Highly transparent Ce:Nd:YAG ceramic with good light conversion capacity for solar-pumped solid-state lasers.

Developing a high quality ceramic laser gain medium for solar directly pumped solid state lasers is essential, and yet the light conversion efficiency of the gain media for solar pumping remains a challenge. In this study, Ce and Nd ions, co-doped YAG transparent ceramics with theoretical transmittance and stable Ce3+ valent state were developed, and revealed that the absorbed visible light and light conversion efficiency in Ce,Nd:YAG ceramics were 3.98 times and 1.34 times higher than those in widely reported Cr,Nd:YAG ceramics, respectively. A concentration matching principle between Ce3+ and Nd3+ ions in YAG was established, and a higher Nd3+ ion doping concentration with a relatively low Ce3+ concentration was favorable to improve both the light conversion efficiency and emission intensity at 1064 nm of Ce,Nd:YAG ceramics. Energy transfer efficiency from Ce3+ to Nd3+ of the 0.3 at.%Ce,1.5at.%Nd:YAG ceramic reached as high as 61.71% at room temperature. Surprisingly, it was further promoted to 64.31% at a higher temperature of 473 K. More excited electrons at the upper energy level of Ce3+ ion under the high temperature accounted for this novel phenomenon. This study proposes a new design strategy of gain materials for solar directly pumped solid state lasers.

Combined Effects of the Serum IgA/C3 Ratio and Glomerular C3 Staining on the Renal Outcome in Adult Immunoglobulin A Nephropathy.

INTRODUCTION: The aim of this study was to evaluate the predictive value of the serum IgA/C3 ratio and glomerular C3 deposits in kidney biopsy in adult IgA nephropathy. METHODS: The study included 718 adult IgAN patients diagnosed based on kidney biopsy. Patients without corticosteroids or immunosuppressive drugs >1 month were regularly followed up for at least 1 year or until the study endpoint. The optimum serum IgA/C3 ratio was calculated by the AUROC-based cutoff ratio. Proteinuria, creatinine, eGFR, serum IgA, and serum C3 were evaluated at baseline. Kidney biopsy was categorized using the Oxford classification, with a calculation of the MEST-C score. The degree of glomerular C3 staining was semiquantitatively determined (grade 0, no or trace; grade 1, mild; grade 2, moderate; grade 3, marked) by immunofluorescence microscopy. The patients were divided into four groups by the serum IgA/C3 ratio and glomerular C3 staining. RESULTS: The baseline data suggested that when the serum IgA/C3 ratio was at the same level, patients with a high glomerular C3 staining score (≥2) always had mesangial proliferation, segmental glomerulosclerosis, and tubular atrophy/interstitial fibrosis (group 1 vs. group 2; group 3 vs. group 4). When glomerular C3 staining was at the same level, proteinuria was significantly higher in patients with serum IgA/C3<2.806 (group 1 vs. group 3; group 2 vs. group 4), which was contrary to previous studies that have suggested that the serum level of IgA/C3 was associated with disease severity. Hence, this study set out to investigate the combined effects of the serum IgA/C3 ratio and glomerular C3 staining on the renal outcome in adult IgA nephropathy. Renal survival analysis indicated that serum IgA/C3 ≥2.806 and glomerular C3 staining ≥2 (group 1) may be correlated with a poorer prognosis, especially in different clinicopathological characteristics of IgAN patients based on the subgroup analysis. Multivariate Cox analysis demonstrated that hypertension, serum creatinine, CKD stage, T1/2 and C3 staining were independent predictive factors of renal survival. CONCLUSIONS: The combination of serum IgA/C3 and C3 staining may contribute to improved optimization of the prognostic model in IgAN patients, especially patients with different sexes and degrees of disease. However, further study is required for validation in the future.

Asymmetric Synthesis of Trisubstituted Vicinal Diols through Copper(I)-Catalyzed Diastereoselective and Enantioselective Allylation of Ketones with Siloxypropadienes.

