TET deficiency perturbs mature B cell homeostasis and promotes oncogenesis associated with accumulation of G-quadruplex and R-loop structures.

Enzymes of the TET family are methylcytosine dioxygenases that undergo frequent mutational or functional inactivation in human cancers. Recurrent loss-of-function mutations in TET proteins are frequent in human diffuse large B cell lymphoma (DLBCL). Here, we investigate the role of TET proteins in B cell homeostasis and development of B cell lymphomas with features of DLBCL. We show that deletion of Tet2 and Tet3 genes in mature B cells in mice perturbs B cell homeostasis and results in spontaneous development of germinal center (GC)-derived B cell lymphomas with increased G-quadruplexes and R-loops. At a genome-wide level, G-quadruplexes and R-loops were associated with increased DNA double-strand breaks (DSBs) at immunoglobulin switch regions. Deletion of the DNA methyltransferase DNMT1 in TET-deficient B cells prevented expansion of GC B cells, diminished the accumulation of G-quadruplexes and R-loops and delayed B lymphoma development, consistent with the opposing functions of DNMT and TET enzymes in DNA methylation and demethylation. Clustered regularly interspaced short palindromic repeats (CRISPR)-mediated depletion of nucleases and helicases that regulate G-quadruplexes and R-loops decreased the viability of TET-deficient B cells. Our studies suggest a molecular mechanism by which TET loss of function might predispose to the development of B cell malignancies.

Toward a New Era of SERS and TERS at the Nanometer Scale: From Fundamentals to Innovative Applications.

Surface-enhanced Raman scattering (SERS) and tip-enhanced Raman scattering (TERS) have opened a variety of exciting research fields. However, although a vast number of applications have been proposed since the two techniques were first reported, none has been applied to real practical use. This calls for an update in the recent fundamental and application studies of SERS and TERS. Thus, the goals and scope of this review are to report new directions and perspectives of SERS and TERS, mainly from the viewpoint of combining their mechanism and application studies. Regarding the recent progress in SERS and TERS, this review discusses four main topics: (1) nanometer to subnanometer plasmonic hotspots for SERS; (2) Ångström resolved TERS; (3) chemical mechanisms, i.e., charge-transfer mechanism of SERS and semiconductor-enhanced Raman scattering; and (4) the creation of a strong bridge between the mechanism studies and applications.

A Comparative Analysis of Data Analysis Tools for Data-Independent Acquisition Mass Spectrometry.

Data-independent acquisition (DIA) mass spectrometry-based proteomics generates reproducible proteome data. The complex processing of the DIA data has led to the development of multiple data analysis tools. In this study, we assessed the performance of five tools (OpenSWATH, EncyclopeDIA, Skyline, DIA-NN, and Spectronaut) using six DIA datasets obtained from TripleTOF, Orbitrap, and TimsTOF Pro instruments. By comparing identification and quantification metrics and examining shared and unique cross-tool identifications, we evaluated both library-based and library-free approaches. Our findings indicate that library-free approaches outperformed library-based methods when the spectral library had limited comprehensiveness. However, our results also suggest that constructing a comprehensive library still offers benefits for most DIA analyses. This study provides comprehensive guidance for DIA data analysis tools, benefiting both experienced and novice users of DIA-mass spectrometry technology.

Multitissue Circadian Proteome Atlas of WT and Per1-/-/Per2-/- Mice.

The molecular basis of circadian rhythm, driven by core clock genes such as Per1/2, has been investigated on the transcriptome level, but not comprehensively on the proteome level. Here we quantified over 11,000 proteins expressed in eight types of tissues over 46 h with an interval of 2 h, using WT and Per1/Per2 double knockout mouse models. The multitissue circadian proteome landscape of WT mice shows tissue-specific patterns and reflects circadian anticipatory phenomena, which are less obvious on the transcript level. In most peripheral tissues of double knockout mice, reduced protein cyclers are identified when compared with those in WT mice. In addition, PER1/2 contributes to controlling the anticipation of the circadian rhythm, modulating tissue-specific cyclers as well as key pathways including nucleotide excision repair. Severe intertissue temporal dissonance of circadian proteome has been observed in the absence of Per1 and Per2. The γ-aminobutyric acid might modulate some of these temporally correlated cyclers in WT mice. Our study deepens our understanding of rhythmic proteins across multiple tissues and provides valuable insights into chronochemotherapy. The data are accessible at https://prot-rhythm.prottalks.com/.

