Cenozoic India-Asia collision driven by mantle dragging the cratonic root.

The driving force behind the Cenozoic India-Asia collision remains elusive. Using global-scale geodynamic modeling, we find that the continuous motion of the Indian plate is driven by a prominent upper-mantle flow pushing the thick Indian lithospheric root, originated from the northward rollover of the detached Neo-Tethyan slab and sinking slabs below East Asia. The maximum mantle drag occurs within the strong Indian lithosphere and is comparable in magnitude to that of slab pull (1013 N m-1). The thick cratonic root enhances both lithosphere-asthenosphere coupling and upper-plate compressional stress, thereby sustaining the topography of Tibetan Plateau. We show that the calculated resistant force from the India-Asia plate boundary is also close to that due to the gravitational potential energy of Tibetan Plateau. Here, we demonstrate that this mantle flow is key for the formation of the Tibetan Plateau and represents part of a hemispheric convergent flow pattern centered on central Asia.

Glioma-Stem-Cell-Derived Exosomes Remodeled Glioma-Associated Macrophage via NEAT1/miR-125a/STAT3 Pathway.

Glioblastoma (GBM), as the most common primary brain tumor, usually results in an extremely poor prognosis, in which glioma stem cells (GSCs) and their immunosuppressive microenvironment prominently intervene in the resistance to radiotherapy and chemotherapy that directly leads to tumor recurrence and shortened survival time. The specific mechanism through which exosomes generated from GSCs support the creation of an immunosuppressive microenvironment remains unknown, while it is acknowledged to be engaged in intercellular communication and the regulation of the glioma immunosuppressive microenvironment. The elevated expression of LncRNA-NEAT1 was found in glioma cells after radiotherapy, chemotherapy, and DNA damage stimulation, and NEAT1 could promote the malignant biological activities of GSCs. Emerging evidence suggests that lncRNAs may reply to external stimuli or DNA damage by playing a role in modulating different aspects of tumor biology. Our study demonstrated a promotive role of the carried NEAT1 by GSC-derived exosomes in the polarization of M2-like macrophages. Further experiments demonstrated the mediative role of miR-125a and its target gene STAT3 in NEAT1-induced polarization of M2-like macrophages that promote glioma progression. Our findings elucidate the mechanism by which GSCs influence the polarization of M2-like macrophages through exosomes, which may contribute to the formation of immunosuppressive microenvironments. Taken together, our study reveals the miR-125a-STAT3 pathway through which exosomal NEAT1 from treatment-resistant GSCs contributes to M2-like macrophage polarization, indicating the potential of exosomal NEAT1 for treating glioma.

A HIMU-like component in Mariana Convergent Margin magma sources during initial arc rifting revealed by melt inclusions.

Compositions of island arc and back-arc basin basalts are often used to trace the recycling of subducted materials. However, the contribution of subducted components to the mantle source during initial arc rifting before back-arc basin spreading is not yet well constrained. The northernmost Mariana arc is ideal for studying this because the transition from rifting to back-arc spreading is happening here. Here we report major and trace element and Pb isotopic compositions of olivine-hosted melt inclusions from lavas erupted during initial rifting at 24°N (NSP-24) and compare them with those in active arc front at 21°N and mature back-arc basin at 18°N. NSP-24 high-K melt inclusions have highly radiogenic Pb compositions and are close to those of the HIMU end-member, suggesting the presence of this component in the magma source. The HIMU-like component may be stored in the over-riding plate and released into arc magma with rifting. HIMU-type seamounts may be subducted elsewhere beneath the Mariana arc, but obvious HIMU-type components appear only in the initial stages of arc rifting due to the low melting degree and being consumed during the process of back-arc spreading.

Optimization of suspended particulate transport parameters from measured concentration profiles with a new analytical model.

