An Investigation of the Performance of the ANN Method for Predicting the Base Shear and Overturning Moment Time-Series Datasets of an Offshore Jacket Structure

The primary purpose of the current study was to investigate the performance of artificial neural networks to predict the time series of the water surface level (WSL), base shear, and overturning moment using two types of ANN models: Nonlinear Autoregressive models with exogenous inputs (NARX) and Nonlinear Autoregressive models (NAR). After determining the suitable model, NARX, the possibility of predicting the time series of the base shear and the overturning moment data was investigated by considering the water surface level and time as the multivariable model inputs. A jacket model with a height of 4.55m was fabricated and tested in the 402m-long wave flume of the NIMALA marine laboratory. The jacket was tested at the water depth of 4m and subjected to random waves with a JONSWAP energy spectrum. Three input wave heights were chosen for the tests: 20cm, 23cm, and 28cm. The findings showed that using the NARX neural network is a convenient method to predict the base shear and overturning moment values based on the water surface level data as input values. Finally, after suitable neural network determination, using the NARX neural network, the correlation value (R) for calculating water surface level (WSL), Base Shear, and Overturning Moment were obtained as 0.994, 0.97, and 0.94, respectively

Effect of gibberellic acid on the quality of sperm and in vitro fertilization outcome in adult male rats

Gibberellic acid (GA3) is a group of plant hormones identified in various plants. The aim of this study was to determine the effects of GA3 on sperm parameters and in vitro fertilization (IVF). Fifty six adult male rats were divided into seven groups as, control, treatment and sham. Following 15, 30 and 45 days of GA3 and methanol alcohol (MA) administration, rats were euthanized and epididymis tail was transferred to human tubular fluid (HTF) medium containing 4 mg mL-1 bovine serum albumin (BSA) .Total number of sperms, the percentage of live sperms, immature sperms and sperms with damaged chromatin and IVF were examined. The oocytes were obtained from immature rats after the injection of pregnant mare's serum (PMSG) and human chorionic gonadotropin (HCG) hormones. Human tubular fluid was used as the fertilization medium and zygotes transferred to fresh 1-cell rat embryos culture medium (mR1ECM) to reach the blastocyst stage. This study showed that GA3 could decrease the number of total sperms on days 30 and 45 in treated group comparison with the control and sham groups. Additionally, GA3 increased the immature sperms and sperms with damaged chromatin. The percentage of fertilization, two-cell embryos and blastocyst resulting from the treatment group on days 30 and 45 also decreased and showed significant differences with the control and sham groups (p < 0.05). The results obtained from this study indicated that the oral use of GA3 could reduce the fertility in rats by influencing the sperm number and the quality of sperm’s chromatins

Prolonged residence of an albumin–IL-4 fusion protein in secondary lymphoid organs ameliorates experimental autoimmune encephalomyelitis

Interleukin-4 (IL-4) suppresses the development of multiple sclerosis in a murine model of experimental autoimmune encephalomyelitis (EAE). Here, we show that, in mice with EAE, the accumulation and persistence in the lymph nodes and spleen of a systemically administered serum albumin (SA)–IL-4 fusion protein leads to higher efficacy in preventing disease development than the administration of wild-type IL-4 or of the clinically approved drug fingolimod. We also show that the SA–IL-4 fusion protein prevents immune-cell infiltration in the spinal cord, decreases integrin expression in antigen-specific CD4+ T cells, increases the number of granulocyte-like myeloid-derived suppressor cells (and their expression of programmed-death-ligand-1) in spinal cord-draining lymph nodes and decreases the number of T helper 17 cells, a pathogenic cell population in EAE. In mice with chronic EAE, SA–IL-4 inhibits immune-cell infiltration into the spinal cord and completely abrogates immune responses to myelin antigen in the spleen. The SA–IL-4 fusion protein may be prophylactically and therapeutically advantageous in the treatment of multiple sclerosis

Enhanced lymph node trafficking of engineered IL‐10 suppresses rheumatoid arthritis in murine models

Objective Rheumatoid arthritis (RA) is a major autoimmune disease that causes synovitis and joint damage. Although clinical trials using interleukin‐10 (IL‐10), an anti‐inflammatory cytokine, have been performed as a potential treatment of RA, its therapeutic effects have been limited, potentially due to insufficient residence in lymphoid organs, where antigen recognition primarily occurs. Here, we engineered IL‐10 as a fusion with serum albumin (SA). Methods SA‐fused IL‐10 was recombinantly expressed. After intravenous injection to mice, retention of SA‐IL‐10 at lymph node (LN), immune cell compositions at paws, and therapeutic effect on arthritis model mice were assessed. Results SA fusion to IL‐10 led to enhanced LN accumulation compared with unmodified IL‐10. Intravenous SA‐IL‐10 treatment restored immune cell composition in the paws to a normal status, elevated the frequency of suppressive M2 macrophages, reduced IL‐17A amount in the paw‐draining LN, and protected joint morphology. Intravenous SA‐IL‐10 treatment showed similar efficacy as treatment with an anti‐TNF‐α antibody. SA‐IL‐10 was equally effective when administered intravenously, locally or subcutaneously, which benefits clinical translation of this molecule. Conclusion SA fusion to IL‐10 is a simple but effective engineering strategy for RA therapy and holds clinical translational potential