Myocardial reperfusion injury exacerbation due to ALDH2 deficiency is mediated by neutrophil extracellular traps and prevented by leukotriene C4 inhibition.

BACKGROUND AND AIMS: The Glu504Lys polymorphism in the aldehyde dehydrogenase 2 (ALDH2) gene is closely associated with myocardial ischaemia/reperfusion injury (I/RI). The effects of ALDH2 on neutrophil extracellular trap (NET) formation (i.e. NETosis) during I/RI remain unknown. This study aimed to investigate the role of ALDH2 in NETosis in the pathogenesis of myocardial I/RI. METHODS: The mouse model of myocardial I/RI was constructed on wild-type, ALDH2 knockout, peptidylarginine deiminase 4 (Pad4) knockout, and ALDH2/PAD4 double knockout mice. Overall, 308 ST-elevation myocardial infarction patients after primary percutaneous coronary intervention were enrolled in the study. RESULTS: Enhanced NETosis was observed in human neutrophils carrying the ALDH2 genetic mutation and ischaemic myocardium of ALDH2 knockout mice compared with controls. PAD4 knockout or treatment with NETosis-targeting drugs (GSK484, DNase1) substantially attenuated the extent of myocardial damage, particularly in ALDH2 knockout. Mechanistically, ALDH2 deficiency increased damage-associated molecular pattern release and susceptibility to NET-induced damage during myocardial I/RI. ALDH2 deficiency induced NOX2-dependent NETosis via upregulating the endoplasmic reticulum stress/microsomal glutathione S-transferase 2/leukotriene C4 (LTC4) pathway. The Food and Drug Administration-approved LTC4 receptor antagonist pranlukast ameliorated I/RI by inhibiting NETosis in both wild-type and ALDH2 knockout mice. Serum myeloperoxidase-DNA complex and LTC4 levels exhibited the predictive effect on adverse left ventricular remodelling at 6 months after primary percutaneous coronary intervention in ST-elevation myocardial infarction patients. CONCLUSIONS: ALDH2 deficiency exacerbates myocardial I/RI by promoting NETosis via the endoplasmic reticulum stress/microsomal glutathione S-transferase 2/LTC4/NOX2 pathway. This study hints at the role of NETosis in the pathogenesis of myocardial I/RI, and pranlukast might be a potential therapeutic option for attenuating I/RI, particularly in individuals with the ALDH2 mutation.

A new era of cancer immunotherapy: combining revolutionary technologies for enhanced CAR-M therapy.

Significant advancements have been made in the application of chimeric antigen receptor (CAR)-T treatment for blood cancers during the previous ten years. However, its effectiveness in treating solid tumors is still lacking, necessitating the exploration of alternative immunotherapies that can overcome the significant challenges faced by current CAR-T cells. CAR-based immunotherapy against solid tumors shows promise with the emergence of macrophages, which possess robust phagocytic abilities, antigen-presenting functions, and the ability to modify the tumor microenvironment and stimulate adaptive responses. This paper presents a thorough examination of the latest progress in CAR-M therapy, covering both basic scientific studies and clinical trials. This study examines the primary obstacles hindering the realization of the complete potential of CAR-M therapy, as well as the potential strategies that can be employed to overcome these hurdles. With the emergence of revolutionary technologies like in situ genetic modification, synthetic biology techniques, and biomaterial-supported gene transfer, which provide a wider array of resources for manipulating tumor-associated macrophages, we suggest that combining these advanced methods will result in the creation of a new era of CAR-M therapy that demonstrates improved efficacy, safety, and availability.

A chromosome-level genome assembly of Ostrea denselamellosa provides initial insights into its evolution.

