Mutational Landscape of Secondary Glioblastoma Guides MET-Targeted Trial in Brain Tumor.

Low-grade gliomas almost invariably progress into secondary glioblastoma (sGBM) with limited therapeutic option and poorly understood mechanism. By studying the mutational landscape of 188 sGBMs, we find significant enrichment of TP53 mutations, somatic hypermutation, MET-exon-14-skipping (METex14), PTPRZ1-MET (ZM) fusions, and MET amplification. Strikingly, METex14 frequently co-occurs with ZM fusion and is present in ∼14% of cases with significantly worse prognosis. Subsequent studies show that METex14 promotes glioma progression by prolonging MET activity. Furthermore, we describe a MET kinase inhibitor, PLB-1001, that demonstrates remarkable potency in selectively inhibiting MET-altered tumor cells in preclinical models. Importantly, this compound also shows blood-brain barrier permeability and is subsequently applied in a phase I clinical trial that enrolls MET-altered chemo-resistant glioma patients. Encouragingly, PLB-1001 achieves partial response in at least two advanced sGBM patients with rarely significant side effects, underscoring the clinical potential for precisely treating gliomas using this therapy.

Incommensurate Spin Density Wave in Antiferromagnetic RuO_{2} Evinced by Abnormal Spin Splitting Torque.

Since the discovery of antiferromagnetism, metallic oxide RuO_{2} has exhibited numerous intriguing spintronics properties such as the anomalous Hall effect and anisotropic spin splitting effect. However, the microscopic origin of its antiferromagnetism remains unclear. By investigating the spin splitting torque in RuO_{2}/Py, we found that metallic RuO_{2} exhibits a spatially periodic spin structure which interacts with the spin waves in Py through interfacial exchange coupling. The wavelength of such structure is evaluated within 14-20 nm depending on the temperature, which is evidence of an incommensurate spin density wave state in RuO_{2}. Our work not only provides a dynamics approach to characterize the antiferromagnetic ordering in RuO_{2}, but also offers fundamental insights into the spin current generation due to anisotropic spin splitting effect associated with spin density wave.

New Insights on the Formation of Nucleation Mode Particles in a Coastal City Based on a Machine Learning Approach.

Atmospheric particles have profound implications for the global climate and human health. Among them, ultrafine particles dominate in terms of the number concentration and exhibit enhanced toxic effects as a result of their large total surface area. Therefore, understanding the driving factors behind ultrafine particle behavior is crucial. Machine learning (ML) provides a promising approach for handling complex relationships. In this study, three ML models were constructed on the basis of field observations to simulate the particle number concentration of nucleation mode (PNCN). All three models exhibited robust PNCN reproduction (R2 > 0.80), with the random forest (RF) model excelling on the test data (R2 = 0.89). Multiple methods of feature importance analysis revealed that ultraviolet (UV), H2SO4, low-volatility oxygenated organic molecules (LOOMs), temperature, and O3 were the primary factors influencing PNCN. Bivariate partial dependency plots (PDPs) indicated that during nighttime and overcast conditions, the presence of H2SO4 and LOOMs may play a crucial role in influencing PNCN. Additionally, integrating additional detailed information related to emissions or meteorology would further enhance the model performance. This pilot study shows that ML can be a novel approach for simulating atmospheric pollutants and contributes to a better understanding of the formation and growth mechanisms of nucleation mode particles.

Sources appointment and health risks of PM2.5-bound trace elements in a coastal city of southeastern China.

To gain a comprehensive understanding of sources and health risks of trace elements in an area of China with high population densities and low PM2.5 concentrations, 15 trace elements (Al, K, Ca, Ti, V, Cr, Mn, Fe, Ni, Cu, Zn, As, Sn, Ba, Pb) in PM2.5 were monitored from December 2020 to November 2021 in a representative city, Xiamen. The concentrations of trace elements in Xiamen displayed an obvious seasonal variation and were dominated by K, Fe, Al, Ca and Zn. Based on Positive Matrix Factorization analysis, source appointment revealed that the major sources of trace elements in Xiamen were traffic, dust, biomass and firework combustion, industrial manufacture and shipping emission. According to health risk assessment combined with the source appointment results, it indicated that the average noncarcinogenic risk was below the threshold and cancer risk of four hazardous metals (Cr, Ni, As, Pb) exceeded the threshold (10-6). Traffic-related source had almost half amount of contribution to the health risk induced by PM2.5-bound trace elements. During the dust transport period or Spring Festival period, the health risks exceeded an acceptable threshold even an order of magnitude higher, suggesting that the serious health risks still existed in low PM2.5 environment at certain times. Health risk assessment reminded that the health risk reduction in PM2.5 at southeastern China should prioritize traffic-related hazardous trace elements and highlighted the importance of controlling vehicles emissions in the future.

