Magnetosome-inspired synthesis of soft ferrimagnetic nanoparticles for magnetic tumor targeting.

Magnetic targeting is one of the most promising approaches for improving the targeting efficiency by which magnetic drug carriers are directed using external magnetic fields to reach their targets. As a natural magnetic nanoparticle (MNP) of biological origin, the magnetosome is a special "organelle" formed by biomineralization in magnetotactic bacteria (MTB) and is essential for MTB magnetic navigation to respond to geomagnetic fields. The magnetic targeting of magnetosomes, however, can be hindered by the aggregation and precipitation of magnetosomes in water and biological fluid environments due to the strong magnetic attraction between particles. In this study, we constructed a magnetosome-like nanoreactor by introducing MTB Mms6 protein into a reverse micelle system. MNPs synthesized by thermal decomposition exhibit the same crystal morphology and magnetism (high saturation magnetization and low coercivity) as natural magnetosomes but have a smaller particle size. The DSPE-mPEG-coated magnetosome-like MNPs exhibit good monodispersion, penetrating the lesion area of a tumor mouse model to achieve magnetic enrichment by an order of magnitude more than in the control groups, demonstrating great prospects for biomedical magnetic targeting applications.

Transition from Flat-Band Localization to Anderson Localization in a One-Dimensional Tasaki Lattice.

We report an extensive experimental investigation on the transition from flat-band localization (FBL) to Anderson localization (AL) in a one-dimensional synthetic lattice in the momentum dimension. By driving multiple Bragg processes between designated momentum states, an effective one-dimensional Tasaki lattice is implemented with highly tunable parameters, including nearest-neighbor and next-nearest-neighbor coupling coefficients and onsite energy potentials. With that, a flat-band localization phase is realized and demonstrated via the evolution dynamics of the particle population over different momentum states. The localization effect is undermined when a moderate disorder is introduced to the onsite potential and restored under a strong disorder. We find clear signatures of the FBL-AL transition in the density profile evolution, the inverse participation ratio, and the von Neumann entropy, where good agreement is obtained with theoretical predictions.

A new preparation method of covalent annular nanodiscs based on MTGase.

The preservation of the native conformation and functionality of membrane proteins has posed considerable challenges. While detergents and liposome reconstitution have been traditional approaches, nanodiscs (NDs) offer a promising solution by embedding membrane proteins in phospholipids encircled by an amphipathic helical protein MSP belt. Nevertheless, a drawback of commonly used NDs is their limited homogeneity and stability. In this study, we present a novel approach to construct covalent annular nanodiscs (cNDs) by leveraging microbial transglutaminase (MTGase) to catalyze isopeptide bond formation between the side chains of terminal amino acids, specifically Lysine (K) and Glutamine (Q). This methodology significantly enhances the homogeneity and stability of NDs. Characterization of cNDs and the assembly of membrane proteins within them validate the successful reconstitution of membrane proteins with improved homogeneity and stability. Our findings suggest that cNDs represent a more suitable tool for investigating interactions between membrane proteins and lipids, as well as for analyzing membrane protein structures.

Homochiral Tetraphenylethene-Based Metal-Organic Frameworks with Circularly Polarized Luminescence for Enantioselective Recognition.

A pair of water-stable and highly porous homochiral fluorescent silver-organic framework enantiomers, namely, R-Ag-BPA-TPyPE (R-1) and S-Ag-BPA-TPyPE (S-1), had been prepared as enantioselective fluorescence sensors. Combining homochiral 1,1'-binaphthyl-2,2'-diyl hydrogen phosphate (BPA) with an AIE-based ligand tetrakis[4-(pyridin-4-yl)phenyl]ethene (TPyPE) in complexes R-1 and S-1 made them possess favorable circularly polarized luminescence (CPL) properties, and their CPL spectra were almost mirror images of each other. The luminescence dissymmetry factors (glum) are ±2.2 × 10-3 for R-1 and S-1, and the absolute fluorescence quantum yields (ΦFs) are 32.0% for R-1 and S-1, respectively. Complex R-1 could enantioselectively recognize two enantiomers of amino acids in water or DMF with high Stern-Volmer constants of 236-573 M-1 and enantioselectivity ratios of 1.40-1.78.