The oyster Ostrea denselamellosa is a live-bearing species with a sharp decline in the natural population. Despite recent breakthroughs in long-read sequencing, high quality genomic data are very limited in O. denselamellosa. Here, we carried out the first whole genome sequencing at the chromosome-level in O. denselamellosa. Our studies yielded a 636 Mb assembly with scaffold N50 around 71.80 Mb. 608.3 Mb (95.6% of the assembly) were anchored to 10 chromosomes. A total of 26,412 protein-coding genes were predicted, of which 22,636 (85.7%) were functionally annotated. By comparative genomics, we found that long interspersed nuclear element (LINE) and short interspersed nuclear element (SINE) made up a larger proportion in O. denselamellosa genome than in other oysters'. Moreover, gene family analysis showed some initial insight into its evolution. This high-quality genome of O. denselamellosa provides a valuable genomic resource for studies of evolution, adaption and conservation in oysters.

High-Density Energetic Materials with Low Mechanical Sensitivity and Twinning Derived from Nitroimidazole Fused Ring.

The innovative synthesis of 3,8-dibromo-2,9-dinitro-5,6-dihydrodiimidazo [1,2-a:2',1'-c]pyrazine and 3,9-dibromo-2,10-dinitro-6,7-dihydro-5H-diimidazo [1,2-a:2',1'-c][1,4]diazepine is described in this study. The tricyclic fused molecular structures are formed by the respective amalgamation of piperazine and homopiperazine with the imidazole ring containing nitro. Compound 1 and 2 possess excellent high-density physical properties (ρ1 = 2.49 g/cm3, ρ2 = 2.35 g/cm3) due to the presence of a fused ring structure and Br atom. In addition to their high density, they have high decomposition temperatures (Td > 290 °C) which means that they have excellent thermal stability and can be used as potential heat-resistant explosives. Low mechanical sensitivities (IS > 40 J, FS > 360 N) are observed. The twinning structure of 2 was resolved by X-ray diffraction. Non-covalent interaction analysis, Hirshfeld surfaces, 2D fingerprint plot, and Electrostatic potential analysis were used to understand the intramolecular interactions in relation to physicochemical properties. The unique structures of this type of compound provide new potential for the evolution of energetic materials.

LINC01376 promotes nasopharyngeal carcinoma tumorigenesis by competitively binding to the SP1/miR-4757/IGF1 axis.

The long non-coding RNA (lncRNA)-microRNA (miRNA) interaction network plays a crucial part in the pathogenesis of nasopharyngeal carcinoma (NPC). Here, we discovered a relationship between LINC01376 and miR-4757 in NPC tumor development. First, LINC01376 was abnormally overexpressed in NPC tissues and cells, and its elevated expression was associated with advanced clinical stage and shorter distant metastasis-free survival time. Moreover, biological experiments showed that LINC01376 facilitated the proliferative, invasive, and migratory abilities of NPC cells in vitro and in vivo. Mechanistically, bioinformatics and RT-qPCR assays revealed that LINC01376 knockdown upregulated the expression level of downstream miR-4757, including miR-4757 primary transcript (pri-miR-4757) and mature miR-4757. Furthermore, LINC01376 competitively sponged the transcription factor SP1 and reduced its enrichment in the upstream promoter region of miR-4757 to repress miR-4757 expression. Finally, insulin-like growth factor 1(IGF1) was identified as the target of miR-4757. Rescue experiments indicated that LINC01376 accelerated NPC cell proliferation, migration, and invasion through the miR-4757-5p/IGF1 axis. In conclusion, the SP1/miR-4757/IGF1 axis, which is regulated by LINC01376 in NPC deterioration and metastasis, is expected to provide new insights into the molecular mechanism of NPC carcinogenesis.

GSDMD-Mediated Cardiomyocyte Pyroptosis Promotes Myocardial I/R Injury.

[Figure: see text].

Expression of the pleiotrophin-midkine axis in a sheep tooth socket model of bone healing.