The water body's suspended concentration reflects many coastal environmental indicators, which is important for predicting ecological hazards. The modeling of any concentration in water requires solving the settling-diffusion equation (SDE), and the values of several key input parameters therein (settling velocity ws, eddy diffusivity Ds, and erosion rates p(t)) directly determine the prediction performance. The time-consuming large-scale simulations would benefit if the parameter values could be estimated through available observations in the target sea area. The present work proposes a new optimization method for synchronously estimating the three parameters from limited concentration observations. First, an analytical solution to the one-dimensional vertical (1DV) SDE for suspended concentrations in an unsteady scenario is derived. Second, the near bottom suspended sediment concentration (SSC) profiles are measured with high-resolution observation. Third, the key parameters are optimized through the best fit of the measured SSC profiles and those modeled with the unsteady solution. Nonlinear least square fitting (NLSF) is introduced to judge the best fits automatically. The high-resolution concentration measurements in a specially-designed cylindrical tank experiment using the Yellow River Delta sediments test the proposed method. The method performs well in the initial period of turbulence generation when sediment resuspension is significant. It optimizes p(t), ws, and Ds with reasonable values and uniqueness of their combination. The proposed theory is a practical tool for quickly estimating key substance transport parameters from limited observations; it also has the potential to construct local parametric models to benefit the 3D modeling of coastal substance transport. Although the present work takes SSC as an example, it can be extended to any suspended particulate concentration in the water.

Tubule system of earliest shells as a defense against increasing microbial attacks.

The evolutionary mechanism behind the early Cambrian animal skeletonization was a complex and multifaceted process involving environmental, ecological, and biological factors. Predation pressure, oxygenation, and seawater chemistry change have frequently been proposed as the main drivers of this biological innovation, yet the selection pressures from microorganisms have been largely overlooked. Here we present evidence that calcareous shells of the earliest mollusks from the basal Cambrian (Fortunian Age, ca. 539-529 million years ago) of Mongolia developed advanced tubule systems that evolved primarily as a defensive strategy against extensive microbial attacks within a microbe-dominated marine ecosystem. These high-density tubules, comprising approximately 35% of shell volume, enable nascent mineralized mollusks to cope with increasing microbial bioerosion caused by boring endolithic cyanobacteria, and hence represent an innovation in shell calcification. Our finding demonstrates that enhanced microboring pressures played a significant role in shaping the calcification of the earliest mineralized mollusks during the Cambrian Explosion.

Combination immunotherapy of glioblastoma with dendritic cell cancer vaccines, anti-PD-1 and poly I:C.

Glioblastoma (GBM) is a lethal cancer with limited therapeutic options. Dendritic cell (DC)-based cancer vaccines provide a promising approach for GBM treatment. Clinical studies suggest that other immunotherapeutic agents may be combined with DC vaccines to further enhance antitumor activity. Here, we report a GBM case with combination immunotherapy consisting of DC vaccines, anti-programmed death-1 (anti-PD-1) and poly I:C as well as the chemotherapeutic agent cyclophosphamide that was integrated with standard chemoradiation therapy, and the patient remained disease-free for 69 months. The patient received DC vaccines loaded with multiple forms of tumor antigens, including mRNA-tumor associated antigens (TAA), mRNA-neoantigens, and hypochlorous acid (HOCl)-oxidized tumor lysates. Furthermore, mRNA-TAAs were modified with a novel TriVac technology that fuses TAAs with a destabilization domain and inserts TAAs into full-length lysosomal associated membrane protein-1 to enhance major histocompatibility complex (MHC) class I and II antigen presentation. The treatment consisted of 42 DC cancer vaccine infusions, 26 anti-PD-1 antibody nivolumab administrations and 126 poly I:C injections for DC infusions. The patient also received 28 doses of cyclophosphamide for depletion of regulatory T cells. No immunotherapy-related adverse events were observed during the treatment. Robust antitumor CD4+ and CD8+ T-cell responses were detected. The patient remains free of disease progression. This is the first case report on the combination of the above three agents to treat glioblastoma patients. Our results suggest that integrated combination immunotherapy is safe and feasible for long-term treatment in this patient. A large-scale trial to validate these findings is warranted.

Erratum: Cytochalasin H isolated from mangrove-derived endophytic fungus inhibits epithelial-mesenchymal transition and cancer stemness via YAP/TAZ signaling pathway in non-small cell lung cancer cells: Erratum.

[This corrects the article DOI: 10.7150/jca.50512.].

Erratum: Cytochalasin H Inhibits Angiogenesis via the Suppression of HIF-1α Protein Accumulation and VEGF Expression through PI3K/AKT/P70S6K and ERK1/2 Signaling Pathways in Non-Small Cell Lung Cancer Cells: Erratum.