Multi-Pleated Alkalized Ti3 C2 Tx MXene-Based Sandwich-Like Structure Composite Nanofibers for High-Performance Sodium/Lithium Storage.

The volume expansion of CoFe2 O4 anode poses a significant challenge in the commercial application of lithium/sodium-ion batteries (LIBs/SIBs). However, metal-organic-frameworks (MOF) offer superior construction of heterostructures with refined interfacial interactions and lower ion diffusion barriers in Li/Na storage. In this study, the CoFe2 O4 @carbon nanofibers derived from MOF are produced through electrospinning, in situ growth followed by calcination, which are then confined within an MXene-confined MOF-derived porous CoFe2 O4 @carbon composite architecture under alkali treatment. The CoFe2 O4 nanofibers anchor on the alkalized MXene that is decorated with the NaOH solution to form a multi-pleated structure. The sandwich-like structure of the composite effectively alleviates the volume expansion and shortens the Li/Na-ion diffusion path, which displays high capacity and outstanding rate performance as anode materials for LIBs/SIBs. As a consequence, the obtained CoFe2 O4 @carbon@alkalized MXene composite anode shows satisfied rate performance at current density of 10 A g-1 for LIBs (318 mAh·g-1 ) and 5 A g-1 for SIBs (149 mAh g-1 ). The excellent cycling performance is further demonstrated at a high current density, where it maintains a discharge capacity of 807 mAh g-1 at 2 A g-1 after 400 cycles for LIBs and 130 mAh g-1 at 1 A g-1 even after 1000 cycles for SIBs.

Scalable Multipartite Entanglement Created by Spin Exchange in an Optical Lattice.

Ultracold atoms in optical lattices form a competitive candidate for quantum computation owing to the excellent coherence properties, the highly parallel operations over spins, and the ultralow entropy achieved in qubit arrays. For this, a massive number of parallel entangled atom pairs have been realized in superlattices. However, the more formidable challenge is to scale up and detect multipartite entanglement, the basic resource for quantum computation, due to the lack of manipulations over local atomic spins in retroreflected bichromatic superlattices. In this Letter, we realize the functional building blocks in quantum-gate-based architecture by developing a cross-angle spin-dependent optical superlattice for implementing layers of quantum gates over moderately separated atoms incorporated with a quantum gas microscope for single-atom manipulation and detection. Bell states with a fidelity of 95.6(5)% and a lifetime of 2.20±0.13 s are prepared in parallel, and then connected to multipartite entangled states of one-dimensional ten-atom chains and two-dimensional plaquettes of 2×4 atoms. The multipartite entanglement is further verified with full bipartite nonseparability criteria. This offers a new platform toward scalable quantum computation and simulation.

Dynamic folding modulation generates FGF21 variant against diabetes.

Fibroblast growth factor 21 (FGF21) is a regulator of glucose and lipid metabolism. It has been widely considered as a promising candidate for the treatment of type 2 diabetes mellitus (T2DM) and other related metabolic disorders. However, lack of structural and dynamic information has limited FGF21-based drug development. Here, using nuclear magnetic resonance (NMR) spectroscopy, we determine the structure of FGF21 and find that its non-canonical flexible ß-trefoil conformation affects the folding of ß2-ß3 hairpin and further overall protein stability. To modulate folding dynamics, we designed an FGF21-FGF19 chimera, FGF21SS . As expected, FGF21SS shows better thermostability without inducing hepatocyte proliferation. Functional characterization of FGF21SS shows its better insulin sensitivity, reduced inflammation in 3T3-L1 adipocytes, and lower blood glucose and insulin levels in ob/ob mice compared with wild type. Our dynamics-based rational design provides a promising approach for FGF21-based therapeutic development against T2DM.

