Endogenous cross-talk of fungal metabolites

Non-ribosomal peptide (NRP) synthesis in fungi requires a ready supply of proteogenic and non-proteogenic amino acids which are subsequently incorporated into the nascent NRP via a thiotemplate mechanism catalyzed by NRP synthetases. Substrate amino acids can be modified prior to or during incorporation into the NRP, or following incorporation into an early stage amino acid-containing biosynthetic intermediate. These post-incorporation modifications involve a range of additional enzymatic activities including but not exclusively, monooxygenases, methyltransferases, epimerases, oxidoreductases, and glutathione S-transferases which are essential to effect biosynthesis of the final NRP. Likewise, polyketide biosynthesis is directly by polyketide synthase megaenzymes and cluster-encoded ancillary decorating enzymes. Additionally, a suite of additional primary metabolites, for example: coenzyme A (CoA), acetyl CoA, S-adenosylmethionine, glutathione (GSH), NADPH, malonyl CoA, and molecular oxygen, amongst others are required for NRP and polyketide synthesis (PKS). Clearly these processes must involve exquisite orchestration to facilitate the simultaneous biosynthesis of different types of NRPs, polyketides, and related metabolites requiring identical or similar biosynthetic precursors or co-factors. Moreover, the near identical structures of many natural products within a given family (e.g., ergot alkaloids), along with localization to similar regions within fungi (e.g., conidia) suggests that cross-talk may exist, in terms of biosynthesis and functionality. Finally, we speculate if certain biosynthetic steps involved in NRP and PKS play a role in cellular protection or environmental adaptation, and wonder if these enzymatic reactions are of equivalent importance to the actual biosynthesis of the final metabolite

Weighing of trapped ion crystals and its applications

We have developed a novel scheme to measure the secular motion of trapped ions. Employing pulsed excitation and analysis of the fluorescence of laser cooled ions, we have measured the centre-of-mass mode frequency of single as well as entire ion crystals with a frequency precision better than 5e-4 within an interrogation time on the order of seconds, limited only by the fluorescence collection efficiency and the background noise. We have used this method to measure the mass of ions and observed charge exchange collisions between trapped calcium isotopes.Comment: 24 pages, 15 figure

A microRNA cluster in the Fragile-X region expressed during spermatogenesis targets FMR1.

Testis-expressed X-linked genes typically evolve rapidly. Here, we report on a testis-expressed X-linked microRNA (miRNA) cluster that despite rapid alterations in sequence has retained its position in the Fragile-X region of the X chromosome in placental mammals. Surprisingly, the miRNAs encoded by this cluster (Fx-mir) have a predilection for targeting the immediately adjacent gene, Fmr1, an unexpected finding given that miRNAs usually act in trans, not in cis Robust repression of Fmr1 is conferred by combinations of Fx-mir miRNAs induced in Sertoli cells (SCs) during postnatal development when they terminate proliferation. Physiological significance is suggested by the finding that FMRP, the protein product of Fmr1, is downregulated when Fx-mir miRNAs are induced, and that FMRP loss causes SC hyperproliferation and spermatogenic defects. Fx-mir miRNAs not only regulate the expression of FMRP, but also regulate the expression of eIF4E and CYFIP1, which together with FMRP form a translational regulatory complex. Our results support a model in which Fx-mir family members act cooperatively to regulate the translation of batteries of mRNAs in a developmentally regulated manner in SCs

On a Knife Edge: A preliminary investigation of clothing damage using rounded-tip knives

The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link. 10.1016/j.scijus.2020.08.002.Bladed weapons are frequently encountered in violent crime offences including street based and armed robberies, murder, sexual assaults and terrorism. A study was conducted involving four frequently encountered clothing fabrics: t-shirt (knitted cotton), denim jeans (twill woven cotton), long sleeved top (knitted synthetic blend), and skirt (non-woven faux leather) and five knives to investigate any damage resulting from a downward stabbing motion, with 300 stabs in total. Any resultant penetrating severance damage was then photographed, measured and analysed. Statistical analysis revealed significant differences between the stab hole size and shape, as a consequence of the design of a bladed weapon (in particular, the tip shape) that caused it. There is a notable correlation between the Assure knife (rounded tip) and no resulting severance damage, as the fabric surfaces were not breached with this knife. This suggests a clear alternative to pointed tip knife blades. These findings will be of interest to investigators of knife crime offences, crime-reduction units, knife manufacturers and practitioners, who share the goal of identifying a safer alternative to conventional knife blade design

Preclinical evaluation of FLT190, a liver-directed AAV gene therapy for Fabry disease