[This corrects the article DOI: 10.7150/jca.29933.].

Preoperative individual-target transcranial magnetic stimulation demonstrates an effect comparable to intraoperative direct electrical stimulation in language-eloquent glioma mapping and improves postsurgical outcome: A retrospective fiber-tracking and electromagnetic simulation study.

Background: Efforts to resection of glioma lesions located in brain-eloquent areas must balance the extent of resection (EOR) and functional preservation. Currently, intraoperative direct electrical stimulation (DES) is the gold standard for achieving the maximum EOR while preserving as much functionality as possible. However, intraoperative DES inevitably involves risks of infection and epilepsy. The aim of this study was to verify the reliability of individual-target transcranial magnetic stimulation (IT-TMS) in preoperative mapping relative to DES and evaluate its effectiveness based on postsurgical outcomes. Methods: Sixteen language-eloquent glioma patients were enrolled. Nine of them underwent preoperative nTMS mapping (n=9, nTMS group), and the other seven were assigned to the non-nTMS group and did not undergo preoperative nTMS mapping (n=7). Before surgery, online IT-TMS was performed during a language task in the nTMS group. Sites in the cortex at which this task was disturbed in three consecutive trials were recorded and regarded as positive and designated nTMS hotspots (HSnTMS). Both groups then underwent awake surgery and intraoperative DES mapping. DES hotspots (HSDES) were also determined in a manner analogous to HSnTMS. The spatial distribution of HSnTMS and HSDES in the nTMS group was recorded, registered in a single brain template, and compared. The center of gravity (CoG) of HSnTMS (HSnTMS-CoG)-based and HSDES-CoG-based diffusion tensor imaging-fiber tracking (DTI-FT) was performed. The electromagnetic simulation was conducted, and the values were then compared between the nTMS and DES groups, as were the Western Aphasia Battery (WAB) scale and fiber-tracking values. Results: HSnTMS and HSDES showed similar distributions (mean distance 6.32 ± 2.6 mm, distance range 2.2-9.3 mm, 95% CI 3.9-8.7 mm). A higher fractional anisotropy (FA) value in nTMS mapping (P=0.0373) and an analogous fiber tract length (P=0.2290) were observed. A similar distribution of the electric field within the brain tissues induced by nTMS and DES was noted. Compared with the non-nTMS group, the integration of nTMS led to a significant improvement in language performance (WAB scores averaging 78.4 in the nTMS group compared with 59.5 in the non-nTMS group, P=0.0321 < 0.05) as well as in brain-structure preservation (FA value, P=0.0156; tract length, P=0.0166). Conclusion: Preoperative IT-TMS provides data equally crucial to DES and thus facilitates precise brain mapping and the preservation of linguistic function.

Reduction of Reactive Oxygen Species Accumulation Using Gadolinium-Doped Ceria for the Alleviation of Atherosclerosis.

Atherosclerosis is a common cardiovascular disease with increasing morbidity and mortality. The pathogenesis of atherosclerosis is strongly related to endothelial dysfunction, which is induced by severe oxidative stress damage derived from reactive oxygen species (ROS). Thus, ROS plays a critical role in the pathogenesis and progression of atherosclerosis. In this work, we demonstrated that the gadolinium doping of CeO2 (Gd/CeO2) nanozymes as effective ROS scavengers delivered high performance for antiatherosclerosis. It was found that the chemical doping of Gd promoted the surface proportion of Ce3+ in the nanozymes and thereby enhanced the overall ROS scavenging ability. In vitro and in vivo experiments unambiguously showed that the Gd/CeO2 nanozymes efficiently scavenged harmful ROS at the cellular and histological levels. Further, Gd/CeO2 nanozymes were demonstrated to significantly reduce vascular lesions by reducing lipid accumulation in macrophage and decreasing inflammatory factor levels, thereby inhibiting the exacerbation of atherosclerosis. Moreover, Gd/CeO2 can serve as T1-weighted magnetic resonance imaging contrast agents, which can generate sufficient contrast to distinguish the location of plaque during living imaging. Through those efforts, Gd/CeO2 may serve as a potential diagnostic and treatment nanomedicine for the ROS-induced atherosclerosis.

3D bioprinted autologous bone particle scaffolds for cranioplasty promote bone regeneration with both implanted and native BMSCs.