Molecular Composition of Anthropogenic Oxygenated Organic Molecules and Their Contribution to Organic Aerosol in a Coastal City.

Organic aerosols (OA) have gained attention as a substantial component of atmospheric aerosols owing to their impact on atmospheric visibility, climate, and human health. Although oxygenated organic molecules (OOMs) are essential contributors to OA formation, the sources, transformations, and fates of the OOMs are not fully understood. Herein, anthropogenic OOMs (AOOMs), anthropogenic volatile organic compounds (AVOCs), and OA were concurrently measured in Xiamen, a coastal city in southeastern China. Our results show that the AOOMs exhibited a high nitrogen content (76%) and a low oxidation degree. Strong photochemical processes of aromatic VOCs were the predominant sources of AOOMs. Also, NOx concentrations and the occurrence of multigeneration OH radical oxidations were the critical factors that might influence the formation of AOOMs. Finally, the newly developed aerosol dynamic model's results show that more than 35% of the OA mass growth rate is attributed to the gas-particle partitioning of AOOMs. Further sensitivity testing demonstrates that the contribution of AOOMs to OA growth is significantly enhanced during high-particulate-concentration periods, especially under low-temperature conditions. This study emphasizes the vital role of photochemically produced AOOMs derived from AVOCs in OA growth in a coastal urban atmosphere.

A preparation technology of volatile components in Linggui Zhugan decoction based on the transfer of cinnamaldehyde and its anti-gastric ulcer effect.

Purpose: This study aims to preserve the volatile components of Linggui Zhugan (LGZG) decoction, offering an experimental foundation for subsequent preparations efforts. Methods: Two modern sample preparation processes were compared with the traditional method approach using HPLC fingerprints. After identifying the main volatile components in LGZG aqueous decoction, the inclusion method of inclusion compounds (IC-LGZG) was established and optimized at laboratory, pilot and production scales. Characterization, stability testing of IC-LGZG, and experiments on gastric ulcer rats were conducted to validate the transferability of chemical composition and pharmaceutical efficacy. Results: The study focused on preserving the volatile components in LGZG modern preparations. HPLC analysis revealed cinnamaldehyde (CA) as the main volatile component in LGZG decoction. The optimized IC-LGZG preparation involved heating aromatic water to 40 °C, adding 20 g/L of ß-Cyclodextrin (ß-CD), keeping warm and stirring at 300 r for 30 min. This process exhibited good repeatability across different verification tests at varying scales. IC-LGZG obtained effectively transferred CA molecules into the ß-CD molecules via encapsulation, remaining stable when stored in sealed and dark conditions. Finally, CA, IC-LGZG and M-LGZG (a mixture of IC-LGZG and water-soluble extract powder) effectively prevented the formation of gastric ulcer by mitigating reductions in IL-10, SOD and the increase of TNF-α, NO, MDA in serum. Conclusion: The IC-LGZG prepared using this process successfully transfers volatile components, both chemically and pharmacologically, making it suitable for modern preparations of LGZG.

Primary adult sellar SMARCB1/INI1-deficient tumor represents a subtype of atypical teratoid/rhabdoid tumor.

