Biology subjects

Wilson, S.

Publications and source records attributed to Wilson, S..

At least 37 records · Page 2Linked to original sources

bioRxiv2023

Gradient organisation of functional connectivity within resting state networks is present from 25 weeks gestation in the human fetal brain

During the third trimester of human gestation, the structure and function of the fetal brain is developing rapidly, laying the foundation for its connectivity framework across the lifespan. During this juncture, resting state functional MRI can be used to identify resting state networks (RSNs) which mature across gestation to resemble canonical RSNs at full term. However, the emergence of finer grain organisation of connectivity within these RSNs in the fetal brain is unknown. Using in-utero resting state fMRI, we performed connectopic mapping analysis to explore the presence of gradients in functional connectivity organisation of 11 cortical RSNs, known as connectopic maps in fetuses aged 25-37 weeks gestation (GW). We hypothesised that, if present, development of connectopic maps would be network specific in the third trimester of gestation, such that this property would be present within the earlier maturing primary sensory and motor networks before those associated with higher association function. In keeping with this, we found smooth connectopic maps in all of the studied RSNs from 25 GW, with the most spatially consistency across gestational age in the primary sensory and motor networks. Voxel-wise permutation testing of the connectopic maps identified local clusters of voxels within networks that significantly covaried with age, specifically in multisensory processing areas, suggesting multisensory processing may be developing during this period. Our analysis shows that functional gradient organisation is already established in the fetal brain and develops throughout gestation, which has strong implications for understanding how cortical organisation subserves the emergence of behaviour in the ensuing period.

neuroscience↗

bioRxiv2023

Multiplexed effector screening for recognition by endogenous resistance genes using positive defense reporters in wheat protoplasts

O_LIPlant resistance (R) and pathogen avirulence (Avr) gene interactions play a vital role in pathogen resistance. Efficient molecular screening tools for crops lack far behind their model organism counterparts, yet they are essential to rapidly identify agriculturally important molecular interactions that trigger host resistance. C_LIO_LIHere, we have developed a novel wheat protoplast assay that enables efficient screening of Avr/R interactions at scale. Our assay allows access to the extensive gene pool of phenotypically described R genes because it does not require the overexpression of cloned R genes. It is suitable for multiplexed Avr screening, with interactions tested in pools of up to fifty Avr candidates. C_LIO_LIWe identified Avr/R-induced defense genes to create promoter-luciferase reporter. Then, we combined this with a dual-color ratiometric reporter system that normalizes read-outs accounting for experimental variability and Avr/R-induced cell-death. Moreover, we introduced a self-replicative plasmid reducing the amount of plasmid used in the assay. C_LIO_LIOur assay increases the throughput of Avr candidate screening, accelerating the study of cellular defense signaling and resistance gene identification in wheat. We anticipate that our assay will significantly accelerate Avr identification for many wheat pathogens, leading to improved genome-guided pathogen surveillance and breeding of disease-resistant crops. C_LI

plant biology↗

bioRxiv2022

Protective human IgE responses are promoted by comparable life-cycle dependent Tegument Allergen-Like protein expression in Schistosoma haematobium and Schistosoma mansoni infection