Although autologous bone (AB) grafting is considered to be the gold standard for cranioplasty, unresolved problems remain, such as surgical-site infections and bone flap absorption. In this study, an AB scaffold was constructed via three-dimensional (3D) bedside-bioprinting technology and used for cranioplasty. To simulate the skull structure, a polycaprolactone shell was designed as an external lamina, and 3D-printed AB and a bone marrow-derived mesenchymal stem cell (BMSC) hydrogel was used to mimic cancellous bone for bone regeneration. Ourin vitroresults showed that the scaffold exhibited excellent cellular affinity and promoted osteogenic differentiation of BMSCs in both two-dimensional and 3D culture systems. The scaffold was implanted in beagle dog cranial defects for up to 9 months, and the scaffold promoted new bone and osteoid formation. Furtherin vivostudies indicated that transplanted BMSCs differentiated into vascular endothelium, cartilage, and bone tissues, whereas native BMSCs were recruited into the defect. The results of this study provide a method for bedside bioprinting of a cranioplasty scaffold for bone regeneration, which opens up another window for clinical applications of 3D printing in the future.

Monitored anesthesia care and asleep-awake-asleep techniques combined with multiple monitoring for resection of gliomas in eloquent brain areas: a retrospective analysis of 225 patients.

BACKGROUND: Awake craniotomy (AC) has become gold standard in surgical resection of gliomas located in eloquent areas. The conscious sedation techniques in AC include both monitored anesthesia care (MAC) and asleep-awake-asleep (AAA). The choice of optimal anesthetic method depends on the preferences of the surgical team (mainly anesthesiologist and neurosurgeon). The aim of this study was to compare the difference in physiological and blood gas data, dosage of different drugs, the probability of switching to endotracheal intubation, and extent of tumor resection and dysfunction after operation between AAA and MAC anesthetic management for resection of gliomas in eloquent brain areas. METHODS: Two-hundred and twenty-five patients with super-tentorial tumor located in eloquent areas underwent AC from 2009 to 2021 in Xijing Hospital. Forty-one patients underwent AAA technique, and the rest one-hundred eighty-four patients underwent MAC technique. Anesthetic management, dosage of different drugs, intraoperative complications, postoperative outcomes, adverse events, extent of resection and motor, and sensory and language dysfunction after operation were compared between MAC and AAA. RESULT: There was no significant difference in gender, KPS score, MMSE score, glioma grade, type, and growth site between the patients in the two groups, except the older age of patients in MAC group than that in AAA group. During the whole process of operation, there were greater pulse pressure difference (P = 0.046), shorter operation time (P = 0.039), less dosage of remifentanil (P = 0.000), more dosage of dexmedetomidine (P = 0.013), more use of antiemetics (81%, P = 0.0067), lower use of vasoactive agent (45.1%, P = 0.010), and lower probability of conversion to general anesthesia (GA, P = 0.027) in MAC group than that in AAA group. Blood gas analysis showed that PetCO2 (P = 0.000), Glu concentration (P = 0.000), and PaCO2 (P = 0.000) were higher, but SPO2 (P = 0.002) and PaO2 (P = 0.000) were lower in MAC group than that in AAA group. In the postoperative recovery stage, compared with that of AAA group, the probability of dysfunction in MAC group at 1, 3, 5, and 7 days after operation was lower, which were 27.8% vs 53.6% (P = 0.003), 31% vs 68.3% (P = 0.000), 28.8% vs 63.4% (P = 0.000), and 25.6% vs 58.5% (P = 0.000), respectively. CONCLUSION: Compared with AAA, it seems that MAC has more advantages in the management for resection of gliomas in eloquent brain areas, and MAC combined with multiple monitoring such as cerebral cortical mapping, neuronavigation, and ultrasonic detection is worthy of popularization for the resection of gliomas in eloquent brain areas.

Notch signaling dependent monocyte conversion alleviates immune-mediated neuropathies by regulating RBP-J/NR4A1 axis.

