Enhanced therapeutic potential of Flotillins-modified MenSCs by improve the survival, proliferation and migration.

Menstrual blood-derived endometrial stem cells (MenSCs) have attracted increasing interest due to their excellent safety, and lack of ethical dilemma as well as their ability to be periodically obtained in a noninvasive manner. However, although preclinical research as shown the therapeutic potential of MenSCs in several diseases, their poor cell survival and low engraftment at disease sites reduce their clinical efficacy. Flotillins (including Flot1 and Flot2) are implicated in various cellular processes, such as vesicular trafficking, signal transduction, cell proliferation, migration and apoptosis. In this study, we aimed to determine the effects of Flotillins on MenSCs survival, proliferation and migration. Our experimental results show that MenSCs were modified to overexpress Flot1 and/or Flot2 without altering their intrinsic characteristics. Flot1 and Flot2 co-overexpression promoted MenSC viability and proliferation capacity. Moreover, Flot1 or Flot2 overexpression significantly promoted the migration and inhibited the apoptosis of MenSCs compared with the negative control group, and these effects were stronger in the Flot1 and Flot2 gene co-overexpression group. However, these effects were significantly reversed after Flot1 and/or Flot2 knockdown. In conclusion, our results indicate that Flot1 and Flot2 overexpression in MenSCs improved their proliferation and migration and inhibited their apoptosis, and this might be an effective approach to improve the efficiency of cell-based therapies.

Non-Fused π-Extension of Endcaps of Small Molecular Acceptors Enabling High-Performance Organic Solar Cells.

The modular structure of small molecular acceptors (SMAs) allows for versatile modifications of the materials and boosts the photovoltaic efficiencies of organic solar cells (OSCs) in recent years. As a critical component, the endcaps of SMAs have been intensively investigated and modified to control the molecular aggregation and photo-electronic conversion. However, most of the studies focus on halogenation or π-fusion extension of the endcap moieties, but overlook the non-fused π-extension approach, which could be a promising strategy to balance the self-aggregation and compatibility behaviors. Herein, we reported two new acceptors namely BTP-Th and BTP-FTh based on non-fused π-extension of the endcap by chlorinated-thiophene, of which the latter molecule has better co-planarity and crystallinity because of the intramolecular noncovalent interactions. Paired with donor PBDB-T, the optimal device of BTP-FTh reveals a greater efficiency of 14.81 % that that of BTP-Th (13.91 %). Nevertheless, the BTP-Th based device realizes a lower energy loss, enabling BTP-Th as a good candidate to serve as guest acceptor. As a result, the ternary solar cells of PM6 : BTP-eC9 : BTP-Th output a champion efficiency up to 18.71 % with enhanced open-circuit voltage. This study highlights the significance of rational decoration of endcaps for the design of high-performance SMAs and photovoltaic cells.

Computed tomography-based radiomics to predict early recurrence of hepatocellular carcinoma post-hepatectomy in patients background on cirrhosis.

BACKGROUND: The prognosis for hepatocellular carcinoma (HCC) in the presence of cirrhosis is unfavourable, primarily attributable to the high incidence of recurrence. AIM: To develop a machine learning model for predicting early recurrence (ER) of post-hepatectomy HCC in patients with cirrhosis and to stratify patients' overall survival (OS) based on the predicted risk of recurrence. METHODS: In this retrospective study, 214 HCC patients with cirrhosis who underwent curative hepatectomy were examined. Radiomics feature selection was conducted using the least absolute shrinkage and selection operator and recursive feature elimination methods. Clinical-radiologic features were selected through univariate and multivariate logistic regression analyses. Five machine learning methods were used for model comparison, aiming to identify the optimal model. The model's performance was evaluated using the receiver operating characteristic curve [area under the curve (AUC)], calibration, and decision curve analysis. Additionally, the Kaplan-Meier (K-M) curve was used to evaluate the stratification effect of the model on patient OS. RESULTS: Within this study, the most effective predictive performance for ER of post-hepatectomy HCC in the background of cirrhosis was demonstrated by a model that integrated radiomics features and clinical-radiologic features. In the training cohort, this model attained an AUC of 0.844, while in the validation cohort, it achieved a value of 0.790. The K-M curves illustrated that the combined model not only facilitated risk stratification but also exhibited significant discriminatory ability concerning patients' OS. CONCLUSION: The combined model, integrating both radiomics and clinical-radiologic characteristics, exhibited excellent performance in HCC with cirrhosis. The K-M curves assessing OS revealed statistically significant differences.