Fabry disease is an X-linked lysosomal storage disorder caused by loss of alpha-galactosidase A (α-Gal A) activity and is characterized by progressive accumulation of glycosphingolipids in multiple cells and tissues. FLT190, an investigational gene therapy, is currently being evaluated in a Phase 1/2 clinical trial in patients with Fabry disease (NCT04040049). FLT190 consists of a potent, synthetic capsid (AAVS3) containing an expression cassette with a codon-optimized human GLA cDNA under the control of a liver-specific promoter FRE1 (AAV2/S3-FRE1-GLAco). For mouse studies FLT190 genome was pseudotyped with AAV8 for efficient transduction. Preclinical studies in a murine model of Fabry disease (Gla-deficient mice), and non-human primates (NHPs) showed dose-dependent increases in plasma α-Gal A with steady-state observed 2 weeks following a single intravenous dose. In Fabry mice, AAV8-FLT190 treatment resulted in clearance of globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3) in plasma, urine, kidney, and heart; electron microscopy analyses confirmed reductions in storage inclusion bodies in kidney and heart. In NHPs, α-Gal A expression was consistent with the levels of hGLA mRNA in liver, and no FLT190-related toxicities or adverse events were observed. Taken together, these studies demonstrate preclinical proof-of-concept of liver-directed gene therapy with FLT190 for the treatment of Fabry disease

Scientists' warning on extreme wildfire risks to water supply

2020 is the year of wildfire records. California experienced its three largest fires early in its fire season. The Pantanal, the largest wetland on the planet, burned over 20% of its surface. More than 18 million hectares of forest and bushland burned during the 2019–2020 fire season in Australia, killing 33 people, destroying nearly 2500 homes, and endangering many endemic species. The direct cost of damages is being counted in dozens of billion dollars, but the indirect costs on water‐related ecosystem services and benefits could be equally expensive, with impacts lasting for decades. In Australia, the extreme precipitation (“200 mm day −1 in several location”) that interrupted the catastrophic wildfire season triggered a series of watershed effects from headwaters to areas downstream. The increased runoff and erosion from burned areas disrupted water supplies in several locations. These post‐fire watershed hazards via source water contamination, flash floods, and mudslides can represent substantial, systemic long‐term risks to drinking water production, aquatic life, and socio‐economic activity. Scenarios similar to the recent event in Australia are now predicted to unfold in the Western USA. This is a new reality that societies will have to live with as uncharted fire activity, water crises, and widespread human footprint collide all‐around of the world. Therefore, we advocate for a more proactive approach to wildfire‐watershed risk governance in an effort to advance and protect water security. We also argue that there is no easy solution to reducing this risk and that investments in both green (i.e., natural) and grey (i.e., built) infrastructure will be necessary. Further, we propose strategies to combine modern data analytics with existing tools for use by water and land managers worldwide to leverage several decades worth of data and knowledge on post‐fire hydrology

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Quantitative gait analysis under dual-task in older people with mild cognitive impairment: a reliability study

<p>Abstract</p> <p>Background</p> <p>Reliability of quantitative gait assessment while dual-tasking (walking while doing a secondary task such as talking) in people with cognitive impairment is unknown. Dual-tasking gait assessment is becoming highly important for mobility research with older adults since better reflects their performance in the basic activities of daily living. Our purpose was to establish the test-retest reliability of assessing quantitative gait variables using an electronic walkway in older adults with mild cognitive impairment (MCI) under single and dual-task conditions.</p> <p>Methods</p> <p>The gait performance of 11 elderly individuals with MCI was evaluated using an electronic walkway (GAITRite^®System) in two sessions, one week apart. Six gait parameters (gait velocity, step length, stride length, step time, stride time, and double support time) were assessed under two conditions: single-task (sG: usual walking) and dual-task (dG: counting backwards from 100 while walking). Test-retest reliability was determined using intra-class correlation coefficient (ICC). Gait variability was measured using coefficient of variation (CoV).</p> <p>Results</p> <p>Eleven participants (average age = 76.6 years, SD = 7.3) were assessed. They were high functioning (Clinical Dementia Rating Score = 0.5) with a mean Mini-Mental Status Exam (MMSE) score of 28 (SD = 1.56), and a mean Montreal Cognitive Assessment (MoCA) score of 22.8 (SD = 1.23). Under dual-task conditions, mean gait velocity (GV) decreased significantly (sGV = 119.11 ± 20.20 cm/s; dGV = 110.88 ± 19.76 cm/s; p = 0.005). Additionally, under dual-task conditions, higher gait variability was found on stride time, step time, and double support time. Test-retest reliability was high (ICC>0.85) for the six parameters evaluated under both conditions.</p> <p>Conclusion</p> <p>In older people with MCI, variability of time-related gait parameters increased with dual-tasking suggesting cognitive control of gait performance. Assessment of quantitative gait variables using an electronic walkway is highly reliable under single and dual-task conditions. The presence of cognitive impairment did not preclude performance of dual-tasking in our sample supporting that this methodology can be reliably used in cognitive impaired older individuals.</p