Chiral trisubstituted vicinal diols are a type of important organic compounds, serving as both common structure units in bioactive natural products and chiral auxiliaries in asymmetric synthesis. Herein, by using siloxypropadienes as the precursors of allyl copper(I) species, a copper(I)-catalyzed diastereoselective and enantioselective reductive allylation of ketones was achieved, providing both syn-diols and anti-diols in good to excellent enantioselectivity. DFT calculations show that cis-γ-siloxy-allyl copper species are generated favorably with either 1-TBSO-propadiene or 1-TIPSO-propadiene. Moreover, the steric difference of TBS group and TIPS group distinguishes the face selectivity of acetophenone, leading to syn-selectivity for 1-TBSO-propadiene and anti-selectivity for 1-TIPSO-propadiene. Easy transformations of the products were performed, demonstrating the synthetic utility of the present method. Moreover, one chiral diol prepared in the above transformations was used as a suitable organocatalyst for the catalytic asymmetric reductive self-coupling of aldimines generated in situ with B2(neo)2.

Cryptococcus neoformans capsule regrowth experiments reveal dynamics of enlargement and architecture.

The polysaccharide capsule of fungal pathogen Cryptococcus neoformans is a critical virulence factor that has historically evaded complete characterization. Cryptococcal polysaccharides are known to either remain attached to the cell as capsular polysaccharides (CPSs) or to be shed into the extracellular space as exopolysaccharides (EPSs). While many studies have examined the properties of EPS, far less is known about CPS. In this work, we detail the development of new physical and enzymatic methods for the isolation of CPS which can be used to explore the architecture of the capsule and isolated capsular material. We show that sonication or Glucanex enzyme cocktail digestion yields soluble CPS preparations, while use of a French pressure cell press or Glucanex digestion followed by cell disruption removed the capsule and produced cell wall-associated polysaccharide aggregates that we call "capsule ghosts", implying an inherent organization that allows the CPS to exist independent of the cell wall surface. Since sonication and Glucanex digestion were noncytotoxic, it was also possible to observe the cryptococcal cells rebuilding their capsule, revealing the presence of reducing end glycans throughout the capsule. Finally, analysis of dimethyl sulfoxide-extracted and sonicated CPS preparations revealed the conservation of previously identified glucuronoxylomannan motifs only in the sonicated CPS. Together, these observations provide new insights into capsule architecture and synthesis, consistent with a model in which the capsule is assembled from the cell wall outward using smaller polymers, which are then compiled into larger ones.

RNA m6A methylation regulates the ultraviolet-induced DNA damage response.

Cell proliferation and survival require the faithful maintenance and propagation of genetic information, which are threatened by the ubiquitous sources of DNA damage present intracellularly and in the external environment. A system of DNA repair, called the DNA damage response, detects and repairs damaged DNA and prevents cell division until the repair is complete. Here we report that methylation at the 6 position of adenosine (m6A) in RNA is rapidly (within 2 min) and transiently induced at DNA damage sites in response to ultraviolet irradiation. This modification occurs on numerous poly(A)+ transcripts and is regulated by the methyltransferase METTL3 (methyltransferase-like 3) and the demethylase FTO (fat mass and obesity-associated protein). In the absence of METTL3 catalytic activity, cells showed delayed repair of ultraviolet-induced cyclobutane pyrimidine adducts and elevated sensitivity to ultraviolet, demonstrating the importance of m6A in the ultraviolet-responsive DNA damage response. Multiple DNA polymerases are involved in the ultraviolet response, some of which resynthesize DNA after the lesion has been excised by the nucleotide excision repair pathway, while others participate in trans-lesion synthesis to allow replication past damaged lesions in S phase. DNA polymerase κ (Pol κ), which has been implicated in both nucleotide excision repair and trans-lesion synthesis, required the catalytic activity of METTL3 for immediate localization to ultraviolet-induced DNA damage sites. Importantly, Pol κ overexpression qualitatively suppressed the cyclobutane pyrimidine removal defect associated with METTL3 loss. Thus, we have uncovered a novel function for RNA m6A modification in the ultraviolet-induced DNA damage response, and our findings collectively support a model in which m6A RNA serves as a beacon for the selective, rapid recruitment of Pol κ to damage sites to facilitate repair and cell survival.