Discovery and Functional Analysis of Secondary Hair Follicle miRNAs during Annual Cashmere Growth.

Secondary hair follicles (SHFs) produce the thermoregulatory cashmere of goats. MicroRNAs (miRNAs) play indispensable roles in hair follicle formation and growth. However, most studies examining miRNAs related to cashmere have been performed on goat skin. It remains unclear which miRNAs are highly expressed in SHFs or how miRNAs affect cashmere growth. In the present study, we isolated the SHFs under a dissecting microscope and analyzed the miRNA signatures during annual cashmere growth. Small-RNA sequencing followed by genome-wide expression analysis revealed that early anagen is a crucial phase for miRNA regulation of the cashmere growth, as revealed by two predominant groups of miRNAs. Although they exhibited opposite expression patterns, both groups demonstrated sharp changes of expression when in transit from early anagen to mid-anagen. In addition, we identified 96 miRNA signatures that were differentially expressed between different phases among 376 miRNAs. Functional analysis of the predicted target genes of highly expressed or differentially expressed miRNAs indicated that these miRNAs were involved in signal pathways associated with SHF development, regeneration, and regression. Furthermore, miR-143-3p was preferentially expressed in SHFs and Itga6 was identified as one of targets. The dual-luciferase and in situ hybridization assay demonstrated that miR-143-3p directly repressed the expression of Itga6, suggesting a possible novel role for miR-143-3p in cashmere growth.

Association between circulating follistatin-like-1 and metabolic syndrome in middle-aged and old population: A cross-sectional study.

AIM: Follistatin-like-1 (FSTL-1) is considered to be a novel cytokine, and it is associated with metabolic diseases. However, it is necessary to investigate further the association of FSTL-1 with metabolic syndrome (MetS) and insulin resistance (IR). We performed a cross-sectional study to investigate the associated of circulating FSTL-1 with the MetS. MATERIALS AND METHODS: A cross-sectional study was performed in 487 Chinese people, including 231 control subjects and 256 patients with MetS. Bioinformatics analysis was used to determine the protein and pathways associated with FSTL-1. The protein and protein interaction (PPI) network was constructed and analysed. Serum FSTL-1 concentrations were determined by an ELISA assay. The association of FSTL-1 with MetS components and IR was assessed. RESULTS: Serum FSTL-1 levels were markedly higher in patients with newly diagnosed MetS than in controls (7.5 [5.6-9.2] vs 5.8 [5.0-7.7] µg/L, P < .01). According to bioinformatics analysis, the top high-degree genes were identified as the core genes, including SPARCL1, CYR61, LTBP1, IL-6, BMP2, BMP4, FBN1, FN1 CHRDL1 and FSTL-3. These genes are mainly enriched in pathways including TGF-ß, AGE-RAGE signalling pathway in diabetic complications, and Hippo signalling pathways; in basal cell carcinoma, cytokine-cytokine receptor interaction and in amoebic and Yersinia infections. Furthermore, serum FSTL-1 levels were positively associated with fasting plasma glucose (FPG), waist circumference (WC), blood pressure, triglyceride levels and visceral adiposity index (VAI). We found that serum FSTL-1 levels were markedly associated with MetS and IR by binary logistic regression analysis. CONCLUSIONS: We conclude that FSTL-1 may be a novel cytokine related to MetS and IR.

Component of oligomeric Golgi complex 1 deficiency leads to hypoglycemia: a case report and literature review.

