuits among functionally related zones. We discovered distinct modular structures and networks for thermal nociception within S1 cortex, a finding that has significant implications for studying chronic pain syndromes and guiding the selection of neuromodulation targets for chronic pain management.SIGNIFICANCE STATEMENT Primate S1 subregions contain discrete heat and cold nociceptive modules. Modules with the same properties exhibit strong functional connection. Nociceptive fMRI response coincides with LFP and spike activities of nociceptive neurons. Functional separation of heat and cold pain is retained within primate S1 cortex.

Activity Patterns Elicited by Airflow in the Olfactory Bulb and Their Possible Functions.

Olfactory sensory neurons (OSNs) can sense both odorants and airflows. In the olfactory bulb (OB), the coding of odor information has been well studied, but the coding of mechanical stimulation is rarely investigated. Unlike odor-sensing functions of OSNs, the airflow-sensing functions of OSNs are also largely unknown. Here, the activity patterns elicited by mechanical airflow in male rat OBs were mapped using fMRI and correlated with local field potential recordings. In an attempt to reveal possible functions of airflow sensing, the relationship between airflow patterns and physiological parameters was also examined. We found the following: (1) the activity pattern in the OB evoked by airflow in the nasal cavity was more broadly distributed than patterns evoked by odors; (2) the pattern intensity increases with total airflow, while the pattern topography with total airflow remains almost unchanged; and (3) the heart rate, spontaneous respiratory rate, and electroencephalograph power in the ß band decreased with regular mechanical airflow in the nasal cavity. The mapping results provide evidence that the signals elicited by mechanical airflow in OSNs are transmitted to the OB, and that the OB has the potential to code and process mechanical information. Our functional data indicate that airflow rhythm in the olfactory system can regulate the physiological and brain states, providing an explanation for the effects of breath control in meditation, yoga, and Taoism practices.SIGNIFICANCE STATEMENT Presentation of odor information in the olfactory bulb has been well studied, but studies about breathing features are rare. Here, using blood oxygen level-dependent functional MRI for the first time in such an investigation, we explored the global activity patterns in the rat olfactory bulb elicited by airflow in the nasal cavity. We found that the activity pattern elicited by airflow is broadly distributed, with increasing pattern intensity and similar topography under increasing total airflow. Further, heart rate, spontaneous respiratory rate in the lung, and electroencephalograph power in the ß band decreased with regular airflow in the nasal cavity. Our study provides further understanding of the airflow map in the olfactory bulb in vivo, and evidence for the possible mechanosensitivity functions of olfactory sensory neurons.