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S-Adenosyl-L-methionine (SAM) is an important intracellular metabolite and widely used for treatment of various diseases. Although high level production of SAM had been achieved in yeast, novel metabolic engineering strategies are needed to further enhance SAM production for industrial applications. Here genome-scale engineering (GSE) was performed to identify new targets for SAM overproduction using the multi-functional genome-wide CRISPR (MAGIC) system, and the effects of these newly identified targets were further validated in industrial yeast strains. After 3 rounds of FACS screening and characterization, numerous novel targets for enhancing SAM production were identified. In addition, transcriptomic and metabolomic analyses were performed to investigate the molecular mechanisms for enhanced SAM accumulation. The best combination (upregulation of SNZ3, RFC4, and RPS18B) improved SAM productivity by 2.2-fold and 1.6-fold in laboratory and industrial yeast strains, respectively. Using GSE of laboratory yeast strains to guide industrial yeast strain engineering presents an effective approach to design microbial cell factories for industrial applications.Circular forms of RNA were first discovered in plant viroids and later found in a variety of animal viruses. These circular RNAs lack free 5' and 3' ends, granting protection from exonucleases. This review is focused on the methods that are used to investigate virus-encoded circular RNAs. Using DNA viruses that are prevalent among human as examples, we begin with features of circular RNAs and the unique methods to enrich for circular RNAs. Next, we discuss the computational methods for RNA-sequencing analysis to discover new virus-encoded circular RNAs. Many strategies are similar to analyzing cellular RNAs, but some unique aspects of virus-encoded circular RNAs that are likely due to highly packed viral genomes and non-canonical use of splicing machinery, are described herein. We illustrate the various methods of validating expression of specific virus-encoded circular RNAs. Finally, we discuss novel methods to study functions of circular RNAs and the current technical challenges that remain for investigating virus-encoded circular RNAs.Herein we analyze two special routes of the multinucleated cells' formation - the fusion of mononuclear cells and the formation of cell-in-cell structures - in the healthy tissues and in tumorigenesis. There are many theories of tumorigenesis based on the phenomenon of emergence of the hybrid cancer cells. We consider the phenomena, which are rarely mentioned in those theories namely, cellularization of syncytium or coenocytes, and the reversible or irreversible somatogamy. The latter includes the short-term and the long-term vegetative (somatic) cells' fusions in the life cycles of unicellular organisms. The somatogamy and multinuclearity have repeatedly and independently emerged in various groups of unicellular eukaryotes. These phenomena are among dominant survival and biodiversity sustaining strategies in protists and we admit that they can likely play an analogous role in cancer cells.Upper gastrointestinal (UGI) cancers are among the most common cancers in the world, four of them being among the top eight causes of cancer related mortality. Included among UGI cancers are oesophageal, gastric, liver, biliary, pancreatic and small intestinal cancers. Despite more than half a century of well designed epidemiological (large cohort and case-control studies) and a limited number of experimental studies into the role of nutrition on UGI cancer, there is much inconsistency in the findings. Studies have reported significant associations of various food types and UGI cancers, but there are issues with reproducibility. Over the years, numerous meta-analyses have been conducted in an attempt to harmonize available data. On the whole, it is well accepted that fruit and vegetables reduce UGI cancer risk, while processed foods increase the risk. The role of antioxidants in protecting against UGI carcinogenesis is of great interest, but controversial. There is evidence that specific diets, such the Mediterranean or Okinawa, are associated with reduced cancer risk at a population level, but it is less clear if adopting them reduces risk in otherwise high-risk locations. In this review, I will discuss some of the available literature from selected original publications, systematic reviews and meta-analyses on the influence of diet on UGI cancers. I will also provide a brief overview of future directions that have the potential to provide specific evidence on how diet could be modified to reduce the growing global burden of UGI cancers.Lipodystrophy syndromes are a group of rare diseases related to the pathological impairment of adipose tissue and metabolic comorbidities, including dyslipidemia, diabetes, insulin resistance, hypoleptinemia, and hypoadiponectinemia. They can be categorized as partial or generalized according to the degree of fat loss, and inherited or acquired disorders, if they are associated with genetic mutations or are related to autoimmunity, respectively. Some types of lipodystrophies have been associated with changes in both redox and endoplasmic reticulum (ER) homeostasis as well as muscle dysfunction (MD). Although ER stress (ERS) has been related to muscle dysfunction (MD) in many diseases, there is no data concerning its role in lipodystrophies' muscle physiopathology. Here we focused on congenital lipodystrophies associated with ERS and MD. We also described recent advances in our understanding of the relationships among ERS, MD, and genetic lipodystrophies, highlighting the adiponectin-protective roles.The liver x receptors LXRα (NR1H3) and LXRβ (NR1H2) are members of the nuclear hormone receptor superfamily of ligand dependent transcription factors that regulate transcription in response to the direct binding of cholesterol derivatives. Studies using genetic knockouts and synthetic ligands have defined the LXRs as important modulators of lipid homeostasis throughout the body. This review focuses on the control of cholesterol and fatty acid metabolism by LXRs in the liver and how modifying LXR activity can influence the pathology of liver diseases.Acute pancreatitis (AP) is one of the most common gastroenterological disorders requiring hospitalization and is associated with substantial morbidity and mortality. Metabolomics nowadays not only help us to understand cellular metabolism to a degree that was not previously obtainable, but also to reveal the importance of the metabolites in physiological control, disease onset and development. An in-depth understanding of metabolic phenotyping would be therefore crucial for accurate diagnosis, prognosis and precise treatment of AP. In this review, we summarized and addressed the metabolomics design and workflow in AP studies, as well as the results and analysis of the in-depth of research. Based on the metabolic profiling work in both clinical populations and experimental AP models, we described the metabolites with potential utility as biomarkers and the correlation between the altered metabolites and AP status. Moreover, the disturbed metabolic pathways correlated with biological function were discussed in the end. A practical understanding of current and emerging metabolomic approaches applicable to AP and use of the metabolite information presented will aid in designing robust metabolomics and biological experiments that result in identification of unique biomarkers and mechanisms, and ultimately enhanced clinical decision-making.Frontotemporal Lobar Degeneration (FTD) is a neurodegenerative disease characterized by a progressive deterioration of cognitive functions. Currently, no effective treatment exists. We have studied cytotoxicity and neuronal functionality in cortical and spinal cord cultures upon exposure to cerebrospinal fluid (CSF) from 39 FTD patients. FTD-CSF alters the miniature excitatory postsynaptic currents in the cortical cultures and it is toxic to spinal cord cultures, particularly to GABAergic+ and calbindin-D28k + neurons.Atrazine (ATZ) is the second most commonly applied agricultural herbicide in the United States. Due to contamination concerns, the U.S. EPA has set the maximum contaminant level in potable water sources at 3 parts per billion (ppb; μg/l). Depending on the time of year and sampling location, water sources often exceed this limit. ATZ is an endocrine disrupting chemical in multiple species observed to target the neuroendocrine system. In this study the zebrafish vertebrate model was used to test the hypothesis that a developmental ATZ exposure generates metabolites similar to those found in mammals and alters morphology and behavior in developing larvae. Adult AB zebrafish were bred, embryos were collected, and exposed to 0, 0.3, 3, or 30 ppb ATZ from 1 to 120 h post fertilization (hpf). Targeted metabolomic analysis found that zebrafish produce the same major ATZ metabolites as mammals desethyl atrazine (DEA), deisopropyl atrazine (DIA), and diaminochloroatrazine (DACT). The visual motor response test at 120 hpf detected hyperactivity in larvae in the 0.3 ppb treatment group and hypoactivity in the 30 ppb treatment group (p 0.05). These findings suggest that a ATZ exposure during early development generates metabolite profiles similar to mammals and leads to behavioral alterations supporting ATZ as a neurodevelopmental toxicant.We and others recently developed rapid tilt-series acquisition methods for cryo-electron tomography on a Titan Krios G3i equipped with a single axis holder and a K-series direct electron detector and showed that one of these, the fast-incremental single exposure (FISE) method, significantly accelerates tilt-series acquisition when compared to traditional methods while preserving the quality of the images. Here, we characterize the behavior of our single axis holder in detail during a FISE experiment to optimally balance data quality with speed. We explain our methodology in detail so others can characterize their own stages, and conclude with recommendations for projects with different resolution goals.