BACKGROUND: Congenital disorders of glycosylation (CDG) are a group of metabolic diseases with clinical and genetic heterogeneity, and CDG-IIg is one of the rare reported types of CDG. The aim of this study is to report the clinical manifestations and gene-phenotype characteristics of a rare case of CDG caused by a COG1 gene mutation and review literatures of CDG disease. CASE PRESENTATION: The patient was male, and the main clinical symptoms were developmental retardation, convulsion, strabismus, and hypoglycemia, which is rarely reported in CDG-IIg. We treated the patient with glucose infusion and he was recovered from hypoglycemia. Genetic analysis showed that the patient carried the heterozygous intron mutation c.1070 + 3A > G (splicing) in the coding region of the COG1 gene that was inherited from the mother, and the heterozygous mutation c.2492G > A (p. Arg831Gln) in exon 10 of the COG1 gene that was inherited from the father. The genes interacting with COG1 were mainly involved in the transport and composition of the Golgi. The clinical data and laboratory results from a patient diagnosed with CDG-IIg were analyzed, and the causative gene mutation was identified by high-throughput sequencing. The genes and signal pathways related to COG1 were analyzed by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses. CONCLUSIONS: The c.2492G > A (p. Arg831Gln) mutation in exon 10 of the COG1 gene may be a potential pathogenetic variant for CDG-IIg. Because of the various manifestations of CDG in clinical practice, multidisciplinary collaboration is important for the diagnosis and treatment of this disease.

Sandstorms and desertification in Mongolia, an example of future climate events: a review.

As global temperatures continue to increase and human activities continue to expand, many countries and regions are witnessing the consequences of global climate change. Mongolia, a nomadic and picturesque landlocked country, has battled with ongoing desertification, recurring droughts, and increasingly frequent sandstorms in recent decades. Here we review the abrupt changes in the climate regime of Mongolia over the recent few decades, by focusing on atmospheric events, land degradation and desertification issues, and the resulted sandstorms. We found that between mid-March to mid-April 2021, the country encountered violent gusts of wind, the Mongolia cyclone, and the largest sandstorms in a decade, causing extensive damages nationwide and trans-regional impact in East Asia including northern China, Japan, and most parts of South Korea. A multitude of factors have contributed to this current ecological crisis. Since 1992, the country has transformed to a market economy with high economic growth driven by mineral and agricultural exports. Overgrazing along with intensified human activities such as coal mining has contributed to the widespread land degradation in Mongolia, while climate change has become a major driving factor for recurring droughts. Annual mean air temperature in Mongolia increased by 2.24 °C between 1940 and 2015, while annual precipitation decreased by 7%, resulting in a higher aridity across the country. A positive feedback loop between soil moisture deficits and surface warming has led to a hotter and drier climate in the region, with over a quarter of lakes greater than 1.0-km2 dried up in the Mongolian Plateau between 1987 and 2010. Increased temperatures, decreased precipitation coupled with land degradation have resulted in a persisting drying trend, with more than three-quarters of land in Mongolia being affected by drought and desertification. The 2021 East Asia sandstorms drew international attention to ecological issues that have culminated for decades in Mongolia. Collaborative efforts from policy makers, local residents, and scientists from both its local and the global research community are urgently needed to address the grand and rapidly aggravating ecological challenges in Mongolia.

Smarter cures to combat COVID-19 and future pathogens: a review.

Prevention is better than cure. A milestone of the anthropocene is the emergence of a series of epidemics and pandemics often characterized by the transmission of a pathogen from animals to human in the past two decades. In particular, the coronavirus disease 2019 (COVID-19) has made a profound impact on emergency responding and policy-making in a public health crisis. Classical solutions for controlling the virus, such as travel restrictions, lockdowns, repurposed drugs and vaccines, are socially unpopular and medically limited by the fast mutation and adaptation of the virus. This is exacerbated by microbial resistance to therapeutic drugs and the slowness of vaccine development. In other words, microbial pathogens are somehow 'smarter' and faster than us, thus calling for more intelligent cures to combat future pandemics. Here, we compare therapeutics for COVID-19 such as synthetic drugs, vaccines, antibodies and phages. We present the strength and limitations of antibiotic and antiviral drugs, vaccines, and antibody-based therapeutics. We describe smarter, cheaper and preventive cures such as bacteriophages, food medicine using probiotics and prebiotics, sports, healthy diet, music, yoga, Tai Chi, dance, reading, knitting, cooking and outdoor activities. Some of these preventive cures have been intuitively developed since thousands of years ago, as illustrated by the fascinating similarity of the Chinese characters for 'music' and 'herbal medicine.'

