High-fat, low-carbohydrate diets, known as ketogenic diets, have been used as a non-pharmacological treatment for refractory epilepsy. A key mechanism of this treatment is thought to be the ...generation of ketones, which provide brain cells (neurons and astrocytes) with an energy source that is more efficient than glucose, resulting in beneficial downstream metabolic changes, such as increasing adenosine levels, which might have effects on seizure control. However, some studies have challenged the central role of ketones because medium-chain fatty acids, which are part of a commonly used variation of the diet (the medium-chain triglyceride ketogenic diet), have been shown to directly inhibit AMPA receptors (glutamate receptors), and to change cell energetics through mitochondrial biogenesis. Through these mechanisms, medium-chain fatty acids rather than ketones are likely to block seizure onset and raise seizure threshold. The mechanisms underlying the ketogenic diet might also have roles in other disorders, such as preventing neurodegeneration in Alzheimer's disease, the proliferation and spread of cancer, and insulin resistance in type 2 diabetes. Analysing medium-chain fatty acids in future ketogenic diet studies will provide further insights into their importance in modified forms of the diet. Moreover, the results of these studies could facilitate the development of new pharmacological and dietary therapies for epilepsy and other disorders.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
The five-year survival rate of epithelial ovarian cancer (EOC) is approximately 35-40% despite maximal treatment efforts, highlighting a need for stratification biomarkers for personalized treatment. ...Here we extract 657 quantitative mathematical descriptors from the preoperative CT images of 364 EOC patients at their initial presentation. Using machine learning, we derive a non-invasive summary-statistic of the primary ovarian tumor based on 4 descriptors, which we name "Radiomic Prognostic Vector" (RPV). RPV reliably identifies the 5% of patients with median overall survival less than 2 years, significantly improves established prognostic methods, and is validated in two independent, multi-center cohorts. Furthermore, genetic, transcriptomic and proteomic analysis from two independent datasets elucidate that stromal phenotype and DNA damage response pathways are activated in RPV-stratified tumors. RPV and its associated analysis platform could be exploited to guide personalized therapy of EOC and is potentially transferrable to other cancer types.
The Gram-negative bacterial envelope is the first line of defence against environmental stress and antibiotics. Therefore, its biogenesis is of considerable fundamental interest, as well as a ...challenge to address the growing problem of antimicrobial resistance. All bacterial proteins are synthesised in the cytosol, so inner- and outer-membrane proteins, and periplasmic residents have to be transported to their final destinations via specialised protein machinery. The Sec translocon, a ubiquitous integral inner-membrane (IM) complex, is key to this process as the major gateway for protein transit from the cytosol to the cell envelope; this can be achieved during their translation, or afterwards. Proteins need to be directed into the inner-membrane (usually co-translational), otherwise SecA utilises ATP and the proton-motive-force (PMF) to drive proteins across the membrane post-translationally. These proteins are then picked up by chaperones for folding in the periplasm, or delivered to the β-barrel assembly machinery (BAM) for incorporation into the outer-membrane. The core hetero-trimeric SecYEG-complex forms the hub for an extensive network of interactions that regulate protein delivery and quality control. Here, we conduct a biochemical exploration of this 'secretosome' -a very large, versatile and inter-changeable assembly with the Sec-translocon at its core; featuring interactions that facilitate secretion (SecDF), inner- and outer-membrane protein insertion (respectively, YidC and BAM), protein folding and quality control (e.g. PpiD, YfgM and FtsH). We propose the dynamic interplay amongst these, and other factors, act to ensure efficient envelope biogenesis, regulated to accommodate the requirements of cell elongation and division. We believe this organisation is critical for cell wall biogenesis and remodelling and thus its perturbation could be a means for the development of anti-microbials.
Accurate chromosomal DNA replication is essential to maintain genomic stability. Genetic evidence suggests that certain repetitive sequences impair replication, yet the underlying mechanism is poorly ...defined. Replication could be directly inhibited by the DNA template or indirectly, for example by DNA-bound proteins. Here, we reconstitute replication of mono-, di- and trinucleotide repeats in vitro using eukaryotic replisomes assembled from purified proteins. We find that structure-prone repeats are sufficient to impair replication. Whilst template unwinding is unaffected, leading strand synthesis is inhibited, leading to fork uncoupling. Synthesis through hairpin-forming repeats is rescued by replisome-intrinsic mechanisms, whereas synthesis of quadruplex-forming repeats requires an extrinsic accessory helicase. DNA-induced fork stalling is mechanistically similar to that induced by leading strand DNA lesions, highlighting structure-prone repeats as an important potential source of replication stress. Thus, we propose that our understanding of the cellular response to replication stress may also be applied to DNA-induced replication stalling.