Loss of function in SMARCB1/INI1 has been observed in a group of malignancies collectively defined as SMARCB1/INI1-deficient neoplasms. Primary intracranial SMARCB1/INI1-deficient tumors in adults are extremely rare. We collected eight primary adult sellar SMARCB1/INI1-deficient tumors to study their clinicopathological and (epi)genetic characteristics. We performed a comprehensive assessment of the clinical, radiological, morphological and immunohistochemical features. FISH analysis for the SMARCB1 locus and target exome sequencing for 425 cancer relevant genes were performed. Furthermore, six bona fide proximal epithelioid sarcoma (PES), fourteen atypical teratoid/rhabdoid tumors (ATRT) in brain and five pediatric poorly differentiated chordomas (PDC) in the clivus were collected for comparative analysis of differential diagnostic maker expression and DNA methylation profile. The median age was 47.1 years, ranging from 26 to 73 years. On morphology, tumors were characterized by sheets of monomorphic larger epithelioid-like cells, in two cases with rhabdoid cells. "Stag-horn" vasculatures were observed in five cases. The loss of INI1 protein expression, co-expression of epithelial makers and mesenchymal markers were observed in all cases. CD34 expression was observed in six cases. Heterozygous deletion of SMARCB1/INI1 was confirmed using FISH in six cases. The results of target exome sequencing showed three patients harbored heterozygous point mutations in SMARCB1. The epigenetic features of the primary adult sellar SMARCB1/INI1-deficient tumors resembled the ATRT-MYC subgroup, but clustered apart from PES and PDC. Based on epigenetic characteristics, primary adult sellar SMARCB1/INI1-deficient tumors represent a subtype of ATRT with similar epigenetic characteristics of ATRT-MYC subgroup. Our findings suggest that DNA methylation profiling should be utilized for differential diagnosis for the majority of epithelioid sarcoma and (sellar) rhabdoid tumor.

Observation of the antiferromagnetic spin Hall effect.

The discovery of the spin Hall effect1 enabled the efficient generation and manipulation of the spin current. More recently, the magnetic spin Hall effect2,3 was observed in non-collinear antiferromagnets, where the spin conservation is broken due to the non-collinear spin configuration. This provides a unique opportunity to control the spin current and relevant device performance with controllable magnetization. Here, we report a magnetic spin Hall effect in a collinear antiferromagnet, Mn2Au. The spin currents are generated at two spin sublattices with broken spatial symmetry, and the antiparallel antiferromagnetic moments play an important role. Therefore, we term this effect the 'antiferromagnetic spin Hall effect'. The out-of-plane spins from the antiferromagnetic spin Hall effect are favourable for the efficient switching of perpendicular magnetized devices, which is required for high-density applications. The antiferromagnetic spin Hall effect adds another twist to the atomic-level control of spin currents via the antiferromagnetic spin structure.

Molecular Composition of Oxygenated Organic Molecules and Their Contributions to Organic Aerosol in Beijing.

The understanding at a molecular level of ambient secondary organic aerosol (SOA) formation is hampered by poorly constrained formation mechanisms and insufficient analytical methods. Especially in developing countries, SOA related haze is a great concern due to its significant effects on climate and human health. We present simultaneous measurements of gas-phase volatile organic compounds (VOCs), oxygenated organic molecules (OOMs), and particle-phase SOA in Beijing. We show that condensation of the measured OOMs explains 26-39% of the organic aerosol mass growth, with the contribution of OOMs to SOA enhanced during severe haze episodes. Our novel results provide a quantitative molecular connection from anthropogenic emissions to condensable organic oxidation product vapors, their concentration in particle-phase SOA, and ultimately to haze formation.

Elevated signature of a gene module coexpressed with CDC20 marks genomic instability in glioma.

Genomic instability (GI) drives tumor heterogeneity and promotes tumor progression and therapy resistance. However, causative factors underlying GI and means for clinical detection of GI in glioma are inadequately identified. We describe here that elevated expression of a gene module coexpressed with CDC20 (CDC20-M), the activator of the anaphase-promoting complex in the cell cycle, marks GI in glioma. The CDC20-M, containing 139 members involved in cell proliferation, DNA damage response, and chromosome segregation, was found to be consistently coexpressed in glioma transcriptomes. The coexpression of these genes was conserved across multiple species and organ systems, particularly in human neural stem and progenitor cells. CDC20-M expression was not correlated with the morphological subtypes, nor with the recently defined molecular subtypes of glioma. CDC20-M signature was an independent and robust predictor for poorer prognosis in over 1,000 patients from four large databases. Elevated CDC20-M signature enabled the identification of individual glioma samples with severe chromosome instability and mutation burden and of primary glioma cell lines with extensive mitotic errors leading to chromosome mis-segregation. AURKA, a core member of CDC20-M, was amplified in one-third of CDC20-M-high gliomas with gene-dosage-dependent expression. MLN8237, a Food and Drug Administration-approved AURKA inhibitor, selectively killed temozolomide-resistant primary glioma cells in vitro and prolonged the survival of a patient-derived xenograft mouse model with a high-CDC20-M signature. Our findings suggest that application of the CDC20-M signature may permit more selective use of adjuvant therapies for glioma patients and that dysregulated CDC20-M members may provide a therapeutic vulnerability in glioma.

