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This study examined the effects of modification of dense-grade asphalt mixtures with chemically engineered crumb rubber (ECR) via the dry process. The ECR mixtures were compared to unmodified and polymer-modified mixtures in various criteria. The study mainly had three objectives: (1) comparison of mixture performance, (2) investigation of warm mix equivalence, i.e., to determine if the chemical coating on the ECR resulted in benefits similar to warm mix additives, and (3) to determine the effects of ECR on mixture draindown. For the first objective, the disk-shaped compact tension test was conducted to determine resistance to thermal cracking, and the Hamburg wheel tracking test was performed to determine resistance to permanent deformation (rutting) and moisture damage. To fulfill the second objective, the mixtures were prepared with warm mix asphalt (WMA) additives wherever necessary, and for the third objective, a stone mastic asphalt (SMA) was employed instead of the dense-grade mixture that was used for the rest of the study. Findings showed that modification with ECR greatly improved resistance to rutting and cracking, indicating that ECR pavements will exhibit longer service life. In terms of warm mix equivalence, a comparison of volumetrics data showed that ECR without WMA additive compacted in a similar manner as a polymer (PG 76-22) mixture containing WMA additive. Additional mix cost savings may be realized with ECR modification because of the ability to avoid the cost of WMA additive for the goal of achieving mix workability and compaction at lower temperatures. Finally, an ECR-SMA mix was used for draindown assessment and was found to pass the draindown test without the need for fibers, nearly matching the draindown resistance of the polymer-WMA mix containing cellulose fibers, thereby presenting another cost-saving avenue for contractors. The study also includes details of three field projects that used ECR and reported excellent field performance. [ABSTRACT FROM AUTHOR]

Efficient gene therapy relies on an efficient gene delivery system. Viral gene delivery approaches excel in transferring and expressing external genes; however, their immunogenicity and difficulty in large-scale production limit their clinical applications. In contrast, nanoparticle-based gene delivery systems have gained increasing attention due to less immunogenicity and more convenience for large-scale production. Nevertheless, their poor transfection efficiency compared to viral systems remains a significant obstacle. In the present study, we investigated the transfection efficiency of our PEI-coated graphene oxides in HEK293T, Calu-3, Calu-6 cell lines, and primary human bone marrow mesenchymal stem cell (MSC). The high surface ratio and good biocompatibility of graphene oxide make it an appealing tool for gene delivery systems. However, the low dispersity of graphene oxide in aqueous environments is the first barrier that needs to be conquered. For this, we enhanced the dispersity and stability of graphene oxide in water by sonicating it for at least 5 hours at a pH of 7. Then, graphene oxide was conjugated with branched PEI (25 kDa) to have a positive charge, enabling it to condense nucleic acids with a naturally negative potential. The physio-chemical characteristics of our synthesized nano-carriers (GO-PEI) were determined by DLS, FT-IR, and AFM. The utilized plasmid in polyplexes contained a GFP gene, allowing us to verify transfection efficiency through fluorescent microscopy and flow cytometry. While GO-PEI carriers were highly efficient in transfecting HEK293T cells, the transfection efficiency in MSCs and Calu-3 cells was notably low. We suppose that the main reason for the low transfection efficiency of GO-PEI in these cells is due to its higher toxicity. Despite this, considering the various advantages of graphene oxide in drug delivery as well as its optical and electrical applications in biomedicine, we propose to functionalize graphene oxide with more biocompatible materials to enhance its potential as a successful gene carrier in these cell types., Competing Interests: NO authors have competing interests., (Copyright: © 2023 Maleki et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Mesenchymal stem cells (MSCs) are multipotent, self-renewing stromal cells found in a variety of adult tissues. MSCs possess a remarkable ability to migrate towards tumor sites, known as homing. This homing process is mediated by various factors, including chemokines, growth factors, and extracellular matrix components present in the tumor microenvironment. MSCs release extracellular vesicles known as exosomes (MSC-Exos), which have been suggested to serve a key role in mediating a wide variety of MSC activities. Through cell-cell communication, MSC-Exos have been shown to alter recipient cell phenotype or function and play as a novel cell-free alternative for MSC-based cell therapy. However, MSC recruitment to tumors allows for their interaction with cancer cells and subsequent regulation of tumor behavior. MSC-Exos act as tumor niche modulators via transferring exosomal contents, such as specific proteins or genetic materials, to the nearby cancer cells, leading to either promotion or suppression of tumorigenesis, angiogenesis, and metastasis, depending on the specific microenvironmental cues and recipient cell characteristics. Consequently, there is still a debate about the precise relationship between tumor cells and MSC-Exos, and it is unclear how MSC-Exos impacts tumor cells. Although the dysregulation of miRNAs is caused by the progression of cancer, they also play a direct role in either promoting or inhibiting tumor growth as they act as either oncogenes or tumor suppressors. The utilization of MSC-Exos may prove to be an effective method for restoring miRNA as a means of treating cancer. This review aimed to present the existing understanding of the impact that MSC-Exos could have on cancer. To begin with, we presented a brief explanation of exosomes, MSCs, and MSC-Exos. Following this, we delved into the impact of MSC-Exos on cancer growth, EMT, metastasis, angiogenesis, resistance to chemotherapy and radiotherapy, and modulation of the immune system. Opposing effects of mesenchymal stem cells-derived exosomes on cancer cells., (© 2023. The International CCN Society.)