Schistosoma haematobium is the most prevalent of the human-infecting schistosome species, causing significant morbidity in endemically exposed populations. Despite this, it has been relatively understudied compared to its fellow species, S. mansoni. Here we provide the first comprehensive characterization of the S. haematobium Tegument Allergen-Like protein family, a key protein family directly linked to protective immunity in S. mansoni infection. Comparable with observations for S. mansoni, parasite phylogenetic analysis and relative gene expression combined with host serological analysis support a cross-reactive relationship between S. haematobium TAL proteins, exposed to the host immune system as adult worms die, and closely related proteins, exposed during penetration by the infecting cercarial and early schistosomulae stages. Specifically, our results strengthen the evidence for host immunity driven by cross-reactivity between family members TAL3 and TAL5, establishing it for the first time for S. haematobium infection. Furthermore, we build upon this relationship to include the involvement of an additional member of the TAL protein family, TAL11 for both schistosome species. Finally, we show a close association between experience of infection and intensity of transmission and the development of protective IgE responses to these antigens, thus improving our knowledge of the mechanisms by which protective host immune responses develop. This knowledge will be critical in understanding how control efforts such as mass drug administration campaigns influence the development of host immunity and subsequent patterns of infection and disease within endemic populations. Author SummaryS. haematobium is the most prevalent of the human infecting schistosomes. Along with S. mansoni, it is responsible for the majority of schistosomiasis cases that are borne by the populations of sub-Saharan Africa, where the global burden of this infection is centered. Here, we provide insight into the IgE antibody response that protects against these infections. Through utilization of in silico analysis and transcriptional studies of parasite life stages, in combination with immuno-epidemiological studies, we explore the relationship between host immune protection and a parasite protein family named the Tegument Allergen-Like (TAL) proteins. Our results show that several members of the TAL protein family are important in host protection to both these major schistosome species. For the first time we demonstrate that a progressive cross-reactive TAL-IgE response occurs against S. haematobium, similar to that previous observed in S. mansoni infection. We additionally expand upon previous knowledge for S. mansoni, identifying further complexity in the cross-reactive relationship between TAL family members, providing evidence of a key role for family member TAL11 in induction of the protective host immune response.

immunology↗

bioRxiv2022

Protected area planning to conserve biodiversity in an uncertain future

Protected areas are a key instrument for conservation. Despite this, they are vulnerable to risks associated with weak governance, land use intensification, and climate change. Using a novel hierarchical optimization approach, we identified priority areas for expanding the global protected area system to explicitly account for such risks whilst maximizing protection of all known terrestrial vertebrate species. We illustrate how reducing exposure to these risks requires expanding the area of the global protected area system by 1.6% while still meeting conservation targets. Incorporating risks from weak governance drove the greatest changes in spatial priorities for protection, while incorporating risks from climate change required the largest increase in global protected area. Conserving wide-ranging species required countries with relatively strong governance to protect more land when bordering nations with comparatively weak governance. Our results underscore the need for cross-jurisdictional coordination and demonstrate how risk can be efficiently incorporated into conservation planning. Article Impact StatementAccounting for governance, land use and climate risks will result in more resilient and effective conservation effort for biodiversity.

ecology↗

bioRxiv2022

Spatiotemporal tissue maturation of thalamocortical pathways in the human fetal brain

The development of connectivity between the thalamus and maturing cortex is a fundamental process in the second half of human gestation, establishing the neural circuits that are the basis for several important brain functions. In this study, we acquired high-resolution in utero diffusion MRI from 140 fetuses as part of the Developing Human Connectome Project, to examine the emergence of thalamocortical white matter over the second to third trimester. We delineate developing thalamocortical pathways and parcellate the fetal thalamus according to its cortical connectivity using diffusion tractography. We then quantify microstructural tissue components along the tracts in the fetal compartments that are critical substrates for white matter maturation, such as the subplate and intermediate zone. We identify patterns of change in the diffusion metrics that reflect critical neurobiological transitions occurring in the second to third trimester, such as the disassembly of radial glial scaffolding and the lamination of the cortical plate. These maturational trajectories of MR signal in transient fetal compartments provide a normative reference to complement histological knowledge, facilitating future studies to establish how developmental disruptions in these regions contribute to pathophysiology.

neuroscience↗

bioRxiv2022

Timing and magnitude of the type-I interferon response are determinants of disease tolerance in arbovirus infection