Efficient and Stable All-Polymer Solar Cells Enabled by Dual Working Mechanism.

Ternary strategy with integration characteristics and adaptability is a simple and effective method for blooming of the performance of photovoltaic devices. Herein, a novel wideband gap polymer donor PBB2-Hs is synthesized as the guest component to optimize all-polymer solar cells (all-PSCs). High-energy photon absorption and long exciton lifetime of PBB2-Hs constitute efficient energy transfer. Good miscibility and cascade energy levels promote the formation of alloy-like structure between PBB2-Hs and host system. The dual working mechanisms greatly improve photon capture and charge transfer in active layers. Additionally, the introduction of PBB2-Hs also optimizes the ordered molecular stacking of acceptors and suppresses molecular peristalsis. Upon adding 15 wt% PBB2-Hs, the ternary all-PSC achieved a champion efficiency of 17.66%, and can still maintain 82% photostability (24 h) and 91% storage stability (1000 h) of the original PCE. Moreover, the strong molecular stacking and entanglement between PBB2-Hs and the host material increased the elongation at break of ternary blend film by 1.6 times (16.2%), allowing the flexible device to maintain 83% of the original efficiency after 800 bends (R = 5 mm). This work highlights the effectiveness of guest polymer on simultaneously improving photovoltaic performance, photostability and mechanical stability in all-PSCs.

Whether the watch-and-wait strategy has application value for rectal cancer with clinical complete response after neoadjuvant chemoradiotherapy? A network meta-analysis.

The aim was to evaluate the efficacy and safety between the watch-and-wait strategy (WW), radical surgery (RS), and local excision (LE) for rectal cancer with clinical complete response (cCR) after neoadjuvant radiotherapy (nCRT). We searched MEDLINE, EMBASE, the Cochrane Library, and clinical trials to compare WW with RS and LE for patients with cCR until March 2023 and collected the following data: local recurrence (LR), distant metastasis (DM), cancer-related death (CRD), overall survival (OS), and disease-free survival (DFS). In total, 2240 patients from 21 studies were included. Pairwise meta-analysis revealed no statistically significant differences between the three groups in terms of CRD and 2-, 3-, and 5-year OS (P < 0.05). The RS group was significantly better than the WW group in terms of the LR rate (odds ratio [OR] = 0.12, 95 % confidence interval [CI]: 0.06-0.21, P < 0.001, I2 = 0 %], 3-year DFS (OR = 1.56, 95 % CI: 1.10-2.21, P = 0.01, I2 = 38 %), and 5-year DFS (OR = 2.30, 95 % CI: 1.53-3.46, P < 0.001, I2 = 34 %). The results of network meta-analysis were also similar. After sensitivity analysis, the 5-year OS of the RS group was significantly better than that of the WW group (OR = 2.77, 95 % CI: 1.28-6.00, P = 0.009, I2 = 33 %). Nevertheless, neither regression analysis nor subgroup analysis provided meaningful results. However, the cumulative meta-analysis of LR, DM, and 3- and 5-year DFS revealed significant turning points (P < 0.05). Our meta-analysis recommends using the WW strategy for patients with cCR having poor underlying conditions and high surgical risk; however, there is a risk of higher LR and worse survival after 3 years.

Identification of Host Factors for Rift Valley Fever Phlebovirus.