The aim of this study is to develop a digital monitoring system to track weight and evaluate its impact on postoperative outcomes after lower extremity surgeries (LES). This parallel randomized controlled trial enrolled 266 patients who underwent LES (fracture or joint replacement) at our medical center between March 11, 2022, and January 10, 2023. Patients were randomly assigned to the intervention and control groups in a 1:1 ratio. The intervention group (n=116) used a cane and shoes equipped with a weight-bearing system after lower limb surgery, while the control group (n=116) used a simple cane and shoes without a weight-bearing system. The primary outcomes included callus formation, duration of union, and success rate of union in the two groups. The intervention group had a significantly higher rate of complete surgical success than the control group (93.9% vs. 79.3%, p=0.001). The intervention group also had a significantly lower risk of non-union than the control group (OR: 2.33, 95% CI: 1.14, 3.48, p=0.001). The mean duration of surgery until the time of union and the meantime of callus formation was significantly lower in the intervention group (p=0.01). The use of a digital monitoring system for weighing in LES significantly increased the success rate and reduced post-operative complications. Therefore, incorporating this system can enhance the rehabilitation process and prevent revision surgeries in patients with LES.

Different immunomodulation strategies have been used to manage COVID-19 due to the complex immune-inflammatory processes involved in the pathogenesis of this infection. Curcumin with its powerful anti-inflammatory and antiviral properties could serve as a possible COVID-19 therapy. In this study, a randomized, double-blinded, placebo-controlled trial was performed to investigate the effectiveness and safety of nano-curcumin oral soft gels as a complementary therapy in moderate-severe COVID-19 patients. Hydroxychloroquine (HCQ) plus sofosbuvir was routinely administered to all 42 COVID-19 patients, who were randomly assigned to receive 140 mg of nano-curcumin or placebo for 14 days. CT scans of the chest were taken, and blood tests were run for all patients at time points of 0, 7, and 14 days. Our results indicated that C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) levels significantly decreased from baseline in the nano-curcumin-treated group on day 7. Furthermore, blood levels of D-dimer, CRP, serum ferritin, ESR, and inflammatory cytokines including IL-6, IL-8, and IL-10 decreased more significantly in the nano-curcumin-treated group after 14 days. Additionally, the nano-curcumin group showed significant improvements in chest CT scores, oxygen saturation levels, and hospitalization duration. Based on our data, oral administration of nano-curcumin may be regarded as a promising adjunct treatment for COVID-19 patients due to its ability to speed up chest clearance and recovery., (© 2023 John Wiley & Sons Ltd.)

