Traumatic brain injury (TBI) is a prominent risk factor for dementias including tauopathies like chronic traumatic encephalopathy (CTE). The mechanisms that promote prion-like spreading of Tau aggregates after TBI are not fully understood, in part due to lack of tractable animal models. Here, we test the putative role of seizures in promoting the spread of tauopathy. We introduce ‘tauopathy reporter’ zebrafish expressing a genetically encoded fluorescent Tau biosensor that reliably reports accumulation of human Tau species when seeded via intraventricular brain injections. Subjecting zebrafish larvae to a novel TBI paradigm produced various TBI features including cell death, post–traumatic seizures, and Tau inclusions. Bath application of dynamin inhibitors or anticonvulsant drugs rescued TBI-induced tauopathy and cell death. These data suggest a role for seizure activity in the prion-like seeding and spreading of tauopathy following TBI. Further work is warranted regarding anti-convulsants that dampen post-traumatic seizures as a route to moderating subsequent tauopathy.

Cancer is one of the leading diseases, causing deaths worldwide. Nearly 10 million deaths were reported in 2020 due to cancer alone. Several factors are involved in cancer progressions, such as lifestyle and genetic characteristics. According to a recent report, extracellular vesicles (EVs) are involved in cancer initiation, progression, and therapy failure. EVs can play a major role in intracellular communication, the maintenance of tissue homeostasis, and pathogenesis in several types of diseases. In a healthy person, EVs carry different cargoes, such as miRNA, lncRNA etc., to help other body functions. On the other hand, the same EV in a tumor microenvironment carries cargoes such as miRNA, lncRNA, etc., to initiate or help cancer progression at various stages. These stages may include the proliferation of cells and escape from apoptosis, angiogenesis, cell invasion, and metastasis, reprogramming energy metabolism, evasion of the immune response, and transfer of mutations. Tumor-derived EVs manipulate by altering normal functions of the body and affect the epigenetics of normal cells by limiting the genetic makeup through transferring mutations, histone modifications, etc. Tumor-derived EVs also pose therapy resistance through transferring drug efflux pumps and posing multiple drug resistances. Such EVs can also help as biomarkers for different cancer types and stages, which ultimately help with cancer diagnosis at early stages. In this review, we will shed light on EVs’ role in performing normal functions of the body and their position in different hallmarks of cancer, in altering the genetics of a normal cell in a tumor microenvironment, and their role in therapy resistance, as well as the importance of EVs as diagnostic tools.

Highlights:• Introduces first Traumatic Brain Injury (TBI) model in larval zebrafish, and its easy • TBI induces clinically relevant cell death, haemorrhage & post-traumatic seizures • Ca 2+ imaging during TBI reveals spike in brain activity concomitant with seizures • Tau-GFP Biosensor allows repeated in vivo measures of prion-like tau aggregation • post-TBI, anticonvulsants stop tauopathies akin to Chronic Traumatic Encephalopathy 3 Summary:Traumatic brain injury (TBI) is a prominent risk factor for neurodegenerative diseases 1 and dementias including chronic traumatic encephalopathy (CTE). TBI and CTE, like all 2 tauopathies, are characterized by accumulation of Tau into aggregates that 3 progressively spread to other brain regions in a prion-like manner. The mechanisms that 4 promote spreading and cellular uptake of tau seeds after TBI are not fully understood, in 5 part due to lack of tractable animal models. Here, we test the putative roles for excess 6 neuronal activity and dynamin-dependent endocytosis in promoting the in vivo spread of 7 tauopathy. We introduce 'tauopathy reporter' zebrafish expressing a genetically-8 encoded fluorescent Tau biosensor that reliably reports accumulation of human tau 9 species when seeded via intra-ventricular brain injections. Subjecting zebrafish larvae to 10 a novel TBI paradigm produced various TBI symptoms including cell death, 11hemorrhage, blood flow abnormalities, post-traumatic seizures, and Tau inclusions. 12Bath application of anticonvulsant drugs rescued TBI-induced tauopathy and cell death; 13 these benefits were attributable to inhibition of post-traumatic seizures because co-14 application of convulsants reversed these beneficial effects. However, one convulsant 15 drug, 4-Aminopyridine, unexpectedly abrogated TBI-induced tauopathy -this was due to 16 its inhibitory action on endocytosis as confirmed via additional dynamin inhibitors. These 17 data suggest a role for seizure activity and dynamin-dependent endocytosis in the prion-18 like seeding and spreading of tauopathy following TBI. Further work is warranted 19 regarding anti-convulsants that dampen post-traumatic seizures as a route to 20 moderating subsequent tauopathy. Moreover, the data highlight the utility of deploying 21 in vivo Tau biosensor and TBI methods in larval zebrafish, especially regarding drug 22 screening and intervention. 23 24 4 Introduction:

Actinobacteria obtained from the least explored Indian regions were studied for their ability to suppress meningitis-causing bacteria in nanoparticle form. Drug-resistant bacteria and long-term treatment with different medications make meningitis control complicated. Thus, new meningitis drugs are required to combat MDR bacteria. In this study, secondary metabolites isolated from actinomycetes strains, Microbacterium proteolyticum LA2(R) and Streptomyces rochei LA2(O), were employed to synthesize silver nanoparticles (AgNPs) at 37 °C for seven days incubation. UV–Vis spectroscopy, TEM, FTIR, and HPLC studies were used for the confirmation of the synthesis of AgNPs. Furthermore, these NPs demonstrated antibacterial and antibiofilm activities against meningitis-causing bacteria. The average size of LA2(R) and LA2(O) isolated secondary metabolites mediated AgNPs was observed to be 27 ± 1and 29 ± 2 nm by TEM analysis. FTIR study of RAgNPs and OAgNPs revealed that presence of peaks with positions of 1637.17 cm1 and 1636.10 cm1 for C=O amide group appearances in the amide I linkage. These NPs were effective against bacterial pathogens such as S. pneumoniae, H. influenzae, and N. meningitidis and confirmed by their MICs, i.e., 109.4, 120.60, and 138.80 μg/ml of RAgNPs and 105.80, 114.40 and 129.06 μg/ml of OAgNPs, respectively. Additionally, the production of biofilms is impeded by these nanoparticles on S. pneumoniae, H. influenzae, and N. meningitidis by 73.14%, 71.89% and 64.81%, respectively. These findings confirm the potential role of synthesized AgNPs against biofilm forming meningitis causing Multidrug resistance (MDR) microbes.