Rift Valley fever phlebovirus (RVFV) is a zoonotic pathogen that causes Rift Valley fever (RVF) in livestock and humans. Currently, there is no licensed human vaccine or antiviral drug to control RVF. Although multiple species of animals and humans are vulnerable to RVFV infection, host factors affecting susceptibility are not well understood. To identify the host factors or genes essential for RVFV replication, we conducted CRISPR-Cas9 knockout screening in human A549 cells. We then validated the putative genes using siRNA-mediated knock-downs and CRISPR-Cas9-mediated knock-out studies. The role of a candidate gene in the virus replication cycle was assessed by measuring intracellular viral RNA accumulation, and the virus titers were analyzed using plaque assay or TCID50 assay. We identified approximately 900 genes with potential involvement in RVFV infection and replication. Further evaluation of the effect of six genes on viral replication using siRNA-mediated knock-downs revealed that silencing two genes (WDR7 and LRP1) significantly impaired RVFV replication. For further analysis, we focused on the WDR7 gene since the role of the LRP1 gene in RVFV replication was previously described in detail. WDR7 knockout A549 cell lines were generated and used to dissect the effect of WRD7 on a bunyavirus, RVFV, and an orthobunyavirus, La Crosse encephalitis virus (LACV). We observed significant effects of WDR7 knockout cells on both intracellular RVFV RNA levels and viral titers. At the intracellular RNA level, WRD7 affected RVFV replication at a later phase of its replication cycle (24 h) when compared with the LACV replication, which was affected in an earlier replication phase (12 h). In summary, we identified WDR7 as an essential host factor for the replication of two different viruses, RVFV and LACV, both of which belong to the Bunyavirales order. Future studies will investigate the mechanistic role through which WDR7 facilitates phlebovirus replication.

Identification of host factors for Rift Valley Fever Phlebovirus.

Background: Rift Valley fever phlebovirus (RVFV) is a zoonotic pathogen that causes Rift Valley fever (RVF) in livestock and humans. Currently, there is no licensed human vaccine or antiviral drug to control RVF. Although multiple species of animals and humans are vulnerable to RVFV infection, host factors affecting susceptibility are not well understood. Methodology: To identify the host factors or genes essential for RVFV replication, we conducted a CRISPR-Cas9 knock-out screen in human A549 cells. We then validated the putative genes using siRNA-mediated knockdowns and CRISPR-Cas9-mediated knockout studies, respectively. The role of a candidate gene in the virus replication cycle was assessed by measuring intracellular viral RNA accumulation, and the virus titers by plaque assay or TCID50 assay. Findings: We identified approximately 900 genes with potential involvement in RVFV infection and replication. Further evaluation of the effect of six genes on viral replication using siRNA-mediated knockdowns found that silencing two genes (WDR7 and LRP1) significantly impaired RVFV replication. For further analysis, we focused on the WDR7 gene since the role of LRP1 in RVFV replication was previously described in detail. Knock-out A549 cell lines were generated and used to dissect the effect of WRD7 on RVFV and another bunyavirus, La Crosse encephalitis virus (LACV). We observed significant effects of WDR7 knock-out cells on both intracellular RVFV RNA levels and viral titers. At the intracellular RNA level, WRD7 affected RVFV replication at a later phase of its replication cycle (24h) when compared to LACV which was affected an earlier replication phase (12h). Conclusion: In summary, we have identified WDR7 as an essential host factor for the replication of two relevant bunyaviruses, RVFV and LACV. Future studies will investigate the mechanistic role by which WDR7 facilitates Phlebovirus replication.

NOS inhibition reverses TLR2-induced chondrocyte dysfunction and attenuates age-related osteoarthritis.

Osteoarthritis (OA) is a joint disease featuring cartilage breakdown and chronic pain. Although age and joint trauma are prominently associated with OA occurrence, the trigger and signaling pathways propagating their pathogenic aspects are ill defined. Following long-term catabolic activity and traumatic cartilage breakdown, debris accumulates and can trigger Toll-like receptors (TLRs). Here we show that TLR2 stimulation suppressed the expression of matrix proteins and induced an inflammatory phenotype in human chondrocytes. Further, TLR2 stimulation impaired chondrocyte mitochondrial function, resulting in severely reduced adenosine triphosphate (ATP) production. RNA-sequencing analysis revealed that TLR2 stimulation upregulated nitric oxide synthase 2 (NOS2) expression and downregulated mitochondria function-associated genes. NOS inhibition partially restored the expression of these genes, and rescued mitochondrial function and ATP production. Correspondingly, Nos2-/- mice were protected from age-related OA development. Taken together, the TLR2-NOS axis promotes human chondrocyte dysfunction and murine OA development, and targeted interventions may provide therapeutic and preventive approaches in OA.

Embedded Host/Guest Alloy Aggregations Enable High-Performance Ternary Organic Photovoltaics.