Infected hosts possess two alternative strategies to protect themselves against the negative impact of virus infections: (i) "resistance", directed to abrogate virus replication, or (ii) "disease tolerance", aimed to avoid organ and tissue damage without overly controlling viral burden. The overall principles governing pathogen resistance are well understood, while less is known about those involved in disease tolerance. Here, we studied bluetongue virus (BTV), the cause of a major disease of ruminants, bluetongue, as a model system to investigate the mechanisms of disease tolerance. BTV induces clinical disease mainly in sheep, while cattle are considered reservoirs of infection, rarely exhibiting clinical symptoms despite sustained viremia. Here, we show that BTV consistently reaches higher titres in ovine primary cells, compared to cells derived from cattle. The variable replication kinetics of BTV in sheep and cattle cells were mostly abolished by abrogating the cell type-I interferon (IFN) response. By screening a library of bovine interferon stimulated genes (ISGs), we identified restriction factors blocking BTV replication, however both sheep and cattle orthologues of these antiviral genes possess anti-BTV properties. Importantly, we demonstrate that BTV induces a faster host cell protein synthesis shutoff in primary sheep cells, compared to cattle cells, which results in an earlier downregulation of antiviral proteins. Moreover, by RNAseq we also show a more pronounced expression of ISGs in BTV infected cattle cells compared to sheep cells. Our data provide a new perspective on how the type-I IFN response in reservoir species can have overall positive effects on both virus and host evolution.

microbiology↗

bioRxiv2022

Development of a polymicrobial checkerboard assay as a tool for determining combinatorial antibiotic effectiveness in polymicrobial communities

AIMSTo establish a methodology for identifying the effects of combinatorial antibiotic treatment on individual members of a polymicrobial community. METHODS AND RESULTSBoth gentamicin and ceftazidime were diluted to concentrations ranging from 0.06 g ml-1 to 128 g ml-1. An equal ratio polymicrobial community of Staphylococcus aureus, Pseudomonas aeruginosa, Enterococcus faecalis, and Acinetobacter baumannii was inoculated into the combined antibiotics in the checkerboard and incubated for 18 hours in static conditions. After incubation, visible turbidity of the overall community was recorded, and bacteria from the wells were diluted to 10-3 and then spot plated on selective and differential media. After 24 hours, colony-forming unit (CFU) counts were obtained for each species. CONCLUSIONSVisible turbidity is not truly indicative of cell viability, and the polymicrobial community can decrease the antibiotic susceptibility of P. aeruginosa, rendering the clinically-established beneficial combination of gentamicin and ceftazidime ineffective. SIGNIFICANCEPrevious checkerboard methodology which focuses on using visible turbidity to determine monomicrobial antibiotic susceptibility fails to account for polymicrobial cooperation that has been shown to reduce antibiotic efficacy. Our new methodology could be implemented in clinical microbiology laboratories with minimal impact on the overall time for diagnosis.

microbiology↗

bioRxiv2022

Sustainable reference points for multispecies coral reef fisheries

Sustainably managing fisheries requires regular and reliable evaluation of stock status. However, most multispecies reef fisheries around the globe tend to be data-poor and lack research and monitoring capacity (e.g., long-term fishery data), preventing the estimation of sustainable reference points against which stocks can be assessed. Here, combining fish biomass data for more than 2000 coral reefs with catch estimates from 99 jurisdictions, we estimate site-specific sustainable reference points for coral reef fisheries and use these to assess the status of coral reef fish stocks. We reveal that more than half of jurisdictions with available information have stocks of conservation concern, having failed at least one fisheries sustainability benchmark. We quantify the trade-offs between biodiversity, mean fish length, and ecosystem functions relative to key benchmarks and highlight the ecological benefits of increasing sustainability. Our approach yields multispecies sustainable reference points for coral reef fisheries using environmental conditions, a promising means for enhancing the sustainability of the worlds coral reef fisheries. TeaserA global assessment of the sustainability of multispecies reef fisheries indicates that more than half of jurisdictions have failed at least one of two key sustainability benchmarks.

ecology↗

bioRxiv2022

Habitat protection and restoration: win-win opportunities for migratory birds in the Northern Andes

