The Talin Dimer Structure Orientation Is Mechanically Regulated

Formation of a stable cell-substrate contact can be regulated by mechanical force, especially at the focal adhesion. Individual proteins that make up the focal adhesions, such as talin, can exhibit mechanosensing. We previously described one mode of talin mechanosensing in which the vinculin-binding site of talin is exposed after force-induced stretch of a single talin rod domain. Here, we describe a second mode of talin mechanosensing in which the talin dimer itself can adopt different orientations in response to mechanical stimulation. Using molecular dynamics models, we demonstrate that the C-terminus region of the talin dimer is flexible mainly at the linker between the dimerization helices and the nearby actin-binding helical bundle. Our molecular dynamics simulations reveal two possible orientations of the talin dimer at its C-terminus. The extracellular matrix (ECM)-bound integrins cross-linked by talin can be forced apart leading to an elongated orientation of the talin dimer, and the ECM-bound integrins can be forced together by the ECM producing a collapsed orientation of the talin dimer. Formation of the elongated orientation is shown to be more favorable. Switching between the two talin dimer orientations constitutes a mode of mechanosensing.     

Anti-epithelial cell adhesion molecule RNA aptamer-conjugated liposomal doxorubicin as an efficient targeted therapy in mice bearing colon carcinoma tumor model

To overcome the lack of selectivity and nonspecific biodistribution of drugs in the body, targeted delivery of chemotherapeutic agents with aptamers is a very effective method. In this strategy, aptamers could be specifically identified and attach to targeted molecules on the cancerous cells and deliver the chemotherapeutic agents to desired tissue with minimal or no damage to the normal cells. In this study, we designed anti-epithelial cell adhesion molecule (EpCAM) RNA aptamer conjugated PEGylated liposomal doxorubicin (ER-lip) to investigate its in vitro and in vivo anticancer abilities. Data showed that EpCAM aptamer was able to enhance cell uptake and cytotoxic effects of Dox in C26 cell line. The biodistribution study indicated that ER-lip enhanced the tumor accumulation of Dox compared to Caelyx. Also, double staining of isolated tumor cells with anti-CD44-PE-cy5 and anti-EpCAM Cy-7 antibodies indicated that tumor cells expressed a high level of EpCAM⁺ CD44⁺ cells (p ≤ .001) compared to cultured C26 cell line. in vivo results showed that ER-lip promoted survival and reduced tumor growth rate in animal model compared to Caelyx. In conclusion, these results suggested that the ER-lip could be served as promising formulation for the treatment of cancers with the high expression of EpCAM.     

Oleanolic acid increases the anticancer potency of doxorubicin in pancreatic cancer cells

Combination therapy is a novel cancer therapy approach that combines two or more chemotherapy drugs. This treatment modality enhances the efficacy of chemotherapy by targeting key pathways in an additive or synergistic manner. Therefore, we investigated the efficacy of combination therapy by widely used chemotherapy drug doxorubicin (DOX) and oleanolic acid (OA) to induction of apoptosis for pancreatic cancer (PC) therapy. The effects of DOX, OA, and their combination (DOX-OA) were investigated on proliferation and viability of PC cell line (PANC-1) by MTT assay. Moreover, migration and invasion of the cancer cells were evaluated by trans-well migration assay and wound healing assay. Flow cytometry and DAPI (4′,6-diamidino-2-phenylindole) staining were employed to investigate apoptosis quantification and qualification of the treated cancer cells. Finally, mRNA expression of apoptosis-related genes was assessed by quantitative real-time polymerase chain reaction. Our results demonstrated that the proliferation and metastasis potential of PC cells significantly decreased after treatment by DOX, OA, and DOX-OA. Moreover, we observed an increase in apoptosis percentage in the treated cancer cells. The apoptosis-related gene expression was modified to increase the apoptosis rate in all of the treatment groups. However, the anticancer potency of DOX-OA combination was significantly more than that of DOX and OA treatments alone. Our study suggested that DOX-OA combination exerts more profound anticancer effects against PC cell lines than DOX or OA monotherapy. This approach may increase the efficiency of chemotherapy and reduce unintended side effects by lowering the prescribed dose of DOX.     