The ternary strategy has been intensively studied to improve the power conversion efficiencies of organic photovoltaics. Thereinto, the location of the guest component plays a critical role, but few reports have been devoted to this concern. Hereon, the distribution of LA1 as a guest acceptor in a variety of ternary scenarios is reported and the dominating driving forces of managing the guest distribution and operating modes are outlined. Governed by the appropriate relationship of compatibility, crystallinity, and surface energies between host and guest acceptors, as well as interfacial interactions between donor and dual acceptors, most of the LA1 molecules permeate into the internal of host acceptor phases, forming embedded host/guest alloy-like aggregations. The characteristic distributions greatly optimize the morphologies, maximize energy transfer, and enhance exciton/charge behaviors. Particularly, PM6:IT-4F:LA1 ternary cells afford high efficiency of 15.27% with impressive fill factors (FF) over 81%. The popularization studies further verify the superiority of the LA1-involved alloy structures, and with the Y6-family acceptor as the host component, an outstanding efficiency of 19.17% is received. The results highlight the importance of guest distribution in ternary systems and shed light on the governing factors of distributing the guests in ternary cells.

Identification and protective role of CD34+ stromal cells/telocytes in experimental autoimmune encephalomyelitis (EAE) mouse spleen.

Experimental autoimmune encephalomyelitis (EAE) is a classical animal model of human multiple sclerosis (MS) that is most commonly used to study the neuropathology and therapeutic effects of the disease. Telocytes (TCs) are a specialized type of interstitial or mesenchymal cell first identified by Popescu in various tissues and organs. However, the existence, distribution and role of CD34+ stromal cells (SCs)/TCs in the EAE-induced mouse spleen remain to be elucidated. We conducted immunohistochemistry, immunofluorescence (double staining for CD34 and c-kit, vimentin, F4/80, CD163, Nanog, Sca-1, CD31 or tryptase) and transmission electron microscopy experiments to investigate the existence, distribution and role of CD34+ SCs/TCs in the EAE-induced mouse spleen. Interestingly, immunohistochemistry, double-immunofluorescence, and transmission electron microscopy results revealed that CD34+ SCs/TCs were significantly upregulated in the EAE mouse spleen. Immunohistochemical or double-immunofluorescence staining of CD34+ SCs/TCs showed positive expression for CD34, c-kit, vimentin, CD34/vimentin, c-kit/vimentin and CD34/c-kit, and negative expression for CD31 and tryptase. Transmission electron microscopy (TEM) results demonstrated that CD34+ SCs/TCs established close connections with lymphocytes, reticular cells, macrophages, endothelial cells and erythrocytes. Furthermore, we also found that M1 (F4/80) or M2 (CD163) macrophages, and haematopoietic, pluripotent stem cells were markedly increased in EAE mice. Our results suggest that CD34+ SCs/TCs are abundant and may play a contributing role in modulating the immune response, recruiting macrophages and proliferation of haematopoietic and pluripotent stem cells following injury to promote tissue repair and regeneration in EAE mouse spleens. This suggests that their transplantation combined with stem cells might represent a promising therapeutic target for the treatment and prevention of multiple autoimmune and chronic inflammatory disorders.

Recent Progress in Self-Powered Wireless Sensors and Systems Based on TENG.

With the development of 5G, artificial intelligence, and the Internet of Things, diversified sensors (such as the signal acquisition module) have become more and more important in people's daily life. According to the extensive use of various distributed wireless sensors, powering them has become a big problem. Among all the powering methods, the self-powered sensor system based on triboelectric nanogenerators (TENGs) has shown its superiority. This review focuses on four major application areas of wireless sensors based on TENG, including environmental monitoring, human monitoring, industrial production, and daily life. The perspectives and outlook of the future development of self-powered wireless sensors are discussed.

Menstrual blood-derived endometrial stem cells inhibit neuroinflammation by regulating microglia through the TLR4/MyD88/NLRP3/Casp1 pathway.