OBJECTIVE AND BACKGROUND: Resorption of alveolar bone after tooth extraction is a common problem often requiring bone grafting. The success of the grafting procedures is dependent on multiple factors including the presence of growth factors. This is the first in vivo study to investigate the role of the pleiotrophin family of cytokines in alveolar bone regeneration. This research investigated the role of the pleiotrophin-midkine (PTN-MDK) axis during osteogenesis, with and without a grafting material, after tooth extraction in a sheep model. METHODS: Thirty Romney-cross ewes were anesthetized, and all premolar teeth on the right side were extracted. The sockets were randomized to controls sites with no treatment and test sites with Bio-Oss® graft material and Bio-Gide® membrane. Samples were harvested after sacrificing animals 4, 8, and 16 weeks post-grafting (n = 10 per time-point). Tissue for qRT2 -PCR gene analysis was recovered from the socket next to the first molar using a trephine (Ø = 2 mm). Each socket was fixed, decalcified, paraffin-embedded, and sectioned. Immunohistochemistry was conducted to localize both PTN and MDK along with their receptors, protein tyrosine phosphatase receptor type Z1 (PTPRZ1), ALK receptor tyrosine kinase (ALK), and notch receptor 2 (NOTCH2). RESULTS: Within the healing sockets, high expression of genes for PTN, MDK, NOTCH2, and ALK was found at all time-points and in both grafted and non-grafted sites, while PTPRZ1 was only expressed at low levels. The relative gene expression of the PTN family of cytokines was not statistically different at the three time-points between test and control groups (p > .05). Immunohistochemistry found PTN and MDK in association with new bone, NOTCH2 in the connective tissue, and PTPRZ1 and ALK in association with cuboidal osteoblasts involved in bone formation. CONCLUSIONS: The PTN-MDK axis was highly expressed in both non-grafted and grafted sockets during osteogenesis in a sheep model of alveolar bone regeneration with no evidence that grafting significantly affected expression. The activation of NOTCH2 and PTPRZ1 receptors may be important during bone regeneration in vivo. The discovery of the PTN-MDK axis as important during alveolar bone regeneration is novel and opens up new avenues of research into these stably expressed highly active cytokines. Growth factor supplementation with PTN and/or MDK during healing may be an approach for enhanced regeneration or to initiate healing where delayed.

CircRNA circ-PDCD11 is highly expressed in lung large-cell carcinoma and predicts poor survival.

BACKGROUND: Circ-PDCD11 (hsa_circ_0019853, 461 bp) has been characterized as an oncogenic circRNA in breast cancer, while its function in other cancers is unclear. In this study, we explored the role of circ-PDCD11 in lung cancer. METHODS: Plasma samples were obtained from patients with lung large-cell carcinoma (LLCC, n = 40), lung squamous cell carcinoma (LSCC, n = 40), lung adenocarcinoma (LA, n = 40) and small-cell lung cancer (SCLC, n = 40) as well as healthy controls (Control, n = 40). Paired tumor and nontumor tissue samples were obtained from all patients. Expression of circ-PDCD11 in these samples was determined by RT-qPCR. The role of plasma circ-PDCD11 in the diagnosis of LLCC was analyzed with ROC curve. A five-year follow-up was performed to analyze the role of plasma circ-PDCD11 in the prognosis of LLCC. RESULTS: Plasma circ-PDCD11 was specifically upregulated in LLCC but not in other lung cancer types, compared to the controls. Increased circ-PDCD11 expression in tumor tissues compared to nontumor tissues was only observed in LLCC patients but not in other lung cancer types. Increased plasma circ-PDCD11 levels effectively separated LLCC patients from patients with other types of cancers. High plasma circ-PDCD11 levels were closely correlated with poor survival of LLCC patients. Plasma circ-PDCD11 levels were closely correlated with tumor metastasis, but not tumor size of LLCC. CONCLUSION: CircRNA circ-PDCD11 is highly expressed specifically in LLCC and predicts poor survival.

A Highly Expressed Antennae Odorant-Binding Protein Involved in Recognition of Herbivore-Induced Plant Volatiles in Dastarcus helophoroides.