Discovery and Characterisation of Highly Cooperative FAK-Degrading PROTACs.

Focal adhesion kinase (FAK) is a key mediator of tumour progression and metastasis. To date, clinical trials of FAK inhibitors have reported disappointing efficacy for oncology indications. We report the design and characterisation of GSK215, a potent, selective, FAK-degrading Proteolysis Targeting Chimera (PROTAC) based on a binder for the VHL E3 ligase and the known FAK inhibitor VS-4718. X-ray crystallography revealed the molecular basis of the highly cooperative FAK-GSK215-VHL ternary complex, and GSK215 showed differentiated in-vitro pharmacology compared to VS-4718. In mice, a single dose of GSK215 induced rapid and prolonged FAK degradation, giving a long-lasting effect on FAK levels (≈96 h) and a marked PK/PD disconnect. This tool PROTAC molecule is expected to be useful for the study of FAK-degradation biology in vivo, and our results indicate that FAK degradation may be a differentiated clinical strategy versus FAK inhibition for the treatment of cancer.

The putative deubiquitinating enzyme MoUbp4 is required for infection-related morphogenesis and pathogenicity in the rice blast fungus Magnaporthe oryzae.

Ubiquitination is a key regulatory mechanism that affects numerous important biological processes, including cellular differentiation and pathogenesis in eukaryotic cells. Attachment of proteins to ubiquitin is reversed by specialized proteases, deubiquitinating enzymes (DUBs), which are essential for precursor processing, maintaining ubiquitin homeostasis and promoting protein degradation by recycling ubiquitins. Here, we report the identification of a novel non-pathogenic T-DNA-tagged mutant T612 of Magnaporthe oryzae with a single insertion in the second exon of MoUBP4, which encodes a putative ubiquitin carboxyl-terminal hydrolase. Targeted gene deletion mutants of MoUBP4 are significantly reduced in mycelial growth, conidiation, and increased in tolerance to SDS and CR (Congo red) cell-wall damage. The ΔMoubp4 mutants are blocked in penetration and invasive growth, which results in the loss of pathogenicity. Many conidia produced by the ΔMoubp4 mutants are unable to form appressoria and mobilization and degradation of glycogen and lipid droplets are significantly delayed. Moreover, immunohybridization analysis revealed that total protein ubiquitination levels of the null mutants were significantly increased, indicating that MoUbp4 functions as a deubiquitination enzyme. Taken together, we conclude that MoUbp4 is required for deubiquitination, infection-related morphogenesis and pathogenicity in M. oryzae.

A Dual Role of ATM in Ischemic Preconditioning and Ischemic Injury.

The ataxia-telangiectasia mutated (ATM) protein is regarded as the linchpin of cellular defenses to stress. Deletion of ATM results in strong oxidative stress and degenerative diseases in the nervous system. However, the role of ATM in neuronal ischemic preconditioning and lethal ischemic injury is still largely unknown. In this study, mice cortical neurons preconditioned with sublethal exposure to oxygen glucose deprivation (OGD) exhibited ATM/glucose-6-phosphate dehydrogenase pathway activation. Additionally, pharmacological inhibition of ATM prior to the preconditioning reversed neuroprotection provided by preconditioning in vitro and in vivo. Meanwhile, we found that ATM/P53 pro-apoptosis pathway was driven by lethal OGD injury, and pharmacological inhibition of ATM during fatal oxygen-glucose deprivation/reperfusion injury promoted neuronal survival. More importantly, inhibition of ATM activity after cerebral ischemia protected against cerebral ischemic-reperfusion damage in mice. In conclusion, our data show the dual role of ATM in neuronal ischemic preconditioning and lethal ischemic injury, involving in the protection of ischemic preconditioning, but promoting neuronal death in lethal ischemic injury. Thus, the present study provides new opportunity for the treatment of ischemic stroke.