Corrigendum: RNA m6A methylation regulates the ultraviolet-induced DNA damage response.

This corrects the article DOI: 10.1038/nature21671.

Uric acid-based ratios for predicting renal failure in Chinese IgA nephropathy patients.

Objective: The uric acid/albumin ratio (UAR), a novel, simple, and compositive laboratory biomarker, has recently attracted attention for predicting disease prediction and disease prognosis. However, whether uric acid-related biomarkers (especially UAR) could serve as prognostic indicator for IgAN is unclear. Methods: In this retrospective cohort study, biopsy-confirmed IgAN patients from 2009 to 2017 from West China Hospital were evaluated. The optimal cutoff value of UAR for renal outcome was defined using the Youden index by the area under receiver operating characteristic curve (AUC). The patients were then categorized into the high UAR group and the low UAR group. Renal endpoints were defined as progression to ESRD, eGFR decreased ≥50% of the baseline level, or initiation of renal replacement treatment. Kaplan‒Meier survival analysis and Cox regression analysis were used to identify factors influencing IgAN outcomes. Results: A total of 1143 patients with a median age of 33.0 (26.0-42.0) (44.2% men) were included in the study. The best cut-off UAR concerned with renal survival was determined to be 9.94 with a specificity of 77.5% and a sensitivity of 61.5% (J, 0.390; AUC, 0.750). Then, the patients were divided into two groups labelled as low and high UAR ratios (≥ 9.94 and <9.94, respectively). More severe clinical manifestations and pathological lesions were observed in the high UAR group. Multivariate Cox regression analysis after adjusted for important clinicopathological parameters manifested that a high UAR was an independent prognostic biomarker for IgAN. (p = 0.036, HR =2.56, 95% CI: 1.07-6.16). Conclusion: UAR might be a novel predictor for renal progression and contribute to targeted management.

BACH1 recruits NANOG and histone H3 lysine 4 methyltransferase MLL/SET1 complexes to regulate enhancer-promoter activity and maintains pluripotency.

Maintenance of stem-cell identity requires proper regulation of enhancer activity. Both transcription factors OCT4/SOX2/NANOG and histone methyltransferase complexes MLL/SET1 were shown to regulate enhancer activity, but how they are regulated in embryonic stem cells (ESCs) remains further studies. Here, we report a transcription factor BACH1, which directly interacts with OCT4/SOX2/NANOG (OSN) and MLL/SET1 methyltransferase complexes and maintains pluripotency in mouse ESCs (mESCs). BTB domain and bZIP domain of BACH1 are required for these interactions and pluripotency maintenance. Loss of BACH1 reduced the interaction between NANOG and MLL1/SET1 complexes, and decreased their occupancy on chromatin, and further decreased H3 lysine 4 trimethylation (H3K4me3) level on gene promoters and (super-) enhancers, leading to decreased enhancer activity and transcription activity, especially on stemness-related genes. Moreover, BACH1 recruited NANOG through chromatin looping and regulated remote NANOG binding, fine-tuning enhancer-promoter activity and gene expression. Collectively, these observations suggest that BACH1 maintains pluripotency in ESCs by recruiting NANOG and MLL/SET1 complexes to chromatin and maintaining the trimethylated state of H3K4 and enhancer-promoter activity, especially on stemness-related genes.

Male Sex Is Associated With Worse Microbiological and Clinical Outcomes Following Tuberculosis Treatment: A Retrospective Cohort Study, a Systematic Review of the Literature, and Meta-analysis.