Malaria as vector-borne disease remains important health concern with over 200 million cases globally. Novel antimalarial medicines and more effective vaccines must be developed to eliminate and eradicate malaria. Appraisal of preceding genome editing approaches confirmed the CRISPR/Cas nuclease system as a novel proficient genome editing system and a tool for species-specific diagnosis, and drug resistance researches for Plasmodium species, and gene drive to control Anopheles population. CRISPR/Cas technology, as a handy tool for genome editing can be justified for the production of transgenic malaria parasites like Plasmodium transgenic lines expressing Cas9, chimeric Plasmodium transgenic lines, knockdown and knockout transgenic parasites, and transgenic parasites expressing alternative alleles, and also mutant strains of Anopheles such as only male mosquito populations, generation of wingless mosquitoes, and creation of knock-out/ knock-in mutants. Though, the incorporation of traditional methods and novel molecular techniques could noticeably enhance the quality of results. The striking development of a CRISPR/Cas-based diagnostic kit that can specifically diagnose the Plasmodium species or drug resistance markers is highly required in malaria settings with affordable cost and high-speed detection. Furthermore, the advancement of genome modifications by CRISPR/Cas technologies resolves contemporary restrictions to culturing, maintaining, and analyzing these parasites, and the aptitude to investigate parasite genome functions opens up new vistas in the better understanding of pathogenesis., Competing Interests: Declaration of Competing Interest Authors declare that they have no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Exosomes derived from mesenchymal stem cells (MSCs) are mostly responsible for the therapeutic effects of MSCs. To show the therapeutic effects of the human bone marrow MSC-derived exosomes (MSC-Exos) on colorectal cancer (CRC) and explore the molecular cross-talks between them, CRC cells were treated with the MSC-Exos. We found that MSC-Exos were enriched with miR-100 and miR-143, which effectively downregulated mTOR, Cyclin D1, K-RAS, HK2 while upregulated p-27 expression. All these effects were reversed by concurrent treatment with MSC-Exos and antagomiR-100, confirming that they were caused by exosomal transfer of miR-100 into recipient CRC cells. Moreover, exosomal miR-100 promoted endogenous miR-143 expression. The flow cytometry, MTT and trypan blue assays revealed that MSC-Exos could efficiently suppress proliferation and induce apoptosis of the CRC cells. Furthermore, wound healing, transwell migration and invasion assays confirmed their inhibitory effects on the migration and invasiveness of SW480 cells. We further confirmed these effects by analyzing the expression levels of epithelial to mesenchymal transition (EMT) factors and metastasis-related genes. Results showed that MSC-Exos significantly suppressed the expression of MMP2 and MMP9 (metastasis-related genes), SNAIL and TWIST (EMT-inducing transcription factors), Vimentin and N-cadherin (mesenchymal cell markers), whereas E-cadherin (epithelial cell marker) was remarkably up-regulated. Collectively, our data indicated that MSC-Exos could suppress proliferation, migration, invasion and metastasis while inducing the apoptosis of the CRC cells via miR-100/mTOR/miR-143 axis. Our findings highlight that MSC-Exo treatment as well as miR-100 restoration might be considered as potential therapeutic strategies for CRC., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Exosomal release pathway and autophagy together maintain homeostasis and survival of cells under stressful conditions. Autophagy is a catabolic process through which cell entities, such as malformed biomacromolecules and damaged organelles, are degraded and recycled via the lysosomal-dependent pathway. Exosomes, a sub-type of extracellular vesicles (EVs) formed by the inward budding of multivesicular bodies (MVBs), are mostly involved in mediating communication between cells. The unfolded protein response (UPR) is an adaptive response that is activated to sustain survival in the cells faced with the endoplasmic reticulum (ER) stress through a complex network that involves protein synthesis, exosomes secretion and autophagy. Disruption of the critical crosstalk between EVs, UPR and autophagy may be implicated in various human diseases, including cancers and neurodegenerative diseases, yet the molecular mechanism(s) behind the coordination of these communication pathways remains obscure. Here, we review the available information on the mechanisms that control autophagy, ER stress and EV pathways, with the view that a better understanding of their crosstalk and balance may improve our knowledge on the pathogenesis and treatment of human diseases, where these pathways are dysregulated., (Copyright © 2022. Published by Elsevier B.V.)

The rice sheath blight disease, caused by Rhizoctonia solani J.G. Kühn fungus, is a major disease of Oryza sativa L. occurring all over the world. Therefore, efforts need to be undertaken to limit the spread of this pathogen, preferably by using environmentally friendly methods. In the present study, 57 fungal isolates were recovered by surface sterilization technique from 120 rice samples collected from paddy fields in Guilan province, Iran. Biological characterizations of the isolated taxa were performed in vitro, in the dual culture, volatile metabolites, and slide culture methods. Among the studied isolates, Trichoderma virens (J. H. Miller, Giddens and A. A. Foster) Arx was most effective in inhibiting the mycelial growth of R. solani in the dual culture (44.16% inhibition level), while Aspergillus fumigatus Fresen and T. virens had a 62.50-68.75% inhibition efficiency by volatile metabolites. In the slide culture, all of the isolates, except for T. harzianum Rifai, were effective in inhibiting the hyphae growth of R. solani . Under greenhouse conditions, rice plants inoculated with these potential antagonistic fungi showed a reduction in disease severity by even 41.4% as in the case of T. virens . Moreover, phenotypic properties of rice, such as plant height, fresh weight, and dry weight were increased in the plants inoculated with all antagonistic fungi tested, compared to the infected plants, except for the fresh weight of plants inoculated with Curnularia lunata (Wakker) Boedijn. The present in vivo and in vitro studies revealed that T. virens and A. fumigatus are the most effective antagonists in rice sheath blight disease control and could be applied in agricultural practice.

