Screening of Bacillus velezensis E2 and the Inhibitory Effect of Its Antifungal Substances on Aspergillus flavus

Aspergilus flavus is the main pathogenic fungus that causes food mold. Effective control of A. flavus contamination is essential to ensure food safety. The lipopeptides (LPs) produced by Bacillus strains have been shown to have an obvious antifungal effect on molds. In this study, an antagonist strain of Bacillus velezensis with obvious antifungal activity against A. flavus was isolated from the surface of healthy rice. Using HPLC-MS analysis, the main components of LPs produced by strain E2 were identified as fengycin and iturins. Further investigations showed that LPs could inhibit the spore germination, and even cause abnormal expansion of hyphae and cell rupture. Transcriptomic analyses showed that some genes, involved in ribosome biogenesis in eukaryotes (NOG1, KRE33) and aflatoxin biosynthesis (aflK, aflR, veA, omtA) pathways in A. flavus were significantly down-regulated by LPs. In conclusion, this study provides novel insights into the cellular and molecular antifungal mechanisms of LPs against grain A. flavus contamination.

Huntingtin Ubiquitination Mechanisms and Novel Possible Therapies to Decrease the Toxic Effects of Mutated Huntingtin

Huntington Disease (HD) is a dominant, lethal neurodegenerative disorder caused by the abnormal expansion (>35 copies) of a CAG triplet located in exon 1 of the HTT gene encoding the huntingtin protein (Htt). Mutated Htt (mHtt) easily aggregates, thereby inducing ER stress that in turn leads to neuronal injury and apoptosis. Therefore, both the inhibition of mHtt aggregate formation and the acceleration of mHtt degradation represent attractive strategies to delay HD progression, and even for HD treatment. Here, we describe the mechanism underlying mHtt degradation by the ubiquitin–proteasome system (UPS), which has been shown to play a more important role than the autophagy–lysosomal pathway. In particular, we focus on E3 ligase proteins involved in the UPS and detail their structure–function relationships. In this framework, we discuss the possible exploitation of PROteolysis TArgeting Chimeras (PROTACs) for HD therapy. PROTACs are heterobifunctional small molecules that comprise two different ligands joined by an appropriate linker; one of the ligands is specific for a selected E3 ubiquitin ligase, the other ligand is able to recruit a target protein of interest, in this case mHtt. As a consequence of PROTAC binding, mHtt and the E3 ubiquitin ligase can be brought to a relative position that allows mHtt to be ubiquitinated and, ultimately, allows a reduction in the amount of mHtt in the cell.

The stress granule protein G3BP1 reduces the levels of different polyglutamine proteins and alleviates spinocerebellar ataxia associated deficits

Polyglutamine (polyQ) diseases are a group of 9 rare neurodegenerative disorders caused by an abnormal expansion of the CAG trinucleotide in the codifying regions of the respective disease-associated gene. The trinucleotide abnormal expansion leads to the translation of a protein containing an overexpanded tract of glutamines. PolyQ mutant proteins undergo a gain of toxic function disrupting normal cellular pathways leading to neuronal death and, consequently, leading to selective neurodegeneration of specific brain regions. Spinocerebellar ataxia (SCA) 2 and SCA3 (also known as Machado-Joseph disease) are two different polyQ diseases in which the ataxin-2 and ataxin-3 proteins, respectively, bear abnormally long polyQ tracts. Until now, there is no treatment for these fatal diseases or therapies that could delay the normal pathologic progression. Stress granules (SGs) are important structures formed in response to cellular stress, having an important role in mRNA triage. A core component of SGs is the RNA-binding protein (RBP) Ras GTPase-activating protein-binding protein 1 (G3BP1), which is also implicated in the SGs assembly. Furthermore, G3BP1 is known to have endoribonuclease activity and an important role in modulating RNA metabolism. In this study, we showed that G3BP1 is decreased in context of SCA2 and SCA3 disease. For that, we assessed whether restoring the expression levels of G3BP1 might positively impact the SCA2 and SCA3 pathology. We showed that gene delivery of G3BP1 in two distinct lentiviral mouse model of SCA2 and SCA3 was able to i) reduce the number of aggregates and ii) reduce the loss of neuronal marker associated with the mutant toxic proteins. Importantly, in a polyQ transgenic mouse model, lentiviral delivery of G3BP1 in the cerebellum was able to i) preserve the number of Purkinje cells, ii) reduce the number of HA-ataxin-3 and, importantly iii) improve the motor performance, balance and coordination. Additionally, we identify the nuclear transport nuclear transport factor 2-like (NTF2-like) domain and the ser149 phosphorylation site of G3BP1 as a key players in the reduction of mutant ataxin-2 and ataxin-3 levels and aggregation. Altogether these results showed that gene delivery of G3BP1 is able of mitigating the disease-associated phenotype in SCA2 and SCA3 disease, in three different disease mouse models. Therefore, this study suggests G3BP1 as a novel therapeutic target for SCA2 and SCA3 diseases.