Identifying strategies that offer co-benefits for biodiversity protection, forest restoration and human well-being are important for successful conservation outcomes. In this study, we identified opportunities where forest restoration and rehabilitation programs in Colombia also align with priority areas for the conservation of Neotropical migratory birds. We used citizen science eBird-based abundance estimates to define regions with the highest richness of Neotropical migratory birds of conservation concern at montane elevations in Colombia and aligned these high richness areas with domestic initiatives for forest protection (Forest Areas), restoration (Restoration Areas) and rehabilitation (Rehabilitation Areas). We quantified the location and amounts of these three areas as well as the type of land protection and designation within them, specifically, National Protected Areas, Indigenous Reserves, Afro-descendent territories, and regions affected by poverty and violence that are prioritized for rural development by the Colombian government in Post-conflict Territorially Focused Development Programs (PDET). Almost half of Forest Areas overlapped with PDETs where goals for economic development present a risk of forest loss if not done sustainably. There was a 20% overlap between Forest Areas and Afro-descendant territories and indigenous reserves; most of this overlap was outside of established protected areas thus presenting an opportunity for community forest conservation that benefits migratory birds. We found an alignment of less than 6% between migrant bird focal areas and the priority Restoration and Rehabilitation Planning Areas identified by the Colombian National Restoration Plan indicating less opportunity for these programs to simultaneously benefit Neotropical migrant species. Our approach highlights that timely and efficient conservation of declining migrants depends on identifying the regions and strategies that incorporate local communities as part of the solution to forest loss and degradation in Colombia. HighlightsColombia covers over half of key wintering areas for migratory birds in South America Most of the migrants overwinter range overlaps with working landscapes Priority national restoration/rehabilitation areas are ineffective to benefit migrants Forest conservation needs actions involving vulnerable and minority groups

ecology↗

bioRxiv2022

A transcriptional mechanism involving R-loop, m6A modification and RNA abasic sites regulates an enhancer RNA of APOE.

The DNA genetic code and the RNA regulatory code determine phenotypes from gene expression to disease susceptibility. DNA sequence variants lead to phenotypic differences among individuals, while within an individual, RNA dynamically confers cell identity and responds to cellular and environmental signals. To provide regulation for different cell types and conditions, the nucleotides of RNA are modified by hundreds of chemical reactions, and RNA folds into innumerable shapes. To decipher the RNA regulatory code is to understand how RNA sequence and structure respond to cellular needs. Here, we deciphered one part of the RNA code where RNA abasic sites in R-loops regulate transcription by pausing RNA polymerase II. We uncovered an enhancer RNA, AANCR, that regulates the transcription and expression of APOE. When AANCR is folded into an R-loop, which is then modified by N6-adenine methylation and N-glycosidic cleavage, it is a partially transcribed nonfunctional enhancer and APOE is not expressed. In contrast, in some cell types and under stress, AANCR does not form a stable R-loop as its sequence is not modified, so it is transcribed into a full-length enhancer that promotes APOE expression. By genetic analysis, we confirmed that AANCR regulates APOE expression. DNA sequence variants in AANCR are associated with APOE expression and also with Alzheimers disease. Our data show that DNA and RNA sequence and structure jointly regulate gene expression that influence disease risk. HighlightsO_LIm6A, RNA abasic sites and R-loops jointly regulate transcription by pausing RNA Polymerase II. C_LIO_LIAn enhancer RNA regulates APOE expression. C_LIO_LIEnhancer RNA of APOE modifies susceptibility to Alzheimers disease. C_LI

molecular biology↗

bioRxiv2022

Tuberculosis treatment failure associated with evolution of antibiotic resilience

Antibiotics are a cornerstone of medicine, placing bacterial pathogens under intense pressure to evolve new survival mechanisms. Analysis of 51,229 Mycobacterium tuberculosis (Mtb) clinical isolates identified an essential transcriptional regulator, Rv1830 (here named resR) as a frequent target of positive (adaptive) selection. resR mutants do not demonstrate canonical drug resistance or drug tolerance but instead have significantly faster recovery after drug treatment across all antibiotics and combinations tested, a phenotype which we term antibiotic resilience. ResR acts in a regulatory cascade with other growth-controlling transcriptional regulators WhiB2 and WhiA, which are also under positive selection in Mtb clinical isolates. Mutations of these genes are associated with treatment failure and the acquisition of canonical drug resistance.

