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Phagocytosis checkpoints, especially targeting CD47, have shown encouraging therapeutic effects. However, there are currently many shortcomings and challenges with immune checkpoint blockades (ICBs). Inspired by the phenomenon of molecular self-assembly, we modify the CD47 targeting peptide (4N1K) onto the self-assembled peptide FY4, as well as the concatenation of PEG at the other terminal

Boron neutron capture therapy (BNCT) is becoming a promising radiation treatment technique dealing with tumors due to its cellular targeting specificity. In this article, based on the biocompatible chitosan oligosaccharide (COS), we designed a boron delivery system using carborane (CB) as a boron drug with cRGD peptide modification and paclitaxel (PTX) loaded in the hydrophobic core. The nanoparticles (cRGD-COS-CB/PTX) realized the boron delivery into tumor sites with an enhanced permeability and retention (EPR) effect and an active targeting effect achieved by the cRGD-integrin interaction on the surface of tumor cells. The uniform spherical nanoparticles can be selectively taken by hepatoma cells rather than normal hepatocytes.

Inefficient tumor penetration caused by the characteristics of tumor microenvironments is a primary obstacle to improving drug delivery efficiency, which restricts the chemotherapy drug efficacy. One such promising idea is to construct micro/nanomotors (MNMs) as an effective delivery vehicle by way of producing autonomous motion and converting exogenous stimuli or external energies from the surrounding environment into mechanical forces. In this research, the Pt/DOX nanomotor was prepared, and the enhanced diffusion and positive chemotaxis driven by substrates were verified

In previous studies, we found that triphenylphosphine-modified doxorubicin (TPP-DOX) can effectively kill drug-resistant tumor cells, but its effect on sensitive tumor cells is weakened. In this research, with albumin from Bovine Serum (BSA) as a carrier, TPP-DOX@MnBSA (TD@MB) nanoparticles were prepared by co-loading TPP-DOX and manganese which can realize the combination of chemotherapy and chemodynamic therapy (CDT). The uniform and stable nano-spherical nanoparticle can promote drug uptake, achieve mitochondrial-targeted drug delivery, increase intracellular reactive oxygen species (ROS) and catalyze the production of highly toxic oxidative hydroxyl radicals (OH·), further inhibiting the growth of both sensitive and drug-resistant MCF-7 cells. Besides, TD@MB can down-regulate the stemness-related proteins and the metastasis-related proteins, potentially decreasing the tumor stemness and metastasis. In vivo experiment indicated that TD@MB was able to exert desired antitumor effect, good tumor targeting and biocompatibility.

Glioblastoma is the most common brain primary malignant tumor with the highest mortality. Boron neutron capture therapy (BNCT) can efficiently kill cancer cells on the cellular scale, with high accuracy, short course and low side-effects, which is regarded as the most promising therapy for malignant brain tumors like glioma. As the keypoint of BNCT, all boron delivery agents currently in clinical use are beset by insufficient tumor uptake, especially in the tumor nucleus, which limits the clinical application of BNCT. In this study, nuclear targeting of boron is achieved by DOX-CB, consisting of doxorubicin (DOX) and carborane (CB) utilizing the nuclear translocation property of DOX. The nucleus of GL261 cells takes up almost three times the concentration of boron required for BNCT. To further kill glioma and inhibit recurrence, a new multifunctional nanoliposome delivery system DOX-CB@lipo-pDNA-iRGD is constructed. It combines DOX-CB with immunotherapy strategy of blocking macrophage immune checkpoint pathway CD47-SIRPα by CRISPR-Cas9 system, coupling BNCT with immunotherapy simultaneously. Compared with clinical drug Borocaptate Sodium (BSH), DOX-CB@lipo-pDNA-iRGD significantly enhances the survival rate of tumor-bearing mice, reduces tumor stemness, and improves the prognosis. The excellent curative effect of this nanoliposome delivery system provides an insight into the combined treatment of BNCT. Graphical Abstract

Introducing magnetism into the ferroelectric Ca2Nb2O7 with high Curie temperature can make it a potential multiferroic material at room temperature. Stoichiometric Ca2Nb2O7, nonstoichiometric Ca1.9Nb2O7-δ and Ca2Nb1.9O7-δ single phase films were deposited on STO (110) substrate by pulsed laser deposition under appropriate conditions. The films were characterized by XRD, FE-SEM, Element mapping and XPS. Both stoichiometric Ca2Nb2O7 and Ca1.9Nb2O7-δ films were diamagnetic in the magnetic measurement and ab initio calculations, while the Ca2Nb1.9O7-δ film with the complex vacancy of VNb+O exhibited ferromagnetic behavior at room temperature, with the saturated magnetization of 3.6 emu/cm3. Calculations on the Ca2Nb2O7 (010) surface indicate that the VNb+O can induce spin polarization on the residual O atoms around the Nb vacancies, and the system was most stable when the Nb and O vacancies were the 4th nearest-neighbored, with FM coupling energetically more stable than the AFM coupling. Our work verified experimentally and theoretically the feasibility of introducing ferromagnetism into Ca2Nb2O7 film by the intrinsic complex vacancy of VNb+O.