Ultrafast and efficient continuous flow organic synthesis with a modified extruder-grinder system

Abstract The study introduces a groundbreaking continuous system that combines an extruder and grinder to enable catalyst-free and solvent-free reactions under mild conditions. This temperature-controlled system facilitates the synthesis of highly functionalized chromenes, which have valuable applications in generating combinatorial libraries and complex target molecules. The newly developed mill extruder machine offers several advantages for industrial production on a large scale. It effectively reduces waste, saves energy, and enhances time efficiency. This system represents a significant advancement in the field, providing a new strategy for one-pot synthesis of various types of highly functionalized spirooxindoles and chromenes. Remarkably, these reactions can be accomplished within a short timeframe of 2–10 min, yielding impressive results of 75–98%. The results demonstrate superior performance compared to traditional reaction methods, making it an appealing tool and hotspot area of research in green chemistry

Adverse effects of long-time exposure to formaldehyde vapour on testicular tissue and sperm parameters in rats

Formalin is widely used in industry and in medicine (as tissue fixative and disinfectant).It contains reactive molecules which have been known for its cytotoxic effects. To evaluate the effect of formalin exposure on the testicular tissue and sperm parameter from neonatal period through physical and sexual maturity, 28 male Wister rats were assigned into two equal test and control groups. The test group was exposed to 1.5 ppm of the vapour of 10% formaldehyde in a special chamber for 2 hr per day at 20-26 ˚C and the air pressure of 760-763 atm. After 55 days, the tubular differentiation (TDI) and repopulation (RI) indexes in testicular tissue, sperm quality parameters, serum total antioxidant capacity and testosterone level were determined. The formaldehyde-exposed animals showed severe seminiferous tubules atrophy, edematous connective tissue, arrested spermatogenesis with negative TDI and RI and vascular thrombosis compared to control group. Histomorphological studies showed a high sperm mortality and abnormality associated with a remarkable decrease in sperm count. Formaldehyde-exposed animals revealed with decreased serum level of testosterone (p < 0.05) and down-regulated antioxidant status versus control group. In conclusion, the current data provide inclusive histological and biochemical information about the chronic exposure to formaldehyde with emphasizing on reproductive disorders including histological adverse effects on the testicular tissue, spermatogenesis, sperm viability, count and the abnormalities which can potentially cause infertility after sexual maturation

Matrix-binding checkpoint immunotherapies enhance antitumor efficacy and reduce adverse events

Immune checkpoint blockade exhibits considerable antitumor activity, but previous studies have reported instances of severe treatment-related adverse events. We sought to explore local immune checkpoint blockade, with an antibody (Ab) form that would be retained intra- or peritumorally, limiting systemic exposure. To accomplish this, we conjugated the checkpoint blockade Abs to an extracellular matrix (ECM)–super-affinity peptide derived from placenta growth factor–2 (PlGF-2123–144). We show enhanced tissue retention and lower Ab concentrations in blood plasma after PlGF-2123–144 conjugation, reducing systemic side effects such as the risk of autoimmune diabetes. Peritumoral injections of PlGF-2123–144–anti-CTLA4 (cytotoxic T lymphocyte antigen 4) and PlGF-2123–144–anti–PD-L1 (programmed death ligand 1) Abs delayed tumor growth and prolonged survival compared to the unmodified Abs in genetically engineered murine tumor models of melanoma and breast cancer. The PlGF-2123–144–Abs increased tumor-infiltrating activated CD8+ and CD4+ T cells, resulting in a delay of distant tumor growth as well. This simple and translatable approach of engineered ECM-binding Abs may present a viable and safer approach in checkpoint blockade

Improving efficacy and safety of agonistic anti-CD40 antibody through extracellular matrix affinity

CD40 is an immune costimulatory receptor expressed by antigen-presenting cells. Agonistic anti-CD40 antibodies have demonstrated considerable antitumor effects yet can also elicit serious treatment-related adverse events, such as liver toxicity, including in man. We engineered a variant that binds extracellular matrix through a super-affinity peptide derived from placenta growth factor-2 (PlGF-2123-144) to enhance anti-CD40′s effects when administered locally. Peritumoral injection of PlGF-2123-144-anti-CD40 antibody showed prolonged tissue retention at the injection site and substantially decreased systemic exposure, resulting in decreased liver toxicity. In four mouse tumor models, PlGF-2123-144-anti-CD40 antibody demonstrated enhanced antitumor efficacy compared with its unmodified form and correlated with activated dendritic cells, B cells, and T cells in the tumor and in the tumor-draining lymph node. Moreover, in a genetically engineered BrafV600E βCatSTA melanoma model that does not respond to checkpoint inhibitors, PlGF-2123-144-anti-CD40 antibody treatment enhanced T-cell infiltration into the tumors and slowed tumor growth. Together, these results demonstrate the marked therapeutic advantages of engineering matrix-binding domains onto agonistic anti-CD40 antibody as a therapeutic given by tumori-regional injection for cancer immunotherapy