microbiology↗

bioRxiv2021

Balancing conservation priorities for grassland and forest specialist bird communities in agriculturally dominated landscapes

Effective conservation planning often requires difficult decisions when at-risk species inhabit economically valuable landscapes or if the needs of multiple threatened species do not align. In the agriculture-dominated landscape of eastern Ontario and southwestern Quebec, Canada, conflicting habitat requirements exist between threatened grassland birds benefiting from certain agriculture practices and those of a diverse woodland bird community dependent on forest recovery. Using multi-scale species distribution models with Breeding Bird Survey (BBS) data, we assessed habitat suitability for 8 threatened grassland and forest specialists within this region. We also identified landscapes that jointly maximize occurrence of the 8 focal species and diversity of the overall grassland and forest communities. Influential habitat associations differed among species at the territory (200m radius) and landscape level (1km), highlighting the importance of considering multiple spatial scales. Species diversity was maximized when forest or grassland/pasture cover approached 40-50%, indicating a positive response to land cover heterogeneity. We identified species diversity hotspots near Lake Huron, as well as along the shore and southeast of the St. Lawrence River. These areas represent mosaic landscapes, balancing forest patches, wetland, grassland/pasture, and row crops such as corn, soybean, and cereals. Despite drastic landscape changes associated with agroecosystems, we demonstrate that targeted habitat protection and enhancement that prioritizes land cover diversity can maximize protection of bird communities with directly contrasting needs. We highlight multiple pathways to achieve this balance, including forest retention or separating row crops with hedgerows and wooded fence-lines, improving flexibility in conservation approaches.

ecology↗

bioRxiv2021

Cell-envelope synthesis is required for surface-to-mass coupling, which determines dry-mass density in Bacillus subtilis

Cells must increase their volumes in response to biomass growth to maintain intracellular mass density, the ratio of dry mass to cell volume, within physiologically permissive bounds. To increase volume, bacteria enzymatically expand their cell envelopes and insert new envelope material. Recently, we demonstrated that the Gram-negative bacterium Escherichia coli expands cell-surface area rather than volume in proportion to mass. Here, we investigate the regulation of cell-volume growth in the evolutionarily distant Bacillus subtilis. First, we demonstrate that the coupling of surface growth to mass growth is conserved in B. subtilis. Therefore, mass density changes with cell shape at the single-cell level. Interestingly, mass density varies by more than 30% when we systematically change cell width by modulation of cell-wall insertion, without any effect on mass-growth rate. Second, we demonstrate that the coupling of surface- and mass growth is broken if peptidoglycan or membrane synthesis are inhibited. Once transient perturbations are relieved, the surface-to-mass ratio is rapidly restored. In conclusion, we demonstrate that surface-to-mass coupling is a conserved principle for volume regulation in bacteria, and that envelope synthesis provides an important link between surface growth and biomass growth in B. subtilis.

microbiology↗

bioRxiv2021

An Exhaustive Multiple Knockout Approach to Understanding Cell Wall Hydrolase Function in Bacillus subtilis