Selective CDK6 degradation mediated by cereblon, VHL, and novel IAP-recruiting PROTACs.

Inhibitors of CDK4 and CDK6 have emerged as important FDA-approved treatment options for breast cancer patients. The properties and pharmacology of CDK4/6 inhibitor medicines have been extensively profiled, and investigations into the degradation of these targets via a PROTAC strategy have also been reported. PROTACs are a novel class of small-molecules that offer the potential for differentiated pharmacology compared to traditional inhibitors by redirecting the cellular ubiquitin-proteasome system to degrade target proteins of interest. We report here the preparation of palbociclib-based PROTACs that incorporate binders for three different E3 ligases, including a novel IAP-binder, which effectively degrade CDK4 and CDK6 in cells. In addition, we show that the palbociclib-based PROTACs in this study that recruit different E3 ligases all exhibit preferential CDK6 vs. CDK4 degradation selectivity despite employing a selection of linkers between the target binder and the E3 ligase binder.

The putative histone-like transcription factor FgHltf1 is required for vegetative growth, sexual reproduction, and virulence in Fusarium graminearum.

The target of rapamycin (TOR) signaling pathway plays critical roles in regulating vegetative development and virulence in Fusarium graminearum. Previously, we have demonstrated that the putative type 2A phosphatase FgPpg1, a downstream component of the pathway, is important for hyphal growth, sporulation, DON biosynthesis and virulence. Here, we report the identification of FgHLTF1 putatively encoding a histone-like transcription factor by the transcriptome analysis of an ΔFgppg1 mutant. The FgHLTF1 expression was significantly down-regulated by the deletion of FgPPG1 or treatment with rapamycin. Analysis of an F. graminearum strain expressing green fluorescent protein (GFP) revealed that FgHltf1-GFP fusion protein mainly localized to the nucleus. Targeted gene deletion mutants of FgHLTF1 exhibited a significant reduction in vegetative growth, sexual reproduction and virulence. Moreover, the growth of the ΔFghltf1 mutants was restricted by hyperosmotic stresses. Unlike the wild-type strain, the mutants showed anomalous subcellular translocation of FgHog1-GFP under hyperosmotic conditions, suggesting that FgHLTF1 is associated with the high osmolarity glycerol response pathway. Taken together, we conclude that FgHLTF1 is transcriptionally regulated by the TOR signaling pathway and plays important roles in regulating vegetative growth, sexual reproduction, virulence and hyperosmotic stresses in F. graminearum.

Integrated analysis of lncRNA-miRNA-mRNA ceRNA network in squamous cell carcinoma of tongue.