Monocytes in peripheral blood and sciatic nerves play vital roles in immune-mediated neuropathies such as Guillain-Barré syndrome (GBS). Different subpopulations of monocytes, including classical and non-classical, exhibit distinct functions as well as phenotypic conversion potentials. However, the mechanisms underlying their development during immune-mediated neuropathy remain unclear. Notch signaling participates in monocyte differentiation and function. In this study, we used a myeloid-specific Notch signaling activation transgenic mouse (NICcA) and investigated the role of Notch signaling in monocytes during experimental autoimmune neuritis (EAN) in a mouse model of GBS. Clinical score assessment and histopathological examination revealed that sciatic nerve injury was attenuated in NICcA EAN mice compared to that in control mice. Flow cytometry and immunofluorescence staining suggested that increasing Ly6Clo monocytes in the peripheral blood and nerve tissue might contribute to the alleviation of neuritis in NICcA mice. Meanwhile, an in vitro study suggested that bone marrow-derived monocytes from NICcA mice are more inclined toward Ly6Clo cells than Ly6Chi cells. Differential expression of monocyte development-associated genes was detected in NICcA and wild-type mice using RNA sequencing. The expression of Nr4a1 is upregulated remarkably when Notch signaling is activated. Treatment with Nr4a1 antagonist on NICcA mice-derived monocytes compromise their Ly6Clo tendency. Consistently, a relationship between monocyte conversion and disease severity was observed in blood samples from patients with GBS. In conclusion, our current study showed that monocyte conversion modulated by Notch signaling plays an essential role in the EAN mouse model.

TRIM22 orchestrates the proliferation of GBMs and the benefits of TMZ by coordinating the modification and degradation of RIG-I.

Tripartite motif 22 (TRIM22) is an agonist of nuclear factor κB (NF-κB) that plays an important role in the proliferation and drug sensitivity of glioblastoma (GBM). However, the molecular mechanism underlying the protein network between TRIM22 and nuclear factor κB (NF-κB) in GBM remains unclear. Here, we found that knockout of TRIM22 effectively inhibited tumor proliferation and increased the sensitivity of GBM cells to temozolomide (TMZ) in vivo and in vitro. Moreover, TRIM22 forms a complex with cytosolic purine 5-nucleotidase (NT5C2) in GBM and regulates the ubiquitination of retinoic acid-inducible gene-I (RIG-I). TRIM22 promotes the K63-linked ubiquitination of RIG-I, while NT5C2 is responsible for K48-linked ubiquitination. This regulation directly affects the RIG-I/NF-κB/cell division cycle and apoptosis regulator protein 1 (CCAR1) signaling axis. Ubiquitin modification inhibitor of RIG-I restores the inhibition of tumor growth induced by TRIM22 knockout. The follow-up results showed that compared with patients with high TRIM22 expression, patients with low TRIM22 expression had a longer survival time and were more sensitive to treatment with TMZ. Our results revealed that the TRIM22-NT5C2 complex orchestrates the proliferation of GBM and benefits of TMZ through post-translational modification of RIG-I and the regulation of the RIG-I/NF-κB/CCAR1 pathway and is a promising target for single-pathway multi-target therapy.

LncRNA GAS5 represses stemness and malignancy of gliomas via elevating the SPACA6-miR-125a/let-7e Axis.

Glioblastoma (GBM) is a highly invasive neurological malignancy with poor prognosis. LncRNA-GAS5 (growth arrest-specific transcript 5) is a tumor suppressor involved in multiple cancers. In this study, we explored the clinical significance, biological function, and underlying mechanisms of GAS5 in GBM. We showed that lncRNA-GAS5 expression decreased in high-grade glioma tissues and cells, which might be associated with poor prognosis. GAS5 overexpression lowered cell viability, suppressed GBM cell migration and invasion, and impaired the stemness and proliferation of glioma stem cells (GSCs). We further discovered that GAS5 inhibited the viability of glioma cells through miR-let-7e and miR-125a by protecting SPACA6 from degradation. Moreover, GAS5 played an anti-oncogenic role in GBM through the combined involvement of let-7e and miR-125a in vivo and in vitro. Notably, these two miRNAs block the IL-6/STAT3 pathway in tumor tissues extracted from a xenograft model. Taken together, our study provides evidence for an important role of GAS5 in GBM by affecting the proliferation and migration of GSCs, thus providing a new potential prognostic biomarker and treatment strategy for GBM.

Active construction of southernmost Tibet revealed by deep seismic imaging.