Most bacteria are surrounded by their cell wall, containing a highly crosslinked protective envelope of peptidoglycan. To grow, bacteria must continuously remodel their wall, inserting new material and breaking old bonds. Bond cleavage is performed by cell wall hydrolases, allowing the wall to expand. Understanding the functions of individual hydrolases has been impeded by their redundancy: single knockouts usually present no phenotype. We used an exhaustive multiple-knockout approach to determine the minimal set of hydrolases required for growth in Bacillus subtilis. We identified 42 candidate hydrolases. Strikingly, we were able to remove all but two of these genes in a single strain; this "{Delta}40" strain shows only a mild reduction in growth rate, indicating that none of the 40 hydrolases are necessary for growth. The {Delta}40 strain does not detectably shed old wall, suggesting that turnover is not essential for growth. The remaining hydrolases in the {Delta}40 strain are LytE and CwlO, previously shown to be synthetically lethal. Either can be removed in {Delta}40, indicating that either hydrolase alone is sufficient for cell growth. Screening of environmental conditions and biochemistry revealed that LytE activity is inhibited by Mg2+ and that RlpA-like proteins may stimulate LytE activity. Together, these results suggest that the only essential function of cell wall hydrolases in B. subtilis is to enable cell growth by expanding the wall and that LytE or CwlO alone is sufficient for this function. These experiments introduce the {Delta}40 strain as a tool to study hydrolase activity and regulation in B. subtilis. IMPORTANCEIn order to grow, bacterial cells must both create and break down their cell wall. The enzymes that are responsible for these processes are the target of some of our best antibiotics. Our understanding of the proteins that break down the wall - cell wall hydrolases - has been limited by redundancy among the large number of hydrolases many bacteria contain. To solve this problem, we identified 42 cell wall hydrolases in Bacillus subtilis and created a strain lacking 40 of them. We show that cells can survive using only a single cell wall hydrolase; this means that to understand the growth of B. subtilis in standard laboratory conditions, it is only necessary to study a very limited number of proteins, simplifying the problem substantially. We additionally show that the {Delta}40 strain is a research tool to characterize hydrolases, using it to identify 3 helper hydrolases that act in certain stress conditions.

microbiology↗

bioRxiv2020

Treeline ecotones shape the distribution of avian species richness and functional diversity in south temperate mountains

Mountains produce distinct environmental gradients that may constrain or facilitate both the presence of avian species and/or specific combinations of functional traits. We addressed species richness and functional diversity to understand the relative importance of habitat structure and elevation in shaping avian diversity patterns in the south temperate Andes, Chile. During 2010-2018, we conducted 2,202 point-counts in four mountain habitats (successional montane forest, old-growth montane forest, subalpine, and alpine) from 211 to 1,768 m in elevation and assembled trait data associated with resource use for each species to estimate species richness and functional diversity and turnover. We detected 74 species. Alpine specialists included 16 species (22%) occurring only above treeline with a mean elevational range of 298 m, while bird communities below treeline (78%) occupied a mean elevational range of 1,081 m. Treeline was an inflection line, above which species composition changed by 91% and there was a greater turnover in functional traits (2-3 times greater than communities below treeline). Alpine birds were almost exclusively migratory, inhabiting a restricted elevational range, and breeding in rock cavities. We conclude that elevation and habitat heterogeneity structure avian trait distributions and community composition, with a diverse ecotonal sub-alpine and a distinct alpine community.

ecology↗

bioRxiv2020

Polygenic Risk Score for Smoking is associated with Externalizing Psychopathology and Disinhibited Personality Traits but not Internalizing Psychopathology in Adolescence

ImportanceLarge consortia of genome wide association studies have yielded more accurate polygenic risk scores (PRS) that aggregate the small effects of many genetic variants to characterize the genetic architecture of disorders and provide a personalized measure of genetic risk. ObjectiveWe examined whether a PRS for smoking measured genetic risk for general behavioral disinhibition by estimating its associations with externalizing and internalizing psychopathology and related personality traits. We examined these associations at multiple time points in adolescence using more refined phenotypes defined by stable characteristics across time and at young ages, which reduced potential confounds associated with cumulative exposure to substances and reverse causality. MethodsRandom intercept panel models were fit to symptoms of conduct disorder, oppositional defiant disorder, major depressive disorder (MDD), and teacher ratings of externalizing and internalizing problems and personality traits at ages 11, 14, and 17 years-old in the Minnesota Twin Family Study (N = 3225). ResultsThe smoking PRS had strong associations with the random intercept factors for all the externalizing measures (mean standardized {beta} = .27), agreeableness ({beta}=-.22, 95% CI: -.28, -.16), and conscientiousness ({beta}=-.19, 95% CI: -.24, -.13), but was not significantly associated with the internalizing measures (mean {beta} = .06) or extraversion ({beta}=.01, 95% CI: -.05, .07). After controlling for smoking at age 17, the associations with the externalizing measures (mean {beta} = .13) and personality traits related to behavioral control (mean {beta} = -.10) remained statistically significant. Conclusions and RelevanceThe smoking PRS measures genetic influences that contribute to a spectrum of phenotypes related to behavioral disinhibition including externalizing psychopathology and normal-range personality traits related to behavioral control, but not internalizing psychopathology. Continuing to identify the correlates and delineate the mechanisms of the genetic influences associated with disinhibition could have substantial impact in mitigating a variety of public health problems (e.g., mental health, academic achievement, criminality). Key PointsO_ST_ABSQuestionC_ST_ABSDoes a polygenic risk scores (PRS) for smoking measure genetic risk for behavioral disinhibition in general? FindingsThe smoking PRS was associated with externalizing psychopathology and personality traits related to behavioral control, but not internalizing psychopathology and extraversion during adolescence, even after controlling for smoking status. MeaningThe smoking PRS measures genetic influences on behavioral disinhibition in general which is associated with a variety of important outcomes including mental health, academic success, and criminality.