Neuroinflammation is a common response in various neurological disorders. Mesenchymal stem cell-based treatment has become a promising therapy for neuroinflammation-associated diseases. However, the effects of mesenchymal stem cells are controversial, and the underlying mechanism is incompletely understood. In the present study, menstrual blood-derived endometrial stem cells were intravenously transplanted into a mouse model of neuroinflammation established by peripheral injection of lipopolysaccharide. Microglial cells challenged with lipopolysaccharide were cultured with conditioned medium from endometrial stem cells. The levels of cytokines were detected by enzyme-linked immunosorbent assay. Cell proliferation and death were detected by Cell Counting Kit 8 and flow cytometry, respectively. The expression levels of Toll-like receptor 4 (TLR4), myeloid differentiation primary response gene 88 (MyD88), NLR family pyrin domain containing 3 (NLRP3) and caspase 1 (Casp1) were evaluated by western blotting. The results showed that intravenous transplantation of endometrial stem cells downregulated proinflammatory factors and upregulated anti-inflammatory factors in the brain of mice with neuroinflammation. Conditioned medium suppressed the inflammatory reaction and hyperactivation of microglial cells and protected microglial cells from cell death induced by lipopolysaccharide in vitro. The expression of TLR4, MyD88, NLRP3 and Casp1 in the brain of mice with neuroinflammation and in lipopolysaccharide-stimulated microglial cells was downregulated by endometrial stem cells and conditioned medium, respectively. These data suggested that menstrual blood-derived endometrial stem cells may suppress neuroinflammatory reactions partially by regulating microglia through the TLR4/MyD88/NLRP3/Casp1 signalling pathway. Our findings may be very useful for the development of an alternative stem cell-based therapy for neuroinflammation-associated disorders.

Isolation and characterization of mammalian orthoreovirus from bats in the United States.

Mammalian orthoreovirus (MRV) infects many mammalian species including humans, bats, and domestic animals. To determine the prevalence of MRV in bats in the United States, we screened more than 900 bats of different species collected during 2015-2019 by a real-time reverse-transcription polymerase chain reaction assay; 4.4% bats tested MRV-positive and 13 MRVs were isolated. Sequence and phylogenetic analysis revealed that these isolates belonged to four different strains/genotypes of viruses in Serotypes 1 or 2, which contain genes similar to those of MRVs detected in humans, bats, bovine, and deer. Further characterization showed that these four MRV strains replicated efficiently on human, canine, monkey, ferret, and swine cell lines. The 40/Bat/USA/2018 strain belonging to the Serotype 1 demonstrated the ability to infect and transmit in pigs without prior adaptation. Taken together, this is evidence for different genotypes and serotypes of MRVs circulating in US bats, which can be a mixing vessel of MRVs that may spread to other species, including humans, resulting in cross-species infections.

Over 19% Efficiency Organic Solar Cells by Regulating Multidimensional Intermolecular Interactions.

Research on organic solar cells (OSCs) has progressed through material innovation and device engineering. However, well-known and ubiquitous intermolecular interactions, and particularly their synergistic effects, have received little attention. Herein, the complicated relationship between photovoltaic conversion and multidimensional intermolecular interactions in the active layers is investigated. These interactions are dually regulated by side-chain isomerization and end-cap engineering of the acceptors. The phenylalkyl featured acceptors (LA-series) exhibit stronger crystallinity with preferential face-on interactions relative to the alkylphenyl attached isomers (ITIC-series). In addition, the PM6 and LA-series acceptors exhibit moderate donor/acceptor interactions compared to those of the strongly interacting PM6/ITIC-series pairs, which helps to enhance phase separation and charge transport. Consequently, the output efficiencies of all LA series acceptors are over 14%. Moreover, LA-series acceptors show appropriate compatibility, host/guest interactions, and crystallinity relationships with BTP-eC9, thereby leading to uniform and well-organized "alloy-like" mixed phases. In particular, the highly crystalline LA23 further optimizes multiple interactions and ternary microstructures, which results in a high efficiency of 19.12%. Thus, these results highlight the importance of multidimensional intermolecular interactions in the photovoltaic performance of OSCs.

Triboelectric Potential Powered High-Performance Organic Transistor Array.

