Characterization of HTT Inclusion Size,Location, and Timing in the zQ175 Mouse Model of Huntington′s Disease: An In Vivo High-Content Imaging Study

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the huntingtin gene. Major pathological hallmarks of HD include inclusions of mutant huntingtin (mHTT) protein, loss of neurons predominantly in the caudate nucleus, and atrophy of multiple brain regions. However, the early sequence of histological events that manifest in region- and cell-specific manner has not been well characterized. Here we use a high-content histological approach to precisely monitor changes in HTT expression and characterize deposition dynamics of mHTT protein inclusion bodies in the recently characterized zQ175 knock-in mouse line. We carried out an automated multi-parameter quantitative analysis of individual cortical and striatal cells in tissue slices from mice aged 2–12 months and confirmed biochemical reports of an age-associated increase in mHTT inclusions in this model. We also found distinct regional and subregional dynamics for inclusion number, size and distribution with subcellular resolution. We used viral-mediated suppression of total HTT in the striatum of zQ175 mice as an example of a therapeutically-relevant but heterogeneously transducing strategy to demonstrate successful application of this platform to quantitatively assess target engagement and outcome on a cellular basis.     

Description of diatoms from the Southwest to West Greenland coastal and open marine waters

Detailed studies on sub-Arctic and Arctic marine diatom assemblages contribute to the understanding of spatial distribution patterns and their physical drivers. In this study, diatom species were analyzed from water samples collected with a Niskin bottle rosette combined with a CTD along the West Greenland coast (63°58′N–71°08′N and 50°49′W–59°06′W) during summer 2007. Diatom community was represented mainly by three genera Thalassiosira, Fragilariopsis, and Chaetoceros and linked to observed hydrographic and environmental conditions. Thalassiosira spp. were common in coastal waters (particularly Godthåbsfjord) and linked to increased surface water temperature, typical of summer water stratification in West Greenland. Fragilariopsis spp., along with other dominant species associated with higher geographic latitudes, dominated in Arctic fjords (Uummannaq Fjord-Qaumarujuk Fjord). These species generally characterized coastal waters influenced by melting sea ice and/or glacial ice. Chaetoceros spp. were linked to more saline open marine waters, particularly in the Davis Strait south of 70°N, probably corresponding to weaker water stratification and the influence of the West Greenland Current. The present paper provides new knowledge on diatom assemblages along a south–north climate gradient in West Greenland, which is necessary in order to understand how observed ocean-climate changes influence Arctic marine ecosystems. This study provides a reference for palaeoenvironmental reconstructions using diatom microfossils deposited in the West Greenland marine sediments.     

Surveillance for peri-elimination trachoma recrudescence: Exploratory studies in Ghana

IntroductionTo date, eleven countries have been validated as having eliminated trachoma as a public health problem, including Ghana in 2018. Surveillance for recrudescence is needed both pre- and post-validation but evidence-based guidance on appropriate strategies is lacking. We explored two potential surveillance strategies in Ghana.Methodology/principal findingsAmongst randomly-selected communities enrolled in pre-validation on-going surveillance between 2011 and 2015, eight were identified as having had trachomatous-inflammation follicular (TF) prevalence ≥5% in children aged 1–9 years between 2012 and 2014. These eight were re-visited in 2015 and 2016 and neighbouring communities were also added (“TF trigger” investigations). Resident children aged 1–9 years were then examined for trachoma and had a conjunctival swab to test for Chlamydia trachomatis (Ct) and a dried blood spot (DBS) taken to test for anti-Pgp3 antibodies. These investigations identified at least one community with evidence of probable recent Ct ocular transmission. However, the approach likely lacks sufficient spatio-temporal power to be reliable.A post-validation surveillance strategy was also evaluated, this reviewed the ocular Ct infection and anti-Pgp3 seroprevalence data from the TF trigger investigations and from the pre-validation surveillance surveys in 2015 and 2016. Three communities identified as having ocular Ct infection >0% and anti-Pgp3 seroprevalence ≥15.0% were identified, and along with three linked communities, were followed-up as part of the surveillance strategy. An additional three communities with a seroprevalence ≥25.0% but no Ct infection were also followed up (“antibody and infection trigger” investigations). DBS were taken from all residents aged ≥1 year and ocular swabs from all children aged 1–9 years. There was evidence of transmission in the group of communities visited in one district (Zabzugu-Tatale). There was no or little evidence of continued transmission in other districts, suggesting previous infection identified was transient or potentially not true ocular Ct infection.Conclusions/significanceThere is evidence of heterogeneity in Ct transmission dynamics in northern Ghana, even 10 years after wide-scale MDA has stopped. There is added value in monitoring Ct infection and anti-Ct antibodies, using these indicators to interrogate past or present surveillance strategies. This can result in a deeper understanding of transmission dynamics and inform new post-validation surveillance strategies. Opportunities should be explored for integrating PCR and serological-based markers into surveys conducted in trachoma elimination settings.     