Natural enemies such as parasitoids and parasites depend on sensitive olfactory to search for their specific hosts. Herbivore-induced plant volatiles (HIPVs) are vital components in providing host information for many natural enemies of herbivores. However, the olfactory-related proteins involved in the recognition of HIPVs are rarely reported. In this study, we established an exhaustive tissue and developmental expression profile of odorant-binding proteins (OBPs) from Dastarcus helophoroides, an essential natural enemy in the forestry ecosystem. Twenty DhelOBPs displayed various expression patterns in different organs and adult physiological states, suggesting a potential involvement in olfactory perception. In silico AlphaFold2-based modeling and molecular docking showed similar binding energies between six DhelOBPs (DhelOBP4, 5, 6, 14, 18, and 20) and HIPVs from Pinus massoniana. While in vitro fluorescence competitive binding assays showed only recombinant DhelOBP4, the most highly expressed in the antennae of emerging adults could bind to HIPVs with high binding affinities. RNAi-mediated behavioral assays indicated that DhelOBP4 was an essential functional protein for D. helophoroides adults recognizing two behaviorally attractive substances: p-cymene and γ-terpinene. Further binding conformation analyses revealed that Phe 54, Val 56, and Phe 71 might be the key binding sites for DhelOBP4 interacting with HIPVs. In conclusion, our results provide an essential molecular basis for the olfactory perception of D. helophoroides and reliable evidence for recognizing the HIPVs of natural enemies from insect OBPs' perspective.

Natural Product-Oriented Photo-Induced Denitrogenative Annulations of 1-Alkenylbenzotriazoles.

The photo-induced denitrogenative annulations of a variety of 1-alkenylbenzotriazoles were investigated. By judiciously manipulating the structural variations of 1-alkenylbenzotriazoles, two characteristic polycyclic skeletons associated with monoterpene indole alkaloids were constructed through a diverted and controllable manner. The present work not only enriches the photochemistry of 1-alkenylbenzotriazoles, but also offers a unified approach to access skeletally diverse indole alkaloid scaffolds.

Improved Bayesian Optimization Framework for Inverse Thermal Conductivity Based on Transient Plane Source Method.

In order to reduce the errors caused by the idealization of the conventional analytical model in the transient planar source (TPS) method, a finite element model that more closely represents the actual heat transfer process was constructed. The average error of the established model was controlled at below 1%, which was a significantly better result than for the analytical model, which had an average error of about 5%. Based on probabilistic optimization and heuristic optimization algorithms, an optimization model of the inverse heat transfer problem with partial thermal conductivity differential equation constraints was constructed. A Bayesian optimization algorithm with an adaptive initial population (BOAAIP) was proposed by analyzing the influencing factors of the Bayesian optimization algorithm upon inversion. The improved Bayesian optimization algorithm is not affected by the range and individuals of the initial population, and thus has better adaptability and stability. To further verify its superiority, the Bayesian optimization algorithm was compared with the genetic algorithm. The results show that the inversion accuracy of the two algorithms is around 3% when the thermal conductivity of the material is below 100 Wm-1K-1, and the calculation speed of the improved Bayesian optimization algorithm is three to four times faster than that of the genetic algorithm.

Chemical Enhancement and Quenching in Single-Molecule Tip-Enhanced Raman Spectroscopy.

Despite intensive research in surface enhanced Raman spectroscopy (SERS), the influence mechanism of chemical effects on Raman signals remains elusive. Here, we investigate such chemical effects through tip-enhanced Raman spectroscopy (TERS) of a single planar ZnPc molecule with varying but controlled contact environments. TERS signals are found dramatically enhanced upon making a tip-molecule point contact. A combined physico-chemical mechanism is proposed to explain such an enhancement via the generation of a ground-state charge-transfer induced vertical Raman polarizability that is further enhanced by the strong vertical plasmonic field in the nanocavity. In contrast, TERS signals from ZnPc chemisorbed flatly on substrates are found strongly quenched, which is rationalized by the Raman polarizability screening effect induced by interfacial dynamic charge transfer. Our results provide deep insights into the understanding of the chemical effects in TERS/SERS enhancement and quenching.