Triboelectric potential gated transistors have inspired various applications toward mechanical behavior controlled logic circuits, multifunctional sensors, artificial sensory neurons, etc. Their rapid development urgently calls for high-performance devices and corresponding figure of merits to standardize the tribotronic gating properties. Organic semiconductors paired with solution processability promise low-cost manufacture of high-performance tribotronic transistor devices/arrays. Here, we demonstrate a record high-performance tribotronic transistor array composed of an integrated triboelectric nanogenerator (TENG) and a large-area device array of C8-BTBT-PS transistors. The working mechanism of effective triboelectric potential gating is elaborately explained from the aspect of conjugated energy bands of the contact-electrification mediums and organic semiconductors. Driven by the triboelectric potential, the tribotronic transistor shows superior properties of record high current on/off ratios (>108), a steep subthreshold swing (29.89 µm/dec), high stability, and excellent reproducibility. Moreover, tribotronic logic devices modulated by mechanical displacement have also been demonstrated with good stability and a high gain of 1260 V/mm. The demonstrated large-area tribotronic transistor array of organic semiconductor exhibits record high performance and offers an effective R&D platform for mechano-driven electronic terminals, interactive intelligent system, artificial robotic skin, etc.

Influenza A virus reassortment in mammals gives rise to genetically distinct within-host subpopulations.

Influenza A virus (IAV) genetic exchange through reassortment has the potential to accelerate viral evolution and has played a critical role in the generation of multiple pandemic strains. For reassortment to occur, distinct viruses must co-infect the same cell. The spatio-temporal dynamics of viral dissemination within an infected host therefore define opportunity for reassortment. Here, we used wild type and synonymously barcoded variant viruses of a pandemic H1N1 strain to examine the within-host viral dynamics that govern reassortment in guinea pigs, ferrets and swine. The first two species are well-established models of human influenza, while swine are a natural host and a frequent conduit for cross-species transmission and reassortment. Our results show reassortment to be pervasive in all three hosts but less frequent in swine than in ferrets and guinea pigs. In ferrets, tissue-specific differences in the opportunity for reassortment are also evident, with more reassortants detected in the nasal tract than the lower respiratory tract. While temporal trends in viral diversity are limited, spatial patterns are clear, with heterogeneity in the viral genotypes detected at distinct anatomical sites revealing extensive compartmentalization of reassortment and replication. Our data indicate that the dynamics of viral replication in mammals allow diversification through reassortment but that the spatial compartmentalization of variants likely shapes their evolution and onward transmission.

Biomimetic FeCo@PDA nanozyme platform with Fenton catalytic activity as efficient antibacterial agent.

The multidrug resistance of bacteria caused by the abuse of traditional antibiotics poses a great threat to public health, so it is urgent to develop effective antibacterial agents to deal with this dilemma. Biomimetics and nanotechnology are expected to provide new strategies for solving this problem. This study takes inspiration from the adhesive protein properties of mussels to design and synthesise biomimetic polydopamine nanospheres (FeCo@PDA NPs), which have strong adhesion and catalytic Fenton reactive enzyme activity. The antibacterial activity of FeCo@PDA NPs against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) is significantly better than that of traditional antibiotics daptomycin (Dap) and vancomycin (Van). PDA NPs with an intrinsic hierarchical structure have the ability to adhere to bacterial surfaces and improve the loading rate of metal ions Fe2+/Co2+. In addition, due to the dual effects of strong adhesion and Co2+, FeCo@PDA NPs can destroy the bacterial membrane structure and release endogenous hydrogen peroxide, which increases the generation of reactive oxygen species by synergistic catalysis of bimetal ions Fe2+/Co2+ to further kill bacteria thoroughly. The cytotoxicity test results show that FeCo@PDA NPs have good cytocompatibility. The impressive antibacterial properties and good biocompatibility of FeCo@PDA NPs make them a potential antibacterial drug.

Menstrual blood-derived mesenchymal stromal cells efficiently ameliorate experimental autoimmune encephalomyelitis by inhibiting T cell activation in mice.