An updated overview of the application of CAR-T cell therapy in neurological diseases

Genetically modified immune cells, especially CAR-T cells, have captured the attention of scientists over the past 10 years. In the fight against cancer, these cells have a special place. Treatment for hematological cancers, autoimmune disorders, and cancers must include CAR-T cell therapy. Determining the therapeutic targets, side effects, and use of CAR-T cells in neurological disorders, including cancer and neurodegenerative diseases, is the goal of this study. Due to advancements in genetic engineering, CAR-T cells have become crucial in treating some neurological disorders. CAR-T cells have demonstrated a positive role in treating neurological cancers like Glioblastoma and Neuroblastoma due to their ability to cross the blood–brain barrier and use diverse targets. However, CAR-T cell therapy for MS diseases is being researched and could be a potential treatment option. This study aimed to access the most recent studies and scientific articles in the field of CAR-T cells in neurological diseases and/or disorders.     

Vitamins E and D3 Attenuate Demyelination and Potentiate Remyelination Processes of Hippocampal Formation of Rats Following Local Injection of Ethidium Bromide

Cognitive deficits have been observed in patients with multiple sclerosis (MS) due to hippocampal insults. Antioxidant vitamins D and E are suggested for patients suffering from neurodegenerative diseases like MS, while their mechanisms of action are not well understood. Here, we have tried to study the effects of these vitamins on demyelination, cell death, and remyelination of rat hippocampus following local ethidium bromide (EB) injection. Animals received 100 mg/kg vitamin E or 5 μg/kg of vitamin D3 for 2, 7, or 28 days. The extent of demyelination, myelin staining intensity, and expression of myelin basic protein and caspase-3 were investigated using histological and immunoblotting verification. Administration of EB alone caused demyelination, cell death, and afterward an endogenous repair. Vitamins E and D3 reduced the EB-induced damage and increased the endogenous remyelination of hippocampus. Although the anti-apoptotic effect of these vitamins and protection against demyelination were predictable based on their antioxidant effect, our results indicated the positive effect of vitamins E and D3 on process of remyelination by endogenous progenitor cells and supported their possible therapeutic effects in the context of demyelinating diseases like MS.     

First record of Aphelinus paramali Zehavi and Rosen 1989 (Hymenoptera,Aphelinidae), parasitoid of Aphis pomi de Geer (Hemiptera,Aphididae) in Iran,and its phylogenetic position based on sequence data of ITS2 and COI genes

The occurrence of Aphelinus paramali (Zehavi & Rosen) (Hym., Aphelinidae) was evidenced from North east Iran, in association with Aphis pomi (de Geer). This species is reported from Iran for the first time, and A. pomi is introduced as a new host for this parasitoid. Detailed morphological characters were studied with scanning electron microscopy (SEM) photographs. Also, sequences of ribosomal internal transcribed spacer 2 (ITS2) and cytochrome oxidase subunit I (COI) genes were used for determining species boundaries and comparing with other Aphelinus species. Different results were obtained in phylogenetic analysis of these two regions. Analysis of COI gene supported the closer relationship of this species with Aphelinus abdominalis. This is the first data about comprehensive characterization of a parasitic wasp using morphological characters, SEM and two‐locus information from Iran.     

The Heliotropium marifolium complex in India and five new combinations in Euploca (Heliotropiaceae) from H. sect. Orthostachys (Boraginaceae s.l.)

This paper includes studies on Heliotropium marifolium complex from India. Five new combinations in Euploca from H. sect. Orthostachys are proposed here. H. marifolium, H. marifolium subsp. wallichii, H. rottleri, H. cornutum and H. madurense are transferred to the genus Euploca. The taxonomic status of the unresolved name H. rottleri is also discussed.     

Large-scale microstructural simulation of load-adaptive bone remodeling in whole human vertebrae

Identification of individuals at risk of bone fractures remains challenging despite recent advances in bone strength assessment. In particular, the future degradation of the microstructure and load adaptation has been disregarded. Bone remodeling simulations have so far been restricted to small-volume samples. Here, we present a large-scale framework for predicting microstructural adaptation in whole human vertebrae. The load-adaptive bone remodeling simulations include estimations of appropriate bone loading of three load cases as boundary conditions with microfinite element analysis. Homeostatic adaptation of whole human vertebrae over a simulated period of 10 years is achieved with changes in bone volume fraction (BV/TV) of less than 5 %. Evaluation on subvolumes shows that simplifying boundary conditions reduces the ability of the system to maintain trabecular structures when keeping remodeling parameters unchanged. By rotating the loading direction, adaptation toward new loading conditions could be induced. This framework shows the possibility of using large-scale bone remodeling simulations toward a more accurate prediction of microstructural changes in whole human bones.