Universal CAR T-cell therapies are poised to revolutionize cancer treatment and to improve patient outcomes. However, realizing these advantages in an allogeneic setting requires universal CAR T-cells that can kill target tumor cells, avoid depletion by the host immune system, and proliferate without attacking host tissues. Here, we describe the development of a novel immune-evasive universal CAR T-cells scaffold using precise TALEN-mediated gene editing and DNA matrices vectorized by recombinant adeno-associated virus 6. We simultaneously disrupt and repurpose the endogenous TRAC and B2M loci to generate TCRαβ- and HLA-ABC-deficient T-cells expressing the CAR construct and the NK-inhibitor named HLA-E. This highly efficient gene editing process enables the engineered T-cells to evade NK cell and alloresponsive T-cell attacks and extend their persistence and antitumor activity in the presence of cytotoxic levels of NK cell in vivo and in vitro, respectively. This scaffold could enable the broad use of universal CAR T-cells in allogeneic settings and holds great promise for clinical applications., (© 2022. The Author(s).)

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Endowing chimeric antigen receptor (CAR) T cells with additional potent functionalities holds strong potential for improving their antitumor activity. However, because potency could be deleterious without control, these additional features need to be tightly regulated. Immune pathways offer a wide array of tightly regulated genes that can be repurposed to express potent functionalities in a highly controlled manner. Here, we explore this concept by repurposing TCR, CD25 and PD1, three major players of the T cell activation pathway. We insert the CAR into the TCRα gene (TRAC CAR ), and IL-12P70 into either IL2Rα or PDCD1 genes. This process results in transient, antigen concentration-dependent IL-12P70 secretion, increases TRAC CAR T cell cytotoxicity and extends survival of tumor-bearing mice. This gene network repurposing strategy can be extended to other cellular pathways, thus paving the way for generating smart CAR T cells able to integrate biological inputs and to translate them into therapeutic outputs in a highly regulated manner.

Percutaneous coronary intervention (PCI) of heavily calcified stenoses remains a significant challenge to interventional cardiologists. Over the last years, high-pressure balloons, cutting balloons as well as atherectomy devices have been used to tackle such lesions. Lithoplasty is a method of lesion modification using intravascular lithotripsy (IVL, shockwave) to treat particularly calcified coronary lesions. A 55-year-old male without previous cardiac history reported chest pain and was found to have ECG changes anterolaterally and significantly elevated troponins. Coronary angiogram showed heavily calcified severe proximal left anterior descending (LAD) stenosis. The attempts to predilate the lesion with semi-compliant and non-compliant balloons at high pressures were unsuccessful so the decision was made to use a shockwave balloon. Subsequently a drug-eluting stent was successfully implanted and post-dilated at high pressure. Final angiography showed an excellent result, also confirmed in optical coherence tomography (OCT)., Competing Interests: Nil.

Cancer-associated fibroblasts (CAFs) have been considered as major players in tumor growth and malignancy. In colorectal cancer (CRC), CAFs are attendance in high affluence and little is known about how they impact tumor progression. An increasing number of studies indicated that dysregulation of human urothelial carcinoma associated 1 (UCA1) is associated with progression of tumor and metastasis in various cancers including CRC. Nonetheless, the possible mechanisms of UCA1 actuation in CRC remain poorly understood. To address this, we elucidated the effects of conditioned medium from SW480 CRC cells/Normal fibroblast co-culture (CAF-CM) on UCA1 expression, and the cell proliferation, EMT, invasion and migration of the treated CRC cell were evaluated in vitro. Our study indicated that CAFs dramatically stimulated cell proliferation and migration of CRC cell. Furthermore, CAFs induced the EMT phenotype in CRC cell, with an associated change in the expression of EMT markers including vimentin, E-cadherin, N-cadherin and metastasis-related genes (MMPs). Moreover, we found an increased percentage of CRC cell in the S and G2/M phase induced by CAFs. Our results revealed that CAFs could induce upregulation of UCA1, leading to upregulation of mTOR. Up-regulation of UCA1/mTOR axis suppressed p27 and miR-143 while the expression of Cyclin-D1 and KRAS were significantly increased compared with control. Furthermore, UCA1 silencing in treated CRC cell suggested that upregulation of UCA1, which was induced by CAFs, regulates the expression of downstream key effectors. Taken together, these results highlight the vital role of cooperation between lncRNA UCA1 and mTOR in proliferation and metastasis which support the hypothesis that CAFs may be a prominent therapeutic target of stroma-based therapy in CRC treatment.