Current knowledge of pyroptosis in heart diseases.

Pyroptosis is a form of pro-inflammatory, necrotic cell death mediated by proteins of the gasdermin family. Various heart diseases, including myocardial ischemia/reperfusion injury, myocardial infarction, and heart failure, involve cardiomyocyte and non-myocyte pyroptosis. Cardiomyocyte pyroptosis also causes the release of pro-inflammatory cytokines. Recent studies have confirmed that pyroptosis is predominantly triggered by both the canonical and non-canonical inflammasome pathways, which independently facilitate caspase-1 or caspase-11/4/5 activation and gasdermin D (GSDMD) cleavage. Cardiac fibroblast and myeloid cell pyroptosis also contributes to the pathogenesis and development of heart diseases. This review summarizes the recent studies on pyroptosis in heart diseases and discusses the associated therapeutic targets.

One-step fermentation for producing xylo-oligosaccharides from wheat bran by recombinant Escherichia coli containing an alkaline xylanase.

BACKGROUND: One-step fermentation is a cheap way to produce xylo-oligosaccharides (XOS), where production of xylanases and XOS is integrated into a single process. In spite of cost advantage, one-step fermentation is still short in yield so far due to the limited exploration. To cope with this issue, production of XOS from wheat bran by recombinant Escherichia coli through one-step fermentation was investigated in this study. RESULTS: An endo-ß-1,4-xylanase gene belonging to glycoside hydrolase family 11 of Bacillus agaradhaerens was employed to construct recombinant E. coli. This xylanase showed maximal activity at 60 °C and pH 8.0-8.5. Its activity retained more than 60% after incubation at 70 °C for 4 h, showing a good stability. The recombinant E. coli BL21(DE3) could secreted xylanases that directly hydrolyzed de-starched wheat bran to XOS in fermentation medium. The XOS generated from hydrolysis consisted of xylose, xylobiose and xylotriose accounting for 23.1%, 37.3% and 39.6%, respectively. Wheat bran concentration was found to be the most crucial factor affecting XOS production. The XOS concentration reached 5.3 mg/mL at 10% loading of wheat bran, which is higher than those of previous researches. Nitrogen source type could also affect production of XOS by changing extracellular xylanase activity, and glycine was found to be the best one for fermentation. Optimal fermentation conditions were finally studied using response surface optimization. The maximal concentration emerged at 44.3 °C, pH 7.98, which is affected by characteristics of the xylanase as well as growth conditions of E. coli. CONCLUSIONS: This work indicates that the integrated fermentation using recombinant E. coli is highly competitive in cost and final concentration for producing XOS. Results can also provide theoretical basis for large-scale production and contribute to the wide adoption of XOS.

Compact generation of robust Airy beam pattern with spatial coherence engineering.

We present a class of partially coherent light sources having Airy-type amplitude and Airy-correlated spatial coherence. We show that the light beam generated by such sources can preserve the Airy beam pattern well during its propagation from source to far field. We demonstrate the robustness of the Airy beam pattern by introducing a hard aperture to largely block the beam source. We find that the coherence-induced Airy beam pattern can still be well reconstructed during propagation. We successfully synthesize such partially coherent source using the principle of complex random modes decomposition by using a single phase-only spatial light modulator. The proposed robust Airy beam pattern may find applications in information transmission through complex media.

Generation of a higher-order Poincaré sphere beam array with spatial coherence engineering.

We propose a protocol to synthesize a class of vector beam array in the far field with periodic higher-order Poincaré sphere (HOPS) polarization states by engineering the second-order spatial coherence structure of a partially coherent light source. We show that the polarization state of a single HOPS beam at the source plane can be mapped into a beam array in the far field when the spatial coherence of the beam source is engineered to have a lattice-like distribution. We demonstrate that the degree of polarization of the generated HOPS beam array can be conveniently controlled by modulating the transverse spatial coherence width of the source. Our method provides an additional way to construct the structured beam array and may find applications, e.g., in multiparticle manipulations.