Long-term winter observation of nitrous acid in the urban area of Beijing.

The particulate matter (PM) pollution has been significantly improved by carrying out various valid emission control strategies since 2013 in China. Meanwhile the variation trend of nitrous acid (HONO) is worthy to investigate due to its vital role in the atmospheric oxidation process. In this study, field observation in the winter is conducted to investigate the concentration of HONO in an urban area of Beijing. In the winter of 2019, the mean HONO concentration is 1.38 ppbV during the whole winter. Photo-enhanced NO2 heterogeneous reactions on the ground and aerosol surfaces were found as the possible daytime sources of HONO. Compared to O3, photolysis of HONO dominates the primary OH sources during the winter time. To understand the HONO pollution patterns by years variation, multi-year data is summarized and finds that primary pollutants including CO and NO decreased, but secondary pollutants i.e., HONO (mostly generated via secondary process) increased. Our study highlights the requirement to mitigate secondary pollution by control HONO concentration.

Genome-wide analysis of differentially expressed mRNAs, lncRNAs, and circRNAs in chicken bursae of Fabricius during infection with very virulent infectious bursal disease virus.

BACKGROUND: Infectious bursal disease virus (IBDV) causes acute, highly contagious, immunosuppressive, and lethal infectious disease in young chickens and mainly infects the bursa of Fabricius (BF). To investigate interactions between IBDV and its host, RNA sequencing was applied to analyze the responses of the differentially expressed transcriptional profiles of BF infected by very virulent IBDV (vvIBDV). RESULTS: In total, 317 upregulated and 94 downregulated mRNAs were found to be significantly differentially expressed in infected chickens, compared to controls. Long non-coding RNA (lncRNA) and circular RNA (circRNA) alterations were identified in IBDV-infected chickens, and significantly different expression was observed in 272 lncRNAs and 143 circRNAs. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were performed to assess the functions of significantly dysregulated genes, which showed that the JAK-STAT signaling pathway, the NOD-like receptor signaling pathway, and apoptosis may be activated by IBDV infection. We predicted interactions between differentially expressed genes and produced lncRNA-mRNA and circRNA-miRNA-mRNA regulator network. CONCLUSIONS: The present study identified the expression profiles of mRNAs, lncRNAs, and circRNAs during vvIBDV infection and provides new insights into the pathogenesis of IBDV and antiviral immunity of the host.

Seasonal Characteristics of New Particle Formation and Growth in Urban Beijing.

Understanding the atmospheric new particle formation (NPF) process within the global range is important for revealing the budget of atmospheric aerosols and their impacts. We investigated the seasonal characteristics of NPF in the urban environment of Beijing. Aerosol size distributions down to ∼1 nm and H2SO4 concentration were measured during 2018-2019. The observed formation rate of 1.5 nm particles (J1.5) is significantly higher than those in the clean environment, e.g., Hyytiälä, whereas the growth rate is not significantly different. Both J1.5 and NPF frequency in urban Beijing show a clear seasonal variation with maxima in winter and minima in summer, while the observed growth rates are generally within the same range around the year. We show that ambient temperature is a governing factor driving the seasonal variation of J1.5. In contrast, the condensation sink and the daily maximum H2SO4 concentration show no significant seasonal variation during the NPF periods. In all four seasons, condensation of H2SO4 and (H2SO4)n(amine)n clusters contributes significantly to the growth rates in the sub-3 nm size range, whereas it is less important for the observed growth rates of particles above 3 nm. Therefore, other species are always needed for the growth of larger particles.

MCL1 gene co-expression module stratifies multiple myeloma and predicts response to proteasome inhibitor-based therapy.