Streptococcus (S.) thermophilus is an important dairy starter in the production of fermented dairy products has important significance, from natural fermentation in the past to industrial production today. While the genetic architecture underlying S. thermophilus traits and phenotypes is largely unknown. Here, we sequenced 185 S. thermophilus strains, which isolated from natural fermented dairy products of China and Mongolia and using comparative genomic and genome wide association study to provide novel point for genetic architecture underlying its traits and phenotypes. Genome analysis of S. thermophilus showed association of phylogeny with environmental and phenotypic features and revealed clades with high acid production potential or with substantial genome decay. A few S. thermophilus isolated from areas with high chloramphenicol emissions had a chloramphenicol-resistant gene CatB8. Most importantly, we defined a growth score and identified a missense mutation G1118698T located at the gene AcnA that were both predictive of acidification capability of S. thermophilus. Our findings provide novel insight in S. thermophilus genetic traits, antibiotic resistant and predictive of acidification capability which both may had huge help in culture starter screening.

In-depth understandings of the interactions between NaOCl and foulants (e.g., alginate) at a molecular level can provide a deeper insight into the optimization of chemical cleaning. In this study, two-dimensional Fourier transform infrared correlation spectroscopic (2D-FTIR-COS) analysis was used to probe the hypochlorite oxidation of alginate at normal wastewater treatment operating pH (i.e., 6, 7, and 8). The 2D-FTIR-COS characterization indicated that the groups in alginate were degraded by NaOCl in a similar sequence at all investigated pHs: carboxylate groups (-COOH at pH 6 and 7)C-O-C bonds, C-O bonds of uronic acidsC-O-C bonds. The results also showed that the presence of hemiacetals, which are formed by uronic acids, can protect alginate chains from oxidation during their initial exposure to NaOCl (30 min) and thus maintain alginate at a constant molecular size. Additionally, the rupture of C-O-C bonds resulting from initial oxidation (30 min) increased the viscosity of alginate solution because of the decreased stiffness of alginate chains and the rise of stronger intermolecular junctions. Long-term exposure to NaOCl (480 min) largely degraded uronic acids and the C-O-C bonds of alginate molecules, leading to decreases in molecular weight and viscosity at pH 6 and 7. However, because of the low degree of oxidation at pH 8, molecular weight and viscosity of alginates were slightly changed after long-term exposure (480 min) to NaOCl. Our results imply that the partial oxidation of alginate during hypochlorite scavenging enhanced its fouling propensity, which could have a potential implication for the implementation of chemical cleaning.

Motivation Whole-genome sequencing (WGS) is widely used for copy number variation (CNV) detection. However, for most bacteria, their circular genome structure and high replication rate make reads more enriched near the replication origin. CNV detection based on read depth could be seriously influenced by such replication bias. Results We show that the replication bias is widespread using ∼200 bacterial WGS data. We develop CNV-BAC (CNV-Bacteria) that can properly normalize the replication bias and other known biases in bacterial WGS data and can accurately detect CNVs. Simulation and real data analysis show that CNV-BAC achieves the best performance in CNV detection compared with available algorithms. Availability and implementation CNV-BAC is available at https://github.com/XiDsLab/CNV-BAC. Supplementary information Supplementary data are available at Bioinformatics online.

Streptococcus (S.) thermophilus, an indispensable dairy starter, has been used in autochthonous as well as industrial milk fermentation. However, the genetic architecture underlying S. thermophilus traits and phenotypes is largely unknown. Here, we sequenced 185 S. thermophilus strains, isolated from natural fermented dairy products of China and Mongolia and used comparative genomic and genome wide association study to provide novel point for genetic architecture underlying its traits and phenotypes. Genome analysis of S. thermophilus showed association of phylogeny with environmental and phenotypic features and revealed clades with high acid production potential or with substantial genome decay. A few S. thermophilus isolated from areas with high chloramphenicol emissions had a chloramphenicol-resistant gene CatB8. Most importantly, we defined a growth score and identified a missense mutation G1118698T located at the gene AcnA that were both predictive of acidification capability of S. thermophilus. Our findings provide novel insight in S. thermophilus genetic traits, antibiotic resistant and predictive of acidification capability which both may had huge help in culture starter screening.