BACKGROUND: Numerous studies have highlighted that long non-coding RNAs (lncRNAs) can bind to microRNA (miRNA) sites as competing endogenous RNAs (ceRNAs), thereby affecting and regulating the expression of mRNAs and target genes. These lncRNA-associated ceRNAs have been theorized to play a significant role in cancer initiation and progression. However, the roles and functions of the lncRNA-miRNA-mRNA ceRNA network in squamous cell carcinoma of the tongue (SCCT) are still unclear. METHODS: The miRNA, mRNA and lncRNA expression profiles from 138 patients with SCCT were downloaded from The Cancer Genome Atlas database. We identified the differential expression of miRNAs, mRNAs, and lncRNAs using the limma package of R software. We used the clusterProfiler package for GO and KEGG pathway annotations. The survival package was used to estimate survival analysis according to the Kaplan-Meier curve. Finally, the GDCRNATools package was used to construct the lncRNA-miRNA-mRNA ceRNA network. RESULTS: In total, 1943 SCCT-specific mRNAs, 107 lncRNAs and 100 miRNAs were explored. Ten mRNAs (CSRP2, CKS2, ADGRG6, MB21D1, GMNN, RIPOR3, RAD51, PCLAF, ORC1, NAGS), 9 lncRNAs (LINC02560, HOXC13 - AS, FOXD2 - AS1, AC105277.1, AC099850.3, STARD4 - AS1, SLC16A1 - AS1, MIR503HG, MIR100HG) and 8 miRNAs (miR - 654, miR - 503, miR - 450a, miR - 379, miR - 369, miR - 190a, miR - 101, and let-7c) were found to be significantly associated with overall survival (log-rank p < 0.05). Based on the analysis of the lncRNA-miRNA-mRNA ceRNA network, one differentially expressed (DE) lncRNA, five DEmiRNAs, and three DEmRNAs were demonstrated to be related to the pathogenesis of SCCT. CONCLUSIONS: In this study, we described the gene regulation by the lncRNA-miRNA-mRNA ceRNA network in the progression of SCCT. We propose a new lncRNA-associated ceRNA that could help in the diagnosis and treatment of SCCT.

Microbially reduced humic acid promotes the anaerobic photodegradation of 17α--ethinylestradiol.

Photolysis and microbial activity are relatively obvious in shallow, eutrophic waters with low dissolved oxygen content. Ubiquitous humic acid (HA) can act as electron acceptor and be reduced by bacterial under such conditions, and the reduced form of humic acid (RHA) plays an important role in the photolysis contaminants. In this study, anaerobic 17α-ethinylestradiol (EE2) photodegradation was performed along with biodegradation by Shewanella putrefaciens mediated by HA. The mechanism of such coupled photolysis and biodegradation of EE2 was thus elucidated. The removal rate in such coupled degradation in the presence of 10 mgC L-1 of HA at pH 8.0 was greater than that of either photolysis or biodegradation alone. HA which had been reduced in a double-chamber microbial fuel cell showed better promotion to EE2 photodegradation than fresh HA. Reactive species scavenging experiments indicated that hydroxyl radical and excited triplet states of HA were primary contributors to EE2 photodegradation in anaerobic conditions. More of them were produced from RHA than from pristine HA. Besides, the degraded EE2 solutions inhibited the proliferation of MCF-7 human cancer Cells. These findings improve our understanding of the environmental transformation of EE2 in the shallow, anoxic waters.

Excessive activated T-cell proliferation after anti-CD19 CAR T-cell therapy.

Excessive activated T-cell proliferation was observed in vivo in one patient after an anti-CD19-chimeric antigen receptor (CAR) T-cell infusion. The patient, who had chemotherapy refractory and CD19+ diffuse large B-cell lymphoma (DLBCL), received an anti-CD19 CAR T-cell infusion following conditioning chemotherapy (fludarabine/cyclophosphamide). The lymphocyte count in the peripheral blood (PB) increased to 77 × 109/L on day 13 post infusion, and the proportion of CD8+ actived T cells was 93.06% of the lymphocytes. Then, the patient suffered from fever and hypoxaemia. Significant increases in serum cytokine, lactate dehydrogenase, aspartate aminotransferase (AST), alanine transaminase (ALT), and glutamic-oxalacetic transaminase (γ-GT) levels were observed. A high-throughput sequencing analysis for T-cell receptors (TCRs) and whole-genome sequencing were used to explore the mechanisms underlying this excessive T-cell proliferation. TCR diversity was demonstrated, but no special gene mutation was found. The patient was found to be infected with the John Cunningham polyomavirus (JCV). It cannot be ruled out the bystander activation pathway induced by JCV infections related the excessive activated T-cell proliferation. Although the clinical and laboratory data do not fully explain the reason for excessive T-cell proliferation after the anti-CD19 CAR T-cell infusion, the risk of this type of toxicity should be emphasized. This study was registered at www.clinicaltrials.gov as NCT01864889.