Multiple myeloma (MM) is the second most common hematologic cancer, characterized by abnormal accumulation of plasma cells in the bone marrow. The extensive biological and clinical heterogeneity of MM hinders effective treatment and etiology research. Several molecular classification systems of prognostic impact have been proposed, but they do not predict the response to treatment nor do they correlate to plasma cell development pathways. Here we describe the classification of MM into two distinct subtypes based on the expression levels of a gene module coexpressed with MCL1 (MCL1-M), a regulator of plasma cell survival. The classification system enabled prediction of the prognosis and the response to bortezomib-based therapy. Moreover, the two MM subtypes were associated with two different plasma cell differentiation pathways (enrichment of a preplasmablast signature versus aberrant expression of B cell genes). 1q gain, harboring 63 of the 87 MCL1-M members including MCL1, was found in about 80% of the MM with upregulated MCL1-M expression. Clonal analysis showed that 1q gain tended to occur as an early clonal event. Members of MCL1-M captured both MM cell-intrinsically acting signals and the signals regulating the interaction between MM cells with bone marrow microenvironment. MCL1-M members were co-expressed in mouse germinal center B cells. Together, these findings indicate that MCL1-M may play previously inadequately recognized, initiating role in the pathogenesis of MM. Our findings suggest that MCL1-M signature-based molecular clustering of MM constitutes a solid framework toward understanding the etiology of this disease and establishing personalized care. Article Summary: A pathogenic mechanism-guided molecular classification would facilitate treatment decision and etiology research of multiple myeloma. On the basis of the expression levels of a gene module coexpressed with MCL1, we have established a classification scheme assigning multiple myeloma into two subtypes with distinct prognosis, treatment responses and pathogenic backgrounds.

Thermal Stability of Particle-Phase Monoethanolamine Salts.

The use of monoethanolamine (MEA, 2-hydroxyethanamine) for scrubbing of carbon dioxide from combustion flue gases may become the dominant technology for carbon capture in the near future. The widespread implementation of this technology will result in elevated emissions of MEA to the environment that may increase the loading and modify the properties of atmospheric aerosols. We have utilized experimental measurements together with aerosol microphysics calculations to derive thermodynamic properties of several MEA salts, potentially the dominant forms of MEA in atmospheric particles. The stability of the salts was found to depend strongly on the chemical nature of the acid counterpart. The saturation vapor pressures and vaporization enthalpies obtained in this study can be used to evaluate the role of MEA in the aerosol and haze formation, helping to assess impacts of the MEA-based carbon capture technology on air quality and climate change.

Single Parameter for Predicting the Morphology of Atmospheric Black Carbon.

Black carbon (BC) from fuel combustion is an effective light absorber that contributes significantly to direct climate forcing. The forcing is altered when BC combines with other substances, which modify its mixing state and morphology, making the evaluation of its atmospheric lifetime and climate impact a challenge. To elucidate the associated mechanisms, we exposed BC aerosol to supersaturated vapors of different chemicals to form thin coatings and measured the coating mass required to induce the restructuring of BC aggregates. We found that studied chemicals fall into two distinct groups based on a single dimensionless parameter, χ, which depends on the diameter of BC monomer spheres and the coating material properties, including vapor supersaturation, molar volume, and surface tension. We show that when χ is small (low-volatility chemicals), the highly supersaturated vapor condenses uniformly over aggregates, including convex monomers and concave junctions in between monomers, but when χ is large (intermediate-volatility chemicals), junctions become preferred. The aggregates undergo prompt restructuring when condensation in the junctions dominates over condensation on monomer spheres. For a given monomer diameter, the coating distribution is mostly controlled by vapor supersaturation. The χ factor can be incorporated straightforwardly into atmospheric models to improve simulations of BC aging.

Remodeling of Dendritic Spines in the Avian Vocal Motor Cortex Following Deafening Depends on the Basal Ganglia Circuit.