A central event in the initiation of DNA replication in eukaryotes is the assembly of pre-replicative complex (pre-RC) on specific chromatin sites known as DNA replication origins. The pre-RC assembly process differs between budding and fission yeasts. In fission yeast, Sap1 directly participates in pre-RC assembly, together with the four initiation factors: ORC, Cdc18/Cdc6, Cdt1, and MCM. In metazoans, the nature of DNA replication origins is not defined and the mechanism of pre-RC assembly remains incompletely known. In this study, Girdin was identified as an essential replication initiation factor in human cells. Similar to the activity of Sap1, human Girdin binds to DNA origins, interacts with ORC, and is required for pre-RC assembly due to its essential role in recruitment of Cdc6 to DNA origins. Thus, DNA origins in human or metazoans are defined as including two elements, one bound by ORC and the other bound by Girdin.

Motivation Single cell RNA-sequencing (scRNA-seq) technology enables whole transcriptome profiling at single cell resolution and holds great promises in many biological and medical applications. Nevertheless, scRNA-seq often fails to capture expressed genes, leading to the prominent dropout problem. These dropouts cause many problems in down-stream analysis, such as significant increase of noises, power loss in differential expression analysis and obscuring of gene-to-gene or cell-to-cell relationship. Imputation of these dropout values can be beneficial in scRNA-seq data analysis. Results In this article, we model the dropout imputation problem as robust matrix decomposition. This model has minimal assumptions and allows us to develop a computational efficient imputation method called scRMD. Extensive data analysis shows that scRMD can accurately recover the dropout values and help to improve downstream analysis such as differential expression analysis and clustering analysis. Availability and implementation The R package scRMD is available at https://github.com/XiDsLab/scRMD. Supplementary information Supplementary data are available at Bioinformatics online.

An eco-friendly process was adopted to treat cooling tower blowdown water (CTBD) and the toxicity of correspondingly produced water/eluate was evaluated using the transcriptional effect level index (TELI) based on toxicogenomics. The objective of the work is to provide a feasible treatment loop including adsorption to remove organics and phosphorus from CTBD, electrocatalytic oxidation to improve the biodegradability of the eluate after desorption. Results showed that PANI/TiO2 was a promising adsorbent in the removal of organics and phosphorus from CTBD and exhibited a satisfied regeneration ability beyond 30 times of reuse. During the electrocatalytic oxidation process the biodegradability of desorption eluate was gradually increasing and BOD5/COD of the oxidized eluate reached 0.4 after 4.8 h of treatment, indicating that the treated wastewater could be returned to the biological treatment loop for further processing. The analysis of the quantitative toxicogenomics assay revealed that the toxicity of CTBD was mainly caused by oxidizing biocides of trichloroisocyanuric acid (TCCA), leading to a significant membrane stress response of bacteria. And the toxicity level of CTBD decreased after adsorption treatment while the desorption eluate experienced increase and then decrease during the electrocatalytic oxidation, meaning that certain oxidation duration was needed to keep the eluate safe for biological treatment. According to economic analysis, the operation cost of treatment loop was estimated at around 0.6 dollars/m3, ensuring high reuse water quality and safe eluate for further biological treatment.

In the present work, acute impact of heavy metals on activated sludge was investigated, specifically the release of biopolymers and nitrogenous soluble microbiological products (N-SMP) that significantly impact tertiary effluent quality. Based on the previously reported studies, Hg2+ and Ag+ were selected as representative “non-essential” heavy metals, while Cu2+ was selected as the “essential” heavy metal. Stress tests show that under the present experimental conditions, adding a higher concentration of heavy metals to the activated sludge increases the concentration of biopolymers and SMP in the supernatant; N-SMP increased more significantly than carbonaceous products, implying a greater risk of formation of toxic nitrogenous disinfection by-products or membrane fouling in relevant tertiary treatment processes. The severity of the release of SMP into the supernatant depended on the heavy metal, with an order of Hg2+ > Ag+ > Cu2+ (“non-essential” > “essential”) under identical molar concentrations. The mass balance of typical organics (e.g., biopolymers) in SMP and extracellular polymeric substances (EPS) in activated sludge was analyzed, and a negative correlation between the organics in the SMP and tightly bound EPS was observed, implying that a significant fraction of the SMP could be quickly released from the tightly bound EPS under heavy metal shock conditions and could be related to cell response or damage.

