Sleeping Beauty mRNA-LNP enables stable rAAV transgene expression in mouse and NHP hepatocytes and improves vector potency.

Recombinant adeno-associated virus (rAAV) vector gene delivery systems have demonstrated great promise in clinical trials but continue to face durability and dose-related challenges. Unlike rAAV gene therapy, integrating gene addition approaches can provide curative expression in mitotically active cells and pediatric populations. We explored a novel in vivo delivery approach based on an engineered transposase, Sleeping Beauty (SB100X), delivered as an mRNA within a lipid nanoparticle (LNP), in combination with an rAAV-delivered transposable transgene.

Fingolimod exerts neuroprotection by regulating S1PR1 mediated BNIP3-PINK1-Parkin dependent mitophagy in rotenone induced mouse model of Parkinson's disease.

The motor impairments brought on by the loss of dopaminergic neurons in the substantia nigra are the most well-known symptoms of Parkinson's disease (PD). It is believed that dopaminergic neurons are especially vulnerable to mitochondrial malfunction. For the maintenance of mitochondrial integrity, selective autophagic removal of dysfunctional mitochondria via mitophagy primarily regulated by PINK1/Parkin pathway is essential.

Role of F-actin-mediated endocytosis and exercise in mitochondrial transplantation in an experimental Parkinson's disease mouse model.

Dopaminergic neurons gradually deteriorate in Parkinson's Disease (PD), which is characterized by the intracellular accumulation of Lewy bodies that are enriched with α-synuclein protein. Mitochondrial dysfunction is one of the primary contributors to this and is considered as the central player in the pathogenesis of PD. Recently, improving mitochondrial function has been extensively explored as a therapeutic strategy in various preclinical PD models.

Inter and intracellular mitochondrial transfer: Future of mitochondrial transplant therapy in Parkinson's disease.

Parkinson's disease (PD) is marked by the gradual degeneration of dopaminergic neurons and the intracellular build-up of Lewy bodies rich in α-synuclein protein. This impairs various aspects of the mitochondria including the generation of ROS, biogenesis, dynamics, mitophagy etc. Mitochondrial dynamics are regulated through the inter and intracellular movement which impairs mitochondrial trafficking within and between cells.

Endodontic Management of Mandibular anterior teeth and premolars with Vertucci's Type VIII canal morphology: A Rare Case.

A thorough knowledge of variable and complex tooth morphology, detailed exploration of the internal anatomy and underlying pathology, proper interpretation of radiographic images, conservative access to explore all the canals, thorough debridement and disinfection of canal system, three-dimensional seal by obturation, and good coronal seal by final restoration are essential steps in the management for a successful endodontic treatment outcome. Clinical management of rare case with extra canals in the lower anterior teeth and premolars had to undergo root canal therapy has been described. Referring to the hard-tissue repository of the human dental internal morphology, carefully interpreting multiangled radiography/cone-beam computed tomography, using tools such as magnifying loupes with illumination and ultrasonics, thermoplasticized gutta-percha system to obturate, are very helpful to the clinician can achieve this goal.

Demonstration of a low-power, local-oscillator-less, and DSP-free coherent receiver for data center interconnects.

Performance limitations of currently employed four-level pulse amplitude modulation links and high power consumption of digital signal processing (DSP)-based coherent links for further increase in capacity create an urgent demand for low-power coherent solutions for short-reach data center interconnects. We propose a low-power coherent receiver with analog domain processing for a self-homodyne link. To validate the proposed scheme, a 10 GBd polarization multiplexed carrier-based self-homodyne quadrature phase-shift keying system with a constant modulus algorithm-based equalizer chip is experimentally demonstrated.

Establishing a novel biosynthetic pathway for the production of 3,4-dihydroxybutyric acid from xylose in Escherichia coli.

3-Hydroxy-γ-butyrolactone (3HBL) is an attractive building block owing to its broad applications in pharmaceutical industry. Currently, 3HBL is commercially produced by chemical routes using petro-derived carbohydrates, which involves hazardous materials and harsh processing conditions. Only one biosynthetic pathway has been reported for synthesis of 3HBL and its hydrolyzed form 3,4-dihydroxybutyric acid (3,4-DHBA) using glucose and glycolic acid as the substrates and coenzyme A as the activator, which involves multiple steps (>10 steps) and suffers from low productivity and yield.

Rational engineering of diol dehydratase enables 1,4-butanediol biosynthesis from xylose.

Establishing novel synthetic routes for microbial production of chemicals often requires overcoming pathway bottlenecks by tailoring enzymes to enhance bio-catalysis or even achieve non-native catalysis. Diol dehydratases have been extensively studied for their interactions with C2 and C3 diols. However, attempts on utilizing these insights to enable catalysis on non-native substrates with more than two hydroxyl groups have been plagued with low efficiencies.

Establishing a synergetic carbon utilization mechanism for non-catabolic use of glucose in microbial synthesis of trehalose.

In nature glucose is a common carbon and energy source for catabolic use and also a building unit of polysaccharides and glycosylated compounds. The presence of strong glucose catabolic pathways in microorganism rapidly decomposes glucose into smaller metabolites and challenges non-catabolic utilization of glucose as C6 building unit or precursor. To address this dilemma, we design a synergetic carbon utilization mechanism (SynCar), in which glucose catabolism is inactivated and a second carbon source (e.

Engineering the Autotroph Methanococcus maripaludis for Geraniol Production.

