SCA8 CAG/CTG Expansions, a Tale of Two TOXICities: A Unique or Common Case?

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Enabling rational gut microbiome manipulations by understanding gut ecology through experimentally-evidenced in silico models

© 2021 The Author(s). The gut microbiome has emerged as a contributing factor in non-communicable disease, rendering it a target of health-promoting interventions. Yet current understanding of the host-microbiome dynamic is insufficient to predict the variation in intervention outcomes across individuals. We explore the mechanisms that underpin the gut bacterial ecosystem and highlight how a more complete understanding of this ecology will enable improved intervention outcomes. This ecology varies within the gut over space and time. Interventions disrupt these processes, with cascading consequences throughout the ecosystem. In vivo studies cannot isolate and probe these processes at the required spatiotemporal resolutions, and in vitro studies lack the representative complexity required. However, we highlight that, together, both approaches can inform in silico models that integrate cellular-level dynamics, can extrapolate to explain bacterial community outcomes, permit experimentation and observation over ecological processes at high spatiotemporal resolution, and can serve as predictive platforms on which to prototype interventions. Thus, it is a concerted integration of these techniques that will enable rational targeted manipulations of the gut ecosystem.University of Sydney’s Centre for Advanced Food and Engineering; JPMO acknowledges a PhD scholarship from the Faculty of Engineering at the University of Sydney. ERS acknowledges the financial support from the à Beckett Cancer Research Trust (University of Sydney Fellowship)

High throughput genome scale modeling predicts microbial vitamin requirements contribute to gut microbiome community structure

Data availability statement: All data generated or analyzed during this study are included in this published article and its supplementary information files.Copyright © 2022 The Author(s). Human gut microbiome structure and emergent metabolic outputs impact health outcomes. However, what drives such community characteristics remains underexplored. Here, we rely on high throughput genomic reconstruction modeling, to infer the metabolic attributes and nutritional requirements of 816 gut strains, via a framework termed GEMNAST. This has been performed in terms of a group of human vitamins to examine the role vitamin exchanges have at different levels of community organization. We find that only 91 strains can satisfy their vitamin requirements (prototrophs) while the rest show various degrees of auxotrophy/specialization, highlighting their dependence on external sources, such as other members of the microbial community. Further, 79% of the strains in our sample were mapped to 11 distinct vitamin requirement profiles with low phylogenetic consistency. Yet, we find that human gut microbial community enterotype indicators display marked metabolic differences. Prevotella strains display a metabolic profile that can be complemented by strains from other genera often associated with the Prevotella enterotype and agrarian diets, while Bacteroides strains occupy a prototrophic profile. Finally, we identify pre-defined interaction modules (IMs) of gut species from human and mice predicted to be driven by, or highly independent of vitamin exchanges. Our analysis provides mechanistic grounding to gut microbiome stability and to co-abundance-based observations, a fundamental step toward understanding emergent processes that influence health outcomes. Further, our work opens a path to future explorations in the field through applications of GEMNAST to additional nutritional dimensions.University of Sydney (PhD scholarship and à Beckett Cancer Research Trust Fellowship)

Investigating local policy drivers for alcohol harm prevention: a comparative case study of two local authorities in England

Background: The considerable challenges associated with implementing national level alcohol policies have encouraged a renewed focus on the prospects for local-level policies in the UK and elsewhere. We adopted a case study approach to identify the major characteristics and drivers of differences in the patterns of local alcohol policies and services in two contrasting local authority (LA) areas in England. Methods: Data were collected via thirteen semi-structured interviews with key informants (including public health, licensing and trading standards) and documentary analysis, including harm reduction strategies and statements of licensing policy. A two-stage thematic analysis was used to categorize all relevant statements into seven over-arching themes, by which document sources were then also analysed. Results: Three of the seven over-arching themes (drink environment, treatment services and barriers and facilitators), provided for the most explanatory detail informing the contrasting policy responses of the two LAs: LA1 pursued a risk-informed strategy via a specialist police team working proactively with problem premises and screening systematically to identify riskier drinking. LA2 adopted a more upstream regulatory approach around restrictions on availability with less emphasis on co-ordinated screening and treatment measures. Conclusion: New powers over alcohol policy for LAs in England can produce markedly different policies for reducing alcohol-related harm. These difference are rooted in economic, opportunistic, organisational and personnel factors particular to the LAs themselves and may lead to closely tailored solutions in some policy areas and poorer co-ordination and attention in others