BACKGROUND: Although the incidence of tuberculosis is higher in men than in women, the relationship of sex with tuberculosis treatment outcomes has not been adequately studied. METHODS: We performed a retrospective cohort study and a systematic review and meta-analysis of observational studies during the last 10 years to assess sex differences in clinical and microbiological outcomes in tuberculosis. RESULTS: In our cohort of 2894 Taiwanese patients with drug-susceptible pulmonary tuberculosis (1975 male and 919 female), male patients had higher adjusted hazards of 9-month mortality due to all causes (hazard ratio, 1.43 [95% confidence interval (CI), 1.03-1.98]) and infections (1.70 [1.09-2.64]) and higher adjusted odds of 2-month sputum culture positivity (odds ratio [OR], 1.56 [95% CI, 1.05-2.33]) compared with female patients. Smear positivity at 2 months did not differ significantly (OR, 1.27 [95% CI, .71-2.27]) between the sexes. Among 7896 articles retrieved, 398 were included in our systematic review describing a total of 3 957 216 patients. The odds of all-cause mortality were higher in men than in women in the pooled unadjusted (OR, 1.26 [95% CI, 1.19-1.34]) and adjusted (1.31 [1.18-1.45]) analyses. Men had higher pooled odds of sputum culture (OR, 1.44 [95% CI, 1.14-1.81]) and sputum smear (1.58 [1.41-1.77]) positivity, both at the end of the intensive phase and on completion of treatment. CONCLUSIONS: Our retrospective cohort showed that male patients with tuberculosis have higher 9-month all-cause and infection-related mortality, with higher 2-month sputum culture positivity after adjustment for confounding factors. In our meta-analysis, male patients showed higher all-cause and tuberculosis-related mortality and higher sputum culture and smear positivity rates during and after tuberculosis treatment.

Lower serum bilirubin is associated with poor renal outcome in IgA nephropathy patients.

Aims: IgA nephropathy (IgAN) is the most prevalent primary glomerulonephritis worldwide. We conducted this study to explore the relationship between serum bilirubin and renal outcome of patients with IgAN. Methods: A total of 1492 biopsy proven IgAN patients were recruited and divided into two groups according to their median serum bilirubin concentration: the low bilirubin group (serum bilirubin≤9.7umol/L, n=753) and high bilirubin group (serum bilirubin>9.7umol/L, n=739). Basic clinical characteristics were assessed at the time of renal biopsy and the relationships between serum bilirubin and the combined endpoints were analyzed. The combined endpoints were defined as a 50% decline in estimate glomerular filtration rate (e-GFR), end-stage kidney disease (ESKD), renal transplantation and/or death. In addition, propensity score matching (PSM) was then performed to improve balance and simulate randomization between patients in different groups. Kaplan-Meier survival analysis was applied to explore the role of serum bilirubin in the progression of IgAN. Three clinicopathological models of multivariate Cox regression analysis were established to evaluate the association of serum bilirubin and renal prognosis of IgAN. Results: During median 5-year follow-up period, significant differences were shown in Kaplan-Meier analysis. In the unmatched group, 189 (12.7%) patients progressed to the renal combined endpoints. Among this, 122 in 753 patients (16.2%) were in low bilirubin group and 67 in 739 patients (9.1%) were in high bilirubin group (p<0.001). After PSM, there were 134 (11.8%) patients reached the combined endpoints, which included 77 in 566 patients (14.6%) in low bilirubin group and 57 in 566 patients (10.1%) in high bilirubin group (p=0.039). The results of three models (including demographics, pathological, clinical indicators and serum bilirubin) demonstrated that a lower basic serum bilirubin level was significantly associated with a higher risk of reaching combined endpoints in IgAN patients both in unmatched and matched cohort. Conclusion: Serum bilirubin level may be negatively associated with the progression of IgAN.

Proteomic Analysis of the Responses to Co-Stimulation of Intestinal Aeromonas and Shewanella in Lamprey Leukocytes.