Southernmost Tibet exhibits an anomalously twice the normal thickness of average continental crust. There is no available theory to explain and the driving mechanism remains uncertain. Here, we interpret a north-striking, 180 km-long deep seismic reflection profile traversing the southern Lhasa terrane (SLT) to the central Lhasa terrane (CLT). In addition to reflections showing subducting Indian crust, our results reveal lateral heterogeneity between the SLT and CLT, where north-dipping reflections beneath the CLT outline a tilted crystalline basement, while the non-reflective domain beneath the SLT represents homogeneous juvenile crust. Our integrated analysis leads to models calling upon episodic magmatism onto the southern margin of the basement to result in progressive construction of the SLT. We hypothesize that this crustal thickening via crustal-scale magma accretion contributed to surface uplift of the southern margin of the Tibetan plateau and leading to the development of the vast internal drainage system of Tibet.

Improved Interhemispheric Functional Connectivity in Postpartum Depression Disorder: Associations With Individual Target-Transcranial Magnetic Stimulation Treatment Effects.

Postpartum depression (PPD) is a depressive condition that is associated with a high risk of stressful life events, poor marital relationships, and even suicide. Neuroimaging techniques have enriched our understanding of cerebral mechanisms underlying PPD; namely, abnormalities in the amygdala-insula-frontal circuit might contribute to the pathogenesis of PPD. Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT) is a recently validated neuroscience-informed accelerated intermittent theta-burst stimulation repetitive transcranial magnetic stimulation (rTMS) protocol. It has been shown to be effective, safe, tolerable, and rapid acting for treating treatment-resistant depression, and may be a valuable tool in the treatment of PPD. The purpose of the current study was to detect inter-hemispheric connectivity changes and their relationship with the clinical treatment effects of rTMS. Resting-state fMRI data from 32 patients with PPD treated with SAINT were collected and compared with findings from 32 age matched healthy controls. Voxel-mirrored homotopic connectivity (VMHC) was used to analyze the patterns of interhemispheric intrinsic functional connectivity in patients with PPD. Scores on the 17-item Hamilton Depression Rating Scale, Edinburgh Postnatal Depression Scale (EPDS) scores, and the relationships between these clinical characteristics and VMHC were the primary outcomes. Patients with PPD at baseline showed reduced VMHC in the amygdala, insula, and medial frontal gyrus compared with the HCs. These properties showed a renormalization after individualized rTMS treatment. Furthermore, increased connectivity between the left and right insula after SAINT was significantly correlated with the improvement of EPDS scores. Our results reveal the disruptions in the intrinsic functional architecture of interhemispheric communication in patients with PPD, and provide evidence for the pathophysiological mechanisms and the effects of rTMS.

Improved Functional Organization in Patients With Primary Insomnia After Individually-Targeted Transcranial Magnetic Stimulation.

Primary insomnia (PI) is among the most prevalent sleep-related disorders and has a far-reaching impact on daytime functioning. Repetitive transcranial magnetic stimulation (rTMS) has drawn attention because of its effectiveness and safety. The purpose of the current study was to detect changes in the topological organization of whole-brain functional networks and to determine their associations with the clinical treatment effects of rTMS. Resting-state functional magnetic resonance imaging (rsfMRI) data from 32 patients with PI were collected and compared with findings from 32 age- and gender-matched healthy controls (HCs). The patients were treated with Stanford accelerated intelligent neuromodulation therapy, which is a recently validated neuroscience-informed accelerated intermittent theta-burst stimulation protocol. Graph theoretical analysis was used to construct functional connectivity matrices and to extract the attribute features of small-world networks in insomnia. Scores on the Insomnia Severity Index (ISI), Pittsburgh Sleep Quality Index, Self-Rating Anxiety Scale, Self-Rating Depression Scale, and the associations between these clinical characteristics and functional metrics, were the primary outcomes. At baseline, the patients with PI showed inefficient small-world property and aberrant functional segregation and functional integration compared with the HCs. These properties showed renormalization after individualized rTMS treatment. Furthermore, low functional connectivity between the right insula and left medial frontal gyrus correlated with improvement in ISI scores. We highlight functional network dysfunctions in PI patients and provide evidence into the pathophysiological mechanisms involved and the possible mode of action of rTMS.