MYOC (myocilin) mutations account for 3% to 5% of primary open-angle glaucoma (POAG) cases. We aimed to understand the true population-wide penetrance and characteristics of glaucoma among individuals with the most common MYOC variant (p.Gln368Ter) and the impact of a POAG polygenic risk score (PRS) in this population.

Cross-sectional population-based study.

Individuals with the p.Gln368Ter variant among 77 959 UK Biobank participants with fundus photographs (FPs).

A genome-wide POAG PRS was computed, and 2 masked graders reviewed FPs for disc-defined glaucoma (DDG).

Penetrance of glaucoma.

Two hundred individuals carried the p.Gln368Ter heterozygous genotype, and 177 had gradable FPs. One hundred thirty-two showed no evidence of glaucoma, 45 (25.4%) had probable/definite glaucoma in at least 1 eye, and 19 (10.7%) had bilateral glaucoma. No differences were found in age, race/ethnicity, or gender among groups (P > 0.05). selleck chemicals llc Of those with DDG, 31% self-reported or had International Classification on368Ter mutation demonstrated evidence of glaucoma, a substantially higher penetrance than previously estimated, with 69% of cases undetected. A large portion of p.Gln368Ter carriers, including those with DDG, have IOP in the normal range, despite similar age. Polygenic risk score increases disease penetrance and severity, supporting the usefulness of PRS in risk stratification among MYOC p.Gln368Ter carriers.

One in 4 individuals with the MYOC p.Gln368Ter mutation demonstrated evidence of glaucoma, a substantially higher penetrance than previously estimated, with 69% of cases undetected. A large portion of p.Gln368Ter carriers, including those with DDG, have IOP in the normal range, despite similar age. Polygenic risk score increases disease penetrance and severity, supporting the usefulness of PRS in risk stratification among MYOC p.Gln368Ter carriers.