Lamprey, one of the most basal jawless vertebrate, is an excellent model for studying vertebrate evolution, embryo development, and the origin of adaptive immunity. This study investigated the differentially expressed proteins in lamprey leukocytes in response to the co-stimulation of intestinal Aeromonas and Shewanella by using quantitative proteomics techniques. Significant differentially expressed proteins were identified. Gene Ontology annotation and the Kyoto Encyclopedia of Genes and Genomes pathway based on the significant differentially expressed proteins were analyzed. Most of the differentially expressed proteins were predicted to be involved in important signaling pathways. Quantitative real-time polymerase chain reaction was used to verify the expression of differentially expressed proteins at the mRNA level. The expression of some differentially expressed proteins was not consistent at the mRNA and protein levels. Differentially expressed proteins that are essential for lamprey-intestinal bacteria interaction should be identified to understand the lamprey adaptive immune response induced by gut microbiota.

Cigarette smoking may accelerate the progression of IgA nephropathy.

BACKGROUND: Whether cigarette smoking is associated with the progression of immunoglobulin A nephropathy (IgAN) remains uncertain; therefore, we aimed to evaluate the effect of cigarette smoking on the prognosis of IgAN. METHODS: We divided 1239 IgAN patients from West China Hospital of Sichuan University who met the inclusion criteria into smoker (current or former) and non-smoker groups. The endpoint was end-stage renal disease (ESRD: eGFR < 15 mL/min/1.73 m2 or undergoing renal replacement treatment) and/or eGFR decreased by > 50%. Kaplan-Meier, correlation, logistic regression and Cox proportional hazards analyses were performed. The association between cigarette smoking and IgAN was further verified by propensity-score-matched cohort analysis. RESULTS: During the mean follow-up period of 61 months, 19% (40/209) of the smoker group and 11% (110/1030) of the non-smoker group reached the study endpoint (p < 0.001). Multivariate Cox regression analysis revealed that cigarette smoking (hazard ratio (HR) = 1.58; p = 0.043) was an independent risk factor predicting poor renal progression in IgAN, and that IgAN patients with chronic kidney disease (CKD) stage 3-4 were more susceptible to cigarette smoking (p < 0.001). After propensity score matching (PSM), a significant correlation between cigarette smoking and renal outcomes in IgAN patients was seen. Furthermore, Spearman's correlation test revealed that smoking dose was negatively correlated with eGFR (r = 0.141; p < 0.001) and positively related with proteinuria (r = 0.096; p = 0.001). CONCLUSIONS: Cigarette smoking is an independent risk factor for IgAN progression, especially for advanced patients.

Simple transabdominal minimally invasive direct coronary artery bypass surgery with right gastroepiploic artery.

For three patients with isolated right coronary artery disease who had drug resistance and were intolerant to interventional therapy, simple transabdominal small incision bypass grafting of the right gastroepiploic artery and the posterior descending branch of the right coronary artery was conducted without cardiopulmonary. All three patients were discharged smoothly without complications, and were followed up for three months, during which time the myocardial bridges were unobstructed and the cardiac functions were good. The surgery needs no thoracotomy and the injury is small, and avoids influences of sternum and pericardium adhesion on other cardiac surgery in the future. The risk of median sternotomy can be avoided for patients undergoing reoperation for coronary artery bypass surgery.

Copper(I)-Catalyzed Asymmetric Vinylogous Aldol-Type Reaction of Allylazaarenes.

A vinylogous aldol-type reaction of allylazaarenes and aldehydes is disclosed that affords a series of chiral γ-hydroxyl-α,ß-unsaturated azaarenes in moderate to excellent yields with high to excellent regio- and enantioselectivities. With (R,RP )-TANIAPHOS and (R,R)-QUINOXP* as the ligand, the carbon-carbon double bond in the products is generated in (E)-form. With (R)-DTBM-SEGPHOS as the ligand, (Z)-form carbon-carbon double bond is formed in the major product. In this vinylogous reaction, aromatic, α,ß-unsaturated, and aliphatic aldehydes are competent substrates. Moreover, a variety of azaarenes, such as pyrimidine, pyridine, pyrazine, quinoline, quinoxaline, quinazoline, and benzo[d]imidazole are well-tolerated. At last, the chiral vinylogous product is demonstrated as a suitable Michael acceptor towards CuI-catalyzed nucleophilic addition with organomagnesium reagents.