Feeding Preference of Native Subterranean Termites (Isoptera: Rhinotermitidae: Reticulitermes) for Wood Containing Bark Beetle Pheromones and Blue-Stain Fungi

Surprisingly little research has been conducted to investigate interactions between subterranean termites and bark beetles. Facilitative interactions between these organisms could easily alter stand dynamics and impact wood utilization strategies. A series of American Wood Protection Association Standard E1-09 “choice tests” were carried out to determine the feeding preference of Reticulitermes flavipes Kollar (Isoptera: Rhinotermitidae) for blue-stained sapwood and sapwood impregnated with various bark beetle pheromones. Reticulitermes flavipes exhibited a feeding preference for both air-dried and kiln-dried blue-stained sapwood, unstained sapwood treated with frontalin, and air-dried blue-stained sapwood treated with a 0.02% solution of both frontalin and endo-brevicomin. The implications of these results are far reaching, with particular relevance to forest health, ecology, and utilization.     

Evaluating future success of whitebark pine ecosystem restoration under climate change using simulation modeling

Major declines of whitebark pine forests throughout western North America from the combined effects of mountain pine beetle (Dendroctonus ponderosae) outbreaks, fire exclusion policies, and the exotic disease white pine blister rust (WPBR) have spurred many restoration actions. However, projected future warming and drying may further exacerbate the species' decline and possibly compromise long‐term success of today's restoration activities. We evaluated successes of restoration treatments under future climate using a comprehensive landscape simulation experiment. The spatially explicit, ecological process model FireBGCv2 was used to simulate whitebark pine populations on two U.S. Northern Rocky Mountain landscapes over 95 years under two climate, three restoration, and two fire management scenarios. Major findings were that (1) whitebark pine can remain on some high mountain landscapes in a future climate albeit at lower basal areas (50% decrease), (2) restoration efforts, such as thinning and prescribed burning, are vital to ensure future whitebark pine forests, and (3) climate change impacts on whitebark pine vary by local setting. Whitebark pine restoration efforts will mostly be successful in the future but only if future populations are somewhat resistant to WPBR. Results were used to develop general guidelines that address climate change impacts for planning, designing, implementing, and evaluating fine‐scale restoration activities.     

Tumor suppressor Tsc1 is a new Hsp90 co‐chaperone that facilitates folding of kinase and non‐kinase clients

The tumor suppressors Tsc1 and Tsc2 form the tuberous sclerosis complex (TSC), a regulator of mTOR activity. Tsc1 stabilizes Tsc2; however, the precise mechanism involved remains elusive. The molecular chaperone heat‐shock protein 90 (Hsp90) is an essential component of the cellular homeostatic machinery in eukaryotes. Here, we show that Tsc1 is a new co‐chaperone for Hsp90 that inhibits its ATPase activity. The C‐terminal domain of Tsc1 (998–1,164 aa) forms a homodimer and binds to both protomers of the Hsp90 middle domain. This ensures inhibition of both subunits of the Hsp90 dimer and prevents the activating co‐chaperone Aha1 from binding the middle domain of Hsp90. Conversely, phosphorylation of Aha1‐Y223 increases its affinity for Hsp90 and displaces Tsc1, thereby providing a mechanism for equilibrium between binding of these two co‐chaperones to Hsp90. Our findings establish an active role for Tsc1 as a facilitator of Hsp90‐mediated folding of kinase and non‐kinase clients—including Tsc2—thereby preventing their ubiquitination and proteasomal degradation.     