Molecular Modulators of Adipogenesis as Treatment Options for Obesity

As a risk factor, obesity is a threat to human well-being and related metabolic disorders such as diabetes mellitus and dyslipidemia. adipogenesis is defined as the proliferation and maturation of adipocyte predecessor cells to adipocyte. As the adipogenesis process decides adipocyte production, it may be considered a therapeutic target for obesity and obesity-related disorders. White adipose tissue abnormal expansion increases the size and number of adipocytes. For that reason, this review aims to spot the molecular mechanisms implicated in adipogenesis that lead to application in the therapeutic targets. Keywords: adipogenesis, signaling pathways, anti-obesity treatment, obesity

Local Hemodynamic Changes Immediately after Correction of an Aberrant Right Subclavian Artery in a Dog: A Contrast Computed Tomographic Study

A 1-year-old female Akita dog was referred for intermittent regurgitation. Computed tomographic angiography (CTA) showed an aberrant right subclavian artery (ARSA), resulting in constriction of the esophagus. After surgical ligation of the ARSA, CTA showed that the ARSA was not enhanced by contrast medium, and that sufficient collateral circulation of the right forelimb was supplied through the vertebral artery. Furthermore, the right and left vertebral arteries merged into the basilar artery at the level of the atlas, and no abnormal expansion of the ventral spinal artery was observed. Overall, we demonstrated the importance of post-surgical CTA for identification of surgical complications, including the formation of abnormal vessel alterations.

A Study on the Supersonic Jet Nozzle to Improve of the Operating Efficiency of the Converter Process

Recently, various worldwide studies have been conducted to improve converter operation by modifying the lance nozzle. In this study, a numerical analysis of the lance nozzle was conducted to improve the dephosphorization efficiency, and to reduce blowing time. The lance nozzle was designed in the form of an abnormal expansion type nozzle capable of increasing the oxygen supply rate. ANSYS FLUENT, a commercial flow analysis program, was used to verify the flow characteristics of the supersonic jet. The nozzle shape was designed according to the ratio of exit diameter to throat diameter, and an analysis was carried out based on the change in inlet flow rate, to confirm the influence of the oxygen supply flow rate. The velocity of the oxygen jet was the fastest for the normal expansion type nozzle and decreased with the abnormal expansion type nozzle. In addition, the oxygen jet velocity tended to increase with the oxygen flow rate.

Structural insights into synthetic ligands targeting A–A pairs in disease-related CAG RNA repeats

The trinucleotide repeat expansion disorders (TREDs) constitute of a group of >40 hereditary neurodegenerative human diseases associated with abnormal expansion of repeated sequences, such as CAG repeats. The pathogenic factor is a transcribed RNA or protein whose function in the cell is compromised. The disorders are progressive and incurable. Consequently, many ongoing studies are oriented at developing therapies. We have analyzed crystal structures of RNA containing CAG repeats in complex with synthetic cyclic mismatch-binding ligands (CMBLs). The models show well-defined interactions between the molecules in which the CMBLs mimic nucleobases as they form pseudo-canonical base pairs with adenosine residues and engage in extensive stacking interactions with neighboring nucleotides. The binding of ligands is associated with major structural changes of the CAG repeats, which is consistent with results of biochemical studies. The results constitute an early characterization of the first lead compounds in the search for therapy against TREDs. The crystallographic data indicate how the compounds could be further refined in future biomedical studies.