Determination of Environmental Micro(Nano)Plastics by Matrix-Assisted Laser Desorption/Ionization-Time-of-Flight Mass Spectrometry.

Micro(nano)plastics (MNPs) are widely acknowledged as global environmental threat while determination methods for MNPs are still lacking and becoming a growing concern. This study provides a novel method for MNPs identification/quantification by matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF MS). Factors affecting the measurement were optimized, including laser energy, matrix (M), analyte (A), cationization agent (C), and MAC volume ratio. Under the optimal conditions, the peaks representative of polystyrene (PS) and polyethylene terephthalate (PET) were identified, and the mass differences were consistent with the molecular weight of the corresponding oligomer. A quantitative correlation was built between normalized signal intensity and ln[polymer concentration] with a correlation coefficient above 0.96 for low-molecular-weight polymers and 0.98 for high-molecular-weight polymers. Furthermore, two types of environmental MNP samples were prepared, including aviation cup particles as fresh plastics and aged MNPs extracted from river sediment. By using MALDI-TOF MS, the PS-related MNPs (in both aviation cup and sediment) consisted of C8H8 and C16H16O oligomers, while the PET-related MNPs (only found in sediment) were identified with repeated units of C10H8O4 and C12H12O4. According to the quantitative correlation curve, the contents of PS and PET MNPs were quantified as 8.56 ± 0.04 and 28.71 ± 0.20 mg·kg-1, respectively, in the collected sediment. This study is the first attempt to propose a quantification method with the employment of MALDI-TOF MS for aged MNPs analysis in environmental samples, which can not only supply an effective method for MNP analysis but also inspire future studies on the in situ distribution and transformation of MNPs in environmental and biological samples.

Dectin-1 stimulates IL-33 expression in dendritic cells via upregulation of IRF4.

Interleukin-33 (IL-33) is a potent contributor to antiviral immune responses and antitumor immunity. We recently discovered that IL-33 is overexpressed in dectin-1-activated dendritic cells (DCs). However, mechanisms of dectin-1-induced IL-33 expression in DCs remain elusive. Curdlan, an agonist of dectin-1, was used to mature DCs in this study. We found that dectin-1-induced IL-33 expression in DCs relies on Syk and Raf-1 pathways. By using nuclear factor (NF)-κB inhibitors, we also found that dectin-1-induced IL-33 expression relies on NF-κB signaling. Furthermore, through Syk/Raf-1-NF-κB pathway, dectin-1 signaling stimulates DCs to overexpress interferon regulatory factor 4 (IRF4), which directly upregulates the expression of IL-33 in dectin-1-activated DCs. Thus, our study provides new insights into the mechanisms of dectin-1-induced IL-33 expression in DCs and may provide new targets for improving DC-based cancer immunotherapy.

Comparative transcriptomics identifies patterns of selection in roses.

BACKGROUND: Roses are important plants for human beings with pivotal economical and biological traits like continuous flowering, flower architecture, color and scent. Due to frequent hybridization and high genome heterozygosity, classification of roses and their relatives remains a big challenge. RESULTS: Here, to identify potential markers for phylogenetic reconstruction and to reveal the patterns of natural selection in roses, we generated sets of high quality and comprehensive reference transcriptomes for Rosa chinensis 'Old Blush' (OB) and R. wichuriana 'Basye's Thornless' (BT), two species exhibiting contrasted traits of high economical importance. The assembled reference transcriptomes showed transcripts N50 above 2000 bp. Two roses shared about 10,073 transcripts (N50 = 2282 bp), in which a set of 5959 transcripts was conserved within genera of Rosa. Further comparison with species in Rosaceae identified 4447 transcripts being common (Rosaceae-common) in Rosa, Malus, Prunus, Rubus, and Fragaria, while a pool of 164 transcripts being specific for roses (Rosa-specific). Among the Rosaceae-common transcripts, 409 transcripts showed a signature of positive selection and a clustered expression in different tissues. Interestingly, nine of these rapidly evolving genes were related to DNA damage repair and responses to environmental stimulus, a potential associated with genome confliction post hybridization. Coincident with this fast evolution pattern in rose genes, 24 F-box and four TMV resistant proteins were significantly enriched in the Rosa-specific genes. CONCLUSIONS: We expect that these Rosaceae-common and Rosa-specific transcripts should facilitate the phylogenetic analysis of Rosaceae plants as well as investigations of Rosa-specific biology. The data reported here could provide fundamental genomic tools and knowledge critical for understanding the biology and domestication of roses and for roses breeding.