Stress-induced effects on feeding behavior and growth performance of the sea bass (<Emphasis Type="Italic">Dicentrarchus labrax</Emphasis>): a self-feeding approach

Repetitive aquaculture-related protocols may act as cyclic stressors that induce chronic stress in cultured fish. The sea bass is particularly sensitive to stressful conditions and the mere presence of humans will disturb feeding behavior. In this paper, we study whether chronic stress induced by repetition of acute stress protocols affects long-term feeding behavior and growth performance in sea bass and whether exogenous cortisol may induce stress-like changes in these parameters. We demonstrate that both chronic stress and dietary cortisol decrease food intake and have a negative effect on feed conversion efficiency, severely impairing sea bass performance. Both experimental approaches induced changes in the daily feeding activity by lengthening the active feeding periods. Fish subjected to a cyclic stressor modify their daily feeding pattern in an attempt to avoid interference with the time of the stressor. The delay in feeding when fish are acutely and repeatedly stressed could be of substantial adaptive importance.     

Mucosal lymphatic-derived gammadelta T cells respond early to experimental Salmonella enterocolitis by increasing expression of IL-2R alpha

To better understand the roles of gammadelta T cells in mucosal infection, we utilized Salmonella enterica serovar Typhimurium (Salmonella serovar Typhimurium) infection in cattle as it closely approximates Salmonella serovar Typhimurium-induced enterocolitis in humans. Protein and gene expression in alphabeta and gammadelta T cells derived from lymphatic ducts draining the gut mucosa in Salmonella serovar Typhimurium-infected calves were analyzed. In calves with enterocolitis, general gene expression trends in gammadelta T cells suggested subtle activation and innate response, whereas alphabeta T cells were relatively quiescent following Salmonella serovar Typhimurium infection. An increase in IL-2R alpha expression on gammadelta T cells from infected calves and results from in vitro assays suggested that gammadelta T cells were primed by Salmonella serovar Typhimurium LPS to better respond to IL-2 and IL-15. Together with gene expression trends in vivo, these data support early priming activation of target tissue gammadelta T cells during Salmonella serovar Typhimurium infection.     

CD8+ CD205+ splenic dendritic cells are specialized to induce Foxp3+ regulatory T cells

Foxp3(+)CD25(+)CD4(+) regulatory T cells (Treg) mediate immunological self-tolerance and suppress immune responses. A subset of dendritic cells (DCs) in the intestine is specialized to induce Treg in a TGF-beta- and retinoic acid-dependent manner to allow for oral tolerance. In this study we compare two major DC subsets from mouse spleen. We find that CD8(+) DEC-205/CD205(+) DCs, but not the major fraction of CD8(-) DC inhibitory receptor-2 (DCIR2)(+) DCs, induce functional Foxp3(+) Treg from Foxp3(-) precursors in the presence of low doses of Ag but without added TGF-beta. CD8(+)CD205(+) DCs preferentially express TGF-beta, and the induction of Treg by these DCs in vitro is blocked by neutralizing Ab to TGF-beta. In contrast, CD8(-)DCIR2(+) DCs better induce Foxp3(+) Treg when exogenous TGF-beta is supplied. In vivo, CD8(+)CD205(+) DCs likewise preferentially induce Treg from adoptively transferred, Ag-specific DO11.10 RAG(-/-) Foxp3(-)CD4(+) T cells, whereas the CD8(-)DCIR2(+) DCs better stimulate natural Foxp3(+) Treg. These results indicate that a subset of DCs in spleen, a systemic lymphoid organ, is specialized to differentiate peripheral Foxp3(+) Treg, in part through the endogenous formation of TGF-beta. Targeting of Ag to these DCs might be useful for inducing Ag-specific Foxp3(+) Treg for treatment of autoimmune diseases, transplant rejection, and allergy.