Deafening elicits a deterioration of learned vocalization, in both humans and songbirds. In songbirds, learned vocal plasticity has been shown to depend on the basal ganglia-cortical circuit, but the underlying cellular basis remains to be clarified. Using confocal imaging and electron microscopy, we examined the effect of deafening on dendritic spines in avian vocal motor cortex, the robust nucleus of the arcopallium (RA), and investigated the role of the basal ganglia circuit in motor cortex plasticity. We found rapid structural changes to RA dendritic spines in response to hearing loss, accompanied by learned song degradation. In particular, the morphological characters of RA spine synaptic contacts between 2 major pathways were altered differently. However, experimental disruption of the basal ganglia circuit, through lesions in song-specialized basal ganglia nucleus Area X, largely prevented both the observed changes to RA dendritic spines and the song deterioration after hearing loss. Our results provide cellular evidence to highlight a key role of the basal ganglia circuit in the motor cortical plasticity that underlies learned vocal plasticity.

RNA-seq of 272 gliomas revealed a novel, recurrent PTPRZ1-MET fusion transcript in secondary glioblastomas.

Studies of gene rearrangements and the consequent oncogenic fusion proteins have laid the foundation for targeted cancer therapy. To identify oncogenic fusions associated with glioma progression, we catalogued fusion transcripts by RNA-seq of 272 gliomas. Fusion transcripts were more frequently found in high-grade gliomas, in the classical subtype of gliomas, and in gliomas treated with radiation/temozolomide. Sixty-seven in-frame fusion transcripts were identified, including three recurrent fusion transcripts: FGFR3-TACC3, RNF213-SLC26A11, and PTPRZ1-MET (ZM). Interestingly, the ZM fusion was found only in grade III astrocytomas (1/13; 7.7%) or secondary GBMs (sGBMs, 3/20; 15.0%). In an independent cohort of sGBMs, the ZM fusion was found in three of 20 (15%) specimens. Genomic analysis revealed that the fusion arose from translocation events involving introns 3 or 8 of PTPRZ and intron 1 of MET. ZM fusion transcripts were found in GBMs irrespective of isocitrate dehydrogenase 1 (IDH1) mutation status. sGBMs harboring ZM fusion showed higher expression of genes required for PIK3CA signaling and lowered expression of genes that suppressed RB1 or TP53 function. Expression of the ZM fusion was mutually exclusive with EGFR overexpression in sGBMs. Exogenous expression of the ZM fusion in the U87MG glioblastoma line enhanced cell migration and invasion. Clinically, patients afflicted with ZM fusion harboring glioblastomas survived poorly relative to those afflicted with non-ZM-harboring sGBMs (P < 0.001). Our study profiles the shifting RNA landscape of gliomas during progression and reveled ZM as a novel, recurrent fusion transcript in sGBMs.

A glioma classification scheme based on coexpression modules of EGFR and PDGFRA.

We hypothesized that key signaling pathways of glioma genesis might enable the molecular classification of gliomas. Gene coexpression modules around epidermal growth factor receptor (EGFR) (EM, 29 genes) or platelet derived growth factor receptor A (PDGFRA) (PM, 40 genes) in gliomas were identified. Based on EM and PM expression signatures, nonnegative matrix factorization reproducibly clustered 1,369 adult diffuse gliomas WHO grades II-IV from four independent databases generated in three continents, into the subtypes (EM, PM and EM(low)PM(low) gliomas) in a morphology-independent manner. Besides their distinct patterns of genomic alterations, EM gliomas were associated with higher age at diagnosis, poorer prognosis, and stronger expression of neural stem cell and astrogenesis genes. Both PM and EM(low)PM(low) gliomas were associated with younger age at diagnosis and better prognosis. PM gliomas were enriched in the expression of oligodendrogenesis genes, whereas EM(low)PM(low) gliomas were enriched in the signatures of mature neurons and oligodendrocytes. The EM/PM-based molecular classification scheme is applicable to adult low-grade and high-grade diffuse gliomas, and outperforms existing classification schemes in assigning diffuse gliomas to subtypes with distinct transcriptomic and genomic profiles. The majority of the EM/PM classifiers, including regulators of glial fate decisions, have not been extensively studied in glioma biology. Subsets of these classifiers were coexpressed in mouse glial precursor cells, and frequently amplified or lost in an EM/PM glioma subtype-specific manner, resulting in somatic copy number alteration-dependent gene expression that contributes to EM/PM signatures in glioma samples. EM/PM-based molecular classification provides a molecular diagnostic framework to expedite the search for new glioma therapeutic targets.