genetics↗

bioRxiv2020

Development of a small molecule that corrects misfolding and increases secretion of Z α1-antitrypsin

Severe 1-antitrypsin deficiency results from the Z allele (Glu342Lys) that causes the accumulation of homopolymers of mutant 1-antitrypsin within the endoplasmic reticulum of hepatocytes in association with liver disease. We have used a DNA-encoded chemical library to undertake a high throughput screen to identify small molecules that bind to, and stabilise Z 1-antitrypsin. The lead compound blocks Z 1-antitrypsin polymerisation in vitro, reduces intracellular polymerisation and increases the secretion of Z 1-antitrypsin three-fold in mammalian cells including an iPSC model of disease. Crystallographic and biophysical analyses demonstrate that GSK716 and related molecules bind to a cryptic binding pocket, negate the local effects of the Z mutation and stabilise the bound state against progression along the polymerization pathway. Oral dosing of transgenic mice at 100 mg/kg three times a day for 20 days increased the secretion of Z 1-antitrypsin into the plasma by 7-fold. There was no observable clearance of hepatic inclusions with respect to controls. This study provides proof-of-principle that mutation ameliorating small molecules are a viable approach to treat protein conformational diseases.

pharmacology and toxicology↗

bioRxiv2020

The ribbon-helix-helix domain proteins CdrS and CdrL regulate cell division in archaea

Precise control of the cell cycle is central to the physiology of all cells. In prior work we demonstrated that archaeal cells maintain a constant size; however, the regulatory mechanisms underlying the cell cycle remain unexplored in this domain of life. Here we use genetics, functional genomics, and quantitative imaging to identify and characterize the novel CdrSL gene regulatory network in a model species of archaea. We demonstrate the central role of these ribbon-helix-helix family transcription factors in the regulation of cell division through specific transcriptional control of the gene encoding FtsZ2, a putative tubulin homolog. Using time lapse fluorescence microscopy in live cells cultivated in microfluidics devices, we further demonstrate that FtsZ2 is required for cell division but not elongation. The cdrS-ftsZ2 locus is highly conserved throughout the archaeal domain, and the central function of CdrS in regulating cell division is conserved across hypersaline adapted archaea. We propose that the CdrSL-FtsZ2 transcriptional network coordinates cell division timing with cell growth in archaea. ImportanceHealthy cell growth and division are critical for individual organism survival and species long-term viability. However, it remains unknown how cells of the domain Archaea maintain a healthy cell cycle. Understanding archaeal cell cycle is of paramount evolutionary importance given that an archaeal cell was the host of the endosymbiotic event that gave rise to eukaryotes. Here we identify and characterize novel molecular players needed for regulating cell division in archaea. These molecules dictate the timing of cell septation, but are dispensable for growth between divisions. Timing is accomplished through transcriptional control of the cell division ring. Our results shed light on mechanisms underlying the archaeal cell cycle, which has thus far remained elusive.

microbiology↗