BACKGROUND: Immunosuppressive properties grant mesenchymal stromal cells (MSCs) promising potential for treating autoimmune diseases. As autologous MSCs suffer from limited availability, the readily available allogeneic MSCs isolated from menstrual blood (MB-MSCs) donated by young, healthy individuals offer great potential. Here, we evaluate the therapeutic potential of MB-MSCs as ready-to-use allo-MSCs in multiple sclerosis, an autoimmune disease developed by the activation of myelin sheath-reactive Th1 and Th17 cells, by application in its animal model experimental autoimmune encephalomyelitis (EAE). METHODS: We assessed the therapeutic effect of MB-MSCs transplanted via either intravenous (i.v.) or intraperitoneal (i.p.) route in EAE in comparison with umbilical cord-derived MSCs (UC-MSCs). We used histology to assess myelin sheath integrity and infiltrated immune cells in CNS and flow cytometry to evaluate EAE-associated inflammatory T cells and antigen-presenting cells in lymphoid organs. RESULTS: We observed disease-ameliorating effects of MB-MSCs when transplanted at various stages of EAE (day - 1, 6, 10, and 19), via either i.v. or i.p. route, with a potency comparable to UC-MSCs. We observed reduced Th1 and Th17 cell responses in mice that had received MB-MSCs via either i.v. or i.p. injection. The repressed Th1 and Th17 cell responses were associated with a reduced frequency of plasmacytoid dendritic cells (pDCs) and a suppressed co-stimulatory capacity of pDCs, cDCs, and B cells. CONCLUSIONS: Our data demonstrate that the readily available MB-MSCs significantly reduced the disease severity of EAE upon transplantation. Thus, they have the potential to be developed as ready-to-use allo-MSCs in MS-related inflammation.

Conjugated Polyelectrolyte/Silver Bromide Nanocomposites: Highly Durable and Robust Antibacterial Materials.

We report the in situ synthesis of silver bromide nanoparticles (AgBr NPs) in a cationic conjugated polyelectrolyte (CPE) matrix. It is interesting that the obtained CPE/AgBr nanocomposite materials exhibit robust and long-term antimicrobial activity against both Gram-negative bacteria and Gram-positive bacteria by producing a large amount of biologically active Ag+. Meanwhile, it is demonstrated that the antimicrobial activity of CPE/AgBr nanocomposites is also related to the size of the AgBr NPs. Smaller particles show a faster AgBr release rate and hence higher antimicrobial activity than big particles. However, the relatively large-sized nanocomposites are beneficial to obtain long-term antimicrobial activity by substantially producing bioactive Ag+. Consequently, the antimicrobial property of the CPE/AgBr nanocomposites can be manipulated by controlling the dimensions of embedded AgBr NPs. The CPE/AgBr nanocomposites can cause a rapid initial drop of bacterial counts in solution, which makes it a potential candidate for antimicrobial therapy in emergency cases. In addition, the sustained release of Ag+ from large-sized nanocomposites makes them suitable for long-term use.

Conduit CAR: Redirecting CAR T-Cell Specificity with A Universal and Adaptable Bispecific Antibody Platform.

The success of chimeric antigen receptor (CAR) T-cell therapy against hematologic malignancies has altered the treatment paradigm for patients with these diseases. Nevertheless, the occurrence of relapse due to antigen escape or heterogeneous antigen expression on tumors remains a challenge for first-generation CAR T-cell therapies as only a single tumor antigen can be targeted. To address this limitation and to add a further level of tunability and control to CAR T-cell therapies, adapter or universal CAR T-cell approaches use a soluble mediator to bridge CAR T cells with tumor cells. Adapter CARs allow simultaneous or sequential targeting of multiple tumor antigens, control of immune synapse geometry, dose control, and the potential for improved safety. Herein, we described a novel CAR T-cell adapter platform that relies on a bispecific antibody (BsAb) targeting both a tumor antigen and the GGGGS (G4S) linker commonly used in single-chain Fv (ScFv) domains expressed on CAR T-cell surfaces. We demonstrated that the BsAb can bridge CAR T cells to tumor cells and potentiate CAR T-cell activation, proliferation, and tumor cell cytolysis. The cytolytic activity of CAR T-cells was redirected to different tumor antigens by changing the BsAb in a dose-dependent manner. This study highlights the potential of G4S-displaying CAR T cells to be redirected to engage alternative tumor-associated antigens (TAA). Significance: New approaches are needed to address relapsed/refractory disease and manage potential toxicities associated with CAR T-cell therapy. We describe an adapter CAR approach to redirect CAR T cells to engage novel TAA-expressing cells via a BsAb targeting a linker present on many clinical CAR T-cell therapeutics. We anticipate the use of such adapters could increase CAR T-cell efficacy and reduce potential CAR-associated toxicities.