The rapid autotrophic growth of the methanogenic archaeon Methanococcus maripaludis on H2 and CO2 makes it an attractive microbial chassis to inexpensively produce biochemicals. To explore this potential, a synthetic gene encoding geraniol synthase (GES) derived from Ocimum basilicum was cloned into a M. maripaludis expression vector under selection for puromycin resistance.

Aerobic biosynthesis of hydrocinnamic acids in Escherichia coli with a strictly oxygen-sensitive enoate reductase.

3-Phenylpropionic acid (3PPA) and 3-(4-hydroxyphenyl) propionic acid (HPPA) are important commodity aromatic acids widely used in food, pharmaceutical and chemical industries. Currently, 3PPA and HPPA are mainly manufactured through chemical synthesis, which contains multiple steps involving toxic solvents and catalysts harmful to environment. Therefore, replacement of such existing petroleum-derived approaches with simple and environmentally friendly biological processes is highly desirable for manufacture of these chemicals.

Resurrecting an unsalvageable lower incisor with a mono-block approach.

Contemporary techniques, as well as the availability of bioactive and adhesive materials in endodontics, have helped revivifying teeth that were deemed hopeless. These newer materials and techniques would enable the clinician: (a) to predictably stop microbial activity (b) to achieve a total corono-apical fluid tight seal and (c) to strengthen mutilated teeth by obtaining intra-radicular reinforcement through mono-block effect. This case report demonstrates the successful treatment of a mutilated anterior tooth with the use of bioactive and adhesive materials to obtain a total seal and mono-block effect.

Enhanced photo-bioelectrochemical energy conversion by genetically engineered cyanobacteria.

Photosynthetic energy conversion using natural systems is increasingly being investigated in the recent years. Photosynthetic microorganisms, such as cyanobacteria, exhibit light-dependent electrogenic characteristics in photo-bioelectrochemical cells (PBEC) that generate substantial photocurrents, yet the current densities are lower than their photovoltaic counterparts. Recently, we demonstrated that a cyanobacterium named Nostoc sp.

Engineering microaerobic metabolism of E. coli for 1,2-propanediol production.

Establishment of novel metabolic pathways for biosynthesis of chemicals, fuels and pharmaceuticals has been demonstrated in Escherichia coli due to its ease of genetic manipulation and adaptability to varying oxygen levels. E. coli growing under microaerobic condition is known to exhibit features of both aerobic and anaerobic metabolism.

Synthesis of chemicals by metabolic engineering of microbes.

Metabolic engineering is a powerful tool for the sustainable production of chemicals. Over the years, the exploration of microbial, animal and plant metabolism has generated a wealth of valuable genetic information. The prudent application of this knowledge on cellular metabolism and biochemistry has enabled the construction of novel metabolic pathways that do not exist in nature or enhance existing ones.

Systematically engineering Escherichia coli for enhanced production of 1,2-propanediol and 1-propanol.

The biological production of high value commodity 1,2-propanediol has been established by engineering the glycolysis pathway. However, the simultaneous achievement of high titer and high yield has not been reported yet, as all efforts in increasing the titer have resulted in low yields. In this work, we overcome this limitation by employing an optimal minimal set of enzymes, channeling the carbon flux into the 1,2-propanediol pathway, increasing NADH availability, and improving the anaerobic growth of the engineered Escherichia coli strain by developing a cell adaptation method.

Microbial production of antioxidant food ingredients via metabolic engineering.

Antioxidants are biological molecules with the ability to protect vital metabolites from harmful oxidation. Due to this fascinating role, their beneficial effects on human health are of paramount importance. Traditional approaches using solvent-based extraction from food/non-food sources and chemical synthesis are often expensive, exhaustive, and detrimental to the environment.

Retrieval of a metallic obstruction from the root canal of a premolar using Masserann technique.

A metallic obstruction in the root canal blocks canal cleaning and shaping procedures and requires either bypassing or retrieval. Many methods have been recommended to retrieve a metallic obstruction from the root canal. This article describes the retrieval of a metallic obstruction from the root canal of a premolar using Masserann technique to facilitate endodontic retreatment.

3D molecular descriptors important for clinical success.

The pharmacokinetic and safety profiles of clinical drug candidates are greatly influenced by their requisite physicochemical properties. In particular, it has been shown that 2D molecular descriptors such as fraction of Sp3 carbon atoms (Fsp3) and number of stereo centers correlate with clinical success. Using the proteomic off-target hit rate of nicotinic ligands, we found that shape-based 3D descriptors such as the radius of gyration and shadow indices discriminate off-target promiscuity better than do Fsp3 and the number of stereo centers.

Inhibition of acetate accumulation leads to enhanced production of (R,R)-2,3-butanediol from glycerol in Escherichia coli.

This work describes the production of (R,R)-2,3-butanediol in Escherichia coli using glycerol by metabolic engineering approaches. The introduction of a synthetic pathway converting pyruvate to (R,R)-2,3-butanediol into wild-type E. coli strain BW25113 led to the production of (R,R)-2,3-butanediol at a titer of 3.

Dehydratase mediated 1-propanol production in metabolically engineered Escherichia coli.

Background: With the increasing consumption of fossil fuels, the question of meeting the global energy demand is of great importance in the near future. As an effective solution, production of higher alcohols from renewable sources by microorganisms has been proposed to address both energy crisis and environmental concerns. Higher alcohols contain more than two carbon atoms and have better physiochemical properties than ethanol as fuel substitutes.