Performance of three adsorbents, polyaniline-modified TiO2 (PANI/TiO2), Dow resin IRA(a) and Dow resin IRA(b), in removing organics from secondary effluent (SE) was evaluated, and the objective of this study is to deliver a treatment loop including membrane fouling control using adsorption and treatment of correspondingly formed desorption eluate using electrochemical oxidation, so that the contaminants could be effectively handled within a wastewater treatment plant. Results show that PANI/TiO2 is a promising adsorbent in the removal of effluent organic matter (>55%) and its regeneration was superior to the two others. Specifically, PANI/TiO2 could remove over 70% of the fraction of biopolymers from the SE and therefore alleviated subsequent membrane fouling to a large extent, while the other two presented less antifouling effect due to limited removal of the major foulants, though they both showed comparable effect as PANI/TiO2 in the removal of other organic fractions. BOD5/COD of the concentrated desorption eluate was gradually increasing along with the extension of the electrochemical oxidation. It reached >0.4 after 4.5 h of treatment, which is of suitable biodegradability for recycling to the influent of the wastewater treatment plant. The improvement on BOD5/COD was due to the mineralization of effluent organic matter and simultaneous minifying of their molecular size. Moreover, the operation cost of the treatment loop was estimated at about 0.12–0.15 USD/m3 for delivering effect fouling control and significant improvement on effluent quality.

Purpose: Innate immunity is an indispensable arm of tumor immune surveillance, and the liver is an organ with a predominance of innate immunity, where mucosal-associated invariant T (MAIT) cells are enriched. However, little is known about the phenotype, functions, and immunomodulatory role of MAIT cells in hepatocellular carcinoma (HCC). Experimental Design: The distribution, phenotype, and function of MAIT cells in patients with HCC were evaluated by both flow cytometry (FCM) and in vitro bioassays. Transcriptomic analysis of MAIT cells was also performed. Prognostic significance of tumor-infiltrating MAIT cells was validated in four independent cohorts of patients with HCC. Results: Despite their fewer densities in HCC tumor than normal liver, MAIT cells were significantly enriched in the HCC microenvironment compared with other mucosa-associated organs. Tumor-derived MAIT cells displayed a typical CCR7−CD45RA−CD45RO+CD95+ effector memory phenotype with lower costimulatory and effector capabilities. Tumor-educated MAIT cells significantly upregulated inhibitory molecules like PD-1, CTLA-4, TIM-3, secreted significantly less IFNγ and IL17, and produced minimal granzyme B and perforin while shifting to produce tumor-promoting cytokines like IL8. Transcriptome sequencing confirmed that tumor-derived MAIT cells were reprogrammed toward a tumor-promoting direction by downregulating genes enriched in pathways of cytokine secretion and cytolysis effector function like NFKB1 and STAT5B and by upregulating genes like IL8, CXCL12, and HAVCR2 (TIM-3). High infiltration of MAIT cells in HCC significantly correlated with an unfavorable clinical outcome, revealed by FCM, qRT-PCR, and multiplex IHC analyses, respectively. Conclusions: HCC-infiltrating MAIT cells were functionally impaired and even reprogrammed to shift away from antitumor immunity and toward a tumor-promoting direction. See related commentary by Carbone, p. 3199

The occurrence of algae bloom would lead to the release of algae-derived organic matter (AOM) and then alter the abundance and behavior of dissolved organic matter (DOM) in aquatic ecosystems. In this study, the characteristics and photodegradation of AOM, naturally occurring organic matter (NOM) derived from soil and plants and their mixtures were explored to reveal the potential interactions between AOM and NOM in water. Results indicated that the protein-like components from AOM and the humic-like components from SRNOM took place inter-component interactions in the AOM-NOM mixtures. Meanwhile, application of two-dimensional Fourier transform infrared correlation spectroscopic (2D-FTIR-COS) analysis revealed that carboxylic C=O had a high priority to bind with other functional groups (e.g., phenolic-OH, polysaccharides C-O, amideⅡC-N/N-H and celluloses C-H). More crucially, it was found that the AOM-NOM mixtures subjected to a very different photodegradation behavior to their end-members (i.e., AOM and NOM), likely because of the occurrence of AOM-NOM interactions as well as their roles in mediating the yield of reactive oxygen species. For instance, the presence of AOM led to increased photodegradation degrees of the chromophoric fraction in NOM. In contrast, the NOM did not exhibit any photosensitization role in the photodegradation of the proteins from AOM. This study has potential implications for our understanding of the carbon cycling in anthropogenically impacted aquatic systems such as inland rivers and lakes.