Tumor-specific IL-9-producing CD8+ Tc9 cells are superior effector than type-I cytotoxic Tc1 cells for adoptive immunotherapy of cancers.

Because cytokine-priming signals direct CD8(+) T cells to acquire unique profiles that affect their ability to mediate specific immune responses, here we generated IL-9-skewed CD8(+) T (Tc9) cells by priming with Th9-polarized condition. Compared with type-I CD8(+) cytotoxic T (Tc1) cells, Tc9 secreted different cytokines and were less cytolytic in vitro but surprisingly elicited greater antitumor responses against advanced tumors in OT-I/B16-OVA and Pmel-1/B16 melanoma models. After adoptive transfer, Tc9 cells persisted longer and differentiated into IFN-γ- and granzyme-B (GrzB)-producing cytolytic Tc1-like effector cells. Phenotypic analysis revealed that adoptively transferred Tc9 cells secreted IL-2 and were KLRG-1(low) and IL-7Rα(high), suggesting that they acquired a signature of "younger" phenotype or became long-term lived cells with capacity of self-renewal. Our results also revealed that Tc9-mediated therapeutic effect critically depended on IL-9 production in vivo. These findings have clinical implications for the improvement of CD8(+) T-cell-based adoptive immunotherapy of cancers.

Targeting beta2-microglobulin for induction of tumor apoptosis in human hematological malignancies.

We discovered that monoclonal antibodies (mAbs) specific to human beta(2)-microglobulin (beta(2)M) induce apoptosis in vitro and were therapeutic in mouse models of myeloma and other hematological tumor cells. Cell death occurred rapidly, without the need for exogenous immunological effector mechanisms. The mAbs induced cell death via recruiting MHC class I molecules to lipid rafts and activating Lyn and PLCgamma2, leading to activated JNK and inhibited PI3K/Akt and ERK, compromised mitochondrial integrity, and caspase-9-dependent cascade activation. Although the expression of beta(2)M on normal hematopoietic cells is a potential safety concern, the mAbs were selective to tumor-transformed cells and did not induce apoptosis of normal cells. Therefore, such mAbs offer the potential for a therapeutic approach to hematological malignancies.

Functionalized extracellular nanovesicles as advanced CRISPR delivery systems.

The clustered regularly interspaced short palindromic repeat (CRISPR) system, an emerging tool for genome editing, has garnered significant public interest for its potential in treating genetic diseases. Despite the rapid advancements in CRISPR technology, the progress in developing effective delivery strategies lags, impeding its clinical application. Extracellular nanovesicles (EVs), either in their endogenous forms or with engineered modifications, have emerged as a promising solution for CRISPR delivery. These EVs offer several advantages, including high biocompatibility, biological permeability, negligible immunogenicity, and straightforward production. Herein, we first summarize various types of functional EVs for CRISPR delivery, such as unmodified, modified, engineered virus-like particles (VLPs), and exosome-liposome hybrid vesicles, and examine their distinct intracellular pathways. Then, we outline the cutting-edge techniques for functionalizing extracellular vesicles, involving producer cell engineering, vesicle engineering, and virus-like particle engineering, emphasizing the diverse CRISPR delivery capabilities of these nanovesicles. Lastly, we address the current challenges and propose rational design strategies for their clinical translation, offering future perspectives on the development of functionalized EVs.