Reading the same storybooks repeatedly helps preschool children learn words. In addition, sleeping shortly after learning also facilitates memory consolidation and aids learning in older children and ...adults. The current study explored how sleep promotes word learning in preschool children using a shared storybook reading task. Children were either read the same story repeatedly or different stories and either napped after the stories or remained awake. Children's word retention were tested 2.5 h later, 24 h later, and 7 days later. Results demonstrate strong, persistent effects for both repeated readings and sleep consolidation on young children's word learning. A key finding is that children who read different stories before napping learned words as well as children who had the advantage of hearing the same story. In contrast, children who read different stories and remained awake never caught up to their peers on later word learning tests. Implications for educational practices are discussed.
Williams shares her first field journal. She documents her first study as principal investigator, and all thoughts and impressions that accompanied it. During a group fieldwork trip to the Belize ...Barrier Reef orchestrated by her future graduate advisor, she took part in a short study examining the territorial, aggressive behaviors of Dusky damselfish (Segastes adustus) to determine whether or not the number of their aggressive displays would vary with the time of day. Though accustomed to the sterile vials and protocols of a plant genetics lab, she planned out her field study as well as she could, determined to learn something outside her comfort zone.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Both ecological and anthropogenic changes constantly shape the form, function, and longevity of tropical marine ecosystems. With emerging technologies in remote sensing and Geographic Information ...Systems (GIS) analysis, these changes can be accurately and efficiently monitored to provide actionable information to help shape the future of marine protected areas (MPAs). The South Water Caye Marine Reserve (SWCMR), an MPA in southern Belize, contains the largest unbroken stretch of the Belize Barrier Reef as well as many small mangrove islands, patch reefs, and seagrass beds that sustain myriad threatened and economically important fisheries. While this is an important marine reserve, no study has documented change within it. This study fills this knowledge gap by applying land use and land cover (LULC) change analysis methods to 3- and 5-m resolution satellite images from Planet taken in 2010 and 2019 to measure changes in open water, seagrass, terrestrial vegetation, and developed and barren land cover within the SWCMR. The results of this study have an accuracy of at least 80%. They reveal decreases in seagrass cover and increases in the developed and barren areas in and around the SWCMR. While greater amounts of change are found outside the marine reserve boundaries, within the SWCMR, the total area of developed and barren land cover increased by 203.77% and 70.97%, respectively, from 2010 to 2019. Documenting these changes in the SWCMR establishes the reserve as a model for understanding the tropical marine environments throughout Belize and provides valuable data for management decision-making.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Perforin-2 (MPEG1) is thought to enable the killing of invading microbes engulfed by macrophages and other phagocytes, forming pores in their membranes. Loss of perforin-2 renders individual ...phagocytes and whole organisms significantly more susceptible to bacterial pathogens. Here, we reveal the mechanism of perforin-2 activation and activity using atomic structures of pre-pore and pore assemblies, high-speed atomic force microscopy, and functional assays. Perforin-2 forms a pre-pore assembly in which its pore-forming domain points in the opposite direction to its membrane-targeting domain. Acidification then triggers pore formation, via a 180° conformational change. This novel and unexpected mechanism prevents premature bactericidal attack and may have played a key role in the evolution of all perforin family proteins.
Repeat and structure-prone DNA sequences comprise a large proportion of the human genome. The instability of these sequences has been implicated in a range of diseases, including cancers and ...neurodegenerative disorders. However, the mechanism of pathogenicity is poorly understood. As such, further studies on repetitive DNA are required. Cloning and maintaining repeat-containing substrates is challenging due to their inherent ability to form non-B DNA secondary structures which are refractory to DNA polymerases and prone to undergo rearrangements. Here, we describe an approach to clone and expand tandem-repeat DNA without interruptions, thereby allowing for its manipulation and subsequent investigation.
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