A seesaw model for intermolecular gating in the kinesin motor protein

Recent structural observations of kinesin-1, the founding member of the kinesin group of motor proteins, have led to substantial gains in our understanding of this molecular machine. Kinesin-1, similar to many kinesin family members, assembles to form homodimers that use alternating ATPase cycles of the catalytic motor domains, or “heads”, to proceed unidirectionally along its partner filament (the microtubule) via a hand-over-hand mechanism. Cryo-electron microscopy has now revealed 8-Å resolution, 3D reconstructions of kinesin-1•microtubule complexes for all three of this motor’s principal nucleotide-state intermediates (ADP-bound, no-nucleotide, and ATP analog), the first time filament co-complexes of any cytoskeletal motor have been visualized at this level of detail. These reconstructions comprehensively describe nucleotide-dependent changes in a monomeric head domain at the secondary structure level, and this information has been combined with atomic-resolution crystallography data to synthesize an atomic-level "seesaw" mechanism describing how microtubules activate kinesin’s ATP-sensing machinery. The new structural information revises or replaces key details of earlier models of kinesin’s ATPase cycle that were based principally on crystal structures of free kinesin, and demonstrates that high-resolution characterization of the kinesin–microtubule complex is essential for understanding the structural basis of the cycle. I discuss the broader implications of the seesaw mechanism within the cycle of a fully functional kinesin dimer and show how the seesaw can account for two types of "gating" that keep the ATPase cycles of the two heads out of sync during processive movement

Therapeutic efficacy of alpha-1 antitrypsin augmentation therapy on the loss of lung tissue: an integrated analysis of 2 randomised clinical trials using computed tomography densitometry

<p>Abstract</p> <p>Background</p> <p>Two randomised, double-blind, placebo-controlled trials have investigated the efficacy of IV alpha-1 antitrypsin (AAT) augmentation therapy on emphysema progression using CT densitometry.</p> <p>Methods</p> <p>Data from these similar trials, a 2-center Danish-Dutch study (n = 54) and the 3-center EXAcerbations and CT scan as Lung Endpoints (EXACTLE) study (n = 65), were pooled to increase the statistical power. The change in 15^thpercentile of lung density (PD15) measured by CT scan was obtained from both trials. All subjects had 1 CT scan at baseline and at least 1 CT scan after treatment. Densitometric data from 119 patients (AAT [Alfalastin^®or Prolastin^®], n = 60; placebo, n = 59) were analysed by a statistical/endpoint analysis method. To adjust for lung volume, volume correction was made by including the change in log-transformed total lung volume as a covariate in the statistical model.</p> <p>Results</p> <p>Mean follow-up was approximately 2.5 years. The mean change in lung density from baseline to last CT scan was -4.082 g/L for AAT and -6.379 g/L for placebo with a treatment difference of 2.297 (95% CI, 0.669 to 3.926; p = 0.006). The corresponding annual declines were -1.73 and -2.74 g/L/yr, respectively.</p> <p>Conclusions</p> <p>The overall results of the combined analysis of 2 separate trials of comparable design, and the only 2 controlled clinical trials completed to date, has confirmed that IV AAT augmentation therapy significantly reduces the decline in lung density and may therefore reduce the future risk of mortality in patients with AAT deficiency-related emphysema.</p> <p>Trial registration</p> <p>The EXACTLE study was registered in ClinicalTrials.gov as 'Antitrypsin (AAT) to Treat Emphysema in AAT-Deficient Patients'; ClinicalTrials.gov Identifier: NCT00263887.</p

Search for Kaluza-Klein Graviton Emission in ppˉp\bar{p} Collisions at s=1.8\sqrt{s}=1.8 TeV using the Missing Energy Signature

We report on a search for direct Kaluza-Klein graviton production in a data sample of 84 ${pb}^{-1}$ of \ppb collisions at $\sqrt{s}$ = 1.8 TeV, recorded by the Collider Detector at Fermilab. We investigate the final state of large missing transverse energy and one or two high energy jets. We compare the data with the predictions from a $3+1+n$-dimensional Kaluza-Klein scenario in which gravity becomes strong at the TeV scale. At 95% confidence level (C.L.) for $n$=2, 4, and 6 we exclude an effective Planck scale below 1.0, 0.77, and 0.71 TeV, respectively.Comment: Submitted to PRL, 7 pages 4 figures/Revision includes 5 figure